Surgical strategies for AMD

Published on 08/03/2015 by admin

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CHAPTER 63 Surgical strategies for AMD


The retinal pigment epithelium (RPE) holds the strategic position of the metabolic gatekeeper between photoreceptors and the choriocapillaries and hence plays a key role in maintaining retinal function. The RPE/photoreceptor complex suffers cumulative damage over a lifetime, which is thought to induce age-related macular degeneration (AMD) in susceptible individuals with a genetic predisposition (including dysregulation of the complement system). Two main routes of the disease occur: a slower progressing atrophic form where most patients currently have limited therapeutic options, and a potentially rapidly blinding exudative/neovascular form1,2. For the latter, intravitreal injections with anti-angiogenic drugs have now replaced laser photocoagulation or photodynamic therapies, offering a highly effective, yet palliative treatment for neovascular AMD. Still, long-term effects remain to be elucidated, and a proportion of patients lose vision despite pharmacologic therapy. A thorough review of intravitreal anti-angiogenic treatments is beyond the scope of this article; the interested reader is therefore referred to comprehensive articles on this matter (see for example, refs 3,4).

This chapter describes the current state for surgical approaches to AMD, and touches on future perspectives. Within this context, the use of the RPE cell as a ‘therapeutic agent’ is a potential strategy, as healthy RPE cells would, in theory, restore the functions of their degenerated counterparts (Fig. 63.1). The ultimate success of these cell-based therapies, however, clearly depends on delivery and maintenance of cells in a properly polarized state, capable to perform most, if not all, complex functions of the RPE. While in dire need for patients with advanced AMD, it is unlikely, in the authors’ opinion, that clinically feasible photoreceptor replacement will be achieved in the mid-term, and this aspect of retinal tissue engineering is therefore not discussed.

Epidemiologic considerations and terminology

Age-related macular degeneration is the leading cause of visual impairment in industrialized countries in patients over 50 years of age5,6. The prevalence of AMD increases with age so that up to one-third of individuals aged 75 and older suffer from some form of AMD7,8. Currently, it is estimated that 1.75 million individuals suffer from this disease in the United States and about 7 million are reported to be ‘at risk’9. Higher expectations on quality of life demanded by the expanding aging population hence result in increasingly significant morbidity from AMD10.

Clinical features

AMD is believed to be caused by progressive deterioration of RPE, Bruch’s membrane, and the choriocapillaris–choroid complex, which consequently leads to subsequent damage of the photoreceptor cells1,2,11. The hallmark of the disease and first visible changes are drusen, which present clinically on funduscopy as subretinal yellowish-white dots. According to their size and margin they are divided into hard and soft drusen. The risk for progression to advanced disease stages correlates to number, size, and density of drusen12. Soft drusen can coalesce and form pigment epithelial detachments (PED). Of these PEDs, 30–50% will become vascularized and may cause severe visual loss within the following years13. In patients with bilateral drusen and good vision in both eyes, the annual incidence of new atrophic or exudative lesions is approximately 8% over 3 years14.

In AMD, the RPE cells may become dysfunctional, which is seen in pigment irregularities with either hyper- or hypopigmentation often accompanied by drusen, which results either in the non-neovascular form with progression to geographic atrophy (‘atrophic AMD’) or in neovascular AMD (‘exudative, wet AMD’) with choroidal neovascularization (CNV) accompanied by exudation and hemorrhage, and subsequent cell death and scar formation10,15. Neovascular membranes secondary to AMD, particularly in patients on anti-coagulants, are prone to extensive bleeding into the subretinal space or vitreous. The hemorrhage in turn prevents metabolic exchange between the RPE and outer neural retina, and is retinotoxic16.

Medical treatments

Neither laser photocoagulation nor photodynamic therapy with verteporfin (Visudyne, QLT/Novartis) do usually led to visual improvement but rather a slowing of the disease process. As a result of a better understanding of molecular mechanisms, a variety of new pharmacologic treatments have recently been developed for patients with AMD. Efficacy and safety have been demonstrated for drugs targeting vascular endothelial growth factor (VEGF), a key player in the pathogenesis of choroidal neovascularization. Both bevacizumab (Avastin®, anti-VEGF antibody, Roche) and ranibizumab (Lucentis®, anti-VEGF antibody fragment, Genentech/Novartis), injected into the vitreous result in significant improvement in visual acuity, and reduction in fluorescein leakage and thinning of the retina on OCT in the majority of patients. Guidelines have been published on the management of patients with neovascular AMD using anti-VEGF therapy. Another anti-VEGF drug currently under investigation is VEGF-trap (Bayer-Schering) for which results in clinical trials seem likewise promising.

CCR3, an eosinophil/mast cell chemokine receptor, has been specifically shown to be expressed in choroidal neovascular endothelial cells in patients with CNV due to AMD. Its suppression in mouse models with induced CNV is more effective, yet less toxic than anti-VEGF treatments and it therefore represents a new, very promising therapeutic strategy in exudative AMD patients22.

Delivery of pigment epithelium-derived factor via viral vector transfection represents another potential target, as do inhibitors of matrix-metallo-proteinases.

A number of ongoing clinical trials aim at decreasing the accumulation of toxic by-products of the visual cycle in the RPE, i.e. lipofuscin compounds, to slow the progression of atrophic patches. These compounds include fenretinide and so-called visual cycle modulators.

Prophylactic measures are still limited. The combination of vitamins C and E, beta-carotene, and zinc as used in the AREDS (Age-Related Eye Disease Study) reduces risk for conversion from early- to late-stage disease in patients with high risk features, at least to some extent. Lutein and zeaxanthin dietary supplements for improvement of macular pigment density are currently being evaluated in various trials including the ongoing AREDS 2 study.

Patient selection and assessment

The most crucial factor for successful postoperative visual rehabilitation is preop macular function. Da Cruz and associates recommend, besides obtaining a history of duration of visual loss and BCVA, performing microperimetry, fixation analysis, and multifocal ERG24. High resolution, spectral domain OCT with 3D rendering allows for better assessment of subretinal pathology. The prognostic value of pre- and postop RPE autofluorescence imaging has recently been addressed, whereby a normal autofluorescence signal would indicate a functioning photoreceptor–RPE complex 24,25. Particularly for patients with primary GA of the RPE, it may serve as an important adjunct to determine remaining subfoveal RPE coverage.

Surgical techniques

Macular surgery for choroidal neovascularization

Surgical interventions in exudative AMD had their beginnings in excisions of subfoveal CNV28,29, which, however, usually resulted in simultaneous removal of the RPE ‘trapped’ within the neovascular complex30

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