Retina

• Age-Related Macular Degeneration (AMD)
• Wet AMD
• Choroidal Neovascularization (CNV)
• Pigment Epithelial Detachment (PED)
• Central Serous Chorioretinopathy (CSCR)
• Retinal Angiomatous Proliferation (RAP)
• DRY AMD Diabetic Retinopathy (DR)
• Diabetic Macular Edema (DME)
• Nonproliferative Diabetic Retinopathy (NPDR)
• Proliferative Diabetic Retinopathy (PDR)
• Clinically Significant Macular Edema (CSME)
• Early Treatment of Diabetic Retinopathy Study (ETDRS)

Age-related Macular Degeneration

Age-related Macular Degeneration (AMD) is the leading cause of irreversible blindness in the developed world. The primary cause is thought to be the premature dysfunction of the retinal pigment epithelium (RPE), a monolayer responsible for most of the maintenance functions of the neurosensory retina.

AMD is the late stage of age-related macular disease (AMD). The early stages present with development of drusen and hyper-pigmentation or hypo-pigmentation of the RPE. Individuals in the late stage usually have severe vision loss and signs of choroidal neovascularization, sub-retinal hemorrhage, or geographic atrophy.

AMD may be categorized as wet (exudative) or dry (non-exudative) types. The dry form is more common. Dry AMD presents clinically as drusen formation and geographic atrophy of the RPE. Drusen are formed by the deposition of lipofuscin (a retinal waste product) and by RPE separation from its underlying basement membrane. This process results from an accelerated aging of the RPE, and accounts for approximately 10% of the cases of severe visual loss seen with AMD.

Approximately 10% of patients with AMD have the wet form. Wet or exudative AMD is a secondary complication in which abnormal choroidal neovascularization breaches the weakened RPE, causing retinal edema, sub-retinal serous exudation, and eventual scarring of the overlying retina. Damage to the macula occurs very rapidly and loss of central vision occurs quickly. Wet AMD and the secondary iatrogenic damage caused by treatment attempts account for 90% of the cases of severe visual loss in AMD.

Researchers have proposed several theories of the causes of AMD, including primary RPE and Bruch membrane senescence, ocular perfusion abnormalities, genetic defects, and oxidative insults.

Traditional theory postulates that senescent RPE accumulates remnants of incomplete degradation from phagocytosed rod and cone membranes and that progressive engorgement of these RPE cells leads to drusen formation with subsequent progressive dysfunction of the remaining RPE.

The vascular theory suggests that lipid deposition in the sclera and Bruch membrane leads to scleral stiffening and impaired choroidal perfusion associated with AMD. This, in turn, adversely affects metabolic transport function of the RPE.

Another theory implicates AMD-specific gene mutations, with studies demonstrated the gene for complement factor H on chromosome 1.

Finally, the small number of native macular pigments lutein and zeaxanthin has been hypothesized to contribute to AMD development. These pigments are thought to play a protective role by limiting oxidative insults or by filtering out harmful wavelengths of light. It is a degenerative condition caused by vascular abnormalities that deprive the sensitive retinal tissue of oxygen and nutrients, and prevent the removal of the waste products of retinal cellular metabolism.

Incidence and Prevalence

AMD is the most prevalent form of macular disease in older persons and the leading cause of blindness in individuals over age 50 in industrialized countries. Epidemiological studies report that variable degrees of age-related macular changes occur in more than 10% of the population between ages 65 to 74 years, and in 25% of the population older than 74 years. The Beaver Dam Eye Study reported that in the population aged 43-86 years, non-exudative AMD occurs in 15.6% of the population and exudative AMD in 1.2%.

Of individuals who progress to blindness, the non-exudative form accounts for roughly 15% while the exudative form is responsible for 85% of blindness. It has been estimated that, in the United States, roughly 1 million people at least 55 years old have exudative AMD and eight times that number are at high risk to develop advanced AMD. In the United States, the number of people affected by AMD is predicted to increase by over 50% by the year 2020, and will account for roughly one sixth of the population.

Fifteen percent of individuals with non-exudative AMD develop vision loss. Ten to 20% of patients with non-exudative AMD progress to the exudative form. Eighty-five percent of exudative cases develop vision loss. As a result, 1.75 million of the 8 million individuals with age-related changes of the macula in the US have advanced disease that manifests as severe vision loss.

Caucasian individuals are far more likely to have AMD and vision loss than those of African or Hispanic descent. Studies, however, fail to show consistent differences between those of Caucasian and Asian descent.

Women, according to several large population-based studies, including the Beaver Dam study, the Third National Health and Nutrition Examination Survey, and the Framingham study, are at increased risk for AMD compared with men.

A strong correlation between the prevalence, incidence, or progression of AMD and increasing age has been shown in nearly every large population-based study.

Risk factors consistently identified in studies are advancing age, a family history of AMD and smoking.

Wet AMD

Wet AMD, or the exudative form, occurs when pathologic choroidal neovascular (CNV) membranes develop under the retina, leak fluid and blood, and ultimately cause a blinding disciform scar in a relatively short time.

Individuals suspected of having exudative AMD typically describe progressive blurring of their central vision, without pain, which can be acute or insidious in onset. Patients who develop sub-retinal hemorrhage from a classic CNV, for example, typically report an acute onset. Patients with occult CNV may experience insidious blurring secondary to shallow sub-retinal fluid or pigment epithelial detachments (PEDs). They also report relative or absolute central scotomas, metamorphopsia, and difficulty reading.

These patients present with sub-retinal fluid, PEDs, sub-retinal lipid, or flecks of sub-retinal hemorrhage in the affected eye, in addition to RPE changes and drusen. The CNV itself may be seen as yellow-green sub-retinal discoloration and is sometimes surrounded by a pigment ring. Sub-retinal hemorrhage typically develops at the margins of the CNV and sometimes obscures the entire complex. On occasion, the sub-retinal hemorrhage can progress and lead to vitreous hemorrhage. Disciform scarring is common end-stage morphology.

Choroidal Neovascularization (CNV)

Choroidal neovascularizations (CNV) are a defining characteristic of non-exudative AMD. These can occur in two distinct and one combined forms:

• Classic CNV symptoms include metamorphasia, worsening visual acuity, and central visual field defects. Definitive diagnosis requires angiography (see below). Classic CNVs appears as a clearly visible and well-demarcated hyperfluorescence in the early phase with increasing leakage in the late phase. Ophthalmoscopic signs are gray-white sub-retinal changes together with retinal edema, hard exudations, and sub-retinal and intra-retinal hemorrhage. If not treated, classic CNVs progress with enlargement of the lesion, formation of a sub-retinal fibrosis or disciform scar, and loss of photoreceptors.
• Occult CNV is seen in approximately 80% of newly diagnosed cases of CNV. Neovascular vessels penetrate the Bruch membrane below the RPE. Invasion under the retina is possible as the disease progresses. Angiography is required to differentiate the two types of occult CNV. Fluorescein angiography (FA) shows the fibrovascular pigment epithelial detachment (PED) and late leakage of undetermined source (LLUS) patterns that characterizes Type 1, the most common form of occult CNV. Type 2 is seen more rarely. It shows an irregular, inhomogeneous hyperfluorescence in the late stages of angiography.

Pigment Epithelial Detachment (PED)

Pigment epithelial detachments (PEDs) are a subtype of exudative AMD. They occur when fluid leaks from the choroid under the RPE even though it appears that no abnormal blood vessels have started to grow. The fluid collects under the retinal pigment epithelium, causing what looks like a blister or a bump under the macula.

This kind of macular degeneration causes similar symptoms to typical wet macular degeneration, but vision can remain relatively stable for many months or even years before it deteriorates. Eventually, however, this form of macular degeneration usually progresses to the more common wet form of macular degeneration that includes newly growing abnormal blood vessels.

Serous detachment of the RPE occurs asymptomatically. Only in those cases in which the macula is affected will patients report blurred vision, metamorphopsia, micropsia, or positive scotomas. Other associated clinical findings may include induced hyperopia.

RPE detachment appears as single or multiple, well-circumscribed round or oval lesions within the posterior fundus. The lesions are typically dome-shaped with slight elevation and appear yellow to orange in color. A reddish “halo” is often seen around the base of the detachment, and overlying pigment defects such as clumping or mottling are commonplace. Lesions may vary in size from one-fifth to over 5 disc diameters (DD), but most are less than 1 DD. Fluorescein and indocyanine green (ICG) angiography show early hyperfluorescence of the entire RPE detachment, which persists throughout the angiogram demonstrating late pooling. Leakage into the sensory retina occurs only in cases of concurrent serous retinal detachment.

Central Serous Chorioretinopathy (CSCR)

Central serous chorioretinopathy (CSCR) is a disease in which a serous detachment of the neurosensory retina occurs over an area of leakage from the choriocapillaris through the retinal pigment epithelium (RPE). Typically, diffuse areas of atrophy of the RPE can be seen with flat neurosensory detachments and PEDs.

The disease predominantly affects patients between the ages of 20 and 50, and mainly presents unilaterally. Women appear to be affected more than men by a factor of almost 3 to 1. The most common symptoms are a deterioration of visual acuity, micropsia, metamorphopsia, reduced dark adaption, color vision deficiencies, and a brownish spot in the central field of vision.

CSCR may be divided into two distinct clinical presentations:

• Classic CSCR with one or more areas of focal leakage
• Chronic CSCR, or sometimes called diffuse pigment epitheliopathy

During FA, broad areas of granular hyperfluorescence that contain one or many subtle leaks are seen. An umbrella or smoke-stack pattern may be seen in approximately one quarter of cases, staring with a small hyperfluorescent spot in the arteriovenous phase with leakage that continues upward in the course of the angiography and then spreads downward along the neurosensory detachment borders.

In approximately 60% of cases, an “expanding pinpoint” can be identified as a hyperfluorescent spot in the early phase which enlarges in all directions simultaneously soon afterward.

A spot with a very small increasingly hyperfluorescent area can be seen in about 15% of cases. One spot is seen in most cases, but two or more hyperfluorescent areas with leakage may be found up to about 30% of cases, according to published research.

The advent of indocyanine green (ICG) angiography has highlighted the importance of the choroidal circulation to the pathogenesis of CSCR. ICG angiography has demonstrated both multifocal choroidal hyperpermeability and hypofluorescent areas suggestive of focal choroidal vascular compromise. Some researchers believe that initial choroidal vascular compromise subsequently leads to secondary dysfunction of the overlying RPE.

Studies employing multifocal electroretinography have demonstrated bilateral diffuse retinal dysfunction even when CSCR was active only in one eye. These studies support the belief of diffuse systemic effect on the choroidal vasculature.

Retinal Angiomatous Proliferation (RAP)

Retinal angiomatous proliferation (RAP) is a newly defined form of exudative maculopathy. It is considered a sub-group of wet AMD, and thought to represent about 10 to 15% of newly diagnosed cases. RAP is usually bilateral, frequently seen in older (age 80 and up) patients, and with a male to female ratio of 2 to 1. The most common clinical features of RAP include retinal and pre-retinal hemorrhages as well as pigment epithelial detachments.

The cause of RAP is a proliferation of retinal capillary vessels with the formation of telangiectases and retino-choroidal anastomoses. The process of RAP is thought to be secondary to a vascular stimulation in the retina. It’s a distinct form of occult CNV associated with proliferation of intra-retinal capillaries in the paramacular area and a contiguous telangiectatic response that has a progressive vasogenic sequence. This deep retinal vascular anomalous complex shows retinal choroidal anastomoses, particularly in the setting of pigmented epithelial detachments, and the presence of retinal-retinal anastomoses without the presence of pigment epithelial detachments.

ICG angiographic imaging may reveal a retino-choroidal anastomosis with an associated hot spot, hypofluorescence of the serous epithelial detachment or filling of the vascular network of the CNV, and retinal vessel anomalies in the presence of retinal hemorrhage.

There is no established treatment for RAP presently. Published research reports that laser coagulation is possible for patients in stage I, and PDT and macular surgery have been performed on patients with advanced stages of RAP. Because of the risk of the fellow eye of an affected eye developing RAP it should be closely followed.

Dry AMD

Over 90% of patients diagnosed with AMD have the dry or non-exudative form of the disease. This form is generally associated with much slower, progressive visual loss over decades, as compared to exudative AMD, which is generally associated with more rapid visual loss which may happen in a few months. More advanced cases of non-exudative AMD can have as profound a visual loss as those suffering from exudative AMD.

Individuals with non-exudative or dry AMD often experience prolonged darkness (delayed dark adaptation) upon entering a darken room or building from bright sunlight as one of the earliest symptoms. This symptom may be noted prior to the presence of any significant atrophy. Patients with dry AMD often have a visual function that is much poorer than suggested by their Snellen acuity. Presence of large areas of atrophy, usually in a perifoveal zone, results in large scotomas near the center of the visual field. These scotomas prevent patients from performing simple tasks such as recognizing faces or reading.

Dry AMD is an inherited autosomal dominant disease that seems to be affected by nutrition and environmental factors. The disease is characterized by the degeneration of the retina and the choroid in the posterior pole due to either atrophy or RPE detachment. The atrophy is generally preceded (or coincident in some cases) with the presence of drusen, the yellow extracellular deposits adjacent to the basal surface of the RPE.

The earliest morphologic features of dry AMD consist of the accumulation of basal laminar and linear deposits just beneath the RPE layer. The accumulation of these deposits is often uneven and associated with RPE hyperplasia and migration. This condition is clinically evident as pigment clumping. As these deposits slowly increase, they can be seen as soft drusen and/or localized RPE detachments.

As these drusen enlarge, they can cause either the development of new blood vessels (exudative or wet AMD) and/or the slow demise of the overlying photoreceptor cells. Photoreceptor cell loss can be accompanied by the thinning (atrophy) of RPE cells, as well as underlying choroidal circulation. The end stage of these changes is the presence of a very thin choroidal layer with the absence of small choroidal vessels underlying an area of atrophic RPE. The rod-cone layer overlying this zone is atrophied, and the middle retinal layers show signs of degeneration. This end stage gradually enlarges and is seen clinically as geographic atrophy.

Geographic Atrophy (GA)

Geographic atrophy (GA) involves extended areas of atrophy of the photoreceptors, the RPE, and choroicapillaris. Drusen may be present at the edge of the lesion. Loss of vision is subtle. Separate areas of GA can enlarge over time and become contiguous. GA usually is bilateral but not always symmetrical. It can develop neovascularization and result in a more rapid loss of vision. Approximately 20% of severe visual loss on AMD is associated with GA.

Diabetic Retinopathy

Diabetes mellitus (DM) is a major medical problem throughout the world. Diabetes causes a wide variety of long-term systemic complications, which have considerable impact on both the patient and the society because it typically affects individuals in their most productive years. Ophthalmic complications of diabetes include corneal abnormalities, glaucoma, iris neovascularization, cataracts, and neuropathies. The most widespread and potentially most debilitating of these complications, however, is diabetic retinopathy.

Diabetic retinopathy (DR) is a leading cause of blindness in adults, causing 12,000 to 24,000 new cases of blindness per year in the United States. The disease is the result of adverse changes in the retinal vasculature which weaken vessels and cause micro-aneurysms, venous beading, ischemic areas of the retina, cotton wool spots, intra-retinal hemorrhages, and macular edema. Scar tissue forming on the surface of the retina (which can lead to retinal tears and detachment) and blood leakage from fragile new vessels (which can hemorrhage) are capable of causing severe vision loss or blindness.

Diabetic macular edema (DME) is associated with certain types of diabetic retinopathy. DME, along with rapid neovascularization are the main causes of visual loss in Type 1 and Type 2 diabetes.

Incidence and Prevalence

Diabetes

DM affects between 16 and 21 million Americans, and half of these are not even aware that they have it. Another 41 million have pre-diabetic conditions which may develop into the disease.

With the number of people with diabetes worldwide expected to increase alarmingly in the coming decades, DM is a global health problem. The incidence of diabetes has increased dramatically throughout the world in recent years. In 1985, an estimated 30 million people worldwide had diabetes; in 2000, the figure had risen to over 150 million. By 2025, the figure is expected to rise to 380 million.

It is thought that the worldwide prevalence of diabetes is increasing at an alarming rate because of:

• Aging population
• Higher fat and carbohydrate content in diet
• More sedentary lifestyles
• Greater incidence of overweight and obese

The prevalence of DM is increasing at a high rate in less industrialized countries. As traditional lifestyles and dietary patterns that have sustained people over generations are disappearing. Diabetes is primarily concentrated in these urban areas where families have relocated from rural areas to seek employment. This characteristic is destined to increase in the future as a result of rapid industrialization in many countries.

Diabetic Retinopathy

Of those individuals who know they have DM, only half receive appropriate eye care. Thus, it is not surprising that diabetic retinopathy is the leading cause of new blindness in persons aged 25 to 74 years in the United States, responsible for 12,000 to 24,000 new cases of new blindness each year. This means that diabetes is responsible for 12% of blindness; the rate is even higher among certain ethnic groups. An increased risk of diabetic retinopathy appears to exist in patients with Native American, Hispanic, and African American heritage. Diabetic retinopathy remains the leading cause of new blindness in the 20 to 74 year old population in the United States. Vision-threatening retinopathy affects an estimated 8% of the 10.2 million adults age 40 years and older with diabetes mellitus.

In individuals with Type 1 diabetes, possible ocular manifestations but no clinically significant retinopathy can be seen in the first five ears after the initial diagnosis of diabetes is made. Within ten years of diagnosis, 60% have some retinopathy. After 15 years or more, 98% are affected. Proliferative Diabetic Retinopathy (PDR) affects 25% of Type 1 patients within 15 years. Within 20 years, 50% progress to PDR.

Among individuals with Type 2 diabetes, about 20% have retinopathy at diagnosis. Thirty percent are affected and 4% progress to PDR in the first 5 years. Almost 80% are affected with some retinopathy and up to 20% have PDR after 15 or more years of systemic disease.

PDR occurs in 30% of Type 1 diabetics, 24% of Type 2 diabetics taking insulin, and 10% of non-insulin-dependent Type 2 diabetics after 10 years of the disease. Macular edema can occur at any stage of diabetic retinopathy. It occurs in 29% of Type 1 and 28% Type 2 diabetics after 20 years of systemic disease.

In patients with Type 2 diabetes, the incidence of non-proliferative diabetic retinopathy (NPDR) also increases with the duration of the disease. Of Type 2 diabetics, 23% have NPDR within 11 to 13 years, 41% have NPDR after 14 to 16 years, and 60% have NPDR after 16 years of the disease.

Approximately 700,000 Americans have PDR with an annual incidence of 65,000.

Diabetic Macular Edema (DME)

The prevalence of diabetic macular edema (DME) among American diabetics approaches 30% in adults who have had diabetes for 20 years or more. It also varies with the stage of diabetic retinopathy. DME can occur at any stage of diabetes and can predate the appearance of other findings of diabetic retinopathy.

In eyes with mild NPDR, the prevalence of DME is 3%. This rises to 38% in eyes with moderate to severe NPDR, and reaches 71% in eyes with PDR. Untreated, 20% to 30% of patients with DME will experience a doubling of the visual angle within three years; with current treatment, this risk drops by 50%.

Diabetic retinopathy becomes nearly ubiquitous with long-standing diabetes. Systemic hypertension is a risk factor for the development of both diabetic retinopathy and DME, and hyperlipidemia increases the risk of leakage and exudative deposits in the macula.

Approximately 500,000 persons have clinically significant macular edema (CSME) with an annual incidence of 75,000.

Clinical Classifications

Progressive damage to blood vessels supplying the retinal tissue is the cause of DR. The classification of retinopathy has been defined by an international group of experts. Because the treatment of DR is based on the type and severity of disease, it is important to properly classify the level of retinopathy. DR is most generally classified as nonproliferative or proliferative, depending on the presence or absence of neovascularization.

Nonproliferative Diabetic Retinopathy (NPDR)

According to the severity of micro-aneurysms, intra-retinal hemorrhages, intra-retinal microvascular abnormalities (IRMA), and retinal vein dilation, NPDR can be classified as:

• Mild NPDR: characterized by the occurrence of micro-aneurysms, usually confined to the region of the posterior pole. This reflects structural changes in the retina caused by the physiological and anatomical effects of diabetes and typically has at least one micro-aneurysm and one or more of the following:
  • retinal hemorrhages
  • hard exudates
  • soft exudates
  • definition not met for any other NPDR stages and PDR

Mild NPDR may not present a threat to vision when there is no ME in the macular area. It has a 5% risk of progressing to PDR in 1 year and a 15% risk of progression to high-risk PDR within 5 years.

• Moderate NPDR is a result of increasing retinal ischemia and typically has:
  • hemorrhages and micro-aneurysms
  • soft exudates
  • venous beading and IRMA definitely present
  • definition not met stages below and PDR

Moderate NPDR differs from mild NPDR in that the severity of micro-aneurysms hemorrhages, cotton wool spots, venous beading, or IRMA of exceeds those in, or mild degree are present. Moderate NPDR has a 12% to 27% risk of progressing to PDR within 1 year and a 33% risk of progressing to high-risk PDR within 5 years.

• Severe NPDR: typically has more than 20 intra-retinal hemorrhages in each of the four quadrants as follows:
  • Hemorrhages and micro-aneurysms in four quadrants
  • Venous beading in at least two quadrants
  • IRMA in at least one quadrant

This “4-2-1″ rule is an important clinical tool for determining when DR is at risk of progressing to proliferative disease. Severe NPDR has a 52% risk of progressing to PDR in 1 year and a 60% risk of progressing to high-risk PDR within 5 years.

• Very Severe NPDR: at least two or more lesions of NPDR (above)

Very severe NPDR carries a substantial risk for progression to PDR in one year and to high-risk PDR within five years.

More advanced stages of NPDR, if left unchecked, have a greater risk of developing into PDR.

Proliferative Diabetic Retinopathy (PDR)

The most severe form of DR is proliferative diabetic retinopathy (PDR). Most patients with PDR are at significant risk for vision loss. In PDR, low or no capillary perfusion and resultant retinal ischemia trigger the release of cytokines such as vascular epithelial growth factor (VEGF), interleukin IL-6, and IL-8, which induce neovascularization of the iris, disc, and retina. Neovascularization is often accompanied by vitreous traction, which may cause vitreous or preretinal hemorrhage and traction retinal detachments. Neovascularization can also close the anterior chamber angle and lead to neovascular glaucoma with severe elevations in intraocular pressure.

Characteristics of the disease include neovascularization of the optic disc (NVD), neovascularization within 3 disc diameters of the major retinal vessels (NVE for neovascularization elsewhere), VE, fibrous proliferation on or within one disc diameter of the optic disc (FPD) or elsewhere on the retina (FPE), PRH, and/or vitreous hemorrhage (VH). PDR that has not reached the high-risk level has a 75% likelihood of becoming high-risk within five years.

Clinically Significant Macular Edema (CSME)

The Early Treatment of Diabetic Retinopathy Study (ETDRS) classified macular edema as either clinically significant (CSME) or non-clinically significant, depending on its location and the presence of any associated exudates. The ETDRS (see below) established a method for classifying and diagnosing DME and determining when treatment is required. In order to diagnose CSME, one of the following characteristics must be present on clinical examination:

• Any retinal thickening within 500 µm of the foveal center.
• Hard exudates within 500 µm of the foveal center that are associated with adjacent retinal thickening (which may lie more than 500 µm from the foveal center).
• An area of retinal thickening at least 1 disc area in size, any part of which is located within 1 disc area of the foveal center.

The Early Treatment of Diabetic Retinopathy Study (ETDRS) was a multicenter, randomized clinical trial designed to assess argon laser photocoagulation and aspirin treatment in the management of patients with non-proliferative or early proliferative diabetic retinopathy. A total of 3,711 patients were recruited to be followed for a minimum of 4 years to provide long-term information on the risks and benefits of the treatments under study.

The purpose of the study was to:

1. Produce natural history data that can be used to identify risk factors and test etiologic hypotheses in diabetic retinopathy.
2. Evaluate the effectiveness of both argon laser photocoagulation and aspirin therapy in delaying or preventing progression of early diabetic retinopathy to more severe stages of visual loss and blindness.
3. Determine the best time to initiate photocoagulation treatment in diabetic retinopathy.
4. Monitor closely the effects of diabetes mellitus and of photocoagulation on visual function.

The results of the ETDRS showed:

• Aspirin use did not affect the progression of retinopathy to the high-risk proliferative stage in eyes assigned to deferral of photocoagulation. Aspirin did not increase the risk of vitreous hemorrhage; however, it did not affect vision, and was associated with a decreased risk of cardiovascular disease.
• Photocoagulation definitely reduced the risk of moderate vision loss, especially for those eyes with macular edema that involved or threatened the center of the macular. There was an increase of moderate visual gain in those eyes that received focal treatment as well as a decrease in the amount of retinal thickening.
• Eyes treated early showed a small but statistically significant reduction in severe visual loss, especially for Type 2 patients.
• Scatter treatment should be deferred for eyes with mild to moderate PDR. As the retinopathy progresses to the severe NPDR or early PDR stage, scatter treatment should be considered, especially for Type 2 patients. Scatter photocoagulation should be performed for virtually all eyes with high-risk PDR. Eyes with CSME be considered for focal photocoagulation. Early vitrectomy should be considered for advanced active PDR, and most importantly, all patients with diabetic retinopathy should receive careful follow-up.

ETDRS set the standard of care for managing diabetic macular edema. One of the most significant medical trials ever conducted, it continues to provide important, new and useful clinical information.

Clinical Retina Bibliography