Diabetic retinopathy
Diabetic retinopathy is a medical condition in which damage occurs to the retina due to diabetes. It is a leading cause of blindness in developed countries and one of the leading causes of sight loss in the world, even though there are many new therapies and improved treatments for helping people living with diabetes.
Diabetic retinopathy affects up to 80 percent of those who have had both type 1 and type 2 diabetes for 20 years or more. In at least 90% of new cases, progression to more aggressive forms of sight-threatening retinopathy and maculopathy could be reduced with proper treatment and monitoring of the eyes. The longer a person has diabetes, the higher their chances of developing diabetic retinopathy. Each year in the United States, diabetic retinopathy accounts for 12% of all new cases of blindness. It is also the leading cause of blindness in people aged 20 to 64.
Signs and symptoms
Nearly all people with diabetes develop some degree of retina damage over several decades with the disease. For many, that damage can only be detected by a retinal exam, and has no noticeable effect on vision. Over time, progressive retinal damage may appear on a retinal exam, first with small bulges in retinal blood vessels called microaneurysms. Then larger abnormalities in retinal vessels: cotton wool spots, hemorrhages, lipid deposits called "hard exudates", intraretinal microvascular abnormalities, and abnormal-looking retinal veins. Eventually, many progress to a stage where new blood vessels grow throughout the retina. These new blood vessels often break and bleed. Minor bleeding can cause dark floating spots obstructing vision; major bleeding can completely block vision.Around half of people with diabetic retinopathy develop swelling of the macula, called macular edema, which can begin at any time. If the swelling occurs near the center of the macula, it can cause vision disruptions ranging from mildly blurred vision to severe loss of the center of an affected person's visual field. Left untreated, around 30% of those with such swelling experience vision disruption over the next 3–5 years. Macular edema is the most common cause of vision loss in people with diabetic retinopathy.
The repeated processes of blood vessel growth, swelling, and scarring can eventually cause retinal detachment, which manifests as the sudden appearance of dark floating spots, flashes of light, or blurred vision.
Causes
Diabetic retinopathy is caused by prolonged high blood glucose damaging the small blood vessels of the retina, though the mechanism by which this occurs is unknown. Progression of diabetic retinopathy is accompanied by loss of capillary cells, increased blood vessel permeability in the retina, and altered retinal blood flow, all of which can reduce the amount of blood oxygen that gets delivered to the retina. Poor oxygenation of tissues drives the formation of new blood vessels throughout the retina, resulting in the proliferative stage of disease. These new blood vessels tend to rupture easily, causing bleeding within the eye, scarring, and damage to the retina or macula. Recent evidence has found a strong association between diabetic retinopathy and inflammation.Risk factors
The major risk factors for developing diabetic retinopathy are duration of diabetes, poor blood sugar control, and, to a lesser extent, high blood pressure. Five years after diabetes diagnosis, around 25% of those with type 1 diabetes have some degree of diabetic retinopathy, while 2% have proliferative diabetic retinopathy. By 15 years after diagnosis, that increases to 80% with some retinopathy, and 25% with proliferative disease. Children are an exception—regardless of duration of diabetes, children rarely experience sight-threatening retinopathy; however, puberty can accelerate retinopathy progression. Pregnancy can also accelerate the progression of diabetic retinopathy.Both chronically high blood sugar and highly variable blood sugar are associated with developing diabetic retinopathy. Several more minor risk factors also exacerbate diabetic retinopathy, namely kidney disease, abnormal blood lipids, high body mass index, and smoking.
Genetic predisposition to diabetic retinopathy in type 2 diabetes consists of many genetic variants across the genome that are collectively associated with diabetic retinopathy and overlaps with genetic risk for glucose, low-density lipoprotein cholesterol, and systolic blood pressure. Several variations in the VEGFC gene have also been associated with an increased risk of developing macular edema.
People with Down syndrome, who have extra chromosome 21 material, rarely acquire diabetic retinopathy. This protection appears to be due to the elevated levels of endostatin, an anti-angiogenic protein, derived from collagen XVIII. The collagen XVIII gene is located on chromosome 21.
Incidence of Retinitis Pigmentosa is observed to result in fewer and less severe microvascular lesions in both humans and mouse models. Retinitis Pigmentosa results in loss of rod receptors in the mid peripheral field, reducing the oxygen consumption that is linked with release of VEGF and growth of unwanted blood vessels in the retina.
Obstructive sleep apnea has been associated with a higher incidence of diabetic eye disease due to blood desaturation caused by intermittent upper airway obstructions. Treatment for OSA can help reduce the risk of diabetic complications.
Pathogenesis
Diabetic retinopathy is the result of damage to the small blood vessels and neurons of the retina. The earliest changes leading to diabetic retinopathy include narrowing of the retinal arteries associated with reduced retinal blood flow; dysfunction of the neurons of the inner retina, followed in later stages by changes in the function of the outer retina, associated with subtle changes in visual function; dysfunction of the blood-retinal barrier, which protects the retina from many substances in the blood, leading to the leaking of blood constituents into the retinal neuropile. Later, the basement membrane of the retinal blood vessels thickens, capillaries degenerate and lose cells, particularly pericytes and vascular smooth muscle cells. This leads to loss of blood flow and progressive ischemia, and microscopic aneurysms which appear as balloon-like structures jutting out from the capillary walls, which recruit inflammatory cells; and advanced dysfunction and degeneration of the neurons and glial cells of the retina. The condition typically develops about 10–15 years after receiving the diagnosis of diabetes mellitus.An experimental study suggests that pericyte death is caused by blood glucose persistently activating protein kinase C and mitogen-activated protein kinase, which, through a series of intermediates, inhibits signaling through platelet-derived growth factor receptors—signaling that supports cellular survival, proliferation, and growth. The resulting withdrawal of this signaling leads to the programmed cell death of the cells in this experimental model.
In addition, excessive sorbitol in diabetics is deposited in the retina tissue, and it is also proposed to play a role in diabetic retinopathy.
Recent studies have found a strong correlation between retinal inflammation and diabetic retinopathy progression.
A genetic study showed that diabetic retinopathy shares a similar genetic predisposition with levels of glucose, low-density lipoprotein cholesterol, and systolic blood pressure, indicating that glycemic control and cardiometabolic factors may be important in the development of diabetic retinopathy.
Lipid peroxidation plays a notable role in the progression of diabetic retinopathy. Free radicals such as hydroxyl and hydroperoxyl species with oxygen as functional group oxidize lipids and phospholipids, and at the cellular level bring about membrane lipid peroxidation and in this way can trigger diabetic retinopathy.
Diagnosis
Diabetic retinopathy is typically diagnosed by retinal exam observations using ophthalmoscopy. The American Academy of Ophthalmology divides diabetic retinopathy into five categories of progressive severity. The first category, "no apparent retinopathy", describes those with a healthy retinal exam. The next three categories: mild, moderate, and severe nonproliferative diabetic retinopathy, describe increasing levels of damage to the retina. People with mild NPDR have microaneurysms in the retina, but no other damage. Those with severe NPDR have 20+ retinal hemorrhages in each quadrant of the retina, a distinctive pattern of damage on the veins of the retina called "venous beading" in at least two retinal quadrants, and obvious intraretinal microvascular abnormalities anywhere on the retina. Moderate NPDR is defined as more severe than mild NPDR, but not yet meeting the criteria for severe NPDR. The fifth stage, proliferative diabetic retinopathy, is for those with new blood vessels forming throughout the retina, or blood leaking into the vitreous humor or between the vitreous membrane and retina.The same guidelines separately categorize macular edema into two categories: "macular edema apparently absent" and "macular edema apparently present." The latter is further subdivided into "mild"—retinal thickening or lipid deposits far from the macula's center; "moderate"— thickening or deposits near the center; and "severe"—thickening or deposits on the macula center. Optical coherence tomography is frequently used to assess macular edema.
Fluorescein angiography is used by retina specialists to assess diabetic retinopathy severity further and to determine sites of macular damage.
Electroretinography or ERGs, especially when combined with the pupillary response, can be used to predict which patients are likely to progress to having treatable disease.
Screening
Due to the lack of symptoms, most people with diabetic retinopathy are unaware that they have the condition until they visit an eye doctor. Both the American Diabetes Association and the International Council of Ophthalmology recommend regular eye exams for those with diabetes to screen for diabetic retinopathy. The ADA recommends a comprehensive eye examination at the time of type 2 diabetes diagnosis, and within five years of the onset of type 1 diabetes. For women with diabetes who become pregnant, the ADA recommends an eye examination before pregnancy, in each trimester, and for a year postpartum. The ICO recommends eye examinations for those with diabetes include a visual acuity examination and a retinal examination via ophthalmoscopy or retinal photography.Iceland, Ireland, and the United Kingdom are the only countries with national diabetic retinopathy screening programs, while substantial regional screening programs have been implemented in parts of mainland Europe, parts of Asia, and Botswana. In the UK, screening for diabetic retinopathy is part of the standard of care for people with diabetes. After one normal screening in people with diabetes, further screening is recommended every year. Teleophthalmology has been employed in these programs.