Management of retinal diseases

Introduction Many recent researches have contributed immensely in the management of retinal diseases. In this critical review, we discuss the management of retinal diseases. Conclusion Currently, age-related macular degeneration is managed primarily by anti-vascular growth factor agents. Newer reports on combination therapy may help in managing this visually debilitating condition in a better way. There are many new reports regarding the use of aflibercept and Ozurdex® (Allergan Inc., Irvine, California, USA) in the management of diabetic macular oedema and macular oedema associated with retinal vein occlusions. In the light of recent reports, retinopathy of prematurity may be often managed with bevacizumab. Introduction of ocriplasmin and Argus-II Retinal Prosthesis System (Second Sight Medical Products, Inc., Sylmar, California, USA) may offer ophthalmologists newer ways to treat some important vitreoretinal conditions. Introduction Retinal diseases constitute a significant part of the visually disabling ocular disease spectrum. Recently, there have been many exciting developments in the understanding, diagnosis and management of retinal diseases. It is important to critically review important ones to adopt them into our clinical practice. In this critical review, we shall discuss conditions like age-related macular degeneration (AMD), diabetic retinopathy (DR), retinal vein occlusion (RVO), vitreomacular traction syndrome and retinopathy of prematurity (ROP), in addition to vitreoretinal surgery. Discussion Age-related macular degeneration AMD is the leading cause of visual loss, in the western world, in adults over 65 years of age. Choroidal neovascular membrane (CNVM; Figure 1) caused due to AMD, has been treated in the past with laser photo coagulation1 and photodynamic therapy2. A macular photocoagulation study group reported benefits of photocoagulation in the management of classical CNVM with well defined boundaries1. Patients with extrafoveal CNVM lost six lines or more in 48% of treated eyes as compared with 64% of untreated eyes, at five years. In cases of juxtafoveal CNVM, the loss was 49% in treated eyes and 68% in untreated eyes at three years. This landmark study, for the first time, showed that some stabilisation of visual acuity could be achieved in selected types of CNVM. However, this form of therapy had many drawbacks like the fact that the selected patients constituted only a minority of AMD cases. Additionally, patients did not have visual improvements. Scar formation and recurrences were common. Treatment of subfoveal CNVM with laser photocoagulation left permanent scars and visual loss. Photodynamic therapy (PDT) was introduced to overcome limitations of laser photocoagulation in the treatment of CNVM2. PDT comprises of a two-step procedure. The first step is to inject a photosensitising drug verteporfin (Visudyne, QLT Inc., Vancouver, British Columbia, Canada), intravenously. The second step is the activation of verteporfin with light from a non-thermal diode laser to treat CNVM. The TAP study2 showed that PDT-treated eyes had * Corresponding author Email: nkumareyemd@gmail.com Al Bahar Eye Center, Ibn Sina Hospital, Shuwaikh, Kuwait Op th al m ol og y Figure 1: Fluorescein angiogram showing CNVM. Critical review Page 2 of 5 Co m pe n g in te re st s: n on e de cl ar ed . C on fl i ct o f i nt er es ts : n on e de cl ar ed . A ll au th or s co nt rib ut ed to th e co nc ep o n, d es ig n, a nd p re pa ra o n of th e m an us cr ip t, a s w el l a s re ad a nd a pp ro ve d th e fi n al m an us cr ip t. A ll au th or s ab id e by th e A ss oc ia o n fo r M ed ic al E th ic s (A M E) e th ic al ru le s of d is cl os ur e. Licensee OA Publishing London 2013. Creative Commons Attribution Licence (CC-BY) F : Kumar N. Management of retinal diseases. OA Case Reports 2013 Jan 31;2(1):9. better visual outcome than placebotreated eyes. It was seen that 61% verteporfin-treated eyes compared with 46% placebo-treated ones, lost fewer than 15 letters of visual acuity from baseline at the end of one-year follow up. Common complications of PDT therapy include severe visual loss, infusion site extravasation, back pain and photosensitivity reaction. Closure of blood vessels in CNVM lesions is seen initially following PDT treatment, but unfortunately, most of them start leaking again after a few weeks. Therefore, retreatments (TAP study2: 3,4 during first year) and regular follow up are necessary. Introduction of anti vascular endothelial growth factor (VEGF) agents has revolutionised the management of AMD3-6. The MARINA study group evaluated ranibizumab, a recombinant, humanised, monoclonal antibody that neutralises all active forms of VGEF for the treatment of neovascular AMD3. They showed that 94.5% of the group given 0.3 mg of ranibizumab and 94.6% given 0.5 mg, lost fewer than 15 letters, as compared with 62.2% of patients receiving placebo injections at 12 months. Visual acuity improved by 15 or more letters in 24.8% of the 0.3-mg group and 33.8% of the 0.5-mg group, as compared with 5.0% of the placebo-injection group. The ANCHOR study group compared the effectiveness of ranibizumab with verteporfin (PDT)4. They showed that 94.3% of those given 0.3 mg of ranibizumab and 96.4% of those given 0.5 mg, lost fewer than 15 letters, as compared with 64.3% of those in the verteporfin group. Visual acuity improved by 15 letters or more in 35.7% of the 0.3-mg group and 40.3% of the 0.5-mg group, as compared with 5.6% of the verteporfin group. These studies demonstrated that monthly intravitreal injections of ranibizumab not only stabilised visual acuity but also improved it in a significant number of patients. However, ranibizumab is an expensive drug. Bevacizumab, an off-label, anti-VEGF drug, was investigated as a cheaper alternative to ranibizumab5. Spaide et al.5 reported mean visual acuity improvement from 20/184 to 20/109 (p < 0.001); 38.3% of patients had visual acuity improvement after intravitreal injection of bevacizumab. The mean central macular thickness improved from 340 micron to 213 micron in the third month (p < 0.001). Later, the CATT and IVAN trials demonstrated similar efficacies of ranibizumab and bevacizumab in the management of neovascular AMD6,7. Bevacizumab was associated with higher cardiovascular complications in these trials although these results were not statistically significant. Another anti-VEGF drug, aflibercept, has recently been studied8. Patients were randomised to intravitreal aflibercept of 0.5 mg monthly, 2 mg monthly, 2 mg every two months after three initial monthly doses or ranibizumab 0.5 mg monthly. They concluded that intravitreal aflibercept dosed monthly or every two months after three initial monthly doses, produced similar efficacy and safety outcomes as monthly ranibizumab. Less frequent dosing of aflibercept is generating lots of interest. Now ranibizumab is being combined with other agents to further enhance its potency. The MONET clinical study group reported that the combination of siRNA PF-04523655 with ranibizumab led to an average gain in best-corrected visual acuity that was more than with ranibizumab monotherapy9. In a prospective, randomised, controlled, phase 2b trial, the combination of anti-platelet derived growth factor Fovista (Ophthotech, Princeton, New Jersey, USA) and ranibizumab, was shown to have superior efficacy as compared with ranibizumab monotherapy10. Patients who received the combination gained a mean of 10.6 letters of vision on the early treatment diabetic retinopathy study (ETDRS) standardised chart, whereas those who received ranibizumab monotherapy gained a mean of 6.5 letters of vision. Diabetic retinopathy DR is the leading cause of blindness in the adult population (20–64 years) in the USA. The DR study was Figure 2: Colour fundus photograph showing PDR (neovascularisation of the optic disc). Critical review Page 3 of 5 Co m pe n g in te re st s: n on e de cl ar ed . C on fl i ct o f I nt er es ts : n on e de cl ar ed . A ll au th or s co nt rib ut ed to th e co nc ep o n, d es ig n, a nd p re pa ra o n of th e m an us cr ip t, a s w el l a s re ad a nd a pp ro ve d th e fi n al m an us cr ip t. A ll au th or s ab id e by th e A ss oc ia o n fo r M ed ic al E th ic s (A M E) e th ic al ru le s of d is cl os ur e. Licensee OA Publishing London 2013. Creative Commons Attribution Licence (CC-BY) F : Kumar N. Management of retinal diseases. OA Case Reports 2013 Jan 31;2(1):9. a randomised, controlled clinical trial involving more than 1700 patients enrolled at 15 medical centres. This pioneering study demonstrated that both argon and xenon photocoagulation reduced the risk of severe visual loss by more than 50% in eyes with proliferative DR (Figure 2) with high risk characteristics11. The ETDRS was a randomised clinical trial supported by the National Eye Institute. In this study, 754 eyes that had macular oedema and mild to moderate DR were randomly assigned to focal argon laser photocoagulation, while 1490 such eyes were randomly assigned to a deferral of photocoagulation. The study demonstrated that laser photocoagulation of ‘clinically significant’ diabetic macular oedema (CSME) substantially reduces the risk of moderate visual loss (24% in treated eyes vs. 12% in untreated eyes)12. This left many patients with diabetic macular oedema (DME) who did not respond to laser photocoagulation. Anti-VEGF agents have helped some of these patients13-15. In a prospective, randomised, interventional, multicentre, clinical trial, the READ-2 study group investigators compared ranibizumab with focal/ grid laser or a combination of both in DME. They concluded that ranibizumab injections had a significantly better visual outcome than focal/ grid laser treatment in patients with DME13. Another anti-VEGF agent, bevacizumab, has also been extensively studied in the management of DME. The BOLT study group investigators, in a prospective, random


Introduction
Retinal diseases constitute a significant part of the visually disabling ocular disease spectrum. Recently, there have been many exciting developments in the understanding, diagnosis and management of retinal diseases. It is important to critically review important ones to adopt them into our clinical practice. In this critical review, we shall discuss conditions like age-related macular degeneration (AMD), diabetic retinopathy (DR), retinal vein occlusion (RVO), vitreomacular traction syndrome and retinopathy of prematurity (ROP), in addition to vitreoretinal surgery.

Discussion
Age-related macular degeneration AMD is the leading cause of visual loss, in the western world, in adults over 65 years of age. Choroidal neovascular membrane (CNVM; Figure 1) caused due to AMD, has been treated in the past with laser photo coagulation 1 and photodynamic therapy 2 .
A macular photocoagulation study group reported benefits of photocoagulation in the management of classical CNVM with well defined boundaries 1 . Patients with extrafoveal CNVM lost six lines or more in 48% of treated eyes as compared with 64% of untreated eyes, at five years. In cases of juxtafoveal CNVM, the loss was 49% in treated eyes and 68% in untreated eyes at three years. This landmark study, for the first time, showed that some stabilisation of visual acuity could be achieved in selected types of CNVM. However, this form of therapy had many drawbacks like the fact that the selected patients constituted only a minority of AMD cases. Additionally, patients did not have visual improvements. Scar formation and recurrences were common.
Treatment of subfoveal CNVM with laser photocoagulation left permanent scars and visual loss.
Photodynamic therapy (PDT) was introduced to overcome limitations of laser photocoagulation in the treatment of CNVM 2 . PDT comprises of a two-step procedure. The first step is to inject a photosensitising drug verteporfin (Visudyne, QLT Inc., Vancouver, British Columbia, Canada), intravenously. The second step is the activation of verteporfin with light from a non-thermal diode laser to treat CNVM. The TAP study 2 showed that PDT-treated eyes had better visual outcome than placebotreated eyes. It was seen that 61% verteporfin-treated eyes compared with 46% placebo-treated ones, lost fewer than 15 letters of visual acuity from baseline at the end of one-year follow up. Common complications of PDT therapy include severe visual loss, infusion site extravasation, back pain and photosensitivity reaction. Closure of blood vessels in CNVM lesions is seen initially following PDT treatment, but unfortunately, most of them start leaking again after a few weeks. Therefore, retreatments (TAP study 2 : 3,4 during first year) and regular follow up are necessary. Introduction of anti vascular endothelial growth factor (VEGF) agents has revolutionised the management of AMD 3-6 . The MARINA study group evaluated ranibizumab, a recombinant, humanised, monoclonal antibody that neutralises all active forms of VGEF for the treatment of neovascular AMD 3 . They showed that 94.5% of the group given 0.3 mg of ranibizumab and 94.6% given 0.5 mg, lost fewer than 15 letters, as compared with 62.2% of patients receiving placebo injec-tions at 12 months. Visual acuity improved by 15 or more letters in 24.8% of the 0.3-mg group and 33.8% of the 0.5-mg group, as compared with 5.0% of the placebo-injection group. The ANCHOR study group compared the effectiveness of ranibizumab with verteporfin (PDT) 4 . They showed that 94.3% of those given 0.3 mg of ranibizumab and 96.4% of those given 0.5 mg, lost fewer than 15 letters, as compared with 64.3% of those in the verteporfin group. Visual acuity improved by 15 letters or more in 35.7% of the 0.3-mg group and 40.3% of the 0.5-mg group, as compared with 5.6% of the verteporfin group. These studies demonstrated that monthly intravitreal injections of ranibizumab not only stabilised visual acuity but also improved it in a significant number of patients. However, ranibizumab is an expensive drug. Bevacizumab, an off-label, anti-VEGF drug, was investigated as a cheaper alternative to ranibizumab 5 . Spaide et al. 5 reported mean visual acuity improvement from 20/184 to 20/109 (p < 0.001); 38.3% of patients had visual acuity improvement after intravitreal injec-tion of bevacizumab. The mean central macular thickness improved from 340 micron to 213 micron in the third month (p < 0.001). Later, the CATT and IVAN trials demonstrated similar efficacies of ranibizumab and bevacizumab in the management of neovascular AMD 6,7 . Bevacizumab was associated with higher cardiovascular complications in these trials although these results were not statistically significant.
Another anti-VEGF drug, aflibercept, has recently been studied 8 . Patients were randomised to intravitreal aflibercept of 0.5 mg monthly, 2 mg monthly, 2 mg every two months after three initial monthly doses or ranibizumab 0.5 mg monthly. They concluded that intravitreal aflibercept dosed monthly or every two months after three initial monthly doses, produced similar efficacy and safety outcomes as monthly ranibizumab. Less frequent dosing of aflibercept is generating lots of interest. Now ranibizumab is being combined with other agents to further enhance its potency. The MONET clinical study group reported that the combination of siRNA PF-04523655 with ranibizumab led to an average gain in best-corrected visual acuity that was more than with ranibizumab monotherapy 9 . In a prospective, randomised, controlled, phase 2b trial, the combination of anti-platelet derived growth factor Fovista (Ophthotech, Princeton, New Jersey, USA) and ranibizumab, was shown to have superior efficacy as compared with ranibizumab monotherapy 10 . Patients who received the combination gained a mean of 10.6 letters of vision on the early treatment diabetic retinopathy study (ETDRS) standardised chart, whereas those who received ranibizumab monotherapy gained a mean of 6.5 letters of vision.

Diabetic retinopathy
DR is the leading cause of blindness in the adult population (20-64 years) in the USA. The DR study was a randomised, controlled clinical trial involving more than 1700 patients enrolled at 15 medical centres. This pioneering study demonstrated that both argon and xenon photocoagulation reduced the risk of severe visual loss by more than 50% in eyes with proliferative DR (Figure 2) with high risk characteristics 11 . The ETDRS was a randomised clinical trial supported by the National Eye Institute. In this study, 754 eyes that had macular oedema and mild to moderate DR were randomly assigned to focal argon laser photocoagulation, while 1490 such eyes were randomly assigned to a deferral of photocoagulation. The study demonstrated that laser photocoagulation of 'clinically significant' diabetic macular oedema (CSME) substantially reduces the risk of moderate visual loss (24% in treated eyes vs. 12% in untreated eyes) 12 . This left many patients with diabetic macular oedema (DME) who did not respond to laser photocoagulation. Anti-VEGF agents have helped some of these patients [13][14][15] . In a prospective, randomised, interventional, multicentre, clinical trial, the READ-2 study group investigators compared ranibizumab with focal/ grid laser or a combination of both in DME. They concluded that ranibizumab injections had a significantly better visual outcome than focal/ grid laser treatment in patients with DME 13 . Another anti-VEGF agent, bevacizumab, has also been extensively studied in the management of DME. The BOLT study group investi-gators, in a prospective, randomised, masked, single-centre, 2-year, 2-arm, clinical trial, compared repeated intravitreal bevacizumab and macular laser therapy in patients with persistent CSME 14 . The study concluded that there is an evidence to support the use of bevacizumab in patients with centre-involving CSME without advanced macular ischemia. Recently, a new anti-VEGF agent, aflibercept, has been investigated in the management of DME 15 . The DA VINCI study group authors compared aflibercept with laser photocoagulation in eyes with DME. They reported significant gains in visual acuity in eyes treated with aflibercept. Intravitreal injection of corticosteroids has also been used in the management of DME. Now a dexamethasone intravitreal implant (Ozurdex ® ; Allergan Inc., Irvine, California, USA) has been studied in the management of DME 16 . Study investigators in a prospective, multicentre, open-label study, reported that treatment with dexamethasone intravitreal implant led to statistically and clinically significant improvements in both vision and vascular leakage from DME with an acceptable safety profile.

Retinal vein occlusions
RVOs (branch and central) are important retinal conditions with significant ocular morbidity. The branch RVO study was a prospective, randomised, controlled, multicentre study 17,18 . It recommended laser photocoagulation for macular oedema due to branch retinal vein occlusion (BRVO; Figure 3) in selected patients. In this study, 63% of lasertreated eyes improved two or more lines of vision compared to 36% of control eyes after three years of follow-up care. It also recommended peripheral scatter laser photocoagulation for patients with branch vein occlusion who had developed neovascularisation. The development of vitreous haemorrhage was significantly less in laser-treated eyes (30% in laser-treated eyes vs. 60% in control eyes). Recently, anti-VEGF agents have been studied in the management of BRVO. The BRAVO study investigators reported that intravitreal injections of ranibizumab provided rapid and effective treatment for macular oedema following BRVO 19 . The percentage of patients who gained > or = 15 letters of vision at six months was 55.2% (0.3 mg) and 61.1% (0.5 mg) in the ranibizumab groups and 28.8% in the placebo group. The management of central retinal vein occlusion (CRVO; Figure 4) was studied by a National Eye Institute sponsored multicentre, central vein occlusion study group 20,21 . CRVO-associated macular oedema was treated by macular grid laser photocoagulation 20 . They found no difference between treated and untreated eyes in visual acuity. So treatment of macular oedema by macular grid photocoagulation in CRVO was not recommended. However, they recommended panretinal laser photocoagulation (PRP) of eyes, which developed two clock hours of iris neovascularisation or any angle neovascularisation following CRVO 21 . They also concluded that prophylactic PRP did not prevent the development of iris neovascularisation and recommended to wait for the development of early iris neovascularisation and then do PRP. The CRUISE investigators studied ranibizumab for macular oedema following CRVO 22 . Ranibizumab-treated patients (0.3 mg = 43.9%; 0.5 mg = 46.9%) had