Current Diabetes Reports (2021) 21: 35

https://doi.org/10.1007/s11892-021-01403-6

MICROVASCULAR COMPLICATIONS—RETINOPATHY (R CHANNA, SECTION EDITOR)

Laser Therapy in the Treatment of Diabetic Retinopathy and Diabetic

Macular Edema
Lesley A. Everett 1 & Yannis M. Paulus 1

Accepted: 1 June 2021 / Published online: 6 September 2021

# The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2021

Abstract
Purpose of Review This review highlights indications and evidence on laser therapy in the management of diabetic retinopathy
and diabetic macular edema. Particular focus is placed upon the benefits and limitations of conventional laser photocoagulation
versus more modern laser photocoagulation techniques, as well as the role of laser photocoagulation in treatment of diabetic
retinopathy and diabetic macular edema with the frequent utilization of pharmacologic, including anti-vascular endothelial
growth factor (VEGF), therapy.
Recent Findings Laser photocoagulation remains the gold-standard therapy for the effective, definitive treatment of PDR, and
also is highly effective in the management of DME. However, numerous recent studies have demonstrated the clinical efficacy
and improved functional and anatomic outcomes of combination therapy with pharmacologic treatment.
Summary Continuing innovations in laser technology and improved understanding of laser-retinal interactions and pathophys-
iology demonstrate that laser therapy will continue to play a critical role in the treatment of diabetic retinopathy and diabetic
macular edema for many years to come.

Keywords Diabetic retinopathy . Diabetic macular edema . Retinal laser therapy . Panretinal photocoagulation . Focal laser
photocoagulation . Selective retinal therapy

Introduction ambulatory clinic setting, as well as in the operating room as

part of the surgical management for complex conditions like
Laser (Light Amplification by Stimulated Emission of tractional retinal detachments in diabetic retinopathy.
Radiation) therapy is utilized widely in nearly all fields of The purpose of this review is to specifically highlight the
medicine including ophthalmology, particularly in the treat- indications and evidence for the role of laser therapy in the
ment of retinal vascular diseases such as proliferative diabetic management of diabetic retinopathy and diabetic macular ede-
retinopathy (PDR), diabetic macular edema (DME), retinal ma. Diabetes is the leading cause of new cases of blindness in
vein occlusions, central serous chorioretinopathy, choroidal adults in the USA [2, 3]. This article focuses on the use of
neovascularization, and vascular tumors [1]. Retinal laser peripheral scatter retinal laser (e.g., panretinal photocoagula-
therapy is used for the management of these conditions in an tion, or PRP) to treat PDR and the use of macular focal or grid
laser photocoagulation to treat DME. Although a comprehen-
This article is part of the Topical collection on Microvascular sive review of the history and development of ophthalmic
Complications—Retinopathy lasers is beyond the scope of this article, this information is
summarized in several recent reviews [4, 5]. Similarly, the use
* Yannis M. Paulus of retinal laser therapy for other indications, such as for cho-
[email protected]
roidal neovascularization, choroidal tumors, and the treatment
Lesley A. Everett of retinal tears or holes, is reviewed elsewhere [6, 7].
[email protected] Since the discovery and implementation of argon laser with
1 emission in the blue and green spectrum range by Bridges in
Department of Ophthalmology and Visual Sciences, Kellogg Eye
Center, University of Michigan, 1000 Wall Street, Ann 1964 [8], retinal laser therapy has been utilized as the standard
Arbor, MI 48105, USA of care for PDR. More recently, it has been used by some
providers in combination with intravitreal injections of anti-
35 Page 2 of 12 Curr Diab Rep (2021) 21: 35

vascular endothelial growth factor (VEGF) agents for the In contrast to the diffuse peripheral retinal treatment ap-
management of PDR. However, there is significant controver- plied in PRP, focal laser is an approach in which laser is
sy about the use of anti-VEGF agents as a mainstay of PDR specifically applied to a limited area of the posterior pole to
treatment, given the risk of progressive disease, tractional ret- reduce macular edema. Although the exact mechanism of fo-
inal detachment, or neovascular glaucoma if treatment is cal laser is also unknown, it has been proposed that focal laser
interrupted or if a patient is lost to follow up as can frequently may work by occluding leaking microaneurysms in the retina,
occur in patients with DM. Retinal laser therapy also has an followed by RPE recovery and the stimulation of cytokine
important role in some patients for the treatment of DME, production that leads to reabsorption of fluid in the macula
often resulting in highly effective treatment of visually signif- [15]. It has also been proposed that reduced retinal tissue fol-
icant macular edema without the requirement of frequent re- lowing photocoagulation leads to changes in retinal vascular
current intravitreal anti-VEGF injections or associated en- autoregulation and a resulting decrease in retinal blood flow
dophthalmitis risk. and macular edema [16, 17], or that reduced retinal blood flow
Laser technology has improved and evolved over the last and macular edema results from improved oxygenation after
several decades in order to maintain important therapeutic laser treatment [16]. Several studies have reported that grid
treatment effects, while minimizing collateral tissue damage, treatment alone (without focal treatment of leaking
complications, and patient discomfort. Since it represents a microaneurysms) has a beneficial effect in the treatment of
critical and highly effective therapy for the treatment and pre- diabetic macular edema, suggesting that there is some compo-
vention of blinding eye disease, this article provides an update nent of a beneficial indirect effect of retinal photocoagulation
on the current role and considerations for retinal laser therapy on macular edema [18–21].
in diabetic retinopathy in the age of pharmacologic, including
anti-VEGF, treatments.
Conventional Photocoagulation

Conventional laser photocoagulation has numerous applica-

How Does Retinal Laser Therapy Treat tions in the treatment of retinal disease, including diabetic
Diabetic Eye Disease? retinopathy, retinal vein occlusions, sickle cell retinopathy,
and retinal tears. For the purpose of treating diabetic retinop-
The principle of retinal laser therapy resulting in therapeutic athy, it is most often used to administer panretinal photocoag-
effects in the target retinal tissue is based upon the absorption ulation of the peripheral retina, and can be delivered through a
of light by ocular pigments, predominantly in the retinal pig- slit lamp system utilizing a contact lens [22], laser indirect
ment epithelium (RPE) and choroid [9, 10] melanin and he- ophthalmoscope (LIO) [23], or endolaser intra-operatively
moglobin. Conventional photocoagulation results in perma- [24]. All of these systems utilize a laser light source connected
nent chorioretinal scars, although some of the newer laser to the output device through a fiber optic cable. Typical laser
modalities utilizing reduced intensity and pulse duration may settings for conventional retinal photocoagulation utilize pulse
not have such permanent tissue effects, based upon studies in durations from 100 to 200 milliseconds (ms), laser spot diam-
animal models [11]. The differences between these laser treat- eters from 100 to 500 micrometers (um), and powers from 100
ment types will be reviewed later in this article. to 750 milliwatts (mW) with the application of 1000 to 2000
The exact mechanism by which retinal laser therapy results medium-intensity burns in the peripheral retina, spaced one-
in effective treatment and improvement of retinal vascular half to one spot width apart [25]. These parameters are titrated
disease is not fully understood. With regards to PRP for to produce visible gray-white burns in the treatment tissue,
PDR, one possible mechanism is that damage to the retinal and variation in each of the parameter settings has direct ef-
cells by laser photocoagulation in areas of poor retinal perfu- fects on the final retinal burns produced. A complete PRP
sion decreases the overall retinal oxygen demand and the level treatment can be divided into two or three treatment sessions
of retinal hypoxia, with subsequent downregulation of angio- to minimize side effects and patient discomfort.
genic factors and VEGF production by the retinal tissue and Conventional retinal photocoagulation has several signifi-
subsequent increased oxygen perfusion to the remaining via- cant possible side effects and disadvantages, including patient
ble retina [12, 13]. Photoreceptors are the most metabolically discomfort during treatment, permanent retinal scarring,
active and numerous cell type within the retina, and PRP prolonged time for the physician to complete the treatment
treatment involves the purposeful destruction of a fraction of (sometimes over multiple sessions), possible choroidal de-
photoreceptors in the peripheral retina to reduce overall oxy- tachments after treatment, elevated intraocular pressure,
gen demand. The resulting decrease in VEGF production by cystoid macular edema, and decreased patient peripheral, col-
the retina also results in decreased retinal vascular permeabil- or, and night vision [26–28]. Direct treatment of retinal blood
ity and retinal edema [14]. vessels or retinal neovascularization may result in
Curr Diab Rep (2021) 21: 35 Page 3 of 12 35

hemorrhage. Although rare, misdirected light can also result in the macula, (2) Hard exudate within 500 um of the center of
burns of the cornea, iris, lens, and fovea [29]. Anterior seg- the macula with associated thickening, or (3) Zone or zones of
ment burns with the laser indirect ophthalmoscope (LIO) re- thickening larger than one disc area in size, any part of which
sult from poor focus. Burns of the iris may result in iritis, is within one disc diameter of the center of the macula.
accommodative difficulties, or posterior synechiae [30]. Investigators in this study used a fluorescein angiogram to
Delayed complications of photocoagulation include second- help direct laser photocoagulation treatment of DME and to
ary choroidal neovascularization, subretinal fibrosis, and mac- identify treatable lesions, defined as discrete angiographic
ular pucker, particularly in an area where laser treatment may points of retinal hyperfluorescence or clinical points of focal
have resulted in rupture of Bruch’s membrane. leakage between 500 and 3,000 um from the center of the
The Diabetic Retinopathy Study (DRS) was the first large, fovea considered to produce retinal thickening or hard exu-
prospective, multi-center, randomized clinical trial of the effi- dates [35]. Two methods of laser photocoagulation were uti-
cacy of retinal laser photocoagulation, specifically to evaluate lized: focal (to treat focal areas of leakage) or grid-pattern (to
the timing of PRP in eyes with advanced non-proliferative treat diffuse retinal thickening secondary to diffuse leakage)
diabetic retinopathy and with PDR [31]. This trial demonstrat- [36, 37]. Focal treatment consists of burns of 50 to 100 um of
ed that PRP was highly effective and reduced the risk of se- moderate intensity and 0.05 to 0.1 second duration, with end-
vere visual loss by 60% at 2 years in patients with high-risk point of treatment as whitening or darkening of focal lesions.
PDR [31, 32]. It also demonstrated that PRP applied with Grid treatment utilizes spot size of 50 to 200 um for a duration
argon laser had a similar clinical efficacy, but a much better of 0.05 to 0.5 seconds, not placed within 500 um of the center
adverse effect profile, as compared to xenon-arc treatment, of the macula or within 500 um of the disc margin, with
which led to the adoption of argon laser as the most common treatment goal of mild retinal pigment epithelium whitening.
conventional laser source utilized for PRP following that This study demonstrated that patients with mild to moderate
study. However, argon lasers have mostly been replaced by non-proliferative diabetic retinopathy and macular edema
air-cooled Nd:YAG lasers (such as Pattern Scanning Lasers benefit from focal/grid laser photocoagulation with an associ-
using frequency-doubled neodymium-doped yttrium alumi- ated reduction in the incidence of vision loss by 50% after 3
num garnet (Nd:YAG) laser technology, described later in this years of follow-up, relative to untreated control subjects [25,
article for application of panretinal, focal, and macular grid 35–37].
photocoagulation) that similarly are able to produce green Although the ETDRS photocoagulation protocol was
(532-nm) light given the smaller size and footprint of the laser found to be very effective, the placement of retinal laser burns
device. According to the DRS protocol for standard argon- close to the center of the macula has the risk of progressive
type laser PRP, the laser settings should be a pulse duration RPE and retinal atrophy (“laser creep”) that enlarge over time
of 100ms, large spot size of 200–500 um, and power of 200– and can extend into the fovea, with possible resulting loss of
300mW utilized to deliver 1500–5000 burns over 1–4 treat- central vision, central scotoma, decreased color vision, cho-
ment sessions, with each laser spot applied one by one [31]. roidal neovascularization, and subretinal fibrosis [38, 39]. To
Macular edema is the main cause of decreased vision in prevent this adverse outcome, altered approaches to utilize
diabetic patients, and conventional laser photocoagulation has laser burns that are lighter and less intense than those used
an important role in the treatment of this condition [33]. in the ETDRS protocol have been developed [40].
Macular edema can be defined as focal or diffuse, and the The resulting modified Early Treatment Diabetic
laser approach utilized to treat it depends on the type of mac- Retinopathy Study direct/grid photocoagulation protocol
ular edema. Focal macular edema is characterized by discrete (mETDRS) entails treating only areas of thickened retina
areas of retinal thickening associated with specific points of and areas of retinal nonperfusion, as well a direct photocoag-
leakage on fluorescein angiography. Diffuse macular edema is ulation of leaking microaneurysms [41]. It was modified from
characterized by widespread thickening and diffuse leakage of the original ETDRS protocol in two main components: (1)
fluorescein dye that reflects extensive breakdown of the there was not a requirement for a treatment-induced change
blood-retinal barrier. in microaneurysm color, and (2) laser burns in the mETDRS
With regards to the use of conventional laser photocoagu- protocol were less intense (gray) and smaller (50 microns)
lation for the treatment of diabetic macular edema, the Early compared to the original ETDRS protocol [42].
Treatment Diabetic Retinopathy Study (ETDRS) was one of Another approach, known as the mild macular grid (MMG)
the earliest prospective, multi-center, randomized clinical tri- protocol, utilized the application of mild, widely spaced burns
als to demonstrate the efficacy of focal (direct/grid) laser ther- throughout the macula in areas of normal and thickened retina,
apy for the treatment of clinically significant macular edema but excluding the foveal region and without direct laser pho-
(CSME) [25, 34]. The ETDRS definition of CSME was based tocoagulation of microaneurysms [41]. The modified ETDRS
on the presence of any one of the following three characteris- direct/grid protocol was directly compared to the mild macular
tics [33]: (1) Retinal thickening within 500 um of the center of grid laser photocoagulation strategy for the treatment of
35 Page 4 of 12 Curr Diab Rep (2021) 21: 35

diabetic macular edema in a randomized control trial [41]. The

mild macular grid laser protocol was considered to be a po-
tentially milder (but more extensive) laser technique in which
microaneurysms were not treated directly, and small burns
were placed throughout the macula, whether or not macular
edema was present. In this study, 263 subjects with previously
untreated diabetic macular edema were randomly assigned to
receive laser photocoagulation either by the modified ETDRS
(162 eyes) or MMG (161) protocol, with clinical outcomes
(visual acuity, fundus photographs, and OCT) obtained at
baseline and at 3.5, 8, and 12-month follow-up. At 12 months
after treatment, the MMG technique was found to be less
effective at reducing OCT-measured retinal thickening as
compared to the modified ETDRS protocol, although visual
acuity outcome was not significantly different between the Fig. 1 Fundus photograph comparing conventional laser (lower left) and
two methods [41]. patterned scanning laser (upper right), demonstrating more uniformly
spaced, small, and less intense spots provided by the pattern scanning
In eyes with CSME and PDR requiring immediate PRP for laser. Reprinted with permission from Paulus, Y. M., Palanker, D., &
proliferative disease, it is generally best to deliver focal treat- Blumenkranz, M. S. (2010). Short-pulse laser treatment: redefining
ment before or at the same time as the PRP, rather than after retinal therapy. Retinal Physician, 7(1), 54–56
PRP, in order to minimize the risk of PRP exacerbating the
macular edema. An alternate approach used commonly today
is also to treat with an initial intravitreal anti-VEGF injection pulse durations result in less patient discomfort due to re-
to temporize the proliferative manifestations and reduce the duced heat diffusion into the choroid [47]. Optimization of
CSME, followed shortly by PRP therapy. laser wavelength along with spatial and temporal modulation
of the laser beam can also be considered to maximize clinical
utility while minimizing damage to surrounding tissue [48,
Modern Scanning Laser Photocoagulation 49].
Pattern scanning laser is commonly used for PRP in the
As laser technology has evolved and improved over the last treatment of PDR with similar clinical efficacy compared to
several decades, emphasis has been placed on developing conventional laser therapy. Pattern scanning laser parameters
modifications to conventional retinal laser therapy in order for PRP include spot size of 200um with duration of 10 to
to minimize retinal damage and adverse side effects, while 20ms placed just outside the arcades (1 disc diameter or more
maintaining the excellent therapeutic effect of the convention- from the arcades), at least three disc diameters temporal to the
al approach. To this end, most of the innovations have focused macula, and at least one disc diameter nasal to the optic disc
on changing the laser pulse duration, wavelength, and spot with patterns varying from 3 × 3 to 7 × 7 laser spot arrays. The
size to achieve these goals. outcomes of PRP performed with the pattern scanning system
For example, the semi-automated pattern scanning retinal have been compared to PRP with conventional laser in several
photocoagulation system (PASCAL®, PAttern SCAn Laser) studies. For example, a 532-nm solid-state green laser (GLX)
represents a modern method of retinal photocoagulation was compared to a multi-spot 532-nm pattern scanning laser
which enables the rapid application of numerous spots (4 to approach in PRP treatment in a prospective, randomized clin-
56 burns) in a defined pattern to reduce treatment time, in- ical trial to compare the efficacy, collateral damage, and con-
crease patient comfort, and improve the accuracy of treat- venience of these PRP approaches [50]. This study demon-
ment using a scanning laser with shorter pulse durations of strated that pattern scanning laser resulted in less collateral
10–30 ms [43]. A 532-nm wavelength is utilized through a tissue damage and similar regression of retinopathy compared
standard slit-lamp system, and a number of laser scanning to the GLX laser, and it was less time consuming and less
patterns are available (arc, grid, circle, etc.) which may be painful for patients. However, in a separate study, the pattern
utilized according to the patient’s retinal anatomy and clini- scanning laser was reported to be less effective compared to
cal indication (Figure 1). Through a number of histologic conventional treatment in the treatment of high-risk PDR
studies, it has been shown that such shorter pulse duration when applying equivalent number of laser treatment spots
burns result in less tissue damage to the inner retina [44], as [51], although subsequently it was shown that the patients
compared to the longer duration (>100ms) laser burns that undergoing pattern scanning treatment in this study received
affect the RPE, photoreceptors, inner nuclear layer, ganglion significantly less treatment than the conventional laser group
layer, and nerve fiber layer [45, 46]. In addition, shorter [52].
Curr Diab Rep (2021) 21: 35 Page 5 of 12 35

Pattern scanning laser is also a highly utilized method for Subthreshold Diode Micropulse Laser
the treatment of diabetic macular edema. Convenient laser
pattern templates may be used for macular photocoagulation Subthreshold diode micropulse (SDM) laser is another novel
that include ring and arc patterns with a central foveal exclu- laser modality for photocoagulation designed to minimize col-
sion zone, ensuring that no laser burn is placed closer than a lateral tissue damage for treatment of the macula. Similar to
preset distance from the center of the foveal avascular zone. SRT, the goal of SDM is to provide selective therapeutic
Pattern scanning is also utilized for “subthreshold” focal-grid targeting of the RPE while sparing of the neurosensory retina,
laser in macular edema, with the goal of avoiding and utilizing a near-infrared diode laser (810 nm) with bursts of
preventing the enlargement of laser photocoagulation scars submillisecond pulses [61, 62]. As the name implies, the term
over time after treatment [53]. These approaches are highly “subthreshold” refers to laser energy applied with no visible
effective for the treatment of macular edema, and in 2012 a intra-retinal damage or scarring, either during or after treat-
large, retrospective observational case series reported that ment. Although the exact mechanism by which SDM induces
clinical and visual outcomes of short-pulse duration laser a therapeutic response is not understood, it is hypothesized
settings with the pattern scanning system were comparable that SDM may alter the metabolic activity of the RPE,
to those of conventional argon laser parameters for the treat- resulting in the release of cytokines that regulate angiogenesis
ment of diabetic macular edema [54]. and vascular leakage without any associated retinal damage
[63–65]. SDM is delivered as microsecond laser pulses with
variable intervals without laser treatment in order to allow the
tissue to return to baseline temperature between pulses [66,
Selective Retinal Therapy 67], and it may be utilized in a low-intensity/high-density
approach for the complete and confluent treatment of an area
As noted above, conventional retinal photocoagulation is of diseased retina, such as an area of central macular edema
limited in its use for macular conditions because of the risk [68]. In fact, the most widely used application of SDM is for
of vision loss from central scars (resulting in scotomas) and the treatment of clinically significant macular edema (CSME)
expansion of the laser scar over time. Selective retinal ther- [69], and it has been shown to have a long-term effect on
apy (SRT) with microsecond pulses that have a shorter du- visual acuity and resolution of macular edema in a 3-year
ration than the time needed for produced heat to diffuse was follow-up case series of 25 treated eyes [70]. In addition,
developed as an alternative laser modality, specifically with SDM has been compared directly to the ETDRS or the mod-
the goal of treating macular diseases that result from RPE ified ETDRS focal laser protocols for the treatment of DME in
dysfunction, including age related macular degeneration, several randomized clinical trials; SDM was found to be equal
DME, and central serous chorioretinopathy. Given the very or superior to modified ETDRS laser photocoagulation with
short pulse duration used in SRT, the high temperature is less associated RPE damage for the treatment of DME [71,
confined primarily to the melanosomes inside RPE cells, 72].
which absorb approximately 50% of the incident green light
[55]. This enables the selective treatment of the RPE cells
without damage to the overlying photoreceptors, neurosen- Upcoming Innovative Clinical Laser
sory retina, and choroid. There are two SRT modalities: a and Delivery Platforms
pulsed and continuous wave scanning mode, and a variety
of clinical trials have validated the safety and efficacy of In addition to the efficacious novel laser approaches outlined
SRT in DME, central serous chorioretinopathy, and macu- above (scanning pattern laser, selective retinal therapy, sub-
lar edema secondary to branch retinal vein occlusions threshold diode micropulse, etc.), several other important clin-
[56–58]. For example, a prospective, two-center interven- ical innovations are likely to become main-stream in busy
tional uncontrolled pilot study of SRT as a treatment of retina practices over the next few years, including endpoint
CSME demonstrated statistically significant improvement management and image-guided navigated laser delivery.
in the mean best-corrected visual acuity in treated patients Table 1 compares the parameters and indications for several
at 6-month follow-up, with no adverse effects [59]. of these novel laser techniques.
However, SRT has not yet been commercialized or imple- Endpoint management refers to a modified laser therapy
mented for routine clinical use despite promising initial re- approach designed to precisely control laser energy relative
sults, in part because it is challenging for physicians to use to titration level [73], and this titration algorithm is commer-
clinically given the lack of visible changes in the retinal cially available for the 532-nm and 577-nm Pattern scanning
appearance when applying laser spots, making it difficult lasers to provide highly predictable laser dosimetry based on
to define the energy required for selective and therapeutic the clinical indication and setting. The Endpoint Management
RPE damage [60]. algorithm is based upon titrating laser power to that needed to
35 Page 6 of 12 Curr Diab Rep (2021) 21: 35

Table 1 Comparison of novel retinal laser techniques with indications for the treatment of PDR and DME

Pattern scanning Navigated laser SDM SRT

(i.e., PASCAL®) (i.e., NAVILAS®)

Laser 532-nm 577-nm yellow laser 810-nm diode laser 527-nm Nd-YLF/532-nm
devices Nd-YAG/514-nm Nd-YAG laser
argon laser
Pulse 10–1000 ms 10–1000 ms 100–300 μs 1.7 μs/15–60 ms
duration
Indications PDR/DME PDR/DME DME DME
Advantages Shorter treatment Eye tracking, improved accuracy Minimize collateral tissue damage Selectively damage RPE
times, increased and safety cells
safety
Limitations Uncontrolled eye No stereoscopic view, cannot Longer treatment time, treatment protocols are Inability to detect or
movements integrate ICG angiography not well established or standardized visualize treatment
effects

generate a barely visible retinal burn (defined as 100% nom- important clinical trials have studied the efficacy of pharma-
inal energy level), and then additional pulse energies can be cologic therapy alone compared to retinal photocoagulation,
utilized as a percentage of the nominal energy level in order to or pharmacologic therapy combined with retinal laser therapy,
provide a spectrum of clinical laser intensities, from subvisible for these conditions. Similarly, additional studies have evalu-
retinal laser to intense coagulative tissue effects. Subthreshold ated the role of intravitreal steroid therapy in the management
PRP using an Endpoint Management algorithm has been di- of DME relative to photocoagulation, or in combination with
rectly compared to conventional pattern scanning PRP for the laser treatment. The DRCR Retina Network (DRCR.net) has
treatment of severe non-proliferative diabetic retinopathy in a coordinated many of these studies, which are summarized
prospective study with regards to the rate of progression to briefly in Table 2. Only a subset of the DRCR Retina
PDR in 12-month follow-up, and Endpoint Management was Network protocols most relevant to the scope of this review
found to be noninferior to conventional threshold pattern are included in Table 2, but a complete list is available on the
scanning PRP [74]. DRCR website, including a number of studies that evaluated
Image-guided laser therapies, such as “Navigated laser only anti-VEGF agents without a laser comparison group
(NAVILAS),” are commercially available systems that utilize (https://public.jaeb.org/drcrnet/stdy).
fundus imaging and treatment device for specific, targeted DRCR Protocol H was a Phase 2, randomized, multi-center
retinal laser photocoagulation in a pre-determined and highly clinical trial to evaluate the efficacy of anti-VEGF therapy
precise manner. It can incorporate various imaging modalities (bevacizumab) for DME, either as primary treatment or in
such as infrared images, color fundus photographs, and fluo- combination with macular photocoagulation in patients 18
rescein angiography images and utilize these to create detailed years or older [83]. Study eyes were randomly assigned to
treatment plans for focal or large treatment areas with high one of five groups: (1) Laser photocoagulation at baseline
reproducibility and precision. NAVILAS has been shown to (with option for intravitreal injection if DME was present at
be safe and effective in the treatment of DME with associated 12-week follow-up), (2) 1.25 mg intravitreal injection of
improvement in visual acuity and macular edema 12 months bevacizumab at baseline and 6 weeks, (3) 2.5mg intravitreal
after treatment [75, 76] in a highly time-efficient manner [77], injection of bevacizumab at baseline and 6 weeks, (4) 1.25 mg
and has also been used for PRP treatment [78]. Nanosecond intravitreal injection of bevacizumab at baseline with sham
pulse duration laser synchronized with concurrent focused injection at 6 weeks, or (5) 1.25 mg intravitreal injection of
ultrasound, termed photo-mediated ultrasound therapy [79, bevacizumab at baseline, laser photocoagulation at 3 weeks,
80], has also been described and used to treat clinically rele- and intravitreal injection of 1.25 mg bevacizumab at 6 weeks.
vant animal models of retinal neovascularization without The main study conclusion after 70 weeks of follow-up was
damaging surrounding tissues [81]. that intravitreal bevacizumab can effectively reduce DME in
some eyes, and there was no apparent short-term benefit or
adverse outcome when intravitreal bevacizumab was com-
Retinal Laser for PDR and DME Compared bined with focal photocoagulation [83]. DRCR Protocol I
and Combined with Pharmacologic Therapies was a randomized clinical trial evaluating the effect of prompt
versus deferred (for ≥ 24 weeks) foal/grid laser treatment in
Since the development and wide-spread use of anti-VEGF eyes treated with intravitreal 0.5mg ranibizumab for DME
agents for the treatment of PDR and DME, a number of [84]. A 3-year follow-up study of the Protocol I subjects
Table 2 Summary of DRCR protocols evaluating the efficacy of laser photocoagulation or combined pharmacologic therapy with laser photocoagulation for the treatment of DME and PDR

Protocol Description Outcomes of interest (primary and Main safety outcomes Follow-up Main conclusions
secondary) period
Curr Diab Rep (2021) 21: 35

B Randomized trial comparing intravitreal Visual acuity improvement (>= 15 letters at 3 Elevated intraocular pressure/glaucoma, 3 years Focal and grid laser photocoagulation are
triamcinolone acetonide and laser years), change in retinal thickening on OCT cataract/cataract surgery, endophthalmitis, more effective and have fewer side effects
photocoagulation for diabetic macular retinal detachment than 1 or 4 mg doses of intravitreal
edema (NCT00367133) triamcinolone in the treatment of CSME
[82].
H A phase 2 evaluation of anti-VEGF therapy Central subfield thickening measured on Visual acuity decrease of 20 or more letters at 70 weeks Combining focal photocoagulation with
for diabetic macular edema: bevacizumab OCT, and visual acuity (ETDRS) any visit within the first 3 weeks after bevacizumab resulted in no apparent
(NCT00336323, randomized, multi-center intravitreal injection, ocular inflammation, short-term benefit or adverse outcome, and
clinical trial to explore the role of endophthalmitis, other reported adverse intravitreal bevacizumab can reduce DME
intravitreal bevacizumab or intravitreal events in some eyes [83].
bevacizumab combined with macular
photocoagulation in the treatment of DME)
I Intravitreal ranibizumab or triamcinolone Visual acuity at 12 months adjusted for the Injection related: endophthalmitis, retinal 1 year (primary Based on 3-year follow-up data, focal/grid
acetonide in combination with laser baseline acuity, change in retinal thickening detachment outcome), 3 laser treatment at initiation of intravitreal
photocoagulation for diabetic macular of central subfield and retinal volume Ocular drug-related: inflammation, cataract, years ranibizumab was no better, and potentially
edema (NCT00444600) measured on OCT, and number of cataract surgery, increased intraocular (secondary worse, for vision outcomes, as compared to
injections in first year pressure, glaucoma medications, glaucoma outcome) deferring laser treatment for ≥ 24 weeks in
surgery eyes with DME involving the fovea and
Systemic drug-related: cardiovascular events with vision impairment [84].
J Intravitreal ranibizumab or triamcinolone Visual acuity at 14 weeks adjusted for baseline Injection related: endophthalmitis, retinal 4 weeks and 14 Addition of 1 intravitreal triamcinolone or 2
acetonide as adjunctive treatment to acuity, change in retinal thickening from detachment weeks ranibizumab injections in eyes receiving
panretinal photocoagulation for baseline (OCT measures), presence and Ocular drug-related: inflammation, (primary focal/grid laser for DME and PRP is
proliferative diabetic retinopathy extent of new vessels on fundus cataract/cataract surgery, IOP/glaucoma outcome), 34 associated with better visual acuity
(NCT00445003, prospective, multi-center, photographs, vitreous hemorrhage, Systemic drug-related: cardiovascular events and 56 weeks outcomes and decreased macular edema at
randomized clinical trial) additional sessions of PRP due to (safety 14-week follow-up [85].
worsening PDR before 14-week visit outcomes)
S Prompt panretinal photocoagulation versus Mean change in visual acuity from baseline to Injection related: endophthalmitis, retinal 2 years (primary Treatment with ranibizumab resulted in visual
intravitreal ranibizumab with deferred 2 years, mean visual acuity of 2 years, detachment, retinal tears, intraocular outcome), 5 acuity that was noninferior to PRP
panretinal photocoagulation for proportion of eyes with 10 and 15 letter hemorrhage years (total treatment at 2 years in eyes with PDR [86],
proliferative diabetic retinopathy vision loss or gain, visual field testing, need Ocular drug-related: inflammation, follow-up) and these groups demonstrated comparable
(NCT01489189) for supplemental PRP after completion or cataract/cataract surgery, IOP/glaucoma, visual acuity at 5-year follow-up [87].
deferred or prompt initial PRP, need for new or worsening neovascular glaucoma, Severe vision loss or serious PDR
vitrectomy, mean change in OCT central glaucoma surgery or medical therapy, new complications were uncommon in both
subfield thickness, percent of eyes with or worsening tractional retinal detachment, groups, though the ranibizumab group had
vitreous hemorrhage, proportion with new or worsening neovascularization of lower rates of visually significant DME and
complete regression of neovascularization the iris less visual field loss at 5 years [87].
on fundus photography Systemic drug-related: hypertension,
cardiovascular or cerebrovascular events
Page 7 of 12 35
35 Page 8 of 12 Curr Diab Rep (2021) 21: 35

suggested that focal/grid laser treatment at initiation of intra- and safe for DME [89]. This conclusion was supported by a
vitreal ranibizumab was no better, and potentially worse, for recent literature review of all studies utilizing a combination of
vision outcomes, as compared to deferring laser treatment for subthreshold diode micropulse laser and intravitreal anti-
≥ 24 weeks in eyes with DME involving the fovea and with VEGF or steroid treatment for the management of DME,
vision impairment [84]. DRCR Protocol J was a randomized which reported that combination therapy resulted in fewer
clinical trial evaluating the short-term effects (14 weeks) of intravitreal injections that pharmacologic monotherapy with
intravitreal ranibizumab or triamcinolone acetonide on macu- noninferior functional and morphologic outcomes [90].
lar edema following focal/grid laser for DME in eyes also Additional studies have evaluated the role of intravitreal
receiving PRP [85]. This study found that the addition of 1 steroid therapy in the management of DME relative to photo-
intravitreal triamcinolone or 2 ranibizumab injections in eyes coagulation, including the DRCR Protocol B, which demon-
receiving focal/grid laser for DME and PRP was associated strated that focal and grid laser photocoagulation are more
with better visual acuity outcomes and decreased macular effective and have fewer side effects than 1 or 4 mg doses of
edema at 14-week follow-up [85]. Finally, DRCR Protocol intravitreal triamcinolone in the treatment of CSME [82].
S was a Phase III, prospective, multi-center randomized clin- Importantly, there are significant clinical considerations and
ical trial evaluating the effect of prompt PRP versus intravit- possible undesired effects when laser photocoagulation and
real ranibizumab with deferred PRP for eyes with PDR. intravitreal steroid therapy are utilized concurrently, particu-
Treatment with ranibizumab resulted in visual acuity that larly relating to laser scar healing and residual tissue effects
was noninferior to PRP treatment at 2 years in eyes with [91, 92]. A rabbit model was utilized to evaluate the effect of
PDR [86], and these groups demonstrated comparable visual intravitreal triamcinolone acetonide (TA) on the healing of
acuity at 5-year follow-up [87]. Severe vision loss or serious retinal photocoagulation lesions using drug and laser dosing
PDR complications were uncommon in both groups, though parameters typically used in the clinical setting [91], relative
the ranibizumab group had lower rates of visually significant to control treatment with balanced salt solution injection rather
DME and less visual field loss at 5 years [87]. than TA. While the TA treatment groups demonstrated signif-
In addition to the DRCR protocols, a number of other stud- icant reduction in retinal thickness and laser-induced edema
ies have investigated the efficacy of combined pharmacologic compared to the balanced salt solution control eyes, this study
and laser therapy for PDR or DME. PRP laser alone versus a demonstrated that TA injection previously or concurrently
combination of intravitreal aflibercept and PRP treatment was with photocoagulation interfered with retinal laser lesion
evaluated in a retrospective study of 72 eyes with high-risk healing, resulting in wider residual scarring that was especial-
PDR [88]. There were no significant differences in best- ly notable in more intense laser burns.
corrected visual acuity, central foveal thickness, and
microaneurysms in the laser group before and after treatment,
but there were statistically significant improvements in the
combination therapy group compared to baseline. The differ- Considerations for pharmacologic therapy
ences between best-corrected visual acuity, central foveal and Laser Photocoagulation “in Real World”
thickness, and microaneurysms were statistically significantly Conditions
different between the PRP only group and the combination
therapy group, suggesting that combination therapy may pro- Despite the well-established efficacy and benefits of intravit-
vide improved morphologic and functional outcomes [88]. real anti-VEGF therapy (alone or in combination with laser)
The efficacy and safety of anti-VEGF monotherapy for the treatment of PDR and DME, any treatment plan that
(bevacizumab) versus combined anti-VEGF and subthreshold relies on regular clinic visits and regular intravitreal injections
micropulse laser therapy for DME was evaluated in a retro- is subject to failure if a patient cannot reliably return for care.
spective study of 80 eyes, with the primary outcomes of inter- A number of personal, social, financial, and medical con-
est defined as the mean number of required intravitreal injec- straints may limit a patient’s ability to return for injections,
tions, change of best-corrected visual acuity, and change in including loss of insurance coverage, other critical illnesses,
central macular thickness [89]. A significant increase in best- psycho/social factors, or (as recently demonstrated), concerns
corrected visual acuity was observed in the combined therapy about seeking medical care during the COVID-19 pandemic
group at 3, 6, 9, and 12 months of follow-up, whereas in the [93–95]. Given these real-world constraints, laser treatment
intravitreal monotherapy group, visual acuity was only signif- has the benefit of reducing the number of required injections
icantly improved at month 3. When compared to baseline, the while offering a highly effective, long-lasting therapeutic ben-
decrease in central macular thickness was statistically signifi- efit [96, 97]. Unfortunately, every retina provider has seen
cant in both groups at 3, 6, 9, and 12-month follow-up. This first-hand the possible devastating outcomes of untreated or
study demonstrated that the use of combined intravitreal anti- incompletely treated PDR when a patient is lost to follow up,
VEGF and subthreshold micropulse laser may be effective including permanent vision loss and complex surgical needs
Curr Diab Rep (2021) 21: 35 Page 9 of 12 35

from neovascular glaucoma, tractional retinal detachments, intravitreal injections place a significant burden on the
and profound retinal nonperfusion and ischemia [98, 99]. healthcare system, patients, and providers, and they are not
without significant possible risks including endophthalmitis
[100]. Continuing innovations in laser technology and im-
Conclusion proved understanding of laser-retinal interactions and patho-
physiology make us think that laser therapy will continue to
Despite the widespread use and high efficacy of anti-VEGF play a critical role in the treatment of diabetic retinopathy and
therapy for diabetic retinopathy and diabetic macular edema, diabetic macular edema for many years to come.
retinal laser photocoagulation remains a vital therapeutic
method for the treatment of these conditions.
PRP laser treatment for PDR offers a definitive, durable Author Contribution Y.M.P. is the corresponding author for the manu-
script. All authors contributed to the design and drafting the paper and
treatment method to prevent severe vision-threatening com-
reviewed and approved the manuscript for scholarly content.
plications such as neovascular glaucoma and tractional retinal
detachments; it remains the gold standard for treatment of Funding L.E. is supported by the Heed Ophthalmic Foundation and the
PDR. Importantly, patients who have complete PRP treatment VitreoRetinal Surgery Foundation.
are not reliant on serial intravitreal anti-VEGF injections for Y.M.P. is supported by the National Eye Institute (1K08EY027458,
1R41EY031219, 1R01EY029489), unrestricted departmental support
the treatment of the PDR, minimizing the risk of rare but
from Research to Prevent Blindness, and Alliance for Vision Research,
devastating complications from post-injection endophthalmi- and Fight for Sight – International Retinal Research Foundation.
tis or worsening of their clinical disease in cases of loss-to-
follow-up or inability to present for routine clinical care (such Declarations
as during the peak of the COVID-19 pandemic, or loss of
insurance coverage) [93]. Although PDR may theoretically Conflict of Interest Lesley Everett declares no conflict of interest.
be managed with regular anti-VEGF injections, PRP laser Yannis Paulus has patents through the University of Michigan, equity
offers a life-long management plan in real-world settings in and patents licenses to PhotoSonoX LLC, and serves as a consultant on
a Department of Defense grant with Hedgefog Research Inc evaluating
which patients cannot return to the clinic every 4–6 weeks. retinal photocoagulation injuries of the retina.
Similarly, focal and grid laser photocoagulation for the treat-
ment of CSME can be highly effective and provide long- Human and Animal Rights and Informed Consent This article does not
standing resolution of macular edema without the need for contain any studies with human or animal subjects performed by any of
serial intravitreal injections, although the final best-corrected the authors.
visual acuity in eyes treated with laser photocoagulation alone
as compared to combination therapy may be lower in some
cases. References
In addition, a number of recent laser technology innova-
1. CR M. Lasers in opthalmology: past, present and future. J Mod
tions and modifications to conventional laser photocoagula- Opt. 2003;50(15-17):2351–60.
tion have led to improved clinical efficacy with simultaneous 2. CDC. Diabetic Retinopathy 2020 [3/21/21]. Available from:
reduction of side effects and adverse permanent vision conse- https://www.cdc.gov/visionhealth/pdf/factsheet.pdf.
quences such as scotoma formation, choroidal neovasculari- 3. Palmberg PF. Diabetic retinopathy. Diabetes. 1977;26(7):703–9.
4. Blumenkranz MS. The evolution of laser therapy in ophthalmol-
zation, retinal scarring, and patient discomfort. For example, ogy: a perspective on the interactions between photons, patients,
pattern scanning laser has decreased the time required and the physicians, and physicists: the LXX Edward Jackson Memorial
discomfort experienced by patients for PRP treatment of PDR. Lecture. Am J Ophthalmol. 2014;158(1):12–25 e1.
Selective retinal therapy (SRT) enables the localized, selective 5. Li J, Paulus YM. Advances in retinal laser therapy. Int J
Ophthalmic Res. 2018;4(1):259–64.
treatment of RPE cells while limiting collateral damage to the
6. Xie X, Liu Q, Paulus YM. Innovations in retinal laser technology.
neurosensory retina. Subthreshold micropulse laser results in Optics and Photonics Journal. 2018;8(6):173–86. https://www.
therapeutic effect without inducing any detectable intra-retinal scirp.org/journal/OPJ/
tissue damage. These advances, along with other innovations 7. Xie X, Liu Q, Paulus YM. Novel retinal laser therapies. Int J
such as Endpoint Management and Navigated Laser, have Ophthalmic Res. 2018;4(1):272–9.
8. WB B. Laser oscillation in singly ionized argon in the visible
improved the safety, efficacy, and efficiency of retinal spectrum. Appl Phys Lett. 1964;4(7):128–30.
photocoagulation. 9. Birngruber R, Hillenkamp F, Gabel VP. Theoretical investigations
Given that intravitreal anti-VEGF and corticosteroid agents of laser thermal retinal injury. Health Phys. 1985;48(6):781–96.
are now common therapeutic agents for the treatment of both 10. Lock JH, Fong KC. Retinal laser photocoagulation. Med J
Malaysia. 2010;65(1):88–94 quiz 5.
PDR and DME, research is ongoing as to the best approaches 11. Paulus YM, Jain A, Gariano RF, Stanzel BV, Marmor M,
and treatment paradigms for the combined use of laser and Blumenkranz MS, et al. Healing of retinal photocoagulation le-
pharmacologic therapy. However, repeated and long-term sions. Invest Ophthalmol Vis Sci. 2008;49(12):5540–5.
35 Page 10 of 12 Curr Diab Rep (2021) 21: 35

12. Wolbarsht ML, Landers MB 3rd. The rationale of photocoagula- 33. Photocoagulation for diabetic macular edema. Early Treatment
tion therapy for proliferative diabetic retinopathy: a review and a Diabetic Retinopathy Study report number 1. Early Treatment
model. Ophthalmic Surg. 1980;11(4):235–45. Diabetic Retinopathy Study research group. Arch Ophthalmol.
13. Stefansson E. The therapeutic effects of retinal laser treatment and 1985;103(12):1796–806.
vitrectomy. A theory based on oxygen and vascular physiology. 34. Patz ASR. The ETDRS and Diabetes 2000. Ophthalmology.
Acta Ophthalmol Scand. 2001;79(5):435–40. 1991;98(5):739–840.
14. Ascaso FJ, Huerva V, Grzybowski A. The role of inflammation in 35. Early photocoagulation for diabetic retinopathy. ETDRS report
the pathogenesis of macular edema secondary to retinal vascular number 9. Early Treatment Diabetic Retinopathy Study
diseases. Mediat Inflamm. 2014;2014:432685. Research Group. Ophthalmology. 1991;98(5 Suppl):766–85.
15. Ogata N, Ando A, Uyama M, Matsumura M. Expression of cyto- 36. Techniques for scatter and local photocoagulation treatment of
kines and transcription factors in photocoagulated human retinal diabetic retinopathy: Early Treatment Diabetic Retinopathy
pigment epithelial cells. Graefes Arch Clin Exp Ophthalmol. Study Report no. 3. The Early Treatment Diabetic Retinopathy
2001;239(2):87–95. Study Research Group. Int Ophthalmol Clin. 1987;27(4):254–64.
16. Arnarsson A, Stefansson E. Laser treatment and the mechanism of 37. Photocoagulation for diabetic macular edema: Early Treatment
edema reduction in branch retinal vein occlusion. Invest Diabetic Retinopathy Study Report no. 4. The Early Treatment
Ophthalmol Vis Sci. 2000;41(3):877–9. Diabetic Retinopathy Study Research Group. Int Ophthalmol
17. Wilson DJ, Finkelstein D, Quigley HA, Green WR. Macular grid Clin. 1987;27(4):265–72.
photocoagulation. An experimental study on the primate retina. 38. Roider J. Laser treatment of retinal diseases by subthreshold laser
Arch Ophthalmol. 1988;106(1):100–5. effects. Semin Ophthalmol. 1999;14(1):19–26.
18. Lee CM, Olk RJ. Modified grid laser photocoagulation for diffuse 39. Schatz H, Madeira D, McDonald HR, Johnson RN. Progressive
d i a b e t i c m a c u l a r e d e m a . L o n g - t e r m vi s u a l r e su l t s . enlargement of laser scars following grid laser photocoagulation
Ophthalmology. 1991;98(10):1594–602. for diffuse diabetic macular edema. Arch Ophthalmol.
19. Olk RJ. Modified grid argon (blue-green) laser photocoagulation 1991;109(11):1549–51.
for diffuse diabetic macular edema. Ophthalmology. 1986;93(7): 40. Friberg TR. Subthreshold (invisible) modified grid diode laser
938–50. photocoagulation and diffuse diabetic macular edema (DDME).
20. Olk RJ. Argon green (514 nm) versus krypton red (647 nm) mod- Ophthalmic Surg Lasers. 1999;30(9):705.
ified grid laser photocoagulation for diffuse diabetic macular ede- 41. Writing Committee for the Diabetic Retinopathy Clinical
ma. Ophthalmology. 1990;97(9):1101–12 discussion 12-3. Research N, Fong DS, Strauber SF, Aiello LP, Beck RW,
Callanan DG, et al. Comparison of the modified Early
21. Striph GG, Hart WM Jr, Olk RJ. Modified grid laser photocoag-
Treatment Diabetic Retinopathy Study and mild macular grid la-
ulation for diabetic macular edema. The effect on the central visual
ser photocoagulation strategies for diabetic macular edema. Arch
field. Ophthalmology. 1988;95(12):1673–9.
Ophthalmol. 2007;125(4):469–80.
22. Little HL, Zweng HC, Peabody RR. Argon laser slit-lamp retinal
42. Romero-Aroca P, Reyes-Torres J, Baget-Bernaldiz M, Blasco-
photocoagulation. Trans Am Acad Ophthalmol Otolaryngol.
Sune C. Laser treatment for diabetic macular edema in the 21st
1970;74(1):85–97.
century. Curr Diabetes Rev. 2014;10(2):100–12.
23. Law NM, Fan RF. Clinical experience with the laser indirect oph-
43. Blumenkranz MS, Yellachich D, Andersen DE, Wiltberger MW,
thalmoscope. Ann Acad Med Singap. 1991;20(6):750–4.
Mordaunt D, Marcellino GR, et al. Semiautomated patterned scan-
24. Smiddy WE. Diode endolaser photocoagulation. Arch ning laser for retinal photocoagulation. Retina. 2006;26(3):370–6.
Ophthalmol. 1992;110(8):1172–4. 44. Paulus YM, Kaur K, Egbert PR, Blumenkranz MS, Moshfeghi
25. Treatment techniques and clinical guidelines for photocoagulation DM. Human histopathology of PASCAL laser burns. Eye
of diabetic macular edema. Early Treatment Diabetic Retinopathy (Lond). 2013;27(8):995–6.
Study Report Number 2. Early Treatment Diabetic Retinopathy 45. Jain A, Blumenkranz MS, Paulus Y, Wiltberger MW, Andersen
Study Research Group. Ophthalmology. 1987;94(7):761–74. DE, Huie P, et al. Effect of pulse duration on size and character of
26. Prskavec FH, Fulmek R, Klemen C, Stelzer N. Changes in the the lesion in retinal photocoagulation. Arch Ophthalmol.
visual field and dark adaptation following panretinal photocoagu- 2008;126(1):78–85.
lation in diabetic retinopathy. Klin Monatsbl Augenheilkd. 46. Sher A, Jones BW, Huie P, Paulus YM, Lavinsky D, Leung LS,
1986;189(5):385–7. et al. Restoration of retinal structure and function after selective
27. Russell PW, Sekuler R, Fetkenhour C. Visual function after pan- photocoagulation. J Neurosci. 2013;33(16):6800–8.
retinal photocoagulation: a survey. Diabetes Care. 1985;8(1):57– 47. Muqit MM, Marcellino GR, Gray JC, McLauchlan R, Henson
63. DB, Young LB, et al. Pain responses of Pascal 20 ms multi-spot
28. Blondeau P, Pavan PR, Phelps CD. Acute pressure elevation fol- and 100 ms single-spot panretinal photocoagulation: Manchester
lowing panretinal photocoagulation. Arch Ophthalmol. Pascal Study, MAPASS report 2. Br J Ophthalmol. 2010;94(11):
1981;99(7):1239–41. 1493–8.
29. Irvine WD, Smiddy WE, Nicholson DH. Corneal and iris burns 48. Sramek C, Leung LS, Leng T, Brown J, Paulus YM, Schuele G,
with the laser indirect ophthalmoscope. Am J Ophthalmol. et al. Improving the therapeutic window of retinal photocoagula-
1990;110(3):311–3. tion by spatial and temporal modulation of the laser beam. J
30. Lobes LA Jr, Bourgon P. Pupillary abnormalities induced by ar- Biomed Opt. 2011;16(2):028004.
gon laser photocoagulation. Ophthalmology. 1985;92(2):234–6. 49. Sramek CK, Leung LS, Paulus YM, Palanker DV. Therapeutic
31. Photocoagulation treatment of proliferative diabetic retinopathy. window of retinal photocoagulation with green (532-nm) and yel-
Clinical application of Diabetic Retinopathy Study (DRS) find- low (577-nm) lasers. Ophthalmic Surg Lasers Imaging.
ings, DRS Report Number 8. The Diabetic Retinopathy Study 2012;43(4):341–7.
Research Group. Ophthalmology. 1981;88(7):583–600. 50. Nagpal M, Marlecha S, Nagpal K. Comparison of laser photoco-
32. Four risk factors for severe visual loss in diabetic retinopathy. The agulation for diabetic retinopathy using 532-nm standard laser
third report from the Diabetic Retinopathy Study. The Diabetic versus multispot pattern scan laser. Retina. 2010;30(3):452–8.
Retinopathy Study Research Group. Arch Ophthalmol. 51. Chappelow AV, Tan K, Waheed NK, Kaiser PK. Panretinal pho-
1979;97(4):654–5. tocoagulation for proliferative diabetic retinopathy: pattern scan
Curr Diab Rep (2021) 21: 35 Page 11 of 12 35

laser versus argon laser. Am J Ophthalmol. 2012;153(1):137–42 71. Figueira J, Khan J, Nunes S, Sivaprasad S, Rosa A, de Abreu JF,
e2. et al. Prospective randomised controlled trial comparing sub-
52. Palanker D, Blumenkranz MS. Panretinal photocoagulation for threshold micropulse diode laser photocoagulation and conven-
proliferative diabetic retinopathy. Am J Ophthalmol. tional green laser for clinically significant diabetic macular oede-
2012;153(4):780–1 author reply 1-2. ma. Br J Ophthalmol. 2009;93(10):1341–4.
53. Muqit MM, Gray JC, Marcellino GR, Henson DB, Young LB, 72. Lavinsky D, Cardillo JA, Melo LA Jr, Dare A, Farah ME, Belfort
Patton N, et al. Barely visible 10-millisecond pascal laser photo- R Jr. Randomized clinical trial evaluating mETDRS versus nor-
coagulation for diabetic macular edema: observations of clinical mal or high-density micropulse photocoagulation for diabetic
effect and burn localization. Am J Ophthalmol. 2010;149(6):979– macular edema. Invest Ophthalmol Vis Sci. 2011;52(7):4314–23.
86 e2. 73. Lavinsky D, Sramek C, Wang J, Huie P, Dalal R, Mandel Y, et al.
54. Muqit MM, Sanghvi C, McLauchlan R, Delgado C, Young LB, Subvisible retinal laser therapy: titration algorithm and tissue re-
Charles SJ, et al. Study of clinical applications and safety for sponse. Retina. 2014;34(1):87–97.
Pascal(R) laser photocoagulation in retinal vascular disorders. 74. Lai, K., et al. Subthreshold Pan-Retinal Photocoagulation Using
Acta Ophthalmol. 2012;90(2):155–61. Endpoint Management Algorithm for Severe Nonproliferative
55. Gabel V-P BR, Hillenkamp F. Visible and near infrared light Diabetic Retinopathy: A Paired Controlled Pilot Prospective
absorption in pigment epithelium and choroid. XXIII Concilium Study. Ophthalmic Res. 2021;64(4):648-655.
Ophthalmologicum. 1978;450:658–62. 75. Jung JJ, Gallego-Pinazo R, Lleo-Perez A, Huz JI, Barbazetto IA.
56. Roider J, Brinkmann R, Wirbelauer C, Laqua H, Birngruber R. NAVILAS laser system focal laser treatment for diabetic macular
Subthreshold (retinal pigment epithelium) photocoagulation in edema-one year results of a case series. Open Ophthalmol J.
macular diseases: a pilot study. Br J Ophthalmol. 2000;84(1): 2013;7:48–53.
40–7. 76. Kozak I, Oster SF, Cortes MA, Dowell D, Hartmann K, Kim JS,
57. Paulus YM, Jain A, Nomoto H, Sramek C, Gariano RF, Andersen et al. Clinical evaluation and treatment accuracy in diabetic mac-
D, et al. Selective retinal therapy with microsecond exposures ular edema using navigated laser photocoagulator NAVILAS.
using a continuous line scanning laser. Retina. 2011;31(2):380–8. Ophthalmology. 2011;118(6):1119–24.
58. Brinkmann R, Roider J, Birngruber R. Selective retina therapy 77. Ober MD, Kernt M, Cortes MA, Kozak I. Time required for nav-
(SRT): a review on methods, techniques, preclinical and first clin- igated macular laser photocoagulation treatment with the Navilas.
ical results. Bull Soc Belge Ophtalmol. 2006;302:51–69. Graefes Arch Clin Exp Ophthalmol. 2013;251(4):1049–53.
59. Roider J, Liew SH, Klatt C, Elsner H, Poerksen E, Hillenkamp J,
78. Kernt M, Cheuteu R, Vounotrypidis E, Haritoglou C, Kampik A,
et al. Selective retina therapy (SRT) for clinically significant dia-
Ulbig MW, et al. Focal and panretinal photocoagulation with a
betic macular edema. Graefes Arch Clin Exp Ophthalmol.
navigated laser (NAVILAS(R)). Acta Ophthalmol. 2011;89(8):
2010;248(9):1263–72.
e662–4.
60. Brinkmann R, Schüle G, Joachimmeyer E, Roider J, Birngruber
79. Hu Z, Zhang H, Mordovanakis A, Paulus YM, Liu Q, Wang X,
R, “Determination of absolute fundus temperatures during retinal
et al. High-precision, non-invasive anti-microvascular approach
laser photocoagulation and selective RPE treatment,” Invest.
via concurrent ultrasound and laser irradiation. Sci Rep. 2017;7:
Ophthalmol. Visual Sci. (2001);42:696.
40243.
61. Paulus YM. Short-pulse laser treatment: redefining retinal therapy.
Retin Physician. 2010;2011:1–9. 80. Zhang H, Xie X, Li J, Qin Y, Zhang W, Cheng Q, et al. Removal
62. Pankratov M P. Pulsed delivery of laser energy in experimental of choroidal vasculature using concurrently applied ultrasound
thermal retinal photocoagulation. Proceedings Volume 1202, bursts and nanosecond laser pulses. Sci Rep. 2018;8(1):12848.
Laser-Tissue Interaction. 1990. https://doi.org/10.1117/12.17626 81. Paulus YM, Qin Y, Yu Y, Fu J, Wang X, Yang X. Photo-mediated
63. Flaxel C, Bradle J, Acott T, Samples JR. Retinal pigment epithe- ultrasound therapy to treat retinal neovascularization. Annu Int
lium produces matrix metalloproteinases after laser treatment. Conf IEEE Eng Med Biol Soc. 2020;2020:5244–7.
Retina. 2007;27(5):629–34. 82. DRCR N. A randomized trial comparing intravitreal triamcino-
64. Hattenbach LO, Beck KF, Pfeilschifter J, Koch F, Ohrloff C, lone acetonide and focal/grid photocoagulation for diabetic mac-
Schacke W. Pigment-epithelium-derived factor is upregulated in ular edema. Ophthalmology Ophthalmology. 2008;115(9):1447–
photocoagulated human retinal pigment epithelial cells. 145010.
Ophthalmic Res. 2005;37(6):341–6. 83. Diabetic Retinopathy Clinical Research N, Scott IU, Edwards AR,
65. Mainster MA. Decreasing retinal photocoagulation damage: prin- Beck RW, Bressler NM, Chan CK, et al. A phase II randomized
ciples and techniques. Semin Ophthalmol. 1999;14(4):200–9. clinical trial of intravitreal bevacizumab for diabetic macular ede-
66. Sivaprasad S, Elagouz M, McHugh D, Shona O, Dorin G. ma. Ophthalmology. 2007;114(10):1860–7.
Micropulsed diode laser therapy: evolution and clinical applica- 84. Diabetic Retinopathy Clinical Research N, Elman MJ, Qin H,
tions. Surv Ophthalmol. 2010;55(6):516–30. Aiello LP, Beck RW, Bressler NM, et al. Intravitreal ranibizumab
67. Kiire CSS, Chong V. Subthreshold micropulse laser therapy for for diabetic macular edema with prompt versus deferred laser
retinal disorders. Retina Today. 2011;JANUARY-FEBRUARY: treatment: three-year randomized trial results. Ophthalmology.
67-70. https://retinatoday.com/articles/2011-jan/subthreshold- 2012;119(11):2312–8.
micropulse-laser-therapy-forretinal-disorders 85. Diabetic Retinopathy Clinical Research N, Googe J, Brucker AJ,
68. Su D, Hubschman JP. A review of subthreshold micropulse laser Bressler NM, Qin H, Aiello LP, et al. Randomized trial evaluating
and recent advances in retinal laser technology. Ophthalmol short-term effects of intravitreal ranibizumab or triamcinolone
Therapy. 2017;6(1):1–6. acetonide on macular edema after focal/grid laser for diabetic
69. Luttrull JK, Dorin G. Subthreshold diode micropulse laser photo- macular edema in eyes also receiving panretinal photocoagulation.
coagulation (SDM) as invisible retinal phototherapy for diabetic Retina. 2011;31(6):1009–27.
macular edema: a review. Curr Diabetes Rev. 2012;8(4):274–84. 86. Writing Committee for the Diabetic Retinopathy Clinical
70. Sivaprasad S, Sandhu R, Tandon A, Sayed-Ahmed K, McHugh Research N, Gross JG, Glassman AR, Jampol LM, Inusah S,
DA. Subthreshold micropulse diode laser photocoagulation for Aiello LP, et al. Panretinal photocoagulation vs intravitreous
clinically significant diabetic macular oedema: a three-year follow ranibizumab for proliferative diabetic retinopathy: a randomized
up. Clin Exp Ophthalmol. 2007;35(7):640–4. clinical trial. JAMA. 2015;314(20):2137–46.
35 Page 12 of 12 Curr Diab Rep (2021) 21: 35

87. Gross JG, Glassman AR, Liu D, Sun JK, Antoszyk AN, Baker 94. Corazza P, D'Alterio FM, Younis S. Proposed algorithm during
CW, et al. Five-year outcomes of panretinal photocoagulation vs COVID-19 pandemic for patient management in medical retina
intravitreous ranibizumab for proliferative diabetic retinopathy: a clinic. Int J Retina Vitreous. 2020;6:20.
randomized clinical trial. JAMA Ophthalmol. 2018;136(10): 95. Yang KB, Feng H, Zhang H. Effects of the COVID-19 pandemic
1138–48. on anti-vascular endothelial growth factor treatment in China.
88. Tao, Y., et al. Retrospective study of aflibercept in combination Front Med (Lausanne). 2020;(7):576275.
therapy for high-risk proliferative diabetic retinopathy and diabetic 96. DA Paulus YM. A conversation with Dr. Paulus, MD, FACS, on
maculopathy. Int Ophthalmol. 2021 Jun;41(6):2157-2165. Endpoint Management™ during COVID. Retina Today.
89. Altinel, MG., et al. Comparison of the efficacy and safety of anti- 2020;15(7). https://retinatoday.com/pdfs/1020_us.pdf
VEGF monotherapy versus anti-VEGF therapy combined with 97. Moussa, M., et al. Intravitreal injections of anti-VEGF agents dur-
subthreshold micropulse laser therapy for diabetic macular edema. ing COVID-19 pandemic: clinical audit from Tanta University
Lasers Med Sci. 2021 Sep;36(7):1545-1553. Hospital. Int Ophthalmol. 2021 Apr;41(4):1437-1443.
90. Gawecki M. Subthreshold diode micropulse laser combined with 98. Obeid A, Su D, Patel SN, Uhr JH, Borkar D, Gao X, et al.
intravitreal therapy for macular edema-a systematized review and Outcomes of eyes lost to follow-up with proliferative diabetic
critical approach. J Clin Med. 2021;10(7). retinopathy that received panretinal photocoagulation versus in-
91. Nomoto H, Lavinsky D, Paulus YM, Leung LS, Dalal R, travitreal anti-vascular endothelial growth factor. Ophthalmology.
Blumenkranz MS, et al. Effect of intravitreal triamcinolone 2019;126(3):407–13.
acetonide on healing of retinal photocoagulation lesions. Retina. 99. Wubben TJ, Johnson MW, Anti VTISG. Anti-vascular endotheli-
2013;33(1):63–70. al growth factor therapy for diabetic retinopathy: consequences of
inadvertent treatment interruptions. Am J Ophthalmol. 2019;204:
92. Dot C, Behar-Cohen F, BenEzra D, Doat M, Jonet L, May F, et al.
13–8.
Influence of triamcinolone intravitreal injection on retinochoroidal
100. Kim LA, D'Amore PA. A brief history of anti-VEGF for the treat-
healing processes. Exp Eye Res. 2007;84(6):1081–9.
ment of ocular angiogenesis. Am J Pathol. 2012;181(2):376–9.
93. Lindeke-Myers, A., et al. Patient Perceptions of SARS-CoV-2
Exposure Risk and Association with Continuity of Ophthalmic
Care. JAMA Ophthalmol. 2021 May 1;139(5):508-515. Publisher’s Note Springer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.