Retinopathy, one
of the major complications of both type 1 and type 2 diabetes,
remains the leading cause of vision loss in adults between the ages
of 20 and 74 in industrialized nations1,2 and the
second-leading cause of blindness in the elderly.3
Substantial retinal damage typically exists before any noticeable
vision loss, with background disease usually persisting for several
years before onset of the proliferative phase.1,4
Incidence rises with duration of diabetes, affecting 50% of all
diabetics; but 90% of those enduring diabetes for over 20 years
develop at least some evidence of retinopathy,3 almost all
type 1 and over 60% of type 2 patients.2 Though the risk
is considerably greater for type 1 patients, the sheer relative
number of type 2 patients make them a substantial proportion of
retinopathy victims.5
Though viable
means of preventing or reversing the damage have yet to be developed,
tight glycemic control can reduce the risk of developing retinal
damage and delay progression. The risk factors other than poor
glucose control common to other diabetic complications are also
shared by diabetic retinopathy, with incidence significantly higher
among those diabetic patients with hypertension, dyslipidemias (also
associated with hard retinal lipid exudates), diabetic nephropathy,
proteinuria, pregnancy (especially for type 1 patients), and
African-American or Native-American ancestry.6,7 Surprisingly,
many patients remain under treated. One study showed that only 46%
of those who would benefit by photocoagulation surgery receive it;
and 11% of type 1 and 7% of type 2 patients at high risk had not seen
an ophthalmologist within 2 years.5
Pathophysiology Diabetic
retinopathy is characterized by the dual primary processes of
abnormal permeability and closure of retinal capillaries.8
In the early stages, increased retinal vascular permeability can
lead to accumulation of fluid in the retina; but later stages
involve vascular closure that causes retinal ischemia. More advanced
disease involves neovascularization, often leading to vitreous
hemorrhage, retinal detachment, and neovascular glaucoma.5
Abnormal
Permeability Capillaries in
most areas of the body are highly fenestrated, with numerous openings
of adequate size to facilitate diffusion of fluids and electrolytes
into the surrounding tissues while retaining larger blood elements
within the vasculature. The vasculature of the retina, though, is
notably lacking in such fenestration and characterized by tight
junctions between endothelial cells. Thus, fluids and small
molecules that must pass out of these capillaries must pass through
the endothelial cells themselves, not around them as in other
tissues. This minimizes the hydration of retinal tissue which helps
to maintain its proper function, as retinal edema causes
distortions in visual acuity.8
Continuous
exposure to elevated blood sugar damages the capillary endothelial
cells and pericytes by impairing ion transport systems and mineral
transport enzymes, and depleting cellular energy resources. Affected
capillaries whose cellular function and integrity become thus
compromised become more porous, causing localized retinal edema.7
Retinal edema is a common cause of impaired vision, even in the
earliest stages of retinopathy; but unless it affects the fovea
itself, edema may not be sufficient to affect vision appreciably. It
becomes clinically significant (clinically significant macular edema,
or CSME) at a stage just before it affects vision. At this point,
discernable by ophthalmic examination as a thickened and slightly
milky appearance to retinal surfaces, carefully focused laser
treatment may be employed to coagulate individual microaneurisms or
leaking vessels to curtail leakage (in the case of focal macular
edema); or laser spots may be delivered in a grid pattern
surrounding the macula to reduce diffuse macular edema.8
Vascular
Closure Whether vessel
closure is secondary to abnormalities in blood component aggregation
or vascular endothelium, swelling of capillary walls, or compression
from surrounding edema, nonperfusion results in hypoxia of retinal
tissues supplied by occluded capillaries. Weakened endothelial walls
in affected vessels lead to bulging and development of
microaneurisms, small focal dilations often visible as tiny red dots
on examination. Unless this nonperfusion affects the fovea itself,
which can profoundly impair vision, it usually goes unnoticed by the
patient.8 As the condition
progresses, more areas of the retina become affected; and as greater
portions of the retina are involved the impact on vision also
increases. Larger arterioles can become occluded, causing more
widespread nonperfusion (often observable as white fluffy areas on
the retina or “cotton wool spots”) and even vascular rupture and
hemorrhage.7,8 Capillaries
surrounding nonperfused areas tend to dilate in response to the
nonperfusion, a natural attempt to prevent permanent tissue damage
from hypoxia; but this increases their permeability and perpetuates
the edematous process. Increased permeability also facilitates
egress of larger blood elements (lipids, proteins, and even blood
cells) into retinal tissues to create further problems.8 Once
the underlying contributing factors are minimized, edematous fluid is
readily resorbed; but not so with lipid and protein molecules and
hemorrhaged blood products, whose elimination is substantially
slower. Proteins and lipids tend to form hard exudates visible as
yellowish clumps or spots on the retina, often forming a ring around
a leakage focus.7,8
Neovascularization As the disease
process continues, an array of growth factors are produced locally
that stimulate growth and development of new capillaries as a natural
response to ischemia associated with non-perfusion. This is a
homeostatic process regulated by opposing growth factors, so the rate
of vasoproliferation can be highly and individually varied. With
sufficient stimulus from extensive non-perfusion, the balance tips
toward rapid neovascularization, and tissues of the eye have been
demonstrated to possess several times the number of normal receptors
for such growth factors as other normal tissues, making the retina
and iris (where it can cause or exacerbate existing glaucoma)I
acutely responsive in this respect.4 Unchecked, fronds
of new vascularization gradually mature and become larger. Though
this natural process improves perfusion, the new vascularization
frequently proliferates in areas of the retina where they may
actually begin to occlude vision. Vessels may also grow away from
the surface of the retina and into the vitreous to further complicate
the situation. Fibroblasts inevitably accompany the new vessels to
create the fibrovascular complex in a collagen matrix of scar tissue,
which eventually tends to shrink and contract as it matures, like any
scar. This can cause distortions in vision, blind spots, and even
lead to traction retinal detachment. This fibrous tissue forms
adhesions among the vessels growing into the vitreous; so when the
vitreous separates from the retina in the normal course of aging,
these adhesions may pull the retina to contribute to the distortion
and retinal separation.2,4 The new vessels
tend to be more fragile than the normal vascularization, with a
higher tendency to rupture and hemorrhage into the vitreous to cloud
vision with black or red strings or cobwebs. Small amounts of blood
can be cleared without intervention, diffusing forward into the
anterior portion of the eye to be removed through the normal drainage
apparatus of the trabecular network or ingested by migratory white
cells in the vitreous. The process may require weeks to years,
depending on the volume of hemorrhage and frequency of recurrence;
and with extensive bleeds, vision may be permanently impaired by
residual inflammatory debris and dead cells that cannot be removed.
Not only does vitreous hemorrhage occlude the patient’s vision, it
also prevents effective visual examination of the retina for further
evaluation of disease progression.2,4
Stages
of Diabetic Retinopathy Preclinical – Changes cannot be detected by routine retinal
exams, and the patient typically has no noticeable change in his
vision. Recent animal research, though, has shown that damage to
glial cells may begin as early as one month after the onset of
diabetes. Previous research focusing on the vasculature of the
retina failed to account for changes in the normal interactions
between neurons, glial cells, and capillaries. Glutamate, a retinal
neurotransmitter, is metabolized by glial cells; and damaged glial
cells lead to elevated levels of the neurotransmitter, which then
lead to neuronal death detectable by electroretinogram.9
Background – Fluctuations in retinal capillary permeability
with fluctuations in blood sugar levels can cause retinal and macular
edema that can blur the vision more or less temporarily;2
and similar swelling of the lens can cause visual changes as well,
often improving poor distance vision in poorly controlled diabetes.
Thus, when glycemic control improves, vision typically blurs and is
not correctable, and at least in the short term, cannot be corrected
with the patient’s normal prescription lenses.7
Nonproliferative – Though some patients in this stage may
not notice changes in vision, hemorrhages and microaneurisms of the
retinal vasculature are often visible via retinal exam and pupillary
dilation. When vessels leak, collection of fluid and lipids within
retinal tissue (macular edema) can begin to impair close vision.1,5,7
Proliferative – Vessels can become occluded, rupture, and
bleed into the vitreous to preclude light reaching the retinal
surface. Collateral neovascularization in response to impaired
circulation can take abnormal paths across the retina to further
impair vision. These changes in addition to more common macular
edema tend to cause spotty or cloudy vision.1,5,6,7
Late Proliferative – As abnormal vascularization continues
to proliferate, glial scars may appear, the retina may begin to
detach, and fluid may collect in the vitreous to cause severe vision
loss or even legal blindness at this stage.5,6,7
Evaluation A report done in
1982 indicated that serious errors were made in retinal examinations
by 50% of internists, 33% of diabetologists, 9% of general
ophthalmologists, and no retina specialists. With that in mind,
exams should be conducted by the most highly qualified whenever
possible.7 The Comprehensive
Adult Eye Evaluation must include pupillary dilation in order to
adequately examine the retinal periphery, as 27% or retinal
abnormalities occur outside the 45-degree area visible without
dilation; and 50% of such evaluations are inaccurate in
classification of diabetic retinopathy without dilation.
Neovascularization of the iris may be missed after pupillary
dilation, so evaluation should take place prior to dilation. Except
for assessment of posterior vitreous detachment and traction or
retinal thickening, color fundus photography is generally more
sensitive than clinical examination, facilitating detection of
disease that might be overlooked in direct ophthalmoscopic
examination. It provides hard-copy documentation for evaluation of
disease progression, and it can be particularly valuable in initial
evaluation of significant pathology.1,5 Slit-lamp
biomicroscopy can aid in the evaluation of retinopathy in the
posterior pole, particularly valuable in unexplained visual loss,
central visual symptoms, suspected macular edema, intraretinal
hemorrhage, hard exudates, suspected preretinal neovascularization,
and optic nerve neovascularization.5 Fluorescein
angioscopy and angiography, although unnecessary for diagnosis of
diabetic retinopathy, can be valuable in assessing capillary leakage
and areas of nonperfusion and neovascularization, and they can help
determine precisely where photocoagulation needs to be applied.1
Angioscopy, utilizing an indirect ophthalmoscope, instead of a
camera as in angiography, requires less equipment, but it provides no
hard-copy documentation. Both entail intravenous injection of a
fluorescein dye with the attendant complications of death (1 in
222,000) and severe medical complications (1 in 2,000). Both can be
valuable in evaluation of disease stage and extent for treatment,
evaluation macular capillary nonperfusion or macular edema as causes
of unexplained loss of vision, or evaluation of subtle areas of
neovascularization or capillary dropout.5
Ultrasonography
is useful when cataracts or vitreous hemorrhage preclude adequate
evaluation for retinal detachment by visual means discussed above.5
Management Depending on the
pathology, three different laser surgeries are currently utilized.
Panretinal photocoagulation (PRP) with an argon or diode laser
over the peripheral central areas of the fundus inhibits
proliferation and enhances regression of widespread
neovascularization both in the anterior chamber angle or on the
retinal surface. Initial treatments utilizing up to 2,000 spots of
laser per eye are generally administered over several outpatient
visits with only local anesthesia. Such treatment reduces production
of vasoproliferative factors by destroying small ischemic regions of
retinal tissue (reducing oxygen demand) and by reducing the thickness
of the pigmented tissue below the retina (facilitating oxygen
perfusion from the vessels beneath the retina).4,5
This does nothing
to existing scar tissue, and treatment may have to be repeated after
months or even years, as individual response is variable.
Vitriectomy, where blood and debris are physically removed from the
vitreous, may be necessary in cases of dense vitreous hemorrhage or
to reattach a detached retina.4,5
Focal
photocoagulation of leaking microaneurisms or grid photocoagulation
applied over larger areas of the retina may be used for macular
edema. Light from argon, diode, or dye laser is absorbed by blood or
pigment as heat energy, causing a tiny burn and creating a scar under
the retina that is usually unnoticed by the patient, but that
eliminates the leakages underlying retinal edema. Edema is commonly
exacerbated temporarily, resolving in days or weeks after
photocoagulation.5,8
Conclusion Type 1 patients
should be screened for retinopathy via dilated examination yearly
beginning 5 years after onset of diabetes, but generally not before
puberty.2
Since type 2
diabetes is more frequently long-standing before detection,
evaluation for retinopathy should be done at initial diagnosis of
diabetes. Examination via dilated ophthalmoscopy should be conducted
yearly, unless seven-field stereoscopy confirms no pathology, in
which case follow-up examination can be delayed for 4 years.
Patients with diabetes who become pregnant are at high risk and
should be evaluated for retinopathy within the first trimester and
periodically throughout pregnancy; though those with gestational
diabetes do not share this elevated risk.2
Though some
degree of retinopathy can be expected by almost all diabetic patients
eventually, especially since survival rates are improving with
improved therapies of the underlying disease state, risks and
progression can be minimized by tight glycemic control. Diabetic
retinopathy deserves its reputation as one of the most feared
complications of diabetes, but with proper screening, diagnosis, and
treatment, loss of vision can generally be curtailed.
References 1. Diabetic Retinopathy. Country Hills Eye Center web site.
http://wwwkonnections.com/eyedoc/drstart.html. 9/16/99.
2. Screening for Diabetic Retinopathy. Clinical Practice
Recommendation from the American Diabetes Association.
http://www.diabetes.org/diabetescare/supplement/s20.htm. 9/16/99.
3. Diabetic Retinopathy. Texas Retina Associates web site.
http://www.dallas.net/!tra/leaflets/diabetic.htm. 9/15/99.
4. Proliferative Diabetic Retinopathy. Country Hills Eye Center web
site. http://wwwkonnections.com/eyedoc/drstart.html. 9/16/99.
5. Diabetic Retinopathy. EYECON: Diabetic Retinopathy Pilot.
http:/www.midnightdesign.com/AAO/diabret.htm. 9/15/99.
6. Shaw K. Diabetes. PowerPak Communications PowerGraph. November
1998 Vol. 2 No. 11.
http://www.powerpak.com/PowerGraphs/1998/November/default.htm.
9/10/99.
7. Eye Changes In Diabetes. The Diabetes
Mall. http://www.diabetesnet.com/eyes.html. 9/15/99.
8. Background Diabetic Retinopathy. Country
Hills Eye Center web site.
http://wwwkonnections.com/eyedoc/drstart.html. 9/16/99.
9. Press Release: Changes In The Retina As A
Result Of Complications From Diabetes May Occur Sooner Than Currently
Thought. Introduction to Diabetic Retinopathy, Penn State Retina
Research Group, Pennsylvania State University College of Medicine
website – http://www.hmc.psu.edu.psrrg/intro/intro.htm. 9/1/99.
