Chapter 30

Diabetic Retinopathy
Brett J. Rosenblatt
William E. Benson
CLINICAL FINDINGS
Diabetic retinopathy is usually divided into nonproliferative diabetic retinopathy (NPDR) and
proliferative diabetic retinopathy (PDR).
EARLY NONPROLIFERATIVE DIABETIC RETINOPATHY
Although microaneurysms are the first ophthalmoscopically detectable change in diabetic
retinopathy, the earliest abnormalities seen histopathologically are thickening of the capillary
basement membrane1,2 and pericyte dropout.3,4 Pericytes are mesothelial cells that surround and
support the retinal capillary endothelial cells. Normally there is one pericyte per endothelial cell.
In people with diabetes, however, the pericytes die off and are decreased in number (Fig. 1).
Their absence weakens the capillaries and permits thin-walled dilatations, called
microaneurysms, to develop. Later, endothelial cells proliferate and lay down layers of basement
membrane material. Fibrin may accumulate within the microaneurysm along with erythrocytes,
and the lumen of the microaneurysm may become occluded (Fig. 2). Initially, most
microaneurysms are on the venous side of the capillaries, but later they are seen on the arterial
side as well. Clinically, they appear as small red dots (Fig. 3). Despite the multiple layers of
basement membrane, microaneurysms are permeable to water and large molecules, allowing the
transudation of fluid and lipid into the retina.
Fig. 1 A. Trypsin digest preparation of early background
retinopathy. Normal retinal capillaries, with one pericyte (closed
arrows) per endothelial cell (open arrows). B. Retinal capillary of
a patient with diabetes with necrotic pericytes (arrows). (Courtesy
View Figure
of Dr. Myron Yanoff)
Fig. 2 Trypsin digest preparation of early background retinopathy.
Early microaneurysm (closed arrow), aneurysm with endothelial
proliferation (open arrow), and aneurysm occluded with fibrin
(curved arrow). (Courtesy of Dr. Myron Yanoff)
View Figure
Fig. 3 A. Diabetic retinopathy with multiple
microaneurysms, dot hemorrhages, and early
neovascularization of the optic disc (NVD). A
small blot hemorrhage is seen inferiorly. B.
Continued. Midphase of the fluorescein
angiogram. Patent microaneurysms are seen as
hyperfluorescent
dots.
Note
that
most
microaneurysms
cannot
be
seen
ophthalmoscopically. There is some enlargement
of the foveal avascular zone because of some

View Figure

occluded capillaries. Temporally there is a larger

zone of capillary nonperfusion. The NVD is
beginning to leak. C. Late phase of the
fluorescein angiogram showing diffuse leakage of
fluorescein into the macula.

It is often difficult to distinguish a small dot hemorrhage from a microaneurysm by

ophthalmoscopy alone. On fluorescein angiography patent microaneurysms will fill with dye
quickly and then leak,5 unlike a small dot hemorrhage that will block fluorescence (see Fig. 3).
However, angiography cannot distinguish a hemorrhage from a microaneurysm filled with
clotted blood. Because fluorescein passes easily though them, we usually see many more
microaneurysms on fluorescein angiography than are apparent on examination.6
When the wall of a capillary or microaneurysm is thin, it may rupture, giving rise to an
intraretinal hemorrhage. If the hemorrhage is deep (i.e., in the inner nuclear layer or outer
plexiform layer), it usually has a round or oval shape (dot or blot) (see Fig. 3). Superficial
(nerve fiber layer) hemorrhages, on the other hand, become flame- or splinter-shaped
indistinguishable from that seen in hypertensive retinopathy. Although people with diabetes with
normal blood pressure may have multiple splinter hemorrhages, they should nevertheless have
their blood pressure checked because a frequent complication of diabetes is systemic
hypertension.
Macular edema (retinal thickening) is an important manifestation of NPDR because it is the
leading cause of legal blindness in patients with diabetes. The intercellular fluid comes from both
leaking microaneurysms and diffuse capillary leakage. It separates retinal cells, causing multiple
intraretinal interfaces which scatter light, decreasing the retina's normal translucency and
blurring the normal retinal pigment epithelial and choroidal background pattern (Figs. 3, 4, and
5). Clinically, macular edema is detected by biomicroscopy with a contact lens or by a 60- or 80diopter hand-held lens. Optical coherence tomography (OCT) is a new diagnostic tool that
accurately defines retinal thickness and cross-sectional anatomy (see Fig. 5). In severe cases of
edema, the pockets of fluid in the outer plexiform layer are large enough to be seen. This is
called cystoid macular edema (CME) (Fig. 6). Usually CME is seen in eyes with other signs of
severe NPDR such as numerous hemorrhages or hard exudates, but in rare cases, generalized
diffuse leakage from the entire capillary network can result in CME with few other signs of
diabetic retinopathy.7
Fig. 4 A Exudates surround an area of hypoperfused retina.
Note soft exudate superiorly. The macular edema thickens
the retina and obscures the normal choroidal appearance. B.
In the center of the hard exudates the fluorescein angiogram
shows
capillary
non
perfusion
surrounded
by
microaneurysms. C. The late phase of the angiogram shows
leakage into the retina.
View Figure

View Figure

Fig. 5 A. Circinate retinopathy inferotemporal to the center

of the macula. B. The midphase of the fluorescein angiogram
shows a cluster of microaneurysms in the center of the
circinate ring. C. The late phase of the angiogram shows
leakage of fluorescein. D. Optical coherence tomogram
centered on the fovea of an eye with diabetic macular edema.
The area of marked retina thickening contains numerous
hyporeflective cystoid spaces (fine arrow). The outer retina
is limited by the hyperreflective pigment epithelial band
(thick arrow).
Fig. 6 A. Background diabetic retinopathy. B. The midphase
of
the
fluorescein
angiogram
shows
multiple
microaneurysms. C. Late phase of the angiogram shows
cystoid macular edema.

View Figure
If the leakage of fluid is severe enough, lipid may accumulate in the retina (see Figs. 4 and 5).
Again, the outer plexiform layer is first to be affected. In some cases, lipid is scattered through
the macula, in others, it accumulates in a ring around a group of leaking microaneurysms, or
around areas of capillary nonperfusion (see Figs. 4 and 5). This pattern is called circinate
retinopathy.
In addition to the retinal vascular abnormalities, the choriocapillaris may be involved in NPDR.
Initially there is a thickening of the basement membrane. 8 Later, a periodic acid-Schiff (PAS)
positive material accumulates, which impinges on and may occlude the lumen of the choroidal
capillaries in the posterior pole.4
ADVANCED NONPROLIFERATIVE DIABETIC RETINOPATHY
In advanced NPDR, signs of increasing retinal hypoxia appear, including multiple retinal
hemorrhages, cotton-wool spots (Fig. 7), venous beading and loops (Figs. 7 and 8), intraretinal
microvascular abnormalities (IRMA) (see Figs. 7 and 8), and large areas of capillary
nonperfusion.
Fig.
7
A.
Severe
nonproliferative
retinopathy
with venous dilatation and
beading, soft exudates, and
intraretinal
microvascular
abnormalities B. The midphase
of the angiogram shows the
intraretinal
microvascular
abnormalities (IRMA) and
severe capillary nonperfusion.
View Figure

Fig. 8 Venous loop (large

arrow)
and
intraretinal
microvascular
abnormalities
(IRMA; small arrow).
View Figure
Cotton-wool spots, also referred to as soft exudates, are actually nerve fiber layer infarctions.
They are white, fluffy-appearing lesions in the nerve fiber layer that result from occlusion of
precapillary arterioles. Fluorescein angiography confirms the lack of capillary perfusion.
Microaneurysms frequently surround older cotton-wool spots as well as larger areas of capillary
nonperfusion.
Venous beading (see Fig. 7) and venous loops (see Fig. 8) indicates sluggish retinal circulation
and are nearly always adjacent to extensive areas of capillary nonperfusion. Focal vitreous
traction is thought to contribute to their formation. 9 Capillaries next to areas of nonperfusion that
dilate and function as collaterals are referred to as IRMA. They are frequently difficult to
differentiate from surface retinal neovascularization. Fluorescein, however, does not leak from
IRMA but leaks profusely from neovascularization (see Fig. 7).
The Early Treatment Diabetic Retinopathy Study (ETDRS)10 found that IRMA, multiple retinal
hemorrhages, venous beading and loops, widespread capillary nonperfusion, and widespread
leakage on fluorescein angiography are all significant risk factors for the development of
proliferative retinopathy. Interestingly, cotton-wool spots, in the absence of the other findings,
are not. Approximately 50% of patients with severe NPDR progress to proliferative retinopathy
with high-risk characteristics (discussed later) within 1 year.11
PROLIFERATIVE DIABETIC RETINOPATHY
Proliferative vessels usually arise from veins and often begin as a collection of fine vessels.
When they arise on or within 1 disc diameter of the optic disc they are referred to as
neovascularization of the disc (NVD) (Fig. 9). When they arise further than 1 disc diameter
away, they are called neovascularization elsewhere (NVE) (Fig. 10). NVE nearly always grows
toward and into zones of retinal capillary nonperfusion, but capillary nonperfusion is nearly
always more widespread in eyes with NVD than it is in NVE. 12 Interestingly, it is seen more
often in patients younger than 40 compared to older patients with diabetes.13
Fig. 9 Advanced neovascularization of the disc.
View Figure
Fig. 10 Neovascularization elsewhere (NVE).

View Figure
Once the stimulus for growth of new vessels is present the vessels grow along the path of least
resistance. The absence of the internal limiting membrane over the optic disc could explain the
proclivity of new vessel growth at that location. Neovascularization grows readily along
connective tissue scaffolding such as the posterior hyaloidal face (Fig. 11).

Fig. 11 Autopsy eye. Neovascular stalk adherent to and growing on the posterior
cortical vitreous which has partially detached. (Courtesy of Dr. Myron Yanoff)
View Figure
The new vessels, initially naked, usually progress through a stage of further proliferation with
associated connective tissue formation. As PDR progresses, the fibrous component becomes
more prominent. Fibrotic tissue can be vascular or avascular. The fibrovascular variety is usually
found in association with vessels extending into the vitreous cavity or with abnormal new vessels
on the surface of the retina or disc. The avascular variety usually results from organization or
thickening of the posterior hyaloid face.
Posterior vitreous detachment in diabetics is characterized by a slow, overall shrinkage of the
entire formed vitreous rather than by the formation of cavities caused by vitreous destruction. 14
Davis15 has stressed the role of the contracting vitreous in the production of vitreous hemorrhage,
retinal breaks, and retinal detachment. Neovascular vessels do not grow forward into the
vitreous cavity; they are pulled into it by the contracting vitreous to which they are adherent (see
Fig. 11). Vitrectomized eyes rarely develop new areas of neovascularization and existent
neovascularization tends to regress. If severe enough, posterior vitreous detachment may result in
retinoschisis, retinal detachment, and retinal break formation. In eyes fortunate enough not to
develop these complications, the neovascularization may burn out, leading to atrophy of the new
vessels.
An additional complication of contracting vitreous is traction involving the optic nerve that
causes stria of the macula or even macular heterotopia (Fig. 13)20; both may cause decreased
visual acuity.
Fig. 13 A. Macula prior to dragging. Arrows have been placed for
reference. B. Two years later. Note the foveola and inferior
vessels have been dragged superonasally.
View Figure
Although the macular edema, exudates, and capillary occlusions seen in NPDR often cause legal
blindness, affected patients usually maintain at least ambulatory vision. PDR, on the other hand,
often results in severe vitreous hemorrhage or retinal detachment with hand-movements vision or
worse. It has long been assumed that sudden vitreous contractions tear the fragile new vessels,
causing vitreous hemorrhage. However, 62% to 83% of diabetic vitreous hemorrhages occur
during sleep,16,17 possibly because of an increase in blood pressure secondary to early morning
hypoglycemia or to rapid eye movement (REM) sleep. Because so few hemorrhages occur
during exercise, we do not restrict the activity of patients with proliferative retinopathy. The
location of the hemorrhage is important in predicting whether it will clear on its own. If blood is
behind the posterior vitreous face it is likely to settle to the bottom of the eye and be absorbed.
However, when hemorrhage breaks into formed vitreous it is less likely to clear spontaneously.
A large superficial hemorrhage may separate the internal limiting membrane from the rest of the
retina. Such hemorrhages usually are round or oval but may also be boat-shaped (Fig. 12). The
blood may remain confined between the internal limiting membrane and the underlying retina for
weeks or months before breaking into the vitreous. Subinternal limiting membrane hemorrhages
were formerly thought to lie between the internal limiting membrane and the cortical vitreous
and were called subhyaloid or preretinal hemorrhages. It is now felt that true subhyaloid

hemorrhages are probably quite rare. Tight subinternal limiting membrane hemorrhages are
dangerous beause they may progress to traction retinal detachment.18,19
Fig. 12 Subinternal limiting membrane
hemorrhages.

View Figure
Two types of diabetic retinal detachments occur, those that are caused by traction alone
(nonrhegmatogenous) (Fig. 14), and those caused by retinal break formation (rhegmatogenous)
(Figs. 15 and 16). Characteristics of nonrhegmatogenous (traction) detachment in PDR include
the following: (1) the detached retina is usually confined to the posterior fundus and infrequently
extends more than two-thirds of the distancd to the equator, (2) it has a taut and shiny surface, (3)
it is concave toward the pupil, and (4) there is no shifting of subretinal fluid.
Fig. 14 Traction retinal detachment. The detached retina has a smooth
noncorrugated appearance and is convex toward the pupil.
View Figure
Fig. 15 Combined traction/rhegmatogenous retinal detachment. The detached
retina has a corrugated appearance and is concave toward the pupil.

View Figure
Fig. 16 Round hole near fibrous proliferation.

View Figure
Vitreous traction may also cause focal areas of retinoschisis that may be difficult to distinguish
from full-thickness traction retinal detachment. In retinoschisis the elevated layer is thinner and
more translucent (Fig. 17).
Fig. 17 Traction retinoschisis nasal to the disc (Stereo). There is a small inner
wall hole along the vessel that leaves the disc at the 2 o'clock position.

View Figure
In combined traction/rhegmatogenous detachment, the borders of the elevated retina usually
extend to the ora serrata; the retinal surface is dull and grayish and undulates because of retinal
mobility caused by shifting subretinal fluid. The causative retinal breaks are usually found in the
posterior pole near areas of fibrovascular proliferation. They are oval in shape and appear to be

partly the result of tangential traction from the proliferative tissue as well as vitreous traction.
Determining the location of retinal holes may be complicated by many factors, particularly poor
dilation of the pupil, lens opacity, increased vitreous turbidity, vitreous hemorrhage, intraretinal
hemorrhage, and obscuration of the breaks by overlying proliferative tissue. Often they are only
located during vitrectomy surgery.
RISK FACTORS OF DIABETIC RETINOPATHY
DURATION OF DIABETES
The best predictor of diabetic retinopathy is the duration of the disease. 21,22,23,24,25,26,27,28 Patients
who have had type 1 or insulin-dependent diabetes mellitus (IDDM) for 5 years or less rarely
show any evidence of diabetic retinopathy.27,29 However, 27% of those who have had diabetes for
5 to 10 years and 71% to 90% of those who have had diabetes for longer than 10 years have
diabetic retinopathy.30 After 20 to 30 years, the incidence rises to 95% and approximately onethird to one-half of these patients have PDR.29
Determining the role of duratioo of diabetes as a predictor of retinopathy in type 2 or noninsulin
dependent diabetes mellitus (NIDDM) is more difficult because of the uncertainty of the onset in
many patients. In some, the diagnosis of diabetes is made only after retinopathy is discovered.
With these limitations, the best studies are from Wisconsin and Israel. Yanko and co-workers 30
found that the prevalence of nonproliferative retinopathy 11 to 13 years after the onset of type 2
diabetes was 23%. After 16 or more years, it was 60%. Eleven or more years after the onset, 3%
of the patients had proliferative retinopathy. Klein found that 10 years after the diagnosis of type
2 diabetes, 67% of patients had retinopathy and 10% had PDR. The risk was lowest in patients
who did not require insulin.31
AGE OF THE PATIENT
Although the duration of diabetes is the most important determinant of retinopathy, the years that
a patient has diabetes before the onset of puberty do not count against him or her. In other words,
the risk of retinopathy is roughly the same in two 25 year-old patients, one of whom developed
type 1 at the age of 6 and the other of whom developed it at age 12 or 13.21,25,28
SYSTEMIC FACTORS
Control of Blood Glucose
The decades-old controversy regarding whether or not intensive metabolic control prevents the
development or progression of retinopathy was finally laid to rest by the Diabetes Control and
Complications Trial (DCCT) 31,32 and the United Kingdom Prospective Diabetes Study
(UKPDS).33 In the DCCT, patients who closely monitored their blood glucose and who were
treated with insulin at least three times per day by injection or by insulin pump were compared to
patients treated with conventional therapy. The intensive-treatment group had a 76% reduction in
the rate of development of any retinopathy and an 80% reduction in progression of established
retinopathy. Ophthalmologists must be aware that after institution of strict control, there is often
an initial worsening of preproliferative retinopathy.36,37,38 Fortunately, after 2 years of control, the
strict-control groups had the same or less retinopathy than groups treated conventionally.39 The
UKPDS was a randomized, controlled clinical trial involving newly diagnosed type 2 diabetics.
Patients were randomly assigned to intensive glycemic control with sulfonylurea agents or
insulin or to conventional control with diet. After 12 years of follow-up, progression of diabetic
retinopathy in the intensive-control group was reduced by 21%.34

The benefits of rigorous control of blood glucose do not extend to all eyes with advanced
retinopathy. Even patients who are made normoglycemic by pancreatic transplantation continue
to show progression.40
Renal Disease
Most patients with renal disease, as evidenced by proteinuria, elevated blood urea nitrogen
(BUN), and elevated blood creatinine, also have retinopathy.28,41,42,43 Even patients with
microalbuminuria are at high risk of having retinopathy.44,45,46,47,48 On the other hand, only 35% of
patients with symptomatic retinopathy have proteinuria, elevated BUN or elevated creatinine.49
Systemic Hypertension
The literature indicates that elevated systolic blood pressure is a moderate risk factor for diabetic
retinopathy.28,42,43,50 Other studies have found, however, that when patients with nephropathy are
excluded, blood pressure is not a strong risk factor.51,52,53
The Hypertension in Diabetes Study (HDS), part of the UKPDS, evaluated the effect blood
pressure control on the progression of diabetic retinopathy. Patients who were kept under strict
control of blood pressure (< 150/85 mm Hg) had a 34% risk reduction in microvascular changes
compared to the conventional blood pressure control group (< 180/105). 54 For every 10-mm Hg
reduction in systolic blood pressure there was an associated 13% reduction of microvascular end
points. Lisinopril, an angiotensin-converting enzyme inhibitor, has been shown in another study
to decrease by 50% the progression of NPDR in normotensive type 1 diabetics; suggesting a
benefit for some antihypertensives independent of there blood pressure lowering effect.55
Pregnancy
Women with diabetes who begin a pregnancy with no retinopathy have a 10% to 26% risk of
developing some NPDR.56,57,58 Those who have NPDR at the onset of pregnancy and those who
have low hemoglobin or systemic hypertension tend to show accelerated progression, with
increased hemorrhages, cotton-wool spots and macular edema. 58,59,60 Fortunately, there is usually
some regression of NPDR after delivery.61,62,63
Women who begin pregnancy with NPDR have a 22% to 40% incidence of progression to
PDR.58,61,64 Those with untreated PDR at the onset frequently do poorly unless they are treated
with aggressive panretinal photocoagulation (PRP),65,66 but those with previously treated PDR
usually do well.
There is no doubt that women who maintain good metabolic control during pregnancy have
fewer spontaneous abortions and fewer children with birth defects.67 Therefore, obstetricians
strive for strict control. However, women who begin pregnancy with poorly controlled diabetes
who are suddenly brought under strict control frequently have severe deterioration of their
retinopathy and do not always recover after delivery.56,59,62,68 It is probably best to gradually bring
the blood glucose under control.
Race
Retinopathy is more likely to be present in blacks than in whites. 69 Moreover, blacks have a
higher rate of severe macular edema and of blindness possibly because of a higher incidence of
systemic hypertension.70 Contrary to these findings, the study by Arfkin and co-workers 71
'suggested that blacks had a slightly slower rate of progression than whites.
Cigarette Smoking
Cigarette smoking, because it increases blood carbon monoxide, platelet aggregation, and causes
vasoconstriction, might be expected to accelerate diabetic retinopathy but a large study recently
found no effect.72
Serum Lipids

Elevated serum cholesterol is a strong predictor for the rate of visual loss. Patients with both
elevated cholesterol and low-density lipoprotein (LDL) cholesterol are much more likely to have
vision loss associated with hard exudates in the macula.73
PATHOGENESIS
The final metabolic pathway which causes diabetic retinopathy is unknown. There are several
theories.
ALDOSE REDUCTASE
Aldose reductase is an enzyme that converts sugars, when present in high concentration, into
alcohols. For example, glucose is converted to sorbitol (and later to fructose by polyol
dehydrogenase) and galactose is converted to dulcitol. Because sorbitol, dulcitol, and fructose
cannot easily diffuse out of cells, their intracellular concentration increases. Osmotic forces draw
water into the cells resulting in electrolyte imbalance. The resultant damage to lens epithelial
cells, which have a high concentration of aldose reductase, is responsible for the cataracts seen in
children with galactosemia and in animals with experimental diabetes mellitus. Because aldose
reductase is also found in high concentration in retinal pericytes and Schwann cells, some
investigators suggest that diabetic retinopathy and neuropathy may be caused by aldose
reductase-mediated damage.74,75 Strong support for this theory is that aldose reductase inhibitors
inhibit cataract formation,76 permeability to small molecules,77 capillary basement membrane
thickening,78,79 and pericyte loss.80 Furthermore, they improve nerve conduction velocity,81,82
decrease pain from peripheral neuropathy,83 decrease proteinuria,84 and decrease vascular
permeability.77,85
However, clinical trials have thus far failed to show a reduction in the incidence of diabetic
retinopathy or of neuropathy by aldose reductase inhibitors, 87,88 possibly because an effective
aldose reductase inhibitor with few systemic side effects has yet to be developed.89
VASOPROLIFERATIVE FACTORS
In 1954, Michaelson90 first proposed that hypoxic retina produces a vasoproliferative factor
that diffuses to nearby blood vessels inducing neovascularization. There is some clinical
evidence for such a substance. First, neoplasms produce a diffusible substance, tumor angiogenic
factor, which causes blood vessels from adjacent normal tissues to grow toward and into the
tumor, thereby providing the tumor with oxygen and other nutrients. Second, in many conditions
(e.g., branch retinal vein occlusion, sickle cell disease, Eales' disease, and retinopathy of
prematurity), ischemic areas of retina are adjacent to or near to areas of neovascularization that
tends to grow into the hypoxic area.91,92,93 Third, the development of neovascularization of the
optic disc and iris, both of which can be reversed by PRP, argues for a diffusible factor. Finally,
several laboratory studies have found substances that induce neovascularization. Experimental
evidence suggests that a diffusible factor exists. 94 Vascular endothelial growth factor (VEGF),
which inhibits the growth of retinal endothelial cells in vitro, has been implicated in diabetic
retinopathy. VEGF is found in the vitreous of patients with diabetic retinopathy and decreases
after PRP.95,96,97 Furthermore, experimental intravitreal injections of VEGF produce retinal
ischemia and microangiopathy in primates. 98 Studies are underway evaluating the use of antiVEGF compounds in patients with diabetic retinopathy.
GROWTH HORMONE
After Poulson99 noted reversal of florid diabetic retinopathy in a woman who had postpartum
hemorrhagic necrosis of the pituitary gland (Simmonds' syndrome), growth hormone was
suspected to play a causative or at least an important supportive role in the development and

progression of diabetic vascular complications. In the 1950's and 1960's surgical pituitary
ablation was considered by some to be an effective treatment for diabetic retinopathy, but was
hotly debated. The success of PRP ended the argument. More recently, growth hormone
deficiency was found to be somewhat protective against retinopathy.100
PLATELETS AND BLOOD VISCOSITY
Several lines of evidence strongly suggest that platelet abnormalities in diabetics may contribute
to retinopathy.101 There are three steps in platelet coagulation: initial adhesion, secretion, and
further aggregation. Adhesion refers to the propensity of platelets, aided by von Willebrand
factor (factor VIII) to stick to basement membrane, damaged endothelial cells, and collagen. 102 It
has been shown that the platelets in diabetic patients are stickier than platelets of patients
without diabetes.103
Once some platelets adhere to the basement membrane or to damaged cell walls, they secrete
prostaglandins which cause other platelets to adhere to them (aggregation) (Fig. 18). This is
initiated shortly after adhesion when phospholipase releases arachadonic acid frol an arachadonic
acidphospholipid ester in the platelet's cell membrane. Arachadonic acid is then convdrted
through several prostaglandin intermediaries to another prostaglandin, thromboxane A2, which is
one of the most potent vasoconstricting and platelet aggregating agents known. As a byproduct
of these events, adenosine diphosphate (ADP), another platelet aggregating agent, is released.
Diabetic platelets are especially sensitive to thromboxane and to other aggregating agents such as
epinephrine.103,104 It has been postulated that abnormal platelet adhesion and aggregation causes
focal capillary occlusion and focal areas of ischemia in the retina, which in turn contribute to the
development of diabetic retinopathy.101 However, it should be mentioned that PDR has been
reported in patients with severe platelet dysfunction.105
Fig. 18 Platelet adhesion and aggregation.

View Figure
OTHER HEMATOLOGIC ABNORMALITIES
Other hematologic abnormalities seen in diabetics are increased blood viscosity, 106 increased
erythrocyte aggregation,107 and decreased erythrocyte deformacility,108 all of which may
contribute to sluggish circulation and endothelial damage.
PSYCHOPHYSICAL AND ELECTROPHYSIOLOGIC ABNORMALITIES
PSYCHOPHYSICAL ABNORMALITIES
One of the early symptoms of diabetic retinopathy is poor night vision (dark adaptation) and
poor recovery from bright lights (photostress). 113,114,115,116 Also, patients with diabetes, even those
without retinopathy, are more likely to have abnormal color vision than are those without
diabetes matched for age.117,118,119,120 Blueyellow discrimination is affected earlier and more
severely than is redgreen discrimination. As retinopathy advances, color vision deteriorates.
Contrast sensitivity may be abnormal in patients without diabetic retinopathy at a time that
Snellen visual acuity is normal.121,122,123 Ocular hypertension worsens both color vision and
contrast sensitivity.124
ELECTROPHYSIOLOGIC ABNORMALITIES
One of the earliest electrophysiologic aboormalities seen in patients with diabetes without
ophthalmoscopically visible retinopathy is diminution of the amplitude of the oscillatory

potentials (OP's) of the electroretinogram at a time when both the a- and b-waves are
normal.125,126,127,128,129 This abnormality probably reflects ischemia in the inner nuclear layer of the
retina. Diminished OP's are a good predictor of progression of retinopathy. 130 As the severity of
diabetic retinopathy increases, the amplitude of the b-wave decreases.
DIFFERENTIAL DIAGNOSIS
Conditions that have features similar to diabetic retinopathy are radiation retinopathy,
hypertensive retinopathy, retinal venous obstruction, the ocular ischemic syndrome, anemia,
leukemia, Coats' disease, retinal telangiectasia, and sickle cell retinopathy.131
TREATMENT
REDUCTION OF SYSTEMIC RISK FACTORS
Medical Therapy
ASPIRIN.
Aspirin blocks the conversion of arachadonic acid to prostaglandins, thereby inhibiting platelet
secretion and aggregation (see Fig. 18). Because of its success in decreasing the incidence of
transient ischemic attacks (TIAs), clinicians theorized that it might retard the progression of
diabetic retinopathy. The Early Treatment Diabetic Retinopathy Study found that 650 mg of
aspirin daily did not influence the progression of retinopathy, did not affect visual acuity, and did
not influence the incidence of vitreous hemorrhages. 109 On the other hand, another group found
that 990 mg of aspirin daily alone or combined with 225 mg of dipyridamole (Persantine)
significantly slowed the annual appearance of new microaneurysms, but the study was not
carried out long enough to demonstrate any clinical significance.110
TICLOPIDINE.
Ticlopidine (Ticlid) inhibits ADP-induced platelet aggregation. Similar to aspirin, the effect is
permanent for the life of a labeled platelet. It has been shown to decrease the risk of stroke in
patients with TIAs. One short-term study showed statistically significant reduction in the
development of diabetic retinopathy.111
PENTOXIFYLLINE.
Pentoxifylline (Trental) increases retinal capillary blood flow velocity probably by improving
erythrocyte and leukocyte flexibility. It decreases blood viscosity. To date, however, a clinical
benefit has not been shown for diabetic retinopathy.112
Panretinal Photocoagulation
When well-focused, intense light is absorbed by pigmented cells (such as erythrocytes or
pigment epithelial cells), it is converted to heat, coagulating the cells and surrounding tissues.
The first photocoagulator, the xenon arc, produced an intense light that was successful in
obliterating neovascularization that was either on the surface of the retina or only slightly
elevated (Fig. 19). Clinicians thought that eyes treated with xenon arc photocoagulation had
good regression of retinopathy and fewer vitreous hemorrhages than would have been expected
had they not been treated. However, xenon arc photocoagulation had severe limitations. First, the
heat generated was often insufficient to obliterate highly elevated neovascularization. Second,
neovascularization arising from the optic nerve could not be directly treated because the intense
light beam damaged the optic nerve. Finally, in many cases, all of the neovascularization was
initially obliterated, but new areas of neovascularization later developed. For these reasons, the
long-term results of photocoagulation were considered by many observers to be no better than no
treatment at all.

Fig. 19 A. Neovascularization immediately after xenon-arc

photocoagulation. B. One year later. The neovascularization
elsewhere (NVE) has been obliterated.
View Figure
To prevent new areas of neovascularization, several ophthalmologists began to photocoagulate
not only neovascularization but all intraretinal hemorrhages as well (shoot the red), on the
grounds that they represented areas of hypoxia that could later develop into proliferative
retinopathy. They soon noted that the cases that had the most intraretinal hemorrhages and
therefore received the most initial photocoagulation frequently had the best long-term results,
with permanent regression of neovascularization (Fig. 20). In such cases, the optic disc often
became pale, indicating optic atrophy.
Fig. 20 A. Neovascularization of the disc (NVD) and a small
vitreous hemorrhage. Panretinal photocoagulation was given. B.
Two months later, the NVD has completely regressed.
View Figure
At about the same time, Aiello and co-workers,132,133 and others134,135,136,137 noted that patients with
unilateral high myopia, extensive chorioretinal scarring, glaucoma, and optic nerve atrophy
frequently had markedly asymmetrical retinopathy. The prior retinal or optic nerve damage
seemed to protect that eye from diabetic retinopathy (Fig. 21). These investigators initiated the
concept of PRP (Fig. 22). They theorized that photocoagulation burns scattered throughout the
retina would decrease the retina's need for oxygen and thereby prevent neovascularization from
developing or might even cause regression of existent neovascularization. Early studies showing
the benefits of PRP were criticized on statistical and other grounds and were not widely
accepted.138,139
Fig. 21 A. Right eye of a patient with neovascularization of the
disc (NVD), numerous retinal hemorrhages, soft and hard
exudates. B. Left eye of the same patient. Note pale optic disc
from previous ischemic optic neuropathy and minimal diabetic
retinopathy.
View Figure
Fig. 22 Panretinal photocoagulation.

View Figure
It remained for a national collaborative study initiated by Davis and sponsored by the National
Institutes of Health (The Diabetic Retinopathy Study (DRS)) to prove that both xenon-arc and
argon-laser PRP significantly decrease the likelihood that an eye with high-risk characteristics
will progress to severe visual loss.140,141,142 High-risk characteristics are defined as eyes with (1)
NVD greater than one-fourth to one-third disc area, (2) any NVD and vitreous hemorrhage, or
(3) NVE greater than one-half disc area and vitreous or preretinal hemorrhage (see Fig. 20). The
main findings of the DRS are summarized in Table 1.

TABLE 1. Results of the DRS at Three Years

VA less than 5/200
With PRP
Without PRP
NVD <1/2 DD with VH
4.3%
25.6%
NVD > 1/2 DD w/o VH
8.5%
26.2%
NVD > 1/2 DD with VH
20.1%
36.9%
NVE > 1/2 DD with VH
7.2%
29.7%
DRS, Diabetic Retinopathy Study; DD, disc diameters; VA, visual acuity; VH, vitreous
hemorrhage.
After PRP, retinal circulation is definitely improved. There is a better regulatory response to
hypoxia and decreased blood flow.143,144 The exact mechanism by which PRP works remains
unknown. Some investigators believe that PRP decreases production of vasoproliferative factors
first by eliminating some of the hypoxic retina or by stimulating the release of anthangiogenic
factors from the retinal pigment epithelium. 145 An alternative hypothesis is that vessel dilatation
caused by chronic hypoxia is the direct stimulus for endothelial cell proliferation and
neovascularization and that PRP works by thinning the retina. Vasodilatation is reduced by
increased diffusion of oxygen from the choroid. 146,147,148,149 Another possibility is that PRP
decreases choroidal circulation in the midperiphery, which in turn shunts blood flow centrally,
(reverse choroidal steal) decreasing the stimulus for NVD.150 Finally, others suggest that PRP
leads to an increase in vasoinhibitors either by stimulating the retinal pigment epithelium to
produce inhibitors of vasoproliferation145,151 or by causing a breakdown of the bloodretinal
barrier so that serum vasoinhibitors can diffuse into the vitreous.152
The goal of PRP is to arrest or to cause regression of the proliferating new vessels. The currently
recommended therapy is 1600 to 2000 burns, 500 m in diameter delivered through a wide-field
or three-mirrored lens.153 The burns should be intense enough to whiten the overlying retina. This
usually requires a power of 200 to 600 mW and duration of 0.1 seconds. The usual PRP
decreases the electroretinogram by 40% to 70%154,155 and destroys approximately 14% of the total
retinal area.155 Most ophthalmologists use the argon bluegreen or green laser, but a large clinical
trial has shown that krypton red is equally effective.156
The number of burns necessary to achieve these goals has not been established. Some retinal
specialists feel that there is no upper limit to the total number of burns and that treatment should
be continued until regression occurs.157,158,159,160 However, it remains to be proven that the eye
benefits from thousands of burns. In fact, the only prospective, controlled study found that eyes
that received supplementary treatment had no difference in reduction in risk factors or better
visual acuity than did eyes that received only a standard PRP.161
Once the DRS had proved that PRP was effective in preventing severe visual loss in patients with
high-risk characteristics, the question arose as to whether treatment of mild PDR or severe
NPDR would lower still further the risk of blindness from diabetic retinopathy. The ETDRS
found that PRP significantly retards the development of high-risk characteristics in eyes with
severe NPDR and macular edema.11 After 7 years of follow-up, 25% of eyes that received PRP
developed high-risk characteristics compared to 75% of eyes in which PRP was deferred until
high-risk characteristics developed. Nevertheless, the ETDRS concluded that treatment of PPDR
and of PDR short of high-risk characteristics was not indicated. First, after 7 years of follow-up,
25% of eyes assigned to deferral of PRP never developed high-risk characteristics. Second, when
patients are closely monitored and PRP is given as soon as high-risk characteristics develop
severe visual loss can be prevented. After 7 years of follow-up, 4.0% of eyes that did not receive

PRP until high-risk characteristics developed had a visual acuity of 5/200 or less compared to
2.5% of eyes assigned to immediate PRP. The difference was neither clinically nor statistically
significant. So, if all eyes with severe NPDR received PRP, many would be treated unnecessarily.
Third, PRP has significant complications. PRP often causes decreased visual acuity by increasing
macular edema162,163,164 or by causing macular pucker. Fortunately, the edema frequently regresses
spontaneously over 6 months. The visual field is usually moderately decreased. 113 Color vision
and dark adaptation, which are often already impaired, are also worsened by PRP.114,115,116 Finally,
PDR is associated with an increased risk of myocardial infarction and increased mortality. 165
Many patients will die before they develop complications of the PDR.
Peripheral Retinal Cryotherapy
Peripheral retinal cryotherapy (PRC) is used to treat eyes with high-risk characteristics and with
media too hazy for PRP. Reported benefits include resorption of vitreous hemorrhages and
regression of NVD, NVE, and NVI.166,167,168,169,170,171,172 The main complication is the development
or acceleration of traction retinal detachment in 25% to 38% of eyes. 170,173 Therefore, this
treatment should be avoided in patients with known traction retinal detachment and all patients
must be carefully monitored. An alternative treatment in eyes with hazy media is transscleral
diode laser photocoagulation.
Treatment of Macular Edema
Patz and co-workers174 were the first to show that focal argon laser photocoagulation decreases or
stabilizes macular edema. Later, the ETDRS confirmed their results. The ETDRS defined
clinically significant macular edema (CSME) as (1) retinal thickening involving the center of the
macula, (2) hard exudates within 400 m of the center of the macula (if they are associated with
retinal thickening), or (3) an area of macular edema greater than one disc area which is within
one disc diameter of the center of the macula. The treatment strategy was to treat all leaking
microaneurysms farther than 500 m from the center of the macula (Fig. 23) and to place a grid
of 100 to 200 burns in areas of diffuse capillary leakage and in areas of capillary nonperfusion.
After 3 years of follow-up, 15% of eyes with eyes with CSME had doubling of the visual angle
as opposed to 32% of nontreated control eyes. 175 Recent subgroup analysis showed that treatment
could be deferred in eyes in which the center of the fovea is not thickened as long as hard
exudates are not threatening the center. However, such eyes must be closely observed.175
Fig. 23 A. Fifty-two-year-old man with clinically significant
macular edema and a partial circinate ring of hard exudates. B.
Midphase of the fluorescein angiogram shows a cluster of
microaneurysms in the center of the are a edema. C. Late phase
shows severe leakage. D. Several months after treatment, the
edema is no longer present and the visual acuity is 20/25.

View Figure
The ETDRS also showed that PRP is not part of the treatment strategy of CSME. Eyes that
received PRP along with their focal treatment were much more likely to have an immediate
decrease in visual acuity than were eyes that received focal treatment alone. 11 An alternative
treatment to the ETDRS strategy is a grid treatment (Fig. 24).176

Fig. 24 A. Thirty-five-year-old woman with diffuse macular

edema and a visual acuity of 20/60. B. The midphase of the
angiogram shows diffuse macular edema C. The late phase shows
severe leakage and cystoid macular edema D. Grid treatment. E.
The midphase of the angiogram done 4 months later shows
minimal leakage. F. The late phase also shows minimal leakage.
The visual acuity is 20/25.

View Figure
Patients with macular edema who have the best prognosis for improved vision have circinate
retinopathy of recent duration or focal, well-defined leaking areas and good capillary perfusion
surrounding the avascular zone of the retina. Patients with an especially poor prognosis have
dense lipid exudate in the center of the fovea (Fig. 25). Other poor prognostic signs include
diffuse edema with multiple leaking areas, capillary closure around the fovea (Fig. 26), increased
blood pressure, and cystoid macular edema. 174,177 Nevertheless, the ETDRS found that even eyes
with these adverse findings benefited from treatment compared to control eyes. 175 The use of
intravitreal steroids is also receiving attention for its potential role in the treatment of persistent
diabetic edema. Small uncontrolled series have demonstrated dramatic reduction of macula
thickness with associated improvement in visual function. 178,179 Although encouraging,
intravitreal corticosteroids are associated with frequent elevated intraocular pressure and
occasionally endophthalmitis.180,181
Fig. 25 Circinate retinopathy with large hard exudates plaque in the center of the
macula.

View Figure
Fig. 26 Ischemic diabetic maculopathy. Notice large central areas of capillary
nonperfusion surrounded by microaneurysms.
View Figure
Vitrectomy techniques are also increasingly being considered for diabetic edema management.
Early reports found up to 90% of eyes undergoing vitrectomy for the treatment of edema
associated with a taut or thickened posterior hyaloid had visual improvement. 182,183 Recent larger
series confirm the efficacy of vitrectomy for eyes with abnormal hyaloidmacula interface. 184,185
The success in this subgroup of patients is predicted by the hypothesis that tangential traction
exerted by attached vitreous contributes to macular edema.186
More modest results have been reported with vitrectomy for the treatment of eyes with attached
hyaloid that were not taut or thickened. Published series report approximately one-half of the

eyes improve by only a line of acuity.187 Interestingly macular edema resolved in most of these
eyes. Otani and colleagues188 reviewed seven patients with symmetric diabetic edema without an
abnormally taut hyaloid who had one eye randomized to vitrectomy. They used OCT to
demonstrate an average decrease in macular thickness of 353 m postoperatively compared to a
60 m average decrease in thickness in the fellow eyes.
In summary, DRS and the ETDRS conclusively proved that timely laser photocoagulation of
diabetic retinopathy can reduce severe visual loss by 95%. 189 Such treatment makes sense not
only from the humanitarian point of view but is extremely cost-effective as well, saving
approximately $250 to $500 million per year by keeping patients off disability and
welfare.190,191,192 Nevertheless, only half of Americans with diabetes, especially the poor and
minority population, fail to receive an annual dilated eye examination. 193,194 The American
Diabetes Association recommends that patients with type 1 diabetes should be screened annually
beginning 5 years after the onset of the disease and patients with type 2 should be screened
immediately and then annually thereafter.195 Alternatives methods of screening when
ophthalmologists are not available include the use of primary care physicians or digital
photography with remote image interpretation. Although primary care physicians commonly fail
to detect significant retinopathy with direct ophthalmoscopy, training significantly improves their
ability.86,196
Vitrectomy in Patients with Diabetes
Regarding this topic, the reader should also consult Chapter 56, Volume 6 for details.202
Vitrectomy, introduced by Robert Machemer, plays a vital role in the management of severe
complications of diabetic retinopathy. The major indications are non-clearing vitreous
hemorrhage, traction retinal detachment, and combined traction/rhegmatogenous retinal
detachment. Less common indications are macular edema with a thickened and taut posterior
hyaloid,203,204 macular heterotopia, and tight preretinal macular hemorrhage,18,19
To evaluate whether early vitrectomy (in the absence of vitreous hemorrhage) might improve the
visual prognosis by eliminating the possibility of later traction macular detachment, the Diabetic
Retinopathy Vitrectomy Study (DRVS) randomized 370 eyes with florid neovascularization and
visual acuity of 10/200 or better to either early vitrectomy or to observation. 205 After 4 years of
follow-up, approximately 50% of both groups had 20/60 or better and approximately 20% of
each group had light perception or worse. Thus, the results indicate that such patients probably
do not benefit from early vitrectomy. They should be observed closely so that vitrectomy, when
indicated, can promptly be undertaken.
If a patient has a vitreous hemorrhage severe enough to cause a visual acuity of 5/200 or less, the
chances of visual recovery within 1 year are only approximately 17%. 206 The DRVS randomized
patients who had a visual acuity of 5/200 or less for more than 6 months into two groups: those
who received an immediate vitrectomy and those for whom vitrectomy was deferred for an
additional 6 months.207 Fifteen percent of those who had a deferred vitrectomy had a final visual
acuity of 20/40 or better as opposed to 25% of those who had an immediate vitrectomy. In
patients with type 1 diabetes, 12% of those who had a deferred vitrectomy had a final visual
acuity of 20/40 or better as opposed to 36% of those who had an immediate vitrectomy. The
reason for this discrepancy was thought to be excessive growth of fibrovascular proliferation
during the waiting period. For this reason, the DRVS concluded that strong consideration should
be given to immediate vitrectomy, especially in type 1 diabetics. (In type 2 diabetics, the final
visual results were similar.) In most cases, vitrectomy should be deferred for approximately 6
months or longer if the retina is attached to give the patient a chance for spontaneous clearing.

Some patients will never need the surgery, but more importantly, 25% of the patients in the
DRVS who received an immediate vitrectomy had a final visual acuity of NLP. Patients with
bilateral visual loss because of vitreous hemorrhage, with chronically recurring hemorrhage, with
no history of PRP, and with known traction retinal detachment close to the macula are offered
surgery sooner. If surgery is deferred, ultrasonography should be performed at regular intervals
to make sure that traction retinal detachment is not developing behind the hemorrhage. The goals
of surgery are to release all anteriorposterior vitreous traction and to perform a complete PRP to
reduce the incidence of recurrent hemorrhage. Furthermore, the results of vitrectomy for
nonclearing vitreous hemorrhage are excellent (Table 2).
TABLE 2. Overal Visual Results
Benson Thompson208
DRVS207
20/2020/40
29
24
25
20/5020/100
29
24
29
20/12020/300
16
22
5
20/400CF
8
12
7
HM-LP
12
13
10
NLP
6
6
25
DRVS, Diabetic Retinopathy Vitrectomy Study. HM-LP, ; NLP, .
In patients who have recurrent vitreous hemorrhage after vitrectomy, a simple outpatient
air/liquid exchange may restore vision without the need for a repeat vitrectomy.209
Traction retinal detachments are usually a much greater challenge. In general, unless the macula
becomes involved, observation is the best therapy for these patients because, in most cases, the
detachment will not progress into the macula. 210 These patients should be counseled to consult
their ophthalmologist without delay should macular vision be suddenly lost, because vitrectomy
at that point becomes a relative emergency.202 The surgical objectives are to clear the media, to
release all anteriorposterior traction, to release tangential traction by cutting bridges between
areas of traction detachment or by delamination, and to perform endophotocoagulation to prevent
neovascularization of the iris. The prognosis is best in patients with small areas of traction. An
alternative technique is to remove the vitreous and preretinal membranes by the en bloc
technique.211,212 The prognosis is poorest in eyes with extensive fibrous adhesion to the retina
(table-top) detachments, significant preoperative vitreous hemorrhage, no prior PRP, and
advanced fibrovascular proliferation. If a lensectomy is required and if iatrogenic breaks are
created, the results are also poorer. 202,203,204,205,206,207,208,210 Approximately 60% to 70% of patients
have increased visual acuity and a final visual acuity of 20/800 or better, but 20% to 35% have
decreased vision after surgery. Cases with severe peripheral fibrovascular proliferation may also
require a scleral buckling procedure. 219 Reoperations are required in approximately 10% of
patients, most commonly the repair of rhegmatogenous retinal detachment or for clearing of
recurrent vitreous hemorrhage.220
In traction/rhegmatogenous retinal detachments, the objectives are to find all of the retinal breaks
and to release all vitreous traction. After air/fluid exchange to flatten the retina, endolaser
photocoagulation is used to treat retinal breaks. Approximately one-half of such detachments can
be cured.221,222 In severe cases, silicone oil is required to reattach the retina.223,224,225
Neovascularization of the iris (NVI) that progresses to neovascular glaucoma is a common cause
of failure following otherwise successful vitrectomy. The risk is higher if there is preoperative
neovascularization of the iris (17% versus 33%) if there is persistent retinal detachment after

surgery, if the lens is removed during surgery, and if there is florid NVD and NVE. In eyes
without these factors, the incidence of neovascular glaucoma is only about 2%.226 The
pathogenesis of this complication is unknown. Some investigators feel that removal of the
vitreous allows vasoproliferative factors produced in hypoxic retina to diffuse forward to the iris.
Others feel that the main problem is that oxygen diffuses posteriorly from the anterior chamber
lowering its oxygen tension too far. Fortunately, if an eye does not develop rubeosis iridis in the
first 4 to 6 months after vitrectomy, it rarely will do so later.
Another vision-threatening complication is neovascularization originating from the anterior
retina and extending along the anterior hyaloid to the posterior lens surface (anterior hyaloidal
fibrovascular proliferation).227
OTHER OCULAR COMPLICATIONS OF DIABETES MELLITUS
CORNEA
Several investigations have found decreased corneal sensitivity in patients with
diabetes.228,229,230,231 The severity of the hypesthesia has been correlated with both the duration of
the disease230 and the severity of the retinopathy.228,231
The adhesion between the basement membrane of the corneal epithelium and the corneal stroma
is not as firm as that found in normal corneas, probably because of a decreased number of
hemidesmosomes between the stroma and the epithelium. When the epithelium is scraped from a
normal cornea, the bottom half of the cells forming the basal layer are broken and remain
attached to the basement membrane, which remains attached to the stroma. In diabetics, the
entire epithelium is removed intact. Hyperglycemia and the aldose reductase pathway probably
play a major role in epithelial abnormalities because aldose reductase inhibitors accelerate
healing of corndal abrasions.232,233,234 After vitrectomy, recurrent corneal erosion, striate
keratopathy, and corneal edema are more common in patients with diabetess than in tjose without
diabetes. Although it has been shown that the endothelial cell density is normal in diabetics, 235 it
is not yet known whether or not endothelial cellular dysfunction contributes to these
complications.
GLAUCOMA
Becker236 found that in patients with diabetes there is a higher incidence of open-angle glaucoma
and marked elevation of intraocular pressure after prolonged administration of topical
corticosteroids than there is in patients without diabetes. Moreover, patients with diabetes are
more susceptible to visual field loss than those who do not have diabetes.
NVI is rarely associated with NPDR alone. It is usually seen only in eyes with PDR. By the end
of the follow-up period of the DRS, Tasman and co-workers 237 found NVI in 3.8% of the patients
who had not received PRP as opposed to 2.0% in those who had. Thus, PRP appears to have
some protective value against NVI. PRP is also an effective treatment against established
NVI.238,239,240 Regression of the iris vessels and stabilization of any areas of angle closure and of
intraocular pressure have been reported in 80% of cases treated. If the media are clear, PRP
should be performed prior to any other treatment of NVI, even in advanced cases. Jacobson and
associates238 reported successful results as long as the intraocular pressure was less than 40 mm
Hg and there was less than 270 degrees of angle closure. We have seen regression and permanent
pressure control in patients with pressures as high as 60 mm Hg. If the media are too cloudy for
PRP, peripheral retinal cryoablation and transscleral diode laser photocoagulation are alternative
means of treatment (see above).

If the angle is completely sealed and there is reasonable visual potential, a Molteno or other tube
shunt offers the best chance for preserving vision.241 Cyclocryodestructive procedures often
result in phthisis.
LENS
Because the lens in patients with diabetes has multiple biochemical abnormalities,242 the risk of
cataract is 2 to 4 times greater in than in patients without diabetes243,244,245,246,247 and may be 15 to
25 times greater in patients with diabetes under 40 years of age. 248 Furthermore, the occurrence
of cataract is a predictor of increased mortality.242
Patients with diabetes mellitus who have no retinopathy have excellent results from cataract
surgery, with 90% to 95% having a final visual acuity of 20/40 or better, but, chronic cystoid
macular edema is approximately 14 times more common in patients with diabetes than in those
without.249,250,251 In patients with mild to moderate NPDR without macular edema, approximately
70% to 80% attain 20/40; outcomes are significantly worse in eyes with more severe
retinopathy.252,253,254 Risk factors for progression and worse vision include an older age, 255 poor
glycemic control,252 poor renal function, and most significant preoperative macular edema. In
many eyes the edema is self-limited and behaves clinically like postcataract CME; focal laser
should be delayed when differentiation between diabetic edema cannot be made. The majority of
eyes with CME will improve in 6 months.256
The most dreaded anterior complication is NVI. It was hoped that modern surgery that leaves an
intact posterior capsule would protect the eye from neovascularization of the iris, by reducing the
diffusion of vasoproliferative factors into the anterior chamber but several studies have shown
that it does not. Eyes of patients with diabetes more frequently develop significant posterior
capsular opacification257; fortunately capsulotomy does not seem to increase the risk of anterior
segment neovascularization.247 Other anterior segment complications that are more common in
patients with diabetes than in those without are pupillary block, posterior synechiae, pigmented
precipitates on the implant, and severe iritis.250
Posterior complications include macular edema and ischemia, 255,256,258 proliferative
retinopathy,249,259 vitreous hemorrhage, and traction retinal detachment. 251,258,260 In patients with
active NPDR and no preoperative macular edema, as many as 50% to 75% will develop it and
30% will develop PDR. Approximately 8% will develop NVH. If macular edema is present prior
to the surgery, it nearly always worsens. Only approximately 50% will have a final visual acuity
of 20/40 or better. The risk of the development of or progression of macular edema is nearly
doubled in patients who are older than 63 years of age. 267 Clearly, caution must be observed
when considering cataract surgery in patients who have diabetic retinopathy.
Cataract surgery in patients with active PDR often results in still poorer postoperative visual
outcome because of the high risk of both anterior 262 and posterior segment complications. In one
series, no patient with active PDR or PPDR achieved better than 20/80. Anteriorly, fibrinous
uveitis is seen in more than 50% of patients with active PDR. Most experts recommend
aggressive preoperative PRP.258,268
OPTIC NEUROPATHY
As demonstrated by increased latency and decreased amplitude of the visual evoked potential,
many patients with diabetes without retinopathy have subclinical optic neuropathy.269,270 In
addition, patients with diabetes can develop two types of acute optic neuropathy. The first,
anterior ischemic optic neuropathy (AION) is identical to that seen in patients without diabetes.
The patients report a sudden decrease in visual acuity or a sudden visual field loss. 271,272,273 The
main ocular finding is a pale swelling of the optic nerve head with, considering the degree of

disc edema, very few hemorrhages (Fig. 27). On fluorescein angiography segmental nonfilling or
slow filling is seen (Fig. 27). An afferent pupillary defect (Marcus Gunn) is nearly always
present. Visual fields commonly show altitudinal or nerve fiber bundle defects. The disc
progresses to optic atrophy (Fig. 27), and improvement in visual function is rare.
Fig. 27 A. Right eye: ischemic optic neuritis. Note pale swelling
of optic disc and blurring of disc margins. Left eye: normal disc.
B. Fluorescein angiogram. Note poor filling on disc
inferotemporally as compared with the rest of the disc. C. Right
eye 6 months after optic neuritis. Note slight pallor.

View Figure
The other type of acute optic neuropathy, commonly called diabetic papillopathy, is characterized
by acute disc edema without the pale swelling of AION. It is bilateral in one-half of cases. The
vision usually recovers to better than 20/50 with or without an afferent pupillary defect. 274
Macular edema is a common finding and is the most common cause of failure of visual
recovery.274 Visual fields may be normal, show an increased blind spot, or have disc-related
defects. The prognosis is excellent as nearly all patients recover to 20/30 or better.275,276,277
CRANIAL NEUROPATHY
Extraocular muscle palsies may occur in patients with diabetes secondary to neuropathy
involving the third, fourth, or sixth cranial nerves. The mechanism is believed to be a localized
demyelination of the nerve secondary to focal ischemia. Pain may or may not be experienced,
and not infrequently an extraocular muscle palsy may be the initial clue to a latent diabetic
condition. Recovery of extraocular muscle function in diabetic cranial nerve neuropathy
generally takes place in 1 to 3 months.278
When the third nerve is involved, pupillary function is usually normal. This pupillary sparing in
the diabetic third-nerve palsy is an important diagnostic feature, distinguishing it from other
causes of oculomotor involvement such as intracranial tumor or aneurysm.
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