Introduction

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 form^1,2. 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.

Fig. 63.1 Current surgical treatment options summary in advanced AMD. Both exudative and atrophic AMD will result in permanent visual loss if untreated. Cell-based RPE therapy represents a curative treatment option. Either the neural retina is rotated away from the diseased area (1), or functional RPE cells are delivered into the lesion (2). The latter can be achieved by means of an RPE suspension (a), full-thickness patch of RPE/choroid (b), or partial thickness patch of RPE/choroid (c).

Epidemiologic considerations and terminology

Age-related macular degeneration is the leading cause of visual impairment in industrialized countries in patients over 50 years of age^5,6. The prevalence of AMD increases with age so that up to one-third of individuals aged 75 and older suffer from some form of AMD^7,8. 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 cells^1,2,11. 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 formation^10,15. 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.

Fundamental principles

Dysfunction of the RPE may alter the extracellular environment for photoreceptors and Bruch’s membrane and thereby contribute to a variety of sight-threatening diseases including AMD. A thorough discussion of its underlying fundamental principles is beyond the scope of this article, as it encompasses factors such as, genetic polymorphisms of the complement system^17,18, accumulation of intralysosomal degradation products affecting RPE function¹⁹, autoimmune mechanisms²⁰, and Bruch’s membrane aging²¹.

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.

Indications for surgery

Most AMD patients suffer from the slowly progressive early dry form, for which there currently are no efficient therapies. Some patients will convert into neovascular AMD, which can now be successfully treated by intravitreal injection of anti-VEGF drugs. However, with long-standing disease and/or associated structural damage to the RPE and surrounding structures, treatment responses may be disappointing and warrant the search for alternative strategies. Surgical approaches in the past have included excision of CNV, and macular translocation as well removal of massive subretrinal hemorrhages. In these instances, a reconstruction of the submacular architecture or maculoplasty would represent a curative treatment^21,23. Currently discussed AMD subforms for which a surgical intervention may be considered include:

It is possible that in future with improved technique this list will (re-)expand to earlier stage AMD.

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 massive hemorrhages

Circumscribed submacular hemorrhages can sometimes be liquified by intravitreal injection of 25–75 µg recombinant tissue plasminogen activator (rt-PA) and gas, followed by face-down positioning for several days to displace the lesion peripherally. The optimal therapeutic window for this intervention is within 2 weeks after the initial event; early treatments are clearly preferable. After this time, the blood clot may begin fibrotic remodeling which can induce strong adhesions within the adjacent neural retina. All subsequent therapies become difficult and fibrinolysis no longer works²⁶.

With extensive bleeding more invasive measures may become necessary. These may encompass, depending on the extent of the hemorrhage, a vitrectomy with a paramacular retinotomy, or 180° retinotomy, removal of the hemorrhage and with subsequent gas, or silicone-oil fill of the eye; see Figure 63.2²⁷.

Fig. 63.2 Management of massive subretinal hemorrhage secondary to CNV in AMD. (A) Schematic drawing of submacular bleed in ‘face-down’ position. (B) Instilling a mixture of gas and rtPA is in the vitreous will result in centrifugal displacement of the hemorrhage, if patient maintains ‘face-down’ position. (C & D) Example of a subretinal hemorrhage treated by pneumatic displacement and rtPA lysis.