I have a long background in ocular pharmacology and began researching drugs for the treatment of diabetic macular edema (DME) many years ago. Over the course of several years, my colleagues and I have tested several agents, including anti-VEGF agents and steroids, with a particular interest in sustained-release steroids. After 1 or 2 years, however, we noted several deleterious side effects, ie, 50% of patients required surgical intervention for glaucoma. We have now largely shifted gears to new laser treatments for DME to address the immediate need of our patients.
Laser was established as the gold standard for treating DME almost 30 years ago in the ETDRS1; however, comparing the laser treatments that we were using 30 years ago to what we have available currently is like comparing a 30-year old generic type of car to a brand new Ferrari. That said, in 30 years, there has been no accurate algorithm for laser treatments. The rationale for using a modified-ETDRS laser technique is based largely on surveys. For example, in the recent Diabetic Retinopathy Clinical Research Network's (DRCR.net) study comparing anti-VEGF plus prompt or deferred laser to steroids plus prompt laser for DME, they chose the modified-ETDRS technique based on a survey,2 which is not a scientific-based decision but rather an observations-based decision. The fact is that there is no evidence in the scientific literature to support the idea that a modified-ETDRS laser technique is better than the standard ETDRS laser technique. The idea that modified-ETDRS laser is superior was born from a few different individual studies using this technique, not direct head-to-head comparisons.3-5
In my opinion, laser has not been explored to its full potential, particularly now that we have newer technologies available, such as subthreshold MicroPulse Laser Therapy (MPLT) with the IQ 577 laser (Iridex). In fact, we are misjudging and proposing an immediate DME therapy paradigm shift to pharmacotherapy without fully exploring the maximal clinical potential of laser. For instance, I have had colleagues refer patients to me who they had identified as “laser failures.” Upon examination, I found they were not laser failures at all, but simply failures in the techniques used to administer the laser.
Dense treatment for maximum effect
We know that density of laser treatment patterns matters. The DRCR.net published data from a study showing that increased density of the laser burns is more effective in reducing retinal thickening caused by DME than using a lower density mild macular grid pattern as evaluated by optical coherence tomography (OCT).6 A mild macular grid is a spot titrated to a barely clinically visible lesion, but the DRCR.net also increased the spacing between the spots, which, in my opinion, makes no sense. When I use low intensity, subthreshold MPLT, I increase the density of my spots to achieve the maximal effect.
We performed a prospective, double-masked, controlled clinical trial evaluating the anatomical effects using 532 nm modified-ETDRS treatment (direct and grid photocoagulation technique) vs 810 nm MPLT using normal-density laser (mild macular grid placed at the macula without direct treatment of microaneurysms) or high-density (increased number of spots to enhance the area of retinal pigment epithelium [RPE] activation) for DME in 123 eyes. We found that at 1 year, the high-density MPLT proved superior to the other 2 treatments (Table 1).7 Vujosevic et al8 also conducted a study comparing modified-ETDRS treatment to MPLT. Their findings at 1 year were that high-density MPLT was as effective as modified-ETDRS treatment, but without any changes or damage to the RPE detectable by fundus autofluorescence, and with increased retinal sensitivity as measured by microperimetry. Recently, Luttrull et al9 confirmed that over the longterm (eyes in this study were treated as early as 2000) high-density MPLT was effective in reducing edema without causing retinal damage.
Sandwich Technique–MPLT delivered over foveal center
Another important consideration is how and where the laser is delivered. According to ETDRS guidelines, initial burns must be placed 500 μm from the foveal center. For retreatments, the ETDRS protocol specifies placing burns 300 μm from the foveal center. Realistically, how can a destructive treatment be applied this close to the foveal center? Using conventional lasers, this would, in some cases, do more harm than good.
Our subthreshold MPLT experience shows that intense burns are definitely not necessary and a comparable outcome can be reached with no visible lesions. Based on the idea that we want to maximize tissue response while minimizing side effects, we currently use a Sandwich Technique for the treatment of DME (See 577 nm Sandwich Grid Treatment Technique for DME With Foveal Leakage). Figure 1 shows a patient with a difficult case of diffuse DME who received 7 monthly injections of bevacizumab (Avastin, Genentech) with no results. I treated her with a single treatment of 577 nm laser using the Sandwich Technique. At 6 months follow-up, the patient's central macular thickness (CRT) reduced from 736 μm to 353 μm. Visual acuity improved from 20/320 to 20/63.
Figure 2 shows a patient with diffuse DME who received 6 monthly injections of bevacizumab with no results. After a single 577 nm laser treatment using the Sandwich Technique with the IQ 577 laser system, the patient's CRT reduced from 715 μm to 278 μm, and visual acuity improved from 20/400 to 20/80 at 6-months follow-up.
I use continuous-wave (CW) 577 nm laser to produce barely visible lesions that will be only detectable on FA, 1 spot apart in a grid pattern 360º around the fovea, up to 500 μm from the center of the foveal avascular zone (FAZ). Then, I switch from CW to MicroPulse emission to paint contiguously with subvisible MPLT in all areas with foveal leakage within 500 μm from the center of the FAZ.
A Wide Range of Indications for MPLT
Studies using 810 nm subthreshold MPLT have shown clinical efficacy in the treatment of central serous chorioretinopathy (CSC) (Table 2). I also have found 577 nm subthreshold MPLT is effective and an ideal therapy for the treatment of chronic CSC.
My colleagues and I conducted a trial using 577-nm MPLT in 10 patients with chronic CSC with foveal and juxtafoveal leakage.13 High-density MPLT was delivered targeting all areas of angiographic leakage including the foveal center as well as adjacent normal retina (Figure 3). At 6 months follow-up, visual acuity improved 3 or more lines in 6 (60%) of the eyes, 9 eyes (90%) required only 1 treatment. Point source and diffuse leakage cases had an equal anatomic response, and complete fluid resolution in 10 eyes (100%) was achieved 15-30 days posttreatment. No visible clinical signs of treatment could be detected on FA, and microperimetry showed no laser-related damage to the treatment area.
MPLT provides sustainable results
Our experiences with anti-VEGF injections and steroids for DME show that patients often experience an immediate response in terms of reduced edema; however, these results are not sustained over the long term, and in most cases patients require monthly or even more frequent injections. This is not a sustainable model for management of a long-term disease. In our trial with MPLT, we are seeing clinical results lasting over 1, 2, or more years. This is comparable to observations reported by the DRCR.net.14
Using combination therapy with anti-VEGF and MPLT would benefit patients by offering an initial boost of effect with the injection and then adding laser to help sustain the effect and reduce the need for frequent injections.
What do I envision for the future? I certainly see a combined laser and drug treatment using a refined and optimized laser technique. I also see laser remaining the gold standard treatment for DME, provided that we adopt new techniques that can maximize benefits while minimizing retinal damage. When treating DME with laser, there is a need to enhance selectivity around the fovea as to not cause harm to this sensitive region. There is no way to do this using the standard ETDRS laser protocol, but with MPLT, it is now possible to address foveal leakage in a safer, more effective manner with subclinical, invisible laser treatment.
José Augusto Cardillo, MD, is Research Coordinator, Department of Retina and Ocular Pharmacology Federal University of São Paulo, Brazil, and Chief of the Retina Department at the Hospital de Olhos de Araraquara.
- No authors listed. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985;103(12):1796-1806.
- Elman MJ, Bressler NM, Qin H, Beck RW et al; Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118(4):609-614.
- Olk RJ. Modified grid argon (blue-green) laser photocoagulation for diffuse diabetic macular edema. Ophthalmology. 1986;93(7):938-950.
- Lee CM, Olk RJ. Modified grid laser photocoagulation for diffuse diabetic macular edema. Long-term visual results. Ophthalmology. 1991;98(10):1594-1602.
- Ladas ID, Theodossiadis GP. Long-term effectiveness of modified grid laser photocoagulation for diffuse diabetic macular edema. Acta Ophthalmol (Copenh). 1993;71(3):393-397.
- Writing Committee for the Diabetic Retinopathy Clinical Research Network, Fong DS, Strauber SF, Aiello LP, et al. Comparison of the modified Early Treatment Diabetic Retinopathy Study and mild macular grid laser photocoagulation strategies for diabetic macular edema. Arch Ophthalmol. 2007;125(4):469-480.
- Lavinsky D, Cardillo JA, Melo LAS, Dare A, Farah ME, Belfort R. Randomized clinical trial evaluating mETDRS versus normal or high-density micropulse photocoagulation for diabetic macular edema. Invest Ophthalmol Clin Sci. 2011;52(7):4314-4323.
- Vujosevic S, Bottega E, Casciano M, Pilotto E, Convento E, Midena E. Microperimetry and fundus autofluorescence in diabetic macular edema: subthreshold micropulse diode laser versus modified early treatment diabetic retinopathy study laser photocoagulation. Retina. 2010;30(6):908-916.
- Luttrull JK, Sramek C, Palanker D, Spink CJ, Musch DC. Long-term safety, high-resolution imaging, and tissue temperature modeling of subvisible diode micropulse photocoagulation for retinovascular macular edema. Retina. 2012;32(2):375-386.
- Lanzetta P, Furlan F, Morgante L, Veritti D, Bandello F. Nonvisible subthreshold micropulse diode laser (810 nm) treatment of central serous chorioretinopathy. A pilot study. Eur J Ophthalmol. 2008;18(6):934-940.
- Gupta B, Elagouz M, McHugh D, Chong V, Sivaprasad S. Micropulse diode laser photocoagulation for central serous chorio-retinopathy. Clin Experiment Ophthalmol. 2009;37(8):801-805.
- Koss MJ, Beger I, Koch FH. Subthreshold diode laser micropulse photocoagulation versus intravitreal injections of bevacizumab in the treatment of central serous chorioretinopathy. Eye (Lond). 2012;26(2):307-314.
- Cardillo JA. 577 nm yellow selective subthreshold laser photocoagulation for the treatment of central serous chorioretinopathy with foveal leakage. The 44th Retina Society Annual Scientific Meeting and the Società Italinana della Retina Society, Rome Italy. September 21-25, 2011.
- No authors listed. Comparison of the modified early treatment diabetic retinopathy study and mild macular grid laser photocoagulation strategies for diabetic macular edema. Arch Ophthalmol. 2007;125:469-480.