CONTROVERSIES IN CARE

Widefield Angiography-guided Laser Photocoagulation for Recalcitrant Macular Edema in Retinal Vascular Disease

EDITED BY MICHAEL COLUCCIELLO, MD

The presence and degree of macular edema in retinal vascular disease is associated with intravitreal VEGF levels.¹ Peripheral capillary nonperfusion in patients with diabetic retinopathy and retinal venous occlusive disease may serve as a driver to upregulate VEGF, which serves as a potent vasopermeability factor.

In fact, on a molar basis, VEGF is 50,000 times more potent than histamine at increasing microvascular permeability.² Laser ablation of areas of peripheral retinal capillary nonperfusion can downregulate VEGF, which theoretically can result in macular edema reduction and a decreased requirement for intravitreal anti-VEGF administration for treatment of macular edema.

To assess peripheral perfusion, clinicians may use the Optos 200Tx camera (Optos PLC, Marlborough, MA). This system incorporates a scanning laser ophthalmoscope (allowing imaging through media opacities and smaller pupil sizes) and an optical system with an ellipsoid mirror, which allows for reliable imaging of the peripheral retina up to the ora serrata.³

Widefield angiography may allow us to predict response to intravitreal anti-VEGF treatment. One recent study of 148 eyes with DME, followed for a minimum of two years, found that eyes with larger areas of retinal nonperfusion were found to have the most recalcitrant DME.⁴

In another recent study of 32 consecutive patients with RVO, patients with more peripheral nonperfusion had worse macular edema and visual acuity and experienced greater decreases in macular edema and gains in VA in response to treatment.⁵ However, another study showed no relationship between peripheral ischemia with macular edema in 47 consecutive eyes with DR studied by widefield angiography.⁶

Studies have also shown mixed results in the ability of peripheral laser to nonperfused areas (disclosed by peripheral angiography) to reduce macular edema in retinal vascular disease. In a recent study of 28 eyes with DME, there were significant improvements in macular edema and VA over six months following targeted laser to areas of nonperfusion based on Optos widefield angiography.⁷

In eyes with central RVO, widefield imaging may show large areas of peripheral nonperfusion, even if the posterior pole appears perfused.⁸ A recent prospective, controlled, randomized study comparing 12 patients receiving ranibizumab (Lucentis, Genentech, South San Francisco, CA) only to 10 patients with central RVO receiving ranibizumab plus peripheral laser suggested that selective laser photocoagulation of peripheral areas of nonperfusion led to additional visual improvement.

Central retinal thickness decreased between baseline and final visit in the ranibizumab plus peripheral laser group from 547 μm to 246.5 μm, compared to the ranibizumab-only group, in which the decrease was from 637.5 μm to 423 μm.⁹

However, in a small study of 10 patients with a six-month follow-up, laser photocoagulation to peripheral areas of nonperfusion did not result in either decreased injection frequency or improved VA in eyes with central RVO treated with ranibizumab. Note that intravitreal ranibizumab 0.5 mg was given on an “as needed” basis for macular edema throughout the study.¹⁰

Therefore, the predictive nature of widefield imaging and the results of laser ablation of disclosed areas of peripheral nonperfusion appear promising but are as yet inconclusive.

To help us with this matter, we are fortunate this month to have the commentary of Szilárd Kiss, MD, director of clinical research and associate professor of ophthalmology at Weill Cornell Medical College, and Seenu Hariprasad, MD, professor of ophthalmology and visual science and chief of the Retina Service at the University of Chicago School of Medicine.

Ultrawidefield angiography image of a left eye with large areas of peripheral retinal capillary nonperfusion and retinal neovascularization of the disc and elsewhere associated with proliferative diabetic retinopathy. Note that the areas of “panretinal” laser reaction do not extend to the extreme retinal periphery.

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UWF Imaging to Guide Treatment

SZILÁRD KISS, MD

Since the seminal clinical trials were performed 30 or more years ago, fundus photography and angiography have been the basis for screening, grading, and even treating a variety of retinal vascular disorders, including diabetic retinopathy and retinal vein occlusion.

The seven standard fields (7SFs) imaged in these studies involved capturing seven photos in a montage, resulting in an approximately 75⁰ field of view of the retina; other montaging techniques were also developed that could portray up to 140⁰ of the retina.¹

However, none of these traditional montage techniques could fully capture the peripheral retina. Moreover, montage techniques posed certain constraints on fluorescein angiography because it is a time-sensitive test, and with montaging, differing parts of the retina cannot be imaged at once.

Because many retinal vascular disorders have significant peripheral retinal involvement, there has been an ever-increasing attempt to better image the retinal periphery. Although wide-angle fluorescein angiography with the use of a contact lens, such as the Staurenghi lens, expanded the view of the fundus to nearly 160⁰, the technique required considerable patient cooperation and photographer skill.¹

Enter the Optos

It was really with the advent of the Optos Optomap that the arena of widefield (and now ultrawidefield [UWF]) imaging became a practical reality.^2,3 The Optomap system uses a noncontact scanning laser ophthalmoscope that allows for high-definition, ultrawidefield color, fluorescein angiography and autofluorescence imaging of the up to 80% of the retina in a single view.^1-3 Fields of view of 100⁰ and 200⁰ can be obtained through an undilated pupil with excellent image quality.^1-3

Over the past several years, UWF imaging with the Optos has begun to revolutionize our understanding of the role of the peripheral retina in a wide range of retina disorders. Our grasp of the role of the peripheral retina in some retinal disorders, such as sickle-cell retinopathy, were already well grounded and were just expanded with UWF imaging.⁴

UWF imaging, however, considerably expanded our insights into the role of the peripheral retina in many unsuspected disorders once thought to involve only the posterior pole, such as AMD.⁵ Importantly, in the realm of retinal vascular disorders, UWF imaging has started to transform our approach to diagnosis, treatment, and follow-up of our patients.

Our Group’s Experience

Using UWF imaging, our group was one of the first to explore a possible link between peripheral retinal ischemia and the presence of DME in patients with diabetic retinopathy.⁶ In our retrospective review of 122 eyes of 70 treatment-naïve diabetic patients who underwent UWF fluorescein angiography, we found that peripheral retinal ischemia was significantly correlated with the presence of DME.⁶

Other groups have similarly found a relationship between the presence of areas of peripheral ischemia and DME that was recalcitrant to anti-VEGF therapy.^2,3 This combination of significant peripheral and posterior-pole pathology in the setting of DR can be observed quite easily in the era of UWF imaging.

Similar to DR, in RVO, the extent of peripheral abnormalities, particularly the extent of ischemia, is only brought to light with UWF imaging.^2,7 Even in central RVO, in which there is generally a consensus about the presence of peripheral ischemia, the true extent is only really appreciated with UWF imaging.⁷

Easing the Burden

While anti-VEGF therapy has revolutionized the treatment of retinal vascular disorders, there nonetheless remains a considerable patient and societal burden due to the need for repeated visits and intravitreal injections.⁸

In fact, it appears from several studies that, in the real-world setting (that is, outside of clinical trials), patients are not evaluated, nor are they treated to the same extent, as in pivotal clinical trials.⁸ As a result of this apparent undertreatment, patients may not be getting the visual outcomes that were observed in the clinical trials.⁹

In an attempt to: (1) lessen the treatment burden in retinal vascular disorders; and (2) improve patient outcomes, several groups have attempted to target the peripheral pathology noted on UWF imaging to treat the posterior-pole edema (either DME in the setting of DR, or macular edema with RVO).¹⁰

While there are compelling theoretical arguments for treating the periphery (eg, elimination of any possible cytokines, such as VEGF, released from the periphery), the clinical evidence is only now beginning to emerge.

Dr. Hariprasad provides an excellent review of the current clinical prospective on several series that have tried such approaches in both DME and RVO. Although some of this early work is encouraging (eg, targeted panretinal photocoagulation for DR and DME, peripheral laser to ischemic retina for recalcitrant edema in RVO), it must all be taken in the context of small series of eyes mostly from single centers. There is, nonetheless, sufficient evidence to undertake larger multicenter, prospective clinical trials with standardized protocols for when and how to target the peripheral retina.

UWF imaging has indisputably transformed our understanding of the role of the periphery with a whole range of retinal disorders. The UWF technology has become the standard and preferred imaging modality for the diagnosis and documentation of retinal vascular disorders.

We are now on the cusp of having UWF imaging guide our treatment decisions. Ultimately, we may start targeting the peripheral retina for posterior-pole pathology, but for now, more prospective evidence is needed before changing the standard of care in the treatment of macular edema.

REFERENCES

Targeted PRP Using UWF Imaging

SEENU M. HARIPRASAD, MD

The literature is replete with studies demonstrating a relationship between peripheral ischemia and macular disease in various retinal vascular diseases, such as RVO and DR, using ultrawidefield (UWF) angiography.^1-4

Targeting panretinal photocoagulation retina laser selectively to ischemic retina has been a topic debated for decades. The premise of this approach, however, is to be able to “identify” the ischemic retina so one can apply laser treatment to these areas.

Prior to the advent of UWF angiography, the identification of ischemic retina was difficult because the peripheral retina was hard to completely image with the technology available at the time (typically, the peripheral retina is more vulnerable to ischemia in retinal vascular diseases, such as RVO and DR).

Therefore, given the limitations of older imaging technologies, it is not surprising that targeted PRP did not appear to be beneficial. Reddy and colleagues were among of the first groups to demonstrate that implementation of UWF-guided targeted PRP could successfully treat patients with PDR.⁵

Another larger prospective study reported the same findings, ie, that targeted PRP using the Pascal laser (OptiMedica, Silicon Valley, CA) and Optos UWF-guided angiography can successfully treat patients with PDR.⁶ It is reasonable to conclude that targeted PRP using UWF angiography can successfully treat PDR in most patients.

Targeted PRP in DME and RVO

The literature, however, is inconclusive regarding whether or not targeted PRP is effective in aiding in the treatment of naïve or recalcitrant macular edema from DME or RVO. We published a paper last year that led to the conclusion that UWF angiography may allow us to predict response to intravitreal anti-VEGF treatment.

This study of 148 eyes with DME, followed for a minimum of two years, found that eyes with larger areas of retinal nonperfusion were found to have the most recalcitrant DME. The study helped elucidate why we have more difficulty treating some DME patients more than others.² Although our findings were very important and clinically relevant, the study did not answer the question of whether implementation of targeted PRP can aid in the treatment of DME.

We eagerly await the results of Dr. David Brown’s prospective, randomized WAVE trial to answer the question of the role of UWF-guided targeted PRP in managing macular edema secondary to RVO. In his trial, 30 patients with ischemic central RVO recalcitrant to previous anti-VEGF therapies are randomized to either 0.5 mg of ranibizumab (Lucentis, Genentech, South San Francisco, CA) monotherapy or 0.5 mg of ranibizumab in combination with UWF-guided targeted PRP to ischemic retina.

The results of this prospective clinical trial are eagerly anticipated, because they will elucidate the role of targeted PRP in possibly decreasing injection burden while hopefully showing at least noninferior efficacy to anti-VEGF monotherapy in managing patients with macular edema secondary to central RVO.

In conclusion, the use of UWF angiography has taught us that a relationship exists between the ischemic retinal periphery and macular edema. With this knowledge, further research is necessary to make treatment recommendations regarding the role of UWF angiography-guided targeted PRP in the management of macular edema due to various retinal vascular diseases. RP

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