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CLINICAL THERAPEUTICS
Panretinal Photocoagulation for Proliferative Diabetic Retinopathy
Neil M. Bressler, M.D., Roy W. Beck, M.D., Ph.D., and Frederick L. Ferris, III, M.D.
N Engl J Med 2011; 365:1520-1526October 20, 2011
ArticleReferences
This Journal feature begins with a case vignette that includes a therapeutic recommendation. A discussion of the clinical problem and the mechanism of benefit of this form of therapy follows. Major clinical studies, the clinical use of this therapy, and potential adverse effects are reviewed. Relevant formal guidelines, if they exist, are presented. The article ends with the authors' clinical recommendations.
A 55-year-old man with a 20-year history of type 2 diabetes mellitus was referred to a retina specialist after noticing a few black floaters in his left eye for the preceding week. His glycated hemoglobin level was 8.2%. He had no history of laser treatment for proliferative diabetic retinopathy in either eye. Ophthalmoscopic examination of the right eye showed venous beading, intraretinal microvascular abnormalities, and no macular edema. Ophthalmoscopic examination of the left eye showed extensive neovascularization of the disk, consisting of new vessels extending beyond the optic disk in all directions (Figure 1AFIGURE 1
Treatment Effects of Panretinal Photocoagulation.
). The retina specialist diagnosed severe nonproliferative diabetic retinopathy in the right eye and high-risk proliferative diabetic retinopathy in the left eye, with no macular edema in either eye. The specialist recommended prompt initiation of panretinal photocoagulation in the left eye.
THE CLINICAL PROBLEM
Diabetic retinopathy is a common complication of diabetes mellitus. An analysis of pooled data from several population-based studies estimated that approximately 40% of patients with diabetes who are over the age of 40 years have some retinopathy, including 8.2% who have vision-threatening retinopathy (usually diabetic macular edema but less frequently proliferative retinopathy). 1 An increased duration of diabetes and poor glucose control are major risk factors for retinopathy.2,3
Diabetic retinopathy is a leading cause of visual loss and new-onset blindness in the United States for patients between the ages of 20 and 74 years,4 with 12,000 to 24,000 new cases of diabetic retinopathy–induced blindness each year.5 Data from the Diabetic Retinopathy Study (ClinicalTrials.gov number, NCT00000160) indicate that approximately half of all eyes with proliferative diabetic retinopathy that are left untreated will have profound vision loss (i.e., visual acuity of <20/800 for at least 4 months), a level of vision that interferes with the ability to identify even large objects.6
The annual economic effect of retinopathy-associated morbidity in the United States has been estimated at more than $620 million.7 As the incidence of obesity and diabetes continues to increase, the public health effect of vision loss from diabetic retinopathy is enormous and growing.5
PATHOPHYSIOLOGY AND EFFECT OF THERAPY
The retinal changes in diabetic retinopathy can be caused by the increased permeability of retinal capillaries, which results in edema of the retina, or to the closure of retinal capillaries, which leads to retinal ischemia. In turn, retinal ischemia can lead to the formation of neovascularization, which may lead to vitreous hemorrhage or traction damage to the retina.
Retinal ischemia leads to the production of a variety of growth factors, including vascular endothelial growth factor (VEGF).7 These growth factors stimulate the formation of abnormal capillaries from the retinal vessels on the surface of the optic disk, a condition that is termed neovascularization of the disk (Figure 1A), or on the surface of the retina but not near or overlying the disk, a condition that is termed neovascularization elsewhere (image not shown). Neovascularization of the disk and neovascularization elsewhere are the hallmarks of proliferative diabetic retinopathy. A patient with these features may have 20/20 vision and no warning symptoms of visual impairment. However, substantial vision loss can occur as these new vessels and the contractile fibrous tissue that eventually surrounds them grow and either bleed into the vitreous cavity or cause detachment of the retina between the level of the photoreceptors and the retinal pigment epithelium.
Scatter, or panretinal, photocoagulation is the mainstay of treatment for proliferative diabetic retinopathy. Typically, 1200 to 1600 laser burns (approximately 500 μm in size) on the retina are evenly spaced or scattered throughout the retinal tissue away from the macula, focally destroying outer photoreceptors and retinal pigment epithelium (Figure 1B and 1C). The treatment, in general, is not applied directly to neovascularization on the surface of the retina and is never applied directly over neovascularization of the disk. Rather, the treatment is thought to exert its effect by destroying pigment epithelial cells and overlying retinal tissue. The pigmented cells absorb the laser light, and the resultant heat causes cellular destruction of the outer retina.
After panretinal photocoagulation, there is improved oxygen supply to areas of inner retina that had become oxygen-deprived because of poor perfusion of inner retinal vessels. This occurs both because the choriocapillaris (the blood-vessel supply to the rods and cones and pigment epithelium) is now physically closer to the inner retina and because the highly metabolically active rods and cones are no longer present to absorb oxygen from the choriocapillaris in the area of the burns. As a result, there is a decreasing number of viable hypoxic cells in the inner retina producing VEGF and other growth factors.7 Without continuous production of VEGF, the new vessels generally regress and may disappear altogether, although stabilization of the neovascularization with no further growth also may occur. Rarely, neovascularization progresses despite laser therapy and can lead to vitreous hemorrhage or retinal detachment; in such cases, vitrectomy may be necessary to preserve or restore vision.
CLINICAL EVIDENCE
Several randomized clinical trials have evaluated the efficacy of panretinal photocoagulation in patients with proliferative diabetic retinopathy; these studies were summarized in a systematic review in 2007.8 The Diabetic Retinopathy Study enrolled 1758 patients with a visual acuity of 20/100 or better in each eye and with either proliferative diabetic retinopathy in at least one eye or severe nonproliferative diabetic retinopathy in both eyes. Each patient was randomly assigned to undergo panretinal photocoagulation in one eye, with the other eye serving as the untreated control. Panretinal photocoagulation reduced the risk of severe vision loss (defined as visual acuity of 20/800 or worse at two consecutive 4-month visits) caused by complications of proliferative retinopathy from 14.0% to 6.2% during a 2-year period6 and from 33.0% to 13.9% during a 5-year period.9
The Early Treatment Diabetic Retinopathy Study (ETDRS; NCT00000151) enrolled 3711 patients with mild-to-severe nonproliferative or early proliferative diabetic retinopathy in both eyes. Each patient was randomly assigned to undergo early photocoagulation in one eye; photocoagulation was deferred in the other eye until high-risk proliferative retinopathy was detected. At 5 years, rates of severe vision loss were 2.6% with early treatment and 3.7% with deferred treatment.4 For patients with severe nonproliferative diabetic retinopathy (typically, extensive dot and blot hemorrhages, definite areas of venous beading, or a moderate amount of intraretinal microvascular abnormalities) or with early proliferative diabetic retinopathy, panretinal photocoagulation and vitrectomy when necessary reduced the 5-year risk of severe vision loss from more than 50% if left untreated to approximately 4% of eyes and 1% of patients.10
CLINICAL USE
The current standard technique for applying panretinal photocoagulation has been elucidated in the guidelines of the Diabetic Retinopathy Clinical Research Network.11 Treatment is usually initiated on the day of diagnosis in patients with high-risk proliferative diabetic retinopathy, a finding that is considered to be an urgent clinical condition, since the risk of vitreous hemorrhage and vision loss in the short term is high if the retinopathy is not treated promptly (Table 1TABLE 1
Risk Factors for High-Risk Proliferative Diabetic Retinopathy.
).
There are no other absolute requirements (other than obtaining consent) before initiating treatment after the diagnosis has been made on ophthalmoscopy. However, a detailed retinal drawing of the neovascularization or retinal fundus photographs can be helpful in determining the response to treatment at follow-up. In addition, there are several elements of a comprehensive ophthalmologic examination that may be relevant to specific patients. For example, it is important to document the visual acuity before treatment so that any subjective changes in vision after treatment can be quantified. Since panretinal photocoagulation can affect peripheral vision, recognition of any peripheral-field defects before treatment is important. Measurement of intraocular pressure before the initiation of treatment is useful; if the pressure is elevated, it is important to differentiate unrelated open-angle glaucoma from neovascularization in the trabecular meshwork (leading to so-called neovascular glaucoma). Such neovascular glaucoma frequently can be managed by panretinal photocoagulation.
If macular edema is present and the proliferative retinopathy is considered to be less than high risk, panretinal photocoagulation often may be delayed (though only for a few weeks or months) until after macular edema has been treated, since the panretinal treatment could worsen the macular edema. The use of antithrombotic agents, including aspirin, is not a contraindication to proceeding with treatment. For patients who are acutely ill, laser therapy can be delayed until the patient is able to attend an outpatient appointment. If hemorrhage does develop, the presence of blood in the vitreous may interfere with the performance of panretinal photocoagulation, since the light energy will be absorbed before reaching the retina and the view of the retina may be compromised. In this situation, there remain the options of waiting for the hemorrhage to clear or eventually proceeding with vitrectomy.
Panretinal photocoagulation typically is performed as an outpatient procedure in the office setting. The pupil is dilated, followed by administration of a topical anesthetic. A specialized contact lens, coupled onto the cornea with an ophthalmic gel, is used to view the retina with a slit-lamp laser delivery system and to focus the laser appropriately onto the retina (Figure 2FIGURE 2
Slit-Lamp Delivery System.
).
An anesthetic injection in the retrobulbar, peribulbar, or sub-Tenon's space can be administered if the patient cannot tolerate the discomfort of the laser burns. However, such anesthesia risks perforation of the eye, hemorrhage into the retrobulbar space, or anesthetizing the extraocular muscles, resulting in a loss of the patient's ability to direct his or her gaze and thereby making it difficult to reach peripheral areas of the retina.
With a slit-lamp delivery system, a green or yellow laser with settings that produce a 500-μm spot size on the retina is typically used, with a laser exposure time of 0.07 to 0.1 seconds. Power is adjusted to produce a mildly white retinal burn. Approximately 1200 to 1600 burns are administered; the edges of the burns are distributed about 1 burn width apart (Figure 1B and 1C). The distribution of burns is planned to avoid the optic disk (to reduce the risk of thermal damage to the optic nerve) and the macula (to reduce the risk of impairing central vision). Laser burns are generally not placed within the temporal retinal vessel arcades, and the burns extend anteriorly at least to the equator of the retina (the midline between the anterior and posterior poles of the retina).
Treatment with the slit-lamp delivery system can be facilitated with an automated-pattern-delivery device that uses extremely short duration burns (0.02 to 0.03 seconds) with smaller spot sizes on the retina (approximately 250 to 300 μm); the total number of burns is increased (typically 1800 to 2400 burns) in order to cover a similar area of retinal tissue.
Instead of a slit-lamp delivery system, some ophthalmologists prefer an indirect laser system, in which a laser is applied by means of a head-mounted ophthalmoscope and a lens that is held above the eye (Figure 3FIGURE 3
Indirect Laser Delivery System.
). This technique creates a virtual (indirect) image of the retina between the lens and the ophthalmoscope. The advantages of the indirect laser system are that it does not require the placement of a contact lens on the cornea and that it can more readily penetrate vitreous hemorrhage. With this system, a spot size of 400 to 500 μm is created with an indirect lens measuring 20, 28, or 30 diopters with an exposure of 0.05 to 0.1 seconds.
Treatment with panretinal photocoagulation is completed in one or more sittings, depending on the patient's tolerance for the discomfort of the laser. The degree of discomfort ranges from mild discomfort to more severe discomfort that can be tolerated only with retrobulbar anesthesia. If more than one sitting is required, the course of therapy is usually completed within a month after the initiation of treatment. If both eyes require treatment, they can be treated on the same day, but most patients prefer to have the second eye treated at a later date (usually within a week after treatment of the first eye).
After any session of panretinal photocoagulation, the patient should be aware that vision in the treated eye will be blurry for the next several hours because of the use of bright light and placement of the corneal contact lens during treatment. In general, the patient should not drive home immediately after the treatment.
Once panretinal photocoagulation is completed, patients are advised to contact the ophthalmologist if they have pain that is not relieved by over-the-counter analgesics or if they note any substantial vision loss. If there are no problems after completion of the treatment, follow-up evaluation usually occurs within the first month and then 3 to 4 months after the completion of treatment in order to confirm that the neovascularization either regresses or stabilizes. If the neovascularization increases in size or if new areas of neovascularization develop, then additional panretinal photocoagulation is applied.
In 2011, the cost of panretinal photocoagulation was estimated to be approximately $1,080 on the basis of the average Medicare charges for this procedure in the mid-Atlantic region. One analysis calculated that the overall cost of screening and treatment for eye disease in patients with diabetes mellitus is approximately $3,190 per quality-adjusted life-year saved.12
ADVERSE EFFECTS
The most common complication of panretinal photocoagulation is the exacerbation of macular edema. In the ETDRS, in patients with such edema involving the center of the macula at baseline, an evaluation that was performed 4 months after baseline panretinal photocoagulation showed that 19% of the patients lost approximately two or more lines on a visual-acuity chart, including 11% who lost approximately three or more lines (unpublished data). Patients with diabetic macular edema involving the center of the macula appear to be more likely to have increased macular edema and loss of visual acuity in the short term after panretinal photocoagulation13 than patients without macular edema who receive such treatment.14
Because panretinal photocoagulation destroys viable retinal tissue, the procedure can cause visual symptoms related to the loss of function of the burned retinal tissue. Such symptoms include peripheral visual-field defects, reduced night vision, diminished color vision, and decreased contrast sensitivity. 15 Other possible adverse effects include choroidal effusions or choroidal detachment (<1% of cases), which may cause transient myopia or increased intraocular pressure. The most serious (but very infrequent) complications are misdirected burns or excessively intense burns, which may cause macular damage, bleeding from the choriocapillaris, or the development of iatrogenic choroidal neovascularization.16-23
AREAS OF UNCERTAINTY
Multiple studies have concluded that VEGF is a major cause of neovascularization in retinal diseases, including proliferative diabetic retinopathy.24-34 Thus, the inhibition of VEGF would be expected to reduce neovascularization in this condition. Several clinical case reports and small case series have shown that anti-VEGF therapy can result in transient regression of neovascularization in proliferative diabetic retinopathy.35-40 Although anti-VEGF treatment has been shown to reduce neovascularization, it remains unclear how many injections would be necessary to sustain this benefit and whether the risks and costs of periodic intravitreal injections would outweigh the benefits of avoiding the side effects of panretinal photocoagulation.
Intravitreal glucocorticoids also have been shown to have a beneficial effect on proliferative diabetic retinopathy.41,42 However, because of the high rate of cataract and glaucoma side effects, such treatment does not seem warranted at this time for most patients.
GUIDELINES
The American Academy of Ophthalmology's Preferred Practice Pattern for Diabetic Retinopathy,43 which is based on the Diabetic Retinopathy Study and the ETDRS (level 1 evidence), recommends panretinal photocoagulation for patients with high-risk proliferative diabetic retinopathy or a condition that is approaching high risk. On the basis of additional analyses of visual outcomes from the ETDRS, the Preferred Practice Pattern also states that for patients with severe nonproliferative diabetic retinopathy or proliferative diabetic retinopathy that is not high risk, panretinal photocoagulation should be considered before the development of high-risk proliferative retinopathy, especially in patients with type 2 diabetes. The Preferred Practice Pattern notes that in some patients with severe vitreous or preretinal hemorrhage, it may be impossible to perform panretinal photocoagulation. In other cases, neovascularization may persist despite extensive panretinal photocoagulation. In each of these circumstances, vitreous surgery may be indicated to remove hemorrhage and fibrous tissue. In such cases, panretinal photocoagulation may be performed at the time of surgery with a laser probe inserted into the middle cavity of the eye.
RECOMMENDATIONS
The patient who is described in the vignette has proliferative diabetic retinopathy in the left eye with four high-risk features, including the presence of neovascularization, severe neovascularization, and neovascularization at the disk. A small amount of vitreous hemorrhage, not seen in the fundus photograph, caused the apparent floaters and is the fourth risk factor. Prompt initiation of panretinal photocoagulation in the left eye is recommended to reduce the risk of severe loss of visual acuity. Because the patient has no macular edema, it is unlikely that vision loss from macular edema that is caused by the treatment will develop. The consent process should include a discussion regarding the risks of permanent loss of peripheral and night vision, as well as discomfort or pain during the procedure and within 24 hours after the procedure. The patient should be advised that whether the treatment is completed in one or more sittings, it is important to complete panretinal photocoagulation as soon as possible before severe vitreous hemorrhage occurs. The patient will need to return for follow-up approximately a month after panretinal photocoagulation is completed. Also, the right eye needs to be monitored approximately every 4 months for progression to proliferative diabetic retinopathy, because of the presence of severe nonproliferative diabetic retinopathy in that eye. Some ophthalmologists might initiate treatment in the right eye at this point, because with long-term follow-up, virtually all such eyes eventually need treatment.44 Finally, the patient should be reminded to work with his primary care provider to try to optimize both diabetes management and general medical care, because control of diabetes and blood pressure can influence the progression of retinopathy.45,46
Dr. Bressler reports that his institution has received grant support from Abbott Medical Optics, Alimera Sciences, Allergan, Bausch & Lomb, ForSight Labs, Genzyme, Lumenis, Notal Vision, Novartis, QLT, Regeneron, and Genentech.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
No other potential conflict of interest relevant to this article was reported.
We thank the Diabetic Retinopathy Clinical Research Network for providing background material on proliferative diabetic retinopathy and diabetic macular edema.
SOURCE INFORMATION
From the Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore (N.M.B.); the Jaeb Center for Health Research, Tampa, FL (R.W.B.); and the National Eye Institute, National Institutes of Health, Bethesda, MD (F.L.F.).
Address reprint requests to Dr. Ferris at the Division of Epidemiology and Clinical Applications, National Eye Institute, 10 Center Dr., MSC 1204, Bethesda, MD 20892, or at ferrisf@nei.nih.gov.