Diabetic retinopathy

Diabetic retinopathy (DR) is a sight threatening complication of systemic diabetes mellitus that results from damage to the blood vessels of the retina.

Diabetes mellitus affects 200 million people worldwide and the incidence appears to be increasing throughout the world, at least in part due to the increasing incidence of obesity and sedentary lifestyle. It is projected that from 2005 to 2050, the number of persons with DR will approximately triple. Diabetes is recognized as the leading cause of new blindness among adults aged 25-74 years in the Western world and responsible for 12% of all cases of blindness. Two of every 100,000 individuals in the general population become blind because of DR every year. An increased risk of DR appears to exist in Native Americans, Hispanics, and African Americans. Male and females seem to be equally affected, though slight male preponderance has been noted. Approximately 50% of people with diabetes have some degree of DR.

Nearly all patients with type 1 diabetes (younger-onset patients) and more than 60% of patients with type 2 diabetes (older-onset patients) develop retinopathy during the first two decades of disease, and approximately 4% and 2% of these patients respectively, become legally blind (defined as visual acuity of 1/20). Retinopathy is already present at the time of diagnosis in 20% of patients with type 2 diabetes. In the younger-onset group, approximately 90% of blindness is attributable to DR. In the older-onset group, in which other eye diseases may be present, one-third of the cases of legal blindness are due to DR.

Risk factors and classification

Risk factors

Among the most consistent risk factors, duration of diabetes is probably the strongest predictor for development and progression of the retinopathy. Among patients with younger-onset diabetes, the prevalence is estimated at approximately 8% at 3 years, 25% at 5 years, 60% at 10 years, and 80% at 15 years. Hyperglycemia, hypertension, hyperlipidemia, and renal disease are considerable risk factors. Male sex, higher severity of diabetes (indicated by use of insulin and oral diabetes treatments versus pills alone or use of pills alone versus no treatment), higher average systolic blood pressure, and higher hemoglobin A1c are additional factors to be considered. Obesity, smoking, alcohol consumption, and physical inactivity are also important risk factors, though considered less consistent. Pregnant women with diabetes are a higher risk for developing DR. If gestational diabetes develops, the patient may be at higher risk of developing diabetes with age.



DR can be classified into 2 stages: nonproliferative (early) and proliferative (advanced).

    • Nonproliferative DR is the most common type of RD that can be described as mild-to-moderate. The most common characteristics include signs of retinal ischemia (microaneurysms, hemorrhages, intraretinal microvascular abnormalities, venous beading, and cotton wool spots). However, patients may be asymptomatic and unaware of vision loss. The earliest ophthalmologically visible signs are microaneurysms and retinal hemorrhages. Microaneurysms are visible as round intraretinal lesions ranging from 1 to 100 µm, red or occasionally white, which may be associated with intraretinal hemorrhage or retinal thickening. They occur most frequently at the posterior pole, especially in the area temporal to the macula. Cotton-wool spots appear as localized whitish elevations of the retinal nerve fibre layer. With large areas of microvascular infarction the retina appears diffusely gray ("cloudy swelling"). Increased severity of cotton-wool spots and presence of more spots may be associated with an increased risk of progression. Intraretinal microvascular abnormalities represent either new vessel growth or remodeling of preexisting vessels (which branch with a frequency, number and angulation different from that of normal retinal vessels) through endothelial cell proliferation within the retinal tissues. They may be seen throughout the fundus as flame-shaped, punctuate dot- or larger blot hemorrhages with irregular margins. Venous beading describes veins with irregular increase in caliber.

  • Proliferative DR occurs with further retinal ischemia. The most common characteristics includes the formation of new blood vessels (neovascularization) elsewhere and on the optic nerve, fibrous proliferation elsewhere and on the optic nerve, preretinal and vitreous hemorrhage, and retinal detachment due to scar tissue formation. As the abnormal vessels of novascularization are fragile, vitreous hemorrhaging potentially leading to severe loss of vision is frequent. Glaucoma is frequent. The increased eye pressure may damage the optic nerve. DR usually affects both eyes and has a few visual or ophthalmic symptoms until visual loss develops. The main symptoms of DR are predominantly associated with proliferative retinopathy and may include poor night vision, blurred vision, floating spots, black spots or flashing lights in the vision field, and sudden, severe painless vision loss (Figure 2). Some of these symptoms may be caused by vitreous hemorrhage (that usually does not cause permanent vision loss) or traction retinal detachment (that may be associated with a severe vision loss). Signs in later stages are macular edema seen on slit-lamp biomicroscopy as elevation and blurring of retinal layers, and venous dilation and intraretinal microvascular abnormalities. DR progresses from mild nonproliferative abnormalities to moderate and severe nonproliferative stage, and proliferative DR. Proliferative DR may occur in up to 50% of the patients with type 1 diabetes and in about 10% of patients with type 2 diabetes who have had the disease for 15 years. It has been noted that prevalence of proliferative retinopathy is somewhat higher among type 2 diabetes patients who require insulin to control the disease. Pregnancy, puberty, poor blood glucose control, hypertension, and cataract surgery can accelerate these changes. If left untreated, proliferative DR can lead to severe vision loss and blindness.

Diabetic macular edema

Diabetic macular edema (DME) is a common complication associated with DR that seems more frequent in type 2 than type 1 diabetes. It can occur at any stage of DR and is characterized by the breakdown of the blood-retinal barrier with leakage of plasma from small blood vessels in the macula (Figure 3). This causes swelling of the central retina that severely compromises the macular function. Resorption of the fluid elements from plasma leads to the deposition of its lipid and lipoprotein components and the formation of hard exudates. DME is considered one of the principal causes of vision loss in persons with diabetes. Loss of vision may occur suddenly and treatment is not as successful. Macular edema, retinal and vitreous hemorrhages from new vessels, retinal detachment, or neovascular glaucoma are the primary causes of blindness in patients with DR.

Ocular associations of diabetes other than DR

A range of ocular diseases that may lead to vision loss is associated with diabetes. Anterior ischemic optic neuropathy (AION) is an acute vascular condition of the optic nerve. Studies suggest that up to 25% of patients with AION have a history of diabetes. Diabetic papillopathy is an uncommon optic nerve condition characterized by acute disc edema and mild vision loss. It is a risk factor for the progression of DR and, occasionally, it can precede the development of AION. Extraocular motility disorders may occur in patients with diabetes, secondary to diabetic neuropathy mostly involving the third, fourth, or sixth cranial nerve.

Condition for which diabetes is a known risk factor includes glaucoma. The risk of glaucoma has been reported to be 2-5 times higher in individuals with diabetes than in nondiabetic individuals. Between 32 and 43% of neovascular glaucoma cases are caused by proliferative DR. Ocular ischemic syndrome (OIS) is an uncommon vascular problem that typically presents with vision loss and dull ocular pain. The prevalence of diabetes in patients with OIS is higher than in the general population, with one study reporting that more than 50% of patients with OIS have diabetes.

Ocular conditions where diabetes is a possible risk factor include retinal vein and artery occlusion, retinal arteriolar emboli, corneal diseases (corneal erosion, persistent epithelial defect, or corneal ulcers).

The risk of cataract (and associated vision impairment) is believed to increase with increasing diabetes duration and severity of hyperglycemia.


Differential diagnosis

Differential diagnosis should consider the following conditions: branch retinal and central retinal vein occlusion, ocular ischemic syndrome, retinopathy, hemoglobinopathies. There are a range of common ocular and systemic conditions that can mimic DR in patients with diabetes: age-related macular degeneration, hypertensive retinopathy, radiation retinopathy, and other causes of retinopathy (such as retinal telangiectasias and various connective tissue diseases, including Bechet's disease, temporal arteritis, systemic lupus vasculitis, sarcoidosis, sickle cell retinopathy, Wegener's granulomatosis).


Patient history should be carefully obtained in order to determine the vision difficulties experienced by the patient. Presence of diabetes and diseases or health conditions that may affect the vision should be considered. Comprehensive eye examination includes visual acuity measurements, refraction, evaluation of the ocular structures, including the evaluation of the retina through a dilated pupil, and measurement of the pressure within the eye.

DR is best diagnosed by funduscopy (dilated indirect ophthalmoscopy coupled with biomicroscopy and seven-standard field fundus photography). The diagnosis is based on the following findings: abnormal blood vessels, swelling, blood or fatty deposits in the retina, damaged nerve tissue, growth of new blood vessels and scar tissue, bleeding in the vitreous, retinal detachment.

Fluorescein angiography and optical coherence tomography (OCT) are used to confirm the diagnosis, determine the extent of damage, treatment planning and monitor the efficacy of the treatment.

On fluorescein angiography it is possible to detect and observe "leaky" blood vessels and compromised circulation in the retina. Microaneurysms appear as pinpoint hyperfluorescence that does not enlarge but rather fades in the later phases of the test. Blot and dot hemorrhages appear as hypofluorescent, thus they can be distinguished from microaneurysms. Areas of nonperfusion appear as homogenous dark patches bordered by occluded blood vessels. Intraretinal microvascular abnormalities are usually found in the borders of the nonperfused retina and are evidenced by collateral vessels that do not leak.

OCT is used to determine the thickness of the retina, the presence of retinal swelling, and vitreomacular traction. It is particularly useful for diagnosis and management of DME.

Etiology and pathogenesis

The exact mechanism by which diabetes causes retinopathy remains unclear. Several theories have been proposed to explain the origin and typical course of the disease. In general, retinopathy and other microvascular complications of diabetes multifactorial, attributed to chronic hyperglycemia, vascular damage and leakage, edema, capillary basement membrane thickening, neovascularization, hemorrhage, and ischemia.

Increased levels of blood glucose are thought to damage the structural and functional integrity of the retinal capillaries. The increase in blood glucose switches the normal glucose metabolic pathway (though aldose reductase activation) leading to sugar conversion into alcohol (e.g. glucose into sorbitol). Increased levels of sorbitol damage the intramural pericytes of the retinal capillaries, causing weakness and eventual saccular outpouching of capillary walls, and loss of retinal capillaries autoregulation and primary function. The relatively selective loss of pericytes from the retinal capillaries is a characteristic lesion that occurs early in the course of DR.

Variety of hematologic abnormalities seen in diabetes (increased erythrocyte aggregation, decreased red blood cell deformability, increased platelet aggregation and adhesion) predispose to sluggish circulation, endothelial damage, and focal capillary occlusion. This leads to retinal ischemia, which contributes to the development of DR.

As the disease progresses, eventual closure of the retinal capillaries occurs leading to hypoxia. More extensive retinal hypoxia triggers compensatory mechanisms within the eye to provide enough oxygen to tissues (e.g. venous caliber abnormalities). Further increases in retinal ischemia trigger the production of vasoproliferative factors that stimulate new vessel formation.

Neovascularization is most commonly observed at the borders of perfused and nonperfused retina, and most commonly occurs along the vascular arcades and at the optic nerve head. The new vessels break through and grow along the surface of the retina and into the scaffold of the posterior hyaloid face. By themselves, these vessels rarely cause visual compromise, but they are fragile and highly permeable. They are easily disrupted by vitreous traction, which leads to hemorrhage into the vitreous cavity or the preretinal space. The new blood vessels initially are associated with a small amount of fibroglial tissue formation, which increases with the increase in the density of the neovascular frond. In later stages, the vessels may regress leaving only networks of avascular fibrous tissue adherent to both the retina and the posterior hyaloid face. As the vitreous contracts, it may exert tractional forces on the retina via these fibroglial connections. Traction may cause retinal edema, retinal heterotropia, and both tractional retinal detachments and retinal tear formation with subsequent detachment.

Increased permeability of the retinal vessels results in leakage of fluid and proteinaceous material, which clinically appears as retinal thickening and exudates. If the swelling and exudation involve the macula, a macular edema and diminution in central vision occur. Another theory to explain the development of DME deals with the increased levels of diacylglycerol from the shunting of excess glucose. This is thought to activate protein kinase C (PKC), which, in turn, affects retinal blood dynamics, especially permeability and flow, leading to fluid leakage and retinal thickening. PKC up-regulates the vascular endothelial growth factor (VEGF) and also is active in "downstream" actions of VEGF following binding of the cytokine to its cellular receptor. VEGF isoforms are specifically mitogenic for vascular endothelial cells and also increase permeability at blood-tissue barriers. VEGF expression is enhanced by hypoxia, which is a major stimulus for retinal neovascularization. Indeed, markedly increased levels of VEGF (x20) in the vitreous humor of patients undergoing vitrectomy, in the presence of active retinal or iris neovascularisation, provided initial evidence that VEGF has a role in proliferative diabetic retinopathy. VEGF and pigment-epithelium-derived factor (PEDF) appear to have a reciprocal relation in the eye. In proliferative DR, it has been shown that the levels of VEGF increase, whereas those of PEDF decrease, suggesting that abnormal production and/or secretion of VEGF and PEDF in retinal tissues may have important role in the pathogenensis of the retinal disease.

Several other biochemical mechanisms have recently been proposed to explain the development and progression of the DR. These involve reactive oxygen species, inflammation, apoptotic death of retinal capillary pericytes and endothelial cells, up-regulation of the transcription factor NF-κB. Altered expression of still unidentified critical gene(s) may also cause alteration of one or more critical cellular pathways associated with the pathogenesis of DR. Growth hormone seems also implicated in the development and progression of diabetic retinopathy. Its action is mediated primarily through stimulation of the production of the insulin-like growth factors (IGF). Indeed, blocking IGF-1 secretion appears to prevent retinal neovascularization.

General considerations and follow-up

Management of DR depends on the stage of the disease and aims at slowing down or prevention the progression of the disease. Prevention of sight-threatening complications of DR is preferable to treatment of established disease. This is why interventions may be most effective if instituted earlier in the disease course, before development of significant retinopathy.Because early detection is important, all patients with diabetes should be routinely evaluated to detect treatable DR.

Patients with type 1 diabetes should have an initial comprehensive eye examination within 3-5 years after the onset of diabetes. In general, evaluation for diabetic eye disease is not necessary before 10 years of age. Patients with type 2 diabetes should have an initial comprehensive eye examination at the time of diagnosis or shortly after that. Early referral to an ophthalmologist is particularly important for patients with type 2 diabetes and severe nonproliferative DR, since laser treatment at this stage is associated with a 50% reduction in the risk of severe visual loss and vitrectomy. In both type 1 and type 2 diabetic patients, repeated subsequent examinations are recommended once a year. More frequent follow-up should be offered to patients with abnormal findings and if retinopathy is progressing. In the early stages of nonproliferative DR, only regular monitoring may be required. For patients without retinopathy or with only few microaneurysms, longer interval between examinations can be considered. For patients with moderate-to-severe nonproliferative DR, frequent eye examinations are necessary to determine when to initiate treatment. Attention should be paid on the fact that patients with a longer duration of diabetes are more likely to progress during the next year of observation. In addition, older people are at higher risk for cataract, glaucoma, age-related macular degeneration, and other potentially blinding disorders.

Women with preexisting diabetes should have a comprehensive eye examination prior to conception and during first trimester. They should be counseled on the risk of development and/or progression of DR. Close follow-up throughout pregnancy should be assured. Vision symptoms are indications for ophthalmologic referral.

Persons with DR can suffer significant vision loss. They should be encouraged to pursue visual rehabilitation with an ophthalmologist or optometrist who is trained or experienced in low-vision care. Special low vision devices such as telescopic and microscopic lenses, hand and stand magnifiers, and video magnification systems can be prescribed to make the most of remaining vision.

Treatment approaches comprise primary and secondary interventions. In general, primary interventions (e.g. intensive glycemic and blood pressure control), can reduce the incidence of DR, while secondary interventions (e.g. laser photocoagulation) may prevent further progression of DR and vision loss. Early and aggressive treatment of DR has been proven to be successful in prolonging vision and preventing severe vision loss.

A. Primary interventions include tight glycemic and blood pressure control, and lipid-lowering therapy. These measures are beneficial in patients with both type 1 and type 2 diabetes.

Glycemic control reduces the incidence and progression of DR, especially when instituted early in the course of diabetes. Laboratory studies performed for diagnosis and long-term follow-up include fasting glucose and hemoglobin A1c (HbA1c). Keeping glucose levels in normal ranges (fasting plasma glucose 90-130 mg/dl equal to 5 to 7.2 mmol/l) and maintaining the HbA1c level in the 6-7% range are the goals in the optimal management of diabetes and DR. Beneficial effects usually persist long after the period of intensive control. Hypertension alone is capable of producing hypertensive retinopathy characterized by macro- and microaneurysms, flame hemorrhages, cotton wool spots, and macular exudates. Tight blood pressure control in patients with hypertension and diabetes is beneficial in reducing visual loss from DR. Observational studies suggest that dyslipidemia increases the risk of DR, particularly DME. Lipid lowering recommendations are currently given to all patients with diabetes and elevated cholesterol irrespective of retinopathy status, though the evidence about the benefits of lipid-lowering therapy for DR prevention remains inconclusive.

B. Secondary interventions

I. Medical interventions

The following systemic agents have been shown to decrease the rate of the DR progression: ruboxistaurin (an orally active antagonist of protein kinase C, PKC-β), fenofibrate (a fibric acid derivative used as a lipid-modifying agent), rosiglitazone (a peroxisome proliferator-activated γ ligand commonly used in the treatment of type 2 diabetes, with possible antiangiogenic properties), and somatostatin and somatostatin analogues (octreotide). Majority of these agents are under clinical investigation.

In addition to lowering plasma triglyceride levels, fenofibrate reduces the total and LDL cholesterol, raises HDL cholesterol, and decreases concentration of small LDL cholesterol particles and apolipoprotein B. Fenofibrate tested in type 2 diabetes has no effect on the incidence of DR but reduces the progression of existing DR, thus lessening the need for laser treatment in both DME and progressive DR. Beneficial effect of fenofibrate in DR seems unrelated to changes in serum lipids, however, the exact mechanism of action remains to be elucidated.

Aspirin alone and/or in combination with dipyridamole (both drugs have antiplatelet activities) have been reported to reduce the microaneurysms. Two aldose reductase inhibitors, sorbinil and tolrestat, have been investigated as promising treatment options in DR. However, clinical trials were disappointing as no statistically significant reducing in incidence or progression of DR has been documented.

The blockade of the renin-angiotensin system (RAS) with an angiotensin-converting-enzyme (ACE) inhibitor or by using angiotensin II type 1-receptor blockers is one of the most used strategies for treatment of hypertension in diabetic patients. Apart from the kidney, the RAS system is expressed in the eye where its activation may have an important role in the pathogenesis of DR. The blockade of the RAS is hypothesized to be beneficial per se in reducing the development and progression of DR. In fact, ACE inhibitors and angiotensin-receptor blockers have been documented to moderately slow the development of DR. There is growing evidence that in addition to reducing the microvascular disease, the angiotensin receptor blockers may exert neuroprotective effects that could be involved in their beneficial effects in DR. Recent pivotal study has reported beneficial effects of candesartan (an angiotensin-receptor blocker), on DR. In normotensive diabetic patients, candesartan was able to reduce the incidence of DR in those with type 1 diabetes and to favor DR regression only in type 2 diabetic patients with mild retinopathy. Fenofibrate and candesartan have been proposed as an adjunct in the management of DR.

Carbonic anhydrase inhibitors, such as dorzolamide, represent a possible drug treatment for slowing the development of DR in the early stages. The locally administered dorzolamide has been shown to dilate the capillaries in the retina and decrease the number of occluded capillaries (thus preventing this cardinal point in the DR pathogenesis) and slow substantially the progression from "no retinopathy" to non-proliferative DR.

II. Laser and surgical interventions

1) Pan-retinal laser photocoagulation

Pan-retinal laser photocoagulation (PRP), also known as scatter laser photocoagulation of the peripheral retina, is a specific treatment for proliferative DR and indicated in certain cases of nonproliferative DR. It aims at preventing the development of new vessels over the retina and elsewhere, to reduce the risk of vitreous hemorrhage and retinal detachment but not to regain lost vision (Figure 4). The benefits of PRP persist and are most marked in patients with high-risk proliferative DR, in whom PRP should be commenced without delay.

During the procedure, a special laser is used to make tiny burns that seal the retina and stop vessels from growing and leaking. The initial treatment consists of approximately 1,500-2,000 spots of laser per eye, performed in one or more individual procedures, usually performed under a local anesthesia. Immediately after the laser treatment, vision may decrease (due to edema or swelling of the retina) and restore within two to three weeks. In rare cases, it may remain permanently deteriorated. Other rare but possible adverse effects of PRP include visual field constriction (with implications for driving), night blindness, color vision changes, inadvertent laser burn, macular edema exacerbation, acute glaucoma, and traction retinal detachment.

2) Surgical vitrectomy for vitreous hemorrhage and proliferative DR

Vitrectomy is used for treatment of eyes with advanced DR, including proliferative DR with nonclearing vitreous hemorrhage or fibrosis, areas of traction involving or threatening the macula, and, more recently, persistent DME with vitreous traction. The procedure surgery (under local or general anesthesia) involves removing the clouded vitreous gel from the eye. Recovery of the vision usually takes about four weeks of receiving the operation but can take several months. Vitrectomy may also be used to remove scar tissue remaining as a result of retinal detachment. Early vitrectomy should be considered in patients with type 1 diabetes and persistent vitreous hemorrhage or when hemorrhage prevents other treatment. Often vitrectomy is followed or accompanied by laser treatment. Vitrectomy may slow or stop the progression of DR, but future retinal damage and vision loss is possible.

III. Interventions for DME

1) Focal laser treatment (focal laser photocoagulation)

Focal laser treatment is effective at slowing the progression of retinopathy and reducing visual loss, but the treatment usually does not restore lost vision. During the procedure (usually done in a single session), leaks from abnormal blood vessels are sealed with laser burns. Possible adverse effects include blurred vision, inadvertent foveal burn, central visual field defect, color vision abnormalities, retinal fibrosis, and spread of laser scars. In patients with coexistent proliferative DR and DME, focal laser treatment concurrent with or prior to PRP is recommended.

2) Pharmacological agents

Intravitreal corticosteroids: Randomized clinical trials have shown that intravitreal triamcinolone acetonide (IVTA) leads to significant improvements in DME and visual acuity. The most common complications of IVTA are cataract formation and increased intraocular pressure that may become significant in about 50% of treated eyes within 1 year. More recently, an extended corticosteroid delivery has been achieved by intravitreal or retinal implants. A surgically implanted intravitreal fluocinolone acetonide and an injectable biodegradable intravitreal dexamethasone extended-release implant were evaluated in patients with DME. Improvement in visual acuity and macular thickness has been reported. However, adverse effects included a substantially higher risk of cataract and glaucoma than that observed in eyes receiving IVTA. In some cases IVTA may be useful in eyes with persistent DME and loss of vision despite conventional treatment, though the evidence is inconclusive so far.

In addition to corticosteroids, various anti-inflammatory agents have been investigated, e.g. nepafenac (a topical non-steroidal anti-inflammatory drug) and etanercept (a recombinant fusion protein with activity against TNF-α).

Intravitreal antiangiogenesis agents: As VEGF has been identified as having a major role in the genesis of DR, agents that attenuate the VEGF action represent a promising therapeutic option. They are expected to reduce permeability and neovascularization, the hallmarks of DME and PDR. Based on successful results obtained in wet age-related macular degeneration and promising preliminary data in DR, several randomized clinical trials are currently evaluating three agents that suppress VEGF (named VEGF antagonists or anti-VEGF drugs) for treatment of DME. These are ranibizumab (a recombinant humanized antibody fragment against all isoforms of VEGF-A), pegaptanib (a pegylated aptamer with efficacy against the VEGF-A 165 isoform) and VEGF-Trap. Intravitreal injection permits antiangiogenic drugs to effectively reach the retina and theoretically overcomes the problem of the systemic blockade of angiogenesis. However, this is an invasive procedure that can have complications such as endophthalmitis and retinal detachment and could even have deleterious effects for the remaining healthy retina. This is especially important in diabetic patients for whom long-term administration is expected. Anti-VEGF agents may also produce some systemic side effects. Accordingly, long-term treatment for patients with hypertension, proteinuria, renal failure, cardiovascular disease and foot lesions with wound healing impairment should be avoided. It should be noted that in contrast to the intravitreal corticosteroids, risks of glaucoma and cataract progression associated with intravitreal VEGF antagonists have not been identified.

Pegaptamib and ranibizumab were approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMEA) for treatment of exudative (wet) age-related macular disease in 2004 and 2006, respectively. Bevacizumab was approved by the FDA (2004) for treatment of disseminated colorectal cancer but not licensed for intraocular use. Ranibizumab was recently approved for treatment of DME in Europe (EMEA, January 2011)

Several other VEGF antagonists are currently under investigation as potential treatments for DR, including aflibercept also known as VEGF Trap-Eye (a recombinant fusion protein active against all VEGF-A isoforms and placental growth factor). In addition to RD/DME, aflibercept is studied in clinical trials for exudative AMD. Sirolimus, also known as rapamycin (a macrolide antifungal drug) seems to have anti-VEGF properties. In an animal model, it has been shown to reduce the retinal and choroidal neovascularisation. Several clinical trials studying the efficacy, safety and tolerability of sirolimus in patients with DME are currently ongoing.

3) Surgical vitrectomy for DME

Widespread or diffuse DME that is nonresponsive to focal laser treatment may benefit from vitrectomy. The presence of vitreous traction and macular edema in association with visual impairment is a common indication for vitrectomy. Complications of vitrectomy include recurrent vitreous hemorrhage, retinal tears and detachment, cataract formation, and glaucoma.

The most extensively studied vitreolytic agent is the purified ovine hyaluronidase. Intravitreal administration of hyaluronidase was shown to promote the clearance of vitreous hemorrhage associated with progressive DR. In an animal model, microplasmin (another vitreolytic agent) was able to increase vitreous oxygenation levels after intravitreal injection.

IV. Cataract surgery in patients with DR

Cataract surgery (removal of the natural lens of the eye and replacement with a synthetic lens) is the standard treatment for patients with cataract and significant vision impairment. In patients with diabetes, cataract usually occurs at a younger age and progresses more rapidly. To improve cataract surgical outcomes, adequate control of DR with laser treatment before cataract surgery may be necessary.

Patient education & prognosis

Patient education

Patient education is one of the important aspects in the management of DR. Patients should know that excellent glucose control is beneficial in any stage of DR and that systemic problems (hypertension, renal disease, hyperlipidemia) contribute to the progression of the retinopathy and should be addressed promptly. Smoking should be reduced, if not outright ceased. Visual symptoms (e.g. changes in vision, redness, pain) could be manifestations of disease progression and should be reported immediately.


Most patients with diabetes develop retinopathy: 50% of patients with type 1 diabetes and 30% of those with type 2 diabetes can expect to develop sight-threatening retinopathy in their lifetime and need intervention to reduce the risk of vision loss. Legal blindness is estimated as 25 times more common in the diabetic population than in the population without the disease. On ophthalmic examination, favorable prognostic factors include circinate exudates of recent onset, well-defined leakage, and good perifoveal perfusion. Unfavorable prognostic factors include diffuse edema/multiple leaks, lipid deposition in the fovea, macular ischemia, cystoid macular edema, preoperative vision of less than 1/10, and hypertension.

DR remains a major cause of preventable blindness worldwide. Prevention of retinopathy should be distinguished from prevention of diabetic blindness. Diabetic blindness can be reduced or prevented without preventing retinopathy. Systematic screening for DR and preventive laser treatment for those who develop macular edema or proliferative retinopathy reduces the rate of blindness in the diabetic population, irrespective of the prevalence of retinopathy. Appropriate and timely laser photocoagulation can reduce the risk of severe visual loss by more than 95%. Similarly, the risk of moderate visual loss from DME can be reduced by 50% with appropriate focal laser photocoagulation.

Conclusion & references


Blindness from DR is now largely preventable with timely detection and appropriate interventional therapy. Routine, repetitive, lifelong, and expert clinical retinal examination is essential for patients with diabetes. Since diabetes mellitus is a systemic disease, the optimal management is complex and requires a multi-disciplinary healthcare team-based approach. DR represents a substantial public health problem that needs improving primary and secondary prevention programs.


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Disclaimer: This document contains information based on published scientific articles and is for educational purposes only. It is in no way intended as a substitute for qualified medical professional help, advice, diagnosis or treatment.

Contributors: Katia Marazova, PhD (January 2011), Dr Jean-François Girmens, CHNO des Quinze-Vingts, Paris
Credit: National Eye Institute, National Institutes of Health