Ординатура / Офтальмология / Английские материалы / Clinical Medicine in Optometric Practice_Muchnick_2007

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homeostasis, and all positive effects must be balanced with negative feedback to maintain homeostasis. One example of homeostasis is the insulin-glucagon feedback mechanism that maintains a euglycemic state whether the organism is starved or well-fed. Another example is thyroid hormone, which controls basal metabolism in almost all tissues.

In cases of shock, hormones called catecholamines are released under sympathetic nervous control and these chemical mediators increase cardiac output and blood pressure and stimulate glucose production. The result is a stimulated musculoskeletal system ready to confront the stressing agent.

Once an appropriate biological response has been generated, continued hormonal influence may actually be detrimental to the organism. Efficient hormonal feedback regulatory systems have evolved to exert both positive and negative control on endocrine systems.

CAUSES OF ENDOCRINE DYSFUNCTION

Endocrine dysfunction can be caused by tumors, surgery, autoimmune reactions, and inflammatory or infectious processes that affect an endocrine gland. Rarer causes of dysfunction include developmental conditions, infarction of the gland, and nutritional deficiencies.

In general, hormone dysfunction may take three forms: overproduction of the hormone, underproduction of the hormone, or normal hormonal levels with reduced physiological response due to hormone resistance. Excessive hormone production occurs in tumors of the thyroid and pituitary gland. In addition, an autoimmune reaction of the thyroid gland increases hormonal production, causing Graves’ disease.

Hypofunctional hormone levels may be the result of autoimmune reactions in such conditions as diabetes, hypothyroidism, and Addison’s disease, and inflammatory conditions such as sarcoidosis of the hypothalamus.

DIABETES MELLITUS Introduction to Diabetes Mellitus

Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, or elevated serum glucose. Several forms of DM exist, and are differentiated by the etiology of the hyperglycemia.

Serum blood glucose is maintained, in part, by the action of insulin. This hormone is the most important regulator of glucose use and supply, although several other pathways contribute to glucose homeostasis. Elevated blood sugar may be caused by an increase in glucose production, a decrease in serum glucose uptake by the cells, or a reduction in insulin production. Approximately 18 million people in the United States

have DM, and 5 million do not know that they have the disease. Of all diabetics, 95% have type 2 diabetes, and only 5% have type 1 diabetes.

Insulin Characteristics

An amino acid polypeptide, insulin is generated in the beta cells of the pancreatic islets. Its production is influenced primarily by serum glucose. Blood sugar levels exceeding 70 mg/dl stimulate insulin production.

Insulin Production

Glucose is transported into the pancreatic beta cell and, by a series of islet transcription factors (such as the enzyme glucokinase), is converted into pyruvate. The mitochondria of the cell modify pyruvate to produce ATP, which causes the cell membrane to depolarize. When the beta cell membrane depolarizes, calcium channels open and allow an influx of calcium into the cell. Calcium ions stimulate the release of secretory granules that contain insulin.

Effect of Insulin

Once insulin is released into the bloodstream through the portal vein it binds with receptor sites on cells of target organs. Binding of insulin to receptor sites induces the insulin signal transduction pathway, wherein cellular proteins initiate the metabolic actions of insulin. By this pathway insulin ultimately increases glucose uptake by skeletal muscle and fat, and stimulates protein synthesis and lipogenesis.

Glucose Homeostasis

The precise balance of sugar production by the liver (which raises serum glucose) and the uptake of glucose by muscle and fat (which lowers serum glucose) is known as glucose homeostasis. Several factors influence this glucose homeostasis, the most important being insulin. Other regulators of the serum glucose level include metabolic signals, neural input, and hormones such as glucagon.

Glucagon

Glucagon is a hormone that acts counter to insulin, reducing cellular uptake of glucose, thus raising blood sugar.

Glucose Metabolism

When a large amount of food is ingested, the liver will produce a large load of glucose that enters the bloodstream and stimulates insulin production. In addition, the level of glucagons falls. These hormonal shifts cause sugar to enter the cell from the bloodstream and serum glucose to drop. As glucose is used by the skeletal muscle for energy, the fasting state in between meals causes the level of insulin to drop and the level of glucagon to rise to preserve some serum glucose. In

addition, a low level of insulin promotes gluconeogenesis by the liver and raises blood glucose, preventing the state of low serum glucose, or hypoglycemia. If insulin levels remain low, uptake of serum glucose is reduced and this stimulates the mobilization of stored fat for energy. Although skeletal muscle and fat require insulin for glucose uptake, the brain and some other tissues use glucose independent of insulin.

The Pathophysiology of Diabetes

A derangement of one or more of the pathways that control glucose homeostasis causes DM. Obviously, if insulin production is reduced, then glucose cannot enter the cell for use as energy. Another possible mechanism is the inability for the cell to efficiently use the glucose molecule despite a normal amount of insulin. A third cause of diabetes is an overproduction of sugar by the liver. In all three of these cases the disease of diabetes is reflected in a rise in serum glucose. Sustained elevated blood sugar above normal, or hyperglycemia, is considered to be diabetes.

Causes of Diabetes

A destruction of pancreatic beta cells would lead to a loss of insulin and an inability for blood sugar to enter peripheral muscle and fat cells. Such destruction of beta cells occurs by autoimmune processes in genetically susceptible individuals, usually children. The autoimmune process may be triggered by an environmental or infectious (viral) source. At least 80% of beta cells must be destroyed before DM is manifested.

Type 1 Diabetes Mellitus

The nearly complete loss of insulin-producing beta cells causes a rise in serum glucose, reflecting the condition of type 1 DM. In the past this condition was known as insulin-dependent DM (IDDM) as classified by the National Diabetes Data Group of 1979. In 1995 the American Diabetes Association dropped the abbreviated designation “IDDM” while maintaining the term “type 1 DM.” One significant reason for this change in designation is that other forms of DM may require insulin supplementation.

Type 1 DM Risk Factors

The patient with Type 1 DM is typically lean, younger than 30 years of age, requires insulin, and often develops ketoacidosis and autoimmune disease.

Type 2 Diabetes Mellitus

Patients with hyperglycemia may not have a complete loss of beta cells but instead may not be able to process glucose because of insulin resistance or lowered insulin production. The cause is as yet unknown, although a genetic predisposition appears to exist stimulated by an as yet unknown environmental factor. This form of

DM is known as type 2 DM and may be caused by genetic defects influencing the pancreatic beta cell. Other causes of type 2 DM include drugs, infections, and diseases of the pancreas and other endocrine glands. Whatever the cause, type 2 DM is characterized by an increase in glucose production by the liver, insulin resistance, and decreased insulin production.

Type 2 DM Risk Factors

This form of DM is more common in obese individuals whose parents or siblings have type 2 DM. An increasing risk of type 2 DM in individuals older than 45 years is associated with aging. In addition, African-Americans, Hispanics, and Native-Americans are diagnosed with type 2 DM at a higher rate than other ethnicities. Elevated blood pressure and cholesterol are also factors related to an increased risk of type 2 DM.

Syndrome “X”

The presence of type 2 DM in a middle-aged obese male with high blood pressure and cholesterol places this individual at significant risk for a major vascular event, and is known as “syndrome X.” Mental depression often exists as part of this constellation of signs and symptoms. The condition appears to be, in part, the result of a genetic proclivity towards obesity, high blood sugar, systemic hypertension, and elevated cholesterol. Treatment includes weight loss, exercise, appropriate dietary changes, and medical control of the diabetes, blood pressure, and cholesterol. Mental health counseling should be considered in individuals with syndrome “X” who are experiencing any of the symptoms of depression.

Pathophysiology of Type 1 DM

Characterized by hyperglycemia and found often in children, the insulin deficiency in type 1A DM is the result of an autoimmune destruction of beta cells. In type 1B DM, no evidence exists of an autoimmune process and the cause of beta cell destruction is idiopathic.

Pathophysiology of Type 2 DM

More common in obese adults older than 45 years, type 2 DM is characterized by increased glucose production by the liver, impaired insulin secretion from the beta cells, and insulin resistance on the cell membrane. These patients, who usually do not require insulin when first diagnosed, may eventually have elevated serum glucose that remains unresponsive to oral medications. These patients will have type 2 DM that requires insulin.

Diagnosis of DM

There are two criteria to establish a diagnosis of DM. One is the level above which serum glucose produces pathological changes because of hyperglycemia. The

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second criteria establishes symptoms or the existence of diabetes-specific complications in a patient.

Glucose tolerance is based on a fasting plasma glucose (FPG) level. Normal FPG is established when a blood sugar level is below 110 mg/dl. An increased fasting plasma glucose (IFG) is found between 110 mg/dl and 125 mg/dl. Patients who exhibit an IFG are at substantial risk for developing DM. DM is diagnosed when the FPG is 126 mg/dl or above in an asymptomatic patient. This result should be repeated on different days for confirmation of the diagnosis.

Acute Symptoms of DM

Most patients with acute hyperglycemia are asymptomatic. When symptoms are present, the three most common are polydipsia (increased thirst), polyuria (increased urination), and polyphagia (increased hunger).

Significant and acute shifts in refractive error occur in patients with rapidly rising serum glucose. For this reason, all ophthalmic patients who demonstrate a large refractive shift should be asked whether any recent increases in hunger, thirst, or urination have been experienced.

In addition, these patients may exhibit a fourth common symptom of acute hyperglycemia; peripheral neuropathy. These patients often seek medical care for hand, wrist, feet, or ankle pain.

Other symptoms of DM include nausea, vomiting, shortness of breath, and altered mental function. These short-term symptoms are most commonly the result of diabetic ketoacidosis.

Diabetic Ketoacidosis

Poorly controlled type 1 or type 2 diabetes may lead to a condition caused by a relative or absolute deficiency of insulin known as diabetic ketoacidosis (DKA). This acute and often life-threatening condition is also characterized by a dramatic increase in the insulin counterhormones glucagon, epinephrine, growth hormone, and cortisol. The principal cause of DKA is the imbalance between insulin and its counterregulatory hormones. The insulin deficiency leads to overproduction of glucose by the liver and an underuse of glucose by the peripheral muscle and fat cells. The liver begins to convert free fatty acids into ketoacids in a pathway known as ketoacidosis. Glucose and ketoacids are both overproduced and underused, leading to hyperglycemia, ketosis, and a loss of potassium. Hyperglycemia causes water to shift out of the intracellular compartment, leading to increased glomerular filtration, osmotic diuresis and urination. Any diabetic patient who goes into shock, coma, dehydration, or cardiac problems should be suspected of having DKA. Laboratory testing will confirm DKA as the lab results usually reveal serum glucose readings of 500 to 600 mg per deciliter and a patient in metabolic acidosis. Therapy of DKA in-

volves appropriate use of insulin, correction of fluid deficits, and replacement of potassium.

Chronic Complications of DM

The long-term effects on tissues in DM may be the result of poor glucose homeostasis, or a toxic effect of hyperglycemia on tissues, although the mechanism of such toxicity has yet to be established. It is unclear how hyperglycemia causes chronic tissue damage, although it is hypothesized that a chronic state of high blood sugar produces damaging compounds that have deleterious biological effects. The chronic complications of DM can be microvascular (eye and nerve effects), macrovascular (carotid artery, peripheral vascular disease [Figure 12-1] and cardiovascular disease), or nonvascular (sexual dysfunction and skin changes).

Targeted end-organ damage in diabetes includes the kidneys (renal disease) (Figure 12-2), nerves (neuropathy), gastrointestinal (upset stomach), heart (congestive heart failure, coronary artery disease, and myocardial infarction), eyes (retinopathy), and an increased risk of systemic infections.

Acute complications can occur at any stage of DM because of a sudden, uncontrolled rise in serum glucose. Chronic complications usually arise after 10 years of DM.

Therapy for DM

For both type 1 and 2 DM the management objectives include the prevention of acute complications and symptoms, the prevention of microvascular and macrovascular complications, the forestalling of atherosclerotic changes, and the achieving of a normal lifestyle.

The patient with type 1 DM must be educated as to the importance of proper nutrition, the balancing of caloric intake with the appropriate amount of insulin, the recognition of plummeting blood sugars, and the

FIGURE 12-1 ■ Gangrenous toe. Gangrene of the toe with cellulitis in a diabetic patient. (From Marx J, Hockberger R, Walls R: Rosen’s emergency medicine: concepts and clinical practice, ed 6, St Louis, 2006, Mosby.)

FIGURE 12-2 ■ Kimmelstiel-Wilson retinopathy. This 63-year- old diabetic patient had advanced renal disease with hypertension. Exacerbations in the severity of retinal microinfarction and vascular tortuosity were not associated with chronic capillary closure, but they did correlate with progressive renal impairment.

monitoring of serum glucose. Because these patients are often children, diligence and understanding must be exercised during instruction to achieve the best possible understanding of the seriousness of the condition. Exercise may modulate insulin requirements in type 1 diabetics by maximizing the general health and well-being of the patient while minimizing the risks of hypoglycemia and diabetic complications. In type 1 diabetics, exercise is not expected to improve glycemic control to any great degree. Exercise helps reduce the plasma lipid profile and blood pressure while improving cardiovascular health, however. In general, exercise has been shown to have no effect on glycemic control as assessed by the HbA1c concentrations, but it does lower the necessary insulin dosage by enhancing insulin sensitivity.

The patient with type 2 DM must be similarly instructed on the causes of diabetes, the possible longterm complications, the role of diet and exercise, and the need to monitor serum glucose. All patients with type 2 DM should be placed on an exercise program. In type 2 diabetes, exercise reduces glucose intolerance, improves insulin sensitivity, and lowers cardiovascular risk factors. Exercise has been shown to reduce the risk of hypoglycemia and lower serum lipid levels in patients with type 2 diabetes. In addition, weight loss is a significant factor in the therapy of patients with type 2 diabetes, and the elimination of obesity is a primary goal. In some cases, exercise and diet with weight loss is enough to control serum glucose levels without need for pharmacological intervention.

The measurement of glycated hemoglobin (the HbA1c blood test) assesses long-term glycemic control. The HbA1c represents a number that reflects the glycemic history during the previous 3 months. This measurement is the primary way to establish a prognosis

for complications of DM. For example, an HbA1c of 6.6 mmol/L equals 120 mg/dl. A 1.7 mmol/L rise in HbA1c translates to a rise of 30 mg/dl serum glucose.

Pharmaceutical Treatment of Type 1 DM

Injected insulin immediately enters the bloodstream, thus patients must eat to avoid a rapid drop in blood sugar. Most patients require approximately 1.0 U/kg per day of insulin divided into multiple doses. Combinations of short (lispro), intermediate (Lente), and long-acting (Ultralente) insulin are used to prevent spiking of serum glucose levels. Continuous subcutaneous insulin infusion (CSII) has been developed to better mimic the natural secretion of insulin from the pancreas. An insulin nasal spray was approved in early 2006 to eliminate the need to constantly use a syringe for injection.

Pharmaceutical Treatment for Type 2 DM

Glucose-lowering agents are the mainstay of therapeusis for type 2 DM. These agents can increase insulin secretion, reduce glucose production, and influence insulin sensitivity. Medications that increase insulin secretion acutely by the beta cell include the firstand second-generation sulfonylureas (glipizide and glyburide) and should be taken just before a meal. Sulfonylureas act to increase insulin and will result in a drop in HbA1c. These drugs have a short onset of action and act to lower fasting blood sugar. Unfortunately, these agents can cause hypoglycemia and weight gain. Metformin acts to reduce glucose production in the liver. Its use can result in weight loss and increase use of glucose, however, metformin may result in diarrhea and nausea.

The thiazolidinediones, such as rosiglitazone, reduce insulin resistance and increase glucose use. This class of medications may improve the triglyceride profile but can result in liver damage.

Diabetic Retinopathy

Epidemiology of Diabetic Retinopathy in Type 1 DM

In young patients who develop type 1 DM, the onset of diabetic retinopathy (DR) does not occur for 3 to 5 years after the onset of the disease. Some form of diabetic retinopathy is present in nearly 100% of individuals with type 1 DM after 20 years. Approximately 50% of these individuals have proliferative diabetic retinopathy (PDR) after 15 years.

Epidemiology of DR in Type 2 DM

In type 2 DM, the onset of DR is more variable because it is more difficult to determine the actual onset of the disease. Sometimes DR is seen as the initial clinical sign of type 2 DM.

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Epidemiology of Macular Edema

This form of diabetic retinopathy is more prevalent in older individuals with type 2 DM. In a young individual with type 1 DM, the presence of macular edema is almost always associated with proliferation. Approximately one fifth of type 1 DM patients develop macular edema within a decade of diagnosis, and approximately one quarter of type 2 DM patients who require insulin develop macular edema within 10 years. The prevalence of macular edema in type 2 diabetic patients who do not require insulin is approximately 14%.

Pathogenesis of Diabetic Retinopathy

Sustained high serum glucose seems to be related to the development of PDR by an as yet unknown mechanism. This state of prolonged elevated blood sugar may alter genetic expression, and the modified gene products change cellular functioning. Additionally, prolonged hyperglycemia may produce excessive oxidative stress that leads to free radical formation and subsequent tissue damage. Some metabolic state of the retina in a young person with type 1 DM may exist that creates an environment conducive towards development of retinal neovascularization.

The most recent proposed mechanism of diabetic retinopathy draws comparisons between the retinopathy and an atypical inflammatory response. Other recent proposals that attempt to explain the relationship between hyperglycemia and the development of DR include changes in certain biochemical pathways, alterations of cellular insulin receptors and glucose transporters, and polypeptide growth factors that regulate retinal vascular growth.

Risk Factors of Diabetic Retinopathy

Certainly the duration and type of diabetes influences the development of DR. Other factors include the onset of puberty (because of hormonal factors), systemic hypertension, pregnancy, genetics, and tight glucose control. Progression of the retinopathy decreases in patients with tightly controlled serum glucose. Although genetic factors may influence the progression of DR (which may explain why only 50% of type 1 patients develop proliferation after 15 years), ethnicity does not seem to be a relevant issue. Interestingly, glaucoma and myopia both seem to reduce the progression of DR.

Histopathology of Diabetic Retinopathy

All microvascular abnormalities that occur in diabetes are the result of prolonged hyperglycemia. Significant lesions occur in the pathogenesis of diabetic retinopathy. The first to occur is usually capillary membrane thickening. In addition, collagen deposits in the base-

ment membrane of the capillary. The cause of this thickening is as yet undiscovered. As the basement membrane of the capillary thickens, a loss of intramural pericytes occurs that causes bulging from the side of the capillary wall. Ophthalmoscopically this bulging would appear as a tiny, red dot indicating the presence of a microaneurysm. This condition is the earliest observable funduscopic lesion related to diabetic retinopathy. The retinal capillary microaneurysm represents either a focal region of endothelial cell proliferation or an area on the capillary wall that has become weakened because of a loss of pericytes. Indeed, pericytes may act as a contractile unit that adds tone to the capillary wall, and loss of pericytes would theoretically create a weak point from which a microaneurysm may form.

After capillary membrane thickening, loss of pericytes, and microaneurysm formation, a breakdown in the blood-retinal barrier occurs. This breakdown is not observed clinically, but is the result of formation of fenestrations within the endothelial cell cytoplasm and opening of the tight junctions between adjacent endothelial cell processes.

Ocular Complications of Diabetes Mellitus

Individuals with DM are 25 times more likely to become legally blind than individuals without DM. In individuals between 20 and 74 years old, DR is the leading cause of blindness in the United States. Blindness in DM is usually the result of diabetic retinopathy or clinically significant macular edema (CSME).

Diabetic retinopathy is divided into nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR).

Nonproliferative Diabetic Retinopathy

Nonproliferative diabetic retinopathy (NPDR) is characterized by intraretinal microvascular changes in the absence of neovascularization. This stage is early and will precede the proliferative stage of DR. The clinical signs of NPDR include microaneurysms and the intraretinal microvascular abnormalities (IRMA) that occur because of retinal vascular permeability changes. Eventually, retinal nonperfusion occurs because of closure of the retinal vessels. Hemorrhages and IRMA are a direct result of nonperfusion of the retina. The characteristics of NPDR (depicted in the standard photographs of the modified Airlie House Classification of Diabetic Retinopathy of 1968 and modified by the Early Treatment of Diabetic Retinopathy Study [ETDRS] research group) include the following.

Microaneurysms

These outpouchings of the blood vessel wall occur in the retinal capillary and are visualized as tiny red dots in the posterior pole (Figure 12-3). A microaneurysm is

FIGURE 12-3 ■ Standard photograph 2A of the Modified Airlie House Classification of Diabetic Retinopathy demonstrating a moderate degree of hemorrhages and/or microaneurysms. (Courtesy the Diabetic Retinopathy Study Research Group.)

considered the hallmark of NPDR but is difficult to differentiate from a dot hemorrhage. Fluorescein studies are needed to distinguish the microaneurysm from the dot hemorrhage, because the aneurysmal sac hyperfluoresces and the dot hemorrhage is dark. The microaneurysms increase in number as the retinopathy develops, but no treatment is necessary at this stage.

Macular Edema

The most significant cause of vision decrease in NPDR is macular edema (ME). The ETDRS classified ME as clinically significant macular edema (CSME) if, “(a) the retina is thickened at or within 500 nm of the center of the macula; (b) hard exudates at or within 500 µm of the center of the macula, if associated with thickening of the adjacent retina; or (c) a zone or zones of retinal thickening one disk area or larger, any part of which is within one disk diameter of the center of the macula” (ETDRS report no. 1, 1985).

Retinal edema develops as the permeability of the retinal vessels increase and fluid accumulates within one disc diameter of the macula. Macular edema represents a collection of intraretinal fluid within the macular space and is often associated with retinal hard exudates visualized on slit-lamp biomicroscopy views. Macular edema is quantified by optical coherence tomography (OCT), which provides high-resolution photographs of the retina and the surrounding structures.

Hard Exudates

This extravasation of lipid deposits in the retina because of lipoprotein leakage from the blood vessels (Figure 12-4). The vessel becomes permeable because

FIGURE 12-4 ■ Hard exudates in the macular area. Adjacent retinal thickening is present that is not appreciated without stereoscopic viewing.

of breakdown in the endothelial tight junctions. These exudates are yellow-white intraretinal deposits with well-circumscribed borders. They are directly related to an elevated serum lipid level.

Intraretinal Microvascular Abnormalities

These areas of tiny and tortuous blood vessels clump adjacent to an area of nonperfusion (Figure 12-5). They may represent preexisting and dilated capillaries, or they may represent early neovascularization. Intraretinal microvascular abnormalities (IRMA) occur because of retinal terminal arteriole closure with subsequent retinal hypoperfusion. As the condition progresses, IRMA becomes associated with hemorrhages and dilated retinal veins (venous beading).

FIGURE 12-5 ■ Standard photograph SA of the Modified Airlie House Classification of Diabetic Retinopathy demonstrating intraretinal microvascular abnormalities (IRMA). (Courtesy the Diabetic Retinopathy Study Research Group.)

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Cotton-Wool Spots

These soft exudates represent the presence of severe NPDR (preproliferative retinopathy). Cotton-wool spots usually disappear in 6 to 12 months.

Venous Beading

Areas of the retinal veins may dilate in a segmental fashion because of weaknesses in the walls of the vessels (Figure 12-6). If venous beading is found in two quadrants of the retina, the retinopathy is considered severe NPDR.

Classification of Nonproliferative Diabetic Retinopathy (Table 12-1)

Four levels of NPDR exist: mild, moderate, severe, and very severe. The level of severity is determined on the basis of the characteristics discussed above, including

FIGURE 12-6 ■ Standard photograph 6B of the Modified Airlie House Classification of Diabetic Retinopathy demonstrating venous beading. (Courtesy of the Diabetic Retinopathy Study Research Group.)

microaneurysms, hemorrhages, exudates, and IRMA. The earliest stage of NPDR is characterized by the presence of microaneurysms. Mild NPDR occurs when there are microaneurysms with retinal hemorrhages and/or hard exudates. If cotton-wool spots or mild IRMA occurs with the microaneurysms and retinal hemorrhages then moderate NPDR is present. Severe NPDR is characterized by microaneurysms plus venous beading, hemorrhages, or both. Severe NPDR is a preproliferative stage of DR and occurs because of increasing ischemia from capillary closure. The examiner should evaluate severe NPDR by dividing the retina into four quadrants and looking for hemorrhages or microaneurysms in all four quadrants. If only venous beading occurs in two quadrants of the retina, then this is also considered severe NPDR. Any single area of moderate IRMA also indicates severe NPDR. If two of these features are present, then the condition is considered very severe NPDR.

“4 2 1 Rule” for NPDR. In cases of NPDR, a convenient rule has been formulated to determine the presence of the severe stage. Known as the “4 2 1 rule,” severe NPDR is said to exist if one of the following criteria is met: 20 or more hemorrhages exist in all four quadrants of the retina, venous beading (segmental venous dilations) is present in at least two quadrants of the retina, or moderate IRMA is present in one quadrant of the retina.

Risk of Progression to Proliferative Diabetic Retinopathy. The ETDRS has established the risk of progression of NPDR to the proliferative stage. NPDR usually begins to appear after approximately 10 years of insulin use. The mildest stage of NPDR has at least one hemorrhage, microaneurysm, or both, with no other diabetic retinopathy changes. This stage does not represent a threat to vision. Mild NPDR has a 5% risk of progression to PDR in 1 year and a 15% risk of progression to high-risk PDR in 5 years. These patients should be examined yearly.

In moderate NPDR the hemorrhage/microaneurysm appearance is greater than or equal to standard photograph 2A (see Figure 12-3). In this stage intraretinal microvascular abnormalities (IRMA) are present. This stage has a 12% to 27% risk of progression to PDR in 1 year and a 33% risk of progression to highrisk PDR in 5 years. These patients should be seen every 6 months. Focal laser treatment is necessary if CSME is present.

In severe NPDR, the hemorrhages/microaneurysms are greater than in standard photograph 2A in four quadrants, or IRMA is present in one quadrant. A 50% risk of progression in 1 year to PDR and a 66% risk of progression to high-risk PDR in 5 years exists. These patients must be seen every 2 to 3 months by the eye doctor. These patients may need panretinal photocoagulation (PRP) laser therapy.

In very severe NPDR two characteristics of severe NPDR are present.

Glycemic Control in NPDR. Poorly controlled serum glucose results in increased severity of DR. The Diabetes Control and Complications Trial (DCCT) of 1993 to 1996 showed conclusively that “intensive insulin treatment is associated with a decreased risk of either the development or the progression of DR in patients with type 1 diabetes.” The DCCT demonstrated that every 10% decrease in HbA1c was associated with a concurrent 40% reduction in the risk of retinopathy progression. The DCCT has been used to formulate the recommendation to keep the HbA1c below 7% in cases of DM.

Systemic Hypertension and Nonproliferative Diabetic Retinopathy. Tight control of systemic hypertension was shown to reduce retinal vascular disease and the necessity of photocoagulation.

Serum Lipids and Nonproliferative Diabetic Retinopathy. Elevated serum cholesterol was found to be associated with an increased severity of retinal exudates (Chew, 1996). Hard exudates (HE) cause several complications including reduced visual acuity and subretinal fibrosis (ETDRS). In 2004 Lyons reported that the severity of the progression of DR is directly related to elevated triglycerides and inversely related to highdensity lipoproteins. No doubt seems to exist that lowering serum triglycerides reduces the risk of visual loss in cases of DM.

Pregnancy and Nonproliferative Diabetic Retinopathy. Pregnancy accelerates the progression of DR. Patients who are diabetic should have their eyes examined before conceiving and during pregnancy in every trimester. Severe NPDR in pregnant individuals should be evaluated every month (AAO, 1998).

Treatment of Nonproliferative Diabetic Retinopathy. The ETDRS of 1987 to 1991 and the Diabetic Retinopathy Study (DRS) of 1978 to 1981 studied the effectiveness of laser photocoagulation on the severity

of the retinopathy and the presence or absence of CSME. In patients with severe NPDR with visual acuity of 20/100 or better who received scatter and focal photocoagulation, a 56% reduction in severe visual loss (5/200 or worse) was noted. The study showed that the risks of scatter photocoagulation did not outweigh the benefits of treatment in cases of mild-to- moderate NPDR. In cases of severe or very severe NPDR, however, scatter photocoagulation is effective in reducing severe visual loss in patients with type 2 diabetes (Ferris, 1996).

Treatment of Macular Edema. The ETDRS demonstrated that “focal/grid photocoagulation reduced the risk of moderate visual acuity loss for all eyes with diabetic macular edema and mild to moderate NPDR by about 50%.” Patients with edema involving the center of the macula are at greatest risk of visual loss, but patients can notice areas of blindness caused by focal laser burns. Therefore, leakage at or near the fovea is best monitored rather than treated. Focal laser is used to treat leaking microaneurysms close to the center of the macula. Diffuse leakage is treated with a grid laser of light intensity burns. In 2004 Massin described the use of intravitreal injections of triamcinolone acetonide in the treatment of macular edema.

Definition of PDR

PDR (Table 12-2) comprises the state of newly formed blood vessels, fibrous tissue, or both that arises from the retina. The neovascular vessels, fibrotic proliferation, or both may form on the retinal surface or disc and extend into the vitreous cavity (Davis and Blodi, 2006).

Pathophysiology of Proliferative Diabetic Retinopathy

Occlusion and closure of the retinal capillary bed causes areas of inner layer retinal ischemia. A retinal angiogenesis factor is produced by ischemic retina. This chemical stimulates the growth of new blood vessels in an attempt to oxygenate hypoxic retinal

TABLE 12-2 CLASSIFICATION OF PROLIFERATIVE DIABETIC RETINOPATHY

HRC, High-risk characteristics, NVD, neovascularization of the disc; NVE, neovascularization elsewhere.

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cells. Angiogenesis-growth factor diffuses to the disc and causes neovascularization of the disc (NVD; Figure 12-7). As the growth factor reaches distant areas of the retina it causes preretinal neovascularization, or neovascularization elsewhere (NVE; Figure 12-8). Retinal angiogenic-growth factor may even diffuse through the vitreous to the anterior chamber to stimulate new blood vessel growth on the iris producing neovascularization of the iris (NVI; Figure 12-9).

Characteristics of New Blood Vessels

Neovascular vessels usually form within 45 degrees of the posterior pole and commonly on the disc. New blood vessels on the disc begin as thin loops, or may appear as a network of fine vessels on the surface of the disc. NVE must be differentiated from IRMA, though in either case a referral to retina specialty is mandatory. The NVE typically demonstrates a “wheellike” network and may extend across arterial and venous branches while being accompanied by fibrous proliferations. IRMA is smaller, unorganized, and unassociated with fibrous proliferations.

Evolution of Proliferative Diabetic Retinopathy

New blood vessels begin as a fine network on the retinal surface, but with time their caliber increases to nearly the size of arterioles. The increase in size takes weeks to months. As they grow, fibrous proliferation appears as white, translucent tissue adjacent to the neovascularization. In time the new blood vessels regress and are replaced by fibrous tissue. Areas of neovascularization adhere to the posterior vitreous surface and adjacent areas of fibrous tissue contract,

FIGURE 12-8 ■ Standard photograph 7 of the Modified Airlie House Classification of Diabetic Retinopathy demonstrating new vessels elsewhere (NVE) in the retina with fresh hemorrhage. (Courtesy the Diabetic Retinopathy Study Research Group.)

FIGURE 12-7 ■ Standard photograph 10A of the Modified Airlie House Classification of Diabetic Retinopathy demonstrating neovascularization of the optic disc covering approximately V4 to V3 of the disc area. (Courtesy the Diabetic Retinopathy Study Research Group.)

FIGURE 12-9 ■ Clinical appearance of rubeosis iridis at the pupil border.

leading to a posterior vitreous detachment. Distortion of the macula may occur when a large fibrovascular sheet contracts. This “dragging” of the macula usually occurs in a nasal direction from the disc. The same process may lead to a retinal detachment. Recurrent vitreous hemorrhage occurs because of the fragility of the newly formed blood vessels. Eventually, vitreous contraction is completed and a severe loss of vision results.

Glycemic Control and Proliferative Diabetic Retinopathy

Tight glycemic control reduces the risk of progression from NPDR to PDR in insulin-dependent diabetes by a significant amount (DCCT, 1996). In type 2 diabetes,

stringent glycemic control also reduced the risk of progression (Ohkubo, 1995).

Risk Factors for Proliferative Diabetic Retinopathy

Hyperglycemia, severe anemia, and elevated serum lipids are all significant risk factors for the development of high-risk PDR. One study showed that systemic hypertension was not a significant risk factor in the progression to high-risk PDR (ETDRS). Hypertension was shown to be a significant contributor to progression to PDR in the United Kingdom Prospective Diabetes Study, however (UKPDS, 1998).

Treatment of Proliferative Diabetic Retinopathy

Because a vasoproliferative angiogenic substance is released by ischemic retina, destruction of the involved tissues would theoretically inhibit proliferation. Patients who have PDR with NVD or vitreous or preretinal hemorrhage should have treatment immediately. Scatter, or panretinal, photocoagulation is not used in mild-to-moderate NPDR, but is reserved for severe NPDR or moderate PDR. Scatter photocoagulation should be performed in cases of extensive neovascularization in the anterior chamber. This treatment will prevent neovascular glaucoma. In patients with macular edema and high-risk NPDR, focal or grid treatment for the macular edema should precede treatment with scatter photocoagulation (ETDRS, 1987). Regression of new blood vessels occurs in days to weeks after application of scatter photocoagulation. Complications of such panretinal laser surgery include constricted visual fields, night blindness, and macular edema.

DISORDERS OF THE THYROID GLAND Introduction to Graves’ Disease

Graves’ disease, or endocrine ophthalmopathy (EO), comprises the characteristics of hyperthyroidism, toxic diffuse goiter, and ophthalmopathy. The ophthalmopathy, however, may occur independently of the thyrotoxic goiter. Therefore, for endocrine ophthalmopathy to be considered a multisystem disorder of endocrine origin, it must be associated with one or more of the following clinical features: thyroid disease (that is autoimmune in nature), an ophthalmopathy that is characterized by infiltrates, and pretibial myxedema (or dermopathy).

Because clinical investigations have traditionally concentrated on the thyrotoxic goiter, little progress has been made in identifying the pathogenesis and evolution of the orbitopathy. Only recently has Graves’ ophthalmopathy received the concentrated attention of researchers and clinicians alike. For this reason no consensus exists yet on the terminology to be used in describing this disorder (Box 12-1).

BOX 12-1

NAMES SYNONYMOUS WITH ENDOCRINE OPHTHALMOPATHY

Graves’ eye disease

Graves’ ophthalmopathy

Graves’ orbitopathy

Dysthyroid eye disease

Dysthyroid orbitopathy

Exophthalmic goiter

Immune exophthalmos

Thyroid-associated ophthalmopathy

Autoimmune orbitopathy

Autoimmune ophthalmopathy

Traditionally, the term “Graves’ eye disease” or “Graves’ ophthalmopathy” has been widely used but remains unsatisfactory, because the orbitopathy includes Hashimoto’s thyroiditis. In 1987, Volpe suggested the term “autoimmune ophthalmopathy” or “autoimmune orbitopathy,” which at least identifies the physiologic underpinning of the disorder but sacrifices its relationship with thyroid disease. In 1990 Wall and How suggested that the term “thyroidassociated ophthalmopathy” be adopted to encompass all the characteristics associated with Graves’ disease. Writing in 1993, Kahaly used the term “endocrine ophthalmopathy” to describe the autoimmune origin, histologic cell infiltration of the orbital tissues, and classic signs and symptoms historically ascribed to Graves’ eye disease. This section refers to thyroidassociated ophthalmopathy as Graves’ disease, and reserves the term endocrine ophthalmopathy for the ocular signs and symptoms associated with thyroideye disease.

That so much ambivalence surrounds the nomenclature of this disease suggests the larger and more complex questions facing researchers: What causes EO and how is it related to thyroid disease? In addition, clinicians are still faced with the issues of how best to diagnose and treat EO.

Optometrists can readily serve in this new focus on EO by acting in coordinated effort with endocrine researchers and clinicians to identify the at-risk group of patients before they show any manifestations of the orbitopathy. These patients can then be closely monitored by all the involved disciplines as signs and symptoms develop. Through such a rational approach, the true biochemical, immunologic, and pathologic basis for EO may at last be discovered.

This chapter presents the latest thoughts on the autoimmune nature of this disease. Also described are the diagnostic strategies available to the optometrist when evaluating a patient with, or suspected of having, EO. Finally, the medical and surgical management of EO is presented, including the use of novel drugs,