Combination of treatments may be ideal for diabetic macular edema

Currently in the United States, 9.3% of the adult population is considered to have diabetes mellitus; one-third of those cases are undiagnosed. Between 40% and 45% of Americans diagnosed with diabetes have some stage of diabetic retinopathy, and about half of those with proliferative retinopathy also have macular edema. Diabetic macular edema is still the major cause of legal blindness in diabetic retinopathy.

The Early Treatment Diabetic Retinopathy Study (ETDRS) demonstrated that photocoagulation reduced the risk of moderate vision loss, especially in eyes with macular edema that involved or threatened the center of the macular. There was a moderate increase in visual gain and a decrease in the amount of retinal thickening in eyes that received focal treatment. This is currently the only clinically proven, long-term method for reducing vision loss. Pharmacologic treatment is increasingly being used as both adjunct and primary therapy in diffuse DME. At the same time, innovative developments are being made in the field of laser therapy. My treatment protocol for DME is adapting to include both of these elements.

How photocoagulation works

Conventional laser photocoagulation works by converting light energy into heat, which denatures proteins and causes coagulation of the treated tissues. With focal photocoagulation, the laser induces endovascular thrombosis while the heat induces contraction of the vessel walls. This results in direct closure of leaking vascular abnormalities.

With grid laser photocoagulation, on the other hand, there are several theories on its mechanism of action. These include:

1. Destruction of high oxygen-consuming photoreceptors, thereby increasing inner retinal oxygenation. This in turn reduces local tissue blood flow, which results in reduced retinal vascular leakage.
2. Induction of proliferation of vascular endothelial cells (RPE factor) with subsequent restoration of the inner blood-retinal barrier.
3. Stimulation of the retinal pigment epithelium (RPE) to release biochemical mediators to antagonize VEGF and other factors.
4. Destruction of the outer retinal layers and RPE, which permits better diffusion of oxygen from the choriocapillaris into the inner retinal layers.
5. Debridement of sick or fatigued RPE cells, which results in enhancement of outer blood-retinal barrier.
6. Alteration in outer blood-retinal barrier favoring movement of fluid from the retina into the choroid.
7. Reduction of total surface area of abnormal vessels, which reduces the overall amount of vascular leakage (minor effect).

The ETDRS recommends photocoagulation in cases of:

1. Focal retinal thickening: all leaking lesions responsible for causing clinically significant macular edema within 500 µm to 3,000 µm from the foveal center;
2. Diffuse retinal thickening: regions of diffuse retinal thickening located 500 µm to 3,000 µm from the foveal center thought to be responsible for clinically significant macular edema; and
3. Avascular retinal zones: areas of avascular retina associated with clinically significant macular edema.

Subthreshold laser treatments

Use of conventional lasers to perform photocoagulation, while effective, has both complications and limitations. Photocoagulation can lead to corneal, iridial and lenticular burns, choroidal neovascularization, foveal photocoagulation or, in cases in which damage is done to perifoveal capillaries, foveal “shutdown.” Additional complications include epiretinal membrane formation, choroidal hemorrhage, avascular submacular fibrosis and RPE atrophy with scar expansion after heavy, confluent treatment.

Subthreshold, or tissue-sparing, treatment modalities are proving to be as effective as conventional lasers without the nontherapeutic, iatrogenic side effects. The intent with subthreshold laser treatments is to produce a therapeutic treatment without inducing intraretinal damage detectable on clinical examination during or after the treatment. Damage to the full retinal thickness is not necessary to obtain the beneficial effects of the laser. This technique can avoid complications associated with conventional laser therapy, such as reductions in visual acuity, visual field defects and reduced contrast sensitivity.

MicroPulse laser therapy

With MicroPulse laser therapy (MPLT), the laser energy is delivered in a train of repetitive short pulses (100 microseconds to 300 microseconds “on” and 1,700 microseconds to 1,900 microseconds “off”) within a period of time typically lasting 200 milliseconds to 300 milliseconds. MPLT power as low as 10% to 25% of the visible threshold power has been demonstrated to be sufficient to show consistent RPE-confined photothermal effects while sparing the neurosensory retina on light and electron microscopy. The inner temperature must remain below the threshold of coagulative damage for the retina to maintain its natural transparency. Absence of chorioretinal laser damage may permit high-density therapy with confluent applicators over the entire edematous area and re-treatment of the same areas.

While subthreshold and MPLT may seem similar, there are some important distinctions. Subthreshold conventionally is understood to consist of applying the laser to a point where the physician is still detecting physical alterations in the pigmentary pattern of the macula on the fluorescein angiogram, even though clinically the physician may not see as much damage to the RPE. With MPLT, the laser beam is “chopped” into small sections, so to speak, which allows for thermal relaxation and cooling of the tissues in between the energized pulses. While subthreshold is light cauterization, MPLT is actually “photo stimulation” of the RPE cells. This stimulation of the RPE releases certain biochemical factors that are thought to reduce the leakage of the retinal vessels as well as improve the strength of the outer blood-retinal barrier.

While conventional laser treatment has shown to be effective at maintaining visual acuity, it is only effective in 50% to 60% of eyes, and there is a possibility that multiple treatment sessions will be required and paracentral scotomas may result. Pharmacologic treatment is increasingly being used to manage refractory cases as well as an initial therapy in diffuse DME. These drug classes include corticosteroid analogues, anti-VEGF compounds and vitreolytic agents.

DME treatment

The goal of DME therapy is to achieve the greatest reduction in macular thickness in the shortest amount of time with the greatest duration, while inciting the least amount of side effects. I find that integrating treatment strategies works best to meet this goal.

I typically divide my clinically significant DME cases into three categories, mild (less than 250 µm), moderate (between 250 µm and 400 µm) and severe (more than 400 µm), based on the central subfield mean thickness (CSMT) as derived from optical coherence tomography imaging. For mild DME, I now go straight to MPLT, including both focal and grid treatments simultaneously. For moderate DME, I will start with two intravitreal anti-VEGF injections spaced 1 month apart. If there is no significant reduction in the macular edema after those injections, I then proceed to MPLT. If there is a response to the initial anti-VEGF injections, I will continue for a maximum of three additional injections before proceeding to MPLT. In cases of severe DME, I will start with three intravitreal anti-VEGF injections spaced 1 month apart. If there is a response to the initial anti-VEGF injections, I will continue for a maximum of three additional injections and then proceed to MPLT, provided that the CSMT is less than 400 µm. If there is an insufficient reduction in the CSMT, I then consider using intravitreal corticosteroid analogues such as triamcinolone or Ozurdex (dexamethasone intravitreal implant, Allergan) after explaining to the patient the risks of glaucoma and cataract with the use of these agents. One month after the corticosteroid analogue injection, I then proceed with MPLT.

While anti-VEGF agents alone are not usually sufficient to resolve macular edema, I find them to be useful in the initial management of DME. After I maximize the pharmacologic therapy to treat macular edema, I find that the use of MPLT is the more definitive therapy. Currently, I use MPLT in a combination of focal and grid treatments with the IQ 577 laser (Iridex). I typically treat my patients in two to three sessions spaced 90 days apart. This combination of treatment modalities allows patients the fastest macular edema remission for the longest period of time.