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Does Laser Still Have a Role in the Management of Retinal Vascular and Neovascular Diseases?
PERSPECTIVES Does Laser Still Have a Role in the Management of Retinal Vascular and Neovascular Diseases? ANKUR M. SHAH, NEIL M. BRESSLER, AND LEE M. JAMPOL ● PURPOSE:
To discuss the current role of laser therapies in the management of retinal vascular and neovascular diseases. ● DESIGN: Perspective. ● METHODS: Laser’s role in the management of diabetic retinopathy, age-related macular degeneration, and venous occlusive disease is discussed, with emphasis on comparing laser with anti–vascular endothelial growth factor (VEGF) therapy and discussion of situations where these treatment methods can be complementary. ● RESULTS: Thermal panretinal photocoagulation remains the usual practice for treatment of neovascularization in proliferative diabetic retinopathy and after venous occlusive events. Focal/grid laser still has a role for patients with macular edema resulting from diabetes or venous occlusion that is poorly responsive to anti-VEGF agents and in patients who are unable or unwilling to return for frequent injections. Focal/grid laser also is used as combination therapy with anti-VEGF agents for these indications. Focal laser can be used for extrafoveal choroidal neovascularization to avoid the treatment burden and risks of multiple injections. Photodynamic therapy may be beneficial in the treatment of central serous chorioretinopathy and idiopathic polypoidal choroidal vasculopathy and as combination therapy with antiVEGF agents in age-related macular degeneration. ● CONCLUSIONS: Anti-VEGF agents are effective in preventing vision loss and improving vision in multiple diseases, including diabetic retinopathy, neovascular agerelated macular degeneration, and retinal vein occlusions. Despite a substantial decrease in its use for these conditions in recent years, laser therapies continue to serve important roles in our ability to combat retinal pathologic features and will remain a pivotal component of our practices for at least the next several years. (Am J Ophthalmol 2011;152:332–339. © 2011 by Elsevier Inc. All rights reserved.) Accepted for publication Apr 1, 2011. From the Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois (A.M.S., L.M.J.); and The Wilmer Institute, Johns Hopkins University, Baltimore, Maryland (N.M.B.). Inquiries to Lee M. Jampol, Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, 645 North Michigan Avenue, Suite 440, Chicago, IL 60611; e-mail: [email protected]
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EYER-SCHWICKERATH FIRST USED THE SUN AND
then xenon arc (1956) to perform thermal coagulation of the retina.1 Campbell, Zweng, Patz, and L’Esperance (1960) were among the first to use the laser to treat retinal diseases.1 The argon laser soon thereafter became a major tool for ophthalmologists. For more than 30 years, laser therapies have served as an effective therapeutic method for retinal diseases. Laser has been the mainstay of treatment for proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME). From the 1970s onward, laser was used frequently to ablate choroidal neovascularization (CNV) secondary to agerelated macular degeneration (AMD) and many other diseases. But in the last decade, new technologies and pharmacotherapies have emerged, and the use of thermal laser has declined dramatically. Treatment options including photodynamic therapy (PDT) and intravitreal injections have come to the forefront. With the advent of anti–vascular endothelial growth factor (VEGF) therapy, some have begun to question whether laser therapy still has a role in the treatment of retinal vascular and neovascular diseases.
DIABETIC RETINOPATHY NUMEROUS HYPOTHESES HAVE BEEN PROPOSED REGARD-
ing the precise mechanisms of action responsible for laser’s benefits in both PRP and focal/grid photocoagulation.2–5 Our current understanding of the mechanisms leading to retinal neovascularization and macular edema is that hypoxia of the inner retina leads to increased production of proangiogenic cytokines such as VEGF that also lead to increased vascular permeability. Budzynski and associates showed that average PO2 across the inner 50% of the retina was higher in photocoagulated feline retinas than in untreated eyes.4 Increased oxygenation of the inner retina after photocoagulation may decrease the stimulus for VEGF production, thus decreasing neovascularization and vascular permeability that leads to macular edema. Alternatively, laser may directly damage or destroy the cells that produce proangiogenic cytokines. In cases with areas of focal leakage from microaneurysms, direct closure also may be important. Finally, effects on retinal pigment epithelial
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function also may be significant. Laser likely changes the microenvironment in important ways, such as cytokine levels.5 Thermal laser first achieved widespread popularity and validity in ophthalmology in 1976 when the Diabetic Retinopathy Study published conclusive evidence that peripheral scatter or panretinal photocoagulation (PRP) reduced the risk of severe visual acuity loss in eyes with PDR by 50% or more.6,7 Side effects included decreased peripheral visual field and dark adaptation, plus occasional loss of a few lines of Snellen visual acuity, presumed to be from exacerbation of macular edema. The Diabetic Retinopathy Study Group recommended treatment for eyes with certain high-risk characteristics.8 Today, argon green laser PRP is still widely used and remains a common practice for treatment of not only PDR, but also anterior or posterior segment neovascularization resulting from other causes, such as central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), sickle cell retinopathy, and the ocular ischemic syndrome. However, it is plausible that pharmacotherapies could supplant laser in the future, because PRP does destroy functioning retinal neurons. In 1985, another therapeutic indication for thermal laser emerged when the Early Treatment Diabetic Retinopathy Study showed that focal/grid photocoagulation of DME reduced the 3-year risk of losing 3 lines or more of vision by approximately 50%, and for eyes with edema involving the center of the macula and visual acuity loss, this treatment also increased the chance of visual improvement.9 The technique of focal/grid photocoagulation involves 2 strategies within areas of retinal thickening: (1) direct treatment to microaneurysms within 2 disc diameters of the center of the fovea, and (2) scatter or grid treatment approximately 2 burn widths apart to other areas of thickening. Over the years, a modified version of the Early Treatment Diabetic Retinopathy Study laser protocol has been used more commonly, employing less intense burns, which seems to result in outcomes similar to those seen in the Early Treatment Diabetic Retinopathy Study, whereas grid treatment alone does not seem to be as effective and certainly has not been shown to be superior to focal/grid treatment.10 Focal/grid laser therapy continued as the primary treatment method for DME with vision impairment involving the center of the macula until very recently. Potential challengers such as preservative-free intravitreal triamcinolone (IVTA) attempted to displace photocoagulation. It was presumed that by inhibiting expression of VEGF as well as other proinflammatory cytokines, corticosteroids could reduce capillary permeability, thus decreasing macular edema,11,12 and preliminary studies with short follow-up suggested that this treatment was superior to laser. However, in 2008, the Diabetic Retinopathy Clinical Research Network (DRCR.net) published data from a multicenter, randomized, clinical trial of 840 eyes that VOL. 152, NO. 3
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compared laser with 2 doses of IVTA.13 Despite early results favoring 4 mg IVTA at 4 months, IVTA was not shown to be superior to focal/grid photocoagulation, and laser seemed to yield better mean visual acuity results at 2 years than 1- and 4-mg doses of IVTA. Optical coherence tomography (OCT) results mirrored the visual acuity results. As expected, rates of intraocular pressure elevation (IOP) and cataract formation were higher in the triamcinolone groups than in the laser groups. Focal/grid photocoagulation thus retained its position as the usual practice for treatment of DME. Although one third of eyes with DME and visual impairment treated with focal/grid photocoagulation see improvement in visual acuity of at least 2 lines, approximately 20% of eyes worsen by at least 2 lines. In addition, photocoagulation does come with inherent risks and side effects. Burns close to the fovea may damage vision acutely or may enlarge over time, leading to atrophic retina and retinal pigment epithelium encroaching on fixation with visual acuity loss.14 Occasionally, choroidal neovascularization may develop and may create permanent central scotomas with substantial vision loss. Recently, researchers have reported more efficacious and potentially safer treatments for DME. In June 2010, the DRCR.net published convincing evidence that the antiVEGF agent ranibizumab (Lucentis; Genentech, South San Francisco, California, USA) with or without prompt laser, leads to superior visual acuity outcomes compared with laser alone.15 The rationale for exploring anti-VEGF agents as a treatment method for DME stems from the knowledge that VEGF increases vascular permeability.11 Thus, anti-VEGF agents theoretically could block VEGF from activating its receptors, prevent increased vessel permeability, thus decreasing DME. The DRCR.net study was a multicenter, randomized clinical trial of 854 eyes with DME involving the center of the macula with vision impairment. At 1 year, the groups assigned to ranibizumab with prompt or deferred (⬎ 24 weeks) focal/grid laser had nearly identical outcomes, gaining an average of 2 lines of vision, with approximately 50% gaining 2 lines or more of visual acuity and less than 5% losing 2 lines or more. Prompt focal/grid photocoagulation yielded no additional visual acuity benefit when compared with the deferred laser group, in which approximately 60% of the study participants did not receive a laser treatment within the 2 years. Results in a triamcinolone plus prompt laser group were not superior to those of the laser alone group. Also noteworthy was the observation that eyes assigned to either ranibizumab group or the triamcinolone group were less likely than the laser control group to have progression of diabetic retinopathy or vitreous hemorrhage or to require PRP for PDR, suggesting an additional benefit for anti-VEGF agents and triamcinolone (other than a decrease in macular edema). These recently published results have changed many retina specialists’ management approach for DME. AntiAND
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VEGF injections not only seem to provide superior visual acuity results, but also are faster acting and potentially safer than focal/grid photocoagulation (except for the risk of rare endophthalmitis). Also, whereas fluorescein angiography was necessary frequently to facilitate or guide placement of focal/grid laser treatment, intravitreal anti-VEGF therapy often can be used based on clinical examination and OCT findings, obviating the need for fluorescein angiograms. The often rapid decrease in retinal thickness and accompanying vision improvement seen with antiVEGF injections provide an incentive for patients to return for treatment, potentially improving compliance and efficacy of the therapy. Also, anti-VEGF agents do not pose the dangers of cataract formation and elevation of IOP seen with intravitreal steroids. The era of solitary focal/grid photocoagulation being the most effective treatment for DME has come to a close. Although the treatment approach for applying antiVEGF therapy in the DRCR.net study may seem complex, the underlying rationale is fairly straightforward. After initiating treatment, it seems reasonable to continue to treat at monthly intervals until one is relatively certain that macular thickness is no longer improving (for example, 2 consecutive OCT measurements showing no further thinning of the macula). After retreatment is not given, injections would be resumed if edema recurs or worsens. If it does not recur or worsen after withholding treatment for at least 1 month, follow-up injections might be extended to 2 months and then 4 months, unless edema recurs or worsens to warrant resumption of monthly intravitreal injections, which are used again until improvement no longer occurs. Focal/grid laser as often as every 4 months can be added if edema persists and no longer improves despite multiple monthly injections of intravitreal antiVEGF drugs. The DRCR.net study showed that such an approach can lead to improvement in visual acuity, on average, without loss if or when injections are withheld, as long as injections are resumed when edema recurs or worsens, with a median of 6 injections within the first 6 months, followed by a median of 2 to 3 injections in the second 6 months and a median of another 2 to 3 injections in the second year. This potential avoidance of monthly injections indefinitely to maintain improvements noted through at least 6 months is different from the use of anti-VEGF drugs for neovascular AMD (see below), where withholding treatment when thickening no longer is improving and resuming treatment when thickening recurs or worsens does not maintain the maximum visual acuity improvements obtained after the first few months of monthly treatments. For some patients with DME, however, focal laser may still be a good treatment option. Patients who cannot tolerate or comply with the potential need for monthly visits and injections may be better suited to laser treatments, rather than no treatment, given their potentially longer-lasting effect and extended interval between visits 334
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of up to 4 months. At present, there is little evidence to suggest that laser therapy in combination with anti-VEGF injections will decrease the injection treatment burden substantially, but further follow-up in a DRCR.net study is addressing this. Because it remains unclear if there is a small increased risk of arterial thromboembolic events with intravitreal anti-VEGF agents (current studies confidently rule out a moderate or large risk), some practitioners are hesitant to use these agents in patients with, or at risk for, cardiovascular or cerebrovascular disease. In addition, intravitreal injections come with their own risks, including rare but devastating endophthalmitis. Although some investigators have reported contraction of fibrovascular tissue after anti-VEGF injection in eyes with proliferative disease about to undergo vitrectomy, presumably increasing the risk of tractional retinal detachment, rhegmatogenous detachment, hemorrhage, or a combination thereof,16 there is no evidence to suggest that an eye with PDR and DME or an eye that has been treated for PDR and in which DME develops has an increased risk of tractional retinal detachment when undergoing intravitreal ranibizumab for DME. At this time, neither IVTA nor ranibizumab are approved by the United States Food and Drug Administration approved for use for DME, and thus are used in an off-label fashion in the United States, although ranibizumab for this indication has been approved in Europe by the European Medical Evaluation Agency. Some retina practices also have used bevacizumab (Avastin; Genentech), rather than ranibizumab, as their anti-VEGF treatment of choice for DME because of its lower price, and evidence, albeit less definitive, of its effectiveness.17,18
AGE-RELATED MACULAR DEGENERATION ALTHOUGH DIABETIC EYE DISEASE IS THE LEADING CAUSE
of vision loss among young to middle-aged individuals, neovascular AMD, left untreated, is the most frequent cause of irreversible severe vision loss among older people in the developed world. Before the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration and Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration trials, exudative AMD was treated with thermal laser or PDT. Thermal laser photocoagulation works by destroying abnormal blood vessels. The Macular Photocoagulation Study reported that laser photocoagulation for extrafoveal, juxtafoveal, and even subfoveal CNV resulting from AMD decreased the risk of severe visual loss.19 –21 Drawbacks to treatment of subfoveal CNV (the most common group) were substantial and included immediate loss of visual acuity as a result of collateral damage to overlying neurosensory retina OF
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and the retinal pigment epithelium, the relatively small number of eligible lesions (small with substantial vision loss), the absence of visual acuity improvement, as well as frequent recurrences. In 2000, cold laser treatment in combination with verteporfin gained acceptance as a therapy for neovascular AMD. PDT is believed selectively to target the photosensitizing compound only within choroidal neovascular vessels, hence leading to much less collateral damage to overlying retina and RPE. The Treatment of Age-related Macular Degeneration with Photodynamic Therapy Study Group showed that for classic CNV lesions, a higher percentage of verteporfin-treated eyes than placebo lost fewer than 15 letters of visual acuity at 12 months,22,23 although few eyes had substantial improvement. Fluorescein angiographic studies also showed that PDT with verteporfin reduced classic lesion growth, leakage, and progression. The Verteporfin in Photodynamic Therapy Study Group shortly thereafter investigated verteporfin therapy for subfoveal lesions with occult but no classic CNV and evidence of recent disease progression.24 Although the rate of 15-letter visual acuity loss was similar among treatment and placebo groups through 12 months, by 24 months, 55% of verteporfin-treated eyes versus 68% percent of placebo eyes had lost at least 15 letters. The benefits seemed greatest for those with smaller lesions and lower initial visual acuity levels. In the United States, PDT with verteporfin was approved by the Food and Drug Administration only for predominantly classic lesions. Although PDT of subfoveal CNV showed better visual acuity results than thermal laser and slowed the progression of vision loss, most patients still continued to lose vision, and very few actually gained vision. Hence, the enthusiasm in 2006 when the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration and Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration trials showed that almost 95% of patients treated monthly for 2 years with intravitreal ranibizumab avoided vision loss of 15 letters25,26 and more than one third of the patients in these 2 studies gained at least 3 lines of vision. These 2 studies were groundbreaking in proving for the first time that a treatment for neovascular AMD could result in visual acuity gain for at least one third of treated patients. Since 2006, the use of anti-VEGF agents has increased markedly, and neovascular AMD patients have benefited, maintaining and often recovering vision in a disease that previously often led to inevitable severe visual loss. In contrast, thermal laser is almost obsolete in the treatment of AMD, and PDT’s use has dwindled dramatically, with some practices not even owning the laser. That being said, thermal laser and PDT may still be beneficial in particular AMD scenarios. Patients with CNV far from the fovea (a rare event) should respond well to treatment with thermal VOL. 152, NO. 3
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laser without the risk, expense, or time investment of repeated injections. In addition, we have all treated patients whose disease process responds minimally if at all to anti-VEGF therapy. PDT may be beneficial in some of these cases. Indocyanine green angiography may reveal the presence of polyps under the retina, leading to the diagnosis of a pattern of CNV termed idiopathic polypoidal choroidal vasculopathy. Authors have shown that idiopathic polypoidal choroidal vasculopathy often responds poorly to anti-VEGF monotherapy.27 Despite decreasing exudation and retinal thickness, anti-VEGF therapy largely is ineffective in actually eliminating the polyps. PDT, however, seems to eradicate the actual root of the disease more successfully. Experience in an Asian population has suggested that this pattern of CNV may respond with an average visual acuity gain that is similar with either anti-VEGF therapy or PDT. The use of reduced-fluence PDT, combined with the fact that the polyps often are peripapillary or extrafoveal, rather than subfoveal, has decreased the apprehension of many retina specialists to treat these lesions with PDT. Trials are ongoing to investigate whether various combinations of anti-VEGF agents, PDT, and intravitreal steroids can yield visual acuity outcomes that are the same or better than those seen with anti-VEGF monotherapy, and with fewer treatments. So for now, hold onto those PDT lasers!
RETINAL VEIN OCCLUSION THE TREATMENT OF RETINAL VENOUS OCCLUSIVE EVENTS
has seen a similar metamorphosis in recent years with the use of intravitreal steroids and anti-VEGF agents. Retinal venous obstructions frequently are responsible for vision loss.28 The Branch Vein Occlusion Study (BVOS) and Central Vein Occlusion Study established the common practice for treatment of these diseases in 1985 and 1994, respectively.29,30 In the BVOS, patients with macular edema and vision worse than 20/40 who were treated with grid pattern photocoagulation had a greater chance of gaining at least 2 lines of vision than untreated eyes. The study thus recommended that fluorescein angiography be performed on patients with persistent edema with visual acuity reduced to 20/40 or worse after hemorrhages had cleared sufficiently. If macular edema persisted and vision was not improving spontaneously to a level better than 20/40, grid photocoagulation was performed. If the FA showed macular nonperfusion as the cause for decreased vision, laser was not recommended. However, the Central Vein Occlusion Study did not find a beneficial effect on visual acuity of grid pattern photocoagulation in eyes with central vein occlusion, angiographically proven macular edema, and vision worse than 20/50. Although laser treatment did reduce angiographic leakage, this did not translate to visual improveAND
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ment; thus, laser was not recommended. The 2 studies also recommended sector or panretinal photocoagulation, respectively, if neovascularization developed, but not prophylactically before its appearance because the risk of neovascular glaucoma was similar whether PRP was initiated at presentation or after iris or angle neovascularization was detected. Sequelae of venous occlusive events were managed in this fashion until recently. Although patients with macular edema from BRVO can be offered laser therapy, 40% of laser-treated eyes in the BVOS still had vision worse than 20/40 after 3 years, and 12% were worse than 20/200. Patients with CRVO have been observed, with follow-up to monitor for the development of neovascularization. PRP has continued to play a major role in salvaging eyes and warding off devastating consequences of ischemia in those patients, such as neovascular glaucoma. Analogous to diabetic retinopathy, recent years have seen multicenter, randomized clinical trials evaluating alternative therapeutic methods for macular edema resulting from venous occlusive events. Sponsored by the National Eye Institute, the Standard Care vs. Corticosteroid for Retinal Vein Occlusion Study published results in September 2009 comparing 1- and 4-mg doses of intravitreal triamcinolone with grid photocoagulation for BRVO and observation for CRVO.31,32 In the branch vein study, there was no significant difference in the percentage of patients who gained 15 letters of vision at 1 year among the 3 treatment groups, with the laser group undergoing a mean of 1.8 treatments and the triamcinolone groups having 2.1 and 2.2 mean injections. Although the 4-mg triamcinolone group initially showed better visual outcomes at the 4-month study visit, the laser group had better outcomes after 1 year. Furthermore, the laser group demonstrated greater decreases in OCT-measured center point thickness out to 3 years. As expected, the 4-mg steroid dose was associated with more elevation of IOP and cataract development. The study group concluded that grid laser should remain the usual practice and benchmark for trials of alternative therapeutic methods for macular edema resulting from BRVO. Although intravitreal triamcinolone did not prove to be more efficacious for BRVO than laser therapy, the Standard Care vs. Corticosteroid for Retinal Vein OcclusionCRVO trial did reveal better outcomes than the natural history of untreated macular edema in perfused CRVO. Although only approximately 7% of untreated patients gained 15 letters of vision by month 12, more than 25% gained 3 lines in the 2 triamcinolone groups. Nevertheless, the treated groups still lost a mean of 1 to 2 letters of vision by month 12, and 30% of patients lost 15 letters or more by month 24. Rates of adverse events, including cataract and IOP rise, were similar to those seen in the Standard Care vs. Corticosteroid for Retinal Vein Occlusion-BRVO trial. Although triamcinolone did provide a means of treating macular edema resulting from CRVO and poten336
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tially improving vision, a more effective treatment still was needed. Enter anti-VEGF therapy. Elevated VEGF levels have been demonstrated in eyes after venous occlusive events, causing neovascularization and increasing vascular permeability, as mentioned previously, and leading to a propensity to macular edema development.11 Whereas corticosteroids may treat macular edema indirectly by decreasing VEGF expression, anti-VEGF agents directly impede VEGF from exerting its harmful effects. The Ranibizumab for the Treatment of Macular Edema after Central Retinal Vein Occlusion: Evaluation of Efficacy and Safety and the Ranibizumab for the Treatment of Macular Edema following Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety studies recently were published.33,34 Both trials were large, multicenter, randomized, sham injection-controlled clinical trials comparing monthly 0.3- and 0.5-mg doses of ranibizumab for 6 months with sham injection. Both studies revealed impressive benefit. In the Ranibizumab for the Treatment of Macular Edema following Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety study, patients already had gained an average of 7.5 letters 7 days after the first injection. At 6 months, the 2 treatment groups gained an average of 17 letters compared with 7 letters for the sham group. Twice as many ranibizumab-treated patients gained 15 letters, and approximately two thirds had vision better than 20/40 at 6 months, compared with 42% in the sham group. The effect on OCT also was rapid and impressive, with a reduction in mean central subfield thickness of more than 250 m at day 7. Results from the Ranibizumab for the Treatment of Macular Edema after Central Retinal Vein Occlusion: Evaluation of Efficacy and Safety study similarly were positive, with a mean gain of 12.7 and 14.9 letters in the 0.3- and 0.5-mg ranibizumab groups, respectively, compared with 0.8 in the sham group. Patients gained, on average, 9 letters by week 1. Almost half of treated patients gained 3 lines, compared with only approximately 17% of control subjects, and more than twice as many treated patients achieved 20/40 or better vision. Reduction in macular thickness was rapid and significant, suggesting that macular edema in venous occlusive events likely is mediated primarily by VEGF. Just as anti-VEGF therapy recently yielded superior visual outcomes to focal/grid photocoagulation for DME, ranibizumab has demonstrated more impressive results than the previous usual practice for BRVO and CRVO. Whereas grid photocoagulation was used almost unanimously by retina specialists in the treatment of visually significant macular edema from BRVO after the BVOS in 1984, its use likely has decreased recently. After having nothing to offer CRVO patients with macular edema in the past, we now have multiple options that provide good odds of gaining vision. Both ranibizumab and the dexamethasone intravitreal implant (Ozurdex; Allergan, IrOF
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vine, California, USA) are now approved by the Food and Drug Administration for treating macular edema resulting from vein occlusions.35 Although the popularity of laser has taken yet another hit at the hands of anti-VEGF therapy, it still has a role in treatment of venous occlusion. Grid photocoagulation either alone or in combination with anti-VEGF therapy may be a good treatment option for BRVO patients with macular edema who are unable or unwilling to return for monthly injections or who have edema refractory to multiple injections. Furthermore, sector or diffuse panretinal photocoagulation to avoid neovascular complications of vein occlusions remains of paramount importance. Although some retina specialists initially used anti-VEGF agents in the face of neovascular glaucoma to help lower pressure or to decrease intraoperative hemorrhage, PRP remains common practice and provides the most effective means of permanently lowering VEGF production from ischemic retina. Anti-VEGF therapy for this indication is a supplemental therapy, rather than a replacement therapy. Ophthalmology is an area of medicine that has undergone tremendous change in recent decades. Technologic advances and intensive research leading to innovative ground-breaking therapies have allowed us to give our patients much better visual outcomes in the face of previously debilitating diseases. Anti-VEGF agents have been shown to be effective in preventing vision loss and improving vision in multiple diseases, including diabetic retinopathy, neovascular AMD, and retinal vein occlusions. Despite a substantial decrease in its use for these conditions in recent years, laser therapies continue to serve important roles in our ability to combat retinal pathologic features. Although rarely used in neovascular AMD (except on occasion as PDT), lasers still are used frequently for persistent DME and macular edema from vein occlusions that responds poorly to anti-VEGF therapy. Furthermore, newer laser treatment approaches such as subthreshold micropulse laser have been introduced, and their safety and efficacy for the aforementioned conditions is being studied. In addition to thermal laser’s use for panretinal photocoagulation, it is vital for other retinal entities not discussed in this article, such as barrier laser retinopexy for retinal tears, ablation of retinal arterial macroaneurysms, and quelling of the proliferative process in retinopathy of prematurity (Table 1). PDT with verte-
TABLE 1. Uses of Thermal Laser for Retinal Diseases in the Anti-VEGF Era 1. Patients with DME with progression toward the center of the macula, but not involving the center. 2. Patients with persistent DME or macular edema secondary to a retinal vein occlusion no longer improving despite multiple anti-VEGF injections or in whom monthly injections are not feasible. 3. Panretinal or scatter photocoagulation for diabetes mellitus, vein occlusions, and other diseases with NVE, NVD, or NVG. 4. Scatter photocoagulation for ischemic and exudative retinopathies, e.g., Coats disease and IRVAN. 5. Retinopathy of prematurity. 6. Barrier for retinal breaks or detachment. 7. Symptomatic or vision threatening extrafoveal CNV. 8. Macroaneurysms. 9. Central serous chorioretinopathy with chronic thickening and a persistent focal leak outside of the center of the macula. CNV ⫽ choroidal neovascularization; DME ⫽ diabetic macular edema; IRVAN ⫽ intraretinal vasculitis, aneurysms, and neuroretinitis; NVD ⫽ neovascularization of the disc; NVE ⫽ neovascularization elsewhere; NVG ⫽ neovascular glaucoma; VEGF ⫽ vascular endothelial growth factor.
TABLE 2. Uses of Photodynamic Therapy for Retinal Diseases in the Anti-VEGF Era 1. Central serous chorioretinopathy with chronic thickening without a discrete lesion. 2. Polypoidal choroidal vasculopathy pattern of CNV. 3. Combination therapy with intravitreal anti-VEGF agents for exudative AMD when retinal thickening persists and is not improving despite monthly injections. AMD ⫽ age-related macular degeneration; CNV ⫽ choroidal neovascularization; VEGF ⫽ vascular endothelial growth factor.
porfin has been shown to be effective for treatment of not only idiopathic polypoidal choroidal vasculopathy, but also central serous chorioretinopathy (Table 2).36 The retina world has embraced anti-VEGF therapy with open arms, but laser therapy remains a pivotal component of our practices for at least the next several years.
PUBLICATION OF THIS ARTICLE WAS SUPPORTED IN PART BY AN UNRESTRICTED GRANT FROM RESEARCH TO PREVENT Blindness, Inc, New York, New York. Dr Shah indicates no financial conflict of interest in this study. Dr Jampol receives consulting fees from Pfizer Pharmaceuticals and Quintiles/Stem Cell Organization. Dr Bressler is Principal Investigator of grants at The Johns Hopkins University sponsored by the following entities (not including the National Institutes of Health): Abbott Medical Optics, Inc; Alimera Sciences; Allergan USA, Inc; Bausch & Lomb, Inc; Carl Zeiss Meditec, Inc; DIAGNOS Inc; The EMMES Corporation; ForSight Labs, LLC; Genentech, Inc; Genzyme Corporation; Lumenis, Inc; Notal Vision; Novartis Pharma AG; Ora, Inc; Pfizer, Inc; QLT, Inc; Regeneron Pharmaceuticals, Inc; and Steba Biotech S.A. Involved in Design of study (A.M.S., L.M.J.); Conduct of study (A.M.S., L.M.J.); and Preparation and review of manuscript (A.M.S., N.M.B., L.M.J.). Institutional review board approval was not necessary or relevant for the completion of the manuscript.
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16. Arevalo JF, Maia M, Flynn HW Jr, et al. Tractional retinal detachment following intravitreal bevacizumab (Avastin) in patients with severe proliferative diabetic retinopathy. Br J Ophthalmol 2008;92(2):213–216. 17. Michaelides M, Kaines A, Hamilton RD, et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2. Ophthalmology 2010;117(6): 1078 –1086. 18. Arevalo JF, Sanchez JG, Fromow-Guerra J, et al. Comparison of two doses of primary intravitreal bevacizumab (Avastin) for diffuse diabetic macular edema: results from the PanAmerican Collaborative Retina Study Group (PACORES) at 12-month follow-up. Graefes Arch Clin Exp Ophthalmol 2009;247(6):735–743. 19. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration: results of a randomized clinical trial. Arch Ophthalmol 1991;109(9):1220 –1231. 20. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal recurrent neovascular lesions in agerelated macular degeneration: results of a randomized clinical trial. Arch Ophthalmol 1991;109(9):1232–1241. 21. Macular Photocoagulation Study Group. Subfoveal neovascular lesions in age-related macular degeneration: guidelines for evaluation and treatment in the Macular Photocoagulation Study. Arch Ophthalmol 1991;109(9):1242–1257. 22. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in agerelated macular degeneration with verteporfin: one-year results of 2 randomized clinical trials. TAP report 1. Arch Ophthalmol 1999;117(10):1329 –1345. 23. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in agerelated macular degeneration with verteporfin: two-year results of 2 randomized clinical trials. TAP report 2. Arch Ophthalmol 2001;119(2):198 –207. 24. Verteporfin in Photodynamic Therapy Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization—verteporfin in photodynamic therapy report 2. Am J Ophthalmol 2001;131(5): 541–560. 25. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for neovascular age-related macular degeneration. N Eng J Med 2006;355(14):1419 –1431. 26. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Eng J Med 2006;355(14):1432–1444. 27. Kokame GT, Yeung L, Lai JC. Continuous anti-VEGF treatment with ranibizumab for polypoidal choroidal vasculopathy: an interim 6-month report. Br J Ophthalmol 2010; 94(3):297–301. 28. Klein R. Retinopathy in a population-based study. Trans Am Ophthalmol Soc 1992;90:561–594. 29. Branch Vein Occlusion Study Group. Argon laser photocoagulation for macular edema in branch vein occlusion. Am J Ophthalmol 1984;98(3):271–282.
REFERENCES 1. L’Esperance FA Jr. Historical aspects of ophthalmic lasers. In: Ophthalmic Lasers. Vol I. Third ed. St Louis: C. V. Mosby, 1989:13–32. 2. Arnarsson A, Stefansson E. Laser treatment and the mechanism of edema reduction in branch retinal vein occlusion. Invest Ophthalmol Vis Sci 2000;41(3):877– 879. 3. Wilson DJ, Finkelstein D, Quigley HA, Green WR. Macular grid photocoagulation: an experimental study on the primate retina. Arch Ophthalmol 1988;106(1):100 –105. 4. Budzynski E, Smith JH, Bryar P, Birol G, Linsenmeier RA. Effects of photocoagulation on intraretinal P02 in cat. Invest Ophthalmol Vis Sci 2008;49:380 –389. 5. Ogata N, Ando A, Uyama M, Matsumura M. Expression of cytokines and transcription factors in photocoagulated human retinal pigment epithelium cells. Graefes Arch Clin Exp Ophthalmol 2001;239(2):87–95. 6. Diabetic Retinopathy Study Research Group. Preliminary report on effects of photocoagulation therapy. Am J Ophthalmol 1976;81(4):383–396. 7. Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy. The second report of diabetic retinopathy study findings. Ophthalmology 1978;85:82–106. 8. Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS report no. 8. Ophthalmology 1981;88(7):583– 600. 9. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 1985(12);103:1796 –1806. 10. Writing Committee for the Diabetic Retinopathy Clinical Research Network. Comparison of the modified early treatment diabetic retinopathy study and mild macular grid laser photocoagulation strategies for diabetic macular edema. Arch Ophthalmol 2007;125(4):469 – 480. 11. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Eng J Med 1994;331(22):1480 –1487. 12. Nauck M, Karakiulakis G, Perruchoud A, Papakonstantinou E, Roth M. Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in human vascular smooth muscle cells. Euro J Pharmacol 1998;341(2–3):309 – 315. 13. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology 2008;115(9):1447–1459. 14. Schatz H, Madeira D, McDonald HR, Johnson RN. Progressive enlargement of laser scars following grid laser photocoagulation for diffuse diabetic macular edema. Arch Ophthalmol 1991;109(11):1549 –1551. 15. Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010;117(6):1064 –1077.
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30. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The Central Vein Occlusion Study Group M report. Ophthalmology 1995;102(10): 1425–1433. 31. SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol 2009;127(9):1101–1114. 32. SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: The Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol 2009;127(9):1115–1128.
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33. Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology 2010;117(6):1124 –1133. 34. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: Six-month primary end point results of a phase III study. Ophthalmology 2010;117(6):1101–1112. 35. Haller JA, Bandello F, Belfort R, et al. Randomized, shamcontrolled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010;117(6):1134 –1146. 36. Ober MD, Yannuzzi LA, Do DV, et al. Photodynamic therapy for focal retinal pigment epithelial leaks secondary to central serous chorioretinopathy. Ophthalmology 2005; 112(12):2088 –2094.
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Biosketch Ankur M. Shah is a medical retina fellow at Northwestern University, Chicago, Illinois. He received a Bachelor of Science degree from the University of Michigan and his medical degree from Northwestern University. He completed his ophthalmology residency at the University of California, San Diego where he served as chief resident. His research interests include medical retina and uveitis.
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To discuss the current role of laser therapies in the management of retinal vascular and neovascular diseases. ● DESIGN: Perspective. ● METHODS: Laser’s role in the management of diabetic retinopathy, age-related macular degeneration, and venous occlusive disease is discussed, with emphasis on comparing laser with anti–vascular endothelial growth factor (VEGF) therapy and discussion of situations where these treatment methods can be complementary. ● RESULTS: Thermal panretinal photocoagulation remains the usual practice for treatment of neovascularization in proliferative diabetic retinopathy and after venous occlusive events. Focal/grid laser still has a role for patients with macular edema resulting from diabetes or venous occlusion that is poorly responsive to anti-VEGF agents and in patients who are unable or unwilling to return for frequent injections. Focal/grid laser also is used as combination therapy with anti-VEGF agents for these indications. Focal laser can be used for extrafoveal choroidal neovascularization to avoid the treatment burden and risks of multiple injections. Photodynamic therapy may be beneficial in the treatment of central serous chorioretinopathy and idiopathic polypoidal choroidal vasculopathy and as combination therapy with antiVEGF agents in age-related macular degeneration. ● CONCLUSIONS: Anti-VEGF agents are effective in preventing vision loss and improving vision in multiple diseases, including diabetic retinopathy, neovascular agerelated macular degeneration, and retinal vein occlusions. Despite a substantial decrease in its use for these conditions in recent years, laser therapies continue to serve important roles in our ability to combat retinal pathologic features and will remain a pivotal component of our practices for at least the next several years. (Am J Ophthalmol 2011;152:332–339. © 2011 by Elsevier Inc. All rights reserved.) Accepted for publication Apr 1, 2011. From the Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois (A.M.S., L.M.J.); and The Wilmer Institute, Johns Hopkins University, Baltimore, Maryland (N.M.B.). Inquiries to Lee M. Jampol, Department of Ophthalmology, Feinberg School of Medicine, Northwestern University, 645 North Michigan Avenue, Suite 440, Chicago, IL 60611; e-mail: [email protected]
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EYER-SCHWICKERATH FIRST USED THE SUN AND
then xenon arc (1956) to perform thermal coagulation of the retina.1 Campbell, Zweng, Patz, and L’Esperance (1960) were among the first to use the laser to treat retinal diseases.1 The argon laser soon thereafter became a major tool for ophthalmologists. For more than 30 years, laser therapies have served as an effective therapeutic method for retinal diseases. Laser has been the mainstay of treatment for proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME). From the 1970s onward, laser was used frequently to ablate choroidal neovascularization (CNV) secondary to agerelated macular degeneration (AMD) and many other diseases. But in the last decade, new technologies and pharmacotherapies have emerged, and the use of thermal laser has declined dramatically. Treatment options including photodynamic therapy (PDT) and intravitreal injections have come to the forefront. With the advent of anti–vascular endothelial growth factor (VEGF) therapy, some have begun to question whether laser therapy still has a role in the treatment of retinal vascular and neovascular diseases.
DIABETIC RETINOPATHY NUMEROUS HYPOTHESES HAVE BEEN PROPOSED REGARD-
ing the precise mechanisms of action responsible for laser’s benefits in both PRP and focal/grid photocoagulation.2–5 Our current understanding of the mechanisms leading to retinal neovascularization and macular edema is that hypoxia of the inner retina leads to increased production of proangiogenic cytokines such as VEGF that also lead to increased vascular permeability. Budzynski and associates showed that average PO2 across the inner 50% of the retina was higher in photocoagulated feline retinas than in untreated eyes.4 Increased oxygenation of the inner retina after photocoagulation may decrease the stimulus for VEGF production, thus decreasing neovascularization and vascular permeability that leads to macular edema. Alternatively, laser may directly damage or destroy the cells that produce proangiogenic cytokines. In cases with areas of focal leakage from microaneurysms, direct closure also may be important. Finally, effects on retinal pigment epithelial
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function also may be significant. Laser likely changes the microenvironment in important ways, such as cytokine levels.5 Thermal laser first achieved widespread popularity and validity in ophthalmology in 1976 when the Diabetic Retinopathy Study published conclusive evidence that peripheral scatter or panretinal photocoagulation (PRP) reduced the risk of severe visual acuity loss in eyes with PDR by 50% or more.6,7 Side effects included decreased peripheral visual field and dark adaptation, plus occasional loss of a few lines of Snellen visual acuity, presumed to be from exacerbation of macular edema. The Diabetic Retinopathy Study Group recommended treatment for eyes with certain high-risk characteristics.8 Today, argon green laser PRP is still widely used and remains a common practice for treatment of not only PDR, but also anterior or posterior segment neovascularization resulting from other causes, such as central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), sickle cell retinopathy, and the ocular ischemic syndrome. However, it is plausible that pharmacotherapies could supplant laser in the future, because PRP does destroy functioning retinal neurons. In 1985, another therapeutic indication for thermal laser emerged when the Early Treatment Diabetic Retinopathy Study showed that focal/grid photocoagulation of DME reduced the 3-year risk of losing 3 lines or more of vision by approximately 50%, and for eyes with edema involving the center of the macula and visual acuity loss, this treatment also increased the chance of visual improvement.9 The technique of focal/grid photocoagulation involves 2 strategies within areas of retinal thickening: (1) direct treatment to microaneurysms within 2 disc diameters of the center of the fovea, and (2) scatter or grid treatment approximately 2 burn widths apart to other areas of thickening. Over the years, a modified version of the Early Treatment Diabetic Retinopathy Study laser protocol has been used more commonly, employing less intense burns, which seems to result in outcomes similar to those seen in the Early Treatment Diabetic Retinopathy Study, whereas grid treatment alone does not seem to be as effective and certainly has not been shown to be superior to focal/grid treatment.10 Focal/grid laser therapy continued as the primary treatment method for DME with vision impairment involving the center of the macula until very recently. Potential challengers such as preservative-free intravitreal triamcinolone (IVTA) attempted to displace photocoagulation. It was presumed that by inhibiting expression of VEGF as well as other proinflammatory cytokines, corticosteroids could reduce capillary permeability, thus decreasing macular edema,11,12 and preliminary studies with short follow-up suggested that this treatment was superior to laser. However, in 2008, the Diabetic Retinopathy Clinical Research Network (DRCR.net) published data from a multicenter, randomized, clinical trial of 840 eyes that VOL. 152, NO. 3
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compared laser with 2 doses of IVTA.13 Despite early results favoring 4 mg IVTA at 4 months, IVTA was not shown to be superior to focal/grid photocoagulation, and laser seemed to yield better mean visual acuity results at 2 years than 1- and 4-mg doses of IVTA. Optical coherence tomography (OCT) results mirrored the visual acuity results. As expected, rates of intraocular pressure elevation (IOP) and cataract formation were higher in the triamcinolone groups than in the laser groups. Focal/grid photocoagulation thus retained its position as the usual practice for treatment of DME. Although one third of eyes with DME and visual impairment treated with focal/grid photocoagulation see improvement in visual acuity of at least 2 lines, approximately 20% of eyes worsen by at least 2 lines. In addition, photocoagulation does come with inherent risks and side effects. Burns close to the fovea may damage vision acutely or may enlarge over time, leading to atrophic retina and retinal pigment epithelium encroaching on fixation with visual acuity loss.14 Occasionally, choroidal neovascularization may develop and may create permanent central scotomas with substantial vision loss. Recently, researchers have reported more efficacious and potentially safer treatments for DME. In June 2010, the DRCR.net published convincing evidence that the antiVEGF agent ranibizumab (Lucentis; Genentech, South San Francisco, California, USA) with or without prompt laser, leads to superior visual acuity outcomes compared with laser alone.15 The rationale for exploring anti-VEGF agents as a treatment method for DME stems from the knowledge that VEGF increases vascular permeability.11 Thus, anti-VEGF agents theoretically could block VEGF from activating its receptors, prevent increased vessel permeability, thus decreasing DME. The DRCR.net study was a multicenter, randomized clinical trial of 854 eyes with DME involving the center of the macula with vision impairment. At 1 year, the groups assigned to ranibizumab with prompt or deferred (⬎ 24 weeks) focal/grid laser had nearly identical outcomes, gaining an average of 2 lines of vision, with approximately 50% gaining 2 lines or more of visual acuity and less than 5% losing 2 lines or more. Prompt focal/grid photocoagulation yielded no additional visual acuity benefit when compared with the deferred laser group, in which approximately 60% of the study participants did not receive a laser treatment within the 2 years. Results in a triamcinolone plus prompt laser group were not superior to those of the laser alone group. Also noteworthy was the observation that eyes assigned to either ranibizumab group or the triamcinolone group were less likely than the laser control group to have progression of diabetic retinopathy or vitreous hemorrhage or to require PRP for PDR, suggesting an additional benefit for anti-VEGF agents and triamcinolone (other than a decrease in macular edema). These recently published results have changed many retina specialists’ management approach for DME. AntiAND
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VEGF injections not only seem to provide superior visual acuity results, but also are faster acting and potentially safer than focal/grid photocoagulation (except for the risk of rare endophthalmitis). Also, whereas fluorescein angiography was necessary frequently to facilitate or guide placement of focal/grid laser treatment, intravitreal anti-VEGF therapy often can be used based on clinical examination and OCT findings, obviating the need for fluorescein angiograms. The often rapid decrease in retinal thickness and accompanying vision improvement seen with antiVEGF injections provide an incentive for patients to return for treatment, potentially improving compliance and efficacy of the therapy. Also, anti-VEGF agents do not pose the dangers of cataract formation and elevation of IOP seen with intravitreal steroids. The era of solitary focal/grid photocoagulation being the most effective treatment for DME has come to a close. Although the treatment approach for applying antiVEGF therapy in the DRCR.net study may seem complex, the underlying rationale is fairly straightforward. After initiating treatment, it seems reasonable to continue to treat at monthly intervals until one is relatively certain that macular thickness is no longer improving (for example, 2 consecutive OCT measurements showing no further thinning of the macula). After retreatment is not given, injections would be resumed if edema recurs or worsens. If it does not recur or worsen after withholding treatment for at least 1 month, follow-up injections might be extended to 2 months and then 4 months, unless edema recurs or worsens to warrant resumption of monthly intravitreal injections, which are used again until improvement no longer occurs. Focal/grid laser as often as every 4 months can be added if edema persists and no longer improves despite multiple monthly injections of intravitreal antiVEGF drugs. The DRCR.net study showed that such an approach can lead to improvement in visual acuity, on average, without loss if or when injections are withheld, as long as injections are resumed when edema recurs or worsens, with a median of 6 injections within the first 6 months, followed by a median of 2 to 3 injections in the second 6 months and a median of another 2 to 3 injections in the second year. This potential avoidance of monthly injections indefinitely to maintain improvements noted through at least 6 months is different from the use of anti-VEGF drugs for neovascular AMD (see below), where withholding treatment when thickening no longer is improving and resuming treatment when thickening recurs or worsens does not maintain the maximum visual acuity improvements obtained after the first few months of monthly treatments. For some patients with DME, however, focal laser may still be a good treatment option. Patients who cannot tolerate or comply with the potential need for monthly visits and injections may be better suited to laser treatments, rather than no treatment, given their potentially longer-lasting effect and extended interval between visits 334
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of up to 4 months. At present, there is little evidence to suggest that laser therapy in combination with anti-VEGF injections will decrease the injection treatment burden substantially, but further follow-up in a DRCR.net study is addressing this. Because it remains unclear if there is a small increased risk of arterial thromboembolic events with intravitreal anti-VEGF agents (current studies confidently rule out a moderate or large risk), some practitioners are hesitant to use these agents in patients with, or at risk for, cardiovascular or cerebrovascular disease. In addition, intravitreal injections come with their own risks, including rare but devastating endophthalmitis. Although some investigators have reported contraction of fibrovascular tissue after anti-VEGF injection in eyes with proliferative disease about to undergo vitrectomy, presumably increasing the risk of tractional retinal detachment, rhegmatogenous detachment, hemorrhage, or a combination thereof,16 there is no evidence to suggest that an eye with PDR and DME or an eye that has been treated for PDR and in which DME develops has an increased risk of tractional retinal detachment when undergoing intravitreal ranibizumab for DME. At this time, neither IVTA nor ranibizumab are approved by the United States Food and Drug Administration approved for use for DME, and thus are used in an off-label fashion in the United States, although ranibizumab for this indication has been approved in Europe by the European Medical Evaluation Agency. Some retina practices also have used bevacizumab (Avastin; Genentech), rather than ranibizumab, as their anti-VEGF treatment of choice for DME because of its lower price, and evidence, albeit less definitive, of its effectiveness.17,18
AGE-RELATED MACULAR DEGENERATION ALTHOUGH DIABETIC EYE DISEASE IS THE LEADING CAUSE
of vision loss among young to middle-aged individuals, neovascular AMD, left untreated, is the most frequent cause of irreversible severe vision loss among older people in the developed world. Before the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration and Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration trials, exudative AMD was treated with thermal laser or PDT. Thermal laser photocoagulation works by destroying abnormal blood vessels. The Macular Photocoagulation Study reported that laser photocoagulation for extrafoveal, juxtafoveal, and even subfoveal CNV resulting from AMD decreased the risk of severe visual loss.19 –21 Drawbacks to treatment of subfoveal CNV (the most common group) were substantial and included immediate loss of visual acuity as a result of collateral damage to overlying neurosensory retina OF
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and the retinal pigment epithelium, the relatively small number of eligible lesions (small with substantial vision loss), the absence of visual acuity improvement, as well as frequent recurrences. In 2000, cold laser treatment in combination with verteporfin gained acceptance as a therapy for neovascular AMD. PDT is believed selectively to target the photosensitizing compound only within choroidal neovascular vessels, hence leading to much less collateral damage to overlying retina and RPE. The Treatment of Age-related Macular Degeneration with Photodynamic Therapy Study Group showed that for classic CNV lesions, a higher percentage of verteporfin-treated eyes than placebo lost fewer than 15 letters of visual acuity at 12 months,22,23 although few eyes had substantial improvement. Fluorescein angiographic studies also showed that PDT with verteporfin reduced classic lesion growth, leakage, and progression. The Verteporfin in Photodynamic Therapy Study Group shortly thereafter investigated verteporfin therapy for subfoveal lesions with occult but no classic CNV and evidence of recent disease progression.24 Although the rate of 15-letter visual acuity loss was similar among treatment and placebo groups through 12 months, by 24 months, 55% of verteporfin-treated eyes versus 68% percent of placebo eyes had lost at least 15 letters. The benefits seemed greatest for those with smaller lesions and lower initial visual acuity levels. In the United States, PDT with verteporfin was approved by the Food and Drug Administration only for predominantly classic lesions. Although PDT of subfoveal CNV showed better visual acuity results than thermal laser and slowed the progression of vision loss, most patients still continued to lose vision, and very few actually gained vision. Hence, the enthusiasm in 2006 when the Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration and Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration trials showed that almost 95% of patients treated monthly for 2 years with intravitreal ranibizumab avoided vision loss of 15 letters25,26 and more than one third of the patients in these 2 studies gained at least 3 lines of vision. These 2 studies were groundbreaking in proving for the first time that a treatment for neovascular AMD could result in visual acuity gain for at least one third of treated patients. Since 2006, the use of anti-VEGF agents has increased markedly, and neovascular AMD patients have benefited, maintaining and often recovering vision in a disease that previously often led to inevitable severe visual loss. In contrast, thermal laser is almost obsolete in the treatment of AMD, and PDT’s use has dwindled dramatically, with some practices not even owning the laser. That being said, thermal laser and PDT may still be beneficial in particular AMD scenarios. Patients with CNV far from the fovea (a rare event) should respond well to treatment with thermal VOL. 152, NO. 3
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laser without the risk, expense, or time investment of repeated injections. In addition, we have all treated patients whose disease process responds minimally if at all to anti-VEGF therapy. PDT may be beneficial in some of these cases. Indocyanine green angiography may reveal the presence of polyps under the retina, leading to the diagnosis of a pattern of CNV termed idiopathic polypoidal choroidal vasculopathy. Authors have shown that idiopathic polypoidal choroidal vasculopathy often responds poorly to anti-VEGF monotherapy.27 Despite decreasing exudation and retinal thickness, anti-VEGF therapy largely is ineffective in actually eliminating the polyps. PDT, however, seems to eradicate the actual root of the disease more successfully. Experience in an Asian population has suggested that this pattern of CNV may respond with an average visual acuity gain that is similar with either anti-VEGF therapy or PDT. The use of reduced-fluence PDT, combined with the fact that the polyps often are peripapillary or extrafoveal, rather than subfoveal, has decreased the apprehension of many retina specialists to treat these lesions with PDT. Trials are ongoing to investigate whether various combinations of anti-VEGF agents, PDT, and intravitreal steroids can yield visual acuity outcomes that are the same or better than those seen with anti-VEGF monotherapy, and with fewer treatments. So for now, hold onto those PDT lasers!
RETINAL VEIN OCCLUSION THE TREATMENT OF RETINAL VENOUS OCCLUSIVE EVENTS
has seen a similar metamorphosis in recent years with the use of intravitreal steroids and anti-VEGF agents. Retinal venous obstructions frequently are responsible for vision loss.28 The Branch Vein Occlusion Study (BVOS) and Central Vein Occlusion Study established the common practice for treatment of these diseases in 1985 and 1994, respectively.29,30 In the BVOS, patients with macular edema and vision worse than 20/40 who were treated with grid pattern photocoagulation had a greater chance of gaining at least 2 lines of vision than untreated eyes. The study thus recommended that fluorescein angiography be performed on patients with persistent edema with visual acuity reduced to 20/40 or worse after hemorrhages had cleared sufficiently. If macular edema persisted and vision was not improving spontaneously to a level better than 20/40, grid photocoagulation was performed. If the FA showed macular nonperfusion as the cause for decreased vision, laser was not recommended. However, the Central Vein Occlusion Study did not find a beneficial effect on visual acuity of grid pattern photocoagulation in eyes with central vein occlusion, angiographically proven macular edema, and vision worse than 20/50. Although laser treatment did reduce angiographic leakage, this did not translate to visual improveAND
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ment; thus, laser was not recommended. The 2 studies also recommended sector or panretinal photocoagulation, respectively, if neovascularization developed, but not prophylactically before its appearance because the risk of neovascular glaucoma was similar whether PRP was initiated at presentation or after iris or angle neovascularization was detected. Sequelae of venous occlusive events were managed in this fashion until recently. Although patients with macular edema from BRVO can be offered laser therapy, 40% of laser-treated eyes in the BVOS still had vision worse than 20/40 after 3 years, and 12% were worse than 20/200. Patients with CRVO have been observed, with follow-up to monitor for the development of neovascularization. PRP has continued to play a major role in salvaging eyes and warding off devastating consequences of ischemia in those patients, such as neovascular glaucoma. Analogous to diabetic retinopathy, recent years have seen multicenter, randomized clinical trials evaluating alternative therapeutic methods for macular edema resulting from venous occlusive events. Sponsored by the National Eye Institute, the Standard Care vs. Corticosteroid for Retinal Vein Occlusion Study published results in September 2009 comparing 1- and 4-mg doses of intravitreal triamcinolone with grid photocoagulation for BRVO and observation for CRVO.31,32 In the branch vein study, there was no significant difference in the percentage of patients who gained 15 letters of vision at 1 year among the 3 treatment groups, with the laser group undergoing a mean of 1.8 treatments and the triamcinolone groups having 2.1 and 2.2 mean injections. Although the 4-mg triamcinolone group initially showed better visual outcomes at the 4-month study visit, the laser group had better outcomes after 1 year. Furthermore, the laser group demonstrated greater decreases in OCT-measured center point thickness out to 3 years. As expected, the 4-mg steroid dose was associated with more elevation of IOP and cataract development. The study group concluded that grid laser should remain the usual practice and benchmark for trials of alternative therapeutic methods for macular edema resulting from BRVO. Although intravitreal triamcinolone did not prove to be more efficacious for BRVO than laser therapy, the Standard Care vs. Corticosteroid for Retinal Vein OcclusionCRVO trial did reveal better outcomes than the natural history of untreated macular edema in perfused CRVO. Although only approximately 7% of untreated patients gained 15 letters of vision by month 12, more than 25% gained 3 lines in the 2 triamcinolone groups. Nevertheless, the treated groups still lost a mean of 1 to 2 letters of vision by month 12, and 30% of patients lost 15 letters or more by month 24. Rates of adverse events, including cataract and IOP rise, were similar to those seen in the Standard Care vs. Corticosteroid for Retinal Vein Occlusion-BRVO trial. Although triamcinolone did provide a means of treating macular edema resulting from CRVO and poten336
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tially improving vision, a more effective treatment still was needed. Enter anti-VEGF therapy. Elevated VEGF levels have been demonstrated in eyes after venous occlusive events, causing neovascularization and increasing vascular permeability, as mentioned previously, and leading to a propensity to macular edema development.11 Whereas corticosteroids may treat macular edema indirectly by decreasing VEGF expression, anti-VEGF agents directly impede VEGF from exerting its harmful effects. The Ranibizumab for the Treatment of Macular Edema after Central Retinal Vein Occlusion: Evaluation of Efficacy and Safety and the Ranibizumab for the Treatment of Macular Edema following Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety studies recently were published.33,34 Both trials were large, multicenter, randomized, sham injection-controlled clinical trials comparing monthly 0.3- and 0.5-mg doses of ranibizumab for 6 months with sham injection. Both studies revealed impressive benefit. In the Ranibizumab for the Treatment of Macular Edema following Branch Retinal Vein Occlusion: Evaluation of Efficacy and Safety study, patients already had gained an average of 7.5 letters 7 days after the first injection. At 6 months, the 2 treatment groups gained an average of 17 letters compared with 7 letters for the sham group. Twice as many ranibizumab-treated patients gained 15 letters, and approximately two thirds had vision better than 20/40 at 6 months, compared with 42% in the sham group. The effect on OCT also was rapid and impressive, with a reduction in mean central subfield thickness of more than 250 m at day 7. Results from the Ranibizumab for the Treatment of Macular Edema after Central Retinal Vein Occlusion: Evaluation of Efficacy and Safety study similarly were positive, with a mean gain of 12.7 and 14.9 letters in the 0.3- and 0.5-mg ranibizumab groups, respectively, compared with 0.8 in the sham group. Patients gained, on average, 9 letters by week 1. Almost half of treated patients gained 3 lines, compared with only approximately 17% of control subjects, and more than twice as many treated patients achieved 20/40 or better vision. Reduction in macular thickness was rapid and significant, suggesting that macular edema in venous occlusive events likely is mediated primarily by VEGF. Just as anti-VEGF therapy recently yielded superior visual outcomes to focal/grid photocoagulation for DME, ranibizumab has demonstrated more impressive results than the previous usual practice for BRVO and CRVO. Whereas grid photocoagulation was used almost unanimously by retina specialists in the treatment of visually significant macular edema from BRVO after the BVOS in 1984, its use likely has decreased recently. After having nothing to offer CRVO patients with macular edema in the past, we now have multiple options that provide good odds of gaining vision. Both ranibizumab and the dexamethasone intravitreal implant (Ozurdex; Allergan, IrOF
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vine, California, USA) are now approved by the Food and Drug Administration for treating macular edema resulting from vein occlusions.35 Although the popularity of laser has taken yet another hit at the hands of anti-VEGF therapy, it still has a role in treatment of venous occlusion. Grid photocoagulation either alone or in combination with anti-VEGF therapy may be a good treatment option for BRVO patients with macular edema who are unable or unwilling to return for monthly injections or who have edema refractory to multiple injections. Furthermore, sector or diffuse panretinal photocoagulation to avoid neovascular complications of vein occlusions remains of paramount importance. Although some retina specialists initially used anti-VEGF agents in the face of neovascular glaucoma to help lower pressure or to decrease intraoperative hemorrhage, PRP remains common practice and provides the most effective means of permanently lowering VEGF production from ischemic retina. Anti-VEGF therapy for this indication is a supplemental therapy, rather than a replacement therapy. Ophthalmology is an area of medicine that has undergone tremendous change in recent decades. Technologic advances and intensive research leading to innovative ground-breaking therapies have allowed us to give our patients much better visual outcomes in the face of previously debilitating diseases. Anti-VEGF agents have been shown to be effective in preventing vision loss and improving vision in multiple diseases, including diabetic retinopathy, neovascular AMD, and retinal vein occlusions. Despite a substantial decrease in its use for these conditions in recent years, laser therapies continue to serve important roles in our ability to combat retinal pathologic features. Although rarely used in neovascular AMD (except on occasion as PDT), lasers still are used frequently for persistent DME and macular edema from vein occlusions that responds poorly to anti-VEGF therapy. Furthermore, newer laser treatment approaches such as subthreshold micropulse laser have been introduced, and their safety and efficacy for the aforementioned conditions is being studied. In addition to thermal laser’s use for panretinal photocoagulation, it is vital for other retinal entities not discussed in this article, such as barrier laser retinopexy for retinal tears, ablation of retinal arterial macroaneurysms, and quelling of the proliferative process in retinopathy of prematurity (Table 1). PDT with verte-
TABLE 1. Uses of Thermal Laser for Retinal Diseases in the Anti-VEGF Era 1. Patients with DME with progression toward the center of the macula, but not involving the center. 2. Patients with persistent DME or macular edema secondary to a retinal vein occlusion no longer improving despite multiple anti-VEGF injections or in whom monthly injections are not feasible. 3. Panretinal or scatter photocoagulation for diabetes mellitus, vein occlusions, and other diseases with NVE, NVD, or NVG. 4. Scatter photocoagulation for ischemic and exudative retinopathies, e.g., Coats disease and IRVAN. 5. Retinopathy of prematurity. 6. Barrier for retinal breaks or detachment. 7. Symptomatic or vision threatening extrafoveal CNV. 8. Macroaneurysms. 9. Central serous chorioretinopathy with chronic thickening and a persistent focal leak outside of the center of the macula. CNV ⫽ choroidal neovascularization; DME ⫽ diabetic macular edema; IRVAN ⫽ intraretinal vasculitis, aneurysms, and neuroretinitis; NVD ⫽ neovascularization of the disc; NVE ⫽ neovascularization elsewhere; NVG ⫽ neovascular glaucoma; VEGF ⫽ vascular endothelial growth factor.
TABLE 2. Uses of Photodynamic Therapy for Retinal Diseases in the Anti-VEGF Era 1. Central serous chorioretinopathy with chronic thickening without a discrete lesion. 2. Polypoidal choroidal vasculopathy pattern of CNV. 3. Combination therapy with intravitreal anti-VEGF agents for exudative AMD when retinal thickening persists and is not improving despite monthly injections. AMD ⫽ age-related macular degeneration; CNV ⫽ choroidal neovascularization; VEGF ⫽ vascular endothelial growth factor.
porfin has been shown to be effective for treatment of not only idiopathic polypoidal choroidal vasculopathy, but also central serous chorioretinopathy (Table 2).36 The retina world has embraced anti-VEGF therapy with open arms, but laser therapy remains a pivotal component of our practices for at least the next several years.
PUBLICATION OF THIS ARTICLE WAS SUPPORTED IN PART BY AN UNRESTRICTED GRANT FROM RESEARCH TO PREVENT Blindness, Inc, New York, New York. Dr Shah indicates no financial conflict of interest in this study. Dr Jampol receives consulting fees from Pfizer Pharmaceuticals and Quintiles/Stem Cell Organization. Dr Bressler is Principal Investigator of grants at The Johns Hopkins University sponsored by the following entities (not including the National Institutes of Health): Abbott Medical Optics, Inc; Alimera Sciences; Allergan USA, Inc; Bausch & Lomb, Inc; Carl Zeiss Meditec, Inc; DIAGNOS Inc; The EMMES Corporation; ForSight Labs, LLC; Genentech, Inc; Genzyme Corporation; Lumenis, Inc; Notal Vision; Novartis Pharma AG; Ora, Inc; Pfizer, Inc; QLT, Inc; Regeneron Pharmaceuticals, Inc; and Steba Biotech S.A. Involved in Design of study (A.M.S., L.M.J.); Conduct of study (A.M.S., L.M.J.); and Preparation and review of manuscript (A.M.S., N.M.B., L.M.J.). Institutional review board approval was not necessary or relevant for the completion of the manuscript.
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Biosketch Ankur M. Shah is a medical retina fellow at Northwestern University, Chicago, Illinois. He received a Bachelor of Science degree from the University of Michigan and his medical degree from Northwestern University. He completed his ophthalmology residency at the University of California, San Diego where he served as chief resident. His research interests include medical retina and uveitis.
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