By Pravin U. Dugel, MD
Special to Ophthalmology Times
Diabetic retinopathy (DR) and diabetic macular edema (DME) are the most common causes of blindness among the working-age populations of the developed world. Yet, treatment for these patients represents a large unmet need.
The Early Treatment Diabetic Retinopathy Study (EDTRS) set focal/grid laser photocoagulation as the standard of care for treatment more than two decades ago,1 but the understanding of laser therapy is evolving and treatment modalities changing. Concurrently, there has been a large focus on therapy with anti-vascular endothelial growth factor (VEGF), and study results suggest the benefits of combined therapy.2
Numerous studies have shown positive results with anti-VEGF injections. In the drcr.net study, patients were treated every 4 weeks until week 16, at which point 25% met the criteria not to receive an injection. Of those 25% that could skip a treatment, 90% had recurrences that required future treatment.
Overall, the first time that a patient met the criteria not to be examined every 4 weeks was at week 64. Thus, the requirement is to see patients with DME every 4 weeks for more than a year, which is not sustainable or realistic. Many patients are young, have jobs and busy lives, and may not be able to be compliant. If patients are not seen every 4 weeks, that may compromise the study results.
In spite of having been the standard of care for decades, there are several misconceptions that have marred the reputation of laser treatment. Initial studies showed that laser photocoagulation stabilized patients but did not necessarily improve vision (Original DRS Study in 1980s).
However, closer analysis of these results show that many patients actually started with sufficiently good vision, so that gaining three lines of visual improvement was not possible. Among those patients that did have potential for greater than three lines of improvement, more than 40% achieved this. The results for laser treatment were actually very good, but this finding was misunderstood because of the study design.
In addition to better interpretation of existing studies of laser photocoagulation, the treatment itself is also changing. It was previously thought that laser photocoagulation provided its therapeutic benefit via the destruction of microaneurysms. Large and intense laser burns were applied that not only caused destruction initially, but also tended to expand over time, impacting the surrounding tissues.
However, recent studies have suggested that laser treatment can best be used as a stimulator of retinal pigment epithelial (RPE) cells creating a cascade of events which release chemical factors that then allow the edema in patients with DME to be resolved.3
Consequently, therapy is evolving to be less destructive and more precise by manipulating the duration and power of the laser energy applied.
Micropulse and subthreshold laser therapies have been developed that allow physicians to provide less destructive treatment, and studies have shown that these modalities are at least as effective as the modified EDTRS recommendations for focal/grid laser photocoagulation.4,5 We are just on the tip of an evolution that will change the vocabulary from destructive photocoagulation to photostimulation of RPE cells.
Duration and power
One treatment option is a new technology (Endpoint Management, Topcon Medical Laser Systems) that, when combined with Topcon’s PASCAL scanning laser, allows physicians very precise management of two important elements of laser treatment: duration and power. The software uses advanced mathematical algorithms to guide laser output in controlled, repeatable doses as a percentage of the initial settings determined by the physician during titration. The technology allows user flexibility in a range the desired endpoints from 95% of the titrated lesion down to subvisible treatment levels less than 50%. This control capability can allow RPE cells to get precise, focused-energy delivery resulting in minimal collateral damage while still maintaining clinical efficacy.
DME can be divided into three different categories, among which there is significant overlap. The first category is true focal DME, with a very precise location of the leak which is away from the fovea. The second category is diffuse DME, in which there is widespread leakage, even under the fovea. The third category is ischemic DME, characterized by swelling due to insufficient blood flow.
The vast majority of patients can be categorized into the second or third groups, and I treat with a combination of laser therapy and anti-VEGF injections. Anti-VEGF begins to work immediately and continues to help as long as it is administered. However, when treatment stops edema recurs, and maintaining frequent injections is often not sustainable. Laser photostimulation is the perfect complement to anti-VEGF treatment because it does not provide an immediate improvement, but rather has a slow, steady and sustainable positive effect.
For patients who fall into the first category, I would treat using only laser therapy. However, focal DME with a distinct round circle of exudate or a particular microaneurysm tends to occur early in the disease state and is seen only in a minority of patients.
Laser photostimulation using the software technology is much like photocoagulation in that the physician programs a certain percentage of treatment effect so that a burn on the retinal pigment epithelium can barely be visualized. Once that benchmark it set, the treatment effect is titrated down by selecting the percentage level of the energy to be delivered.
I currently use the 50% level in my patients and studies. Once I choose my percentage level, the software automatically adjusts both power and duration to achieve this energy level.
Another capability of Endpoint Management are “landmark” patterns where the edges of a pattern can be selected to remain barely visible and provide reference points, while the remainder of the pattern itself cannot be seen. These patterns are useful to identify the treated zones and prevent overlapping.
Titration can also be fine-tuned to allow treatment over the entire macula. We are currently titrating to 50% energy, but experimentation is still in the early stages, and there is the possibility of greater reductions and going to lower levels. While it is not at this point yet, there is even potential to be able to treat directly over the fovea.
This is a very exciting time in the development of laser therapy, and there are phenomenal possibilities for the future of combined treatment algorithms. The more precision we have with our laser treatments, the greater our ability will be to fine tune treatment and achieve even better results. If photostimulation continues to show that it is a safe and effective modality, we may even see the use expanded as a compliment to other treatment modalities for diseases such as branch retinal vein occlusion, central serous choroidopathy and other pathologies that involve fluid leakage.OT
1. Early Treatment Diabetic Retinopathy Study Research Group. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 2. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1987;94:761-774.
2. Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117:1064-1077.
3. Sramek C, Mackanos M, Spitler R, et al. Non-damaging retinal phototherapy: dynamic range of heat shock protein expression. Invest Ophthalmol Vis Sci. 2010;52:1780-1787.
4. 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;30:908-916.
5. 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;32:375-386.
Pravin U. Dugel, MD, is managing partner, Retinal Consultants of Arizona, Phoenix, and clinical associate professor, Department of Ophthalmology, Doheny Eye Institute, University of Southern California, Los Angeles. He has no financial interest in Topcon Medical Laser Systems.