Age-related macular degeneration (AMD) is the leading cause of blindness in industrialized countries with a reported 1.47% prevalence and 1.75 million people affected in the United States alone.1,2 More than 80% of all AMD cases manifest as the nonexudative form characterized by the presence of macular drusen without choroidal neovascularization (CNV).3 Over time, approximately 15% of patients with nonexudative AMD progress to advanced AMD characterized by severe vision loss, central geographic atrophy (GA), and / or CNV.4
Appearance of macular drusen during nonexudative AMD represents a risk of progression to advanced AMD. Given this intimate association, attempts to target this major risk factor with retinal laser treatment can be found as early as the 1970s.5–7 These clinical trials demonstrated that laser photocoagulation leads to significant reduction of drusen, but also a slight increase in the incidence of CNV and GA.8 Subthreshold laser therapy has emerged as an alternative laser delivery system designed to minimize these complications seen with conventional laser photocoagulation.
To reduce collateral damage induced by photocoagulation, subthreshold laser therapy modifies laser parameters including power, pulse duration, and repetition to reduce temperature rise in the retina. Although the exact mechanism of action of subthreshold retinal laser therapy remains to be elucidated, onset of therapeutic response is thought to involve expression of heat shock proteins, including Hsp70.9,10 Heat shock proteins act as chaperones for refolding misfolded proteins in aging cells, thereby potentially rejuvenating retinal pigment epithelium (RPE) cells and restoring their cellular function.9 In rabbit models, subthreshold therapy is found to heat the chorio-retino-RPE complex above the onset of therapeutic response by heat shock proteins but below the threshold of retinal tissue damage.10
In preliminary clinical studies, subthreshold retinal laser therapy has shown efficacy in the treatment of central serous chorioretinopathy,11 diabetic macular edema,12–16 macular edema secondary to retinal vein occlusion,17 and macular telangiectasia.10 This review summarizes trends in clinical outcomes and treatment methodologies among peer-reviewed publications that evaluated subthreshold retinal laser therapy as prophylactic treatment of nonexudative AMD.
Patients and Methods
This systematic review was conducted according to PRISMA guidelines.18 The PubMed, Medline, and Embase databases were searched for all English language articles containing varying combinations of the terms “subthreshold,” “non-damaging,” “laser,” “macular degeneration,” “age-related macular degeneration,” and “age-related maculopathy.” Relevant articles were also selected from the references of identified articles. As of April 2018, a broad search resulted in 1,373 peer-reviewed publications from January 1997 to April 2018, among which 12 relevant articles were eligible for systematic review.19–30 Only manuscripts that described the attempted use of subthreshold retinal laser therapy to prevent the progression of nonexudative AMD were included. All other manuscripts were excluded. Articles were analyzed qualitatively based upon study design, treatment parameters, adverse outcomes, and therapeutic effectiveness as measured by drusen reduction, changes in visual acuity (VA), and development of CNV or GA.
Two independent authors selected the articles and graded the strength of the clinical data based on the Oxford Centre for Evidence-Based Medicine's “Levels of Evidence 2 Table”.31 The authors resolved any discrepancies in a joint discussion. Drusen reduction was evaluated based on the investigators' definition. Change in VA was determined by a gain or loss of letters / lines as determined by ETDRS or Snellen, or by numerical report of logMAR. Development of CNV and GA was evaluated based on their respective incidence during the follow-up period. Study level bias was assessed using the latest version of the Cochrane Risk of Bias 2.0 and ROBINS-I tools. All data were extracted by the authors and recorded on an electronic data collection sheet.
This systematic review analyzed 12 peer-reviewed publications (Table 1), exploring the effect of various forms of subthreshold laser therapies on AMD, representing a total of 1,603 patients and 2,481 eyes studied. The types of studies ranged from randomized clinical trials (82.8%, eyes n = 2,055) to prospective, nonrandomized, interventional case series (10.5%, eyes n = 260) and retrospective case series (6.7%, eyes n = 166). Several studies adopted a unilateral design that included one eye of each patient.22,23,28 Some studies adopted a bilateral design wherein both eyes of participants were included in the study with one eye randomly allocated to treatment and the fellow eye to the other group.20,21,24–27,29 Other studies had a mixed design in that both eyes of some participants were evaluated and only one eye of the remaining participants was retrospectively studied.19,30
Overview of the Studies
The inclusion criteria of the studies varied. All of the prospective studies recruited patients aged 50 years or older except the study by Scorolli et al., which recruited patients 55 years or older.21 The majority of prospective studies included patients with at least five or 10 medium (> 63 μm) or large (> 125 μm) drusen in the study eye if unilateral in design or both eyes if bilateral in design. The minimum VA ranged from 20/25,21,23 20/60,25,27 or 20/6319,20,22,24,28 to 20/100.21 Other inclusion criteria characterizing the majority of prospective unilateral study groups included neovascular lesion in the non-study eye (CNV, pigment epithelial detachment [PED], tear of the RPE, or fibrovascular scar).
The exclusion criteria common to most of the bilateral study groups was that neither eye was to have CNV, PED, or other ocular conditions likely to compromise VA or contraindicate application of laser treatment. Patients with the presence of GA were completely excluded in some bilaterally designed studies, whereas other studies adopted more liberal exclusion criteria ranging from excluding patients if they had GA within 500 μm of the foveal center, more than 1 Macular Photocoagulation Study disc area in size, or if the edge of the GA was closer than 750 μm from the foveal avascular zone. A notable exception was the study by Prahs et al., which specifically enrolled patients with nonexudative AMD with existing GA in order to evaluate whether laser therapy slows GA progression.26
Table 1 also details the highly variable laser parameters from studies analyzed in this review. Six studies employed the subthreshold pulsed 810-nm infrared diode laser (IRIS Medical OcuLight SLx; Iridex Corporation, Mountain View, CA) and, except for one study, all treated with 48 mean number of laser spots, a spot size of 125 μm, and laser burn duration of 0.10 seconds.19–22,24,29 Luttrull et al. used the same 810-nm infrared diode laser, but applied 1,800 to 3,000 spots to “paint” the entire posterior retina.30 All other studies preferred scattering several laser spots throughout the posterior retina rather than completely covering it. Scorolli et al. employed the argon 514-nm green laser and the subthreshold pulsed 810-nm infrared diode laser, but data for the subset of patients treated with the argon 514-nm green laser were excluded from this review because its treatment endpoint resulted in a suprathreshold visible gray lesion.21 Frennesson et al. attempted subthreshold treatment with the argon 514-nm green laser with a mean number of 100 spots, spot size of 200 μm, and laser burn duration of 0.05 seconds.23 Nili-Ahmadabadi et al. used a G KTP 532-nm laser (ARC Laser Gmblt, Nürnberg, Germany) with a mean number of 48 spots, 100 μm spot size, and 0.10 second laser burn duration.25 Guymer et al. and Jobling et al. employed the 2RT nanosecond 532-nm laser (Ellex, Adelaide, SA, Australia) with a mean number of 12 spots, 400 μm spot size, and three nanosecond laser burn duration.27,28 Prahs et al. used a prototype 527-nm micropulse laser (Medical Laser Center Lübeck, Lübeck, Germany) with 30 pulses per GA spot at 200 nanosecond laser burn duration.26
Seven of the eight prospective studies assessed drusen reduction and found that treated eyes experienced more drusen reduction as compared with the control eyes (Table 2).19–22,24,25,27,28 Seven studies measured drusen reduction by the decrease of its surface area,19,20,22,24,25,27,28 and one study measured drusen reduction based on number count.21 Four studies quantified the percent of treated and control eyes with drusen reduction and reported P values showing a significant difference in reduction (P < .05).19,20,24,28 Scorolli et al. did not quantify the percentages of drusen reduction but reported a significantly higher percentage of drusen reduction in the treated group (P < .001).21 Neither of the retrospective studies assessed drusen reduction.29,30
VA was assessed in nine of the 12 studies analyzed in this review, as summarized in Table 3. Five of these nine studies revealed no statistically significant difference (P < .05) in VA between treatment and control groups.20,22,23,25,30 Four of the eight studies showed better VA outcomes in the treated group as compared with the observed group.19,21,24,27 Olk et al. observed a significant increase in the proportion of patients with a gain in VA at 24 month follow-up.19 Scorolli et al. similarly observed that subthreshold treatment led to a significantly larger percentage of patients with improved acuity along with a significant decrease in the percentage of patients with vision loss.21 Friberg et al.'s study in 2006 showed a higher rate of VA loss at 3 months of follow-up relative to observed eyes (P = .02), but this difference in VA was not significant after 36 months (P = .52).22 Friberg et al.'s 2009 study revealed a modest VA benefit in treated eyes at 24 months (P = .04), but this was statistically insignificant at 36 months (P value not reported).24
The occurrence of CNV as detailed in Table 4 was evaluated in nine of the 12 studies. In three of these nine studies, no eyes developed CNV during the follow-up period.20,25,27 Three of the eight studies reported a greater number of laser-treated eyes with development of CNV as compared with observed eyes, but the difference was not statistically significant in any of these three studies.22–24 Scorolli et al. had only one treated patient develop CNV versus four control patients who developed CNV, but the authors did not provide a statistical calculation for the significance of the difference.21 Olk et al. similarly saw a decrease in CNV incidence among treated eyes, but this difference was not significant.19 Jobling et al. showed that while none of the laser-treated eyes developed CNV, 9% of the observed eyes did develop advanced AMD as determined by development of CNV or GA (percentages of CNV and GA not detailed).28
As illustrated in Table 5, the occurrence of GA was not reported in the majority of studies analyzed herein. Of the three studies from which data regarding the development of GA could be extracted, two studies showed reduced development of GA in the treated eyes.21,27 Scorolli et al. noted 3.9% of treated eyes developing central GA compared with 14.0% in the control arm.21 Guymer et al. reported no instances of GA in the treated group, but two control eyes developed GA by the 12-month follow-up.27 However, both of these authors did not report associated P values, and thus statistical significance of the difference between the treatment and control groups could not be ascertained. Jobling et al. reported 8% of treated eyes developed GA but did not make a comparison with GA development in the control group.28 Incidence of geographic atrophy in the Prahs et al. study is not included in Table 5 because its inclusion criteria selected for participants with preexisting GA. Atrophy in laser-treated eyes progressed 58% faster than control eyes, but this difference was not found to be significant (P = .132).26
Other notable outcomes assessed in these studies include the effect of mild laser treatment on pigment epithelial thickness, retinal structure, and outer retina (RPE and retinal photoreceptors). Jobling et al. found that retinal structure was not compromised in human retina after laser treatment, with only a discrete RPE injury.28 Mojana et al. assessed for abnormalities in the reflectivity of outer retinal layers as seen with spectral domain optical coherence tomography/scanning laser ophthalmoscopy (SD-OCT/SLO). They found a focal discrete disruption in the reflectivity of outer retinal layers in 29% of laser-treated eyes. The junction between the inner and outer segment of the photoreceptor was more frequently affected, with associated focal damage of the outer nuclear layer.29
In a recently published Cochrane review,8 four subthreshold laser studies were compared to assess prevention of progression toward advanced AMD. The Cochrane review concluded that photocoagulation targeting drusen was effective for reducing the amount of drusen but does not provide benefits for vision nor prevent CNV or GA development.8 However, the authors acknowledged that their evaluation was limited due to the low number of subthreshold studies reviewed. In this review, an additional eight studies using subthreshold laser are included, with the most recent study (Luttrull et al.) having been published in 2016.20,21,25–30 This review differs from the Cochrane review by assessing subthreshold studies independent of conventional laser studies. Furthermore, given the variability in the treatment methods among the 12 studies, this review is also the first to evaluate trends in subthreshold laser treatment application that suggests its safety and efficacy.
Although few studies have treated AMD patients with subthreshold laser, the 12 studies identified in this review confirm the short-term efficacy of subthreshold laser therapy in reducing drusen among nonexudative AMD patients. All short-term studies with follow-up periods up to 24 months demonstrated statistically significant treatment of drusen.19,21,22,24,25,27,28 Subthreshold retinal laser therapy can therefore be considered effective for reducing drusen for the first 2 years after treatment. Extending beyond 24 months, Nili-Ahmadabadi et al. did not find a significant difference in drusen burden after 30 months when using the G KTP 532-nm laser.25 However, the authors did note a general decreasing trend of drusen incidence over time among laser-treated eyes as compared with an increasing incidence trend among untreated control eyes.25 The long-term effect of subthreshold treatment on drusen reduction remains inconclusive due to the scarcity of studies that track drusen load beyond 2 years.
In terms of clinically meaningful endpoints (visual acuity, CNV, GA), most studies failed to find a significant difference in VA between treated and control groups.22,23,25,27,30 However, there appears to be a relationship between drusen reduction and VA benefits in the three studies that reported significance.19,21,24 Between these three, Scorolli et al. reported decreased loss of acuity in treated eyes, Friberg et al. reported increase in best-corrected VA in treated eyes, and Olk et al. reported both a decreased loss of acuity and increased gain of acuity in treated eyes.19,21,24 These three studies also represent three of five total studies that found significant drusen reduction after subthreshold treatment. The remaining two studies that reported significant drusen reduction either did not monitor VA during follow-up or did not find significant changes in VA.20,28 It is possible that significant visual benefits occur only if substantial drusen is cleared by laser treatment.
The application of subthreshold retinal laser therapy did not reduce the overall incidence of CNV. Three studies observed a decrease in CNV events among treated eyes, whereas three others observed an increase in CNV events.19,21–24,28 However, the possibility of iatrogenic burns may explain the increased development of CNV in several studies. Frennesson et al.'s 2009 study and Friberg et al.'s 2006 study occasionally produced barely visible lesions that may have sufficiently stimulated CNV formation.22,23 Friberg et al.'s 2006 study specifically qualified their finding by suggesting that the early incidence of CNV among their treated patients was likely due to iatrogenic burns.22 In addition to the increased risk of CNV by visible lesions, their unilateral study was further complicated due to its inclusion of patients who already had exudative AMD in the fellow eye. In their subsequent paper in 2009, the authors believe that eyes with exudative AMD have a more fragile Bruch's membrane, which is more likely to suffer tissue damage even with subthreshold treatment.24
The delay of central GA onset by subthreshold laser therapy cannot yet be determined from the three studies that tracked GA. The treated groups of two studies demonstrated reduced occurrences of GA, but the significance of the results is unknown.21,27 Prahs et al. applied subthreshold laser in six eyes with GA from AMD, and laser treatment showed an insignificantly higher rate of GA progression in treated eyes when compared with untreated fellow eyes.26 More data are required to make a conclusion on the efficacy of subthreshold laser in preventing central GA.
Aside from the incidence of CNV, there were no reports of subthreshold laser causing adverse events such as constricted visual field, decreased night vision, choroidal detachment, corneal or lens opacification, or macular edema.32,33 Of the 2,481 treated eyes, only one patient experienced an adverse ocular event: Guymer et al. reported a patient who developed a dot hemorrhage during the titration phase when 0.45 mJ was applied.27 The maximal laser energy was then limited to 0.3 mJ for the remaining patients with no further reports of adverse events. Funduscopy was also performed in most studies after laser treatment to verify the absence of laser spots. However, Mojana et al. found via spectral-domain optical coherence tomography / scanning laser ophthalmoscopy (SD-OCT/SLO) that permanent photoreceptor loss had occurred in 29% of treated eyes.29 Their observation of photoreceptor damage after treatment serves as a caution for future clinical trials, which should seek to achieve truly subthreshold therapy as determined by adaptive optics.
Although the main objective of this review was to summarize the overall suitability of subthreshold therapy in delaying advanced AMD, the numerous laser parameters utilized by the 12 studies make it additionally necessary to evaluate the results with respect to the laser employed. Five studies employing the subthreshold 810-nm infrared diode laser monitored drusen load, and four reported significant drusen reduction in treated eyes.19–21,24 The fifth study also found substantial drusen reduction in the treated arm but did not report whether the difference was significant.22 Furthermore, the only studies that found significant visual benefits after subthreshold treatment all utilized the 810-nm diode laser with a mean number of 48 spots, 125 μm spot size, and treatment duration of 0.1 seconds.19,21,24 These results demonstrate promise in implementing subthreshold therapy with the 810-nm laser, and its adoption over the traditional 514-nm argon thermal photocoagulation laser may be preferred due to the theoretical advantage of the 810-nm laser to selectively target the RPE layer without damaging the neurosensory retina.29 Sato et al. also documented fewer breakdown of the blood-retinal barrier with the 810-nm laser due to its greater tissue penetration; breakdown of the blood-retinal barrier has been associated with increased proliferative vitreoretinopathy.34,35
A direct comparison, however, is not possible in this review due to the lack of studies that have attempted subthreshold treatment with the argon 514-nm laser. Large clinical trials by the Choroidal Neovascularization Prevention Trial Research Group, Complications of Age-related Macular Degeneration Prevention Trial Research Group, and Drusen Laser Study Group failed to slow AMD progression or elicit visual benefits with suprathreshold argon laser treatment.36–38 The only ongoing subthreshold argon study (Frennesson et al.) was halted prematurely as a result of these findings, and no study has since replicated subthreshold therapy with the argon laser.23
Similar to the 810-nm infrared diode laser, the 2RT 532-nm nanosecond laser selectively targets the RPE with the added benefit of delivering low-energy pulses in the nanosecond range.27 Nanosecond therapy vaporizes melanosomes and forms microbubbles that lead to RPE destruction without damaging the surrounding retina.39 Use of the 2RT 532-nm laser, along with the G KTP laser of the same 532-nm wavelength, yielded no CNV development in any treated eye.25,27,28 Although the 810-nm laser studies appear to provide visual benefits in nonexudative AMD patients, the 532-nm laser studies may be prophylactic against exudative lesions. The significance of this prophylaxis was not reported in these three studies. Thus, future trials with the 532-nm are needed to assess its potential in preventing CNV. A multicenter, randomized clinical trial using the 2RT 532-nm nanosecond laser to slow AMD progression is currently underway (NCT01790802).40
The results of these 10 studies emphasize the importance of accurately and objectively establishing threshold to prevent damage to the retina. To address this concern, the EndPoint Management (EpM) protocol was developed as a computational model-based titration algorithm that reliably optimizes laser parameters to yield reproducible therapeutic response. As performed by the physicians in the studies reviewed herein, titration to a visible retinal lesion is subjective. Instead, the EpM protocol uses a binary criterion to determine if the initial titration lesion is visible or not, and then adjusts both power and pulse duration to elicit a desired change in retinal morphology ranging from non-damaging to intense coagulative tissue effects. A study of subthreshold laser therapy titrated using the EpM protocol showed no cone cell or RPE damage via SD-OCT / SLO imaging at all time points during a 9-month period.41 Wherein the greatest challenge of subthreshold retinal laser therapy is setting the laser parameters high enough to prevent subtherapeutic treatment yet low enough to avoid damage to the RPE or neurosensory retina, the EpM algorithm may help to define the therapeutic window and standardize this form of therapy. A clinical trial (NCT02569892) utilizing the EpM protocol is currently underway at the Byers Eye Institute at Stanford University and other worldwide sites, and will provide greater clarity into the clinical benefits of drusen reduction in preventing the progression toward advanced AMD.
The studies presented in this review provide evidence that subthreshold laser therapy is effective in lowering drusen load for patients with nonexudative AMD and may improve visual acuity in patients who achieve significant drusen reduction. Standardized laser protocols that ensure subthreshold treatment and eliminate the confounding effect of retinal damage will aid in better understanding the efficacy of drusen reduction on the incidence of CNV or GA.
- Hyman L. Epidemiology of eye disease in the elderly. Eye (Lond). 1987;1(Pt 2):330–341. doi:10.1038/eye.1987.53 [CrossRef]
- Friedman DS, O'Colmain BJ, Muñoz B, et al. Eye Diseases Prevalence Research Group. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol. 2004;122(4):564–572. doi:10.1001/archopht.122.4.564 [CrossRef]
- Klein R, Davis MD, Magli YL, Segal P, Klein BE, Hubbard L. The Wisconsin age-related maculopathy grading system. Ophthalmology. 1991;98(7):1128–1134. doi:10.1016/S0161-6420(91)32186-9 [CrossRef]
- Hageman GS, Gehrs K, Johnson LV, Anderson D. Age-Related Macular Degeneration (AMD). In: Kolb H, Fernandez E, Nelson R, eds. Webvision: The Organization of the Retina and Visual System. 2008:1–54.
- Gass JD. Photocoagulation of macular lesions. Trans Am Acad Ophthalmol Otolaryngol. 1971;75(3):580–608.
- Cleasby GW, Nakanishi AS, Norris JL. Prophylactic photocoagulation of the fellow eye in exudative senile maculopathy. A preliminary report. Mod Probl Ophthalmol. 1979;20:141–147.
- Hsu J, Maguire MG, Fine SL. Laser prophylaxis for age-related macular degeneration. Can J Ophthalmol. 2005;40(3):320–331. doi:10.1016/S0008-4182(05)80075-4 [CrossRef]
- Virgili G, Michelessi M, Parodi MB, Bacherini D, Evans JR. Laser treatment of drusen to prevent progression to advanced age-related macular degeneration. Cochrane Database Syst Rev. October2015;(10):CD006537.
- Sramek C, Mackanos M, Spitler R, et al. Non-damaging retinal phototherapy: Dynamic range of heat shock protein expression. Invest Ophthalmol Vis Sci. 2011;52(3):1780–1787. doi:10.1167/iovs.10-5917 [CrossRef]
- Lavinsky D, Wang J, Huie P, et al. Nondamaging retinal laser therapy: Rationale and applications to the macula. Invest Ophthalmol Vis Sci. 2016;57(6):2488–2500. doi:10.1167/iovs.15-18981 [CrossRef]
- Wood EH, Karth PA, Sanislo SR, Moshfeghi DM, Palanker DV. Nondamaging retinal laser therapy for treatment of central serous chorioretinopathy: What is the evidence?Retina. 2017:37(6):1021–1033. doi:10.1097/IAE.0000000000001386 [CrossRef]
- Pei-Pei W, Shi-Zhou H, Zhen T, et al. Randomised clinical trial evaluating best-corrected visual acuity and central macular thickness after 532-nm subthreshold laser grid photocoagulation treatment in diabetic macular oedema. Eye (Lond). 2015;29(3):313–322. doi:10.1038/eye.2015.1 [CrossRef]
- Vujosevic S, Bottega E, 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. doi:10.1097/IAE.0b013e3181c96986 [CrossRef]
- Luttrull JK, Sinclair SH. Safety of transfoveal subthreshold diode micropulse laser for fovea-involving diabetic macular edema in eyes with good visual acuity. Retina. 2014;34(10):2010–2020. doi:10.1097/IAE.0000000000000177 [CrossRef]
- Luttrull JK, Sramek C, Palanker D, Spink CJ, Musch DC. Long-term safety, high-resolution imaging, and tissue temperature modeling of subvisible diode micropulse photocoagulation for retinovascular macular edema. Retina. 2012;32(2):375–386. doi:10.1097/IAE.0b013e3182206f6c [CrossRef]
- 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(10):1341–1344. doi:10.1136/bjo.2008.146712 [CrossRef]
- Parodi MB, Iacono P, Bandello F. Subthreshold grid laser versus intravitreal bevacizumab as second-line therapy for macular edema in branch retinal vein occlusion recurring after conventional grid laser treatment. Graefes Arch Clin Exp Ophthalmol. 2015;253(10):1647–1651. doi:10.1007/s00417-014-2845-6 [CrossRef]
- Moher D, Liberati A, Tetzlaff J, Altman DGPRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med. 2009;6(7):e1000097. doi:10.1371/journal.pmed.1000097 [CrossRef]
- Olk RJ, Friberg TR, Stickney KL, et al. Therapeutic benefits of infrared (810-nm) diode laser macular grid photocoagulation in prophylactic treatment of nonexudative age-related macular degeneration: Two-year results of a randomized pilot study. Ophthalmology. 1999;106(11):2082–2090. doi:10.1016/S0161-6420(99)90487-6 [CrossRef]
- Rodanant N, Friberg TR, Cheng L, et al. Predictors of drusen reduction after subthreshold infrared (810 nm) diode laser macular grid photocoagulation for nonexudative age-related macular degeneration. Am J Ophthalmol. 2002;134(4):577–585. doi:10.1016/S0002-9394(02)01691-4 [CrossRef]
- Scorolli L, Corazza D, Morara M, Vismara S, Lugaresi ML, Meduri RA. Argon laser vs. subthreshold infrared (810-nm) diode laser macular grid photocoagulation in nonexudative age-related macular degeneration. Can J Ophthalmol. 2003;38(6):489–495. doi:10.1016/S0008-4182(03)80028-5 [CrossRef]
- Friberg TR, Musch DC, Lim JI, et al. Prophylactic treatment of age-related macular degeneration report number 1: 810-nanometer laser to eyes with drusen. Unilaterally eligible patients. Ophthalmology. 2006;113(4):622. e1. doi:10.1016/j.ophtha.2005.10.066 [CrossRef]
- Frennesson CI, Bek T, Jaakkola A, Nilsson SEProphylactic Laser Treatment Study Group. Prophylactic laser treatment of soft drusen maculopathy: A prospective, randomized Nordic study. Acta Ophthalmol. 2009;87(7):720–724. doi:10.1111/j.1755-3768.2008.01396.x [CrossRef]
- Friberg TR, Brennen PM, Freeman WR, Musch DCPTAMD Study Group. Prophylactic treatment of age-related macular degeneration report number 2: 810-nanometer laser to eyes with drusen: Bilaterally eligible patients. Ophthalmic Surg Lasers Imaging. 2009;40(6):530–538. doi:10.3928/15428877-20091030-01 [CrossRef]
- Nili-Ahmadabadi M, Espandar L, Mansoori MR, Karkhane R, Riazi M, Ardestani E. Therapeutic effect of macular grid photocoagulation in treatment of nonexudative age-related macular degeneration. Arch Iran Med. 2007;10(1):14–19.
- Prahs P, Walter A, Regler R, et al. Selective retina therapy (SRT) in patients with geographic atrophy due to age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2010;248(5):651–658. doi:10.1007/s00417-009-1208-1 [CrossRef]
- Guymer RH, Brassington KH, Dimitrov P, et al. Nanosecond-laser application in intermediate AMD: 12-month results of fundus appearance and macular function. Clin Experiment Ophthalmol. 2014;42(5):466–479. doi:10.1111/ceo.12247 [CrossRef]
- Jobling AI, Guymer RH, Vessey KA, et al. Nanosecond laser therapy reverses pathologic and molecular changes in age-related macular degeneration without retinal damage. FASEB J. 2015;29(2):696–710. doi:10.1096/fj.14-262444 [CrossRef]
- Mojana F, Brar M, Cheng L, Bartsch DU, Freeman WR. Long-term SD-OCT/SLO imaging of neuroretina and retinal pigment epithelium after subthreshold infrared laser treatment of drusen. Retina. 2011;31(2):235–242. doi:10.1097/IAE.0b013e3181ec80ad [CrossRef]
- Luttrull JK, Margolis BW. Functionally guided retinal protective therapy for dry age-related macular and inherited retinal degenerations: A pilot study. Invest Ophthalmol Vis Sci. 2016;57(1):265–275. doi:10.1167/iovs.15-18163 [CrossRef]
- OCEBM Levels of Evidence Working Group. The Oxford Levels of Evidence 2. Oxford Centre for Evidence-Based Medicine. http://www.cebm.net/index.aspx?o=5653. Accessed December 12, 2017.
- Frank RN. Retinal laser photocoagulation: Benefits and risks. Vision Res. 1980;20(12):1073–1081. doi:10.1016/0042-6989(80)90044-9 [CrossRef]
- Fong DS, Girach A, Boney A. Visual side effects of successful scatter laser photocoagulation surgery for proliferative diabetic retinopathy: A literature review. Retina. 2007;27(7):816–824. doi:10.1097/IAE.0b013e318042d32c [CrossRef]
- Sato Y, Berkowitz BA, Wilson CA, de Juan EJ Jr, . Blood-retinal barrier breakdown caused by diode vs argon laser endophotocoagulation. Arch Ophthalmol. 1992;110(2):277–281. doi:10.1001/archopht.1992.01080140133040 [CrossRef]
- Sen HA, Robertson TJ, Conway BP, Campochiaro PA. The role of breakdown of the blood-retinal barrier in cell-injection models of proliferative vitreoretinopathy. Arch Ophthalmol. 1988;106(9):1291–1294. doi:10.1001/archopht.1988.01060140451051 [CrossRef]
- Choroidal Neovascularization Prevention Trial Research Group. Laser treatment in fellow eyes with large drusen: Updated findings from a pilot randomized clinical trial. Ophthalmology. 2003;110(5):971–978. doi:10.1016/S0161-6420(03)00098-8 [CrossRef]
- Complications of Age-Related Macular Degeneration Prevention Trial Research Group. Laser treatment in patients with bilateral large drusen: the complications of age-related macular degeneration prevention trial. Ophthalmology. 2006;113(11):1974–1986. doi:10.1016/j.ophtha.2006.08.015 [CrossRef]
- Owens SL, Bunce C, Brannon AJ, et al. Drusen Laser Study Group. Prophylactic laser treatment hastens choroidal neovascularization in unilateral age-related maculopathy: Final results of the drusen laser study. Am J Ophthalmol. 2006;141(2):276–281. doi:10.1016/j.ajo.2005.08.019 [CrossRef]
- Schuele G, Rumohr M, Huettmann G, Brinkmann R. RPE damage thresholds and mechanisms for laser exposure in the microsecond-to-millisecond time regimen. Invest Ophthalmol Vis Sci. 2005;46(2):714–719. doi:10.1167/iovs.04-0136 [CrossRef]
- Lek JJ, Brassington KH, Luu CD, et al. Subthreshold nanosecond laser intervention in intermediate age-related macular degeneration: Study design and baseline characteristics of the Laser in Early Stages of Age-Related Macular Degeneration Study (report number 1). Ophthalmol Retina. 2017;1(3):227–239. doi:10.1016/j.oret.2016.12.001 [CrossRef]
- Wood EH, Leng T, Schachar IH, Karth PA. Multi-modal longitudinal evaluation of subthreshold laser lesions in human retina, including scanning laser ophthalmoscope-adaptive optics imaging. Ophthalmic Surg Lasers Imaging Retina. 2016;47(3):268–275. doi:10.3928/23258160-20160229-10 [CrossRef]
Overview of the Studies
|Study Group (Publication Year)||Type of Study||No. of Patients(No. of Eyes)||Design of Treatment (No. of Eyes)||Laser Type||Laser Parameters|
|Olk et al. (1999)19||Randomized, Controlled, Clinical Trial*||107 (166)||Unilateral (16), Bilateral (41)||Subthreshold 810-nm infrared diode laser||Titration: Placed nasal to the optic disc, power titrated to produce a mild gray lesion, 0.2 sec duration; Treatment: Power unchanged, 0.1 sec duration, invisible lesion endpoint; Mean # spots per TX: 48; Spot Size: 125 μm|
|Rodanant et al. (2002)20||Randomized, Controlled, Clinical Trial*||50 (100)||Bilateral (50)||Subthreshold 810-nm infrared diode laser||Titration: Applied nasal to optic nerve to produce a mild gray lesion, 0.2 sec duration; Treatment: Energy kept constant, duration halved to 0.1 sec; Mean # spots per TX: 48; Spot Size: 125 μm|
|Scorolli et al. (2003)21||Randomized, Controlled, Clinical Trial*||132 (132)||Bilateral (66)||Subthreshold 810-nm infrared diode laser||Titration: Applied to the peripheral retina, 0.2 sec duration, power increased to produce a mild gray lesion; Treatment: Energy kept constant, duration halved to 0.1 sec, power halved to 150 mW; Mean # spots per TX: 48 spots; Spot Size: 125 μm|
|Friberg et al. (2006)22||Randomized, Controlled, Clinical Trial*||244 (244)||Unilateral (124)||Subthreshold 810-nm infrared diode laser||Titration: Placed outside of the macula, power titrated in 50 mW increments to produce a faint gray (threshold) lesion, 0.2sec duration; Treatment: Power unchanged, 0.1 sec duration, invisible lesion endpoint; Mean # spots per TX: 48; Spot Size: 125 μm|
|Frennesson et al. (2009)23||Randomized, Controlled, Clinical Trial*||135 (135)||Unilateral (67)||Argon 514-nm green laser (source of laser not provided)||Titration: Adjusted peripherally to the major drusen area to produce subthreshold or barely visible retinal effects; Treatment: 0.05 sec duration; Mean # spots per TX: 100; Spot Size: 200 μm|
|Friberg et al. (2009)24||Randomized, Controlled, Clinical Trial*||639 (1,278)||Bilateral (639)||Subthreshold 810-nm infrared diode laser||Titration: Placed nasal to the optic disc, 0.2 sec exposure time, power titrated to produce a barely visible tissue reaction; Treatment: Same threshold power, duration reduced to 0.1 sec; Mean # spots per TX: 48; Spot Size: 125 μm|
|Nili-Ahmadabadi et al. (2007)25||Prospective, Nonrandomized, Controlled, Clinical Trial†||18 (36)||Bilateral (18)||G KTP 532-nm laser||Titration: Placed nasal to the optic disc, 0.2 sec duration, power was increased to produce a mild gray lesion; Treatment: Power kept constant, duration decreased to 0.1 sec. Mean laser power intensity was 218 mW (range 100 to 330 mW); Mean # spots per TX: 48; Spot Size: 100 to 125 μm|
|Prahs et al. (2009)26||Prospective, Nonrandomized, Controlled, Clinical Trial†||6 (12)||Bilateral (12)||SRT 527-nm laser||Titration: 5 to 16 spots in lower vessel arcade to produce visible lesion; Treatment: Power kept between 200 to 400 μJ; Mean # spots per TX: NR; Spot Size: NR|
|Guymer et al. (2014)27||Prospective, Nonrandomized, Controlled, Clinical Trial†||52 (104)||Bilateral (52)||2RT Nanosecond 532-nm laser (source not provided)||Titration: Placed inferiorly outside the arcades until visible retinal blanching, 400 μm spot size, 3 nanosecond duration; Treatment: Laser energy was reduced by 20%; Mean # spots per TX: 12; Spot Size: 400 μm|
|Jobling et al. (2015)28||Prospective, Nonrandomized, Controlled, Clinical Trial†||108 (108)||Unilateral (50)||2RT Nanosecond 532-nm laser||Titration: Energy levels titrated to be below the visual threshold for retinal change (range 0.15 to 0.45 mJ, average energy0.24 mJ); Treatment: 3 nanosecond duration; Mean # spots per TX: 12 spots; Spot Size: 400 μm|
|Mojana et al. (2011)29||Retrospective, Case Series‡||4 (8)||Bilateral (8)||Subthreshold 810-nm infrared diode laser||Titration: NR; Treatment: Power used was one-half the power needed to produce a minimally visible threshold burn; Mean# spots per TX: 48; Spot Size: 125 μm|
|Luttrull et al. (2016)30||Retrospective, Case Series‡||108 (158)||Unilateral (133), Bilateral (25)||Subthreshold 810-nm infrared diode laser||Titration: NR; Treatment: 5% duty cycle, 1.4-W power, 0.15 sec duration; Mean # spots per TX: NR (range 1,800 to 3,000); Spot Size: 200 μm|
|Study Group||Measurement Variable||Percent of Treated Eyes with Drusen Reduction||Percent of Control Eyes with Drusen Reduction||P Value||Timing of Outcome Measurement|
|Guymer et al. (2014)†||Surface Area||44.0||22.0||NR||12 months|
|Rodanant et al. (2002)*||Surface Area||48.0||6.0||< .00001||18 months|
|Scorolli et al. (2003)*||Number Count||NR||NR||< .001||18 months|
|Friberg et al. (2006)*||Surface Area||50.0||< 1.0||NR||18 months|
|Olk et al. (1999)*||Surface Area||69.4||3.3||< .0001||24 months|
|Friberg et al. (2009)*||Surface Area||47.1||9.0||< .0001||24 months|
|Jobling et al. (2015)*||Surface Area||35.0||11.0||< .01||24 months|
|Nili-Ahmadabadi et al. (2007)†||Surface Area||NR||NR||0.50||30 months|
|Study Group||Measurement Variable||Percentage of Treated Eyes with Gain of Acuity||Percentage of Treated Eyes with Loss of Acuity||Timing of Outcome Measurement|
|Guymer et al. (2014)†||Gain / loss of ≥ 5 letters on ETDRS||Increased (P = NR)||Increased (P = NR)||12 months|
|Rodanant et al. (2002)*||logMAR||Decreased (P = .62)||Decreased (P = .57)||18 months|
|Scorolli et al. (2003)*||Gain / loss of ≥ 1 line on ETDRS||Increased (P < .001)||Decreased (P < .001)||18 months|
|Olk et al. (1999)*||Gain / loss of ≥ 2 lines on ETDRS||Increased (P < .001) unilateral and bilateral||Increased(P > .40) unilateral;(P > .05) bilateral||24 months|
|Friberg et al. (2009)*||Gain / loss of ≥ 2 lines on ETDRS||Increased (P = NR)||Decreased (P = .04)||24 months|
|Nili-Ahmadabadi et al. (2007)†||logMAR||NR||Increased (P = .30)||30 months|
|Friberg et al. (2006)*||Gain of ≥ 2 lines or loss of ≥ 3 lines on ETDRS||Decreased (P > .05)||Decreased (P = .52)||36 months|
|Frennesson et al. (2009)*||logMAR||NR||Increased(P = .17) unilateral; Decreased(P = .62) bilateral||84 months unilateral; 85 months bilateral|
|Luttrull et al. (2016)‡||Snellen||No change (P = NR)||No Change (P = NR)||NR|
|Study Group||Number of Treated Eyes With CNV||Number of Control Eyes With CNV||Percentage of CNV in Treated Group||Percentage of CNV in Control Group||P Value||Timing of Outcome Measurement|
|Friberg et al. (2006)*||15||4||15.8||1.4||.05||12 months|
|Guymer et al. (2014)†||0||0||0||0||—||12 months|
|Rodanant et al. (2002)*||0||0||0||0||—||18 months|
|Olk et al. (1999)*||4 (unilateral);0 (bilateral)||7 (unilateral);3 (bilateral)||26.7 (unilateral);0 (bilateral)||26.9 (unilateral);4.6 (bilateral)||NR, NR||24 months,24 months|
|Jobling et al. (2015)†||0||NR||0||NR||—||24 months|
|Nili-Ahmadabadi et al. (2007)†||0||0||0||0||—||30 months|
|Friberg et al. (2009)*||36||32||11||9||.63||36 months|
|Frennessonet al. (2009)*||3 (unilateral);4 (bilateral)||2 (unilateral);3 (bilateral)||23.1 (unilateral);7.4 (bilateral)||14.3 (unilateral);5.6 (bilateral)||.32 (unilateral); .28 (bilateral)||84 months,84 months|
|Scorolli et al. (2003)*||1||4||NR||NR||—||NR|
|Study Group||Percentage of GA in Treated Group||Percentage of GA in Control Group||P Value||Timing of Outcome Measurement|
|Scorolli et al. (2003)*||3.9||14.0||NR||NR|
|Guymer et al. (2014)†||0.00||0.04||NR||12 months|
|Jobling et al. (2015)†||8.0||NR||—||24 months|