Article

Subthreshold Laser Treatment of Retinal Diseases

A potential alternative for treating center-involving macular edema.

Related

Subthreshold laser treatment, which uses a segmented “low duty cycle” pulse instead of a continuous wave (CW), allows delivery of low-dose light energy to the retina. This low-energy approach could have less impact on adjacent tissue, and it may achieve treatment goals for retinal diseases such as diabetic macular edema (DME) and central serous chorioretinopathy with less collateral damage compared to traditional treatments.1-9

Subthreshold laser treatment can be an alternative for patients with center-involving DME who do not respond well to intravitreal injections of steroids or anti-VEGF therapy. When treating the center of the macula, traditional laser treatment can cause significant thermal damage that may result in permanent loss of vision. Today’s subthreshold laser therapy may offer an alternative to traditional laser treatment for treating over the central macula and fovea. Recent studies have examined the safety and efficacy of this approach with good results, but large-scale studies have not yet been completed.

RECENT STUDIES

Although subthreshold laser has been studied and used in practice for years,1-9 the precise mechanism of action is still not clear. Recent studies support the theory that low-level thermal stress activates cells in the retinal pigment epithelium (RPE) that have been affected by disease, whereas excessive thermal stress damages the cells.10,11 Another likely mechanism of action of SML is downregulation of angiogenic stimulators like VEGF-A, transforming growth factor beta, and basic fibroblast growth factor, and upregulation of angiogenic inhibitors like pigment epithelium-derived factor.12 The damage from subthreshold laser may be much less than conventional laser, evidenced by significantly higher retinal sensitivity as measured by postoperative microperimetry.13

Newer studies have shown that subthreshold laser is an effective treatment for DME based on outcome measures of best-corrected visual acuity, central macular thickness, and contrast sensitivity.14-17

In our pilot study done in 2017, we used the Smart Pulse technology of the Smart532 laser (Lumenis) to assess the safety and efficacy of subthreshold laser treatment in patients with clinically significant macular edema (CSME). Ten consecutive patients were enrolled in this prospective study. After the presence of CSME was established, we treated the area of retinal thickening with subthreshold laser treatment using a green laser wavelength (532 nm). The duration of subpulses was 100 microseconds, the duty cycle was 5%, the spot size was 200 microns, and power was titrated up to 400 mW. Treatment was delivered in square patterns of 4 x 4, one spot-width apart, using the Array LaserLink (Lumenis).

During follow-up exams at 6 weeks to 8 weeks, results were evaluated using biomicroscopy, infrared photos, fundus autofluorescence, and spectral-domain OCT. Visual acuity trended toward improvement, although this was not statistically significant. Central foveal thickness remained the same, which may be attributable to the study’s short duration given that the effects of even conventional laser can take several months.18 There were no adverse events in this small sample.

RESEARCH CHALLENGES

Many studies of subthreshold laser therapy are small, but show similar results. Future avenues of research would involve studies with larger populations and randomized, double-blinded studies. Currently, a prospective, randomized controlled trial sponsored by Sun Yat-Sen University (China) is comparing the efficacy of subthreshold lased treatment using yellow and green wavelengths (NCT02406157). The results of this study will shed further guidance on the safety and efficacy of these treatments.

In the past, if injections were not effective, the only options were to use a traditional laser that could produce lasting thermal damage to the retina or to perform an invasive procedure such as internal limiting membrane peel. Given the biochemical and physical principles of subthreshold laser, treatment using less thermal energy than a standard laser is theoretically safer. This is particularly important in DME cases involving the central fovea. This said, several factors have made widespread adoption difficult.

One barrier to research is a positive one: There are already several very effective current treatments for DME. Physicians are less likely to try new technologies on patients with good vision or minimal edema and on patients who require infrequent intravitreal treatment dosing. By limiting subthreshold laser to patients who have failed traditional therapy, the current data and experiences are based on subthreshold laser results in patients with more severe disease and worse vision who have less potential for improvement. Broader study would elucidate whether response to subthreshold laser would be better if used earlier in the progression of DME.

OUTLOOK FOR THE FUTURE

Subthreshold laser technology has advanced in recent years to offer surgeons more options and finer control. Some additional features currently in development are aimed at improving ease of use and treatment delivery for the surgeon. For example, enhanced targeting features using precise visit-to-visit registration will improve how surgeons see the treatment area and possibly automatically target it with the laser. As physicians become more comfortable with the procedure and convinced of its safety, especially relative to traditional laser for patients with DME, more retina specialists may adopt the subthreshold laser procedure. In retinal diseases, treatments should be accompanied by high-level studies to become the standard of care. While we await the results of the current prospective trial, subthreshold laser may already be an option for patients who had few options in the past. RP

REFERENCES

  1. Fazel F, Bagheri M, Golabchi K, Jahanbani Ardakani H. Comparison of subthreshold diode laser micropulse therapy versus conventional photocoagulation laser therapy as primary treatment of diabetic macular edema. J Curr Ophthalmol. 2016;28(4):206-211.
  2. Lanzetta P, Furlan F, Morgante L, Veritti D, Bandello F. Nonvisible subthreshold micropulse diode laser (810 nm) treatment of central serous chorioretinopathy. A pilot study. Eur J Ophthalmol. 2008(6);18(6):934-940.
  3. Parodi MB, Spasse S, Iacono P, Di Stefano G, Canziani T, Ravalico G. Subthreshold grid laser treatment of macular edema secondary to branch retinal vein occlusion with micropulse infrared (810 nanometer) diode laser. Ophthalmology. 2006;113(12):2237-2242.
  4. Parodi MB, Iacono P, Ravalico G. Intravitreal triamcinolone acetonide combined with subthreshold grid laser treatment for macular oedema in branch retinal vein occlusion: a pilot study. Br J Ophthalmol. 2008;92(8):1046-1050.
  5. Hoshikawa Y, Ohkoshi K, Yamaguchi T. [Retinal sensitivity following subthreshold diode laser micropulse photocoagulation for diabetic macular edema]. Nippon Ganka Gakkai Zasshi. 2011;115(1):13-19.
  6. Inagaki K, Iseda A, Ohkoshi K. [Subthreshold micropulse diode laser photocoagulation combined with direct photocoagulation for diabetic macular edema in Japanese patients]. Nippon Ganka Gakkai Zasshi. 2012;116(6):568-574.
  7. Mansouri A, Sampat KM, Malik KJ, Steiner JN, Glaser BM. Efficacy of subthreshold micropulse laser in the treatment of diabetic macular edema is influenced by pre-treatment central foveal thickness. Eye (Lond.). 2014;28(12):1418-1424.
  8. Vujosevic S, Martini F, Longhin E, Convento E, Cavarzeran F, Midena E. Subthrehold micropulse yellow laser versus subthreshold micropulse infrared laser in center-involving diabetic macular edema: morphologic and functional safety. Retina. 2015;35(8):1594-1603.
  9. Chen G, Tzekov R, Li W, Jiang F, Mao S, Tong Y. Subthreshold micropulse diode laser versus conventional laser photocoagulation for diabetic macular edema: A meta-analysis of randomized controlled trials. Retina. 2016;36(11):2059-2065.
  10. Lavinsky D, Sramek C, Wang J, et al. Subvisible retinal laser therapy: titration algorithm and tissue response. Retina. 2014;34(1):87-97.
  11. Luttrull JK, Dorin G. Subthreshold diode micropulse laser photocoagulation (SDM) as invisible retinal phototherapy for diabetic macular edema: a review. Curr Diabetes Rev. 2012;8(4):274-284.
  12. Li Z, Song Y, Chen X, Chen Z, Ding Q. Biological modulation of mouse RPE cells in response to subthreshold diode micropulse laser treatment. Cell Biochem Biophys. 2015;73(2):545-552.
  13. Vujosevic S, Bottega C, 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(6):908-916.
  14. Takatsuna Y, Yamamoto S, Nakamura Y, Tatsumi T, Arai M, Mitamura Y. Long-term therapeutic efficacy of the subthreshold micropulse diode laser photocoagulation for diabetic macular edema. Jpn J Ophthalmol. 2011;55(4):365-369.
  15. Ohkoshi K, Yamaguchi T. Subthreshold micropulse diode laser photocoagulation for diabetic macular edema in Japanese patients. Am J Ophthalmol. 2010;149(1):133-139.
  16. Nakamura Y, Mitamura Y, Ogata K, Arai M, Takatsuna Y, Yamamoto S. Functional and morphological changes of macula after subthreshold micropulse diode laser photocoagulation for diabetic macular oedema. Eye (Lond). 2010;24(5):784-788.
  17. Sivaprasad S, Sandhu R, Tandon A, Sayed-Ahmed K, McHugh DA. Subthreshold micropulse diode laser photocoagulation for clinically significant diabetic macular oedema: a three-year follow up. Clin Experiment Ophthalmol. 2007;35(7):640-644.
  18. Focal photocoagulation treatment of diabetic macular edema. Relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline: ETDRS report no. 19. Early Treatment Diabetic Retinopathy Study Research Group. Arch Ophthalmol. 1995;113(9):1144-1155.