Surgical strategies for AMD

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CHAPTER 63 Surgical strategies for AMD

Boris V. Stanzel, Frank G. Holz

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 patients ²².

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:

• Massive subretinal hemorrhages

• Breakthrough vitreous hemorrhage

• CNV refractory to anti-VEGF therapy

• (Large) pigment epithelial detachments

• RPE tears

• Advanced non-exudative AMD (GA).

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 ERG ²⁴. 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 works ²⁶.

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 63.2 ²⁷.

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.

Macular surgery for choroidal neovascularization

Surgical interventions in exudative AMD had their beginnings in excisions of subfoveal CNV ^28,²⁹, which, however, usually resulted in simultaneous removal of the RPE ‘trapped’ within the neovascular complex³⁰. Extensive loss of subfoveal RPE leads inadvertently to irreversible loss of vision³⁰. In a retrospective meta-analysis evaluating 26 different studies and a total of 647 cases of subretinal membrane excision in AMD patients, it was shown that improvement was achieved in about 33% and deterioration occurred in 27%. A mean recurrence rate of the CNV in 25% (0–55%) was found in addition, which added to further visual loss in primary successful cases³¹. In a prospective multicenter study comparing submacular surgery with laser photocoagulation, the two treatment options were found to be equivalent. After 2 years, 65% of laser treated cases versus 50% of surgically treated eyes had a visual acuity that was better than or no more than one line worse than baseline³². Therefore submacular membrane extraction alone nowadays no longer represents a promising functional outcome³¹. Photoreceptor survival requires an intact functional RPE, therefore counteracting the bystander damage during CNV extraction poses two options: (1) rotate the still functional neurosensory retina away from the RPE defect; or (2) replace the RPE defect with cell transplantation (see Fig. 63.1).

Macular translocation (MT360)

The concept of macular translocation was initially proposed by Machemer and Steinhorst ³³. Improvements of the technique have enabled some patients to retain their reading vision. Aisenbrey and associates found for a mean follow-up of 38 months, a stabilization or improvement in half of the patients³⁴. This technique involves a pars plana vitrectomy followed by 360° retinotomy and a complete retinal detachment by subretinal injection of calcium magnesium free BSS³⁵. The retina is then rotated about 45° (typically upward) around its attachment at the optic disc. Retinal reattachment is achieved by a silicone oil tamponade with subsequent circular laser photocoagulation at the margin of the retinotomy. A counter-rotation of the globe is recommended, either during the primary procedure or at the time of silicone oil removal, to avoid diplopia from cyclorotation.

Shortcomings of this procedure include a relatively elaborate surgery, secondary procedures (silicone oil removal, counter-rotation of the globe, etc.), as well as potential complications such as proliferative vitreoretinopathy (PVR), rhegmatogenic retinal detachment, macular edema, etc. Postoperative double vision is not always treated satisfactorily. The initially high complication rates of about 30% could be reduced to 8–18% in centers with more experience ³⁶^–³⁹.

Cellular replacement strategies of the RPE

The concept of RPE transplantation evolved out of promising results in animal experiments with RPE gene mutations ^40,⁴¹. Peyman et al. were the first group to transplant a patch of RPE and choroid in a patient with CNV due to AMD⁴². Since then many techniques for homologous and autologous RPE replacement have been developed^21,^24,^43,⁴⁴.

RPE-cell transplantation using an injection of cells injected into the subretinal space

Cell suspensions of homologous fetal RPE were first transplanted in humans by Algvere and associates ⁴⁵^–⁴⁷. Central retinal function, however, could not be retained in the long term, for which immune rejection was blamed. The immune privilege of the subretinal space may be compromised through pathologic changes in neovascular AMD and iatrogenic damage incurred during the transplantation^48,⁴⁹.

To avoid rejection, autologous RPE replacement strategies were pursued. Binder and coworkers were able to show, in a prospective case–control study in patients with CNV secondary to AMD, a statistically significant improvement (near vision and multifocal ERG) in the transplanted group ⁵⁰. Eighty percent of patients achieved stabilization or improved visual acuity within the follow-up of 1 year.

Following vitrectomy, RPE cells were obtained from the retinal periphery in the affected eye during the surgical procedure and injected underneath the macula; see Figures 63.1 and 63.4 ⁵¹.

Fig. 63.4 Retinal pigment epithelium (RPE) suspension transplant in exudative age-related macular degeneration (AMD). A patient with a preoperative vision of 0.05 at 2 m (ETDRS) and a large choroidal neovascularization due to AMD received a suspension of autologous RPE harvested in the nasal periphery. One month postoperatively, her vision remained stable at 0.06 at 2 m (ETDRS).

From Stanzel and Binder (Ch.50) in Nguyen, Rodrigues, Eid Farah & Mieler. Retinal Pharmacotherapy. WB Saunders; 2010, Elsevier.

In vitro studies pointed out that age-related changes in Bruch’s membrane compromise attachment and/or function of RPE ^52,⁵³. To address the latter situation, van Meurs and colleagues used poly-L lysine (a common adhesive used in cell culture) in their suspension transplants. They were not able to demonstrate an advantage of this method and observed high PVR rates⁵⁴.

RPE/choroid patch transplantation

Clinical trials with RPE/choroid patch translocations have elegantly bypassed the dilemma of cell attachment and distribution in RPE suspension therapies; potential advantages include the preservation of the physiologic monolayer, the simultaneous provision of a substrate, as well as minimizing trauma to the transplanted cells. After few weeks, choroidal vessels of most patches will anastomose with the underlying choroidal vasculature ⁵⁵.

Adapted from Stanga et al., van Meurs et al. suggested a technique where a free graft/patch of RPE/choroid is harvested from the midperiphery, and then translocated underneath the macula; see Figures 63.1 and 63.5 ^56,^57,⁶³. Many centers worldwide have now adopted this technique and confirmed fixation over the patch graft, as well as its revascularization in a high proportion of patients. It appears that preoperative macular function correlates with postoperative visual recovery (Fig. 63.5).

Fig. 63.5 Retinal pigment epithelium (RPE)/choroid patch transplant in exudative age-related macular degeneration. A 72 y/o female patient presented 20/320 (BCVA) due a massive subretinal hemorrhage in her left eye. She had a full-thickness RPE-choroid patch translocation, which in this ideal-case scenario resulted in a BCVA of 20/40 at 4 years follow-up.

Images courtesy of J. van Meurs.

Fig. 63.3 Full macular translocation in a patient with massive subretinal hemorrhage secondary to AMD. (A) Color fundus photograph shows preop situation. (B) Postop view of fundus with upward rotation of the vascular arcades and removed submacular hemorrhage.

Holz et al. suggested in a small case series a modified technique ⁵⁹, whereby choroidal vessels of the RPE/choroid-sheets are ablated with a 308 nm excimer laser. The rationale was to reduce diffusion distance from the choroidal wound bed to the graft and outer retinal layers, as well as untoward cellular reactions that would limit subsequent visual recovery. In vitro studies have demonstrated safety of the laser irradiation⁶⁰. Ma and associates then used a mechanical intraocular ablation technique⁶¹, and achieved promising results in a small case series⁶².

Visual rehabilitation in RPE patch therapies, however, suffers from frequent complication rates, of which the most common include postoperative subretinal bleeds, macular holes, PVR, fibrosis of the patch ²⁴. Overall, a mean decline of visual loss is reported if postoperative complications are included. If these cases are excluded from visual analysis, the mean gain in visual acuity is 2–3 lines²⁴. Van Meurs’ group underscored the latter correlation in a prospective statistical analysis of 48 cases⁶³. It is noteworthy that, in a single center, multiple surgeon comparison of macular translocation with patch translocation, the former yielded better long-term results⁶⁴. As long as the complication rates remain high, the possible gain of vision limits this surgical technique to cases otherwise not treatable with pharmacologic treatments⁶⁵. It is therefore encouraging that the mere mechanical ablation in analogy to Holz’ technique by Ma and associates was able to demonstrate low PVR rates (14.3%) at 1-year follow-up and good functional outcomes in exudative AMD cases complicated by subretinal hemorrhage⁶⁶.

Macular surgery for non-exudative AMD

Advanced dry AMD, i.e. geographic atrophy (GA), is the second most common cause for irreversible visual loss ⁶⁷. Effective cell-based RPE therapy would need to intervene early, ideally when the GA has yet spared the foveal region (see Fig. 63.1). In a pilot study, Algvere et al. implanted a sheet of homologous fetal RPE in four patients with GA; however, no visual improvement was reported⁴⁷. A number of surgeons performed full macular translocation (MT360) in patients with GA secondary to AMD, but only eyes with relatively short-term visual loss and preserved preoperative foveal function showed stabilization or gain of visual acuity, particularly in near vision^68,⁶⁹. A puzzling, ‘copy-paste phenomenon’ was observed after a few months in roughly 40% of all accumulated (thus far published) cases with MT360 in GA due to AMD: a new atrophic zone appeared underneath the neofovea which resembled the preoperative lesion⁶⁸.

In a case series with autologous free RPE/choroid patch grafts by Kirchhof and coworkers, the majority of GA patients with retained preop central fixation achieved stabilization or gain of visual acuity ²⁵. In patients where BM had been intentionally ruptured intraoperatively, the patch showed revascularization, which also correlated with better functional results. This series, however, was compromised by postop complications. It is noteworthy though that even in long-term follow-up (beyond 12 months) no copy-paste phenomenon had been observed, perhaps suggesting that the peripheral RPE differs in disease potential (personal communication, B. Kirchhof 9/2009).

The group around R. Aramant and M. Seiler has been perfecting a technique for co-transplantation of fetal sheets of neural retina together with RPE over the past two decades ⁷⁰. The Phase II studies have included patients with non-exudative (late stage) AMD⁷¹; none had experienced rejection of the transplants. None of the patients had improved sensitivity in postop microperimetry, which was perhaps related to bad VA at baseline⁷¹.

Upcoming trends

Stem cell derived RPE-like cells

Reports are accumulating about cells derived from mammalian stem cells which acquire RPE-like phenotypes. Six different sources (embryonic stem cells, ciliary margin stem cells, adipose mesenchymal stromal cells, neural stem cells, bone marrow derived cells, and induced pluripotent stem cells) have been reported to date, of which induced pluripotent cells (iPSC-s) hold the greatest promise ^72,⁷³. These cells behave like fetal RPE and are derived from the patient (=autologous), thus eliminating immune rejection. Virtually any somatic cell can be reprogrammed by gene transfection into a pluripotent stage to then yield cells of all tissue types upon redifferentiation⁷⁴.

Tissue engineering to reconstruct the RPE/Bruch’s membrane complex

Based on the successful proof of principle from various animal studies and some promising cases treated with macular translocation, it seems there is still more potential for surgical therapy of the macula. Future cell-based RPE therapies will be aided by the field of tissue engineering, where carrier matrices for cell transport and/or reconstruction of defective organs are already in clinical trials (see, for example, ref. 75). The concept of a prosthetic Bruch’s membrane is likewise inspired by this vastly expanding research area²¹. RPE (-like) cells are placed in vitro on a carrier matrix (i.e. Bruch’s membrane prosthesis), which encourages physiologic RPE function, facilitates implantation, and protects the graft from deleterious influences of aged submacular Bruch’s membrane. Meanwhile, over 20 different biologic as well as artificial substrates were proposed (for an overview see ref. 21). It is possible that, with optimized instrumentation, techniques, and cell sources, RPE replacement therapy will one day become comparable to current treatment standards in cataract surgery.

To date, all the surgical approaches for AMD are regarded as experimental surgery, and have to be observed carefully.

References

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3 Ciulla TA, Rosenfeld PJ. Antivascular endothelial growth factor therapy for neovascular age-related macular degeneration. Curr Opin Ophthalmol. 2009;20(3):158-165.

4 Eter N, Krohne TU, Holz FG. New pharmacologic approaches to therapy for age-related macular degeneration. BioDrugs. 2006;20(3):167-179.

5 Ambati J, Ambati BK, Yoo SH, et al. Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies. Surv Ophthalmol. 2003;48(3):257-293.

6 Fine SL, Berger JW, Maguire MG, et al. Age-related macular degeneration. N Engl J Med. 2000;342(7):483-492.

7 Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol. 2004;122(4):598-614.

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10 Klein R, Klein BE, Jensen SC, et al. The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology. 1997;104(1):7-21.