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REVIEW ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 2  |  Page : 57-60

Laser in diabetic macular edema


Department of Ophthalmology, Kasr Elaini Hospital, Cairo University, Cairo, Egypt

Date of Submission14-Apr-2022
Date of Acceptance27-May-2022
Date of Web Publication01-Sep-2022

Correspondence Address:
Dr. Tamer A Macky
29th, 1th Street, Apt. 11 Maadi 1141, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/erj.erj_2_22

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  Abstract 


Laser photocoagulation has been an integral part of the management of diabetic macular edema (DME) for decades. And despite the dramatic changes in retinal imaging and the availability of new treatment options over the years it is still has a role in the pharmacotherapy era. First, as a supplementary treatment in eyes with CI-DME inadequately responding to antiVEGFs and steroids; to reduce the number and frequency of injections. And secondly, it is the only scientifically proven option for eyes with non CIDME with CSME features.

Keywords: Diabetic macular edema, laser, treatment


How to cite this article:
Macky TA. Laser in diabetic macular edema. Egypt Retina J 2021;8:57-60

How to cite this URL:
Macky TA. Laser in diabetic macular edema. Egypt Retina J [serial online] 2021 [cited 2022 Nov 30];8:57-60. Available from: https://www.egyptretinaj.com/text.asp?2021/8/2/57/355266




  Introduction Top


Laser photocoagulation has been an integral part of the management of diabetic macular edema (DME) for decades. However, the dramatic changes in retinal imaging and the availability of new treatment options over the years has led to an evolution of the laser role, parameters, and technique with time.


  Evolution of Laser Photocoagulation Role in Diabetic Macular Edema Top


The Early Treatment Diabetic Retinopathy Study (ETDRS) 1985 report has placed argon focal and/or grid laser therapy as the benchmark for DME.[1] Using clinical examination and fluorescein angiography (FA) as the sole retina imaging, the ETDRS has identified specific clinical criteria for treatment and FA features to guide laser and assess the visual prognosis. Patients with Clinically Significant Macular Edema (CSME), as defined by the ETDRS, were found to significantly benefit from macular laser photocoagulation by reducing the risk of moderated visual loss by 50%. CSME was defined as having any of the following; (1) Thickening of the retina at or within 500 mm of the center of the macula, (2) Hard exudates at or within 500 mm of the center of the macula, if associated with thickening of the adjacent retina (not residual hard exudates remaining after the disappearance of retinal thickening), and/or (3) A zone or zones of retinal thickening 1 disc area or larger, any part of which is within 1 disc diameter of the center of the macula. Moreover, the moderate visual loss was defined as doubling of visual angle or defined as a loss of 15 or more letters on ETDRS visual acuity charts.[1]

At the turn of the century, the availability of commercial time-domain optical coherence tomography (TD-OCT) has added another perspective for retina specialists' view of macular pathologies and hence DME.[2] This was happening at the same time with the first clinical use of intravitreal injections of steroids, triamcinolone acetonide (TA),[3] for DME showing immediate initial reduction of macular thickening on TD-OCT compared to laser photocoagulation.[4] This has led, to some extent, to a shift to intravitreal TA as the first line for many specialists for few years.

In 2008, the Diabetic Retinopathy Clinical Research Network (DRCR. net) released the results of Protocol B to address the above-raised issue between laser and TA intravitreal injections for DME.[5] Protocol B compared laser photocoagulation to two doses of intravitreal TA; 1 and 4 mg. While the 4 mg TA appeared to have a statistically significant improvement of visual acuity by 4 months compared to laser and the 1 mg group, that difference was lost by 1 year. In the 2nd year, patients who had received laser alone had a significant improvement of visual acuity compared to the two doses of intravitreal TA, an effect that continued for 3 years [Figure 1]. The visual acuity difference was not due to cataract developments in the TA groups for multiple reasons. First, there was a corresponding significant anatomical improvement for the laser group compared with the two TA groups on OCT [Figure 2]. Second, in a subanalysis to eyes that maintained clear lens through the study period and pseudophakic eyes, laser still showed statistically significant visual gains compared to the TA-injected eyes.
Figure 1: DRCR Protocol B: Mean Visual Acuity Letter Score over 3 years (in months) for the three groups: Laser, 1, and 4 mg Triamcinolone Acetonide Intravitreal Injections Groups. DRCR: Diabetic Retinopathy Clinical Research

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Figure 2: DRCR Protocol B: Mean Central Subfield (microns) over 2 years (in months) for the 3 groups: Laser, 1, and 4 mg Triamcinolone Acetonide Intravitreal Injections Groups. DRCR: Diabetic Retinopathy Clinical Research

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The DRCR Protocol B[5] has not only solidified the role of laser photocoagulation as the standard therapy at that time but also added significant information about the nature of TA response in eyes with DME. The 4 mg dose appeared to have its best response in the first 4 months and gradually that effect waned. The 1 mg TA intravitreal dose had a slower initial response compared to the 4 mg, but later, both doses had equal functional and anatomical outcomes at 2 and 3 years. On the other hand, the 1 mg group had about 50% reduction in the rate of development of cataracts and glaucoma compared to the 4 mg dose throughout the study 3 years period.

It is also worth mentioning that the use of OCT retinal imaging in that period has led the DRCR network and other studies to redefine DME. Center-Involved DME (CIDME) was the main inclusion criteria for these studies[5],[6],[7] together with diminution of vision, and hence, CIDME has become the indication for all available therapies; laser, intravitreal steroid, and/or later anti-vascular endothelial growth factor (anti-VEGFs). CIDME is defined as retinal subfield thickening; which is the 500μ radius area around the foveal center. Despite the changed definition/indication criteria for interventions to CIDME, yet the term CSME is not abandoned. In today's world, with the advent of OCT, “clinically significant” DME is now classified into CIDME and non-CIDME (non-CIDME).

DRCR Protocol I (2010, 2 years results)[6] could be considered the bases of the current management of CIDME. Protocol I investigated the benefits of adding intravitreal steroids or anti-VEGFs (ranibizumab) to the standard and first-line therapy at that time, laser photocoagulation. In addition, a crucial part of Protocol I was dividing the ranibizumab group into two separate groups; “Prompt” laser group with initial laser photocoagulation for all patients at baseline, and “Deferred” laser group with delaying laser photocoagulation to 6 months for only patients that needed it. This group of deferred laser could be practically considered a justified ranibizumab monotherapy with laser as a rescue route when at that time laser should have been the first-line therapy.

Protocol I has shown substantial visual and anatomical benefits of the two ranibizumab groups compared to the laser monotherapy and compared to the combined laser and TA injection group. However, a sub-analysis for pseudophakic patients has shown similar anatomical and functional outcomes for combined TA with laser as in the ranibizumab groups. One of the important information we learned from Protocol I was the timing of laser application. Over a follow-up of 5 years, the deferred laser group showed a significantly better visual acuity compared to those eyes that received prompt laser, an effect that was maintained. The difference between the two groups was not only about the timing of laser application but also the percentage of patients receiving laser therapy. Only 28% in the deferred group received laser compared to 100% of the prompt group at 1 year and 2 years. In addition, only 44% in the deferred group needed laser by 5 years. That means that there are substantial amount of patients with CIDME (56%) who will not need laser therapy at all and could be fully treated with intravitreal anti-VEGFs alone. Those eyes will be harmed visually by adding laser therapy and the only way to identify them is by waiting for 6 months and reassessing the response to intravitreal anti-VEGF injections.

Based on the above results, the DRCR network later designed Protocol T[7] to compare the efficacy of the available anti-VEGFs agents: aflibercept, ranibizumab, and bevacizumab. In Protocol T, patients were initiated with one of the randomly assigned drugs, and then, participants underwent follow-up examinations every 4 weeks during the 1st year and every 4–16 weeks during the 2nd year. At each visit, study eyes were assessed for retreatment with the anti-VEGF agent based on VA and OCT criteria. Starting at the 6-month visit, focal/grid laser photocoagulation was administered if DME persisted and was not improving. During the 2 years period, laser therapy was used 41%, 64%, and 52% in the aflibercept, bevacizumab, and ranibizumab groups, respectively. This protocol “initial” regimen is the closest to what is practically applied by most specialists, irrespective of later using pro re nata or treat and extend as a “maintenance” regimen.

The American Academy of Ophthalmology Intelligent Research in Sight[8] Registry (electronic health records in the United States), found in real practice DME patients were overall undertreated. The percentage of patients receiving anti-VEGFs in 1st month and 1st year were low, as well as the number of injections. Laser was found to be delivered in only 12% of patients in the 1st year.

Modified ETDRS focal/grid laser photocoagulation for non-CIDME with CSME features is also still a reasonable option for many eyes in today's world, and should be considered as the main treatment option, where intravitreal anti-VEGFs or steroid injections are lack the evidence and rationale for their use. The advent of modern ultra-widefield FA (UWF-FA) devices permits relatively easy imaging of the mid-peripheral and peripheral retina allowing detection of peripheral capillary nonperfusion. Targeted laser photocoagulation guided by UWF-FA has been suggested to decrease the treatment burden and improve visual outcomes, by reducing the VEGF vitreous level produced by the nonperfused retina.

However, studies[9],[10] have shown conflicting results which may be attributed to the inability of UWF-FA to distinguish between the ischemic retina and necrotic retina.[11] Whereas the ischemic retina will secrete VEGF, the necrotic retina is dead and no longer able to secrete VEGF. Photocoagulating dead necrotic retina will not modify intraocular levels of VEGF. In addition, there is a differential topographic density of photoreceptors across the retina.[12] There are many more photoreceptors in the posterior pole than in the peripheral retina. To decrease metabolic demand to reduce VEGF levels, one would have to target and destroy those photoreceptors in the posterior pole as well.


  Laser Photocoagulation Mechanism of Action Top


The effectiveness of focal laser treatment may be due in part to the closure of leaky microaneurysms, but the specific mechanisms by which grid photocoagulation reduces DME are not known. The effectiveness of grid treatment alone (without focal treatment of microaneurysms) supports an indirect effect of retinal photocoagulation on macular edema.[13] It is hypothesized that with reduced retina tissue, autoregulation results in decreased retinal blood flow with lower fluid flow, resulting in decreased edema.[14],[15] It is also has been suggested that the reduce retinal blood flow is due to improved oxygenation following photocoagulation.[15] Histopathologically, it was shown that changes are located in the retina and retinal pigment epithelium (RPE).[16],[17] Biochemical and physiological studies also found that the resolution of the edema may result from biochemical processes within the RPE.[18]


  Evolution of Laser Photocoagulation Techniques and Parameters Top


The original ETDRS photocoagulation protocol, although effective, required the placement of burns close to the center of the macula.[1] Over time, these laser burns develop into areas of progressive RPE and retinal atrophy that become larger than the original laser spot and encroach on fixation.[19],[20] In an attempt to reduce these adverse effects, many retinal specialists now treat using burns that are lighter and less intense than originally specified in the ETDRS (modified-ETDRS [mETDRS] technique).[20],[21]

Mild macular grid (MMG)[22] is another technique that applies mild, widely spaced burns throughout the macula, avoiding the foveal region, where some burns could be placed in the clinically normal retina if the entire retina was not abnormally thickened. The lighter burns applied to the macula are theoretically less likely to result in thermal injury to the overlying retina and less likely to break Bruch's membrane. The widespread application also might lead to improved oxygenation, the development of healthier RPE, and overall physiologic improvement of the entire macula.

The DRCR network Protocol A[22] study compared the MMG technique with the mETDRS technique in eyes with previously untreated DME, showed at 12 months of follow-up, there was no indication that the eyes treated with MMG had a better outcome than those receiving mETDRS. In fact, eyes in the mETDRS group experienced a slightly greater reduction in retinal thickening and a trend toward a slightly better visual acuity outcome.

The mETDRS laser technique used in protocol A,[22] is the one used in all DRCR clinical trial protocols (B, I, and T)[5],[6],[7] and is the currently recommended laser technique and parameters for treating DME. The mETDRS technique and parameters are described in [Figure 3].
Figure 3: Burn Characteristic for Direct/Grid Photocoagulation Modified-ETDRS Technique: (a) Treatment Area Limits: 500–3000μ superiorly, nasally, and inferiorly and 500–3500μ temporally from the macular center. No burns are placed within 500μ of disc. (b) Identifying Treatment Area: All areas with diffuse leakage or nonperfusion within the area described in (a). (c) Focal/Direct Treatment: Directly treat all leaking microaneurysms in areas of retinal thickening until change in microaneurysms color. Burn Size: 50μ. Burn Duration: 0.05–0.1 s. (d) Grid Treatment: Burn Size: 50μ. Burn Duration: 0.05–0.1 s. Burn Intensity: Barely visible (light gray) Burn Separation: 2 visible burn widths apart. Wavelength (Grid and Focal Treatment) Green to yellow wavelengths Green to yellow wavelengths. Modified-ETDRS: Modified-Early Treatment Diabetic Retinopathy Study

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  Micropulse Laser Top


In the 1990s, Friberg and Karatza,[23] developed micropulse laser, which fragments laser emission into a sequence of short (microsecond) pulses with a low duty cycle (90%+ off time). In contrast to conventional longer duration continuous-wave laser therapy, this delivers the same magnitude of energy throughout the entire exposure time (millisecond time scale) and causes significant collateral damage. Since it does not cause any visible damage, it allows for several retreatments in close proximity to the fovea. A meta-analysis of six randomized trials found superior visual outcomes with micropulse compared to conventional laser with no differences in macular thickness,[24] which may be related to decreased iatrogenic macular damage as evidenced by microperimetry.[25] A randomized clinical trial comparing both lasers is currently underway in the UK.[26]

In conclusion, the macular laser still has a role in the management of DME in the pharmacotherapy era. First, it is a supplementary option in eyes with CI-DME inadequately responding to anti-VEGFs and steroids; to reduce the number and frequency of injections. Moreover, second, it is the only scientifically proven option for eyes with non-CIDME with CSME features.

Financial support and sponsorship

Nil.

Conflicts of interest

Author doesn't have any competing interest with any material used in this study.



 
  References Top

1.
Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 1985;103:1796-806.  Back to cited text no. 1
    
2.
Hee MR, Puliafito CA, Wong C, Duker JS, Reichel E, Rutledge B, et al. Quantitative assessment of macular edema with optical coherence tomography. Arch Ophthalmol 1995;113:1019-29.  Back to cited text no. 2
    
3.
Jonas JB, Söfker A. Intraocular injection of crystalline cortisone as adjunctive treatment of diabetic macular edema. Am J Ophthalmol 2001;132:425-7.  Back to cited text no. 3
    
4.
Martidis A, Duker JS, Greenberg PB, Rogers AH, Puliafito CA, Reichel E, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology 2002;109:920-7.  Back to cited text no. 4
    
5.
Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema diabetic retinopathy clinical research network. Ophthalmology 2008;115:1447-50.  Back to cited text no. 5
    
6.
Elman MJ, Paul Aiello LP, Beck RW, Bressler NM, Bressler SB, Edwards AR, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. The Diabetic Retinopathy Clinical Research Network. Ophthalmology 2010;117:1064-77.  Back to cited text no. 6
    
7.
Wells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, Bressler SB, et al. Aflibercept, Bevacizumab, or Ranibizumab for diabetic macular edema: Two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology 2016;123:1351-9.  Back to cited text no. 7
    
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Cantrell RA, Lum F, Chia Y, Morse LS, Rich WL 3rd, Salman CA, et al. Treatment patterns for diabetic macular edema: An intelligent research in sight (IRIS®) registry analysis. Ophthalmology 2020;127:427-9.  Back to cited text no. 8
    
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Suñer IJ, Peden MC, Hammer ME, Grizzard WS, Traynom J, Cousins SW. RaScaL: A pilot study to assess the efficacy, durability, and safety of a single intervention with ranibizumab plus peripheral laser for diabetic macular edema associated with peripheral nonperfusion on ultrawide-field fluorescein angiography. Ophthalmologica. 2014. doi: 10.1159/000367902. Online ahead of print.  Back to cited text no. 9
    
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Brown DM, Ou WC, Wong TP, Kim RY, Croft DE, Wykoff CC, et al. Targeted retinal photocoagulation for diabetic macular edema with peripheral retinal nonperfusion: Three-year randomized DAVE trial. Ophthalmology 2018;125:683-90.  Back to cited text no. 10
    
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Spaide RF. Prospective study of peripheral panretinal photocoagulation of areas of nonperfusion in central retinal vein occlusion. Retina 2013;33:56-62.  Back to cited text no. 11
    
12.
Curcio CA, Sloan KR, Kalina RE, Hendrickson AE. Human photoreceptor topography. J Comp Neurol 1990;292:497-523.  Back to cited text no. 12
    
13.
Olk RJ. Modified grid argon (blue-green) laser photocoagulation for diffuse diabetic macular edema. Ophthalmology 1986;93:938-50.  Back to cited text no. 13
    
14.
Wilson DJ, Finkelstein D, Quigley HA, Green WR. Macular grid photocoagulation. An experimental study on the primate retina. Arch Ophthalmol 1988;106:100-5.  Back to cited text no. 14
    
15.
Arnarsson A, Stefánsson E. Laser treatment and the mechanism of edema reduction in branch retinal vein occlusion. Invest Ophthalmol Vis Sci 2000;41:877-9.  Back to cited text no. 15
    
16.
Tso MO, Wallow IH, Elgin S. Experimental photocoagulation of the human retina. I. Correlation of physical, clinical, and pathologic data. Arch Ophthalmol 1977;95:1035-40.  Back to cited text no. 16
    
17.
Apple DJ, Goldberg MF, Wyhinny G. Histopathology and ultrastructure of the argon laser lesion in human retinal and choroidal vasculatures. Am J Ophthalmol 1973;75:595-609.  Back to cited text no. 17
    
18.
Ogata N, Tombran-Tink J, Jo N, Mrazek D, Matsumura M. Upregulation of pigment epithelium-derived factor after laser photocoagulation. Am J Ophthalmol 2001;132:427-9.  Back to cited text no. 18
    
19.
Schatz H, Madeira D, McDonald HR, Johnson RN. Progressive enlargement of laser scars following grid laser photocoagulation for diffuse diabetic macular edema. Arch Ophthalmol 1991;109:1549-51.  Back to cited text no. 19
    
20.
Roider J. Laser treatment of retinal diseases by subthreshold laser effects. Semin Ophthalmol 1999;14:19-26.  Back to cited text no. 20
    
21.
Mainster MA, White TJ, Tips JH, Wilson PW. Retinal-temperature increases produced by intense light sources. J Opt Soc Am 1970;60:264-70.  Back to cited text no. 21
    
22.
Diabetic Retinopathy Clinical Research Network; Fong DS, Strauber SF, Aiello LP, Beck RW, Callanan DG, et al. Comparison of the modified Early Treatment Diabetic Retinopathy Study and mild macular grid laser photocoagulation strategies for diabetic macular edema. Arch Ophthalmol 2007;125:469-80.  Back to cited text no. 22
    
23.
Friberg TR, Karatza EC. The treatment of macular disease using a micropulsed and continuous wave 810-nm diode laser. Ophthalmology 1997;104:2030-8.  Back to cited text no. 23
    
24.
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;36:2059-65.  Back to cited text no. 24
    
25.
Vujosevic S, Martini F, Longhin E, Convento E, Cavarzeran F, Midena E. Subthreshold micropulse yellow laser versus subthreshold micropulse infrared laser in center-involving diabetic macular edema: Morphologic and functional safety. Retina 2015;35:1594-603.  Back to cited text no. 25
    
26.
Lois N, Gardner E, Waugh N, Azuara-Blanco A, Mistry H, McAuley D, et al. Diabetic macular oedema and diode subthreshold micropulse laser (DIAMONDS): Study protocol for a randomised controlled trial. Trials 2019;20:122.  Back to cited text no. 26
    


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