Can Peripheral Laser Therapy Aid DME Management?

Photocoagulation of ischemic retinal tissue has the potential to resolve diabetic macular disease with minimal intravitreal injections.

Paul E. Tornambe, MD

Ophthalmologists’ approaches to treating diffuse diabetic macular edema have shifted in recent years from primarily scatter laser photocoagulation of the macula to injections of VEGF inhibitors and/or intravitreal steroids given every month or two. This approach effectively decreases the macular edema but does not resolve it permanently, because essentially we are treating the disease’s effect and not its cause. In the face of unsatisfactory outcomes, many patients then require vitrectomy as a treatment of last resort.

Over the past year I have adopted a new approach to diffuse diabetic macular edema that directly targets its causes — mainly VEGF, but also other cytokines such as interleukin 6, interleukin 8 and MCP1. This novel strategy uses widefield fluorescein angiography to locate areas of significant peripheral ischemia — from which VEGF and other cytokines are produced and elaborated — followed by photocoagulation targeted specifically to these sites. VEGF inhibitor injections at the time of laser treatment and one month later complete the regimen.

Although only time will tell whether this represents a safe and effective treatment over the long term, the outcomes at the eight- or nine-month points have been encouraging in the subset of patients who have received this intervention and experienced complete resolution of their macular edema. If it stands the test of time, we may be looking at an efficacious treatment for diffuse DME that spares the patient a lifetime of routine VEGF inhibitor or steroid injections.

Figure 1. Several peripheral retinal diseases — including Coats' disease — can be associated with macular edema. Treatment of the peripheral lesion resolves the edema.

THE TREATMENT’S RATIONALE

Spearheading research in this area has been Steven D. Schwartz, MD, chief of the Retina Division at UCLA’s Jules Stein Eye Institute, whose insightful papers on these diseases’ pathogeneses using widefield angiography to demonstrate poor peripheral retinal perfusion prompted me to devise and implement this treatment in the first place. Several retinal diseases — among them Coats’ disease, familial exudative vitreoretinopathy, von Hippel’s angioma and radiation retinopathy — produce peripheral ischemic lesions and are likewise associated with macular edema. Our treatment of these entities is directed not to the macula but to the peripheral pathology.

It’s likely the case that all of these diseases, as well as diabetic retinopathy, are elaborating VEGF with consequent macular leakage and edema. The macula’s unique anatomy — namely, the manner in which the photoreceptors and associated neural cells of Henle’s layer are configured — makes it especially susceptible to edema. A potent vasodilator, VEGF weakens the walls of the macular capillaries, inviting leakage of lipids and subsequent edema.

Previous and present treatments for diffuse DME have been inadequate at best and potentially detrimental. Panretinal photocoagulation applied to well-perfused retinal tissue is known to upregulate VEGF, the very pathological culprit we wish to vitiate. We also have observed that VEGF upregulation in one eye may affect the fellow eye; this crossover effect is not completely understood. What’s more, direct laser to the macula produces burns that enlarge with time; excessive heat applied to this area can itself lead to a choroidal neovascular membrane as well as retinal pigment epithelial creep and vision loss.

VEGF inhibitors and intravitreal steroids do a great job of mopping up cytokine leakage and thereby tightening and enhancing the structural integrity of porous macular capillary walls. But their effect is diminished over time, even as areas of poorly perfused peripheral retina continue to churn out more VEGF. It’s almost like setting a bucket to catch rain under a leaky roof while leaving the crack through which it pours untouched — a quick fix at best. The subsequent need for frequent and long-term injections imposes a treatment burden on the patient in terms of inconvenience, on insurers in terms of cost and on the practice in terms of a clogged clinic schedule with greater expenditure of administrative resources.

THERE’S GOT TO BE A BETTER WAY

For all of these reasons, it’s clear that we need to address the root cause of diffuse DME, which evidence indicates stems from VEGF and other cytokines produced and expressed by ischemic peripheral retinal lesions. If macular leakage is due to VEGF emanating from areas of retinal ischemia, then targeted laser treatment to these sites should decrease macular edema, and perhaps diminish or eliminate the number of VEGF inhibitor injections needed to control the disease.

New technology has helped greatly in this effort, particularly the advent in recent years of widefield fluorescein angiography to identify peripheral areas of poor perfusion. With the Optos unit, it’s relatively easy to obtain equator-to-equator angiograms with a range of 160º, allowing one to view all retinal quadrants simultaneously in real time.

Figure 2. This case demonstrates the effect of panretinal photocoagulation and a single Avastin injection to treat extensive and severe diabetic macular edema in both eyes in a 42-year-old Latina woman.
Focal macular laser treatment had been applied six months earlier with no effect. The left eye underwent wide-field angiography and then targeted PRP in October 2010, with no additional macular laser treatment (A, B).
At six weeks after just PRP to the left eye, the patient shows significantly less edema (C, D).
Interestingly, the edema in the fellow right eye also improved. The patient denied any change in diabetic control. PRP evidently improved the DME in both the treated and untreated eyes, with no Avastin injections.
Figures E and F show the right eye at initial presentation in October 2010. Figures G and H present the findings at the six-week follow-up visit. Although the DME improved in the untreated right eye, she later developed high-risk proliferative disease, and underwent panretinal photocoagulation.

Compare this with conventional fluorescein angiography, which offers a narrower view and therefore does not allow for real-time widespread retinal-vasculature evaluation.

My regimen is as follows. Candidates for this treatment are those for whom widefield fluorescein angiography shows significant areas of poor peripheral retinal perfusion, with significant diffuse DME and subsequent visual loss. These would be cases that, conventionally, physicians would treat with scatter macular photocoagulation, a VEGF inhibitor, plus perhaps intravitreal triamcinolone or a sustained-release steroid implant. These are the same cases for which you might consider vitrectomy.

I would consider a contraindication to be DME caused by focal disease such as a microaneurysm with circinate threatening the fovea. In these cases, conventional focal laser should be used. Otherwise, the treatment is an option to consider in most cases, provided that patients are under optimal diabetic control before you start. Cases involving renal failure or uncontrolled hypertension may exacerbate DME and yield unsatisfactory outcomes. As such, make it a priority to work with the patient’s internist in getting blood sugar and blood pressure under control.

My approach calls for one VEGF inhibitor injection at the time of laser treatment and another about a month later. Ideally, that should be the extent of medical therapy, although I reserve the option of giving additional injections as needed. In the patients I’ve treated so far, that hasn’t been necessary.

Why give the anti-VEGF injections at all? This blunts any potential VEGF response and possibly worsens macular edema occurring immediately after laser treatment. I have noticed that macular edema that worsens right after laser treatment is exquisitely sensitive to VEGF inhibitors —more so than run-of-the-mill DME.

The best way to treat these eyes, I believe, is with a pattern scan laser that applies laser pulses homogenously, treating only areas of poor peripheral perfusion and sparing the macula. Photocoagulation of this ischemic tissue with the laser prevents further upregulation of VEGF. Be careful to avoid lasering healthy well-perfused retina, in which case you risk aggravating the patient’s poor night vision and compromising the peripheral visual field.

After the initial treatment, the patient returns in one month for a second anti-VEGF injection. It takes a few months for the laser to begin taking effect, during which time there may be continued upregulation of VEGF due to the laser while the burns are healing. The second injection helps to forestall this turn of events. This one-month follow-up visit, of course, also gives me the opportunity to take a close look at the macula to see how it is faring so far. The laser treatment’s full effect takes hold within six to nine months.

I’ll typically see the patient at three-month intervals. At six months I’ll obtain another widefield fluorescein angiogram to check for any new areas of nonperfusion and to make sure I didn’t miss any. The nice thing about the pattern laser is that you can apply a more confluent and homogenous treatment to areas of poor perfusion than you can with the usual techniques we use with manual delivery.

A NEW APPROACH TO DME

As with anything else that’s new in the clinic, I’m mindful to temper my initial enthusiasm with the test of time. But I have been very excited about the early results. Those for whom I described the treatment and presented results at the American Society of Retina Specialists meeting showed great interest. Peer-reviewed publication will await a larger patient population and lengthier follow-up.

In the meantime, this is a treatment avenue I plan to pursue for those with significant diffuse DME. Keep an eye out for further articles and lectures on this promising new clinical development. RP

REFERENCES

1. Gardner TW, Eller AW, Friberg TR. Reduction of severe macular edema in eyes with poor vision after panretinal photocoagulation for proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 1991;229:323-328.
2. Gaucher D, Fortunato P, LeCleire-Collet A, Bourcier T, Speeg-Schatz C, Tadayoni R, Massin P. Spontaneous resolution of macular edema after panretinal photocoagulation in florid proliferative diabetic retinopathy. Retina. 2009;29:1282-1288.
3. Friberg TR, Gupta A, Yu J, et al. Ultrawide angle fluorescein angiographic imaging: a comparison to conventional digital acquisition systems. Ophthalmic Surg Lasers Imaging. 2008;39:304-311