Photodynamic therapy (PDT) is a treatment modality designed to selectively occlude ocular choroidal neovascular tissue. The therapy is a 2-step process, consisting initially of an injection of the photosensitizer verteporfin, followed 15 minutes later by laser treatment to the targeted sites of neovascularization in the retina. The laser treatment selectively damages the vascular endothelium. Patients may be re-treated if leakage from choroidal neovascularization (CNV) persists.
Severe vision loss can occur with ocular neovascularization, the growth of abnormal blood vessels in the retina or choroid. Neovascularization occurs in a number of ocular diseases, including age-related macular degeneration (AMD). Available therapeutic options for CNV include photodynamic therapy (PDT), antioxidants, thermal laser photocoagulation, corticosteroids, and vascular endothelial growth factor (VEGF) antagonists or angiostatics. The safety and efficacy of each treatment depends on the form and location of the neovascularization. For those whose visual losses impair their ability to perform daily tasks, low-vision rehabilitative services offer resources to compensate for deficits.
Prior to the availability of photodynamic therapy, CNV was treated with photocoagulation using either argon, green, or infrared lasers. This conventional photocoagulation was limited to extrafoveal lesions due to the risk of retinal burns. Introduction of a scotoma or enlargement of a pre-existing scotoma, with or without visual acuity loss, is an immediate and permanent effect of photocoagulation surgery. Because of the loss of vision associated with laser photocoagulation, photocoagulation is no longer recommended as the initial treatment of subfoveal neovascularization. More recently, infrared lasers used at a low-power setting have been investigated as a technique to photocoagulate subfoveal lesions.
Combining PDT with angiostatic agents, either concurrently or sequentially, has a biological basis and is under active investigation. Angiostatic agents block some stage in the pathway leading to new blood vessel formation (angiogenesis). Drugs currently under study target various parts of the angiogenic pathway: messenger RNA (ribonucleic acid); vascular endothelial growth factors (VEGFs); and endothelial cell proliferation, migration, and proteolysis. The angiostatic agents being studied in trials include pegaptanib, ranibizumab, bevacizumab, anecortave acetate, squalamine, vatalanib, and triamcinolone acetonide. In contrast to palliative treatments for CNV (e.g., thermal photocoagulation and photodynamic therapy), they are potentially disease modifying by inhibiting the development of newly formed vessels.
Intravitreal triamcinolone acetonide was one of the first pharmacologic compounds evaluated for the treatment of choroidal neovascularization secondary to AMD. The most important effects of this treatment consist of the stabilization of the blood-retinal barrier and the down-regulation of inflammation. Triamcinolone acetonide also has anti-angiogenic and anti-fibrotic properties and remains active for months after intravitreal injection.
Age-Related Macular Degeneration (AMD)
AMD is a painless, insidious process. In its earliest stages, it is characterized by minimal visual impairment and the presence of large drusen and other pigmentary abnormalities on ophthalmoscopic examination. As AMD progresses, 2 distinctively different forms of degeneration may be observed. The first, called the atrophic or areolar or dry form, evolves slowly. Atrophic AMD is the most common form of degeneration and is often a precursor of the second form, the more devastating exudative neovascular form, also referred to as disciform or wet degeneration. The wet form is distinguished from the atrophic form by serous or hemorrhagic detachment of the retinal pigment epithelium and the development of CNV, sometimes called neovascular membranes. Risk of developing severe irreversible loss of vision is greatly increased by the presence of CNV. The pattern of CNV, as revealed by fluorescein or indocyanine angiography, is further categorized as classic or occult. For example, classic CNV appears as an initial lacy pattern of hyperfluorescence followed by more irregular patterns as the dye leaks into the subretinal space. Occult CNV lacks the characteristic angiographic pattern, either due to the opacity of coexisting subretinal hemorrhage or, especially in CNV associated with AMD, by a tendency for epithelial cells to proliferate and partially or completely surround the new vessels. Interestingly, lesions consisting only of classic CNV carry a worse visual prognosis than those made up of only occult CNV, suggesting that the proliferative response that obscures new vessels may also favorably alter the clinical course of AMD.
Polypoidal Choroidal Vasculopathy
Polypoidal choroidal vasculopathy arises primarily due to abnormal choroidal circulation, resulting in characteristic lesions comprising well-defined vascular networks of vessels ending in polyp-like structures. A less common subtype is polypoidal CNV, and it may be considered a subtype of AMD. Eyes that develop a cluster of grape-like polypoidal dilations are at high risk for severe vision loss.
Presumed Ocular Histoplasmosis
Presumed ocular histoplasmosis may be the second most common cause of blindness in patients younger than 50 years of age in certain endemic areas (the Ohio and Mississippi River Valleys in the United States). It is a condition characterized by a positive skin test for histoplasmosis, miliary opacities of the lungs, tiny choroidal scars, peripapillary disruption of the choriocapillaris, and exudation or hemorrhage from choroidal lesions in or near the macula. The condition is asymptomatic and benign, unless the choroidal neovascular lesions, which may develop many years after chorioretinal scarring has taken place, affect the macula.
Pathologic myopia refers to an abnormal elongation of the eye associated with severe near-sightedness. It generally occurs among people over 30 years of age and can result in a progressive, severe loss of vision, frequently related to the development of CNV.
Central Serous Chorioretinopathy
Central serous chorioretinopathy refers to an idiopathic disease in which there is a serous detachment of the macula due to leakage of fluid from the choriocapillaris through the retinal pigment epithelium. This condition is avascular; however, neovascularization can occur as a secondary complication. Although central serous chorioretinopathy often resolves spontaneously in 3 to 4 months, chronic or recurrent central serous chorioretinopathy can result in progressive decline of visual acuity. Central serous chorioretinopathy has been treated with medication and laser photocoagulation, but these treatments have limited efficacy.
Choroidal hemangioma is an uncommon, benign vascular tumor, manifesting as an orange-red mass in the posterior pole of the eye. Visual loss may be progressive and irreversible because of chronic foveal detachment.
Angioid streaks are dehiscences in Bruch’s membrane and occur in patients with some systemic diseases such as pseudoxanthoma elasticum, Paget’s disease of bone, or sickle hemoglobinopathy. Vision loss in eyes with angioid streaks occurs most frequently as a result of CNV.
CNV can occur as a complication of inflammatory conditions such as uveitis, multifocal choroiditis, and panuveitis, and punctate inner choroidopathy. About one-third of patients develop choroidal neovascularization, which can result in severe vision loss if it is subfoveal.
There is currently one intravenous photodynamic therapy (PDT) agent that has received approval by the U.S. Food and Drug Administration (FDA), verteporfin (Visudyne®, Novartis). The FDA-approved indications include the treatment of predominantly classic subfoveal CNV due to age-related macular degeneration (AMD), pathologic myopia, and presumed ocular histoplasmosis. The label notes that there is insufficient evidence for verteporfin use in predominately occult subfoveal CNV, and it is contraindicated in patients with porphyria.
In addition, the FDA labeling for verteporfin indicates that the physician should re-evaluate the patient every 3 months and, if choroidal neovascular leakage is detected on fluorescein angiography, therapy should be repeated. However, the total number of treatments is not addressed by the FDA. Evidence defining when treatment should stop is not available, but expert opinion (convened by Novartis, Visudyne manufacturer) suggested stopping “when the situation is judged to be ‘futile’” (Verteporfin Roundtable Participants 2005). FDA labeling states “safety and efficacy of Visudyne beyond 2 years have not been demonstrated.” (50)