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New Treatments In Retinal Disease

Michael W. Stewart, M.D.
Michael W. Stewart, M.D. is an Assistant Professor of
Ophthalmology, Mayo School of Medicine, Mayo Clinic Jacksonville.

The past 30 years have been marked by tremendous advancements in the diagnosis and treatment of vitreoretinal disorders. Improved visualization of retinal and choroidal circulations due to the introduction of stereoscopic fundus photography with fluorescein angiography has led to significant advances in both the classification and diagnosis of posterior segment disorders. The development of laser photocoagulation and the invention of vitreous surgery have enabled the successful repair of what were previously untreatable diseases. Diabetic retinopathy used to frequently lead to near total, untreatable blindness due to vitreous hemorrhage. Today, timely panretinal photocoagulation for retinal neovascularization, followed by vitrectomy surgery when indicated, maintains functional vision in most of even the most severely affected diabetics. However, despite the improved ability to restore the vision of some patients, many other patients face unpreventable visual loss. Many conditions, such as macular degeneration, involve treatments that do not cure, but instead only stop disease progression.

Advances in pharmacology and technology over the past several years have led to the development of new treatments. These earlier and less destructive methods of intervention may improve the ultimate visual outcomes in many currently untreatable diseases. This paper will concentrate on recent medical advancements, and will discuss current investigational treatments some of which may become routine therapy in the near future.

Diabetic Retinopathy

No ophthalmologic disease has been more favorably affected by the introduction of laser photocoagulation and vitrectomy surgery than has diabetic retinopathy. The Diabetic Retinopathy Study (DRS)1 and the follow-up Early Treatment Diabetic Retinopathy Study (ETDRS)2 established the effectiveness of panretinal photocoagulation for proliferative diabetic retinopathy and focal and grid laser for macular edema. Concurrent improvements in surgical instrumentation and techniques have led to earlier interventions with correspondingly improved visual outcomes. The Diabetic Retinopathy Vitrectomy Study (DRVS)3 showed that surgery for both traction retinal detachments and vitreous hemorrhage improves visual outcome. The routine use of endolaser photocoagulation during vitrectomy surgery has led to improved visual acuity in over 85% of patients with non-clearing vitreous hemorrhage.

Despite the application of the ETDRS results to the treatment of diabetic macular edema (DME), diabetic retinopathy remains the number one cause of visual loss in the 20-65 year age group. Furthermore, timely laser photocoagulation for DME is only 50% effective in preventing visual loss and the actual rate of visual improvement is only 15%.
 

Figure 1: (Top) Right eye with untreated background diabetic retinopathy.

Figure 2: (Bottom) Same eye 3 months following vitrectomy, showing a significant decrease in fluorescein dye leakage.

 

Figure 3: Intravitreal triamcinolone
immediately after injection.

 Some eyes with DME have a taut posterior hyaloid surface or an epiretinal membrane causing co-existing macular traction. This traction is believed to cause foveal detachments and cystoid macular edema. Several authors have relieved the traction with vitrectomy and membrane stripping and reported decreased macular thickening and improved visual acuity.4 Yamamoto, et al.5 reported similar anatomic and visual results in a series of patients without hyaloid traction. Their data suggest that there may exist a subset of diabetic macular edema patients for whom vitrectomy surgery may offer hope of visual improvement when laser photocoagulation fails. Stefannson proposed a mechanism by which vitrectomy surgery transfers oxygen from high tension tissues such as the iris and ciliary body to areas of ischemic retina decreasing macular edema and improving visual acuity.6 The oxygen may facilitate autoconstriction of the retinal arterioles or decrease the production of vascular endothelial growth factor, a potent cause of vascular leakage. Many investigators are now attempting to identify the macular edema patients with the greatest chance of responding favorably to vitrectomy. (Figures 1 and 2)

Macular edema due to diabetes and other retinal vascular diseases has been found to decrease following the use of intravitreal corticosteroids. These work by decreasing the production of vascular endothelial growth factor. Martidis, et al.7 have reported improved visual acuity following intravitreal triamcinolone injections. The drug is administered in the office and is well tolerated by patients, although a major side effect is a 30% incidence of increased intraocular pressure. (Figure 3) The therapeutic effect of the steroid is typically seen within 1 week, though it often fades by 6 months, thus requiring re-injection. A more elegant, longer duration adaptation of this technique features the intraocular placement of a sustained-release flucinolone implant through the pars plana. This promising procedure is currently in early FDA phase 2 trials.

Age-related Macular Degeneration

Age-related macular degeneration (AMD) remains the leading cause of visual loss in the industrial world in patients over the age of 65 years. "Dry" macular degeneration, characterized by drusen, retinal pigment epithelial changes, and atrophy of the pigment epithelium is the most common form of AMD. The more severe "wet" form of AMD, characterized by the ingrowth of choroidal neovascular membranes beneath the retina or pigment epithelium, occurs in 10% of AMD patients but accounts for 90% of the severe visual loss. This significant, adverse impact on visual function in the elderly, combined with the increased life expectancy of the American population, makes AMD a major national health issue.

The International Classification of AMD differentiates drusen (yellow deposits beneath the retinal pigment epithelial {RPE} cell layer) from age-related maculopathy (larger, more numerous drusen with or without pigment epithelial changes) and AMD (atrophy of the RPE or choroidal neovascular membrane formation). Though drusen cause only mild visual loss, they are recognized as a risk factor for progression to macular degeneration. Low intensity, prophylactic, grid laser photocoagulation treatment of the macula has been shown to cause regression of drusen; however, some subgroups of patients respond unfavorably by developing choroidal neovascularization from the laser scar sites.8 Further randomized studies are underway to determine the long-term efficacy of prophylactic laser.

Since Newsome, et al.9 reported decreased progression of AMD in patients receiving zinc supplementation (100 mg/day), nutritional supplements have been extensively investigated. Subsequent research has studied antioxidants (beta carotene, vitamin C and vitamin E) as well as carotenoids (lutein and zeaxanthine). Study results have been mixed and definitive evidence showing the efficacy of supplements in preventing the progression of AMD was lacking until the publication of the Age-Related Eye Disease Study (AREDS) in October of 2001.10 This 5-year, double-blind, randomized study evaluated the effects of high dose zinc (80 mg/day) and antioxidant (beta carotene 16 mg/day, vitamin c 500 mg/day, vitamin E 400 mg/day) supplementation on patients with early AMD. The mild AMD baseline group (drusen and RPE changes) that consumed both zinc and antioxidants had a 25% reduction in the rate of progression to advanced AMD. The group taking zinc alone exhibited a smaller, though significant protective effect, whereas the group receiving antioxidants alone showed a trend toward less progression. Vitamin-induced side effects were rare but other studies suggest that smokers should not take beta carotene (due to the risk of lung cancer) and zinc may cause copper deficiency anemia.

Ocular photodynamic therapy (PDT) is the most important recent advance in the treatment of neovascular AMD. This treatment combines the intravenous infusion of photo-sensitive verteporfin (Visudyne) followed by low-intensity, transpupillary, infrared laser. Since its approval by the FDA in 2000, PDT has become the treatment of choice for predominantly classic, subfoveal choroidal neovascular membranes.11 Subsequent studies have also shown PDT to be effective for the treatment of 100% occult, sub-foveal neovascular membranes.12 Though treatment stabilizes many lesions, unfortunately only a small minority of patients experience any improvement in visual acuity.

The decision of treating with PDT is based solely on the leakage characteristics and size of the neovascular membrane as visualized with a fluorescein angiogram. The Visudyne dose is based upon the body surface area of the patient. The Visudyne is prepared in the office and infused over 10 minutes. Five minutes later a single 83 second application of laser is delivered. Significant treatment side effects are unusual but include transient visual loss and back pain. Due to the high risk of sunburn from Visudyne sequestration in the skin, the patient must remain indoors for 2-5 days following each treatment. Since the goal of the treatment is to close the neovascular complex while avoiding "collateral damage" of the uninvolved retina and choroid, the average patient requires 5 treatments spaced at 3-month intervals. Other photodynamic dyes with different tissue half-lives and solubilities are being tested in phase I and II trials.13

Transpupillary thermotherapy, originally introduced to treat small choroidal melanomas, is being evaluated for the treatment of subfoveal choroidal neovascular membranes. This long-duration, low-intensity, infrared laser causes mild thermal damage to the RPE, choriocapillaris and membrane with the hope of sparing the overlying retina. Early pilot studies aimed at preventing progressive visual loss appear promising and a multi-center study (TTT4CNV) is currently underway.14

Several pharmacologic approaches to suppress neovascular macular degeneration are being evaluated in early FDA trials. Anecortave, an anti-angiogenic steroid without glucocorticoid activity, is injected periocularly and VEGF inhibitors such as Rhu Fab 2 and an anti-VEGF aptamer are injected intravitreally.15-17 Early trials indicate a modest effect in suppressing neovascular progression. These drugs may be most promising as adjuvents to other treatments such as photodynamic therapy.

Surgical removal of subfoveal neovascular membranes became popular during the 1990s but most studies have failed to show that this approach gives superior results compared to the natural history of the disease.18 Macular translocation surgery, based on the premise that the overlying neurosensory retina is relatively healthy and may provide better vision if moved away from an area of choroidal neovascularization and damaged retinal pigment epithelium, has been recently developed. A limited retinal translocation procedure detaches 50% of the retina, surgically shortens the underlying choroid and sclera and moves the macula approximately 1 mm inferiorly. Laser photocoagulation of the choroidal neovascular membrane is performed in the early post-operative period. A restropective study showed that the average post-operative visual acuity remained the same as the pre-operative acuity.19 A more aggressive surgical approach creates a 360 degree peripheral retinotomy and total retinal detachment followed by manual rotation of the macula up to 3 mm from the original location.20 Both surgical techniques have resulted in some dramatic successes but their complication rates, including post-operative retinal detachment, are high. Since neither technique has been directly compared to PDT, their relative efficacies are unknown.

Retinopathy of Prematurity

Patz, et al.21 linked advanced retinopathy of prematurity (ROP) to excessive oxygen administration, causing supplemental oxygen use in premature babies to be carefully regulated. The result was an immediate, dramatic fall in the incidence of ROP. In the 1970s and 1980s improved neonatal survival particularly because of advances in the treatment of hyaline membrane disease, resulted in a second epidemic of ROP. In an effort to prevent severe visual loss due to traction retinal detachment, cryoablation treatment of the ischemic peripheral retina was performed. The Cryo-ROP study showed that cryoablation reduced the incidence of unfavorable outcomes by 50%.22 The more recent introduction of the infrared diode laser for peripheral photoablation has supplanted cryoablation, and is now viewed by most surgeons as the standard of care. Studies have shown laser treatment to be more effective than cryotherapy, with improved long-term visual outcomes.23

Despite timely laser photocoagulation, a significant number of ROP babies will become blind. The recently concluded STOP-ROP study showed that supplemental oxygen (95-99% saturation) given at 33-37 weeks corrected gestational age neither exacerbated the retinopathy nor prevented progression to threshold disease. However, the higher oxygen levels improved growth and pulmonary function, both important to the babies' development.24 These data suggest that neonatologists may safely administer supplemental oxygen as babies approach 38 weeks corrected gestational age.

Ambient light in the newborn nursery was briefly considered as a possible cause of ROP. However the Light-ROP study showed that protecting babies with 97% filtering "sunglasses" did not reduce the incidence of ROP.25 The Early Treatment for Retinopathy of Prematurity (ETROP) study is treating some high risk, pre-threshold ROP babies with laser photoablation in an attempt to further reduce the number of eyes with unfavorable outcomes.26

 
Figure 4: (Top) Small choroidal melanoma immediately
after transpupillarfy thermotherapy.

Figure 5: (Bottom) Same choroidal melanoma three
months later with only a flat scar remaining.

Choroidal Melanomas

Following the pathology study by Zimmerman, et al., much of the choroidal melanoma treatment debate for the past 40 years centered on whether enucleation or radiation resulted in better long-term survival.27 The Collaborative Ocular Melanoma Study (COMS) showed that 5-year survival for medium sized choroidal melanomas (3-10 mm thick) is the same whether the involved eye is enucleated or treated with an episcleral radioactive iodine plaque.28 Though progressive visual loss following radiation is common, when given a choice, most patients choose the eye-saving radiation technique. The COMS also showed that pre-enucleation external beam irradiation for large melanomas provides no survival advantage.29

Observation has been the traditional approach to small melanomas (1-3 mm thick). However, recent data show that 31% of small melanomas grow to medium size and 6% will metastasize within 5 years.30 Transpupillary thermotherapy now allows a non-surgical, ablative treatment for these tumors. This treatment results in full thickness necrosis of the tumor and overlying retina with a resultant flat scar. (Figures 4 and 5) Localized tumor recurrence is seen in 30% of cases though most of these can be effectively retreated.31 Tumors located in the macula, far peripheral retina or adjacent to the optic nerve are not treatable by TTT.

Macular Holes

A macular hole is a full thickness defect of the central retina causing decreased visual acuity and a dense central scotoma. The posterior hyaloid causes localized tangential traction leading to "tearing" of the macula. Macular holes were long believed to cause irreversible central visual loss until Kelley and Wendel showed that a vitrectomy with complete posterior hyaloid removal and air/fluid exchange, followed by face down positioning to tamponade the macula, closes the majority of holes resulting in improved visual acuity.32 Current surgical series report closure rates exceeding 90%.33 Many investigators have used different adjuvants (biological "glues" such as whole blood, serum, thrombin, TGF-beta) to improve the closure rate, though none has been shown to be superior to meticulous surgical technique.34

Indocyanine green (ICG), a photosensitive dye used in retinal angiography, has recently been used to stain the internal limiting membrane of the retina. ICG facilitates easy visualization and surgical removal of this thin translucent structure. Proponents of ICG claim that this technique provides relief of surface traction, improving closure rates of holes. Study data on surgical closure rates and subsequent visual outcomes are thus far inconclusive.35 However, the intraoperative use of ICG has been expanded to facilitate the removal of membranes in other disorders such as diabetic retinopathy and macular pucker.

Retinal Vein Occlusions

Retinal vein occlusions are some of the most difficult ophthalmologic diseases to treat. Traditional management of these disorders has focused upon treating the late complications of these diseases: macular edema from branch vein occlusion36 and neovascularization of the iris due to ischemic central retinal vein occlusion.37 Recent treatments have attempted to relieve the venous occlusion to restore a normal circulatory pattern.

Branch retinal vein occlusion is due to thrombosis at an arteriovenous crossing site where the artery and vein share a common adventitial sheath. Venous compression by the adjacent hypertensive artery leads to hemodynamic turbulence, thrombus formation and subsequent occlusion. Opremcak and others have described surgical decompression of the crossing site by elevating the vessels out of the retina, thus relieving the venous compression that had existed between the artery and the choroid. Some surgeons have attempted to manually separate the artery from the vein by incising the adventitial sheath. Early reports show restoration of circulation, with resolution of macular edema and improved visual acuity in some patients.38 A collaborative, randomized trial is now underway to further evaluate the surgery.

Central retinal vein occlusion is caused by venous thrombosis within the optic nerve at the level of the lamina cribosa. Two surgical approaches to restore venous circulation are currently being investigated. Weiss has developed an external fixation system that allows cannulation of the major retinal veins and high pressure infusion of a tPA solution. The results of a pilot series show impressive improvements in VA and retinal perfusion.39 Opremcak, et al. have attempted to relieve the external compressive forces on the central vein by performing a transvitreal, radial sheathotomy of the optic nerve.40 Both of these techniques are being evaluated in larger studies.

Artificial Retina

Perhaps no ophthalmic issue has captured the public's attention more than the artificial retina. A University of Illinois research group has developed a small photosensitive silicone wafer that is surgically implanted into the submacular space. This device absorbs photons and generates a low amplitude electrical signal that stimulates the overlying retina. A small number of severely visually-impaired retinitis pigmentosa patients have undergone surgery. The implant has been well tolerated by the eyes and patients have reported light sensitivity and some form recognition.41 Other researchers have developed a camera-assisted device to project images to the surface of the retina, thereby bypassing much of the damaged retinal anatomy.42

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Jacksonville Medicine / August-September 2002

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