Perspectives on verteporfin therapy combined with intravitreal corticosteroids.

S INCE ITS APPROVAL IN 1999, photodynamic therapy (PDT) using verteporfin has become the most important strategy in the treatment of neovascular age-related macular degeneration (AMD). Verteporfin therapy has a proven benefit seen in many subtypes of choroidal neovascularization (CNV). In predominantly classic lesions, 59% of verteporfin-treated patients lost fewer than 3 lines as compared with 31% of sham-treated eyes. In patients with occult CNV with smaller lesions or lower levels of visual acuity, stable vision is seen in 51% of eyes in the verteporfin group while only 25% of sham-treated eyes maintained stable vision. Subgroup analysis suggests that verteporfin may also reduce the risk of vision loss in lesions with minimally classic features smaller than 4 Macular Photocoagulation Study disc areas. Most importantly, vision stabilization and absence of leakage activity was maintained during an extended follow-up of as long as 5 years with no relevant need for retreatment beyond 18 months. Although limited to specific subtypes of lesions, such a solid benefit has not been demonstrated so far by any other modality in the field. Clearly, the monotherapy approach is compromised by several concerns. A reduction in mean visual acuity despite treatment was observed in all treated subgroups, and this was particularly true for lesions with better visual acuity at baseline. A real improvement in visual acuity was a rare event with 9% of treated patients improving by 3 or more lines after 24 months. In occult only and minimally classic subtypes, lesions larger than 4 Macular Photocoagulation Study disc areas appeared not to benefit at all. Finally, the high number of patients requiring retreatment results in significant costs and effort for patients, treating ophthalmologists, and health care institutions. A major cause of the limitations of the monotherapy procedure may be related to the underlying photodynamic tissue effects. The vasoocclusive mechanism, triggered by selective damage to vascular endothelial cells, is not completely selective for neovascular endothelia but also affects normal choroidal vasculature. Resulting choroidal hypoxia and oxidative stress of the retinal pigment epithelium lead to increased expression of vascular endothelial growth factor as documented following verteporfin therapy in human eyes. Experimentally, PDT induced a rapid inflammatory tissue response, including infiltration with leucocytes and increased expression of cytokines, eg, intracellular adhesion molecule 1 and interleukin 6. Hence, some photodynamic mechanisms seem to enhance effects primarily associated with the pathogenesis of neovascular AMD. The pharmacologic profile of corticosteroids has the potential to simultaneously counteract AMDand PDT-related mechanisms. Steroids inhibit angiogenesis, fibrotic proliferation, and inflammatory activity by reducing the migration and activation of inflammatory cells. Upregulation of extracellular matrix protein plasminogen activator inhibitor-1 leads to a direct angiostatic effect. Steroids downregulate expression of intracellular adhesion molecules, an important stimulus in the development of CNV and an inflammatory mediator released by PDT. Moreover, intravitreal administration of triamcinolone acetate (IVTA) was efficient in treating macular edema in multiple conditions, such as diabetic maculopathy, vein occlusion, IrvineGass syndrome, and uveitis. Intravitreal administration of triamcinolone acetate given solely in neovascular AMD has a limited anatomic effect but no relevant clinical benefit. Intravitreal administration of triamcinolone acetate inhibited neovascular growth in an experimental model of laser-induced CNV. A single IVTA resulted in 55% stabilization of visual acuity but could not prevent vision decrease in 30% of patients over an 18-month follow-up. In predominantly occult lesions, CNV enlargement was reduced to 31% in the IVTA group compared with a growth rate of 70% in the control group. A single 4-mg IVTA injection in eyes with predominantly classic lesions reduced lesion growth at 3 months but failed to show any difference in vision outcome at 12 months. Following high-dose IVTA with 25 mg, visual acuity increased after each injection, but the overall effect was transient during follow-up. Author Affiliations: Department of Ophthalmology, University of Vienna, Vienna, Austria (Drs Schmidt-Erfurth and Michels); and Department of Ophthalmology, Stadt Klinikum, Karlsruhe, Germany (Dr Augustin).