Are You Sure the Patient Has Diabetic Retinopathy?

The patient may be asymptomatic but may present with blurred vision, floaters and dark shadows in vision, and diplopia.
Difficulty focusing, reading, and blurred vision are the most common symptoms. Other symptoms are less frequent, but may present in more advanced retinopathy.
Patients have a history of diabetes or elevated hemoblobin (Hb)A1c.

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What Else Could the Patient Have?

Retinal venous occlusive diseases such as central retinal vein occlusion or branch retinal vein occlusion are sometimes seen in patients with hypertension, hyperlipidemia, or diabetes. Clinical features include retinal hemorrhages that follow the vascular tree, retinal edema that may involve the fovea, “cotton wool” spots, and exudates. Retinal or iris neovascularization may also be present.

Carotid occlusive diseases may also present with retinal hemorrhages and vascular tortuosity. These hemorrhages differ from diabetic disease in that the location of the hemorrhages is typically in the mid-periphery. Radiation retinopathy may also show retinal hemorrhages, retinal edema, and areas of poor retinal perfusion. This usually occurs in a patient with a history of radiation therapy, often for head and neck cancer (especially cancer involving the sinuses). Seen most commonly 5-10 years post treatment.

Inflammatory retinal disease caused by systemic conditions such as sarcoidosis and systemic lupus erythematosus can also show retinal hemorrhages and neovascularization. There is often a history of chronic ocular inflammation.

Key Laboratory and Imaging Tests

Diabetic retinopathy is the most common cause of blindness in the working population (21 to 64 years). The disease is caused by poor retinal circulation and vascular remodeling. Cogan and Kuwabara demonstrated vasodilatation of the capillary bed as well as pericyte dropout, loss of endothelial cells, and microaneurysm formation. More recently, the upregulation of vascular endothelial growth factor has been demonstrated to be a key factor in the development of capillary leakage and the development of neovascularization. Poor perfusion is sometimes seen due to leukocyte plugging of the capillaries or degeneration of the retinal microcirculation.

The most common cause of visual loss is macular edema, which is swelling that involves the macula area, especially swelling involving the center of the fovea. This is called “center-involved macular edema.” Several factors are associated with the risk for the development of retinopathy and its severity; the most important is the duration of diabetes. Another is the degree of diabetic control as well as the presence of systemic hypertension. There may also be racial and genetic factors that contribute to the retinopathy (e.g., Hispanics and African Americans tend to have more severe retinal disease than whites.). Laboratory data are not very helpful in managing retinopathy.

However, one should strive for good control of blood sugar levels, so the HbA1c is important to measure. The patient should be encouraged to maintain an HbA1C level of 7 or less. The eye physician should be in good communication with the internist or endocrinologist about the state of the patient’s retina and follow-up intervals that are recommended. As a team, they are better able to ensure good patient outcomes.

The Diabetes Control and Complications Trial (type 1 diabetics) and the United Kingdom Prospective Diabetes Study (type 2 diabetics) confirmed the reduction of diabetic retinopathy in patients who have good sugar control. This reduction affected both the occurrence and the progression of diabetic retinopathy. Significant worsening of the patient’s health status, such as blood pressure control, renal failure, or hyperlipidemia, should be communicated to the eye care practitioner, as the patient may require an earlier follow-up retinal examination.

A dilated examination of the retina is important to determine the level of retinopathy and the clinical investigations needed for further patient evaluation. Dilated fundus examination should be performed 5 years after diagnosis or at puberty in type 1 diabetics. After puberty, there is evidence of the increase in insulin-like growth factor 1 and other growth factors that may enhance the development of diabetic retinopathy. Dilated fundus examination should be performed upon diagnosis in patients who are type 2 diabetics. Thereafter, examinations should be performed at least annually. Following appropriate screening guidelines for retinopathy can reduce the risk of blindness from retinopathy by 50%.

The clinical features seen in retinopathy are categorized as nonproliferative or proliferative. The following findings are seen in nonproliferative diabetic retinopathy (NPDR).

Microaneurysms
Intraretinal hemorrhages — these may be superficial in the nerve fiber layer, seen as striate or flame hemorrhages, or deeper dot and blot retinal hemorrhages
Cotton wool spots — these are infarcts in the nerve fiber layer
Lipid (hard) exudates
Retinal edema — this may or may not involve the macula
Intraretinal microvascular abnormalities — these are dilated capillaries that are signs of increasing retinal ischemia

NPDR is classified as mild, moderate, or severe. Examination results should be recorded as:

Mild retinopathy: Occasional microaneurysms and rare intraretinal hemorrhages
Moderate retinopathy: More scattered retinal hemorrhages, cotton wool spots, and exudates
Severe retinopathy. This stage is associated with increased risk of progression to proliferative retinopathy and is defined as any of the following:

intraretinal hemorrhages in all 4 quadrants

venous tortuosity and beading in two quadrants

intraretinal microvascular abnormalities in 1 quadrant.
Very severe nonproliferative retinopathy will have two or more of these characteristics and have a higher risk of progression to proliferative diabetic retinopathy. According to the Early Treatment of Diabetic Retinopathy Study (ETDRS), 50% of patients with severe NPDR will progress to proliferative diabetic retinopathy (PDR). Of this group, 15% will have high-risk findings for visual loss. Patients with very severe NPDR have a 75% risk of developing PDR within 1 year, with 45% showing high-risk characteristics for visual loss.

In addition to the findings present in NPDR, eyes with proliferative diabetic retinopathy (PDR) may manifest the following clinical findings:

neovascularization of the disc – new vessels present on the optic disc
neovascularization elsewhere – new vessels present elsewhere on the retina
preretinal and vitreous hemorrhage – hemorrhages that are overlying the retina or staining the vitreous gel
traction retinal detachment – advanced neovascularization and fibrosis may lead to a contraction of membranes that results in retinal detachment
iris neovascularization (rubeosis iridis) – in eyes with severe ischemia, new vessels may develop on the surface of the iris. As the vessels grow larger, they form a membrane on the iris that may advance peripherally to cover the angle of the anterior chamber, causing scarring and a specific form of secondary angle closure glaucoma called neovascular glaucoma. This condition has a high risk for visual loss. Eyes with neovascular glaucoma are usually very sick due to severe ischemia and upregulation of vascular endothelial growth factor (VEGF).

The Diabetic Retinopathy Ocular Examination

Initial Exam History (Key Elements)

Ocular symptoms
Duration of diabetes
Glycemic control (HbA1c)
Medications both systemic and ocular
General medical history (e.g., other complications of diabetes, hypertension, hyperlipidemia, renal disease, sleep apnea, obesity, exercise, smoking history, pregnancy in female of child-bearing age)
Past ocular history of surgery or disease

Ocular Examination

Visual acuity
Assessing ocular alignment and ocular motility
Intraocular pressure (IOP) measurement
Gonioscopy if iris neovascularization is present or the IOP is elevated
Slit lamp biomicroscopy of the anterior and posterior segment
Dilated fundus evaluation with stereoscopic examination of the posterior pole
Indirect ophthalmoscopy of the vitreous, posterior, and peripheral retina.

Diagnostic tests are not as useful in determining whether a patient has retinopathy, but they are helpful in determining severity, progression, and response to treatment.

Fundus photography: Useful to stage retinopathy and for following the patient.
Spectral domain optical coherence tomography (SDOCT) is useful in documenting the severity of diabetic macular edema. The latest concepts in diabetic macular edema therapy include “center involved” macular edema, where the center of the fovea has a thickness at or above 250 microns on the time domain OCT or 310 microns on the Fourier (spectral) domain OCT. OCT is also very useful for following response to therapy. It has mostly replaced the fluorescein angiogram in following these patients because it is faster to perform, and is non-invasive.
Fluorescein angiography (FA) can still be useful in evaluating the extent of areas of nonperfusion, especially in the macula. It also is used as a guide for laser therapy in the treatment of macular edema, although laser therapy is used much less frequently than it was used in the past. Note that patients may be effectively managed without this diagnostic modality, but FA may prove invaluable in retreatments and for following patients.
OCT Angiography (OCT-A): OCT-A is a new imaging modality that is based on OCT technology. In a nutshell, it uses light to repeatedly sample sections of the retina. Moving red blood cells on sequential images act as contrast media in comparison to the rest of the retina, which is not moving. In this way, detailed vascular images of the retina are obtained. OCT-A is becoming a very useful way to study different vascular layers of the retina in diabetic eyes.

Other Tests That May Prove Helpful Diagnostically

Ultra Widefield fundus imaging and FA may be performed with newer testing modalities like Optos ultra widefield imaging system or the Heidelberg Spectralis system. These systems are very useful in demonstrating the level of peripheral retinal disease. They can capture peripheral nonperfusion, which often is a precursor to neovascularization and can contribute to macular edema.

B-mode ultrasonography is useful in patients with opaque media where there is limited or no visualization of the posterior segment. This occurs in patients with severe vitreous hemorrhaging or opaque cataracts.

Management and Treatment of the Disease

Screening for retinopathy through dilated retinal exams is the most important recommendation for preserving vision and preventing blindness from diabetes. The Diabetic Control and Complications Trial showed that intensive glycemic control was associated with decreased incidence of the development of retinopathy and reduction in the progression of existing retinopathy in type 1 diabetics. Subjects in the primary prevention cohort experienced a 76% reduction in the risk of developing retinopathy and 54% reduction of the risk of retinopathy progression in the secondary intervention cohort. Thus control of blood sugar is important in reducing the risk of microvascular complications.

This finding was confirmed in the United Kingdom Prospective Diabetes Study in type 2 diabetics. This study demonstrated a 25% risk reduction in microvascular complications seen in the intensive treatment group compared to conventional therapy. In these patients, both blood pressure and glycemic control were associated with reduction of visual loss at 4.5 to 6 years after randomization.

Managing Diabetic Macular Edema

The ETDRS study demonstrated the benefit of laser photocoagulation in the treatment of patients with CSDME. Laser may be performed in a grid pattern over areas of diffuse leakage and focally to microaneurysms and IRMA.
Grid/focal laser photocoagulation reduces the incidence of severe visual loss by 50% in patients with CSDME. Severe visual loss is defined as the loss of 3 lines (15 letters) on the ETDRS visual acuity chart. This level of visual loss is equivalent to doubling of the visual angle.
Laser therapy by itself seldom improves the vision in patients with CSDME; 40% of patients will continue to lose vision despite laser therapy.
Diabetic Retinopathy Research Network (DRCR net) protocol B looked at a comparative trial using triamcinolone acetonide intravitreal injection versus focal/grid laser for center involved CSDME. There was very short-term benefit (3 months) associated with the use of steroids. This benefit was not seen at 1 year and beyond; thus, there was no significant advantage for steroid over laser therapy. An interesting finding in this study was that despite previous laser therapy in patients randomized, following a careful retreatment protocol resulted in improvement in macular leakage.
With the advent of intraocular use of anti–vascularendothlial growth factors (anti-VEGFs), clinical trials in diabetic retinopathy treatment have been shown to result in improved outcomes including improved visual acuity in patients with center involved CSDME.
The DRCR net protocol I evaluated the use of intravitreal ranibizumab with either immediate or delayed laser therapy for center involved CSDME. The study also looked at triamcinolone combined with immediate focal laser therapy. Both ranibizumab arms demonstrated significantly improved visual acuity letter scores at 1 and 2 years compared with laser alone or triamcinolone combined with laser. There was a +9 letter gain in the ranibizumab groups compared with +3 letters in the laser only group and compared with +3 letters in the triamcinolone plus laser group. This benefit was also seen in the RISE and RIDE studies. These studies showed improved visual outcomes at 24 weeks using intravitreal ranibizumab versus sham injection. In both arms, laser was allowed. Both doses (0.3 mg and 0.5 mg) of ranibizumab were equally efficacious in reducing macular edema and improving vision. The 0.3-mg dose of ranibizumab is therefore the recommended dosage for treating CSDME and the dosage approved by the FDA. In the DRCR net protocol I study, there was a median of nine injections done in the first year and three in the second year.
There are numerous smaller studies that have also demonstrated the benefit of bevacizumab injected intravitreally for the treatment of CSDME. In the PACORES study, there was a mean number of 5.8 injections over the 2 years of the study. There was improvement in vision and normalization of retinal edema and macular anatomy; 64% of patients gained at least 10 letters of vision in the 1.25 mg group. The BOLT study compared the use of bevacizumab with focal/grid laser therapy. the bevacizumab recipients gained a median of 9 letters (cf 2.5 letters) in the laser group through 2 years with a mean on four injections.
Several studies have evaluated bevacizumab, ranibizuman, and aflibercept. The DRCR net conducted a randomized trial comparing all three agents for DME. Over a 2-year period, they found that patients in all three groups had visual acuity improvement with decreased numbers of injections in the second year. Aflibercept had superior 2-year visual acuity outcomes compared to bevacizumab in eyes with worse baseline visual acuity. The DaVINCI study evaluated the use of aflibercept (soluble VEGF decoy receptor protein). Visual acuity improved 8.5 to 11.4 letters over 24 weeks. This compared to 2.5 letters in the laser group.
Given the efficacy and good safety profile of anti-vegf medications, in addition to the fact that the injections do not create permanent macular scars, these therapies have largely displaced focal and grid laser therapy as the gold standard of treatment for patients with diabetic macular edema. Intravitreal injections introduce the risk of severe ocular infection, or endophthalmitis, but fortunately this complication occurs very rarely. Although laser therapy still has a role in the treatment of DME, it is used far less frequently than intravitreal injections.

Managing Proliferative Diabetic retinopathy (PDR)

The DRS and ETDRS trials made recommendations regarding therapy for PDR; these recommendations are still important and relevant today.
Pan-retinal laser photocoagulation is the treatment for patients with proliferative diabetic retinopathy. Studies have shown that use of anti-VEGF therapy may also be used as adjunctive therapy for patients with proliferative retinopathy. In some of these patients, one can see propagation of rpe-retinal fibrosis requiring early vitrectomy in these patients; however, the majority will see amelioration of their proliferative disease. We therefore recommend close follow-up for patients with proliferative disease, especially patients with existing preretinal fibrosis.
Pan-retinal laser photocoagulation is helpful in patients with chronic macular edema, where widefield angiography show extensive mid peripheral capillary nonperfusion.
Vitrectomy is useful in patients with vitreomacular traction and taut posterior hyaloid syndrome, chronic or recurrent vitreous hemorrhage, and tractional retinal detachment.

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