Diabetes and the Eye

James E. Stottlemyer O.D., F.A.A.O.

Reviewed by Matthew A. Speicher M.D. September 2004 The epidemic of Diabetes Mellitus is growing at an alarming rate. The 2002 prevalence data from the Center for Disease Control estimates that 18.2 million Americans suffer from diabetes, a number that has more than doubled since 1980. Unfortunately, only 13 million have been formally diagnosed, while the remainders are unaware of their condition. Diabetes can lead to multi-system damage and dysfunction; complications may include cardiovascular disease, renal disease, circulatory complications, nervous system damage, and blindness. Diabetic retinopathy is the leading cause of blindness in Americans aged 20 through 74. The visual loss that is associated with diabetic retinopathy is often preventable through better glycemic control and appropriate eye care. Types of Diabetes: Type 1 diabetes, formerly known as insulin dependent diabetes or juvenile diabetes, is usually diagnosed in children and young adults. Type 1 diabetes is thought to be caused by an environmental trigger such as a viral infection resulting in destruction of the insulin-producing beta cells of the pancreas. Due to the lack of insulin production, these patients require insulin supplementation to live. Approximately 5-10% of all Americans who have diabetes have type 1. Type 2 diabetes, formerly known as non-insulin dependent diabetes or adult onset diabetes accounts for 90-95% of diabetics. Type 2 diabetes results from insulin resistance. Risk factors for developing type 2 diabetes include obesity, family history, older age, physical inactivity, women with a history of gestational diabetes, African American, Hispanic or American Indian race, and glucose intolerance. These patients are typically managed with diet, oral medications, and/or insulin. Diagnosis of Diabetes The diagnosis of diabetes is based on laboratory testing, but symptoms often will alert the patient or patients family members to the problem. These symptoms include frequent urination, excessive thirst, extreme hunger, unusual weight loss, fatigue, irritability, and blurry vision. Patients that suffer from type 1 diabetes often present with diabetic ketoacidosis. Signs and symptoms of ketoacidosis include acetone breath odor, frequent urination, abdominal pain, nausea, vomiting, hypotension, a decreased level of consciousness which can range from drowsiness to coma, and Kussmauls respiration (slow, deep breathing). Laboratory testing is crucial in diagnosing and managing diabetes. The criteria for the diagnosis of diabetes include positive findings on any two of the following tests on different days: symptoms of diabetes mellitus plus a plasma glucose concentration>200 mg/dL, fasting plasma glucose concentration >126 mg/dL, and/or a plasma glucose level of >200 2 hours following ingesting a 75 gram glucose load (oral glucose tolerance test).

Diagnostic criteria: Any one of the following criteria met on two separate dates: 1. Symptoms of diabetes (polyuria, polyphagia, unexplained weight loss and a random plasma glucose >200 mg/dL. 2. FBG > 126 mg/dL. 3. Plasma glucose >200 mg/dL at 2 hours post-glucose load during an OGTT with 75g glucose load.

Glocosylated hemoglobin (HbA1c) is a blood test that measures the amount of glucose that is attached to the hemoglobin in a red blood cell. This result is expressed as a percentage (normal <6). The test gives an average of glucose levels over a 3-4 month period due to the fact that the life of a red blood cell is approximately 3- 4 months. This test is typically used to follow glucose control in previously diagnosed diabetics and not used in diagnosing the disease due to the lack of standardization. The HbA1c is of great importance to the clinician due to its strong relationship to the development and progression of retinopathy. As the HbA1c levels increase, the incidence and progression of retinopathy increase exponentially. Diabetic Retinopathy -Risk Factors The exact underlying pathologic mechanisms of diabetic retinopathy remain unclear, but the factors that do contribute to the incidence and progression of retinopathy include duration of the disease, poor glycemic control, hypertension, hyperlipidemia, and kidney disease. Understanding the risk factors for retinopathy is paramount in the screening and management of diabetic patients. Patients who are diagnosed with type 1 diabetes (typically < 30 years of age) generally do not develop retinopathy for at least 5 years after the diagnosis and do not develop retinopathy prior to puberty. 90% of type 1 diabetics develop some degree of retinopathy by 15 years and 50% develop proliferative retinopathy by 20 years following the diagnosis. Patients with type 2 diabetes may have significant retinopathy upon diagnosis due to the common lag between onset and detection. Like type 1 diabetics, the incidence and severity of retinopathy increase with the duration of the disease. Pathophysiology of Diabetic Retinopathy The pathophysiology of diabetic retinopathy is based on microvascular insult, but the exact biochemical mechanism responsible for initiating vessel damage has been controversial. It is now believed that at the biochemical level, hyperglycemia causes an increased production of sorbitol, protein kinase C, and advanced glycation end products, which lead to the destruction of pericytes, the cells responsible for supporting the vascular endothelium. Loss of pericytes can result in endothelial compromise. The dysfunctional capillary beds may begin to leak blood, proteins, lipids, and fluid. Chronic glycemic insult often leads to capillary closure, retinal hypoxia, production of vasoproliferative factors, and loss of function. The production of vasoproliferative factors by the hypoxic retina may promote neovascularization and increased capillary permeability. 2

Hyperglycemia can cause changes in the crystalline lens of the eye. A common symptom in undiagnosed or uncontrolled diabetics is fluctuating vision. The lens may swell when hyperglycemia exists causing a myopic shift. These refractive shifts are typically rapid and may change daily. Diabetes may also lead to premature cataract formation. The most common type of opacity being posterior subcapsular cataracts. Clinical Features Retinal manifestations of diabetes may include microaneurysms, retinal hemorrhages, hard exudate, retinal edema, nerve fiber layer infarcts, intraretinal microvascular abnormalities, venous beading, neovascularization, and glial proliferation. The severity of retinopathy and risk of vision loss can be determined by the presence or absence of these lesions. Non-proliferative Diabetic Retinopathy Microaneurysms are small outpouchings from capillaries. They appear as well defined round lesions that are <125 microns in size. Microaneurysms can lead to retinal edema due to increased vessel wall permeability. Hard exudates appear as yellow-white deposits with sharp borders. Hard exudates are located in the outer retinal layers and are composed of lipoprotein. Hard exudates form due to leakage from microaneurysms and damaged capillaries. The degree of exudates can correlate to systemic lipid levels. Cotton wool spots are lesions that are a result from infarction of the nerve fiber layer. They appear as pale-white spots with feathery borders. Although once thought to be an indicator for progression of diabetic retinopathy, their presence does not have a significant predictive value. Retinal hemorrhages vary in appearance depending on their location. Hemorrhages within the nerve fiber layer take on a flame shaped appearance; in deeper layers they appear as dot and blot hemorrhages due to confinement from adjacent retinal cells. The severity of retinal hemorrhages is a strong predictor of progression and risk of vision loss. Venous beading is a powerful predictor for the development of proliferative diabetic retinopathy. Venous beading appears as localized irregularities in venous caliber. Intra-retinal microvascular abnormalities (IRMA) appear as tiny thread-like vessels that resemble new blood vessels. These tortuous vascular segments are located within the retina as opposed to frank neovascularization which proliferates toward the vitreous cavity. IRMA is the strongest predictor of progression to proliferative diabetic retinopathy. Proliferative diabetic retinopathy Neovascularization (NV) is comprised of new vessels that grow as a result of ischemia and the production of specific hormones. NV occurs on the surface of the retina, disc, and/or iris and can lead to profound loss of vision via vitreous hemorrhage, traction retinal detachment, or neovascular glaucoma.

Macular edema Retinal edema or thickening is caused by abnormal permeability of the retinal microvasculature. The extent and location relative to the fovea are critical. Macular edema is the most common etiology of decreased vision in diabetic patients, and may be present in association with any level of retinopathy. Macular edema may exist in asymptomatic patients with vision of 20/20 or better. Macular edema is defined as retinal thickening within two disc diameters of the foveal center. Clinically significant macular edema (CSME) is particularly threatening to vision. The diagnostic criteria for CSME are one or more of the following: 1. Thickening of the retina at or within 500 microns (1/3 disc diameter) of the center of the macula. 2. Hard exudates at or within 500 microns of the center of the macula, with adjacent thickening of the retina. 3. A zone of retinal thickening one disc diameter or larger within 1 disc diameter of the center of the macula. If CSME is present, prompt referral to a retinal specialist is required for evaluation and treatment. Prompt treatment reduces the risk of further vision loss by at least 50%. Classification of Diabetic Retinopathy (See following Page) Prior to the completion of the Early Treatment of Diabetic Retinopathy Study (ETDRS), Diabetic retinopathy was classified as background, pre-proliferative, and proliferative diabetic retinopathy. The ETDRS divided retinopathy into two main categories, non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). NPDR was subdivided into mild, moderate, or severe and PDR into early, high risk, or advanced. These new criteria allow for a better description of the severity of retinopathy and a more accurate way to monitor progression of the disease. Management of Retinopathy It is critical for any clinician evaluating patients with diabetes to be familiar with the identification and classification of diabetic retinopathy. Patients who present with clinically significant macular edema or proliferative diabetic retinopathy need immediate referral to a retina specialist or ophthalmologist who is comfortable treating diabetic complications. Patients who have mild or moderate non-proliferative diabetic retinopathy deserve close monitoring. Patients with mild NPDR without macular edema should be monitored at least annually for progression. Patients who have moderate NPDR without CSME should be dilated at least every 6 months. Patients who have severe NPDR must be monitored very closely or be referred to an ophthalmologist for monitoring. These patients have a much higher risk of developing proliferative diabetic retinopathy and must be evaluated every 3 months. In some situations, patients with severe NPDR are treated before progression to PDR as earlier treatment may better preserve visual function.

Classification of Diabetic Retinopathy and Predictive Value Stage Mild NPDR Definition Rate of progression (to PDR) at least 1 Ma 5% (1 year) does not meet moderate standards 12-26% (1 yr) H/Ma> standard 2A in at least one quadrant and one of the following: -nerve fiber layer infarct -IRMA -Venous beading Does not meet severe standards One of the following: 56% (1yr) -H/Ma > standard 2A in 4 quadrants -Venous beading > standard 6A in 2 or more quadrants -IRMA > standard 8A in one or more quadrants One or More of the following -NVE -NVD -Vitreous/pre-retinal heme with NVE < disc area without NVE One or more of the following: -NVD > 1/3-1/4 disc diameter -NVD with vitreous/pre-retinal hemorrhage -NVE > 1/2 disc diameter with hemorrhage (to high risk PDR) 1 %( 1 year)

Moderate NPDR

8-18% (1 yr)

Severe NPDR

15 %( 1yr)

PDR

46% (1yr)

High risk PDR

Severe vision loss (<20/200) in 25-40% (2yrs)

Standard photographs may be viewed on the web at: http://eyephoto.ophth.wisc.edu

Diagnostic Testing Color fundus photography is a sensitive way to monitor the progression of diabetic retinopathy. Fundus photography may detect retinopathy that may be otherwise overlooked during clinical evaluation. Fluorescein angiography is useful in evaluating CSME, capillary nonperfusion and identifying PDR. Fluorescein angiography is performed by injecting a 5 or 10% sodium fluorescein bolus into a vein (typically antecubital) in the patients arm. Photographs are taken through the Choroidal arterial, capillary, venous, and late stages (recirculation) to identify the specifics of the retinal pathology. Fluorescein angiography side effects may include temporary discoloration of the skin and urine, nausea, vomiting, syncope, anaphylaxis, and rarely cardiac and/or respiratory arrest. Ultrasound is useful in identifying major retinal pathology in the presence of media opacities. Vitreous hemorrhage and mature cataracts may preclude adequate retinal evaluation. Ultrasound is especially useful in identifying tractional detachments in patients with dense vitreous hemorrhage. Treatment of Retinopathy Vision loss in patients with diabetes may be secondary to CSME, capillary nonperfusion, vitreous hemorrhage, tractional retinal detachment, or cataracts, but the most common cause of vision loss is CSME. The Early Treatment of Diabetic Retinopathy Study proved that treatment of CSME reduces the risk of further visual loss by >50%. Treatment of CSME is guided by the use of diagnostic fluorescein angiography. Fluorescein angiography is performed to identify areas of leakage. After the areas of leakage are identified, focal and/or grid laser photocoagulation are applied to decrease vascular permeability. The full effect of treatment may take several months to be realized. According to the Diabetic Retinopathy Study, panretinal photocoagulation (PRP) reduces the risk of severe vision loss (VA<5/200) by at least 50% in patients with high risk PDR. A typical treatment protocol involves 1200-1600 laser spots that are applied over two to three sessions. This procedure is performed to reduce the risk of further neovascularization, vitreous hemorrhage, and visual loss. Patients with high risk PDR require urgent PRP. Patients with PDR without high risk characteristics have less risk of significant vision loss, but prompt referral is crucial. When CSME and PDR are simultaneously present, treatment may be difficult because PRP may exacerbate CSME. In patients with CSME associated with PDR that does not meet high risk standards, initial focal is often performed prior to PRP. When high risk PDR is present, simultaneous treatment with both focal and PRP are often performed. Although laser photocoagulation is very effective in treating diabetic complications, occasionally patients do not fully respond to treatment or have progressive retinopathy. Vitrectomy is indicated for patients with non-clearing vitreous hemorrhage, progressive PDR that does not respond to PRP, or traction retinal detachments threatening the macula.

New Developments Evidence is mounting supporting the role of naturally found factors that have affects on vascular permeability and new vessel growth, specifically vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF). Studies have shown the absence of these factors in healthy eyes, but high levels within the vitreous cavity in eyes with significant diabetic retinopathy. By removing these factors, vitrectomy may be a beneficial adjunct treatment for persistent CSME. Studies evaluating pharmocolgic inhibition of VEGF are in the early stages. Lastly, these factors are inhibited by corticosteroids. For this reason, many retina specialists are using intravitreal injections of triamcinolone to treat intractable CSME that does not respond to traditional laser photocoagulation. Conclusion Optometrists play a crucial role in diagnosing and caring for diabetic patients. Thorough knowledge regarding the manifestations and appropriate management is paramount. Vision loss secondary to diabetic retinopathy can be prevented if proper action is taken when high risk characteristics are identified. References:
CDC 2003 diabetic statistics Early Treatment Diabetic Retinopathy Study Research Group (reports 1, 2, 9, 10, and 12) Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy: clinical application of diabetic retinopathy study (DRS) findings. DRS Report 8. Ophthalmology. 1981:88:583-600. Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy: two-year results of a randomized trial. DRVS report 2. Arch Ophthalmol. 103:1644-52, 1985. Preferred Practice Patterns Committee, Retina Panel. Diabetic Retinopathy. San Francisco: American Academy of Ophthalmology; 1998. Martidis et al.Ophth May 109 (5) 920-7. 2002 Otani T., Kishi S. Am J Ophthalmol Aug 134 (2) 214-9. 2002