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Retinal Physician

Article

The Current Role of Laser Therapy in the Management of Diabetic Retinopathy

Laser continues to play an important role.

By: Sam Mansour, MD, David J. Browning, MD
Retinal Physician October 1, 2021 Vol 18, Issue October 2021 Page(s): 32-34, 41

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Over the past 2 decades, new approaches in pharmacotherapeutic management of diabetic retinopathy (DR) and diabetic macular edema (DME) have overshadowed developments in laser therapy for these conditions. Historically, the effectiveness of laser therapy for managing DR has been proven in several major clinical trials.1-5 However, conventional continuous wave (CW) laser is destructive to retinal cells and can result in scotomas.4,6-9 In addition, CW laser can worsen night vision and delay light-to-dark adaptation.10-12 Indirect macular changes attributable to PRP have also been reported.13-15 As such, there has been a decline in the use of laser therapy in DR and DME management by clinicians.16,17

LASER MODALITIES

In the late 1980s, clinicians began to investigate the use of lower laser power to treat DME. The Early Treatment of Diabetic Retinopathy Study (ETDRS) demonstrated the effectiveness of a “modified-ETDRS” pattern of less intense burns (Figure 1).3,4 A change in the microaneurysm color was not required for direct focal treatment and for grid treatment, the burn intensity was to be “barely visible.5 The “mild macular grid photocoagulation” varied from the ETDRS pattern of grid treatment in that the intensity was “barely visible” and also that the area of treatment was to both thickened and nonthickened retina within the macula.18,19

Figure 1. Fundus color (A), fluorescein angiography (B), and optical coherence tomography scan (C) of left eye 6 months following modified ETDRS sectoral grid laser application for diabetic macular edema. Focal, outer retinal pigmentary disturbances (arrows) are noted on all 3 imaging modalities.
Figure 1. Fundus color (A), fluorescein angiography (B), and optical coherence tomography scan (C) of left eye 6 months following modified ETDRS sectoral grid laser application for diabetic macular edema. Focal, outer retinal pigmentary disturbances (arrows) are noted on all 3 imaging modalities.

More recently, newer modes of laser retinal therapy, best termed low-intensity photo stimulation (LIPS), involve grid type application of nonphotocoagulative laser spots to “photostimulate” outer retinal tissues, primarily the retinal pigment epithelium (RPE), to either increase production of metabolites that inhibit neovascularization and reduce vascular permeability activity or to downregulate production of mediators that increase vascular permeability and neovascularization (Figure 2).20-27 To qualify as LIPS, a laser treatment session must not result in any detectable outer retinal or RPE damage on current imaging modalities such as fundus photography, angiography, autofluorescence, or optical coherence tomography. With this type of “subthreshold” laser, many of the benefits of CW lasers are theoretically obtained without the adverse side effects. Several laser manufacturers offer LIPS lasers systems, which include Micropulse and Endpoint Management (Iridex), Smartpulse (Lumenis), Easyret in subliminal mode (Quantel Medical), Navilas Microsecond Pulse (OD-OS), 2RT (Ellex), SP-Mode (Lightmed), and LPM (Nidek), all of which can be safely applied near the fovea without visible damage when used according to published safety protocols. There have been several small, uncontrolled studies that have shown the benefits of LIPS lasers in treating DME either alone or in combination with pharmacotherapy, yielding results comparable to those obtained with conventional laser but with no tissue damage or scotomas.18,19,28-44

Figure 2. Optical coherence tomography images of a right eye of a patient with chronic diabetic macular edema before (A) and after (B) low-intensity photo stimulation (Micropulse; Iridex) grid application. There was no evidence of outer retinal structural changes seen 4 months following the procedure.
Figure 2. Optical coherence tomography images of a right eye of a patient with chronic diabetic macular edema before (A) and after (B) low-intensity photo stimulation (Micropulse; Iridex) grid application. There was no evidence of outer retinal structural changes seen 4 months following the procedure.

LASER USE IN PROLIFERATIVE DIABETIC RETINOPATHY

Treatment of neovascularization by panretinal laser photocoagulation (PRP) remains unchanged since the Diabetic Retinopathy Study (DRS) proved its efficacy in proliferative diabetic retinopathy (PDR). Recently, attempts to integrate pharmacotherapy to minimize the visual side effects of PRP have been shown to work in adherent patients. Several studies have demonstrated improved visual outcomes of intravitreal anti-VEGF injections vs PRP.45-47 In patients with PDR-related vitreous hemorrhage (VH), there was no statistically significant difference in visual acuity over 24 weeks following initial treatment with intravitreous aflibercept vs vitrectomy with PRP integration.48 The use of targeted PRP to ischemic retina as delineated on widefield fluorescein angiography has not been demonstrated to be superior to standard PRP in preventing neovascularization.49 Likewise, with limited study, there is no advantage of LIPS laser compared to conventional PRP for PDR.42 Panretinal laser photocoagulation for PDR is superior to pharmacotherapy when either medical and financial resources are limited or patient adherence is poor.47,50,51

LASER USE IN DIABETIC MACULAR EDEMA

The management of nonproliferative diabetic retinopathy (NPDR) and DME continues to evolve with regards to laser modalities and integration of pharmacotherapeutics. The initial clinical trial of the DRCR Retina Network published in 2007 illustrates the modest evolution of laser techniques for management of DME.52,53 In cases with mild, center-involving DME, focal or grid laser treatment was shown in protocol V of the DRCR Network to be equivalent to observation or anti-VEGF therapy.54,55 As a result, a “watchful wait” approach to managing patients with mild DME and best-corrected visual acuity of 20/25 or better is supported. Attempts to lessen the burden of anti-VEGF injections in the setting of DME by integrating peripheral PRP have had mixed results.49,56,57 Data from the DAVE trial examining widefield, targeted PRP in conjunction with intravitreal ranibizumab for DME have demonstrated no significant reduction in the frequency of prn injections.49,56

COMBINATION LASER AND PHARMACOTHERAPY

To date, there have been few clinical trials examining whether integration of laser therapy, either conventional, targeted, or in LIPS mode, with pharmacotherapy can result in a reduced treatment burden for the patient while achieving optimal clinical efficacy. The results of some clinical trials have demonstrated that supplementing pharmacotherapy with laser therapy, both as focal and grid application for macular edema and as PRP application for proliferative disease may provide a more durable response.58-64 In PDR, some reports have suggested that combination treatment with anti-VEGF and PRP may reduce treatment burden compared to anti-VEGF monotherapy.62,65-69 Other studies have shown no significant benefit of the combination treatments.55,70-72 Data from protocol S of the DRCR Retina Network demonstrated that both PRP and intravitreal ranibizumab were similar in the prevention of severe visual loss and other complications in PDR, suggesting that patient-specific factors such as compliance and financial impact be considered primarily in management decisions.46,73

Protocol I of the DRCR Retina Network demonstrated no short-term benefit in combining prompt macular laser with anti-VEGF therapy for center-involved DME.74 However, patients who were treated with deferred laser therapy achieved the best outcome in terms of 2-year visual improvement. Protocol T of the DRCR Network was a comparative effectiveness trial utilizing bevacizumab, ranibizumab, or aflibercept.58 As part of the protocol, laser treatment was mandated for persistent centrally involved macular edema at the 24 week follow-up examination following monthly initial treatment by 1 of the 3 agents. At the 1 year follow-up examination, 50% of eyes in the study had received laser treatment because of persistent macular edema. There was a slightly higher percentage of patients receiving laser in the bevacizumab group and a lower percentage in the aflibercept treated group compared to the 2 other agents. In addition, deferred macular laser was still required in more than 30% of study eyes with center-involved DME receiving ranibizumab in the RISE and RIDE studies.74

These studies emphasize the beneficial influence of specific targeted focal and grid laser treatment in eyes not responding initially to anti-VEGF agents alone. In addition, the same trial demonstrated that regardless of the anti-VEGF agent used, there was nearly a 50% reduction in the frequency of needed injections in the second year.75

Results of clinical trials examining integration of LIPS laser therapy and pharmacotherapeutics in DME have yielded mixed results.76-79 Many studies have demonstrated a synergistic effect. Other studies have shown equivalency of effect between anti-VEGF therapy and LIPS particularly in early, mild DME.80 Recently, some potential benefit of LIPS laser in DME patients with subretinal fluid has been demonstrated in a retrospective series, while other studies have shown no added benefit of LIPS to intravitreal anti-VEGF agents.81-83

The result of combining laser therapy with intravitreal corticosteroids have also been inconsistent in terms of both visual acuity stabilization or improvement, and reduction in overall treatment burden.72,76,77,84-86 Concerns regarding elevated intraocular pressure and acceleration of cataract formation associated with the use of corticosteroids limit their use in DME.77,87 However a few studies have demonstrated potential benefit of intravitreal corticosteroids in conjunction with laser therapy in DME.76,78,79

A methodologically sound, adequately sized trial to determine supplemental laser treatment might reduce anti-VEGF treatment burden has not yet been done. Despite the lack of high-quality evidence, guidelines for the integration of laser and pharmacotherapy in DME management have been proposed.84-86,88

ADVANCES IN LASER THERAPY FOR DR

Another new development in retinal laser therapy for DR is a fundus camera-based photocoagulation system that is integrated with retinal eye-tracking technology (Navilas; OD-OS).89-91 This technique allows the ophthalmologist to take an image of the retina of a patient with DR or DME, digitally encircle the areas requiring treatment, and have the device automatically deliver the laser spots to the specified areas. Higher accuracy of laser delivery compared with conventional, manually operated lasers can be achieved.89-92 In managing patients with proliferative disease, this system is able to deliver a “navigated” pattern PRP that is selectively applied to areas of ischemia identified by widefield fluorescein angiography. Fewer, more uniform laser burns are delivered in shorter time and with less discomfort and potentially less overall retinal tissue damage.93,94 Recent, uncontrolled studies have demonstrated that when used in combination with pharmacotherapy, the patients receiving Navilas-guided focal laser required fewer injections of anti-VEGF agents than would otherwise have been required to maintain remission of the macular edema.95,96

A novel use of lasers in DR involves the use of pulsed mode, near-infrared (NIR) lasers to activate the release of liposomes within an intravitreal injected, biodegradable capsule.97,98 The goal of this on-demand, dose-controllable drug delivery system is to reduce the frequency of intravitreal injections.

CONCLUSION

For clinicians, therapy for managing DR and DME that arrests neovascularization, quickly eliminates macular edema, has few side effects and long duration, and is low cost remains elusive. It is hoped that with additional, well structured, large, controlled, prospective clinical trials examining combination therapies that this ideal will be achieved. Further studies to explore potential benefits of combination treatment are planned, perhaps involving widefield imaging-guided peripheral laser to ischemic retina and a subthreshold technique. For now, use of laser therapy for managing diabetes-related retinal disease will continue to play a role. Situations that preclude the use of pharmacotherapy in DME and DR, such as unreliable patient visit compliance, pregnancy, or nonresponse to anti-VEGF, can be managed by laser therapy. Large, prospective comparative trials are needed to determine if the newer subthreshold and navigated laser techniques are superior to conventional laser methods. RP

Sam E. Mansour, MD, is the medical director at Virginia Retina Center in Warrenton, Virginia, and a clinical professor of ophthalmology at The George Washington University in Washington, DC. He reports grants from Alimera Sciences, Inc.; consultancy to, lectures for, and grants from Iridex; and research for Genentech, Allergan, Alcon, Clearside Biomedical, Chengdu Kanghong Biotechnology, and Mylan GmbH. David J. Browning, MD, is a retina specialist with Charlotte Eye, Ear, Nose, and Throat Associates in Charlotte, North Carolina. Dr. Browning reports grants from DRCR Retina Network. Reach Dr. Mansour at sm@virginiaretina.com. Editor’s note: Listen to discussion of this article on the Retina Podcast at retinapodcast.com .

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