P ERSPECTIVE Pathogenesis of Lesions in Late Age-related Macular Disease FRANK G. HOLZ, DANIEL PAULEIKHOFF, RONALD KLEIN, AND ALAN C. BIRD ● PURPOSE: To review the evidence that exists concern- ing the pathogenesis of lesions in late age-related macular disease (AMD). ● DESIGN: Review of the literature. ● METHODS: A review of both experimental evidence and clinical observations that address these problems. ● RESULTS: There is good evidence that choroidal neo- vascularization (CNV) is due to a change in the balance of growth factors derived from the retinal pigment epi- thelial basolateral plasma membrane domain (retinal pig- ment epithelium). Retinal angiomatous proliferation may also have a similar pathogenesis involving the apical domain. Detachment of the retinal pigment epithelium is likely to be a consequence of increased resistance of the Bruch membrane to water flow due to deposition of lipids. Geographic atrophy is preceded by accumulation of autofluorescent material in the retinal pigment epithe- lium and possible causal relationships between the two have been demonstrated. ● CONCLUSION: There is increasing understanding con- cerning the sequence of events that lead to those lesions causing loss of central vision in AMD. Therapeutic approaches that address the underlying mechanisms are more likely to succeed than current treatment options. Such an approach has already been initiated in the management of choroidal neovascularization. (Am J Ophthalmol 2004;137:504 –510. © 2004 by Elsevier Inc. All rights reserved.) I N HIS 1967 MONOGRAPH GASS 1 WAS THE FIRST TO MAKE a serious attempt to reconstruct the events leading to loss of central vision due to disciform macular degener- ation. It was evident that blood vessels penetrating the Bruch membrane from the choroid was the initiating event, and numerous treatments have been directed to- ward destroying the blood vessels. Until recently these were physical means such as the use of heat in photoco- agulation 2,3 or free radical generation by ionizing radiation or illumination of photosensitizing dyes. 4 It was hoped that it would be possible to destroy the new vessel complex but not the retinal pigment epithelium upon which survival of the photoreceptor cells and therefore preservation of vision depends. Surgical approaches include the removal of subfoveal neovascular tissue 5 with or without retinal pig- ment epithelium cell transplantation, as well as transloca- tion of the fovea over adjacent healthier retinal pigment epithelium. These treatments have been largely disap- pointing because new vessel growth often continues and in general the visual outlook is poor. Recently, treatments have been introduced that are based on knowledge of the biologic mechanisms that cause new vessels to grow. It is hoped that they will be much more selective in their physiologic influences and result in better visual outcomes than can be expected with current treatment. In this paper we attempt to reconstruct the events that lead to late lesions causing visual loss in age-related macular disease (AMD) including neovascularization, pig- ment epithelial detachments, and geographic atrophy on the basis of current evidence. NEOVASCULARIZATION THERE IS EVIDENCE TO SUGGEST THAT AN IMBALANCE OF growth factors induces growth of blood vessels inward from the choroid (Figure 1). 6 Vascular endothelial growth factor (VEGF) that stimulates growth and pigment epithelial- derived factor (PEDF) that suppresses growth have re- ceived the greatest attention. In humans with choroidal neovascularization there is an increased level of VEGF and reduction of PEDF. In experimental choroidal neovascu- larization caused by photocoagulation new vessel growth occurs in the first few days following photocoagulation. Within a few weeks the retinal pigment epithelium covers the inner surface of the lesion and the new vessels close down. During the growth phase there is increase in both the level and retinal pigment epithelium expression of VEGF and reduction of PEDF. During spontaneous reso- Biosketches and/or additional material at www.ajo.com Accepted for publication Nov 5, 2003. From the Department of Ophthalmology (F.G.H.), University of Heidelberg, Heidelberg, Germany; the Department of Ophthalmology (D.P.), St. Franziskus Hospital, Mu ¨nster, Germany; the Department of Ophthalmology and Visual Sciences (R.K.), University of Wisconsin Medical School, Madison, Wisconsin; and the Department of Clinical Ophthalmology (A.C.B.), Institute of Ophthalmology, University Col- lege London, London University, London, United Kingdom. Inquiries to Alan C. Bird, MD, Department of Clinical Ophthalmol- ogy, Institute of Ophthalmology, University College London, London University, City Road, London EC1V 2PD, United Kingdom; e-mail: alan.bird@ucl.ac.uk © 2004 BY ELSEVIER INC.ALL RIGHTS RESERVED. 504 0002-9394/04/$30.00 doi:10.1016/j.ajo.2003.11.026