ST laser therapy may reduce DME intravitreal injections


Used as an adjunct, ST laser therapy may reduce the treatment burden for patients while maintaining visual acuity.

Diabetic macular edema (DME) is a significant cause of vision loss in patients with diabetes.

In the 1980s, the Early Treatment Diabetic Retinopathy Study (ETDRS) established focal laser photocoag­ulation as the standard of care for eyes with clinically significant macular edema (CSME).1

Although laser treatment decreased the risk of moderate vision loss by 50%, the rate of visual gain following focal laser treat­ment is low.

Over the past decade, ETDRS focal laser treatment for CSME has largely been replaced by anti- VEGF injections.2,3

Patients who receive anti-VEGF injections are more likely to achieve visual gain than those who undergo conventional focal laser treatment. However, regular ongoing injections are required and can carry risks, including endophthalmitis and uveitis. Systemic risks are low, but are also a consideration in patients with diabetes.

From a practical standpoint, monthly visits are a significant burden, and not all patients respond completely to anti-VEGF injections.3

Intravitreal steroid injections are also available for patients with DME and may extend the treatment interval from several months (Ozurdex, Allergan) 4 to 3 years (Iluvien, Alimera Sciences).5

In addition to the possibility of endophthalmi­tis, intraocular steroid injections pose significant risks of glaucoma and cataract progression. Re­searchers have continued their effort to develop effective treatment for DME with a more advan­tageous risk profile.

Subthreshold laser development

Conventional ETDRS focal laser treatment uses a continuous wave (CW) laser, where the clinical endpoint is a visible retinal burn.6

The mechanism of action involves the laser ra­diation absorption primarily by melanin in the retinal pigment epithelium and choroid, where it is converted into heat. This heat may spread to adjacent tissues, increasing the risk of causing collateral thermal damage.7 The size of the laser scars increases over time.8

If such laser burns are placed too close to the fovea, risk of central vision loss may increase. Even with properly per­formed CW focal laser treatment, there can be loss of contrast sensi­tivity and/or visual field.

With the development of sub­threshold (ST) laser treatment— which breaks the laser exposure into a train of brief subpulses—ther­mal injury is reduced while still inducing the outer retinal metabo­lism.9 There is also evidence that this approach decreases the collateral damage.10


In 2009, a study comparing ST micropulse laser treatments with CW focal laser for CSME showed the ST treatment proved to be equally effective with less reti­nal scarring.11

In 2011, a randomized controlled study of 123 patients showed greater improvement in func­tional and anatomical outcome measures with high-density ST micropulse laser treatment com­pared with the modified ETDRS focal/grid laser.12

Based on these results, ST laser therapy could provide an adjunctive treatment option for pa­tients with CSME, with a safer risk profile com­pared with the standard ETDRS CW focal laser treatment or anti-VEGF or steroid injections alone.

For CSME treatment, my colleagues and I have been offering the addition of ST laser therapy com­bined with CW focal laser treatment where indi­cated, in hopes of reducing the number of intra­vitreal injections patients may need while main­taining excellent visual and anatomic outcomes.

Study: Adjunctive treatment with ST laser therapy

With institutional review board approval, we per­formed a retrospective chart review of patients with at least 6 months follow-up after adjunctive treatment with the ST laser.

Endpoints included best-corrected visual acuity (BCVA) (in logMAR), central foveal thickness (CFT), and macular vol­ume. Values were reported at base­line and at a 6-month follow-up.

In addition, the number of in­travitreal injections during the 6 months before baseline was com­pared with the number of treat­ments (intravitreal injections and/ or additional lasers) during the 6 months after baseline. All statistics were performed with a spreadsheet program (Microsoft Excel).

Means before and after baseline were compared with paired t tests.

All treatments were performed using a laser (Smart532, Lumenis) featuring a multi-wavelength photocoagulator with green wavelengths.

In eyes with focal extrafoveal leakage on fluo­rescein angiography, extrafoveal microaneurysms were treated in the CW mode; the laser signal consisted of a single pulse with a duration of 50 to 100 msec.

The spot size was 50 to 100 μm. Power was titrated to obtain a light-gray endpoint, usually between 90 to 140 mW.

Areas of leakage identified on fluorescein an­giography and thickening on optical coherence tomography (OCT) were treated with ST laser ther­apy, using the SmartPulse mode.

In this mode, each pulse consisted of a train of brief (100 ms) subpulses, delivered at a duty cycle of 5%, with a 200-μm spot size.

A titration procedure was also performed to determine the power.

Starting in the CW mode, a single spot was applied in an extrafoveal area, using an initial power of 80 mW and gradually increasing it until a gray response was obtained.

Next, the laser was switched to SmartPulse mode, and the power was multiplied by 3 (up to a maximum of 400 mW). With these settings, the tissue reaction was subthreshold. A scanner was used to deliver 3 x 3 patterns with a spacing of 0.25 spot size. Patterns were overlapped to en­sure contiguous treatment.

During the 6 months after baseline testing, eyes were evaluated to determine whether they were stable or improving or if further treatment was needed.

Additional treatment could be an intravitreal anti-VEGF, a steroid injection, or an additional ST laser treatment.

Outcomes suggest possible benefits of ST laser therapy

Twenty eyes of 15 patients with DME had 6-month follow-up after ST laser treatment (Table 1). Six eyes (30%) had proliferative diabetic retinopa­thy, and 14 (70%) had nonproliferative diabetic retinopathy.

In 18 eyes (90%), there was a history of prior intravitreal injections, and 12 eyes (60%) had re­ceived focal laser treatment.

In the 6 months prior to baseline, 15 eyes (75%) were treated with 3.07 ± 0.96 (mean ± SD; range, 1-4) anti-VEGF injections. Two eyes (10%) were treated with 1 steroid injection each. For the en­tire cohort of 20 eyes, the average number of in­travitreal injections (anti-VEGF or steroids) was 2.4 ± 1.64.

Outcome measures at baseline and final 6-month follow-up are shown in Table 2. BCVA and CFT remained stable (P = .584 and P = .478, respec­tively), while macular volume decreased by 3% (P <.05).

The number of anti-VEGF injections decreased by 72%, from 2.3 to 0.65 (P <.001), and the total number of intravitreal injections decreased by a similar proportion, from 2.4 to 0.7 (P <.001). In 2 cases, additional ST laser treatments were given after the baseline.

For a fair comparison, we tallied any treatments given during these 2 periods, including both types of injections and ST laser therapy. The number of treatments significantly decreased by 67%, from 2.4 to 0.8 (P <.001). No adverse events or com­plications were observed.

CFT indicates central foveal thickness; SD, standard deviation; VEGF, vascular endothelial growth factor.

Figure 1, on Page 20, shows OCT scans of a 56-year-old male with a history of stroke and non­proliferative diabetic retinopathy/DME in his left eye, with a BCVA of 20/50 at presentation. The CFT was 270 μm with intraretinal fluid.

In the 6 months before baseline, his eye was treated with 2 ranibizumab injections (Lucentis, Genentech). At baseline, extrafoveal microaneu­rysms were treated focally with a CW laser, and then the central DME was treated with ST laser therapy.

With no additional injections, at the 6-month follow-up, the patient’s BCVA improved to 20/40 and the CFT decreased 15% to 229 μm. On OCT, the intraretinal fluid was essentially resolved.

Future outlook for ST laser therapy

In this retrospective study of patients with DME treated with the Lumenis Smart532 laser, there was a good safety profile.

Following treatment, the number of injections decreased by more than half, while visual acuity and central retinal thickness were maintained. This decrease in treatment burden is encourag­ing for patients.

Most studies of anti-VEGF treatment for CSME (eg, RISE/RIDE,13 RESTORE,14 VISTA/VIVID,15 and PROTOCOL T of the Diabetic Retinopathy Clinical Research network16) excluded patients with very good vision and/or with mild macular edema.

ST laser therapy is of particular interest for in­vestigators in light of Diabetic Retinopathy Clini­cal Research Protocol V. Patients with 20/25 or better vision and CSME treated with observation only, CW focal laser, or aflibercept (Eylea, Regen­eron) showed no significant differences in visual acuity at 2 years, but there was a trend toward better vision with laser or aflibercept, compared with observation.17


Given the excellent safety profile of the ST laser, this may be a reasonable treatment approach in such patients, either alone or in combination with a CW focal laser.

It is encouraging to find that ST laser therapy may help reduce the treatment burden for pa­tients with DME by decreasing the number of intravitreal injections needed, while maintain­ing visual acuity.

Randomized prospective studies are needed to further elucidate the merits of this approach.

1. Early treatment diabetic retinopathy study research group. Early treatment diabetic retinopathy study report number 1. Arch Ophthalmol. 1985;103:1796-1806.
2. Elman M, Ayala A, Bressler N, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: 5-year randomized trial results. Ophthalmology. 2015;122:375-381.
3. Wells J, Glassman A, Ayala A, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372:1193-1203.
4. Singer M, Dugel P, Fine H, Capone AJ, Maltman J. Real-world assessment of dexamethasone intravitreal implant in DME: findings of the prospective, multicenter REINFORCE study. Ophthalmic Surg Lasers Imaging Retina. 2018;49:425-435.
5. Augustin A, Bopp S, Fechner M, et al. Three-year results from the Retro-IDEAL study: real-world data from diabetic macular edema (DME) patients treated with ILUVIEN (0.19 mg fluocinolone acetonide implant). Eur J Ophthalmol. 2019.
6. Mainster M. Decreasing retinal photocoagulation damage: principles and techniques. Semin Ophthalmol. 1999;14:200-209.
7. Desmettre T, Mordon S, Buzawa D, Mainster M. Micropulse and continuous wave diode retinal photocoagulation: visible and subvisible lesion parameters. Br J Opthalmol. 2006;90:709-712.
8. Schatz H, Madeira D, McDonald H, Johnson R. Progressive enlargement of laser scars following grid laser photocoagulation for diffuse diabetic macular edema. Arch Ophthalmol. 1991;109:1549-1551.
9. Yu A, Merrill K, Truong SFK, Morse LTD. The comparative histologic effects of subthreshold 532- and 810-nm diode micropulse laser on the retina. Invest Ophthalmol Vis Sci. 2013;54:2216-2224.
10. Jain A, Blumenkranz M, Paulus Y, et al. Effect of pulse duration on size and character of the lesion in retinal photocoagulation. Arch Ophthalmol. 2008;126:78-85.
11. Figueira J, Khan J, Nunes S, et al. Prospective randomised controlled trial comparing sub-threshold micropulse diode laser photocoagulation and conventional green laser for clinically significant diabetic macular oedema. Br J Ophthalmol. 2009;93:1341-1344.
12. Lavinsky D, Cardillo J, Melo LJ, Dare A, Farah M, Belfort RJ. Randomized clinical trial evaluating mETDRS versus normal or high-density micropulse photocoagulation for diabetic macular edema. Invest Ophthalmol Vis Sci. 2011;52:4314-4323.
13. RIDE and RISE Research Group. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. 2013;120:2013-2022.
14. Mitchell P, Bandello F, Schmidt-Erfurth U, et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118:615-625.
15. Heier J, Korobelnik J, Brown D, et al. Intravitreal aflibercept for diabetic macular edema: 148- week results from the VISTA and VIVID studies. Ophthalmology. 2016;123:2376-2385.
16. Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness Randomized Clinical Trial. Ophthalmology. 2016;123:1351-1359.
17. Diabetic Retinopathy Clinical Research Network. Effect of initial management with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular edema involving the center of the macula and good visual acuity: a randomized clinical trial. JAMA. 2019;321:1880-1894.


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Dr Merrill is a partner at Illinois Retina Associates, as well as associate professor and section director for uveitis, Rush University, Chicago. She has received numerous honors, including the American Academy of Ophthalmology Achievement Award and the American Society of Retina Specialists Senior Honor Award.

Dr Merrill reports research grants/funding from Gilead, Lumenis, the National Eye Institute, and Santen, and has served as a consultant with Alimera Sciences, Genentech, Graybug, Lumenis, and Santen. The author thanks Yair Manor, PhD, clinical director, BU Vision, for his assistance with the study and statistical analysis.

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