Photodynamic Therapy In The Treatment Of
Neovascular Age Related Macular Degeneration

John P. Sullivan, M.D.
John P. Sullivan, M.D. is a Retina Specialist with the Florida Retina Institute.

Introduction

Age-related macular degeneration (AMD) is the leading cause of blindness in persons age 55 and older in the United States.¹ Of the 30,000,000 people over age 65 in the United States in 1990, it is estimated that 31%, or 9,400,000 people, had evidence of age-related macular degeneration. With the prediction that there will be a doubling of the United States' population over age 65 by the year 2030, AMD is a growing public health concern.

AMD is divided into two forms, non-neovascular and neovascular. The non-neovascular, or "dry" form of AMD includes the presence of drusen and abnormalities of the retinal pigment epithelium (RPE). The neovascular form, sometimes termed "wet", or "exudative", is characterized by the growth of fibrovascular tissue from the choroidal circulation through Bruch's membrane into the sub-RPE and subretinal space. The vision loss caused by the resultant subretinal fibrosis, which occurs over weeks to months, is irreversible. Although neovascular AMD occurs in only 8% of eyes with AMD, it is responsible for 85% of the severe vision loss caused by AMD. Despite advances in the management of AMD, the majority of neovascular cases are not amenable to present treatment; i.e., laser photocoagulation.

Non-neovascular AMD

Age-related macular degeneration is a degenerative process limited to the macula, or central portion of the retina. Asymptomatic patients in the early stages of AMD have evidence of drusen and areas of increased pigment, or hyperpigmentation. Drusen are yellow round spots predominantly found in the central macula. They represent an abnormal thickening of the inner aspect of Bruch's membrane. Hard drusen, (less than 63 um), do not appear to increase with age and do not appear to pre-dispose an eye to advanced AMD (Figure 1A). Soft drusen, (greater than 63 um), have ill-defined borders and vary in size and shape. Soft drusen often increase in size and number with increasing age (Figures 1B and 1C). Soft drusen are a hallmark of AMD and their presence is a significant risk factor for the development of AMD.

Focal hyperpigmentation represents clumps of pigmented cells at the level of the retinal pigment epithelium, versus pigment that has migrated to the level of the photoreceptor nuclei in the outer retina. The presence of focal hyperpigmentation, as well as a history of systemic hypertension, are additional risk factors for the development of neovascular AMD.

The late stages of non-exudative AMD include the development of geographic and non-geographic areas of RPE atrophy. ^Fig.1D Although most eyes experiencing severe vision loss with AMD do so as a result of complications of choroidal neovascularization, 5% to 10% lose central vision as a result of progressive RPE atrophy. This vision loss tends to occur slowly and progressively, as the area of atrophy enlarges. Unfortunately, this complication of AMD does not respond to treatment, leaving affected patients with a permanent central scotoma in its end stage.

Neovascular AMD

Choroidal neovascularization represents the growth of new capillaries from the choroidal circulation through disruptions in degenerated Bruch's membrane. The capillaries proliferate under the RPE and may break through to proliferate between the RPE and retina. The abnormal blood vessels leak blood products, resulting in the presence of subretinal fluid, lipid and/or hemorrhage (Figure 2).

These blood products are seen clinically. The presence of choroidal neovascularization should be suspected in any patient who complains of metamorphopsia (distorted vision), central or paracentral scotoma, or any sudden non-specific change in central vision.

If signs or symptoms of choroidal neovascularization are present, a fluorescein angiogram is performed as soon as possible to determine the presence, location, and extent of any choroidal neovascularization, prior to considering treatment. A fluorescein angiogram includes the injection of a dye into a vein in the arm, followed by multiple photographs of the retina. This allows evaluation of the retinal circulation, as well as any choroidal neovascularization, which may be present.

Choroidal neovascularization may have a variety of appearances on fluorescein angiography. The basic patterns are "classic" and "occult." Being able to distinguish the two patterns is important, since treatment recommendations and prognosis depend upon this recognition. Classic choroidal neovascularization has well demarcated boundaries in the early phase of the angiogram (Figure 3A). This is followed by leakage, blurring the edge of the membrane, in the late phase of the angiogram. These classic membranes grow in the space between the retina and the retinal pigment epithelium, allowing excellent visualization of the complete membrane on fluorescein angiogram.

The second pattern of choroidal neovascularization is termed "occult." As its name suggests, these blood vessels do not have well defined boundaries on fluorescein angiogram, making it difficult to determine the full extent of the lesion (Figure 3B). These occult membranes grow in the space between the retinal pigment epithelium and Bruch's membrane (Figure 3C). The overlying retinal pigment epithelium acts as a barrier, preventing adequate visualization of the choroidal neovascularization on fluorescein angiogram. The majority of choroidal neovascular membranes involve varying degrees of both classic and occult components.

Treatment

Most cases of choroidal neovascularization have evidence of foveal involvement on presentation. The Macular Photocoagulation Study (MPS) proved laser treatment to be beneficial for these lesions.^2-3 Unfortunately, less than 20% of patients with subfoveal choroidal neovascularization meet the eligibility criteria for laser treatment as determined by the MPS guidelines.⁴ Laser photo-coagulation is recommended only for small primarily classic membranes no larger than two disc areas in size (approximately 2.0 mm in diameter).⁵ Although laser treatment of these lesions has been shown to significantly limit the risk of visual loss when compared to no treatment, the benefits of laser treatment are limited because laser photocoagulation damages the viable neurosensory retina overlying the treated choroidal neovascularization. This treatment creates a scar with a resultant permanent blind spot. (Figure 4 A-B), The goal of laser treatment is to keep this blind spot as small as possible. Despite these efforts, 88% of treated patients have postoperative visual acuities of 20/200, or worse, at 48 months. In those eyes in which the choroidal neovascularization does not involve the fovea on presentation, the rate of recurrence of the choroidal neovascularization into the fovea following the laser treatment, may be as high as 50%.⁶

Photodynamic Therapy (PDT)

New therapies designed to reduce the risk of visual loss, or improve the chance for visual improvement in neovascular AMD, are being investigated. One such treatment that recently gained FDA approval is photodynamic therapy (PDT) with verteporfin. Verteporfin is a photosensitizing (light-activated) dye. It is complexed with low-density lipoprotein and injected intravenously. The verteporfin is taken up selectively by rapidly proliferating endothelial cells, which have an increased number of LDL receptors active in their plasma membranes. The verteporfin is then activated by a non-thermal laser light directed at the area of choroidal neovascularization. The laser light has a wave length of 689 nm corresponding to the absorption peak of the verteporfin dye. The excited photosensitizer generates singlet oxygen and reactive oxygen intermediates, resulting in damage to the endothelial cells of the abnormal vessels. This results in thrombosis and occlusion of the abnormal vessels. No thermal energy is created with treatment, preventing damage of the overlying neurosensory retina. Photodynamic therapy with verteporfin results in complete occlusion of the choroidal neovascularization for one to four weeks. In the majority of cases, however, leakage reoccurs by twelve weeks although often the area of leakage is smaller than prior to treatment (Figure 5).

Figure 5. Treatment of subfoveal choroidal neovascularization with photodynamic therapy. Figure 5A. Choroidal neovascularization prior to treatment with adjacent subretinal hemorrhage (white). Figure 5B. Choroidal neovascularization three months following photodynamic therapy. Note persistent leakage, however, decreased size of lesion with resolution of subretinal hemorrhage.

The Treatment of Age-related Macular Degeneration With Photodynamic Therapy (TAP) study investigated the benefits of verteporfin therapy, when compared to placebo for choroidal neovascular lesions up to 5.4 mm in diameter, with at least some classic component. This study reported that 61% of treated eyes, compared to 46% of eyes assigned to placebo, lost less than three lines of vision at one year. In addition, treated eyes more often had improvement of one or more lines of visual acuity than placebo (16% vs. 7%).

The benefit of photodynamic therapy is even more dramatic in the sub-group of patients in which the area of classic choroidal neovascularization occupied fifty percent, or more, of the area of the entire lesion. In this sub-group 67% of treated eyes lost less than three lines of vision at one year, compared to only 39% of untreated eyes. In contrast, no significant differences in visual acuity were noted when the area of classic choroidal neovascularization was less than 50 percent of the area of the entire lesion.

The TAP investigation reported that patients required an average of 3.4 treatments in the first year. Ocular or systemic side effects associated with verteporfin therapy are rare, the most common being transient blurred vision. Patients are instructed to stay out of direct sunlight or indoor light for five days, as they are susceptible to mild to moderate sunburn.

In summary, photodynamic therapy with verteporfin can safely reduce the risk of severe vision loss in patients with predominantly classic subfoveal choroidal neovascularization from AMD. Prompt evaluation of these patients remains vital. Should a patient experience symptoms of metamorphopsia or visual change, clinical evaluation is paramount. Early detection and treatment can significantly limit the severe vision loss that AMD might cause.

1. Klein R. Klein BEK, Linton KLP. Prevalence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology. 1992; 99:933-943.
2. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal recurrent neovascular lesions in age-related macular degeneration: results of a randomized clinical trial. Archives of Ophthalmology. 1991; 109:1232-1241.
3. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration: results of a randomized clinical trial. Archives of Ophthalmology. 1991; 109: 1220-1231.
4. Bressler NM, Bressler SB. Preventative ophthalmology, age-related macular degeneration. Ophthalmology. 1995; 102:1206-1211.
5. Macular Photocoagulation Study Group. Visual outcome after laser photocoagulation for subfoveal choroidal neovascularization secondary to age-related macular degeneration: the influence of initial lesion size and initial visual acuity. Archives of Ophthalmology. 1994; 112:480-488.
6. Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy: five year results from randomized clinical trials. Archives of Ophthalmology. 1991; 109: 1109-1114.
7. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin. Archives of Ophthalmology. 1999; 117: 1329-1345.

Jacksonville Medicine / September, 2000

What's New · Northeast Florida Medicine Journal · Know Your Physician · Legal & Legislative
· DCMS Alliance · Academy of Medicine · Member Websites · Community Health
About the DCMS · Meetings Calendar · Member Benefits · Employment Connection · Home

Duval County Medical Society   ·   555 Bishopgate Lane  ·   Jacksonville, FL  32204
Phone: (904) 355-6561   ·     FAX:  (904) 353-5848   
General Email: dcms@dcmsonline.org    ·   Webmaster's Email: mdoran@dcmsonline.org
Privacy Policy and Disclaimers