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clinical therapeutics

Panretinal Photocoagulation for Proliferative

Diabetic Retinopathy
Neil M. Bressler, M.D., Roy W. Beck, M.D., Ph.D., and Frederick L. Ferris III, M.D.
This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion
of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies,
the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines,
if they exist, are presented. The article ends with the authors clinical recommendations.

A 55-year-old man with a 20-year history of type 2 diabetes mellitus was referred to a
retina specialist after noticing a few black floaters in his left eye for the preceding
week. His glycated hemoglobin level was 8.2%. He had no history of laser treatment
for proliferative diabetic retinopathy in either eye. Ophthalmoscopic examination of
the right eye showed venous beading, intraretinal microvascular abnormalities, and
no macular edema. Ophthalmoscopic examination of the left eye showed extensive
neovascularization of the disk, consisting of new vessels extending beyond the optic
disk in all directions (Fig. 1A). The retina specialist diagnosed severe nonproliferative
diabetic retinopathy in the right eye and high-risk proliferative diabetic retinopathy
in the left eye, with no macular edema in either eye. The specialist recommended
prompt initiation of panretinal photocoagulation in the left eye.

The Cl inic a l Probl em

From the Department of Ophthalmology, Johns Hopkins University School of
Medicine, Baltimore (N.M.B.); the Jaeb
Center for Health Research, Tampa, FL
(R.W.B.); and the National Eye Institute,
National Institutes of Health, Bethesda,
MD (F.L.F.). Address reprint requests to
Dr. Ferris at the Division of Epidemiology
and Clinical Applications, National Eye Institute, 10 Center Dr., MSC 1204, Bethesda,
MD 20892, or at ferrisf@nei.nih.gov.
N Engl J Med 2011;365:1520-6.
Copyright 2011 Massachusetts Medical Society.

Diabetic retinopathy is a common complication of diabetes mellitus. An analysis of

pooled data from several population-based studies estimated that approximately
40% of patients with diabetes who are over the age of 40 years have some retinopathy, including 8.2% who have vision-threatening retinopathy (usually diabetic macular edema but less frequently proliferative retinopathy).1 An increased duration of
diabetes and poor glucose control are major risk factors for retinopathy.2,3
Diabetic retinopathy is a leading cause of visual loss and new-onset blindness in the
United States for patients between the ages of 20 and 74 years,4 with 12,000 to 24,000
new cases of diabetic retinopathyinduced blindness each year.5 Data from the Diabetic Retinopathy Study (ClinicalTrials.gov number, NCT00000160) indicate that approximately half of all eyes with proliferative diabetic retinopathy that are left untreated
will have profound vision loss (i.e., visual acuity of <20/800 for at least 4 months), a
level of vision that interferes with the ability to identify even large objects.6
The annual economic effect of retinopathy-associated morbidity in the United States
has been estimated at more than $620 million.7 As the incidence of obesity and diabetes continues to increase, the public health effect of vision loss from diabetic retinopathy is enormous and growing.5

Pathoph ysiol o gy a nd Effec t of Ther a py

The retinal changes in diabetic retinopathy can be caused by the increased permeability of retinal capillaries, which results in edema of the retina, or to the closure
of retinal capillaries, which leads to retinal ischemia. In turn, retinal ischemia can lead
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Figure 1. Treatment Effects of Panretinal Photocoagulation.

A fundus photograph taken before treatment with panretinal photocoagulation shows neovascularization (arrows)
extending beyond the optic disk in all directions (Panel A).
A fundus photograph of the same eye taken 4 days after
treatment shows nearly complete disappearance of the
neovascularization (Panel B). A follow-up fundus photograph taken 3 weeks after treatment shows the absence
of neovascularization and the presence of pigmentation
and increasing visibility of the laser burns (Panel C).

to the formation of neovascularization, which may

lead to vitreous hemorrhage or traction damage to
the retina.
Retinal ischemia leads to the production of a
variety of growth factors, including vascular endothelial growth factor (VEGF).7 These growth
factors stimulate the formation of abnormal capillaries from the retinal vessels on the surface of the
optic disk, a condition that is termed neovascularization of the disk (Fig. 1A), or on the surface of
the retina but not near or overlying the disk, a
condition that is termed neovascularization elsewhere (image not shown). Neovascularization of
the disk and neovascularization elsewhere are the
hallmarks of proliferative diabetic retinopathy. A
patient with these features may have 20/20 vision
and no warning symptoms of visual impairment.
However, substantial vision loss can occur as these
new vessels and the contractile fibrous tissue that
eventually surrounds them grow and either bleed
into the vitreous cavity or cause detachment of
the retina between the level of the photoreceptors
and the retinal pigment epithelium.
Scatter, or panretinal, photocoagulation is the
mainstay of treatment for proliferative diabetic
retinopathy. Typically, 1200 to 1600 laser burns
(approximately 500 m in size) on the retina are
evenly spaced or scattered throughout the retinal
tissue away from the macula, focally destroying
outer photoreceptors and retinal pigment epithelium (Fig. 1B and 1C). The treatment, in general, is
not applied directly to neovascularization on the
surface of the retina and is never applied directly
over neovascularization of the disk. Rather, the
treatment is thought to exert its effect by destroying pigment epithelial cells and overlying retinal
tissue. The pigmented cells absorb the laser light,
and the resultant heat causes cellular destruction
of the outer retina.
After panretinal photocoagulation, there is improved oxygen supply to areas of inner retina that

n engl j med 365;16

had become oxygen-deprived because of poor perfusion of inner retinal vessels. This occurs both
because the choriocapillaris (the blood-vessel supply to the rods and cones and pigment epithelium)
is now physically closer to the inner retina and

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because the highly metabolically active rods and

cones are no longer present to absorb oxygen from
the choriocapillaris in the area of the burns. As a
result, there is a decreasing number of viable hypoxic cells in the inner retina producing VEGF and
other growth factors.7 Without continuous production of VEGF, the new vessels generally regress and
may disappear altogether, although stabilization of
the neovascularization with no further growth also
may occur. Rarely, neovascularization progresses
despite laser therapy and can lead to vitreous hemorrhage or retinal detachment; in such cases, vitrectomy may be necessary to preserve or restore vision.

Cl inic a l E v idence
Several randomized clinical trials have evaluated
the efficacy of panretinal photocoagulation in patients with proliferative diabetic retinopathy; these
studies were summarized in a systematic review in
2007.8 The Diabetic Retinopathy Study enrolled
1758 patients with a visual acuity of 20/100 or better in each eye and with either proliferative diabetic
retinopathy in at least one eye or severe nonproliferative diabetic retinopathy in both eyes. Each patient was randomly assigned to undergo panretinal photocoagulation in one eye, with the other eye
serving as the untreated control. Panretinal photocoagulation reduced the risk of severe vision loss
(defined as visual acuity of 20/800 or worse at two
consecutive 4-month visits) caused by complications of proliferative retinopathy from 14.0% to
6.2% during a 2-year period6 and from 33.0% to
13.9% during a 5-year period.9
The Early Treatment Diabetic Retinopathy Study
(ETDRS; NCT00000151) enrolled 3711 patients
with mild-to-severe nonproliferative or early proTable 1. Risk Factors for High-Risk Proliferative Diabetic Retinopathy.*
Any retinal neovascularization
Neovascularization at the disk or within one disk diameter of the optic disk
Severe neovascularization of the disk (i.e., at least one quarter of the area of
the optic disk) or severe neovascularization elsewhere (i.e., at least half
the area of the optic disk)
Preretinal hemorrhage (blood between the surface of the retina and the posterior surface of the vitreous) or vitreous hemorrhage (blood within the
vitreous cavity)
* High-risk proliferative diabetic retinopathy is defined as proliferative diabetic
retinopathy with at least three of the four risk factors listed. Patients who have
neovascularization that is not severe and not at the disk and who do not have
preretinal or vitreous hemorrhage have only one risk factor. An additional risk
factor is counted for each of the other features present.

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liferative diabetic retinopathy in both eyes. Each

patient was randomly assigned to undergo early
photocoagulation in one eye; photocoagulation
was deferred in the other eye until high-risk proliferative retinopathy was detected. At 5 years, rates
of severe vision loss were 2.6% with early treatment
and 3.7% with deferred treatment.4 For patients
with severe nonproliferative diabetic retinopathy
(typically, extensive dot and blot hemorrhages,
definite areas of venous beading, or a moderate
amount of intraretinal microvascular abnormalities) or with early proliferative diabetic retinopathy,
panretinal photocoagulation and vitrectomy when
necessary reduced the 5-year risk of severe vision
loss from more than 50% if left untreated to approximately 4% of eyes and 1% of patients.10

Cl inic a l Use
The current standard technique for applying panretinal photocoagulation has been elucidated in
the guidelines of the Diabetic Retinopathy Clinical
Research Network.11 Treatment is usually initiated
on the day of diagnosis in patients with high-risk
proliferative diabetic retinopathy, a finding that is
considered to be an urgent clinical condition, since
the risk of vitreous hemorrhage and vision loss in
the short term is high if the retinopathy is not treated promptly (Table 1).
There are no other absolute requirements (other
than obtaining consent) before initiating treatment
after the diagnosis has been made on ophthalmoscopy. However, a detailed retinal drawing of the
neovascularization or retinal fundus photographs
can be helpful in determining the response to treatment at follow-up. In addition, there are several elements of a comprehensive ophthalmologic examination that may be relevant to specific patients.
For example, it is important to document the visual acuity before treatment so that any subjective
changes in vision after treatment can be quantified.
Since panretinal photocoagulation can affect peripheral vision, recognition of any peripheral-field
defects before treatment is important. Measurement of intraocular pressure before the initiation
of treatment is useful; if the pressure is elevated, it
is important to differentiate unrelated open-angle
glaucoma from neovascularization in the trabecular meshwork (leading to so-called neovascular
glaucoma). Such neovascular glaucoma frequently
can be managed by panretinal photocoagulation.
If macular edema is present and the proliferative
retinopathy is considered to be less than high risk,

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Figure 2. Slit-Lamp Delivery System.

In this procedure, a specialized contact lens, coupled
onto the cornea with an ophthalmic gel, is used to view
the retina during panretinal photocoagulation. The lens
is needed to view the retina, assist with immobilization
of the eye during treatment, and allow the ophthalmologist to focus the laser appropriately onto the retina.

Figure 3. Indirect Laser Delivery System.

In this procedure, the ophthalmologist applies the laser
using a head-mounted ophthalmoscope and an indirect
lens measuring 20, 28, or 30 diopters held above the
eye. This creates a virtual (indirect) image of the retina
between the lens and the ophthalmoscope and avoids
the placement of a contact lens on the cornea.

panretinal photocoagulation often may be delayed

(though only for a few weeks or months) until after
macular edema has been treated, since the panretinal treatment could worsen the macular edema.
The use of antithrombotic agents, including aspirin,
is not a contraindication to proceeding with treatment. For patients who are acutely ill, laser therapy
can be delayed until the patient is able to attend an
outpatient appointment. If hemorrhage does develop, the presence of blood in the vitreous may interfere with the performance of panretinal photocoagulation, since the light energy will be absorbed
before reaching the retina and the view of the retina may be compromised. In this situation, there
remain the options of waiting for the hemorrhage
to clear or eventually proceeding with vitrectomy.
Panretinal photocoagulation typically is performed as an outpatient procedure in the office
setting. The pupil is dilated, followed by administration of a topical anesthetic. A specialized
contact lens, coupled onto the cornea with an
ophthalmic gel, is used to view the retina with a
slit-lamp laser delivery system and to focus the
laser appropriately onto the retina (Fig. 2).
An anesthetic injection in the retrobulbar, peribulbar, or sub-Tenons space can be administered
if the patient cannot tolerate the discomfort of the
laser burns. However, such anesthesia risks perforation of the eye, hemorrhage into the retrobulbar
space, or anesthetizing the extraocular muscles,
resulting in a loss of the patients ability to direct
his or her gaze and thereby making it difficult to
reach peripheral areas of the retina.

With a slit-lamp delivery system, a green or yellow laser with settings that produce a 500-m spot
size on the retina is typically used, with a laser
exposure time of 0.07 to 0.1 seconds. Power is
adjusted to produce a mildly white retinal burn.
Approximately 1200 to 1600 burns are administered; the edges of the burns are distributed about
1 burn width apart (Fig. 1B and 1C). The distribution of burns is planned to avoid the optic disk (to
reduce the risk of thermal damage to the optic
nerve) and the macula (to reduce the risk of impairing central vision). Laser burns are generally
not placed within the temporal retinal vessel arcades, and the burns extend anteriorly at least to
the equator of the retina (the midline between the
anterior and posterior poles of the retina).
Treatment with the slit-lamp delivery system
can be facilitated with an automated-patterndelivery device that uses extremely short duration
burns (0.02 to 0.03 seconds) with smaller spot
sizes on the retina (approximately 250 to 300 m);
the total number of burns is increased (typically
1800 to 2400 burns) in order to cover a similar area
of retinal tissue.
Instead of a slit-lamp delivery system, some
ophthalmologists prefer an indirect laser system,
in which a laser is applied by means of a headmounted ophthalmoscope and a lens that is held
above the eye (Fig. 3). This technique creates a
virtual (indirect) image of the retina between the
lens and the ophthalmoscope. The advantages of
the indirect laser system are that it does not require
the placement of a contact lens on the cornea and

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that it can more readily penetrate vitreous hemorrhage. With this system, a spot size of 400 to
500 m is created with an indirect lens measuring 20, 28, or 30 diopters with an exposure of
0.05 to 0.1 seconds.
Treatment with panretinal photocoagulation is
completed in one or more sittings, depending on
the patients tolerance for the discomfort of the
laser. The degree of discomfort ranges from mild
discomfort to more severe discomfort that can be
tolerated only with retrobulbar anesthesia. If more
than one sitting is required, the course of therapy
is usually completed within a month after the initiation of treatment. If both eyes require treatment,
they can be treated on the same day, but most
patients prefer to have the second eye treated at a
later date (usually within a week after treatment
of the first eye).
After any session of panretinal photocoagulation, the patient should be aware that vision in the
treated eye will be blurry for the next several hours
because of the use of bright light and placement of
the corneal contact lens during treatment. In general, the patient should not drive home immediately after the treatment.
Once panretinal photocoagulation is completed, patients are advised to contact the ophthalmologist if they have pain that is not relieved by
over-the-counter analgesics or if they note any
substantial vision loss. If there are no problems
after completion of the treatment, follow-up evaluation usually occurs within the first month and
then 3 to 4 months after the completion of treatment in order to confirm that the neovascularization either regresses or stabilizes. If the neovascularization increases in size or if new areas of
neovascularization develop, then additional panretinal photocoagulation is applied.
In 2011, the cost of panretinal photocoagulation was estimated to be approximately $1,080 on
the basis of the average Medicare charges for this
procedure in the mid-Atlantic region. One analysis
calculated that the overall cost of screening and
treatment for eye disease in patients with diabetes
mellitus is approximately $3,190 per quality-adjusted life-year saved.12

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ma involving the center of the macula at baseline,

an evaluation that was performed 4 months after
baseline panretinal photocoagulation showed that
19% of the patients lost approximately two or more
lines on a visual-acuity chart, including 11% who
lost approximately three or more lines (unpublished data). Patients with diabetic macular edema
involving the center of the macula appear to be
more likely to have increased macular edema and
loss of visual acuity in the short term after panretinal photocoagulation13 than patients without
macular edema who receive such treatment.14
Because panretinal photocoagulation destroys
viable retinal tissue, the procedure can cause visual symptoms related to the loss of function of
the burned retinal tissue. Such symptoms include
peripheral visual-field defects, reduced night vision, diminished color vision, and decreased contrast sensitivity.15 Other possible adverse effects
include choroidal effusions or choroidal detachment (<1% of cases), which may cause transient
myopia or increased intraocular pressure. The
most serious (but very infrequent) complications
are misdirected burns or excessively intense burns,
which may cause macular damage, bleeding from
the choriocapillaris, or the development of iatrogenic choroidal neovascularization.16-23

A r e a s of Uncer ta in t y

Multiple studies have concluded that VEGF is a

major cause of neovascularization in retinal diseases, including proliferative diabetic retinopathy.24-34
Thus, the inhibition of VEGF would be expected
to reduce neovascularization in this condition.
Several clinical case reports and small case series
have shown that anti-VEGF therapy can result
in transient regression of neovascularization in
proliferative diabetic retinopathy.35-40 Although
anti-VEGF treatment has been shown to reduce
neovascularization, it remains unclear how many
injections would be necessary to sustain this
benefit and whether the risks and costs of periodic intravitreal injections would outweigh the
benefits of avoiding the side effects of panretinal
photocoagulation.
Intravitreal glucocorticoids also have been
shown
to have a beneficial effect on proliferative
A dv er se Effec t s
diabetic retinopathy.41,42 However, because of the
The most common complication of panretinal high rate of cataract and glaucoma side effects,
photocoagulation is the exacerbation of macular such treatment does not seem warranted at this
edema. In the ETDRS, in patients with such ede- time for most patients.
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R ec om mendat ions

fourth risk factor. Prompt initiation of panretinal

photocoagulation in the left eye is recommended
to reduce the risk of severe loss of visual acuity.
Because the patient has no macular edema, it is
unlikely that vision loss from macular edema that
is caused by the treatment will develop. The consent
process should include a discussion regarding the
risks of permanent loss of peripheral and night vision, as well as discomfort or pain during the procedure and within 24 hours after the procedure.
The patient should be advised that whether the
treatment is completed in one or more sittings, it
is important to complete panretinal photocoagulation as soon as possible before severe vitreous
hemorrhage occurs. The patient will need to return
for follow-up approximately a month after panretinal photocoagulation is completed. Also, the
right eye needs to be monitored approximately every 4 months for progression to proliferative diabetic retinopathy, because of the presence of severe
nonproliferative diabetic retinopathy in that eye.
Some ophthalmologists might initiate treatment in
the right eye at this point, because with long-term
follow-up, virtually all such eyes eventually need
treatment.44 Finally, the patient should be reminded to work with his primary care provider to try
to optimize both diabetes management and general medical care, because control of diabetes and
blood pressure can influence the progression of
retinopathy.45,46

The patient who is described in the vignette has

proliferative diabetic retinopathy in the left eye with
four high-risk features, including the presence of
neovascularization, severe neovascularization, and
neovascularization at the disk. A small amount of
vitreous hemorrhage, not seen in the fundus photograph, caused the apparent floaters and is the

Dr. Bressler reports that his institution has received grant

support from Abbott Medical Optics, Alimera Sciences, Allergan,
Bausch & Lomb, ForSight Labs, Genzyme, Lumenis, Notal Vision,
Novartis, QLT, Regeneron, and Genentech. No other potential
conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank the Diabetic Retinopathy Clinical Research Network
for providing background material on proliferative diabetic retinopathy and diabetic macular edema.

Guidel ine s
The American Academy of Ophthalmologys Preferred Practice Pattern for Diabetic Retinopathy,43
which is based on the Diabetic Retinopathy Study
and the ETDRS (level 1 evidence), recommends
panretinal photocoagulation for patients with
high-risk proliferative diabetic retinopathy or a
condition that is approaching high risk. On the
basis of additional analyses of visual outcomes
from the ETDRS, the Preferred Practice Pattern also
states that for patients with severe nonproliferative
diabetic retinopathy or proliferative diabetic retinopathy that is not high risk, panretinal photocoagulation should be considered before the development of high-risk proliferative retinopathy,
especially in patients with type 2 diabetes. The
Preferred Practice Pattern notes that in some patients with severe vitreous or preretinal hemorrhage, it may be impossible to perform panretinal
photocoagulation. In other cases, neovascularization may persist despite extensive panretinal photocoagulation. In each of these circumstances,
vitreous surgery may be indicated to remove hemorrhage and fibrous tissue. In such cases, panretinal photocoagulation may be performed at the
time of surgery with a laser probe inserted into the
middle cavity of the eye.

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