When shots and steroids won’t do

Centrally involved DME requires a special laser, at a special setting.

By Steven A. Agemy, MD, Jessica G. Lee, MD, Ronald Gentile, MD, FACS

The number of patients afflicted with diabetic retinopathy, a leading cause of blindness worldwide, is expected to rise to epidemic proportions due to increasing obesity.^1-3 Diabetic macular edema (DME) is the most frequent cause of vision loss related to diabetes with a 14-year incidence just over 25% among type I diabetics.⁴ Considering that up to 90% of cases of vision loss from diabetes can be prevented, prompt and effective treatment are important.⁵

DME treatment has evolved in the past 30 years. In 1985, focal laser photocoagulation was the standard treatment for clinically significant macular edema, guided by the results of the Early Treatment for Diabetic Retinopathy study (ETDRS).⁶ Now, intravitreal injections of anti-VEGF for centrally involved DME are the most widely used treatment due to their proven efficacy and safety. (Trying to keep pace with 80-year-olds). Intravitreal steroids also play a role, especially in pseudophakic eyes with persistent macular edema despite anti-VEGF treatment and no issues with steroid-induced glaucoma (To treat DME, keep steroids close). Laser treatment still plays a role in DME treatment. Safer methods of obtaining that treatment, including micropulse laser, have been developed.

Figure 1. 67-old-male with DME of the right eye who had received multiple intravitreal bevacizumab (Avastin, Genentech) injections in the past. A. OCT of the macula showing persistent macular edema despite treatment. B. OCT five months following one session of micropulse laser treatment (Laser parameters: 5% duty cycle, 200 ms duration, 400 mW energy, 16 spots).

Micropulse laser: an explanation

Micropulse laser uses a continuous wave laser beam that is chopped into short repetitive microsecond pulses. This allows tissue to cool between pulses, reducing thermal buildup.⁷ Laser “on” time is the duration of each micropulse, and “off” time is the time between micropulses that allows for heat reduction and thermal isolation of each pulse.⁸ The ratio between “on” and “off” time is known as the “duty cycle” — the lower the duty cycle, the greater the heat reduction. Duty cycle can be adjusted and is commonly set at 5% for subthreshold laser. Micropulse lasers on average have exposure times that are 50 times less than conventional lasers. Thermal tissue-damage is proportional to exposure time, so a short duty cycle would only be expected to increase the temperature of the RPE.⁹ Multiple lasers that are commercially available have micropulse capability (see Table 1). Micropulse has been used with infrared (810 nm), yellow (577 nm), and green (532 nm) wavelengths.

Micropulse laser: what it treats

Micropulse lasers primarily treat macular diseases. They help to avoid laser-induced thermal damage by improving tissue selectivity and minimizing lateral heat spread.⁸ Electron microscopy studies show that laser power as low as 10% to 25% of visible threshold power only affects the retinal pigment epithelium while sparing the overlying retina.¹⁰ Micropulse laser treated eyes do not exhibit damage to the photoreceptors and/or choriocapillaris or develop the post-laser pigmentary changes typically seen with threshold laser treatments, avoiding scotoma, color vision loss and loss of contrast sensitivity.^11-13 Due to the micropulse’s safety, it can be repeated without limit.

Besides DME, micropulse laser can treat a variety of other macular diseases including retinal vein occlusion, proliferative diabetic retinopathy, central serous retinopathy, retinal macroaneurysm, radiation retinopathy, juxtafoveal telangiectasia and recalcitrant uveitis.

Micropulse laser: an evolution

In 1997, Friberg and Karatza reported on using an infrared diode laser with a micropulse waveform to treat DME. They also used it to treat retinal vein occlusions and choroidal neovascularization caused by AMD. They found micropulse laser to be effective but more difficult to use than the argon laser.¹⁴

Since its inception, the micropulse laser delivery method has been modified to deliver “subthreshold” treatment, which applies the same repetitive short pulses without a clinically visible endpoint. Even though the endpoint of micropulse laser is difficult to gauge, its absence coincides with an absence of a thermally induced protein denaturation. Less protein denaturation is consistent with less cellular damage and less potential vision loss. The mechanism of subthreshold micropulse laser is believed to be due to the release and/or downregulation of various factors from recovering RPE cells.⁷ These have been postulated to include cytokines, VEGF, heat shock protein, pigment epithelium derived factor and matrix metalloproteinase (MMP).¹¹ Since downregulation of VEGF can occur at low laser exposures, subthreshold micropulse laser may be as effective as a clinically visible lesion.7 Micropulse laser spots do not appear on fluorescein angiography following treatment, believed to represent intact RPE tight junctions.⁹ Subthreshold micropulse laser may promote healing of the retina without causing damage; however, there are cautions. (Please see Guest Editorial, page 1.)

Figure 2. 58-year-old male with DME of the right eye. The patient was a poor candidate for anti-VEGF therapy due to a history of cerebrovascular accidents. A. OCT of the macula prior to micropulse laser showing macular edema. B. OCT at five months shows resolution of the macular edema after one session of micropulse laser treatment (Laser parameters: 5% duty cycle, 200 ms duration, 400 mW energy, 147 spots 7x7 grid).

Micropulse laser: Conventional comparisons

Micropulse laser was found to be superior to standard ETDRS laser in eyes with DME. Eyes that underwent micropulse laser gained more vision and had less vision loss than eyes that underwent standard threshold laser.¹³ Vujosevic et al. found favorable outcomes in fundus autofluorescence and microperimetry when comparing micropulse laser with conventional laser.¹¹ Also, multiple studies have shown micropulse to be as effective as conventional argon laser. In a meta-analysis of six randomized controlled trials of micropulse laser versus conventional laser to treat DME, Chen et al. found micropulse to be superior in terms of visual acuity at 12 months. But, using OCT, they found no anatomic difference.¹⁵ A small retrospective review by Thinda et al. compared patients who underwent combination micropulse laser and anti-VEGF treatment versus anti-VEGF alone. They found that the frequency of anti-VEGF injections was significantly reduced in the combination group.¹⁶ ReCall, a randomized controlled trial, is currently investigating Lucentis (ranibizumab, Genentech) therapy with micropulse laser for the treatment of DME.

Micropulse laser: limitations

As with any technology, micropulse laser has its limitations. The most significant one is the lack of standardized treatment parameters as a result of multiple uncontrolled small retrospective studies and case series.¹¹ Laser settings can differ depending on the study due to various duty cycles, spot sizes and durations.¹²

Micropulse lasers also lack a visible endpoint that other types of threshold lasers usually provide. Having this instant feedback on treatment to reassure the surgeons that the laser was used properly is not currently possible with micropulse laser. Use of imaging modalities and functional tests such as adaptive optics, high resolution OCT, mfERG and microperimetry might be able to address this shortcoming in the future. Confirming a therapeutic effect in the absence of measurable data requires a fundamental shift in the practice among vitreoretinal specialists when using micropulse laser. OM

REFERENCES

About the Authors
	Steven Agemy, MD Clinical Assistant Professor of Ophthalmology Vitreoretinal Surgery and Disease SUNY Downstate Medical Center SUNY Downstate College of Medicine
	Jessica Lee, MD is Assistant Professor of Vitreoretinal Surgery, Department of Ophthalmology New York Eye and Ear Infirmary of Mt. Sinai, Icahn School of Medicine at Mt. Sinai.
	Ronald C. Gentile, MD is Professor of Ophthalmology at The New York Eye and Ear Infirmary of Mount Sinai and attending surgeon at Winthrop University hospital on Long Island. Dr. Gentile is a retinal specialist and surgeon with expertise in diabetic eye disease, retinal vascular disorders, macular diseases, ultrasonography, UBM, retinal detachments and ocular trauma.