Clinically significant macular edema (CSME) has been defined by the Early Treatment of Diabetic Retinopathy Study (ETDRS) as (1) retinal thickening at or within 500 µm of the macular center; (2) hard exudates at or within 500 µm of the macular center with adjacent retinal thickening; or (3) 1 disc area or more of retinal thickening within 1 disc diameter of the center of the macula.¹ Diagnosis of retinal edema can be made on clinical funduscopic exam, stereo fundus photography and/or OCT. OCT has currently become one of the most important imaging devices for confirming, diagnosing, and quantifying diabetic macular edema.

LASER THERAPY IN DIABETIC MACULAR EDEMA

Prior to anti-VEGF treatment, macular laser therapy (MLT) was the mainstay of CSME treatment for over 3 decades, since the publication of ETDRS in 1985. This study demonstrated that focal or grid laser photocoagulation reduced the risk of moderate visual loss in patients with CSME by 50% at 3 years. Despite the decrease in vision loss, VA improved by 15 letters in only about 3% of patients.² The low percentage of 15 letter vision gainers appears to be related to the destructive nature of the laser used during these early studies. As seen in the original publications, the laser spots used were larger and more intense than are used today.

Laser intensity correlates with the whiteness of the laser spot during treatment and is directly proportional to the thermal damage of the photoreceptors, RPE, and choriocapillaris. This can induce gliosis and hyperplasia in RPE cells and over time can be associated with RPE atrophy, enlarging or creeping laser scars, choroidal neovascularization, subretinal fibrosis, and scotoma.³ Some of these scotomas are asymptomatic and not be detectable on routine testing unless microperimetry is performed.⁷ Newer lasers minimize thermal damage to the retina and aim to prevent complications while maximizing therapeutic effect.

The effectiveness of macular laser treatment appears to be related to the morphology of the retinal edema and its relationship to leaking microaneurysms. Morphologically, DME has been defined as either focal or diffuse. Eyes may occasionally have combinations of both. Focal DME has discrete leaking microaneurysms on clinical exam and fluorescein angiogram (FA), while diffuse DME is characterized by generalized areas of leakage that involve the central fovea. Focal DME responds better to focal laser photocoagulation, whereas diffuse DME seems to be more refractory to focal laser and grid laser photocoagulation.^4,5 Although FA is the gold standard for identifying leaking microaneurysms, indocyanine green angiography (ICG) has been used to find occult microaneurysms in diffuse areas of fluorescein leakage. Indocyanine green angiography-guided laser photocoagulation has been reported to be helpful in treating DME.⁵

The mechanisms by which MLT improves DME may include occlusion of leaking microaneurysms, RPE stimulation, inducing endothelial division, reducing oxygen consumption, and increasing choroidal oxygen diffusion.⁶ DRCR.net clinical trials show that study-based outcomes with MLT have improved significantly,^7,8 likely due to improved glycemic control, BP control, and improved laser technologies.⁹ Though anti-VEGF injections are increasingly used for DME, focal laser was being used 2.5x as frequently as anti-VEGF as recently as 2011-2012. In fact, focal laser treatments increased from 22.7% to 36.6% (P<.001) from 2002 to 2012.¹⁰ Even in the DRCR.net protocol T published in 2015, which compared the various available anti-VEGF agents for DME, 36% to 39% of subjects in each treatment group had focal/grid laser before injection, and 37% to 56% of subjects had focal/grid laser during the first year of the study.¹¹ Though the effect of laser was not studied in this trial, the percentage of eyes in each group having focal laser remains significant. Focal laser as the primary treatment is reserved for those eyes with focal perifoveal or extrafoveal DME and microaneurysms on FA amenable to laser treatment, especially in eyes with excellent vision without foveal threatening lipids.¹²

LASER THERAPY VS ANTI-VEGF

Anti-VEGF therapy has evolved to surpass MLT as the standard of care for most patients with DME. In a meta-analysis of 7 studies comparing 1,749 patients with DME randomized to either laser only (n=713), anti-VEGF only (n=394), and combination anti-VEGF and laser (n=642), laser monotherapy was inferior to the anti-VEGF groups. Anti-VEGF-treated eyes had better VA and better anatomic outcomes.¹³

Most randomized, controlled trials have demonstrated superior mean visual outcomes with a variety of anti-VEGF therapy when compared with MLT.^14-19 Occasionally in subgroup analysis, laser treatment has been as effective as anti-VEGF therapy. For example, the RESTORE trial that compared ranibizumab, ranibizumab combined with laser, and laser alone for DME, found that in patients with a retinal thickness of <300 mm, laser and ranibizumab therapy had a similar visual outcome.²⁰ Which subgroup of patients with DME could benefit from focal laser and avoid repetitive intravitreal injections is still not known.

There is an ongoing 2-year DRCR.net Protocol V study of center involving DME in eyes with excellent vision (VA ≤20/25) (NCT01909791). Protocol V is comparing 3 treatment arms that include prompt anti-VEGF, baseline focal/grid laser, and observation. All patients may receive anti-VEFG at each visit depending on VA loss. This study may be able to elucidate the role of focal laser in eyes with DME and good vision and give insight into how laser might prevent the need for anti-VEGF treatment or reduce the injection treatment burden. Some speculate that the injection burden may increase by waiting for DME to become more visually significant. Other laser modalities remain an area of active interest, especially subthreshold and micropulse laser that if performed early in the disease may be able prevent or decrease the need for anti-VEGF injections.¹⁴

LASER AND STEROIDS

MLT and steroids in combination play a role in some patients with CSME. This is especially true for those patients who do not respond to anti-VEGF or have a relative and absolute contraindication to anti-VEGF treatment (ie, inflammation related to the agent, recent adverse thromboembolic, stroke, pregnancy). Some studies of patients with DME receiving intravitreal triamcinolone (IVT) combined with grid laser had reported visual improvement at 6 months, whereas the IVT-only cohort did not.²¹ One study of patients with diffuse DME had better BCVA if laser treatment was preceded by posterior subtenon triamcinolone.²² MLT appeared to help maintain VA following IVT, and this is believed to be due to increased responsiveness to MLT with reduced CMT following steroid treatment. With new advances in sustained-release steroid implants, further studies evaluating the effects of combination therapy with laser are warranted.

MICROPULSE LASER

Subthreshold micropulse lasers of 577 nm and 810 nm wavelengths produce an effect without causing visible intraretinal damage detectable on clinical exam during or after treatment. The treatment consists of repetitive pulses (typically 100-300 µs on, 1,700-1,900 µs off) within a 200 ms to 300 ms envelope. This low energy decreases the risk of hemorrhage, temperature build-up, and thermal damage while localizing the photothermal effects.^4,6

Micropulse has been shown to be as effective as argon laser therapy for DME in multiple studies,²³ and results in better preservation of retinal function on electrophysiological studies.⁶ Infrared micropulse laser has been shown to have no visible signs of retinal damage on color fundus photos, OCT, FA, and even fundus autofluorescence. Micropulse laser has also been shown to have better preserved retinal sensitivity compared with standard modified Early Treatment Diabetic Retinopathy Study (mETDRS) laser.^24-26 Micropulse applied in a fully contiguous manner is more effective at increasing BCVA and reducing CMT in DME compared with mETDRS or normal-density micropulse laser treatment.²⁷ Thus, micropulse offers the potential for repeat treatments and more aggressive/confluent treatment through the fovea.

Confluent 810 nm micropulse laser has been shown to be more effective in eyes with a CMT <400 µm. One study showed that the subgroup of eyes with a CMT of <400 µm had a decrease of 55 µm in retinal thickness and 2 lines of visual gain, without the need for retreatment with laser or anti-VEGF. Subthreshold laser may not work if the CMT is >400 µm. As with conventional laser, one may consider decreasing CMT with anti-VEGF or steroid treatments before performing micropulse laser.²⁸

Intravitreal injections have a small but cumulative risk of visually catastrophic endophthalmitis, which discourages clinicans from administering injections in DME with good VA. Transfoveal micropulse laser has been shown to be safe and effective in treating fovea-involving DME in eyes with good preoperative VA that were not candidates for conventional photocoagulation or intravitreal injections.²⁹ A retrospective study that compared micropulse laser and PRN ranibizumab to ranibizumab monotherapy for DME found that micropulse laser significantly decreased injection burden at 12 months (1.7 vs 5.6) and at final follow-up (2.6 vs 9.3) (P<.001 for both).³⁰

NAVILAS LASER

The Navilas laser (OD-OS) incorporates retinal eye-tracking and aligns laser treatment to a preplanned treatment map with real-time fundus images. The system allows accurate laser treatment to microaneurysms and limits the possibility of inadvertent placement of laser burns. The eye tracking ability of the Navilas was 20% more accurate (92% from 72%) than a slit lamp based laser.³¹ Theoretically, the more accurately the microaneurysms are treated with the desired reaction, the better the treatment effect. One study compared monthly ranibizumab for DME, with or without Navilas focal/grid laser. The laser was performed after 3 injections in one group and after CMT decreased to ≤450 µm in the other group. The group of eyes that underwent Navilas focal/grid laser had improved VA and reduced injection burden.^32,33

CURRENT ROLE OF MACULAR LASER

Laser treatment that decreases DME and improves vision is cost effective when compared with antiangiogenic injections.³⁴ Even though few eyes with DME are candidates for focal laser as a first-line treatment, the role of macular laser is still significant. The use of MLT has shifted from first-line treatment in the 1990s to being used to stabilize visual and anatomical improvements after initial anti-VEGF or steroid treatment, and to decrease injection burden while maintaining therapeutic response. Results of the READ-2 study implied that combination therapy with laser may decrease residual edema and injection burden.¹⁹ Deferred focal laser better targeted to microaneurysms (Navilas/ICG angiography) or using micropulse laser may further decrease injection burden, but many retina specialists recommend reducing retinal edema with medical therapy before adding laser therapy.¹²

Since it has been shown that clinicians tend to underinject compared to randomized controlled trials,10,35,36 any combination treatment that decreases injection burden may improve real-world outcomes.

Subthreshold laser holds promise in DME treatment, both in reducing injection burden and reducing cardiovascular risk factors in patients unable to tolerate intravitreal injections due to good vision. Micropulse laser, while promising, still requires long-term, prospective, randomized, multicenter data.¹²

Many specialists are hesitant to use anti-VEGF treatments within 6 months after arteriothrombotic events such as myocardial infarction, active CHF, stroke, or transient ischemic attack due to the potential increased risk of complications. If these patients have glaucoma or are a steroid responder or phakic, MLT may still be an option at the clinician’s discretion.

CONCLUSION

Focal retinal laser for DME has come far since the first report from ETDRS in the 1980s. While current treatment modalities, such as VEGF inhibitors and steroids, have replaced laser as first-line treatment for many eyes with DME, laser treatment still plays an important role. With the absence of collateral thermal retinal damage with micropulse lasers and the accuracy of navigated lasers, focal retinal lasers are evolving in an attempt to harness beneficial effects while minimizing risk. Further research in this area will be the driving force for advances in technology to meet our expectations of optimal patient care. RP

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