ABSTRACT

Diabetic retinopathy is a significant life-altering complication affecting patients with diabetes. Understanding its pathogenesis, prevention, and treatment is critical to delivering effective and comprehensive care for patients with diabetes at all stages. This review discusses the risk factors, epidemiology, pathogenesis, clinical features, and treatment options for diabetic retinopathy, with an emphasis on practical information useful for endocrinologists and other non-ophthalmologists. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes and a leading cause of blindness worldwide and in the US (1-3). The individual lifetime risk of DR is estimated to be 50–60% in patients with type 2 diabetes and over 90% in patients with type 1 diabetes (4). It is the most frequent cause of blindness in adults between 20-74 years of age in developed countries (5). The same pathologic mechanisms that damage the kidneys and other organs affect the microcirculation of the eye (6). With the global epidemic of diabetes, one expects that diabetes will be the leading global cause of vision loss in many countries (1,2). While DR is specific for diabetes, other eye disorders, such as glaucoma and cataracts, occur earlier and more frequently in people with diabetes (5).

Often, by the time patients seek ophthalmologic examination and treatment, there are significant alterations of the retinal microvasculature. Therefore, it is important for non-ophthalmologists to recognize the importance of eye disease in patients with diabetes so that appropriate referral to eye-care specialists can be a part of their diabetes management program.

EPIDEMIOLOGY

In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), the prevalence of DR in patients with type 1 diabetes was 17% in those with less than 5 years of diabetes vs 98% in those with 15 or more years of diabetes (6). Proliferative diabetic retinopathy (PDR) was absent in patients with type 1 diabetes of short duration but present in 48% of those with 15 or more years of diabetes. In patients with type 1 diabetes, the 25-year rate of progression of DR was 83%, with progression to PDR occurring in 42% of patients (7). Improvement of DR was observed in 18% of patients with type 1 diabetes. In the WESDR, 3.6% of patients with type 1 diabetes were legally blind, and 86% of the blindness was attributable to DR (8). The risk of blindness increases with the duration of diabetes.

In the WESDR, patients with type 2 diabetes of less than 5 years had a prevalence of DR of 28%, while in patients with greater than 15 years of diabetes, the prevalence was 78% (6). A considerable number of patients with type 2 diabetes (12-19%) have DR at the time of the diagnosis of diabetes (1). The prevalence of PDR was relatively low in patients with type 2 diabetes (2%) in patients with less than 5 years duration vs 16% in patients with greater than 15 years duration of diabetes (6). The prevalence of DR and PDR was greater in the patients with type 2 diabetes using insulin. In the patients with type 2 diabetes, 1.6% were legally blind, and one-third of cases of legal blindness were due to DR (8).

Of note, the WESDR cohort is 99% white, and data suggest a higher prevalence of DR in Mexican-Americans and African-Americans with type 2 diabetes (6,9,10). Asians appear to have the same or lower prevalence of DR (1,10). DR occurs in both males and females with diabetes, but males appear to be at a slightly higher risk (9). Diabetic macular edema (DME) occurs more commonly in patients with type 2 diabetes, and with the marked increase in the prevalence of type 2 diabetes, DME is becoming more common (2). DME is over two times more prevalent than PDR (9).

In a pooled analysis of 35 studies between 1980 and 2008, among 22,896 individuals with diabetes, the overall prevalence of DR was 34.6%, PDR 6.96%, DME 6.81%, and vision-threatening DR 10.2% (11). The longer the duration of diabetes, the greater the prevalence of all of these diabetic eye manifestations (11). Moreover, the prevalence of DR, PDR, and DME was greater in patients with type 1 diabetes (77%, 32%, and 14%) compared to patients with type 2 diabetes (32%, 3, and 6%) (1,11).

In developed countries the incidence and the risk of progression of DR have greatly declined in patients with type 1 and type 2 diabetes (1,2,12). The WESDR showed that from 1980 to 2007, the estimated annual incidence of PDR decreased by 77%, and vision impairment decreased by 57% in patients with type 1 diabetes (12). In an analysis of 28 studies with 27,120 patients, the rates of DR and PDR were lower among participants in 1986-2008 than in 1975-1985 (13). Thus, patients with recently diagnosed type 1 or type 2 diabetes in developed countries have a much lower risk of PDR, DME, and visual impairment as compared with patients who developed diabetes in the past (1,12). This marked decrease in the prevalence and incidence of DR and vision impairment is likely due to improved glycemia control, early screening for eye disease, and the more aggressive treatment of blood pressure (1). However, in countries with limited medical resources, this reduced risk of DR and vision impairment is not occurring (2).

In caring for patients with diabetes, health care providers must bear in mind the substantial risks of developing visual loss that these patients face and the treatments that can reduce this risk. For affected patients, diabetes-related visual loss decreases the quality of life and interferes with the performance of daily activities.

RISK FACTORS

SCREENING

The American Academy of Ophthalmology has recommended screening for diabetic retinopathy 5 years after diagnosis in patients with type 1 diabetes, and at the time of diagnosis in patients with type 2 diabetes. Patients without retinopathy should undergo dilated fundus examination annually. If mild non-proliferative diabetic retinopathy (NPDR) is present, exams should be repeated every 9 months. Patients with moderate NPDR should be examined every 6 months. In severe NPDR, exams should be conducted every 3 months. Patients with a new diagnosis of proliferative diabetic retinopathy should be examined every 2 to 3 months, until they are deemed stable, at which point examinations can be performed less frequently. During pregnancy, patients should be examined every 3 months, since retinopathy can progress rapidly in this setting (2019 AAO preferred practice pattern document for monitoring diabetic retinopathy: https://www.aao.org/preferred-practice-pattern/diabetic-retinopathy-ppp).

The American Diabetes Association 2020 guidelines (5) recommends the following:

• Adults with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 5 years after the onset of diabetes.
• Patients with type 2 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist at the time of the diabetes diagnosis.
• If there is no evidence of retinopathy for one or more annual eye exams and glycemia is well controlled, then screening every 1–2 years may be considered. If any level of diabetic retinopathy is present, subsequent dilated retinal examinations should be repeated at least annually by an ophthalmologist or optometrist. If retinopathy is progressing or sight-threatening, then examinations will be required more frequently.
• Programs that use retinal photography (with remote reading or use of a validated assessment tool) to improve access to diabetic retinopathy screening can be appropriate screening strategies for diabetic retinopathy. Such programs need to provide pathways for timely referral for a comprehensive eye examination when indicated.
• Women with preexisting type 1 or type 2 diabetes who are planning pregnancy or who are pregnant should be counseled on the risk of development and/or progression of diabetic retinopathy.
• Eye examinations should occur before pregnancy or in the first trimester in patients with preexisting type 1 or type 2 diabetes, and then patients should be monitored every trimester and for 1 year postpartum as indicated by the degree of retinopathy.

PATHOGENESIS

Various mechanisms account for the features of diabetic retinopathy. Histopathologic analysis shows thickening of capillary basement membranes, microaneurysm formation, loss of pericytes, capillary acellularity, and neovascularization. Microaneurysms, outpouchings of the capillary wall, serve as sites of fluid and lipid leakage, which can lead to the development of diabetic macular edema. Theories on the biochemistry of these end-organ changes include toxic effects from sorbitol accumulation, vascular damage by excessive glycosylation with crosslinking of basement membrane proteins, and activation of protein kinase C-ß2 by vascular endothelial growth factor (VEGF), leading to increased vascular permeability and endothelial cell proliferation. VEGF, produced by the retina in response to hypoxia, is believed to play a central role in the development of neovascularization (1,82).

CLINICAL FEATURES

Nonproliferative Diabetic Retinopathy (NPDR)

Studies have found that retinopathy in both insulin-dependent and non-insulin-dependent diabetes occurs 3 to 5 years or more after the onset of diabetes. In the WESDR, the prevalence of at least minimal retinopathy was almost 100% after 20 years (83). A more recent study has confirmed that at least 39% of young persons with diabetes developed retinopathy within the first 10 years (84). The earliest clinical sign of diabetic retinopathy is the microaneurysm, a red dot seen on ophthalmoscopy that varies from 15 to 60 microns in diameter (Figure 1).

Figure 1.

Microaneurysms and intraretinal hemorrhages in nonproliferative retinopathy. (UCSF Department of Ophthalmology)

The lesions can be difficult to distinguish from intraretinal hemorrhages on examination, but with fluorescein angiography microaneurysms can be identified easily as punctate spots of hyperfluorescence (Figure 2, 3). By contrast, hemorrhages block the background fluorescence and therefore appear dark.

Figure 2.

Microaneurysms: hyperfluorescent dots in early phase of fluorescein angiogram (arrows). (Zuckerberg San Francisco General Hospital, Dept. of Ophthalmology)

Figure 3.

Two minutes later, fluorescein leakage from the microaneurysms gives them a hazy appearance. (Zuckerberg San Francisco General Hospital, Dept. of Ophthalmology)

The severity of NPDR can be graded as mild, moderate, severe, or very severe. In mild disease, microaneurysms are present with hemorrhage or hard exudates (lipid transudates). In moderate NPDR, these findings are associated with cotton-wool spots (focal infarcts of the retinal nerve fiber layer or areas of axoplasmic stasis) or intraretinal microvascular abnormalities (vessels that may be either abnormally dilated and tortuous retinal vessels, or intraretinal neovascularization). The “4-2-1 rule” is used to diagnose severe NPDR: criteria are met if hemorrhages and microaneurysms are present in 4 quadrants, or venous beading (Figure 4) is present in 2 quadrants, or moderate intraretinal microvascular abnormalities are present in 1 quadrant. In very severe NPDR, two of these features are present.

The correct evaluation and staging of NPDR is important as a means of assessing the risk of progression. In the ETDRS, eyes with very severe NPDR had a 60-fold increased risk of developing high-risk proliferative retinopathy after 1 year compared with eyes with mild NPDR (85). For eyes with mild or moderate NPDR, early treatment with laser was not warranted, as the benefits in preventing vision loss did not outweigh the side effects (1). By contrast, in very severe NPDR, early laser treatment was often helpful.

Figure 4.

Venous beading (arrows) in a case of proliferative diabetic retinopathy. (UCSF Department of Ophthalmology)

Capillary closure can also result in macular ischemia, another cause of vision loss in NPDR. This can be identified clinically as an enlargement of the normal foveal avascular zone on fluorescein angiography (Figure 5).

Figure 5.

Capillary dropout around the fovea (white arrow) and in the temporal macula (black arrow). (Zuckerberg San Francisco General Hospital, Dept. of Ophthalmology)

Diabetic Macular Edema (DME)

Macular edema may be present at all the stages of diabetic retinopathy and is the most common cause of vision loss in nonproliferative diabetic retinopathy. Because of the increased vascular permeability and breakdown of the blood-retinal barrier, fluid and lipids leak into the retina and cause it to swell. This causes photoreceptor dysfunction, leading to vision loss when the center of the macula, the fovea, is affected. In the ETDRS, diabetic macular edema (DME) was characterized as "clinically significant" if any of the following were noted (Figure 6): retinal thickening within 500 microns of the fovea, hard exudates within 500 microns of the fovea if associated with adjacent retinal thickening, or an area of retinal thickening 1 disc diameter or larger if any part of it is located within 1 disc diameter of the fovea (86).

Figure 6.

Clinically significant macular edema with hard exudates in the fovea. Cotton-wool spots are present near the major vessels. (UCSF Department of Ophthalmology)

Although the cause of the microvascular changes in diabetes is not fully understood, the deficient oxygenation of the retina may induce an overexpression of vascular endothelial growth factor (VEGF), with a consequent increase in vascular leakage and retinal edema (87). Besides ischemia, inflammation may also play a role in the development of macular edema in diabetic retinopathy. In fact, elevated levels of extracellular carbonic anhydrase have been discovered in the vitreous of patients with diabetic retinopathy (88). Carbonic anhydrase may originate from retinal hemorrhages and erythrocyte lysis and may activate the kallikrein-mediated inflammatory cascade, contributing to the development of DME.

Optical Coherence Tomography (OCT) is a widely used imaging technique that provides high-resolution imaging of the retina (Figure 7) (89). Working as an “optical ultrasound,” OCT projects a light beam and then acquires the light reflected from the retina to provide a cross-sectional image. Most patients with DME have diffuse retinal thickening or cystoid macular edema (presence of intraretinal cystoid-like spaces). In some patients, DME may be associated with posterior hyaloidal traction, serous retinal detachment or traction retinal detachment (90). Cystoid macular edema and posterior hyaloid traction are significantly associated with worse visual acuity (90).

Figure 7.

OCT image showing diabetic macular edema (UCSF Department of Ophthalmology).

Proliferative Diabetic Retinopathy (PDR)

In proliferative diabetic retinopathy, many of the changes seen in NPDR are present in addition to neovascularization that extends along the surface of the retina or into the vitreous cavity (Figure 8). These vessels are in loops that may form a network of radiating spokes or may appear disorganized. In many cases the vessels are first noted on the surface of the optic disc, although they can be easily missed due to their fine caliber. Close inspection often reveals that these new vessels cross over both the normal arteries and the normal veins of the retina, a sign of their unregulated growth.

Figure 8.

Active neovascularization in PDR. Fibrovascular proliferation overlies the optic disc (white arrow). Loops of new vessels are especially prominent superior to the disc and extending into the macula, where leakage of fluid has led to deposition of a ring of hard exudate around the neovascular net (black arrow). (UCSF Department of Ophthalmology)

New vessels can also appear on the iris, a condition known as rubeosis iridis (Figure 9). When this occurs, careful inspection of the anterior chamber angle is essential, as growth of neovascularization in this location can obstruct aqueous fluid outflow and cause neovascular glaucoma.

Figure 9.

Rubeosis iridis in a case of PDR. Abnormal new vessels are growing along the surface of the iris (arrows). (UCSF Dept. of Ophthalmology)

Neovascularization can remain relatively stable or it can grow rapidly; progression can be noted ophthalmoscopically over a period of weeks. Preretinal new vessels often develop an associated white, fibrous tissue component that can increase in size as the vessels regress. The resulting fibrovascular membrane may then develop new vessels at its edges. This cycle of growth and fibrous transformation of diabetic neovascularization is typical. The proliferation occurs on the anterior surface of the retina, and the vessels extend along the posterior surface of the vitreous body. Fibrous proliferation takes place on the posterior vitreous surface; when the vitreous detaches, the vessels can be pulled forward and the thickened posterior vitreous surface can be seen ophthalmoscopically, highlighted by areas of fibrovascular proliferation.

The severity of PDR can be classified as to the presence or absence of high-risk characteristics. As determined in the Diabetic Retinopathy Study, eyes are classified as high-risk if they have 3 of the following 4 characteristics: the presence of any neovascularization; neovascularization on or within 1-disc diameter of the optic disc; a moderate to severe amount of neovascularization (greater than 1/3 disc area neovascularization of the disc, or greater than 1/2 disc area if elsewhere), or vitreous hemorrhage.

Vision loss in proliferative diabetic retinopathy results from three main causes. First, vitreous hemorrhage occurs because the neovascular tissue is subject to vitreous traction. Coughing or vomiting may also trigger a hemorrhage. Hemorrhage may remain in the preretinal space between the retina and the posterior vitreous surface, in which case it may not cause much vision loss if located away from the macula (Figure 10). In other cases, though, hemorrhage can spread throughout the entire vitreous cavity, causing a diffuse opacification of the visual media with marked vision loss (Figure 11, 12).

Figure 10.

Preretinal hemorrhage: blood trapped between the retina and the vitreous in a case of incomplete vitreous detachment. Visual acuity is unaffected. (UCSF Department of Ophthalmology)

Figure 11.

Left: moderate vitreous hemorrhage; vision = 20/150. Right: 1 year later after spontaneous clearing of the hemorrhage; vision = 20/30. (Zuckerberg San Francisco General Hospital, Dept. of Ophthalmology)

Figure 12.

Dense vitreous hemorrhage almost completely obscuring the view of the fundus. (Zuckerberg San Francisco General Hospital, Dept. of Ophthalmology)

Another cause of severe vision loss in PDR is retinal detachment. As the fibrovascular membranes and vitreous contract, their attachments to the retina can cause focal elevations of the retina, resulting in a traction retinal detachment (Figure 13). In other cases the retinal vessels can be avulsed or retinal holes may be created by this traction, leading to a combined traction-rhegmatogenous retinal detachment (Figure 14).

Figure 13.

Marked fibrosis with traction exerted on the retina outside the central macula (arrows). The macula does not appear to be elevated centrally. (UCSF Dept. of Ophthalmology)

Figure 14.

Traction retinal detachment outside the macula. Note elevation of retinal vessel out of the plane of focus (white arrow). Scatter photocoagulation scars are seen peripherally (black arrow). (UCSF Dept. of Ophthalmology)

Finally, patients with PDR may have macular nonperfusion or coexisting diabetic macular edema that causes vision loss through photoreceptor dysfunction.

TREATMENT

Tight glucose and blood pressure control are critical systemic factors in controlling the progression of diabetic retinopathy. Ocular complications of diabetes are addressed directly through treatment with laser photocoagulation, intravitreal injections, or surgery. Laser treatment has been the primary approach to vision-threatening diabetic retinopathy for decades. Recent randomized clinical trials have demonstrated that intravitreal anti-VEGF agents are more effective than laser under certain conditions.

Laser Photocoagulation for NPDR

Diabetic macular edema is believed to result from fluid and lipid transudation from microaneurysms and telangiectatic capillaries. Focal laser photocoagulation is used to heat and close the microaneurysms, causing them to stop leaking (Figure 15). Macular edema often improves following this form of treatment. Some clinicians apply laser burns in a grid pattern overlying areas of retinal edema without directing treatment to specific microaneurysms; this method can also be effective in reducing retinal thickening. The mechanism by which grid laser treatment achieves these results is not known.

The ETDRS found that the risk of moderate visual loss in eyes with diabetic macular edema was reduced by 50% by photocoagulation (91,92). At 3 years, 24% of untreated eyes experienced a 3-line decrease in vision compared with 12% of treated eyes. Eyes meeting the criteria for clinically significant macular edema in which the edema was closest to the center were most likely to benefit from treatment. Side effects of laser treatment can include scotomata, noticeable immediately after the procedure, if treatment is performed too close to the fovea. Late enlargement of laser scars can also occur, causing delayed visual loss. Inadvertent photocoagulation of the fovea is a risk of the procedure. Since the amount of energy used is minimal, the treatment is performed under topical anesthesia.

In the ETDRS study, only a very small percentage of eyes improved with focal laser treatment, highlighting the fact that the goal of laser treatment is not to improve vision, but rather to stabilize it and prevent worsening. It is also true that inclusion criteria for that study were based on the presence of “clinically significant” macular edema threatening the macula, even if the visual acuity was not yet reduced. For this reason, it has been argued that the study enrolled patients with excellent visual acuity, making it difficult to demonstrate small improvements in vision after laser treatment.

Due to the recent evidence on the efficacy and safety of anti-VEGF therapy for diabetic macular edema, different modalities of laser therapy have been proposed. Laser may be able to stabilize macular edema and reduce the need for multiple anti-VEGF injections. Modified ETDRS laser techniques include lower intensity laser burns, and they take particular care in maintaining a greater space from the center of the fovea (93). Subthreshold laser therapy and minimalistic FA-guided treatment of microaneurysms may also induce less damage to the macula than the classic ETDRS approach (94).

Figure 15.

Focal laser scars in the macula following treatment for macular edema (arrow). Edema has resolved. (Zuckerberg San Francisco General Hospital, Dept. of Ophthalmology)

Laser Photocoagulation for PDR

Scatter laser photocoagulation, also known as panretinal photocoagulation (PRP), is an important treatment modality for PDR and severe NPDR (92). Laser spots are placed from outside the major vascular arcades to the equator of the eye, with burns spaced approximately 1/2 to 1 burn width apart (Figure 16, 17). Although the treatment destroys normal retina, the central vision is unaffected since all spots are placed outside the macula. The theory underlying this treatment is that photocoagulation of the ischemic peripheral retina decreases the elaboration of vasoproliferative factors contributing to PDR. Indeed, VEGF levels in the vitreous are increased in eyes with neovascularization, and they are lower after scatter photocoagulation (95). Other factors such as insulin-like growth factor-1 are similarly elevated in the vitreous of eyes with PDR (96).

Side effects of scatter photocoagulation can include decreased night vision and dark adaptation, and visual field loss. The procedure can be painful, so treatment may be divided into several sessions, and either topical or retrobulbar anesthesia may be used.

Figure 16.

Scatter photocoagulation scars in an eye with active PDR. Note that all scatter laser scars are located outside the macula. (UCSF Department of Ophthalmology)

Figure 17.

View of laser scars superior to the macula in the same eye. Spots are approximately one-half burn width apart. In the treated area, the retinal vessels are sclerotic (arrows). (UCSF Department of Ophthalmology)

The Diabetic Retinopathy Study evaluated the effects of scatter photocoagulation in over 1700 patients with PDR or severe NPDR. Patients had one eye randomized to treatment and one eye to observation. Treatment was shown to reduce severe visual loss by 50% (97). The ETDRS also found a positive risk-benefit ratio for early scatter treatment in patients with severe NPDR or early PDR. Interestingly, a subsequent study demonstrated that scatter laser performed at a single sitting was not worse than treatment divided over four sessions in terms of inducing macular edema or decreasing visual acuity (98).

Panretinal photocoagulation may induce or aggravate diabetic macular edema, reduce contrast sensitivity and affect the peripheral visual field (85). Macular edema can be approached by focal laser or intravitreal injections before or at the time of panretinal photocoagulation. However, it is not recommended to delay panretinal photocoagulation in high-risk PDR.

The DRCR.net study protocol S has shown that intravitreal anti-VEGF agents may be a substitute for panretinal laser treatment (99). This multicenter randomized clinical trial compared ranibizumab to PRP in patients with PDR. Mean visual acuity letter improvement at 2 years was +2.8 in the ranibizumab group vs +0.2 in the PRP group (P < 0.001). Mean peripheral visual field sensitivity loss was worse, vitrectomy was more frequent, and DME development was more common in the PRP group. Further studies are needed in order to evaluate the long-term implications of using anti-VEGF agents alone. Ranibizumab may be a reasonable treatment alternative to consider for patients with severe NPDR or non-high-risk PDR who can follow-up regularly.

NOVEL THERAPIES FOR DIABETIC RETINOPATHY

Current therapies are limited in their ability to reverse vision loss in diabetic retinopathy. For example, although focal laser photocoagulation can help stabilize vision by reducing macular edema, it rarely improves vision. Corticosteroids induce cataract progression and intraocular pressure elevation. Anti-VEGF agents do not increase cataract formation rates but they generally need more frequent intravitreal injections, carrying the risk of endophthalmitis; they can temporary increase IOP; they might have systemic adverse effects. For addressing these issues, new sustained-release devices are being designed, and studies are ongoing to test new intravitreal medications.

The development of new treatment modalities is being guided by an understanding of the mechanisms of the disease. From this perspective, researchers are now focusing on the role of inflammation on DME. NSAIDs, anti-TNF agents (Etanercept and Remicade), mecamylamine (an antagonist of nACh receptors), and intravitreal erythropoietin are currently under investigation for the treatment of refractory diabetic macular edema (123).

In order to create a national taskforce to study and treat diabetic retinopathy, in 2002 the National Eye Institute instituted the Diabetic Retinopathy Clinical Research Network (www.drcr.net). DRCR is a collaborative network dedicated to design and carry out multicenter clinical trials on diabetic retinopathy and diabetic macular edema. The DRCR network currently includes over 150 participating sites with over 500 physicians throughout the United States.

The DRCR Network has an ongoing project to study genes involved in diabetic retinopathy.

CONCLUSION

Retinopathy remains a challenging complication of diabetes that can adversely affect a patient’s quality of life. Although ophthalmologists can often stabilize the condition or reduce vision loss, prevention and early detection remain the most effective ways to preserve good vision in patients with diabetes. Ensuring tight glucose and blood pressure control and referring patients for ophthalmologic examination are important ways in which internists and other clinicians can help to maximize their patients’ vision and therefore their quality of life. New treatments may offer greater hope for sustained visual improvement in patients with diabetic retinopathy.

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