Diabetic Retinopathy

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Disease Entity

Diabetes mellitus as a disease was identified as far back as 250-300 BC and was characterized by the sweet properties of urine. In 1889 Mering and Minkowski discovered the relevance of the pancreas in this disease process after inducing a severe and fatal form of diabetes in a dog following removal of the pancreas. Since then, advancements in medicine have led to multiple new medication therapies and approaches to treat diabetes mellitus.

Despite this, diabetes remains one of the top ten most prevalent and important non-infectious causes of morbidity and mortality worldwide. An estimated 34.1 million Americans aged 18 years or older, 13.0% of all U.S. adults, had diabetes in 2018. This prevalence, in concert with the associated diseases that usually coincide with (and result from) diabetes should solidify the importance of being familiar with this disease process.

Disease

Diabetic retinopathy represents microvascular end-organ damage as a result of diabetes. It ranges from non-proliferative diabetic retinopathy (NPDR) and its stages to proliferative diabetic retinopathy (PDR). As the disease progresses, associated diabetic macular edema (DME) may also become apparent.

Among patients aged 25-74, diabetic retinopathy is a leading cause of vision loss worldwide. By 2030 an estimated 191.0 million people globally will have diabetic retinopathy, and approximately 56.3 million will have vision-threatening diabetic retinopathy. The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) Cohort showed that after 20 years of diabetes mellitus, 99% of patients with type 1 and 60% of patients with type 2 show some degree of retinopathy. There are several other key risk factors for the development of diabetic retinopathy beyond years since diagnosis and type of diabetes. Additionally, elevated hemoglobin A1c (HbA1c) levels and blood pressure are associated with increased risk of diabetic retinopathy.

Etiology

Type 1 diabetes mellitus (T1DM) is characterized by the destruction of beta cells in the pancreas by an autoimmune mechanism, whereas type 2 diabetes mellitus (T2DM) is a relationship between lifestyle and genetics. Etiology of these two subtypes describes the etiology of diabetic retinopathy, as retinal disease is an end-organ manifestation of the principal disease.

There is a stronger genetic association between T2DM compared to T1DM. Multiple genetic factors have been named in the development of T2DM including TCF7L2 , NOTCH2, KCNQ1, JAZF1, and MODY (a heterogeneous disorder with autosomal dominant transmission). Poor lifestyle, in conjunction with genetic influences, increases the risk of developing T2DM.

Over 90% of people with a new diagnosis of T1DM have measurable antibodies against specific pancreatic β-cell proteins (insulin, islet antigen 2, zinc transporter 8, etc.). These antibodies lead to a chain of progressive loss of β-cells, decreased insulin release, and recognizable diabetes.

Risk Factors

  • Diabetes duration
  • Uncontrolled glucose or blood pressure levels are associated with increased risk (see NHANES, UKDPS, WESDR references below)
  • Hypertension
  • Dyslipidemia
  • Ethnicity
  • Pregnancy
  • Smoking

General Pathology

The main types of diabetic retinopathy are non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). The distinguishing feature between these two categories is the presence (proliferative) or absence (non-proliferative) of abnormal new blood vessels (retinal, optic disc, or iris/angle neovascularization).

Of primary concern are the factors that lead to visual impairment in this patient population.  The three items listed below are the foundation of this disease process, and the presence of them can be correlated with disease severity.

1.    Capillary leakage (DME)

2.    Capillary occlusion

3.    Sequelae of retinal ischemia (retinal neovascularization, vitreous hemorrhage, tractional retinal detachment, neovascular glaucoma)

Pathophysiology

Vascular endothelial growth factor (VEGF) is secreted by the ischemic retina. VEGF leads to a) increased vascular permeability resulting in retinal swelling/edema and b) angiogenesis or new blood vessel formation

Diabetic retinopathy pathophysiology

Primary prevention

Control of glucose and blood pressure. Each 1% reduction in updated mean HbA1c was associated with a reduction in risk of 21% for any end point related to diabetes (95% confidence interval 17% to 24%, P<0.0001), 21% for deaths related to diabetes (15% to 27%, P<0.0001), 14% for myocardial infarction (8% to 21%, P<0.0001), and 37% for microvascular complications (33% to 41%, P<0.0001). (UKDPS report 35).

Diagnosis

History

Symptoms of decreased vision or fluctuating vision (lens or macular edema), presence of floaters (vitreous hemorrhage), or visual field defects (tractional detachment). It is important to know the hemoglobin A1c and whether or not the patient’s blood pressure is under control.

Physical examination and Signs

Slit lamp examination and dilated fundus examination should be performed. One should look carefully for the presence of abnormal blood vessels on the iris [neovascularization of the iris (NVI) or rubeosis], cataract (associated with diabetes) and vitreous cells (blood in the vitreous or pigmented cells if there is a retinal detachment with hole formation). Intraocular pressure (IOP) should be checked especially when NVI is seen. Dilated fundus examination should include a macular examination (contact lens or non-contact lens) to look for microaneurysms, hemorrhage, hard exudates, cotton wool spots, retinal swelling (DME). The optic disc and area surrounding it (for one disc diameter) should be examined for presence of abnormal new blood vessels (neovascularization of the disc, NVD), optic nerve head pallor or glaucomatous changes. The remainder of the retina should also be examined for presence of abnormal new blood vessels (neovascularization elsewhere, NVE).

Symptoms

Clinical diagnosis

The central retinal area that is located between the main branches (superior and inferior arcades) of the central retinal vessels (central retinal artery and central retinal vein) in the eye is known as the “macular area.” The retina beyond this is considered “peripheral retina.” The central retinal area can develop abnormal findings in diabetic retinopathy. These findings can be present in the non-proliferative or the proliferative forms of the disease. These changes in the macula include the presence of abnormally dilated small vessel outpouchings (called microaneurysms), retinal bleeding (retinal hemorrhages) and yellow lipid and protein deposits (hard exudates). The macula can get thicker than normal, which is referred to as macular edema.

Classification of Non-proliferative diabetic retinopathy

Non-proliferative diabetic retinopathy can be classified into mild, moderate or severe stages based upon the presence or absence of retinal bleeding, abnormal beading of the venous wall (venous beading) or abnormal vascular findings (intraretinal microvascular anomalies or IRMA).

  • Mild: few microaneurysms
  • Moderate: increased number of microaneurysms and dot-blot hemorrhages. Cotton wool spots and hard exudates may be present.
  • Severe: "4-2-1 rule" -- 4 quadrants of diffuse retinal hemorrhages and microaneurysms, 2 or more quadrants of venous beading, or 1 or more quadrant of IRMA

No treatment is usually done at this stage though there is evidence that anti-vascular endothelial growth factor (VEGF) injections may help decrease the severity of retinopathy and lower the risk of vision complications.

Proliferative diabetic retinopathy

High Risk Characteristics
  • NVD > 1/4 to 1/3 disc area
  • Any NVD associated with vitreous or preretinal hemorrhage
  • Any NVE associated with vitreous or preretinal hemorrhage

This is progressive and often requires treatment to prevent bleeding and scar tissue formation, especially in patients who meet high risk characteristics.

Diagnostic procedures

Fluorescein angiography (FA) may be used to determine the degree of ischemia or the presence of retinal vascular abnormalities. The areas of microaneurysms appear as hyperfluorescent spots and may leak on the late frames resulting in areas of retinal edema clinically. The areas of NVD/ NVE also show leakage on the FA. Areas of capillary dropout and non-perfusion will appear hypofluorescent.

Optical coherence tomography (OCT) is useful to determine the presence and location of intraretinal and/or subretinal fluid as well as retinal thickness measurements. The OCT can be sequentially obtained to determine whether the macular edema is responding to therapy.

Laboratory test

Hemoglobin A1c is a measure of the degree of glycemic control over the past 3 months. A goal of 5.5 % - 6.0 % is ideal, although difficult to achieve in some patients. Generally, HbA1c ≤ 7 is the goal. Sometimes, for older patients (≥70 years), diabetologists aim for a slightly higher HbA1C since levels below 7 have been associated with increased morbidity in that age group.

Differential diagnosis

Macular edema with retinal hemorrhages

Retinal neovascularization

Iris Neovascularization

  • Vein occlusion
  • Ocular ischemic syndrome

Management

General treatment

Systemic control of diabetes, hypertension, hyperlipidemia, hypercholesterolemia, nephropathy and other diseases are of paramount importance.

Medical therapy and follow up

Diabetic Macular Edema

Treatment of macular edema is usually needed in order to prevent loss of vision or to try to improve vision. Treatment includes the use of lasers or injection of drugs (anti-VEGF therapies or corticosteroids) that decrease the retinal swelling/macular edema. Patients may be initially seen monthly if being injected or every 3 months post-laser for macular edema. (DRCR, RIDE, RISE, DAVINCI and ETDRS studies). Several studies indicate that anti-VEGF drugs are more effective than focal laser (DRCR, READ2, RIDE, RISE, DAVINCI). A recent study by the DRCR network has shown all three drugs (bevacizumab, ranibizumab and aflibercept) are effective for macular edema therapy. Recently, the DRCR has shown that for very good visual acuity (20/25 or better), watchful and careful observation compared well with those treated with anti-VEGF therapy.[1] For observed eyes, prompt treatment with anti-VEGF once sustained visual acuity decline was found, resulted in good visual acuity outcomes.

Proliferative Diabetic Retinopathy

The primary treatment option for PDR is laser photocoagulation of the peripheral retina, known as panretinal photocoagulation (PRP). The laser is used to obliterate some of the ischemic peripheral retina in order to decrease VEGF release and induce regression of neovascularization. If successful, vitreous hemorrhage and tractional retinal detachment may be averted. Sometimes the proliferative disease is advanced and there is blood filling the eye (and preventing application of laser) or scar tissue that wrinkles the retina or pulls it off the eyewall (tractional retinal detachment). In these situations, surgery may be necessary (see vitrectomy for more information).

In some cases, anti-VEGF injections into the eye can also be used to induce regression of neovascularization. DRCR protocol S showed that the anti-VEGF drug ranibizumab was noninferior to PRP in managing patients with PDR. In situations where PRP is not possible, such as in the presence of vitreous hemorrhage, anti-VEGF injections may help to improve the likelihood of clearance of the hemorrhage. Follow-up is crucial for patients receiving anti-VEGF injections alone as this therapy does not appear to provide long-term involution of the neovascularization after the injections are halted, whereas PRP generally has long-lasting effects. Thus, in a patient who is for any reason unlikely to return for follow-up, anti-VEGF injections alone should not be the treatment of choice and PRP should be done.

Anti-VEGF injections may sometimes be used in concert with PRP when rubeosis and neovascular glaucoma are present. Another common scenario is using anti-VEGF injections initially in eyes with vitreous hemorrhage that is too dense to permit PRP then later performing laser once the hemorrhage has adequately cleared. Anti-VEGF injections are also sometimes given prior to vitrectomy surgery in selected cases to lower the risk of intraoperative hemorrhage.

Surgery and Surgical follow up

The goal of surgery is to remove blood and scar tissue from the retinal surface and to place laser treatment as needed. Intraoperatively, intraocular gas or silicone oil may be needed to maintain reattachment of the retina to the underlying layers and eyewall.

Complications

There is always the low, but real risk of infection of the eyeball (endophthalmitis) with any injection of drugs into the eye or with eye surgery. There is also the risk of cataract progression with retinal surgery. Vitrectomy accelerates the rate of cataract formation.

Prognosis

ETDRS studies show that the stage of retinopathy is correlated with progression to more advanced stages or retinopathy and visual loss.

Additional Resources

References

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