Not too long ago, laser was a considerably more prominent tool for treating retinal diseases including age-related macular degeneration (AMD), proliferative diabetic retinopathy (PDR), and diabetic macular edema (DME). Current treatment paradigms favor anti-VEGF injections over laser; however, laser is still important to patients’ overall treatment strategy.

Medical lasers are used in retinal vascular disease to produce photocoagulation of the retinal tissues. Large randomized clinical trials such as the Diabetic Retinopathy Study (DRS) and the Early Treatment Diabetic Retinopathy Study (ETDRS) demonstrated the benefit of laser therapy in DR.^1,2 Thus, laser photocoagulation became the standard of care for DR.

The advent of the argon laser, which can use 488-nm blue wavelength and 514-nm green wavelength light absorbed by hemoglobin and melanin, allowed for the practical use of laser. These lasers were studied in the DRS and ETDRS.^1,2 Later, treatment indications widened as it was found that other conditions like AMD and retinal vein occlusion benefit from photocoagulation.³ Various protocols have emerged, and the variety of lasers employed to achieve photocoagulation has grown. The available laser platforms use different delivery systems, from contact lens slit-lamp laser to indirect ophthalmoscope and camera-based navigated techniques.

BACKGROUND

During retinal photocoagulation, the laser’s energy is absorbed in the retinal pigment epithelium (RPE) and the choroid, where it is converted from light energy into thermal energy. Ensuing cellular processes create a heat wave.^4,5 The wavelength, power, and duration of the laser are adjusted based on the intended retinal therapy. For example, conventional retinal laser photocoagulation typically uses a continuous-wave laser in green, yellow, or red range at a wavelength of 514 nm to 577 nm, a pulse duration of 100 ms to 200 ms, and a power between 100 mW and 750 mW. Depending on the application, variable spot sizes between 100 µm to 500 µm are used.⁶

The primary modes of continuous-wave laser treatment are panretinal photocoagulation (PRP), focal, and grid. Panretinal photocoagulation destroys large peripheral areas of retina in the presence of vascular ischemia. Focal laser treatment is used to treat focal DME by aiming the laser energy directly at the affected area and closing the leaking microaneurysms with photothermal energy. Grid laser treatment is used to treat diffuse DME.

Laser treatment can be considered in retinal vascular disorders with inflammation and hypoxia as the underlying pathophysiology. Photocoagulation destroys ischemic retina in areas of capillary nonperfusion, decreasing the production of cytokines like vascular endothelial growth factor (Table 1).⁷

INTRODUCTION OF SUBTHRESHOLD APPROACHES

Because laser photocoagulation works by damaging retinal tissue, atrophy and thinning can cause scotomas and lesion enlargement as the tissue heals. Concern about these damaging effects led researchers to investigate methods of applying energy that would produce the same therapeutic effect while minimizing collateral destruction. Subthreshold or low-power lasers implement various optical and thermodynamic principles to produce photostimulation that produces little to no evidence of retinal damage. The shorter duration pulses also result in a more comfortable treatment that is better tolerated by patients.

Endpoint Management

Topcon’s PASCAL laser with Endpoint Management (EpM) rapidly applies pattern scanning with a pulse duration of 10 ms to 30 ms, which is shorter than the pulse duration of other similar technologies. The EpM software determines optimal laser parameters, while the algorithm modulates the power and duration at the same time. In this manner,⁷ the laser application can be optimized to induce therapeutic protein expression while preventing thermal damage to the RPE.⁸ With EpM, surgeons have the option to treat closer to the fovea without fear of causing retinal damage or vision loss, and the treatment can be repeated. Using the system’s Landmark Pattern feature, the surgeon can choose to leave visible markers for reference and documentation of the treatment region.

Micropulse

The development of the Iridex MicroPulse laser in the 1990s represented the first subthreshold laser. Micropulse technology fragments laser emission into a sequence of short, repetitive microsecond pulses with a low duty cycle, ie, short “on” time and long “off” time, which allows heat to dissipate in the tissues between applications.⁵ Other subthreshold protocols have followed, delivering similar benefits as continuous-wave laser, but with improved overall retinal sensitivity.

More Subthreshold Protocols

Micropulse and the next wave of subthreshold protocols mentioned herein result in no visible tissue damage, which means that surgeons can repeat applications and treat close to the fovea. Most subthreshold treatments use a higher density of laser spots and much lower power than traditional focal and grid macular laser therapy.⁵

Subthreshold laser works by inducing thermal stress on RPE cells, which in turn activates a therapeutic cellular response. The goal is to maintain a temperature rise that, while therapeutic, stays below the threshold of irreversible thermal damage. By adjusting the various laser parameters, a specific optimal level of heat generation in tissue can be determined. This has resulted in different treatment protocols.⁹

Selective Retinal Therapy

Selective retinal therapy (SRT) is a subthreshold laser therapy approach that incorporates pulse durations of microseconds or nanoseconds. The short pulses target certain RPE cells while preserving photoreceptors and neural retina. By selectively damaging the RPE, cells are stimulated to migrate and proliferate into the treated areas, thus improving the metabolism of diseased retina.¹⁰

A likely reason for the efficacy of SRT is that it stimulates the release of matrix metalloproteinases 2 and 9, which are inflammatory markers. Several pulse laser systems perform SRT, including the R:GEN Laser System from Lutronic Corporation.⁶

Targeted Retinal Photocoagulation

Targeted retinal photocoagulation (TRP) is any therapy aimed at a specific target. It can selectively treat ischemic retinal areas and adjacent intermediate areas showing angiographic leakage while at the same time reducing the risks and complications of conventional PRP. Investigators note that wide-angle fluorescein angiography has been instrumental in identification of peripheral areas of nonperfusion and has opened the door for this application. More data are needed to assess the real benefit of TRP.^11-16

Nanopulse Laser

Retina Regeneration Therapy (2RT; Ellex) is a subthreshold laser modality using a 532-nm laser to produce 3-ns pulses. According to the company, the nanosecond pulses stimulate renewal of the RPE. The device combines subthreshold with micropulse laser protocols and uses a speckle-beam profile, providing a wider therapeutic range of energies over which RPE treatment can be safely performed than conventional laser.¹⁷ The use of lower energy levels causes sublethal injury to targeted RPE, rather than destroying it, leading to cytokine release by recovering RPE cells.

LASER TREATMENT INDICATIONS

Proliferative Diabetic Retinopathy

The efficacy of PRP was established in ETDRS and DRS, but Protocol S of the Diabetic Retinopathy Clinical Research Network (DRCR.net ) found anti-VEGF monotherapy to be as effective as conventional PRP.¹⁸ However, based on clinical situations and economic considerations, PRP is still a popular treatment option in the real world.

Diabetic Macular Edema

Although most specialists will start with anti-VEGF therapy in center-involving DME, focal laser is useful in the treatment of extrafoveal edema. Protocols that use focal laser targeting leaking microaneurysms or grid laser targeting diffuse leakage can help reduce repeated anti-VEGF injections and reduce the burden on health care systems.¹⁹ Subthreshold micropulse laser has been shown to be as effective as focal laser in reducing edema and subsequently reducing the need for frequent injections.¹⁹ PASCAL with EpM subthreshold photocoagulation has been shown to be safe and effective for DME treatment and preserves macular sensitivity.²⁰

Age-Related Macular Degeneration

Nanosecond laser is showing promise in studies for AMD. Clinical results show that Ellex 2RT offers the potential to slow the rate of progression of macular degeneration.^21-23 Subthreshold micropulse laser may have a restorative effect in RPE function and, therefore, may resensitize RPE in wet AMD that is unresponsive to anti-VEGF therapy. In a small retrospective study of eyes unresponsive to anti-VEGF injections, investigators performed an 810-nm laser treatment. When the eyes were retreated with monthly aflibercept, more than 90% responded with improved foveal thickness and most had complete resolution in macular exudates.²⁴

An investigation of “functionally guided retina protective therapy” with panmacular subthreshold micropulse laser looked at the strategy for high-risk dry AMD. The authors advocated it as a retinal protective therapy in early stages of chronic progressive retinal diseases, guided with pattern electroretinography.²⁵ In a recent retrospective study, the same team suggested that panmacular laser may reduce the incidence of choroidal neovascularization in high-risk dry AMD more than vitamin therapy alone.²⁶ The exact role of this approach remains to be fully illustrated.

NEW DIRECTIONS

Because of subthreshold laser’s safety and repeatability, its use in retinal vascular disorders continues to be vital. Its specific role alone and in treatment algorithms with anti-VEGF and steroid treatments continues to be elucidated. Not all patients respond to anti-VEGF therapies, and it is important that retina specialists have alternative treatments to ease the treatment burden of frequent injections. Clinical trials are needed to evaluate the optimal treatment algorithms with laser as well as how it is best used in combination with other agents and at what stage to initiate therapy. RP

REFERENCES

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