Macular Laser in the RVO Treatment Paradigm

This treatment option remains useful in many situations and is being examined anew as part of combination therapy.

By Seenu M. Hariprasad, MD, & Eric W. Schneider, MD

Anti-vascular endothelial growth factor (VEGF) therapy has certainly raised our expectations regarding treatment of macular edema secondary to retinal vein occlusion (RVO). However, there remains a distinct role for macular grid laser (MGL) treatment, either alone or as part of combination therapy.

We recently completed a textbook¹ on current concepts in RVO management, which includes a discussion of the utility of MGL for treating macular edema, the most common cause of vision loss after RVO. This article is a summary of the body of literature and expert experience on which the book is based.

Macular Grid Laser as Monotherapy

As prospective, randomized, controlled clinical trials, the Branch Vein Occlusion Study (BVOS) and Central Vein Occlusion Study (CVOS) were the first to provide us with Level I evidence on the use of laser photocoagulation in the treatment of RVO and its sequelae. From the BVOS, we learned that argon MGL is preferable to observation for patients with macular edema secondary to branch retinal vein occlusion (BRVO) and vision of 20/40 or worse.

Patients in the BVOS were divided into four groups. One group included 139 eyes with vision loss from macular edema secondary to BRVO. Key inclusion criteria were onset of BRVO from 3 to 18 months prior to the study, presence of macular edema involving the fovea, and best-corrected visual acuity of 20/40 or worse. Eyes with foveal hemorrhage or foveal capillary nonperfusion were excluded, as were those with any other ocular disease that could compromise visual acuity. Patients were randomized to either observation or treatment with argon MGL (n=71). The treatment group received MGL treatment in the area of capillary leakage — as identified by fluorescein angiography (FA) — within the vascular arcades but not closer to the fovea than the outer edge of the avascular zone. Additional MGL was performed at 4 months if foveal edema remained with attendant decreased visual acuity.

The majority of treated eyes required only a single session of laser. At 3 years, 65% of the eyes that underwent MGL gained at least 2 lines of vision compared with 37% in the untreated group. Mean visual acuity at the 3-year follow-up visit was 20/40 to 20/50 in the treated group and 20/70 in the untreated group. BVOS thus established that MGL applied to discrete areas of leakage can be useful as monotherapy in eyes with macular edema secondary to BRVO. We have further confirmation of this finding from the Standard Care versus Corticosteroid for Retinal Vein Occlusion (SCORE) study. SCORE compared MGL with intravitreal corticosteroid injections for BRVO-related macular edema. In this large, prospective comparative clinical trial, MGL was shown to result in similar visual acuity gains when compared with steroid monotherapy, but with fewer complications.

According to the results of the CVOS, macular grid photocoagulation is not recommended for treating macular edema due to central retinal vein occlusion (CRVO). Out of the 150 patients enrolled in the macular edema portion of this study, 77 were randomized to receive argon MGL while the remainder were observed. Patients were included if they had confirmed CRVO for at least 3 months, foveal-involving macular edema verified by FA, visual acuity between 20/50 and 5/200 and intraocular pressure less than 30 mmHg. Exclusion criteria included foveal nonperfusion documented on FA as well as a history of retinal laser photocoagulation, diabetic retinopathy, retinal neovascularization or lens abnormalities (significant opacity, aphakia/pseudophakia).

In the treatment group, eyes received argon MGL applied to areas of capillary leakage not extending into the foveal avascular zone. Collateral vessels and/or hemorrhages were avoided. Patients received additional laser treatment after their first treatment if they gained nine or fewer letters of vision and had persistent macular edema at a follow-up visit. At the end of 1 year, all of the eyes in the observation group had some degree of edema. In contrast, 31% of patients in the treatment group experienced complete resolution of angiographically evident edema 1 year after MGL. Despite the disparity in anatomic outcomes, however, no significant difference in post-treatment visual acuity was observed between the two groups.

Case Report
Macular Grid Laser Following Incomplete Response to Anti-VEGF Injections

Anti-VEGF therapy does not lead to complete resolution of RVO-associated macular edema in every patient. Adding macular grid laser treatment to the therapy regimen may dry the retina and allow cessation of anti-VEGF injections, as this case demonstrates.

The patient is a 48-year-old female with a history of hypertension and waxing/waning blurry vision in the left eye for 10 months for which she had not sought treatment. Her initial dilated fundus exam revealed macular edema in the superior foveal region OS secondary to non-ischemic BRVO with exudates extending through the fovea (Figure 1). Fluorescein angiography was consistent with a diagnosis of chronic BRVO with macular edema (Figure 2). OCT imaging was performed (Figure 3). Visual acuity was 20/20 OD and 20/20-2 OS. Given the visual acuity at this visit, the decision was made to observe the patient.

Figure 1. Prior to treatment, BRVO-associated macular edema was observed in the superior foveal region of the patient’s left eye. Exudates extended through the fovea.

Figure 2. The initial fluorescein angiogram demonstrated micro-vascular abnormalities in the distribution of a macular branch vein with associated leakage consistent with a diagnosis of chronic BRVO with macular edema.

The patient returned for follow-up 3 months later. Visual acuity OS had declined to 20/25 and macular edema was still present. The patient was treated at this visit with intravitreal bevacizumab (Avastin, Genentech). One month later, visual acuity OS was reduced to 20/30, persistent macular edema was noted, and the patient was given a second bevacizumab injection. After another month, the edema OS improved slightly but vision did not, and the patient was given a third anti-VEGF injection.

Approximately 6 weeks after the third injection, edema in the affected eye had stabilized, but vision declined further to 20/40 (Figure 4). At this visit, the patient received a macular grid laser treatment OS. By 3 months post laser, macular edema in the treated eye had significantly improved and visual acuity increased to 20/30 (Figure 5) Since that time, no further treatment has been needed. Macular edema OS completely resolved, and VA improved to 20/20-1 (Figure 6).

Figures 3-6. OCT thickness maps and representative B-scans of the patient’s left eye from presentation to last follow-up visit. After initial treatment with 3 anti-VEGF injections, macular edema was still present, and the patient underwent one macular grid laser treatment. By 3 months post laser, the edema in the treated eye had significantly improved. Since that time, no further treatment has been needed. The macular edema is completely resolved, and visual acuity is 20/20-1.

Macular Grid Laser in Combination Therapy

It is notable that while MGL did not improve patients’ vision in the CVOS, it did reduce macular leakage. Since that study was conducted, intravitreal pharmacologic therapies (i.e., steroid and anti-VEGF agents) have proven to be effective, albeit short-term, treatments for macular edema associated with RVO. In light of these new therapeutic options, it makes sense to re-evaluate the potential utility of MGL applied in combination with intravitreal agents for CRVO.

In BRVO, in which laser monotherapy has been proven beneficial, combination therapy may have the added advantage of limiting toxicity and/or lessening the treatment burden as smaller doses or less frequent treatments may achieve similar results. Combination therapy may also be used to increase efficacy in patients who are not adequately responsive to monotherapy. In either situation, the benefit of combination treatments is due to the synergistic effects achieved. Each agent has a different pharmacokinetic profile and acts at a different point in the pathway leading to macular edema.

Unfortunately, only a small number of studies exploring RVO combination therapies have been published to date. Most are short-term, retrospective and/or involve small numbers of patients. Nonetheless, as retinal specialists are increasingly using MGL in combination with other treatments, it remains a treatment paradigm very much worth exploring.

MGL + Anti-VEGF

Laser in addition to intravitreal anti-VEGF therapy is an often-used combination in clinical practice. Given the previously documented high levels of VEGF in the aqueous and vitreous of eyes with RVO, it is not surprising that anti-VEGF monotherapy is effective in combating the associated macular edema. Although the exact mechanism whereby MGL reduces macular edema is unclear, one possible explanation relates to a reduction in VEGF levels secondary to a decrease in retinal hypoxia induced by laser. When laser is combined with anti-VEGF agents, which bind to and directly inhibit VEGF, a synergistic anti-VEGF effect is produced. Furthermore, anti-VEGF agents mitigate some of the limitations of MGL, including the inability to treat in the presence of dense macular hemorrhage and the need for increased laser power in the setting of severe macular edema with an associated greater risk of collateral tissue damage. In contrast, because anti-VEGF injections work quickly and can be given regardless of the severity of macular hemorrhage or edema, they may quiet the eye to allow us to utilize MGL earlier with greater efficacy and safety.

The studies¹ of anti-VEGF/MGL combination therapy published to date have shown mixed results. In some, the combination clearly outperformed standalone anti-VEGF treatment in achieving better anatomic and visual outcomes. In others, impressive anatomical improvements were not matched by gains in vision. In published studies in which injection frequency was tracked, however, combination laser/anti-VEGF treatment resulted in a reduced need for anti-VEGF injections.

MGL + Corticosteroid

Combining MGL with corticosteroid may also increase the efficacy of our treatment for RVO-related macular edema compared to either treatment alone. The literature¹ confirms that in addition to VEGF, inflammatory factors play a role in RVO-related edema. A combination of steroid therapy with MGL may result in synergistic effects as it targets both the inflammatory component (steroids) while also addressing VEGF-related drivers of macular edema at multiple different points along the pathway (reduced VEGF production due to lessened retinal hypoxia from laser; reduced activity of effectors downstream of the VEGF receptor from steroids).

Only two prospective studies¹ of an intravitreal triamcinolone/MGL combination for BRVO-related macular edema have been published. In one, MGL applied after an average of 1.13 steroid injections led to impressive structural and functional improvements. In a separate comparative study, both a combination therapy group (consisting of patients receiving steroid therapy after failed MGL) and a steroid monotherapy group demonstrated significant anatomic and functional improvements at early timepoints. However, these improvements were maintained at later timepoints only in the steroid monotherapy group. The inclusion of only patients refractory to MGL in the combination group may be a significant confounder in this study. Of note, in both studies,¹ the rate of IOP elevation was similar to the rate with intravitreal triamcinolone monotherapy.

Two abstracts¹ presented in 2012 described non-comparative studies in which the dexamethasone implant (Ozurdex, Allergan) was utilized in conjunction with MGL. Significant decreases in retinal thickness were observed in both studies, but corresponding visual gains were noted in only one study. The authors of a prospective study¹ comparing subthreshold micropulse grid laser (Iridex) alone to micropulse laser plus intra-vitreal triamcinolone for macular edema in BRVO reported better visual results in the combination group.

While these initial results are promising, future studies will be required to further evaluate safety and efficacy of these MGL combination therapies as well as to establish the ideal timing, frequency and optimal settings for adjunctive laser therapy.

Role of MGL May Be Expanding

Although retina specialists have been utilizing MGL as a treatment for RVO-related macular edema for decades, recent technological developments in laser delivery may lead to even greater efficacy and safety. For example, image-guided laser platforms, such as Navilas (OD-OS), have the potential to drastically improve treatment accuracy. Moreover, improvements in diagnostic imaging capabilities and laser lenses offer further hope for improved MGL application. Indeed, in light of these technological advances and the potential for synergistic effects when used in combination with intravitreal therapy, it appears now may be an ideal time to revisit the role of MGL in the treatment of macular edema secondary to RVO.

Reference

	Dr. Hariprasad is an Associate Professor, Chief of the Vitreoretinal Service and Director of Clinical Research in the Department of Ophthalmology and Visual Science at the University of Chicago Medical Center. He is the editor of the 2014 book Management of Retinal Vein Occlusion: Current Concepts.
	Dr. Schneider is a Senior Vitreoretinal Fellow at the Duke Eye Center in Durham, N.C. He is a contributing author for Management of Retinal Vein Occlusion: Current Concepts.