Nonproliferative Diabetic Retinopathy

Pre-proliferative (or Background) diabetic retinopathy is primarily a disease of retinal blood vessels. It is the result of two major processes affecting the retinal blood vessels: vessel closure and abnormal vessel permeability.

The earliest vessel closures in diabetic retinopathy are usually the capillaries. These small vessels are critical to the health of the retina, since they are needed to deliver oxygen and nutrients to the area and to carry away carbon dioxide and other waste products. The source of this capillary closure is not completely understood. Theories as to why these vessels close off include:

  • Clumping of blood cells or other blood elements.
  • Abnormality or damage to the endothelium (the cells lining the inner wall of the capillary).
  • Swelling of an abnormally permeable vessel wall.
  • Compression of the capillary by surrounding retinal swelling.

Regardless of the exact mechanism, diabetics tend to have capillary closure causing areas of decreased oxygen supply to the small patches of retina corresponding to these capillaries. There is an associated dilation of the adjacent capillaries, probably in response to the decreased oxygen level in that part of the retina. In addition, small focal dilations of the retinal capillaries called microaneurysms can develop. These microaneurysms are small sacs budding off from the vessel, often visible as tiny red dots on ophthalmologic examination. It is thought that microaneurysms are the result of weakened capillary walls that allow a bulging outward of the endothelial lining of the capillary.


This is a photograph of retinal vessels which shows the larger artery (A) and vein (V) as well as a tangle of smaller retinal capillaries. Multiple round microaneurysms (arrowhead) can be seen attached to the retinal capillaries.

Localized closure of retinal capillaries (nonperfusion) is not usually noticed by the patient, since the nonperfused area is so small. However, if the nonperfusion is in the central portion of the retina (the fovea), the vision can be significantly reduced. There is no known treatment for this visual loss due to foveal nonperfusion.

Retinal capillary closure can produce Proliferative diabetic retinopathy in more severe cases. When multiple areas of the retina have lost their blood supply, they start to send out chemical signals called neurogenic factors. These neurogenic factors stimulate the development of new blood vessels that are fragile and can cause bleeding and scar the retina. This is one way blindness associated with diabetes occurs.

In addition to the closure of capillaries, the very small arteries within the retina may close off. When this happens, larger patches of the retina are deprived of their blood supply. This is manifest clinically by retinal signs identified as “cotton-wool spots”, small fluffy white patches in the retina. Blockage of arterioles may also result in hemorrhages within the retina if the pressure causes a vessel to burst.

Retinal blood vessels are different from vessels elsewhere in the body. Most blood vessels are fenestrated, meaning that they have tiny openings that allow fluid to pass through the vessel wall. The openings are small enough to prevent the egress of larger blood elements such as blood cells and large proteins), but large enough to allow water and small molecules such as ions to pass. Retinal blood vessels, on the other hand, have tight junctions between the cells of the blood vessel wall, so all fluid and molecules exiting the vessel have to pass through the cells. This lack of fenestration helps keep the retina relatively dehydrated, which is necessary for proper function.

In diabetic retinopathy, the vessels become more permeable. Water, blood cells, proteins, fats, and other large molecules may leak out into the surrounding retinal tissue. Accumulation of this fluid in the central region of the retina (the macula) is called macular edema or diabetic maculopathy. Diabetic Maculopathy is the most common cause of decreased vision in patients with background or non-proliferative diabetic retinopathy. These retinal signs are visible on examination as a thickening and slight graying of the retina, and is often associated with exudates (yellow clumps or spots within the retina). Exudates are the result of fats and proteins leaking out of the permeable vessels along with water. The water can be quickly reabsorbed into the vessels or into the tissue under the retina, but the fatty material is absorbed only very slowly. These fatty exudates are left behind like a “bathtub ring”, often in a ring-like shape surrounding the leakage site.

This photograph of a retina shows multiple microaneurysms (small arrowheads) and hemorrhages scattered through the macular region. There is an area of diabetic maculopathy to the left of center, with some associated retinal signs; yellow exudate (large arrowhead).


Swelling, retinal signs fairly common in background diabetic retinopathy, but it is not always significant swelling. In other words, retinal edema does not always affect vision and does not always need to be treated. Edema in the retina is considered “clinically significant” if it is close enough to the center of the retina to pose a risk to vision. This was defined more precisely in the Early Treatment Diabetic Retinopathy Study (ETDRS), a large multi-center study designed to evaluate the usefulness of laser treatment for diabetic maculopathy. The diagnosis of clinically significant macular edema (CSME) requiring treatment is made by your eye care professional. If possible, it is best to find diabetic maculopathy when it is clinically significant, but before it affects the vision, since treatment is most effective at this stage.

The treatment of diabetic maculopathy is primarily by laser treatment. Several different lasers are used for this, including the argon laser, dye laser, and diode laser. All of these lasers produce coherent light in visible wavelengths. When the laser light hits blood or pigment, it is absorbed as heat energy, producing a small burn. The most commonly used wavelengths in treatment of macular edema are in the yellow and green portion of the spectrum, since these wavelengths are best absorbed by hemoglobin. Red laser is also used occasionally. Macular laser treatments are usually painless. The burn produced by the laser creates a faint scar under the retina which usually is not noticed by the patient. It takes approximately one month to see the effect of the laser treatment (decreased edema and improved vision), although it may occur within a few days or take as long as several months.

Complications of macular laser do occur, but they are unusual. The most feared complication is accidental laser treatment of the center of the macula, which can cause marked permanent decrease in vision. Fortunately, this complication is quite rare. A more common complication is an increase in the macular edema lasting several days to weeks following the laser treatment. Although the decreased vision in these cases is annoying, it usually resolves spontaneously.

Diabetic Maculopathy is often described as being either focal or diffuse, and treatment of the edema is specific to the type. Focal macular edema is swelling due to leakage from a few specific spots in the retina, usually leaking microaneurysms or dilated retinal vessels. Treatment of focal macular edema is done by coagulating the individual microaneurysms or leaking vessels in order to stop the leakage. A 50-100 micron spot of laser is applied to the microaneurysm with sufficient power to produce whitening or coagulation. Diffuse macular edema is caused by leakage from multiple retinal vessels as well as from the pigmented cells under the retina. It would be impossible to treat all areas of leakage in a case of diffuse edema. Instead, a grid pattern of laser spots are placed around the center of the macula. The mechanism by which grid laser treatment works is unknown, but may have to do with destroying abnormal pigmented cells and allowing more normal cells to replace them.

The efficacy of laser treatment for macular edema (diabetic maculopathy) has been documented in large multi-center clinical trials. The ETDRS was the largest of these trials. It showed that eyes with clinically significant macular edema that did not receive laser treatment were twice as likely to have severe loss of vision as compared with similar eyes that received laser treatment. These results indicate that treatment of macular edema should be based on the location and severity of the edema, not necessarily on the visual acuity.