DR.BERCOVICH: RETINOPATIA DIABETICA, UP DATED 2016

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 HbA_1c 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 HbA_1c 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 (HbA_1c)
• 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.

Fluorescein Angiography

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

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 HbA_1c 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 HbA_1c) 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.