Proliferative

DIABETIC RETINOPATHY (PDR)

Proliferative diabetic retinopathy (PDR) refers to a severe stage of diabetic eye disease in which new blood vessels proliferate on the surface of the retina. Most patients with PDR have had Nonproliferative Diabetic Retinopathy for at least a few years prior to developing the proliferative form of the disease. The diagnosis of PDR requires the presence of new proliferating blood vessels (neovascularization) arising from the retina or optic disc and growing on the retinal surface or into the vitreous cavity. This diagnosis is made primarily by examination of the retina and sometimes by fluorescein angiography.

The photograph on the left shows a tuft of neovascularization (arrowhead) extending from the optic nerve head into the vitreous cavity. These new vessels take on a frond-like configuration as they grow, similar in appearance to a sea fan. The photograph on the right is a fluorescein angiogram of a different patient showing a frond of vessels (arrowhead) extending from the disc. Neovascularization leaks fluorescein dye (white in this photograph), giving it a fluffy appearance.

Diabetes-proliferative-retina-color-and-BW

The most likely cause for the neovascularization in PDR is ischemia (decreased blood supply) of the retina. In diabetes, multiple small patches of the retina lose their blood supply because of closure of retinal capillaries. As these patches of the retina are deprived of oxygen and nutrients, they probably produce a chemical signal: a vessel-producing or vasoproliferative factor. This factor diffuses into the vitreous cavity, and stimulates growth of new vessels throughout the retina and on the iris. A growth factor has been isolated from the vitreous of diabetic patients that can produce this neovascular response in otherwise normal animal eyes. These stimulating factors may be opposed by other growth factors that inhibit new vessel growth. However, when enough segments of the retina have been deprived of their blood supply and are producing vasoproliferative factors, the balance is tipped toward new vessel formation.

The rate of growth of these new vessels can be quite variable. Some patients have rapid growth over a few weeks, while other show little or no change in the new vessels over months or years. This variability may have to do with the balance between proliferative and inhibitory growth factors in the eye.

If allowed to progress unchecked, neovascularization tends to go through a “life cycle” of growth, fibrosis, and regression. Over time, the fronds of tiny, fine new vessels gradually become larger and more mature. Cells called fibroblasts grow along with the new vessels. The fibroblasts lay down collagen fibers, producing a fibro vascular complex. Eventually, the newer vessels tend to regress, leaving behind the fibrous tissue and the larger, more mature vessels.

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COMPLICATIONS OF PROLIFERATIVE DIABETIC RETINOPATHY
This neovascular response in a retina that needs more blood supply may sound like a positive effect. However, the new blood vessels are not necessarily in the same location as the ischemic part of the retina. Also, the new vessels tend to be very fragile and may bleed, filling the eye with blood. When these vitreous hemorrhages occur, patients notice black or red “strings” or “cobwebs” in the vision. As the blood disperses through the vitreous cavity, the vision becomes blurred or dim. If enough bleeding occurs, the vision is seriously impaired.

The eye is able to clean this blood out of the vitreous cavity as long as there is not too much blood. Some of the red blood cells diffuse forward into the anterior portion of the eye and are removed through the normal drainage apparatus, the trabecular meshwork. White blood cells probably also travel into the vitreous, ingest old red blood cells, and carry them away. Both of these processes are slow, and the speed at which the blood is removed can be quite variable from patient to patient. A small amount of blood in the vitreous can sometimes be removed in a few weeks, whereas larger hemorrhages may take months or years to clear. In cases of dense blood or multiple recurrent hemorrhages, the vision may not return because of residual inflammatory debris and dead cells that cannot be removed. Vitreous hemorrhage is a concern not only because of the poor vision, but also because of the poor visibility into the eye. With the eye full of blood, it is difficult or impossible for your eye care professional to tell if the proliferating vessels are continuing to grow and if they are damaging the retina with traction or scarring.

One of the most feared complications of diabetic eye disease is traction retinal detachment. As mentioned above, the new vessels tend to lay down fibrous scar tissue as they grow and then regress. Like any scar, this fibrous tissue contracts or shrinks as it matures. If the neovascularization is on the surface of the retina, the contraction of the fibrous scar may produce some distortion of the retina. Vessels that grow out into the vitreous cavity develop adhesions between the fibro vascular complex and the collagen fibers that make up the vitreous gel. When the vitreous separates away from the retina (a normal aging change) or when the fibrous scar contracts, the scar tissue pulls on the retina, producing traction that can distort or detach the retina. These traction detachments can be limited and have little effect on the vision, or they may be extensive and cause complete blindness. Once the central part of the retina has detached, the chance of getting good vision back is low, even is the retina can be successfully re-attached. For this reason, the emphasis in diabetic eye care should be on prevention and early treatment whenever possible.

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TREATMENT OF PROLIFERATIVE DIABETIC RETINOPATHY
When neovascularization is detected, laser treatment should be considered. Cases in which only very small tufts of new vessels are seen can be watched closely without treatment, since the new vessels may not continue to grow. However, most patients with new vessels should undergo a laser treatment known as pan retinal photocoagulation (PRP) See photo’s to the right. PRP involves extensive treatment with an argon or diode laser to the peripheral and middle portions of the retina.

Diabetic-panretinal-cross-section

The central or macular region is not treated, since this would likely cause serious loss of vision. This PRP is usually done in the office without anesthesia, although some patients have pain and require an anesthetic injection near the eye for pain relief. The initial treatment usually consists of approximately 1500-2000 spots of laser per eye. This is done in two or more sessions, since it can be dangerous to the eye to give more than 1000 spots in a single session. The vision is usually poor immediately after the treatment, but recovers to the pre-treatment level within a few hours.

Diabetic-proliferative-Retina-national-eye-inst

This is a color photograph of an eye with proliferative diabetic retinopathy and laser scars. There is a large frond of neovascularization (large arrowhead) extending from the optic nerve head. Multiple laser scars (small arrowhead) can be seen throughout the retina, except for in the macular region. (The laser scars in this patient are closer to the center of the retina than usual).

Diabetic-proliferative-Retina-laser

Pan retinal photocoagulation probably works by reducing the level of vasoproliferative factors produced by the ischemic retina. This is thought to be accomplished by two mechanisms. First, laser treatment destroys small patches of ischemic retina, reducing the oxygen demand of the retina and reducing the production of vasoproliferative growth factors. Second, the laser thins the pigmented tissue under the retina, allowing more oxygen to diffuse in from the vessels under the retina. Microelectrode studies have shown higher levels of oxygen in the vitreous directly over a laser scar than in the vitreous over adjacent untreated retina. By increasing oxygen supply and decreasing demand, the stimulus for new vessels is reduced, and the neovascularization tends to shrivel up and go away. The larger, more mature vessels do not always regress, and the fibrous scar tissue persists despite the laser treatment, so early detection and treatment are advantageous.

Laser treatment of neovascularization is a titration effect; there seems to be a threshold above which new vessels will form and below which new vessels will regress. For any individual patient, this means that careful observation is necessary. If the vessels do not regress with the initial treatment, further treatment is needed. If the vessels regress, but then begin to grow again after months or years, more treatment is indicated.

Although PRP is helpful in causing regression of neovascularization, it will not destroy scar tissue that has formed, and it cannot be done through dense vitreous hemorrhage. A surgical procedure known as a vitrectomy can be performed to remove blood and debris from the vitreous cavity and to re-attach the retina in cases of traction detachment. In a vitrectomy, three small (1 mm) incisions are made into the eye. Through one of these incisions, an infusion cannula is placed and sutured into place. This allows constant infusion of saline solution to keep the eye inflated at the proper pressure. A fiber optic light source is inserted through one incision, and a suction/cutter device through another. The suction/cutter has a small port with a rotating or sliding blade inside. Vitreous gel and blood are sucked into the port, cut off by the blade, and removed from the eye. The surgeon watches through a contact lens on the eye, looking through a microscope. After the blood and vitreous are removed, any additional treatment needed can be performed, including laser treatment, cautery of bleeding sites, and removal of scar tissue.

Vitrectomy is a very useful procedure, but it does have potential risks and complications. There is a 5% risk of retinal tears or detachments caused by the procedure itself, which may necessitate further surgery. There is a 10%-40% risk of visually significant cataract in patients who have not already had cataract surgery. Also, in diabetics, there is a 20-30% risk of recurrent bleeding in the eye in the first few days following the surgery. This recurrent bleeding tends to clear more quickly then the initial hemorrhage, and usually does not require further surgery, but does slow the return of vision. For these reasons, vitrectomy is used only when the potential risks are outweighed by the benefits expected. In cases with relatively mild hemorrhage, patients are often better off waiting for the blood to clear on its own, despite the inconvenience of decreased vision for several months. In cases where the blood has not cleared spontaneously in 4-6 months, or where waiting would be dangerous due to retinal detachment or untreated progressing neovascularization, early surgery is indicated.

PREVENTATIVE TREATMENTS:
VITREOSOLVE, now in phase 3 trials. Appears to be very promising.