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 in care for treating diabetes mellitus.

Despite this, diabetes remains one of the top ten most prevalent and important non-infectious causes of morbidity and mortality world-wide. An estimated 34.1 million Americans aged 18 year 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 developments of diabetic retinopathy beyond years since diagnosis and type of diabetes. Additionally, elevated hemoglobin A1C 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 feater between these two categories is the presence (proliferative) or absence (non-proliferative) of abnormal new blood vessels (retinal or optic disc neovascularization).

Of primary concern are the factors that lead to visual impairment in the 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- new blood vessel formation

Diabetic retinopathy pathophysiology

Primary prevention

Control of glucose and blood pressure. Each 1% reduction in updated mean HbA(1c) was associated with reductions 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

Ask for symptoms of decreased vision or fluctuating vision, presence of floaters (vitreous hemorrhage) or defects in the field of vision. It is important to know the hemoglobin A1c and whether 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 (rubeosis or NVI), 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 examination lens) to look for microaneurysms, hemorrhage, hard exudates, cotton wool spots, retinal swelling (edema)/ cystoid macular edema. 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 retina area that 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- referred to as macular edema. Non-proliferative retinopathy can be classified into mild, moderate or severe stages based upon the presence or absence of retinal bleeding, abnormal venous beading of the vessel wall (venous beading) or abnormal vascular findings (intraretinal microvascular anomalies or IRMA). No treatment is usually done at this stage.

Proliferative retinopathy is progressive and requires treatment to prevent bleeding and scar tissue formation.

Diagnostic procedures

Fluorescein angiography is 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 show leakage on the FA.

Ocular coherence tomography (OCT) is useful to determine the retinal thickness measurements. The OCT can be sequentially obtained to determine whether the macular thickening is responding (swelling/ edema is decreasing) 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, a HgbA1c </= 7 is the goal. Sometimes, for older patients (age 70's plus), diabetologists aim for a slightly higher A1C since A1C's below 7 are associated with increased morbidity in that age group.

Differential diagnosis

Macular edema from radiation retinopathy (history of radiation), vein occlusion (occluded vessel seen, telangiectasia present), parafoveal telangiectasia (telangiectatic vessels seen).

NVD/NVE from vein occlusion, retinal vasculitis, sarcoidosis, ocular ischemic syndrome, sickle cell retinopathy.

NVI from vein occlusions, ocular ischemia.

Sickle cell retinopathy, although in sickle cell , the NV is generally peripheral.

Management

General treatment

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

Medical therapy and follow up

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 that cause the retinal swelling/macular edema (from leaking blood vessels) to resolve. Patients are 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. ( Baker CW, Glassman AR, Beaulieu WT, Antoszyk AN, Browning DJ, Chalam KV, Grover S, Jampol LM, Jhaveri CD, Melia M, Stockdale CR, Martin DF, Sun JK; DRCR Retina Network. Effect of Initial Management With Aflibercept vs Laser Photocoagulation vs Observation on Vision Loss Among Patients With Diabetic Macular Edema Involving the Center of the Macula and Good Visual Acuity: A Randomized Clinical Trial. JAMA. 2019 May 21;321(19):1880-1894. )For observed eyes, prompt treatment with anti-VEGF once sustained visual acuity decline was found, resulted in good visual acuity outcomes. Treatment of PDR is laser photocoagulation of the peripheral retina/panretinal photocoagulation (PRP). The laser is used to create scars on the peripheral retina. If successful, vitreous bleeding may be averted. Sometimes the proliferative disease is advanced and there is bleeding filling the eye (and preventing laser to be done) or scar tissue that wrinkles the retina or pulls it off the eyewall surface. In these situations, surgery is necessary (see vitrectomy for more information). In cases of NVD/ NVE with NVI, anti-VEGF injections into the eye can also be used. DRCR protocol S showed that anti-VEGF drug ranibizumab was noninferior to PRP in PDR. Anti-VEGF injections are sometimes used in concert with laser when rubeosis and neovascular glaucoma are present. Anti-VEGF are also given prior to vitrectomy surgery in selected cases. Follow-up is crucial for these patients. Thus, in a patient who is for any reason unliely to return for follow-up, anti-VEGF is not the treatment of choice and PRP should be done.

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 reattach 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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