Diabetic retinopathy: Classification and clinical features

INTRODUCTION — Diabetic retinopathy (DR) is one of the most important causes of visual loss worldwide and is the principal cause of impaired vision in patients between 25 and 74 years of age. Visual loss from DR may be secondary to macular edema (ME; retinal thickening and edema involving the macula), hemorrhage from new vessels, retinal detachment, or neovascular glaucoma.

DR is often asymptomatic until the very late stages. Because the rate of progression may be rapid and therapy can be beneficial for visual improvement, prevention of further visual loss, and reduction in the rate of disease progression, it is important to screen patients with diabetes regularly for the development of retinal disease.

The classification, clinical features, and natural history of DR will be reviewed here. The pathogenesis, screening, and treatment of DR are discussed elsewhere. (See "Diabetic retinopathy: Pathogenesis" and "Diabetic retinopathy: Screening" and "Diabetic retinopathy: Prevention and treatment".)

Cataracts associated with diabetes are also a major cause of visual impairment, especially in type 2 diabetes. Cataracts are reviewed separately. (See "Cataract in adults".)

CLASSIFICATION — Diabetic retinopathy (DR) is divided into two major forms: nonproliferative and proliferative, respectively named for the absence or presence of abnormal new blood vessels emanating from the retina. DR can be further classified by severity (picture 1 and picture 2 and table 1). Diabetic macular edema (ME) may develop at any point along the spectrum of mild nonproliferative disease to proliferative diabetic retinopathy. These designations have been useful for analysis of treatment efficacy in the literature and general indicators for treatment strategies. However, each patient with DR has a unique combination of findings, symptoms, and rate of progression, which necessarily requires an individualized approach to treatment in the effort to preserve vision.

Nonproliferative retinopathy — Nonproliferative DR (NPDR) consists of the variable presence of nerve-fiber layer infarcts (cotton wool spots), intraretinal hemorrhages, hard exudates, and microvascular abnormalities (including microaneurysms, occluded vessels, and dilated or tortuous vessels) primarily in the macula and posterior retina (picture 3). Visual loss in NPDR is primarily through the development of ME. (See 'Macular edema' below.)

NPDR can be further classified into mild, moderate, and severe categories (picture 1 and picture 2 and table 1). This stratification primarily impacts the risk of progression to proliferative retinopathy, which influences follow-up intervals and treatment strategies. Whereas the one-year risks of progression to proliferative retinopathy for mild and moderate NPDR are 5 and 15 percent, respectively, the severe and very severe categories have respective one-year risks of 52 and 75 percent [1].

Proliferative retinopathy — Proliferative DR (PDR) is marked by the presence of neovascularization (abnormal new vessels) arising from the disc and/or retinal vessels (picture 4 and picture 5) and the consequences of this neovascularization (table 1), including preretinal and vitreous hemorrhage (picture 6), subsequent fibrosis, and traction retinal detachment (picture 7 and picture 8). PDR may develop in the setting of prior or coexisting severe nonproliferative changes or may arise without substantial NPDR. Diabetic ME may also occur in the presence of PDR.

Visual loss in PDR may occur acutely if bleeding from the abnormal vessels into the vitreous blocks the light path to the retina; however, the blood is often reabsorbed and vision clears spontaneously over several weeks to months. More permanent loss of vision may occur through retinal detachment, ischemia of the macula, or combinations of these factors.

In early PDR, new vessels are present as fine loops or networks, but they do not meet criteria for the high-risk category.

High-risk PDR is defined by moderate to severe neovascularization of the optic disc (greater than one-third to one-half disc area), any neovascularization of the optic disc if vitreous or preretinal hemorrhage is present, or moderate to severe neovascularization elsewhere on the retina (at least one-half disc area) if vitreous or preretinal hemorrhage is present. Untreated high-risk PDR results in a 60 percent risk of severe vision loss at five years [1]. ME can be present with any degree of PDR and should be addressed as part of the overall treatment strategy.

Macular edema — ME can occur at any stage of DR. It is defined as retinal thickening and edema involving the macula, and it may be visualized by specialized fundus examination with stereoscopic viewing, fluorescein angiography, and, most directly, by optical coherence tomography (OCT; a noninvasive, low-energy laser imaging technology) (image 1).

Diabetic ME is categorized as center involved (retinal thickening in the macula that involves the central subfield zone) or non-center involved (table 1).

The ophthalmologic features of ME are discussed in more detail below. (See 'Retinal thickening and edema' below.)

CLINICAL MANIFESTATIONS

Visual symptoms — Many patients who develop diabetic retinopathy (DR) have no symptoms until the very late stages (by which time it may be too late for effective treatment). Because the rate of progression may be rapid and therapy can be beneficial for both symptom amelioration and reduction in the rate of disease progression, it is important to screen patients with diabetes regularly for the development of retinal disease (table 2). (See "Diabetic retinopathy: Screening".)

In later stages of DR, patients may have some symptoms depending upon the type of eye problem (eg, a curtain falling with a vitreous bleed, floaters during the resolution of vitreous bleeds, and decreased visual acuity that cannot be corrected with refraction in the setting of macular edema [ME]).

Ophthalmologic features — The development of clinical DR is complex and is the result of many interrelated factors, which lead to damage to the retinal neurovascular unit. The neurovascular unit is a concept that highlights the functional connectivity between retinal neural cells and retinal vasculature [2]. Clinically evident features primarily result from two basic changes within the retinal vessels, namely abnormal permeability and vascular occlusion with ischemia and subsequent neovascularization. Several studies have demonstrated that decreased retinal neural function can be measured prior to the onset of clinical retinopathy [3,4]. (See "Diabetic retinopathy: Pathogenesis".)

The retina is one of the most metabolically active organs in the body and is particularly susceptible to substrate imbalance or ischemia [5]. Retinal pericytes and microvascular endothelial cells are lost at a very early stage of diabetes [6]. Thickening of the retinal basement membrane is another early change in DR, a finding similar to that seen in glomeruli.

Death of retinal pericytes and microvascular cells and impairment of basement membrane function are associated with the formation of retinal capillary microaneurysms and excessive vascular permeability. Microaneurysms (hypercellular outpouchings of retinal capillaries with weakened walls due in part to pericyte loss) and the leakage of lipid and proteinaceous material ("hard" exudates) are the initial clinical signs of DR.

Neovascularization — The initial stage of cell death and increased capillary permeability may be followed by cycles of renewal and further cell death, leading to progressive microvascular obliteration and ischemic injury with the subsequent release of vasoproliferative factors (such as vascular endothelial growth factor [VEGF], erythropoietin, and many others) in the ischemic retinal area [6]. These diffusible factors incite the development of new vessels (neovascularization) from the adjacent retinal vessels in an abortive attempt to revascularize the diseased tissue. This process is associated with the following clinical changes:

●The intraluminal proliferation of cells, as well as changes in platelet function, erythrocyte and leukocyte aggregation, and high plasma fibrinogen concentrations, results in vascular occlusion and rupture. This can cause small flame-shaped and blot hemorrhages proximal to the occlusion (picture 9) and intraretinal infarcts ("cotton wool" or "soft exudates") distal to the occlusion (picture 10).

●Proliferation of the endothelial cells of retinal veins results in marked changes in the caliber of the veins with formation of tortuous loops (picture 11).

●More severe ischemia results in vasoproliferation with formation of new vessels (neovascularization or proliferative DR [PDR]) (picture 5) [5].

Although PDR can be diagnosed by fundus examination, fluorescein angiography (a photographic study in which the transit of intravenously injected fluorescein dye is recorded by photography with a special camera) is useful to document capillary nonperfusion and leakage from new blood vessels (image 2). An alternative, rapid, and dye-free noninvasive technique called optical coherence tomographic angiography (OCT-A) can also be used to document retinal circulatory abnormalities, but it is less widely used and less sensitive than fluorescein angiography.

New vessels are categorized by four variables: presence, location, severity, and associated hemorrhagic activity. In PDR, the vessels initially grow along the plane of the retina under the posterior hyaloid or outermost layer of the vitreous body, but as the vitreous gradually pulls away and detaches from the retina, the new vessels grow out from the retina plane and into the vitreous cavity.

The consequences of neovascularization are severe because the fragile new vessels invariably rupture, resulting in the development of intraocular (usually vitreous) hemorrhage (picture 6). Alternatively, they can create a fibrovascular overgrowth of the retina that can cause distortion of the retina and tractional retinal detachment, especially if forward-growing vessels have attached to the posterior pole of the vitreous body and pull the retina anteriorly when they contract (picture 12 and picture 13).

New vessel proliferation can also occur on the surface of the iris (rubeosis [neovascularization of the iris]) and in the anterior chamber. The latter change can block the outflow path for aqueous humor in the eye, leading to acute glaucoma (neovascular glaucoma).

Retinal thickening and edema — Capillary leakage is associated with retinal thickening and edema. This can result in loss of visual acuity if edema involves the central macula [7]. ME can develop at all stages of retinopathy. It typically presents with the gradual onset of blurring of near and distant vision in patients who have other evidence of microvascular eye disease, such as perimacular microaneurysms.

The yellow exudates typically seen in association with ME in DR represent a residuum of more copious leakage that has been principally reabsorbed, leaving behind the least soluble lipid components. These hard exudates are often noted in a "circinate" pattern (picture 14), with an arc-like appearance because of demarcation of areas of damaged retinal vessels from those adjacent more normal areas that are capable of reabsorbing the edema.

PREVALENCE AND NATURAL HISTORY

Conventional therapy — The Wisconsin Epidemiologic Study of Diabetic Retinopathy is one of the most comprehensive studies documenting the natural history of retinal disease in patients with diabetes. Ninety-nine percent of clinicians in an 11-county area of southern Wisconsin participated in a series of studies involving over 10,000 patients with diabetes starting in the early 1980s [7]. The following data, largely representing retinopathy incidence and prevalence prior to "tight" blood glucose management, were noted:

●The prevalence of retinopathy increased progressively in patients with both type 1 and type 2 diabetes with increasing duration of disease.

●Diabetic retinopathy (DR) began to occur in patients with type 1 diabetes three to five years after diagnosis, and almost all patients were affected at 15 to 20 years (figure 1).

●The incidence of DR in patients with type 2 diabetes was 50 to 80 percent at 20 years. Some had retinopathy at the time of diagnosis; extrapolating backward suggested that their retinopathy began four to seven years before the clinical diagnosis of diabetes (figure 2). This observation is primarily a reflection of the typically insidious onset of hyperglycemia and delayed diagnosis of type 2 diabetes.

These older studies included patients treated predominantly with conventional therapy.

Impact of intensive insulin therapy — The Diabetes Control and Complications Trial (DCCT) found that glycemic management is a major determinant of the rate of development and progression of DR in patients with type 1 diabetes [8]. The United Kingdom study indicated that glycemic management is similarly important for preventing retinopathy in patients with type 2 diabetes [9]. (See "Glycemic control and vascular complications in type 1 diabetes mellitus", section on 'Retinopathy'.)

●Reduced retinopathy prevalence and severity – The prevalence of DR has significantly decreased as intensive insulin therapy for the management of type 1 diabetes has become more widespread [10]. Prevalence rates for retinopathy at 8 to 10 years' duration of type 1 diabetes vary between 32 and 59 percent in reports from Finland, Sweden and a follow-up cohort from Wisconsin [11]. The severity of DR has decreased as well, with only 18 percent of retinopathy patients found to have vision-threatening levels of retinopathy at 20 years follow-up compared with 43 percent at 20 years in the earlier Wisconsin study [12]. Similarly, in studies from the United States and the United Kingdom, rates of DR and the proportion of patients with type 2 diabetes requiring laser therapy have decreased over a six-year interval [13,14].

In addition to the effectiveness of glycemic management, the incidence of severe visual loss is influenced by other forms of therapy, including photocoagulation and control of hypertension [15]. These issues are discussed elsewhere. (See "Diabetic retinopathy: Prevention and treatment".)

●Transient worsening after treatment initiation – Another observation from DCCT and other trials is that intensive insulin therapy is often associated with worsening of retinopathy during the first year (figure 3) [8,16]. The deterioration is associated with an increased number of soft exudates (due to retinal infarcts in the superficial layers) [16]. This probably represents the closure of small retinal blood vessels that were narrowed but patent. Correction of hyperglycemia lowers the plasma volume, which can put marginal vessels at risk. As noted above, increased insulin-like growth factor 1 (IGF-1) levels also may contribute to the exacerbation of the retinopathy [17].

●Improved long-term outcomes – Importantly, however, despite an initial progression of retinopathy after initiation of intensive glycemic management, long-term outcomes are improved with intensive treatment compared with standard treatment. In fact, in the DCCT, despite resumption of conventional glycemic management after the trial ended, those who achieved intensive glycemic targets continued to demonstrate reduced incidence of retinopathy progression and vision-threatening disease for up to 18 years after study completion, suggesting a "legacy" effect of intensive treatment [18].

Worsening during pregnancy — The modest increase in risk of worsening DR during pregnancy is sufficient to recommend more frequent retinal evaluations during this time and for one year postpartum (table 2) [19]. However, women can be reassured that over time, their long-term risk of retinopathy progression is not altered by pregnancy. In addition, women who develop gestational diabetes should be reassured that they are not at increased risk for developing DR.

●Risk of progression – The effect of pregnancy on the natural history of DR has been addressed in several studies; progression has been observed in 16 to 85 percent of patients, and the rate of progression may be accelerated [19-23]. In a report from the DCCT, as an example, the likelihood of worsening retinopathy was significantly greater during pregnancy and in the first year postpartum in the 180 women who became pregnant during the course of the study compared with 500 women who did not become pregnant [19]. The risk was higher in women who were receiving conventional therapy before pregnancy than in those receiving intensive therapy (odds ratio 2.5 versus 1.6), even though the conventional therapy group women were advised to initiate intensive therapy when planning for pregnancy.

A substantial number of pregnant women had a greater than three-step progression in retinopathy, including a small number who required laser photocoagulation during pregnancy [19]. Despite these short-term risks, however, the long-term risk of progression (over an average of 6.5 years of follow-up) was not different between the women who did or did not become pregnant.

●Contributing factors – The Diabetes in Early Pregnancy (DIEP) study found that the likelihood of progression is related in part to the severity of retinal involvement before pregnancy [23]. Among 140 women who did not have proliferative retinopathy at the time of conception, retinopathy appeared in 10 percent of those who had no baseline retinopathy, and it worsened in 19 percent of those with mild background retinopathy and 55 percent of those with moderate-to-severe nonproliferative DR (NPDR).

The importance of glycemia as a contributing factor was also confirmed in the Diabetes in Early Pregnancy (DIEP) study [23]. The risk for progression of DR during pregnancy was increased in those with the highest initial glycated hemoglobin (A1C) values and in those with the greatest reduction in A1C values. The rate of worsening retinopathy was significantly higher than that during the first two years on intensive therapy in the DCCT, suggesting that factors other than improved glycemia contribute to the acceleration of retinopathy in pregnant women.

Retinal blood flow may also be important. In one study, retinal venous diameter and retinal volumetric blood flow decreased during the third trimester of pregnancy significantly more in mothers with diabetes than in those without diabetes [24]. This lower retinal blood flow may exacerbate retinal ischemia and hypoxia, thereby causing progression of retinopathy. Changes in hormones, growth factors, and systemic hemodynamics (such as a fall in systemic blood pressure) during pregnancy also play a contributory role. (See "Maternal adaptations to pregnancy: Renal and urinary tract physiology".)

Morbidity and mortality — The presence of DR appears to be a marker of excess morbidity and mortality risk (primarily cardiovascular) [25-30], as illustrated by a prospective study of 2013 patients with type 2 diabetes, free of known cardiovascular disease (CVD) at baseline [29]. Patients with NPDR or proliferative DR (PDR) had a greater risk of incident CVD events, including myocardial infarction, stroke, revascularization, and CVD death, compared with those without retinopathy [29]. Although the presence of other cardiovascular risk factors may explain the association, the risk of CVD events remained twofold higher in individuals with PDR, but not in those with NPDR, after adjustment for hypertension and nephropathy.

The topic of diabetes mellitus and CVD is discussed in detail elsewhere. (See "Prevalence of and risk factors for coronary heart disease in patients with diabetes mellitus".)

SUMMARY AND RECOMMENDATIONS

●Classification of diabetic retinopathy – Diabetic retinopathy (DR) is divided into two major forms: nonproliferative and proliferative, respectively named for the absence or presence of abnormal new blood vessels emanating from the retina. DR can be further classified by severity (picture 1 and picture 2 and table 1). Macular edema (ME; retinal thickening and edema involving the macula) is a visually significant type of DR and can occur at any stage of DR. (See 'Classification' above.)

These stratifications have been useful for analysis of treatment efficacy in the literature and general indicators for treatment strategies. However, each patient with DR has a unique combination of findings, symptoms, and rate of progression, which necessarily requires an individualized approach to treatment in the effort to preserve vision.

●Clinical manifestations – Because the majority of patients who develop DR have no symptoms and the rate of progression may be rapid, it is important to screen patients with diabetes regularly for the development of retinal disease (table 2). (See 'Clinical manifestations' above and "Diabetic retinopathy: Screening".)

The development of clinical DR is complex and is the result of many interrelated factors, which cause two basic changes within the retinal vessels, namely abnormal permeability and vascular occlusion with ischemia and subsequent neovascularization. (See 'Ophthalmologic features' above.)

●Prevalence and natural history – In individuals with both type 1 and type 2 diabetes, glycemic management is a major determinant of the rate of development and progression of DR. The prevalence of DR increases progressively in patients with both type 1 and type 2 diabetes with increasing duration of disease. Some patients with type 2 diabetes have retinopathy at the time of diagnosis; this observation reflects the typically insidious onset of hyperglycemia in type 2 diabetes many years before the diagnosis is established. (See 'Conventional therapy' above.)

•Impact of intensive insulin therapy – Data from the Diabetes Control and Complications Trial (DCCT) and other trials suggest that intensive insulin therapy may be associated with worsening of DR during the first year of treatment (figure 3). However, intensive treatment improves long-term outcomes, and the prevalence and severity of DR have significantly decreased as intensive insulin therapy for the management of type 1 diabetes has become more widespread. (See 'Impact of intensive insulin therapy' above.)

•Worsening during pregnancy – The modest increase in risk of worsening DR during pregnancy is sufficient to recommend more frequent retinal evaluations during this time and for one year postpartum. However, women can be reassured that over time, their long-term risk of retinopathy progression is not altered by pregnancy. In addition, women who develop gestational diabetes should be reassured that they are not at increased risk for developing DR. (See 'Worsening during pregnancy' above and "Diabetic retinopathy: Screening", section on 'Pregnancy'.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Claire E Fraser, MD, PhD, who contributed to earlier versions of this topic review.