RETINOPATIA DIABETICA (Puesta al Día)
INTRODUCTION
Two forms of diabetes mellitus are recognized. Type 1,
previously called juvenile-onset or insulin-dependent diabetes, is
characterized by cellular-mediated autoimmune destruction of the beta-cells in
the pancreas and usually leads to severe insulin deficiency. Type 2 diabetes
was previously referred to as adult-onset or noninsulin-dependent diabetes.
Type 2 is characterized by a range of disease from insulin resistance with
relative insulin deficiency to predominately an insulin secretory defect
combined with insulin resistance. Type 2 patients usually have a relative
rather than an absolute insulin deficiency, may take insulin, yet typically do
not need insulin for survival.Many patients with Type 2 diabetes are obese, and
obesity itself causes relative insulin resistance. Between 90% and 95% of all
patients with diabetes have Type 2 diabetes. Because of the disproportionately
large number of patients with Type 2 diabetes, this group comprises a larger
proportion of the disease burden in patients with visual impairment from
diabetic retinopathy, even though Type 1 diabetes is associated with more
frequent and more severe ocular complications
Prevalence of Diabetes
An estimated 25.6 million Americans aged 20 years or older have either
been diagnosed or remain undiagnosed with diabetes mellitus (11% of people in
this age group), and about one-third
are not aware that they have the disease. An additional 79
million persons have impaired fasting blood glucose levels (based on both
fasting blood glucose levels and HbA1c levels). In the United
States, an estimated three out of five people with diabetes have one or more of
the complications associated with the disease. Americans of
African descent or Hispanic ethnicity have a disproportionately high prevalence
of diabetes compared with Americans of European descent (12.6%, 11.8%, 7.0%,
respectively), whereas Asian Americans have only a slightly higher prevalence
(8.4%). Native Americans
and Alaskan Natives have an approximate diabetes prevalence of 9%, with a 46%
increase between 1990 and 1998 among this group under age 35. Other research suggests a high prevalence of diabetes in Asia. In addition, there
is evidence suggesting that diabetes develops at earlier ages and carries a
higher incidence of complications among ethnic minorities.
According to estimates based from the United States Census Bureau data,
approximately one-third of Americans are at risk of developing diabetes
mellitus during their lifetime. With increasing
industrialization and globalization, there is a concomitant increasing
prevalence of diabetes that is leading to a worldwide epidemic. An alarming
increase in the frequency of Type 2 diabetes in the pediatric age group has
been noted in several countries, including in the
United States, and has been associated with the increased frequency of
childhood obesity. Diabetes is one of
the most common diseases in school-aged children. Clearly, these trends predict
an increase in the number of individuals with diabetes as well as the
associated increased costs for health care and the burdens of disability
associated with diabetes and its complications.
Prevalence of Diabetic Retinopathy
Diabetic retinopathy is a leading
cause of new cases of legal blindness among working-age Americans and
represents a leading cause of blindness in this age group worldwide. The prevalence rate
for retinopathy for all adults with diabetes aged 40 and older in the United
States is 28.5% (4.2 million people); worldwide, the prevalence rate has been
estimated at 34.6% (93 million people). An estimate of the prevalence rate for
vision-threatening diabetic retinopathy (VTDR) in the United States is 4.4%
(0.7 million people). Worldwide, this prevalence rate has been estimated at
10.2% (28 million people). Assuming a similar prevalence of
diabetes mellitus, the projected prevalence of individuals with any diabetic
retinopathy in the United States by the year 2020 is 6 million persons, and
1.34 million persons will have VTDR.
RISK FACTORS
Duration of diabetes is a major risk factor associated with the
development of diabetic retinopathy. After 5 years, approximately 25% of Type 1
patients will have retinopathy. After 10 years, almost 60% have retinopathy,
and after 15 years, 80% have retinopathy. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) for
patients ages 30 and younger, proliferative diabetic retinopathy (PDR), the
most vision-threatening form of the disease, was present in approximately 50%
of Type 1 patients who had the disease for 20 years. In the Los Angeles
Latino Eye Study (LALES) and in Proyecto VER (Vision, Evaluation and Research),
18% of participants with diabetes of more than 15 years’ duration had PDR, with
no difference in the percentage with PDR between those with Type 1 versus Type
2 diabetes.
Of Type 2 patients over the age of 30 who have a known duration of
diabetes of less than 5 years, 40% of those patients taking insulin and 24% of
those not taking insulin have retinopathy. These rates increase to 84% and 53%,
respectively, when the duration of diabetes has been documented for up to 19
years. Proliferative diabetic retinopathy develops in 2% of Type 2 patients who
have diabetes for less than 5 years and in 25% of patients who have diabetes
for 25 years or more. Comparisons of
information from WESDR and more recent population-based studies such as
Proyecto VER and LALES may account for differences in blood glucose and hypertension
management that have occurred over time.
Glycemic control is the key modifiable risk factor associated with the
development of diabetic retinopathy. Support for this association is based on
both clinical trials and epidemiologic studies. There is general
agreement that duration of diabetes and severity of hyperglycemia are the major
risk factors for developing retinopathy. Once retinopathy is present, duration
of diabetes appears to be a less important factor than glycemic control in
forecasting progression from earlier to later stages of retinopathy. It is recommended
that a HbA1c of 7% or lower is the target for
glycemic control in most patients, whereas in selected patients, there may be
some benefit to setting a lower target of 6.5%. Intensive
management of hypertension may slow retinopathy progression, yet the data
remain inconclusive. Large studies have suggested that management of serum lipids may reduce
retinopathy progression and the need for treatment. There is less
agreement among studies concerning the importance of other factors such as age,
type of diabetes, clotting factors, renal disease, physical inactivity,
inflammatory biomarkers, and use of angiotensin-converting enzyme inhibitors. Many of these factors are associated with substantial cardiovascular
morbidity and mortality and other complications associated with diabetes. Thus,
ophthalmologists should encourage patients with diabetes to be as compliant as
possible with therapy of all medical aspects of their disease.
NATURAL HISTORY
Diabetic retinopathy progresses in an orderly fashion from mild to more
severe stages when there is not appropriate intervention. It is important to
recognize the stages when treatment may be most beneficial. Several decades of
clinical research have provided excellent data on the natural course of the
disease and on treatment strategies that are 90% effective in preventing the
occurrence of severe vision loss. The outcomes of key
clinical trials form a solid foundation in support of treating diabetic
retinopathy. The results of these studies are summarized in Appendices 4 and 5.
Major studies include the following (see Glossary):
- Diabetes Control and Complications Trial
(DCCT)
- Follow-up study to the DCCT titled
Epidemiology of Diabetes Interventions and Complications (EDIC)
- Diabetic Retinopathy Study (DRS)
- Early Treatment Diabetic Retinopathy Study
(ETDRS)
- Diabetic Retinopathy Vitrectomy Study (DRVS)
- Wisconsin Epidemiologic Study of Diabetic
Retinopathy (WESDR)
- Fenofibrate Intervention and Event Lowering in
Diabetes (FIELD) study
- Action to Control Cardiovascular Risk in Diabetes
(ACCORD) trial
- Diabetic Retinopathy Clinical Research Network
(DRCR.net) Protocol I study
- United Kingdom Prospective Diabetes Study
(UKPDS)
The nonproliferative stages of diabetic retinopathy are characterized by
retinal vascular related abnormalities, such as microaneurysms, intraretinal
hemorrhages, venous dilation, and cotton-wool spots. Increased retinal vascular
permeability thatoccurs at these or later stages of retinopathy may result in
retinal thickening (edema) and lipid deposits (hard exudates). Clinically
significant macular edema (CSME)is a term commonly used to describe retinal
thickening and/or adjacent hard exudates that either involve the center of the
macula or threaten to involve it. Patients with CSME should be considered for
prompt treatment, particularly when the center of the macula is already
involved or if retinal thickening and/or hard exudates are very close to the center(see
Care Process). Clinically significant macular edema can be divided into
center-involving and non-center-involving macular edema. (See Glossary.)
As diabetic retinopathy progresses, there is a gradual closure of
retinal vessels that results in impaired perfusion and retinal ischemia. Signs
of increasing ischemia include venous abnormalities (e.g., dilation, beading,
loops), IRMA, and more severe and extensive vascular leakage characterized by
increasing retinal hemorrhages and exudation.When these signs progress beyond
certain defined thresholds, severe nonproliferative diabetic retinopathy (NPDR)
is diagnosed.Such patients should be considered candidates for treatment with
panretinal (scatter) photocoagulation (see Care Process).
The more advanced stage, PDR, is characterized by the onset of
neovascularization at the inner surface of the retinainduced by more global
retinal ischemia. New vessels on or near the optic disc (NVD) and new vessels
elsewhere in the retina (NVE) are prone to bleed, resulting in vitreous
hemorrhage. These new vessels may undergo fibrosis and contraction; this and
other fibrous proliferation may result in epiretinal membrane formation,
vitreoretinal traction bands, retinal tears, and traction or rhegmatogenous
retinal detachments. When new vessels are accompanied by vitreous hemorrhage,
or when new vessels at the optic disc occupy greater than or equal to about
one-quarter to one-third disc area, even in the absence of vitreous hemorrhage,
PDR is considered high-risk. (See Glossary.)Neovascular glaucoma can result
from new vessels growing on the iris (NVI) and anterior chamber angle
structures. Patients with neovascular glaucoma or high-risk PDR should receive
prompt panretinal photocoagulation,and their treating ophthalmologist should
also consider initiating anti-vascular endothelial growth factor (VEGF) therapy
(see Care Process and Glossary).
Table 1 classifies diabetic retinopathy by severity based on clinical
findings. In an attempt to improve communication worldwide between ophthalmologists
and primary care physicians caring for patients with diabetes, an
internationalclinical disease severity scale has been developed for diabetic
retinopathy and macular edema. This scale is based on the ETDRS classification of diabetic retinopathy and
on the data collected from clinical trials and epidemiologic studies of diabetic
retinopathy.
CARE
PROCESS
The care process for
diabetic retinopathy includes a medical history, a regular ophthalmologic
examination or screening of high-quality retinal photographs of patients who
have not had previous treatment for diabetic retinopathy or other eye disease,
and regular follow-up. The purpose of an effective screening program is to
determine who needs to be referred to an ophthalmologist for close follow-up
and possible treatment, and who may simply be screened annually. Early
detection of retinopathy depends on educating patients who have diabetes, as
well as their family, friends, and health care providers, about the importance
of regular eye examination even though the patient may be asymptomatic. In lay
terms, patients must be informed that they may have good vision and no ocular
symptoms but that they may still have significant disease that needs treatment.
They should be educated that early treatment works best and that is why they
need to return for an annual eye examination, even when their vision is
good.Individuals with Type 2 diabetes mellitus without diabetic retinopathy
should be encouraged to have an annual dilated eye examination to detect the
onset of diabetic retinopathy. Individuals with Type 1 diabetes mellitus
without diabetic retinopathy should have annual dilated eye examinations
beginning 5 years after the onset of diabetes. The recommended timing of the first ophthalmic
examination and subsequent follow-up examinations for patients with diabetes is
listed in Table 3 and described in the Management section.
Maintaining near-normal glucose
levels and near-normal blood pressure lowers the risk of retinopathy developing
and/or progressing, so patients should be informed of the
importance of maintaining good glycosylated hemoglobin levels, serum lipids,
and blood pressure. Aspirin may be used by diabetic patients for other medical
indications without concern that the aspirin therapy will worsen diabetic
retinopathy.
PATIENT OUTCOME CRITERIA
Patient outcome criteria include the following:
- Improvement or stabilization of visual
function
- Improvement or stabilization of vision-related
quality of life
- Optimal control of glucose, blood pressure,
and other risk factors through close communication with the patient’s
primary care physician regarding the status of the diabetic retinopathy
and the need for optimal metabolic control
DIAGNOSIS
The initial examination for a patient with diabetes
mellitus includes all features of the comprehensive adult medical eye
evaluation, with particular attention to those aspects relevant
to diabetic retinopathy.
History
An initial history should consider the following elements:
- Duration of diabetes
- Past glycemic control (HbA1c)
- Medications
- u Medical history(e.g., obesity, renal
disease, systemic hypertension, serum lipid levels, pregnancy, neuropathy)
- Ocular history(e.g., trauma, other eye
diseases, ocular injections, surgery, including retinal laser treatment
and refractive surgery)
Physical Examination
The initial examination should include the following elements:
- Visual acuity
- Slit-lamp biomicroscopy
- Intraocular pressure (IOP)
- Gonioscopy before dilation, when indicated.
Iris neovascularization is best recognized prior to dilation. When
neovascularization of the iris is present or suspected, or if the IOP is
elevated, undilated gonioscopy can be used to detect neovascularization in
the anterior chamber angle.
- Pupillary assessment for optic nerve
dysfunction
- Thorough funduscopy including stereoscopic
examination of the posterior pole
- Examination of the peripheral retina and
vitreous
A dilated pupil is preferred to ensure optimal examination of the
retina, because only 50% of eyes are correctly classified for the presence and
severity of retinopathy through undilated pupils. Slit-lamp
biomicroscopy is the recommended method to evaluate retinopathy in the
posterior pole and midperipheral retina. Examination of the
peripheral retina is best performed using indirect ophthalmoscopy or slit-lamp
biomicroscopy.
Because treatment is effective in reducing the risk of visual loss, a
detailed examination is indicated to assess for the following features that
often lead to visual impairment:
- Macular edema
- Signs of severe NPDR (extensive retinal
hemorrhages/microaneurysms, venous beading, and IRMA)
- Optic nerve head neovascularization and/or
neovascularization elsewhere
- Vitreous or preretinal hemorrhage
Examination Schedule
Type 1 Diabetes
Many studies of patients with Type 1 diabetes have reported a direct
relationship between the prevalence and severity of retinopathy and the duration
of diabetes. The development of vision-threatening retinopathy is rare in children
prior to puberty. Among patients with Type 1 diabetes, substantial retinopathy may become
apparent as early as 6 to 7 years after onset of the disease. Ophthalmic
examinations are recommended beginning 5 years after the diagnosis of Type 1
diabetes and annually thereafter, which will detect the vast majority of Type 1
patients who require therapy. Patient education about the visual impact of early glucose control is
important and should begin with the onset of disease.
Type 2 Diabetes
The time of onset of Type 2 diabetes is often difficult to determine and
may precede the diagnosis by a number of years. Up to 3% of
patients whose diabetes is first diagnosed at age 30 or later will have CSME or
high-risk features at the time of the initial diagnosis of diabetes. About 30% of
patients will have some manifestation of diabetic retinopathy at diagnosis.
Therefore, the patient should be referred for ophthalmologic evaluation at the
time of diagnosis.
Diabetes Associated with Pregnancy
Diabetic retinopathy can worsen during pregnancy due to the physiologic
changes of pregnancy itself or changes in overall metabolic control. Patients with
diabetes who plan to become pregnant should have an ophthalmologic examination
prior to pregnancy and counseled about the risk of development and/or
progression of diabetic retinopathy. The obstetrician or primary care physician
should carefully guide the management of the pregnant patient with diabetes’
blood glucose, blood pressure, as well as other issues related to pregnancy. During the first
trimester, an eye examination should be performed with repeat and follow-up
visits scheduled depending on the severity of retinopathy. (See Table 3.) Women
who develop gestational diabetes do not require an
eye examination during pregnancy and do not appear to be at increased risk for
diabetic retinopathy during pregnancy.
After the examination, the ophthalmologist should
discuss the results and their implications with the patient. Both eyes should
be classified according to the categories of diabetic retinopathy and macular
edema discussed in the Natural History and Treatment sections. Each category
has an inherent risk for progression and is dependent upon adherence to overall
diabetes control. Thus, the diagnostic category, combined with the level of
diabetes control, determines the timing for both the intervention and follow-up
examination.
Ancillary Tests
If used appropriately, a number of tests ancillary to the clinical
examination may enhance patient care. The most common tests include the
following:
- Color and red-free fundus photography
- Optical coherence tomography (OCT)
- Fluorescein angiography (FA)
- Ultrasonography
Color Fundus Photography
Fundus photography is a reproducible technique for detecting diabetic
retinopathy and has been used in large clinical research studies. Fundus
photography is also useful for documenting the severity of the diabetes, the
presence of NVE and NVD, the response to treatment, and the need for additional
treatment at future visits.
Optical Coherence Tomography
Optical coherence tomography provides high-resolution imaging of the
vitreoretinal interface, neurosensory retina, and subretinal space. Optical
coherence tomography can be used to quantify retinal thickness, monitor macular
edema, identify vitreomacular traction, and detect other forms of macular
disease in patients with diabetic macular edema. (See Table 4.)
Large clinical trials testing anti-VEGF treatment have utilized OCT rather than
stereoscopic photographs or clinical examination to evaluate and follow macular
edema status because it allows an objective, accurate assessment of the amount
and location of retinal thickening., In clinical practice, decisions are often based on OCT findings. For
example, the decision to repeat anti-VEGF injections, change therapeutic agents
(e.g., intraocular corticosteroids), initiate laser treatment, or even consider
vitrectomy surgery is often based in part on OCT findings. Nevertheless,
retinal thickness, even when measured by OCT, is not always consistently
correlated with visual acuity.
Routine FA is not indicated as a part of the regular examination of
patients with diabetes. Macular edema and PDR are best diagnosed by means of
clinical examination and/or FA. As the use of anti-VEGF agents and intraocular
corticosteroids has increased for the treatment of macular edema, the use of
focal laser surgery has decreased. Therefore, the need for angiography that
localizes leaking microaneurysms or areas of capillary dropout has also
declined.
Nevertheless, FA is useful to differentiate diabetic macular swelling
from other macular disease or for a patient with unexplained vision loss. (See
Table 5.) Angiography can identify macular capillary nonperfusion in the foveal or even in the entire macular
region as an explanation for vision loss that is unresponsive to therapy.
Fluorescein angiography may also detect areas of untreated retinal capillary
nonperfusion that could explain persistent retinal or disc neovascularization
after previous scatter laser surgery. Thus, FA remains a valuable tool, and
facilities for conducting FA should be available to physicians who diagnose and
treat patients with diabetic retinopathy.
An ophthalmologist who orders FA must be aware of the potential risks
associated with the procedure, because severe medical complications may occur,
including death in about 1/200,000 patients. Each angiography
facility should have in place an emergency care plan and a clear protocol to
minimize the risks and to manage complications. Fluorescein dye crosses the
placenta into the fetal circulation, but detrimental
effects of fluorescein dye on a fetus have not been documented.
Ultrasonography is an extremely valuable diagnostic tool that enables
assessment of the status of the retina in the presence of a vitreous hemorrhage
or other media opacity. Furthermore, B-scan ultrasonography may be helpful to
define the extent and severity of vitreoretinal traction, especially on the
macula of diabetic eyes. Currently, ultrasonography is used secondary to OCT
testing when there is clear media.
MANAGEMENT
A healthy diet and lifestyle that includes exercise and weight control
may decrease the risk of developing diabetes in some patients; however, diabetes complications simply cannot be prevented in all cases.
Nevertheless, the visual complications of diabetes mellitus can at least be
moderated by a healthy lifestyle. When visual complications occur, treatment is
believed to yield a substantial cost savings when compared with the direct
costs for individuals disabled by vision loss (see Socioeconomic Considerations
section). According to the National Committee for Quality Assurance’s Health
Plan Employers Data Information Set System, national monitoring of quality data
has shown a slow but definite trend toward improving rates of screening
examinations and blood glucose control. Still, screening
rates remain lower than ideal in spite of evidence supporting the effectiveness
of treatment. Physicians who care for patients with diabetes, and patients
themselves, need to be educated about indications for ophthalmologic referral.
Prevention and Early Detection of Diabetic
Retinopathy
Analyses from two clinical trials show that treatment for diabetic
retinopathy may be 90% effective in preventing severe vision loss (visual
acuity <5/200) using current therapeutic treatment strategies. Although effective
treatment is available, fewer patients with diabetes are referred by their
primary care physicians for ophthalmic care than would be expected according to
guidelines by the American Diabetes Association and the American Academy of
Ophthalmology. In two
community-based studies, 43% to 65% of participants had not received a dilated
eye examination at the time of enrollment.
The purpose of an effective screening program for diabetic retinopathy
is to determine who needs to be referred to an ophthalmologist for close
follow-up and possible treatment and who may simply be screened annually. Some
studies have shown that screening programs using digital retinal images taken
with or without dilation may enable early detection of diabetic retinopathy
along with an appropriate referral. Digital cameras
with stereoscopic capabilities are useful for identifying subtle
neovascularization and macular edema. Optical coherence
tomography appears to be an effective and sensitive imaging tool for detecting
diabetic macular edema as long as there are no other causes for cystoid macular
edema.
Studies have found a positive association between participating in a
photographic screening program and subsequent adherence to receiving
recommended comprehensive dilated eye examinations by a clinician. Of course, such screening programs are more relevant when access to
ophthalmic care is limited. Screening programs
should follow established guidelines. Given the known gap
in accessibility of direct ophthalmologic screening, fundus photographic
screening programs may help increase the chances that at-risk individuals will
be promptly referred for more detailed evaluation and management.
Secondary Prevention
The DCCT showed that the development and progression of diabetic
retinopathy in patients with Type 1 diabetes can be delayed when the HbA1c is optimized. Establishing a close
partnership with the ophthalmologist and the primary care physician is an
important step to ensure optimal patient care. Furthermore, it is important to
help educate patients with diabetes as well as their primary care physician
about the ophthalmologic implications of controlling blood glucose (as
monitored by HbA1c) to as near normal as is safely possible. Results from multiple studies
have demonstrated the value of controlling blood glucose, serum lipid levels,
and blood pressure in patients with Type 2 diabetes.
Aspirin therapy has been evaluated for use in the management of diabetic
retinopathy. The ETDRS found that aspirin therapy at a dose of 650 mg per day
does not slow the progression of diabetic retinopathy. Also, aspirin
therapy did not cause more severe, more frequent, or longer-lasting vitreous
hemorrhages in patients with PDR. As such, aspirin
appears to be neither helpful nor harmful in the management of diabetic
retinopathy. Therefore, no recommended changes in medically administered
aspirin therapy are indicated in the setting of diabetic retinal disease.
Medical and Surgical Management
Management recommendations for patients with diabetes are summarized in
Table 6 and are described according to severity of the retinopathy. Given the
recent evidence on the efficacy of anti-VEGF therapies in patients with
center-involved CSME, the population may be further distinguished as having
center-involving or non-center-involving diabetic macular edema. The table
provides guidance for a preferred practice pattern for the general population
of patients with diabetes; however, specific needs may vary on a case-by-case
basis.
Normal or Minimal NPDR
The patient with a normal retinal examination or minimal NPDR (i.e.,
with rare microaneurysms) should be re-examined annually, because within 1
year 5% to 10% of patients without retinopathy will develop diabetic
retinopathy. Existing retinopathy will worsen by a similar percentage. Laser surgery, color fundus photography, and FA are not necessarily
indicated.
Mild to Moderate NPDR without Macular Edema
Patients with retinal microaneurysms and occasional blot hemorrhages or
hard exudates should be re-examined within 6 to 12 months, because disease
progression is common. The natural history
of Type 1 diabetic patients suggests that approximately 16% of patients with
mild retinopathy (hard exudates and microaneurysms only) will progress to
proliferative stages within 4 years.
Laser surgery and FA are not indicated for this group of patients. Color
fundus photography and OCT imaging of the macula may occasionally be helpful to
establish a baseline for future comparison and for patient education.
For patients with mild NPDR, the 4-year incidence of either CSME or
macular edema that is not clinically significant is approximately 12%. For
moderate NPDR, the risk increases to 23% for patients with either Type 1 or 2
diabetes. Patients with
macular edema that is not clinically significant should be re-examined within 3
to 4 months, because they are at significant risk of developing CSME.
Mild to Moderate NPDR with CSME
Clinically significant macular edema is defined by the ETDRS to include
any of the following features:
- Thickening of the retina at or within 500 µm
of the center of the macula
- Hard exudates at or within 500 µm of the
center of the macula, when associated with adjacent retinal thickening.
(This criteria does not apply to residual hard exudates that remain after
successful treatment of prior retinal thickening.)
- A zone or zones of retinal thickening one disc
area or larger, where any portion of the thickening is within one disc
diameter of the center of the macula
It is now appropriate to subdivide diabetic macular edema according to
involvement at the center of the macula, because the risk of visual loss and
the need for treatment is greater when the center is involved. The diagnosis of
diabetic macular edema can be difficult. Macular edema is best evaluated by
dilated examination using slit-lamp biomicroscopy, OCT, and/or stereoscopic
fundus photography. An ophthalmologist who treats patients for this condition
should be familiar with relevant studies and techniques as described in the
ETDRS and subsequent studies, such as the DRCR.net Protocol trial and other studies
involving anti-VEGF treatment. Fluorescein angiography prior to laser surgery for CSME is often helpful
for identifying treatable lesions. Fluorescein angiography is less relevant
when there are circinate lipid exudates and the leaking lesions are clearly
detected within the lipid ring. Fluorescein angiography is also useful for
detecting capillary dropout and pathologic enlargement of the foveal avascular
zone, a feature that may be useful when planning treatment. Color fundus photography is often helpful to
document the status of the retina even if laser surgery is not performed. Optical coherence tomography is also a helpful
screening tool that is able to detect subtle edema and also to follow the
course of edema after treatment.
The traditional treatment for CSME has been laser surgery. However,
current data from multiple well-designed studies demonstrate that intravitreal
anti-VEGF agents provide a more effective treatment for center-involved CSME
than monotherapy with laser surgery. The visual acuity gain and reduction in macular thickness following the
administration of the combination of intravitreal ranibizumab, with prompt or
deferred laser surgery, had better outcomes than laser alone after 2 years of
follow-up. Recent clinical
trials have divided clinically significant diabetic macular edema into
center-involving (ci-CSME) and non-center-involving (nci-CSME). Enrollment in
these recent clinical trials included only subjects with ci-CSME. When ci-CSME
is present, the anti-VEGF therapies provide a better visual acuity and anatomic
(less macular edema) outcome than focal/grid laser surgery alone. (See
Glossary.) Deferred laser surgery may ultimately decrease the need for repeat
anti-VEGF injections. For nci-CSME, the role of laser surgery is guided by the
ETDRS. The ETDRS demonstrated a definite benefit in favor of laser
photocoagulation surgery in both ci-CSME and nci-CSME. Therefore, both
anti-VEGF and laser remain effective treatment options for CSME .
Anti-VEGF Therapy
Multiple studies have demonstrated the benefit of anti-VEGF therapy in
cases of center-involving diabetic macular edema. At the
present time, anti-VEGF therapy is the initial treatment choice for
center-involving macular edema, with possible subsequent or deferred focal
laser treatment. The Ranibizumab for Edema of the macula in Diabetes (READ-2)
study involved 126 patients randomized to either anti-VEGF therapy (in this
case ranibizumab alone), laser alone, or focal/grid laser combined with
anti-VEGF therapy. The group that received anti-VEGF therapy
alone or with laser treatment did better than the group treated with laser
alone. The Diabetic
Retinopathy Clinical Research Network (DRCR.net) Protocol I also showed that
anti-VEGF with either prompt or deferred laser photocoagulation was better than
either laser alone or laser combined with triamcinolone acetonide. These referenced studies used ranibizumab, while the Bevacizumab or Laser
Treatment (BOLT) study also showed favorable outcomes for bevacizumab use over
macular laser treatment in eyes with ci-CSME. The
DME and VEGF Trap-Eye: Investigation of Clinical Impact (DA VINCI) study
demonstrated better outcomes using aflibercept over laser treatment for
ci-CSME. Most recently, the DRCR.net protocol T demonstrated that anti-VEGF therapy using
bevacizumab, ranibizumab, or aflibercept is an effective treatment for
center-involving CSME. However, at worse levels of initial visual acuity (20/50
or worse), aflibercept was more effective at improving visual acuity than the
other anti-VEGF agents tested. Treating physicians should note that the use of betadine antiseptic
drops and a lid speculum is recommended during intravitreal injections. The use
of routine antibiotic eye drops is not recommended before or following
intravitreal injection procedures. Individuals
receiving the intravitreal injections of anti-VEGF agents may be examined at 1
month following therapy. (See Table 6.) Uncommon, yet severe, adverse side
effects are associated with intravitreal injections. These include infectious endophthalmitis,
cataract formation, retinal detachment, and elevated IOP, particularly for the
corticosteroids such as triamcinolone.
Laser Photocoagulation
Effective laser treatment and retreatment protocols have been detailed
in the DRS and the ETDRS. With the advent of anti-VEGF therapy for macular edema, many retina
specialists prefer to use a modified ETDRS treatment approach. This includes a
less intense laser treatment, greater spacing, directly targeting
microaneurysms, and avoiding foveal vasculature within at least 500 µm of the
center of the macula. Preoperatively, the
ophthalmologist should discuss with the patient the side effects and risks of
treatment. A follow-up
examination for individuals with CSME should be scheduled within 3 to 4 months
of laser surgery. Rarely, focal laser
photocoagulation may induce subretinal fibrosis with choroidal
neovascularization, a complication that may be associated with permanent
central vision loss. Other than
choroidal neovascularization, the most important factor associated with the
development of subretinal fibrosis includes both the more severe levels of
subretinal hard exudates and elevated serum lipids prior to laser
photocoagulation. Approximately 8% of
cases of subretinal fibrosis can be directly related to focal laser
photocoagulation.
Effects Related to Other Treatments
There have been case reports of idiosyncratic macular edema that is
temporally associated with use of the glitazone class of oral antihyperglycemic
agents.When substantial
vitreomacular traction is present, pars plana vitrectomy may improve visual
acuity in selected patients who have diffuse CSME that is unresponsive to
previous macular laser photocoagulation and/or anti-VEGF therapy. However, the value
of vitrectomy in CSME is difficult to study in a randomized clinical trial, as
there are many variables.
Treatment Deferral
When treatment for macular edema is deferred, the patient should be
observed closely (at least every 3 to 4 months) for signs of progression.
Severe NPDR and Non-High-Risk PDR
Severe NPDR and non-high-risk PDR are discussed together because the
ETDRS data showed that they have a similar clinical course and subsequent
recommendations for treatment are similar. In eyes with severe NPDR, the risk
of progression to proliferative disease is high. Half of patients with severe
NPDR will develop PDR within 1 year, and 15% will have high-risk PDR. For patients with
very severe NPDR, the risk of developing PDR within 1 year is 75%. Furthermore,
45% will become high-risk PDR in this same time frame. Therefore, these
patients should be re-examined within 2 to 4 months.
The ETDRS compared early panretinal photocoagulation with deferral of
photocoagulation with careful follow-up (at 4-month intervals) and prompt
panretinal photocoagulation if progression to high-risk PDR occurred. Although the study did not provide definitive guidelines, the
ETDRS suggested that panretinal photocoagulation should not be recommended for
eyes with mild or moderate NPDR, provided that follow-up could be maintained.
When retinopathy is more severe, panretinal photocoagulation should be
considered and should not be delayed when the eye reaches the high-risk
proliferative stage. Careful follow-up at 3 to
4 months is important: if the patient will not or cannot be followed closely or
if there are associated medical conditions such as impending cataract surgery
or pregnancy, early laser panretinal photocoagulation may be warranted. Laser photocoagulation may be indicated, particularly when access to
health care is difficult. If laser surgery is elected, full panretinal
photocoagulation is a proven treatment approach. Partial or limited panretinal
photocoagulation treatment is not recommended.
Additional analyses of visual outcome in ETDRS patients with severe NPDR
to non-high-risk PDR suggest that the recommendation to consider panretinal
photocoagulation before the development of high-risk PDR is particularly
appropriate for patients with Type 2 diabetes. The risk of severe vision loss
or vitrectomy was reduced by 50% (2.5% vs. 5%, P=0.0001) in patients
with Type 2 diabetes who were treated early when compared with deferral
panretinal photocoagulation until high-risk PDR developed. For patients with
Type 1 diabetes, the timing of the panretinal photocoagulation depends on the
patient’s compliance with follow-up and the status and response to treatment of
the fellow eye. For both patients with Type 1 and Type 2 diabetes, impending or
recent cataract surgery or pregnancy may increase the risk of progression and
may influence the decision to perform panretinal photocoagulation.
The goal of laser surgery is to reduce the risk of vision loss.
Preoperatively, the ophthalmologist should assess for the presence of macular
edema, discuss side effects of treatment and risks of visual loss with the
patient, and obtain informed consent.
When panretinal photocoagulation for severe NPDR ornon-high-risk PDR is
to be performed on eyes with macular edema, many experts think that it is
preferable to perform focal photocoagulation and/or anti-VEGF therapy prior to
panretinal photocoagulation. (See Glossary.) There is evidence based on
clinical trials that panretinal photocoagulation, as used in the DRS and ETDRS,
may exacerbate macular edema and may increase the rate of moderate visual loss
(i.e., doubling of the visual angle) compared with untreated control eyes. However, panretinal photocoagulation surgery should not be delayed when PDR is
at the high-risk stage (i.e., if NVD is extensive or vitreous/preretinal
hemorrhage has occurred recently). In such cases, anti-VEGF therapy and
panretinal photocoagulation may be performed concomitantly. Currently, the role
of anti-VEGF therapy in the management of severe NPDR and non-high-risk PDR is
under investigation.
Fluorescein angiography may be helpful to determine the presence or
absence of areas of nonperfusion and/or clinically undetected areas of retinal
neovascularization and to establish the cause for a loss in visual acuity.
High-Risk PDR
The presence of any three of the following four features characterizes
DRS high-risk PDR:
- Neovascularization (at any location)
- Neovascularization at the optic disc
- Severe neovascularization:
- New vessels within one disc diameter of the
optic nerve head that are larger than one-quarter to one-third disc area
in size
- New vessels elsewhere that
are at least one-half disc area in size
- Vitreous or preretinal hemorrhage
The risk of severe visual loss among patients with high-risk PDR is
reduced substantially by treatment using panretinal photocoagulation as
described in the DRS and ETDRS. Most patients with high-risk
PDR should receive panretinal photocoagulation surgery expeditiously. Panretinal photocoagulation usually induces regression of retinal
neovascularization.
Very recently, the DRCR.net study protocol S has demonstrated that
alternative use of anti-VEGF agents (ranibizumab was used in this protocol),
may be an alternative to panretinal laser photocoagulation. However, many feel that panretinal photocoagulation remains the first
choice for management of PDR. The anti-VEGF alternative could be considered for
patients who can follow-up regularly. Further studies are required to determine
the long-term implications of using anti-VEGF agents alone.
Additional panretinal photocoagulation, anti-VEGF therapy, or vitrectomy
surgery may be necessary to address increasing neovascularization of the iris
and should be considered for the following situations:
- Failure of the neovascularization to regress
- Increasing neovascularization of the retina or
iris
- New vitreous hemorrhage
- New areas of neovascularization
For patients who have CSME in addition to high-risk PDR, combined
anti-VEGF therapy and panretinal photocoagulation at the first treatment
session and in the early stages of such higher risk eyes could also be
considered. Fluorescein angiography does not usually need to be performed in
order to apply the panretinal photocoagulation effectively. However, a
fluorescein angiogram may be used to guide focal photocoagulation.In some
cases, vitreous hemorrhage may recur in patients who have had extensive
panretinal photocoagulation. These hemorrhages may be due to traction on
pre-existing or involuted neovascularization. They may clear spontaneously and
do not necessarily require additional panretinal laser surgery.
Some patients with previously untreated PDR who have vitreous opacities
and active neovascular or fibrovascular proliferation should be considered as
candidates for pars plana vitrectomy. The value of early vitrectomy tends to increase with the increasing
severity of neovascularization. The role of anti-VEGFs in
these later stages of proliferative retinopathy is under investigation.
High-Risk PDR Not Amenable to Photocoagulation
In some patients with severe vitreous or preretinal hemorrhage, it may
not be possible to deliver laser photocoagulation adequately. Furthermore,
advanced active PDR may persist despite extensive panretinal photocoagulation.
In such cases, vitrectomy surgery may be indicated. Vitreous surgery is
frequently indicated in patients with macula-threatening traction retinal
detachment (particularly of recent onset), combined traction-rhegmatogenous
retinal detachment, and vitreous hemorrhage precluding panretinal
photocoagulation. Patients with vitreous hemorrhage and rubeosis iridis also
should be considered for prompt vitrectomy and intraoperative panretinal
photocoagulation surgery. The role of anti-VEGFs in treatment of these cases is
under investigation.
Other Treatments
Several studies have evaluated the use of intravitreal administration of
short- and long-acting corticosteroids for the treatment of diabetic macular
edema and the use of anti-VEGF agents in the treatment of PDR. An earlier
DRCR.net study evaluated the role of intravitreal triamcinolone acetonide
compared with focal laser photocoagulation. Treatment with intravitreal
triamcinolone acetonide resulted in an early decrease in retinal thickness at 4
months, yet by 24 months those patients randomized to focal/grid laser
photocoagulation had better mean visual acuity and fewer adverse effects of
cataract development and elevation of IOP.173 At 3 years, these
results were largely unchanged. However, this study
did not evaluate the role of intravitreal corticosteroids plus standard
focal/grid laser photocoagulation compared with laser photocoagulation alone. A
subsequent study showed increased visual gain in pseudophakic eyes that were
given the combination of the intravitreal triamcinolone acetonide and laser;
however, even in this group the eyes treated with anti-VEGF agents tended to do
better overall. Future studies will help define the role of corticosteroids in the
treatment strategies for persons with diabetic macular edema.
Micropulse laser treatment as well as FA-guided therapy have also been
advocated. Studies suggest that micropulse laser induces less damage to
the macula, and several studies using this method have shown encouraging
results. This method has not been compared with standard or modified ETDRS
laser surgery in randomized clinical trials.
PROVIDER AND SETTING
Although the ophthalmologist will perform most of the examination and
all surgery, certain aspects of data collection may be performed by trained
individuals under the ophthalmologist’s supervision and review. Because of the
complexities of the diagnosis and treatment for diabetic retinopathy, the
ophthalmologist caring for patients with this condition should be familiar with
the specific recommendations of relevant clinical trials.
PHYSICIAN QUALITY REPORTING
SYSTEM
The Physician Quality Reporting System (PQRS) program, initially
launched by the Centers for Medicare and Medicaid Services in July 2007,
encourages quality improvement through the use of clinical performance measures
on a variety of clinical conditions. Measures in the 2014 program for diabetic
eye care include an annual dilated eye examination for patients with diabetes,
documentation of the level of severity of retinopathy and the presence or
absence of macular edema, and communication of examination results to the
physician managing ongoing diabetes care for patients with diabetic
retinopathy.
COUNSELING AND REFERRAL
The ophthalmologist should refer patients with diabetes to a primary
care physician for appropriate management of their systemic condition and
should communicate examination results to the physician managing the patient’s
ongoing diabetes care.An Eye MD Examination Report Form is available from the
American Academy of Ophthalmology.
Some patients with diabetic retinopathy will lose
substantial vision despite being treated according to the recommendations in
this document. Patients whose conditions fail to respond to
surgery and those for whom further treatment is unavailable should be provided
with proper professional support and offered referral for counseling, vision
rehabilitation, or social services as appropriate.Vision
rehabilitation restores functional ability, and patients with functionally limiting postoperative
visual impairment should be referred for vision rehabilitation and social
services. More
information on vision rehabilitation, including materials for patients, is
available at www.aao.org/smart-sight-low-vision.
SOCIOECONOMIC CONSIDERATIONS
One analysis of medical and economic effects of diabetic retinopathy
control predicted that over their lifetime, 72% of patients with Type 1
diabetes would eventually develop PDR requiring panretinal photocoagulation and
that 42% will develop macular edema. If treatments are
delivered as recommended in the clinical trials, the model predicted a cost of
$966 per person-year of vision saved for patients with PDR and $1120 per
person-year of central visual acuity saved for patients with macular edema.
These costs are less than the cost of a year of Social Security disability
payments for patients disabled by vision loss. Therefore, treatment yields a
substantial savings compared with the direct cost to society of untreated PDR
in a Type 1 diabetic patient. The indirect costs
in lost productivity and human suffering are even greater.
Another analysis estimated that screening and treatment of eye disease
in patients with diabetes costs, on average, $3190 per quality adjusted life
year (QALY) saved. For patients with
Type 1 diabetes, it costs $1996 per QALY saved; for patients with Type 2
diabetes who use insulin, it costs $2933 per QALY saved; and for patients with
Type 2 diabetes who do not use insulin, it costs $3530 per QALY saved. Insofar
as patients with Type 2 diabetes not using insulin represent the largest subset
of the patient population, most of the economic benefits of screening and
treatment are realized among these patients.
A recent (2013) cost-effectiveness
analysis of various interventions for diabetic macular edema evaluated the cost
effectiveness of anti-VEGF therapies for CSME. Compared with laser alone, the
incremental cost-effectiveness of laser plus bevacizumab is $11,138/QALY and
thus seems to confer the greatest value among the various treatment options for
CSME. By comparison, the
cost-utility of laser photocoagulation for diabetic macular edema is
$3101/QALY, whereas laser
photocoagulation for extrafoveal choroidal neovascularization is $23,640/QALY. Finally, a
cost-utility analysis of detection and treatment of diabetic retinopathy in
patients with Type 1 and Type 2 diabetes demonstrates that provision of
recommended ophthalmic care would reduce the prevalence of blindness by 52% and
that the direct costs of care would be less than the losses in productivity and
the costs of facilities provided for disability.
