D R UG TH ERA PY
Drug Therapy
A L A S T A I R J . J . W O O D , M. D. , Editor
T REATMENT OF D IABETIC
R ETINOPATHY
FREDERICK L. FERRIS III, M.D., MATTHEW D. DAVIS, M.D.,
AND LLOYD M. AIELLO, M.D.
D
IABETIC retinopathy has been and proba-
bly remains one of the four major causes of
blindness in the United States.1,2 The risk of
retinopathy is directly related to the degree and du-
ration of hyperglycemia.3 After diabetes mellitus has
been present for 20 years, almost all persons in whom
the onset of diabetes occurred before the age of 30
years have some evidence of retinopathy, and about
half have proliferative retinopathy. Persons who are
30 years of age or older when diabetes develops are
at lower risk for retinopathy, but in this group reti-
nopathy may be the first sign of diabetes. In these
older patients, those who require insulin are at high-
er risk for retinopathy than those who do not re-
quire insulin. The 20-year prevalence of any type of
retinopathy is about 80 percent among older pa-
tients who require insulin and 20 percent among
those who do not require insulin; the respective rates
of proliferative retinopathy are 40 percent and 5 per-
cent. The risk of clinically important macular edema
is 10 to 15 percent after diabetes has been present for
15 to 20 years, regardless of the age at onset or
whether insulin is required. Blindness occurs not only
as a result of the sequelae of proliferative diabetic
retinopathy and macular edema, but also because of
an increase in cataracts and glaucoma.4-8
Prevention of retinopathy is the best approach to
reducing the risk of blindness among patients with
diabetes, but this is not yet possible in most patients.9
Without treatment, patients in whom proliferative
diabetic retinopathy develops have at least a 50 per-
cent chance of becoming blind within five years.10-12
The appropriate use of treatments that have been de-
veloped in the past three decades can reduce this risk
of blindness to less than 5 percent.13
In this review we define diabetic retinopathy, de-
From the National Eye Institute, National Institutes of Health, Bethesda,
Md. (F.L.F.); the Department of Ophthalmology and Visual Sciences,
University of Wisconsin, Madison (M.D.D.); and Beetham Eye Institute,
Joslin Diabetes Center, Boston (L.M.A.). Address reprint requests to Dr.
Ferris at the Division of Biometry and Epidemiology, 31 Center Dr., MSC-
2510, Bldg. 31, Rm. 6A52, Bethesda, MD 20892-2510, or at rickferris@
nei.nih.gov.
©1999, Massachusetts Medical Society.
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scribe the treatments that are available, and evaluate
the efficacy of these treatments.
CLINICAL MANIFESTATIONS
The retinal changes in patients with diabetes re-
sult from five fundamental processes: the formation
of retinal capillary microaneurysms, the develop-
ment of excessive vascular permeability, vascular oc-
clusion, the proliferation of new blood vessels and
accompanying fibrous tissue on the surface of the
retina and optic disk, and the contraction of these
fibrovascular proliferations and the vitreous.14-20 Ret-
inal capillary microaneurysms are the first visible le-
sions of diabetic retinopathy, but they also occur in
patients with other retinal vascular diseases, particu-
larly those associated with vascular occlusion. These
microaneurysms are hypercellular saccular outpouch-
ings from the capillary wall. Histologic studies of
eyes of humans with diabetic retinopathy, particular-
ly studies using the trypsin or elastase digest tech-
nique,21 and of experimental diabetic retinopathy in
dogs and rats indicate that the initial lesion is the
loss of intramural capillary pericytes (Fig. 1), with
subsequent formation of microaneurysms and the
eventual development of acellular capillaries and clo-
sure of capillaries.22-25 Although the mechanism un-
derlying the formation of microaneurysms is un-
known, possible mechanisms include the release of a
vasoproliferative factor from dying cells, weakness of
the capillary wall (perhaps from loss of pericytes),
and increased intraluminal pressure caused by abnor-
malities of the adjacent retina.26-28
Microaneurysms without any of the other compo-
nents of diabetic retinopathy have no apparent clinical
importance except as a marker of the development of
diabetic retinopathy. However, the total number of
microaneurysms present in the retina is correlated
with the risk of progression of retinopathy.29-31 When
excessive vascular permeability is associated with
microaneurysms, vision can be threatened by the de-
velopment of macular edema.32,33 Fluorescein angi-
ography can be used to identify patients with exces-
sive vascular permeability, but leakage of fluorescein
into the retina does not necessarily indicate macular
edema.
Macular edema is defined as retinal thickening
resulting from the accumulation of fluid and can
best be seen with the use of a binocular slit lamp or
stereoscopic fundus photography. Although retinal
thickening is difficult to recognize with use of the
ophthalmoscope, it is often associated with hard ex-
udates. These well-defined, yellow-white lipid deposits
within the outer retina are easily recognized and are
often present at the border of the retinal edema (Fig.
2). Edema may come and go within the retina, with
no visual consequences, but lipid deposits, especially
when they are beneath the center of the macula, are
often associated with retinal damage and permanent
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 The Ne w E n g l a nd Jo u r n a l o f Me d ic ine

P
PG
AC P
P

PG
EN MA AC
P
AC

AC
PG

EN
PG PG
P EN
P 10 µm
EN
10 µm

A B

Figure 1. Photomicrographs of Elastase Digest Preparations of the Retinal Vasculature of the Eye of a Patient with Mild, Nonprolif-
erative Diabetic Retinopathy (Periodic Acid–Schiff and Hematoxylin).
Panel A shows normal pericytes (P) and endothelial cells (EN) as well as degenerated pericytes, seen as pericyte “ghosts” (PG), and
acellular capillaries (AC). A saccular microaneurysm (MA) is present in Panel B. (Photographs courtesy of W. Gerald Robison, Jr.)

loss of vision.34,35 The extent of these lipid deposits is Figure 2 (facing page). Eye of a Patient with Mild, Nonprolifer-
correlated with serum lipid concentrations.36,37 Pa- ative Diabetic Retinopathy and Macular Edema.
tients whose eyes have microaneurysms, with or with- In Panel A, a small zone of retinal thickening is present above
the center of the macula. This finding can be seen in stereopho-
out associated retinal edema, are classified as having tographs, but its presence can only be inferred in this photo-
mild, nonproliferative diabetic retinopathy. graph. The area of retinal thickening includes several small-
Vaso-obliteration occurs as small areas of acellular to-medium-sized microaneurysms and is partially surrounded
capillaries become confluent or terminal arterioles be- by hard exudates. The retinal thickening and hard exudates ex-
tend to within 500 µm of the center of the macula, but the center
come occluded. Clusters of microaneurysms and tor- is not involved. Panel B shows the early-phase fluorescein angio-
tuous, hypercellular vessels are often present adjacent gram. Two clumps of moderately large microaneurysms are
to these areas of nonperfused retina. It is difficult to present in the thickened zone approximately 1500 to 2000 µm
determine whether these vessels are new or are just from the center of the macula; there are scattered microaneu-
preexisting capillaries that have become dilated. The rysms elsewhere. The capillaries appear slightly dilated, partic-
ularly in the thickened areas. Panel C shows the late-phase
term “intraretinal microvascular abnormalities” is used fluorescein angiogram. There is leakage of fluorescein into the
to include both possibilities. As capillary closure be- thickened retina, principally from the two clumps of micro-
comes widespread, it is common to see many intra- aneurysms.
retinal hemorrhages and dilated segments of retinal
veins (venous beading). The severity of intraretinal
microvascular abnormalities, intraretinal hemorrhag-
es, and venous beading is directly associated with the
risk of proliferative retinopathy. A patient is classi-
fied as having moderate or severe nonproliferative
diabetic retinopathy, depending mostly on the extent
and severity of these three lesions (Fig. 3).38 In this
review we have included “red-free” photographs, in
which the red hue has been filtered out to increase
the contrast between the microvascular lesions and
the background. This effect can be achieved clinically
with the green filter on the ophthalmoscope.

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic ine

Figure 3. Fundus Photographs of the Eyes of Patients with Diabetic Retinopathy.

Panel A shows retinal hemorrhages and microaneurysms. The severity of nonproliferative diabetic ret-
inopathy is classified as moderate if these abnormalities are present in one of the four quadrants of
the fundus, as moderately severe if they are present in two or three quadrants, and as severe if they
are present in all four quadrants. Other intraretinal findings used to determine the severity of nonpro-
liferative diabetic retinopathy include venous beading and intraretinal microvascular abnormalities.
Panel B shows the eye of a patient with severe nonproliferative diabetic retinopathy or early prolifer-
ative diabetic retinopathy. The hemorrhages and microaneurysms are somewhat more severe than
those in Panel A, and there is venous beading. There are several areas of small, tortuous vessels that
are either intraretinal microvascular abnormalities or new vessels.

Proliferative diabetic retinopathy is defined as the
presence of new vessels on the surface of the retina
or optic disk. New vessels tend to arise in the pos-
terior part of the retina and are associated with ret-
inal ischemia. When such vessels are on or within
1 disk diameter of the optic disk, the finding is com-
monly designated as neovascularization near the disk
(Fig. 4) and is considered separately from new ves-
sels elsewhere. This distinction is made because of the
worse prognosis for patients with neovascularization
near the disk.12,38-43
The usual course of diabetic neovascularization is

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 D R UG TH ERA PY

Figure 4. Fundus Photograph of the Eye of a Patient with Neovascularization near the Optic Disk.
Patients whose eyes have new vessels of this size or greater on or within 1 disk diameter of the optic
disk are at high risk for blindness without treatment.

one in which proliferation is followed by regression,
but the time course of the development of new ves-
sels varies greatly, from weeks to many years.15,16
Initially, the neovascularization consists of budding
endothelial cells. These new vessels are eventually sur-
rounded by translucent fibrous tissue, which becomes
increasingly opaque as the neovascularization regress-
es. The fibrovascular tissue usually becomes adherent
to the posterior vitreous and can remain attached
even after the new vessels regress. Contraction of the
vitreous, which occurs normally with aging and at a
more rapid rate in patients with proliferative diabetic
retinopathy, can cause traction on the new vessels,
with resultant hemorrhage or retinal detachment.
Traction on the new vessels and retina can also result
if the fibrous tissue associated with the new vessels
contracts sufficiently.
Loss of vision in patients with proliferative diabet-
ic retinopathy is most commonly related to traction
on the new vessels and not to the new vessels them-
selves. In the absence of fibrovascular tissue, the vit-
reous can usually pull away from the retina as it con-
tracts. In the presence of fibrovascular proliferations,
these abnormalities and the retina from which they
arise can be pulled forward, often resulting in local-
ized areas of tractional retinal detachment. In addi-
tion, the fibrovascular proliferations themselves can
contract, further increasing the tension on the fragile
new vessels.16,17 This tension can lead to vitreous
hemorrhage. The amount ranges from virtually un-
noticeable bleeding to complete filling of the eye with
blood, causing loss of all vision except light percep-
tion. Hemorrhages then tend to recur periodically,
usually without any obvious precipitating event and
often during sleep.44,45 Although the proliferative ret-
inopathy tends to regress eventually, the recurrent
hemorrhages and traction on the retina usually lead
to severe visual loss before regression is complete.
The prevalence of proliferative retinopathy — and
of blindness related to this condition — is directly
associated with the duration of diabetes and the de-
gree to which blood glucose concentrations have
been elevated.46-48
PREVENTION
Preventing diabetic retinopathy from developing
or progressing would be the most effective approach
to preserving vision. For years, there was debate about
whether improved control of blood glucose concen-
trations would reduce the long-term complications
of diabetes, including diabetic retinopathy. The Di-
abetes Control and Complications Trial (DCCT)
was initiated to address this important clinical and
scientific question.49 In this study, 1441 patients with
type 1 diabetes (726 with no retinopathy and 715
with mild-to-moderate nonproliferative retinopathy at
base line) were randomly assigned to receive either
intensive or conventional therapy and were followed
for a mean of 6.5 years. There was not only a remark-
able reduction in the rate of the development or pro-
gression of retinopathy (on the basis of the central
grading of fundus photographs with use of a scale
that ranged from no retinopathy to proliferative ret-
inopathy) among patients assigned to intensive treat-
ment (Fig. 5), but also a reduction in the progression
of diabetic nephropathy and neuropathy.9,50,51

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60
Percentage of Patients
50
40
Conventional therapy
30
20
10
0
0 1 2 3
Year of Study
NO. OF PATIENTS
Conventional< 378 375
therapy
Intensive< 348 342
therapy
Figure 5. Cumulative Incidence of a Sustained Change in Reti-
nopathy among Patients Who Had Type 1 Diabetes without
Diabetic Retinopathy at Base Line and Who Were Randomly
Assigned to Receive Intensive or Conventional Therapy.
Reprinted from the Diabetes Control and Complications Trial9
with the permission of the publisher.
A smaller randomized clinical study of 102 pa-
tients with type 1 diabetes who were followed for
more than seven years also found that intensive treat-
ment reduced all three of the major microvascular
complications of diabetes.52 These results, combined
with those of observational studies,48 implicate hy-
perglycemia in the development of the chronic mi-
crovascular complications of diabetes.
Glycemic control has similar beneficial effects on
the incidence and progression of microvascular com-
plications in patients with type 2 diabetes as in
patients with type 1 diabetes,53 as demonstrated by
randomized studies in the United Kingdom and
Japan.54-56
The microvascular complications associated with
hyperglycemia take years to develop.9,48,52,53 It may
also take years for the benefits of lowering blood glu-
cose concentrations to be realized. Early studies of
the effect of glycemic control on retinopathy dem-
onstrated an unanticipated and paradoxical worsen-
ing of retinopathy during the first several years of
follow-up among patients in whom hyperglycemia
was markedly reduced.57-63 However, among patients
with mild-to-moderate nonproliferative retinopathy,
this early worsening was not usually associated with
visual loss, and the long-term benefits of intensive
treatment counterbalanced the early worsening.64
When intensive treatment is to be instituted in pa-
tients who have proliferative or severe nonprolifera-
tive retinopathy, ophthalmologic consultation is de-
sirable because photocoagulation may be indicated.64
Better control of hyperglycemia lowers but does
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The Ne w E n g l a nd Jo u r n a l o f Me d ic ine
not eliminate the risk of retinopathy and other com-
P<0.001 plications of diabetes. The search for additional meth-
ods of averting and treating retinopathy continues.
Some currently available treatments slow the pro-
gression of diabetic retinopathy or reduce its com-
plications, whereas others, such as aspirin, do not.
Intensive therapy Patients with diabetes are at increased risk for hy-
pertension,65,66 and hypertension was a risk factor for
diabetic retinopathy in most but not all epidemiologic
4 5 6 7 8 9 studies.6,47,67-70 A randomized clinical trial of lisino-
pril, an inhibitor of angiotensin-converting enzyme,
suggested that inhibition of this enzyme or blood-
pressure lowering, even in normotensive persons,
220 79 52 may slow the progression of diabetic retinopathy.71
Data from the United Kingdom Prospective Diabe-
202 78 49
tes Study suggest that the blood-pressure lowering,
rather than a specific retinal vascular response to the
inhibition of angiotensin-converting enzyme, may
be responsible for slowing the progression of reti-
nopathy.72,73 In that placebo-controlled study, both
captopril, another angiotensin-converting–enzyme
inhibitor, and atenolol, a beta-adrenergic antagonist,
slowed the progression of retinopathy equally well.
Patients with diabetes who have high serum lipid
concentrations have an increased risk of both prolif-
erative retinopathy and vision loss from macular ede-
ma and associated retinal hard exudates.36,37 Reducing
the hyperlipidemia may lower this risk.
Aldose reductase facilitates the conversion of glu-
cose to sorbitol, which accumulates in cells during
hyperglycemia and may result in cell death.74-76 Ex-
periments in animals suggest that inhibition of al-
dose reductase could slow the development of dia-
betic retinopathy.77,78 However, clinical studies in
patients with diabetes have not yet demonstrated any
slowing of the progression of retinopathy with the
use of this approach. In the placebo-controlled Sor-
binil Retinopathy Trial, which included 497 patients
with type 1 diabetes and little or no retinopathy, the
progression of diabetic retinopathy and neuropathy
was not reduced by the administration of sorbinil for
three to four years.79,80 In addition, clinical trials of
drugs that impede angiogenesis, such as inhibitors
of vascular endothelial growth factor and antagonists
of the secretion and action of growth hormone, and
inhibitors of protein glycosylation are under way.81-84
PHOTOCOAGULATION
Blindness resulting from proliferative diabetic ret-
inopathy was a growing public health problem in the
1960s. Although several possible treatments were be-
ing tried, there was uncertainty about the best ap-
proach.19 Photocoagulation had been introduced in
the 1950s and was initially used to coagulate patches
of new vessels on the surface of the retina.85 It soon
became apparent that extensive retinal photocoagu-
lation seemed to have a beneficial, although unex-
plained, indirect effect on both neovascularization
The New England Journal of Medicine
Copyright © 1999 Massachusetts Medical Society. All rights reserved.
 D R UG TH ERA PY

Patients with Severe<

and macular edema.86 By the early 1970s, a few small 40
clinical trials had indicated that photocoagulation

Visual Loss (%)

might be an effective treatment.87 30
Because of the public health importance of the Control
disease and doubt about the optimal treatment, the 20
Argon treatment
Diabetic Retinopathy Study was organized in 1971 by
the newly formed National Eye Institute to test the 10
Xenon treatment
effect of photocoagulation on diabetic retinopathy.
This study enrolled 1742 patients with severe non- 0
0 1 2 3 4 5
proliferative or proliferative diabetic retinopathy and
visual acuity of 20/100 or better in each eye.88 The Follow-up (yr)
age distribution of the patients was bimodal: 23 per- NO. OF EYES
cent were 20 to 29 years of age, 17 percent were 30 Control 1742 1624 1381 1187 960 519
to 39, 18 percent were 40 to 49, and 27 percent were Argon< 867 818 738 658 560 310
50 to 59. The majority were white (94 percent), and treatment
more than half were men (56 percent). One eye of Xenon< 875 816 754 700 597 341
treatment
each patient was randomly assigned to undergo pho-
tocoagulation, and the other eye no treatment. One Figure 6. Cumulative Incidence of Severe Visual Loss among
of two photocoagulation techniques, either the xenon Patients with One Untreated (Control) Eye and One Eye Treated
arc or the newly developed argon laser, was random- with Either an Argon Laser or a Xenon-Arc Photocoagulator.
ly selected. Severe visual loss was defined as visual acuity that was worse
than 5/200 on two consecutive follow-up visits four months
All treated eyes received both direct and scatter apart. P<0.001 for the comparison of both treated groups with
photocoagulation. Direct treatment involved photo- the control group.
coagulation of abnormal new vessels. All neovascu-
larization elsewhere was treated directly with either
method, but neovascularization near the disk was
treated directly only with the argon laser. Direct treat- group were 11 percent and 3 percent, respectively.
ment was also used for microaneurysms or other Subjectively, many patients noticed difficulties in
lesions thought to be causing macular edema. Scat- dark adaptation and driving at night after either
ter photocoagulation consisted of photocoagulation treatment.
throughout the middle and peripheral portions of In an attempt to identify patients for whom the
the retina, with each burn separated from its neigh- benefits of treatment clearly outweighed the risks,
bors by 1 burn-width. This resulted in a polka-dot the Diabetic Retinopathy Study identified features of
pattern of burns in the retina that extended from the retinopathy associated with a particularly high risk of
temporal vascular arcades to beyond the equator. In severe visual loss.40,90-92 These features were neovas-
general, the argon-laser burns were smaller and less cularization accompanied by vitreous hemorrhage or
intense than the xenon-arc burns. obvious neovascularization on or near the optic disk
Analysis of follow-up data from that five-year study (Fig. 4), even in the absence of vitreous hemorrhage.
demonstrated a 50 percent reduction in severe visual After two years of follow-up, the rates of severe vis-
loss in the eyes that had been treated with photoco- ual loss in eyes with these high-risk characteristics
agulation (Fig. 6).89,90 Severe visual loss was defined were 26 percent in the control group and 11 percent
as visual acuity of 5/200 or worse (i.e., an inability in the treated group. The risk of severe visual loss at
to read the top line of the Snellen chart at a distance two years was much lower (7 percent and 3 percent,
of 1.5 m [5 ft]) on two or more consecutive follow- respectively) among the patients who had prolifera-
up visits four months apart. Both treatments had tive diabetic retinopathy but no high-risk character-
some harmful effects, but they were greater in the istics. The rates were even lower among patients with
eyes that had been treated with the xenon arc.40,91,92 nonproliferative retinopathy.90
There was a small decrease in the visual field in 25 On the basis of these results and clinical experi-
percent of the xenon-treated eyes and a more severe ence, photocoagulation with the argon laser rather
decrease in an additional 25 percent, as compared than the xenon arc is recommended, because the ar-
with a small decrease in the visual field in only 5 per- gon laser has fewer side effects. Direct treatment of
cent of the eyes that were treated with the argon la- neovascularization near the disk, although part of the
ser. About 19 percent of the xenon-treated eyes had original protocol of the Diabetic Retinopathy Study,
a persistent decrease in visual acuity of one line on has generally been discontinued. In the Diabetic Ret-
the Diabetic Retinopathy Study visual-acuity chart inopathy Study, the argon-laser treatment included
that was probably related to the treatment, and an ad- direct photocoagulation of neovascularization near
ditional 11 percent had a persistent decrease of two the disk, whereas this approach was not possible with
or more lines. The estimates for the argon-treated the xenon arc. There was no increase in the rate of

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic ine

regression of neovascularization near the disk in the

Patients with Severe<

20
argon-treated group, but there was an increased risk

Visual Loss (%)

of hemorrhage during focal treatment. 15
Although scatter photocoagulation was beneficial
for patients with high-risk retinopathy, the question 10
P<0.01
remained whether treatment at an earlier stage would
offer greater benefits. The Early Treatment Diabetic 5 Deferred treatment

Retinopathy Study (ETDRS) was designed to ad- Early treatment

dress this question, as well as questions related to the
treatment of diabetic macular edema and the admin-
istration of aspirin.93,94 The 3711 patients enrolled in
the study had mild-to-severe nonproliferative or ear-
ly proliferative diabetic retinopathy, with or without
diabetic macular edema. As compared with the pa-
tients in the Diabetic Retinopathy Study, those in
the ETDRS were somewhat older (52 percent were
older than 50 years of age), a smaller percentage was
white (76 percent), and the same percentage was
male (56 percent); 70 percent of patients had type
2 diabetes. All the patients were randomly assigned
to take 650 mg of aspirin or placebo per day in order
for the investigators to assess whether the antiplate-
let effect of aspirin would affect the microcirculation
of the retina and slow the development of diabetic
retinopathy.95-99 One eye of each patient was random-
ly assigned to immediate photocoagulation, whereas
the other eye was assigned to deferred photocoagu-
lation (i.e., careful follow-up and prompt scatter pho-
tocoagulation if high-risk retinopathy developed). If
the eye assigned to immediate photocoagulation had
macular edema, photocoagulation of areas of edema
was also performed, including direct (focal) treatment
of leaking microaneurysms and “grid” treatment with
scattered, small laser burns in areas of diffuse leakage.93
Treatment with aspirin did not affect the progres-
sion of retinopathy, the risk of visual loss,94 or the
risk of vitreous hemorrhage among patients with pro-
liferative retinopathy.100 It reduced the risk of mor-
bidity and death from cardiovascular disease by 17
percent.101 Therefore, aspirin therapy should be con-
sidered for patients with diabetes, not because of any
effect on diabetic retinopathy but because of its ef-
fect in patients at increased risk for cardiovascular
disease. The presence of proliferative diabetic retinop-
athy should not be considered a contraindication to
aspirin therapy.
The ETDRS used a factorial study design with re-
spect to aspirin (randomization of patients) and pho-
tocoagulation (randomization of eyes). Because as-
pirin had little if any effect on any of the ocular
outcome variables and it was not associated with any
statistically significant interactions with photocoag-
ulation treatment, all comparisons of early and de-
ferred photocoagulation combined the aspirin and
placebo groups. Early photocoagulation resulted in
a slightly lower incidence of severe visual loss than
did deferred treatment (Fig. 7), but the five-year rates
were low in both groups (2.6 percent and 3.7 per-
0
0 1 2 3 4 5 6 7
Follow-up (yr)
NO. OF EYES
Deferred< 3711 3599 3467 3300 2887 2160 1418 767
treatment
Early< 3711 3601 3465 3313 2921 2212 1454 788
treatment
Figure 7. Cumulative Incidence of Severe Visual Loss among
Patients Who Had One Eye Assigned to Deferred Photocoagu-
lation and One Eye Assigned to Early Photocoagulation.
Severe visual loss was defined as visual acuity that was worse
than 5/200 on two consecutive follow-up visits four months
apart.
cent, respectively).102 For patients with only mild-to-
moderate nonproliferative retinopathy, the rates of
severe visual loss were even lower, and any reductions
in the incidence of visual loss as a result of early pho-
tocoagulation did not seem sufficient to compensate
for the unwanted side effects of treatment. Among
patients with very severe nonproliferative or early
proliferative retinopathy, the risk–benefit ratio was
more favorable. Therefore, it is reasonable to consider
the use of scatter photocoagulation before high-risk
proliferative retinopathy has developed.
A more recent analysis of the ETDRS data sug-
gests that early treatment with scatter photocoagula-
tion may be particularly effective in reducing the risk
of severe visual loss in patients with type 2 diabe-
tes.103 These data provide an additional reason to rec-
ommend early scatter photocoagulation in older pa-
tients with very severe nonproliferative or early
proliferative diabetic retinopathy.
The ETDRS results also provided important in-
formation that can be used to guide the treatment
of patients with diabetic macular edema,104-107 since
treatment with a combination of focal and grid pho-
tocoagulation reduced the risk of moderate loss of
visual acuity in patients with macular edema by
about 50 percent (Fig. 8). However, not all patients
with macular edema need immediate treatment. Im-
mediate photocoagulation is beneficial if the edema
involves or threatens the center of the macula, but
treatment may be deferred if this is not the case. Pa-
tients can perceive the scotomas related to the focal
laser burns. Careful follow-up, with intervention only
when retinal thickening or lipid deposits threaten or

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 D RUG TH ERA PY

Patients with Loss of<

40
TABLE 1. RECOMMENDED SCHEDULE FOR EYE EXAMINATIONS
Visual Acuity (%) IN PATIENTS WITH DIABETES MELLITUS.
30
No treatment
20 MINIMAL INTERVAL
RECOMMENDED TIME BETWEEN ROUTINE
TIME OF ONSET OF DIABETES OF FIRST EXAMINATION FOLLOW-UP VISITS
10
Argon treatment At less than 30 years of age 5 Years after onset 12 Months
or at puberty
0
0 1 2 3 At 30 years of age or older At time of diagnosis 12 Months
Before pregnancy Just before or soon At least every
Follow-up (yr) after conception 3 months
NO. OF EYES
No treatment 853 717 497 311
Argon< 434 375 249 168
treatment

Figure 8. Proportion of Eyes in Patients with Mild-to-Moderate

thy is still among the leading causes of visual loss
Nonproliferative Diabetic Retinopathy and Macular Edema In- among working-age persons in the United States.
volving the Center of the Macula That Had a Loss of Visual Acu- This fact is surprising because, when proliferative di-
ity, According to Whether They Were Assigned to Immediate abetic retinopathy is properly treated, the five-year risk
Focal Treatment with an Argon Laser for Macular Edema or No of blindness is reduced by 90 percent and the risk of
Treatment for Macular Edema.
visual loss from macular edema is reduced by 50 per-
Loss of visual acuity was defined as a doubling of the initial vis-
ual angle from base line (e.g., from 20/40 at base line to 20/80). cent.13,104 Only 50 percent of patients with diabetes
P<0.01 for the comparison of the results of each visit after the undergo regular eye examinations involving dilation of
four-month visit. the pupils, and many patients go blind without treat-
ment,118-120 despite the fact that the value of screen-
ing has been well documented.121
Many professional groups, including the Ameri-
involve the center of the macula, can reduce the risk can Diabetes Association, the American College of
of visual loss and limit the need for treatment.107 Physicians, the American Academy of Ophthalmolo-
gy, and the American Optometric Association, have
VITRECTOMY provided guidelines for the scheduling of eye exam-
While photocoagulation was being developed, the inations in patients with diabetes (Table 1). Height-
availability of new instruments and techniques made ened emphasis on identifying patients at risk and the
it possible for surgeons to remove the vitreous gel availability of new screening methods should reduce
and operate in the posterior aspect of the eye. Using the number of patients who do not have regular eye
small instruments inserted in the eye at the pars plana, examinations. Improved patient-education programs,
surgeons can cut the vitreous, suction the gel, and such as the National Eye Health Education Program,
replace it with aqueous fluid. Fibrous tissue can be can motivate patients to take better care of them-
removed, and areas of retinal detachment flattened. selves.122-124 Access to educational materials and facil-
This type of surgery, referred to as vitrectomy, dra- ities that will enable patients to improve the control
matically improved the vision of many patients with of their diabetes will also reduce the incidence of
severe vitreous hemorrhage.108-110 The Diabetic Ret- secondary complications. Although methods of treat-
inopathy Vitrectomy Study identified the benefits and ment have improved, prevention remains the ulti-
risks of vitrectomy in patients with severe vitreous mate goal.125-128
hemorrhage or very severe neovascularization even
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