Perspective on Visible Light Therapy As Prophylaxis Against DR
In the January/February 2014 issue, Geoffrey B. Arden, PhD, FRCOphth, eloquently summarized the case for the role of retinal hypoxia, and particularly the possible influence of increased oxygen demand dark-adapted rod photoreceptors generate in the pathogenesis of diabetic retinopathy (“Phototherapy for Diabetic Eye Disease,” pages 22-29). Pursuing this theory to its logical conclusion, he suggests diabetics therapeutically avoid dark adaptation to slow and even reverse the progression of DR.
Employing ideal visible light wavelengths to avoid light toxicity and sleep disturbance to minimize the potential for adverse treatment effects, he suggests light therapy as a preventive treatment for DR. This is an interesting theory worthy of further investigation, as we cannot have too many useful options in the treatment of DR.
Dr. Arden recognizes that despite the wide availability of new potent pharmacologic agents to treat DR and continued judicious use of retinal photocoagulation, management of the sight-threatening complications of DR remains unsatisfactory.
Due to the risks and adverse effects of these effective therapies, not to mention expense, they cannot be well used as preventive treatments in asymptomatic diabetics who have not yet developed visual loss or “clinically significant” or “high-risk” DR.
He notes that the difficulties we continue to have, despite modern advances, in improving and preserving normal visual function in DR suggest strongly that our focus should move to earlier, prophylactic treatments, aimed at preventing visual loss. Many others join him in this opinion.1,2
But what is “early”? In general, chronic physiologic dysfunction precedes anatomic derangement. Thus, with all due respect to the ETDRS, even “mild” nonproliferative DR actually represents advanced disease with end-organ damage. Thus, the risks of treatment (such as argon laser photocoagulation), as much as the physical findings, defined “early” in the ETDRS as now. 3
It is clear, then, that to intervene prior to the development of clinical DR and visual loss, effective measures must be developed that have, ideally, no treatment risks or adverse effects. Light therapy as proposed by Dr. Arden may be one. What about subthreshold diode micropulse (SDM) laser, which Dr. Arden singled out as suggesting a gap in the hypoxia theory he proposes?
Before we get to SDM, we should note other therapeutic approaches based on the theories Dr. Arden described. Short-pulse continuous-wave lasers, such as the PASCAL, aim to reduce retinal oxygen demand by selective destruction of retinal photoreceptors.
As with conventional thermal argon laser photocoagulation, it works.4 But at what cost? Even if selective destruction of photoreceptors can improve DR, is it not somewhat oxymoronic that we intentionally sacrifice the vehicles of vision to preserve vision?
The RPE, not mentioned by Dr. Arden, is increasingly appreciated as the most influential part of the retina in DR, mediating the retinal response to diabetes via elaboration of innumerable cytokines, known and unknown, including VEGF and PEDF. 2
HURTING TO HELP
Ultra short-pulse continuous-wave lasers now offer treatment consisting of selective destruction of the RPE while largely sparing photoreceptors.5 It works, too. However, this approach must solve the same philosophic problems as selective photoreceptor destruction.
In both, tissue damage occurs, as does at least temporary breakdown of the blood-retinal barrier. Healing is by debridement and filling in from adjacent tissue, not regeneration of new replacement elements. Retinal function is lost, and inflammation, however slight, is incited; the potential for retreatment is limited.
Thus, while even these minimally destructive approaches might be justifiable relative to the risk of visual loss in the untreated diabetic eye or the adverse effects of conventional photocoagulation, neither appears suitable — as inherently damaging to the retina — as an early treatment to prevent DR.
SDM LASER THERAPY
So we can now treat DR with full-thickness chorioretinal ablation (ETDRS photocoagulation), selective photoreceptor destruction, selective RPE destruction, and possibly simply avoidance of dark adaptation. All may conceivably function, at least in part, by reducing retinal oxygen demand, as Dr. Arden described. What about SDM?
As Dr. Arden pointed out, SDM is the notable exception. With SDM the RPE is selectively treated but not damaged in any currently detectable way (“low-intensity” treatment). 6
Subthreshold diode micropulse treatment actually improves retinal sensitivity by microperimetry at the locus where the treatment is applied.7 The neurosensory retina does not absorb SDM, ideally via an 810-nm laser, so it has no direct effect on photoreceptors.
By exclusion, then, SDM appears to work by sustainably influencing the treated, preserved, and viable RPE cells to normalize cytokine expression. The “high-density” treatment (recruitment) of all of the RPE in areas of retinal pathology to achieve a therapeutic effect maximizes the “low-intensity” treatment effect. 6
Subthreshold diode micropulse has been demonstrated as clinically effective in the treatment of DR and other disorders in the absence of any known risk or adverse treatment effect.6-8 SDM can be safely treat the fovea in eyes with fovea-involving DME and 20/20 vision to eliminate DME and decrease the risk of vision loss. 9-10
A randomized clinical trial found SDM superior to ETDRS photocoagulation, with results comparable to anti-VEGF therapy. 11
In a retrospective study, SDM panretinal photocoagulation appeared to arrest the progression of DR without any treatment associated retinal damage or adverse effect 12 — all of this, without directly affecting retinal oxygen demand.
It has become clear that all therapeutically effective treatments for DR also slow, arrest, or reverse DR severity.1,2 This should surprise no one. However, only one therapeutically effective treatment — SDM — has been shown to do this in the absence of any retinal damage or any adverse treatment effect or treatment risk. 6-12
The future of DR management lies in prevention. Light therapy, as Dr. Arden proposed, may be one such strategy. More will certainly emerge.
However, SDM has been shown in more than 13 years of clinical practice and multiple studies to be effective and clinically harmless (without known risk or adverse treatment effect) in the treatment of DR.
The unique safety profile of SDM makes it not only the obvious first-line treatment for DR, but also the only suitable tool available to begin the transition to preventive treatment of DR. It is available to us now.
Jeffrey K. Luttrull, MD
1. Bressler SB, Hajing Q, Melia M, et al. Exploratory analysis of the effect of intreavitreal ranibizumab or triamcinolone on worsening of diabetic retinopathy in a randomized clinical trial. JAMA Ophthlmol. 2013;131:1033-1040.
2. Kiire C, Porta M, Chong V. Medical management for the prevention and treatment of diabetic macular edema. Surv Ophthlmol. 2013;58:459-465.
3. Early Treatment of Diabetic Retinopathy Study. Photocoagulation for diabetic macular edema. ETDRS report no. 4. Int Ophthalmol Clin. 1987;27:265-272.
4. Paulus YM, Jain A, Nomoto H, et al. Selective retinal therapy with microsecond exposures using a continuous line scanning laser. Retina. 2011;31:380-388.
5. Pelosini L, Hamilton R, Mohamed M, Marshall J. Retina rejuvenation therapy for diabetic macular edema: a pilot study. Retina. 2013;33:548-558.
6. Luttrull JK, Musch DC, Mainster MA. Subthreshold diode micropulse photocoagulation for the treatment of clinically significant diabetic macular oedema. Br J Ophthalmol. 2005;89:74-80.
7. Vujosevic S, Bottega E, Casciano M, et al. Microperimetry and fundus autofluorescence in diabetic macular edema. Subthreshold micropulse diode laser versus modified Early Treatment Diabetic Retinopathy Study Laser photocoagulation. Retina. 2010;30:908-916.
8. 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;32:375-386.
9. Luttrull JK, Dorin G. Subthreshold diode micropulse laser photocoagulation (SDM) as invisible retinal phototherapy for diabetic macular edema: a review. Cur Diab Rev. 2012;8:274-284.
10. Luttrull JK, Sinclair SH. Safety of transfoveal subthreshold diode micropulse laser for intra-foveal diabetic macular edema in eyes with good visual acuity. Paper presented at: Annual meeting of the American Society of Retina Specialists; Toronto, Canada; August 28, 2013.
11. Lavinsky D, Cardillo JA, Melo LA Jr, et al. Randomized clinical trial evaluating mETDRS versus normal or high-density micropulse photocoagulation for diabetic macular edema. Invest Ophthalmol Vis Sci. 2011;52:4314-4323.
12. Luttrull JK, Spink CJ, Musch DA. Subthreshold diode micropulse panretinal photocoagulation for proliferative diabetic retinopathy. Eye. 2008;22:607-612.
Sneezing and PVD
I read with interest the article by Peter A. Karth, MD, MBA, and Theodore Leng, MD, MS, in the October 2013 issue (“Antiobiotic Controversies in Vitreoretinal Practice,” pages 22-25). I’m writing to share my thoughts on the conundrum they raised regarding the absence of an effect of recent fluoroquinolone use on rates of retinal detachment.
The obvious flaw in the study they cited by Etminan et al1 is that the risk-set sampling the authors used to select controls was based on matching age and month and year of cohort entry, with no effort to match for a similar proclivity for Valsalva maneuvers.
Valsalva maneuvers, such as coughing and sneezing, are associated with posterior vitreous detachment, which in turn is associated with retinal RD. Upper respiratory illnesses (URIs) cause coughing and sneezing, and they are also a common reason for patients to be prescribed oral fluoroquinolones.
It could be that the sneezing and coughing URI bring on are the precipitating events for a PVD that leads to RD, and it just so happens that fluoroquinolones get caught up in the statistics because the patients’ primary care doctors prescribe them for URIs.
In other words, the causal link to RD is URIs, and the association of URIs with fluoroquinolones creates a confounding link between fluoroquinolones and RD.
The absence of a causal link seems all the more likely given the observed absence of an association with recent or past fluoroquinolone use. RP
Rodger Bodoia, MD, PhD