detachments. Frequent retreatments are necessary to maintain efficacy.

The observation has been made that AMD may be a predictor of stroke and in the last 3 years, the tertiary intervention for AMD-related CNV has shifted from a predominantly laser-based treatment approach to a more targeted pharmacotherapeutic approach. The pharmacotherapy is superior to laser-based treatment in many patients with AMD-related CNV, allowing for better outcomes in visual acuity and retinal anatomy and is a treatment available to neovascular AMD patients who were previously poor candidates for laser-based therapy. However, access to treatments such as ranibizumab and bevacizumab that block vascular endothelial growth factor remains limited or non-existent in some countries. Recent concerns about systemic toxicity including a cerebrovascular accident could theoretically limit the use of antiVEGF therapies in patients who are at a high risk of arterial thromboembolic events. When anti-VEGF therapies are available, retina specialists are faced with many difficult management questions: deciding whether to switch patients from other therapies; determining when re-treatment is indicated; and selecting whether or not to combine therapies. Physicians ought to know which patients treated with PDT are at the highest risk of recurrence, possibly warranting closer follow-up and/or earlier intervention. Although the literature includes several suggestions for decreasing follow-up intervals (after PDT and even more after anti-VEGF) once relative stability has been achieved, exudative AMD remains a lifelong condition. Therefore, information on PDT monotherapy for AMD is still clinically relevant. Cardiovascular events have potential implications for intravitreal anti-VEGF therapies.

The use of combination therapy, involving manipulation of multiple aspects of the angiogenesis cascade, is being investigated in patients with AMD-related CNV. Providing rapid and sustained improvement in vision and function while reducing the risks and treatment burden of administering pharmaco-monotherapy may be the way ahead for the very near future. While pharmacotherapy has helped tremendously in the care of these patients with VEGF-mediated disease, longterm goals in the management of AMD will also need to address other sequelae, such as vision-limiting macular ischemia, atrophy, and subretinal fibrosis in those

patients with disease that is nonresponsive to antiVEGF agents or those patients with inactive but advanced disease. Caution still needs to be exercised, as the long-term risks of nonselective VEGF blockade are entirely unknown. Given the potential neuroprotective role of VEGF, in theory, complete and sustained VEGF blockade might result in long-term vision loss in AMD-related CNV.

13.8Perspectives

Anti-vascular endothelial growth factor A antibodies have revolutionized the treatment of AMD-related CNV [11]. Adding selective verteporfin therapy may increase the number of patients experiencing angiographic and functional improvement. A number of approaches tackling VEGF are under evaluation. However, VEGF is not only a potent angiogenic and permeability inducing factor, but is also essential in maintaining normal vascular structures [12]. Inhibiting a physiological angiogenic response secondary to choriocapillary hypoxia after standard PDT may prevent choriocapillary recanalization and lead to more extensive and persistent choriocapillary closure.

Improvement in the effective treatments of CNV secondary to AMD is the goal, while expecting customized therapies that should offer a more efficacious intervention. VEGF is not the only contributor to angiogenesis, and may play a further role in combination therapy. Steroids in the treatment and prevention of CNV have shown promise in controlled trials. A variety of molecules acting on non-VEGF pathways may emerge soon. At this time, there is no algorithm to select a particular therapy to which a specific patient may respond best. The great advantage is that therapy can be tailored to address not only the specific characteristics of a patient’s disease (i.e., minimally classic or predominantly classic lesions), but the patient’s personal circumstances as well.

The developments discussed here as well as the future advances, are built upon the strengths of their predecessors, continually improving the effective treatment of CNV secondary to AMD. Several authors have noted that as our therapeutic options increase, retina specialists are increasingly resembling our colleagues in oncology: combining therapies to attack

disease from multiple pathways and switching therapies when medications are no longer effective at holding disease at bay. It is worthwhile to note that both PDT and anti-VEGF antibodies were initially developed with oncological applications in mind. The promise of combination therapy to synergistically target multiple branches in the pathogenesis of CNV remains a powerful idea [13].

However, all of these tremendous advances are focused on exudative AMD, with a major improvement in visual acuity (and no more stabilization). The road to curing AMD still seems long.

treatment of neovascular AMD, following improvements in visual acuity reported with the intravitreal antivascular endothelial growth factor (VEGF) therapy ranibizumab. Alone or combined, these pioneers not only opened the way for improvement of clinical knowledge, for sophisticated diagnostic technologies, for bustling research activity, but may be of efficient help in desperate cases.

Summary for the Clinician

›The two first treatments for choroidal neovascularization due to age-related macular degeneration attempted to achieve the closure of the new vessels. Laser photocoagulation was the first breakthrough to stop the progression of the vessels before the destruction of the central vision. Despite the limited cases amenable to this approach (extraand juxta-foveal classic CNV), the high recurrence rates in the first year, and the destructive effects on the retinal pigment epithelium and neural retina, some patients treated 30 years ago were able to read for the rest of their life time. With the diagnostic refinements available today, this historical treatment can be considered in particular cases.

›The next step was already close to pharmaco-

logical treatment. Photodynamic therapy 10 years later enlarged the number of eligible patients (30% to 50%), the clinical forms responding to this procedure (classic, occult, minimally classic, predominantly classic CNV) and the subfoveal location. Verteporfin photodynamic therapy (VPDT) has been shown to inhibit leakage of blood and fluid from CNV, and has been an effective alternative option to thermal laser.

›Both these treatments demonstrated a statistical efficacy in well-designed randomized clinical trials. The best result they can achieve is vision stabilization. There has been a recent paradigm shift in the favored standard-of-care

References

1. Kang SJ, Schmack I, Benson HE, Grossniklaus HE (2007) Histopathological findings in postmortem eyes after photodynamic therapy for choroidal neovascularisation in agerelated macular degeneration: report of two cases. Br J Ophthalmol 91:1602–1606

2.Verteporfin Roundtable Participants (2005) Guidelines for using verteporfin (Visudyne) in photodynamic therapy for choroidal neovascularization due to age-related macular

degeneration and other causes: update. Retina 25:119–134 3. Virgili G, Bini A (2007) Laser photocoagulation for neovas-

cular age-related macular degeneration. Cochrane Database Syst Rev 18(3):CD004763

4.Kaiser PK (2006) Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: 5-year results of two randomized clinical trials with an open-label extension: TAP report no. 8. Graefes Arch Clin Exp

Ophthalmol 244:1132–1142

5. Kaiser PK, Visudyne In Occult CNV (VIO) study group (2009) Verteporfin PDT for subfoveal occult CNV in AMD: two year results of a randomized trial. Curr Med Res Opin 25:1853–1860

6. Azab M, Boyer DS, Bressler NM, Visudyne in Minimally Classic Choroidal Neovascularization Study Group et al (2005) Visudyne in Minimally Classic Choroidal Neovascularization Study Group. Verteporfin therapy of subfoveal minimally classic choroidal neovascularization in age-related macular degeneration. 2-year results of a randomized clinical trial. Arch Ophthalmol 123:448–457

7. Augustin AJ, Scholl S, Kirchhof J (2009) Treatment of neovascular age-related macular degeneration: current therapies. Clin Ophthalmol 3:175–182

8. Michels S, Hansmann F, Geitzenauer W, Schmidt-Erfurth U (2006) Influence of treatment parameters on selectivity of verteporfin therapy. Invest Ophthalmol Vis Sci. doi:10.1167/ iovs.05-0354

9. Maberley D, Canadian Retinal Trials Group (2009) Photodynamic therapy and intravitreal triamcinolone for neovascular age-related macular degeneration: a randomized clinical trial. Ophthalmology 116:2149–2157

10.Pauleikhoff D (2005) Neovascular age-related macular degeneration: Natural history and treatment outcomes.

Retina 25:1065–1084

11. Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, Sy JP, Schneider S, ANCHOR Study Group (2006) Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 355:1432–1444

12.Shah GK, Sang DN, Hughes MS (2009) Verteporfin combination regimens in the treatment of neovascular age-related macular degeneration. Retina 29:133–148

13. Emerson MV, Lauer AK (2008) Current and emerging therapies for the treatment of age-related macular degeneration. Clin Ophthalmol 2:377–388

Core Messages

›Vascular endothelial growth factor (VEGF) refers to several factors and isoforms that bind to distinguished receptors, which initiate different pathways and modulate a multitude of complex mechanisms including neovascularization.

›Angiogenesis and vascular permeability play an essential role in ocular neovascularization.

›The VEGF pathway can be inhibited at different sites including the synthesis of the factor and its receptors, the released factor itself, its binding to the receptors, its intracellular cascade and its upstream effects.

›New developments and drugs targeting core processes of the intracellular signaling are expected to be more effective but with a higher risk proÞle.

14.1Introduction

Angiogenesis is a physiological and vital process. Under certain circumstances, however, it may reßect a pathological situation and is referred to as neovascularization. This may occur in neoplastic diseases or as a

S. Grisanti (*) ¥ J. LŸke ¥ S. Peters

Department of Ophthalmology, The University of Luebeck, Luebeck, Germany

e-mail: salvatore.grisanti@uk-sh.de; julia.lueke@uk-sh.de; swaantje.peters@uk-sh.de

reaction to a changing microenvironment such as under hypoxic or inßammatory conditions. Neovascular processes within the ocular system risk affecting the visual function and potentially lead to blindness or even loss of the organ. Many studies have identiÞed VEGF (vascular endothelial growth factor) as one major player in ocular neovascularizations. Inhibition of VEGF, therefore, was successful both as a concept and in clinical practice. This recent therapeutical strategy for the neovascular form of AMD, however, is only the Þrst step in this new concept. Besides the drugs that have already been introduced into clinical practice, new medications and strategies are being tested in order to inhibit VEGF and its functions in different ways.

14.2Vascular Endothelial Growth Factor (VEGF)

VEGF-A (hereafter called VEGF) is the best-examined representative of the VEGF-platelet-derived growth factor (PDGF) supergene family. This also includes VEGF-B, VEGF-C, VEGF-D, VEGF-E (a virally encoded protein) and placental growth factor (PlGF), which all show varying degrees of homology with VEGF (Fig. 14.1). Alternative splicing of the VEGF gene results in the generation of four major homodimeric polypeptides and other less frequent splice variants with different biological activities. The four dominant VEGF isoforms of 121, 165, 189, and 206 amino acids contain consensus signal sequences for secretion. Depending on their binding domains, these isoforms are more or less soluble. VEGF121 is a freely diffusible protein; VEGF165 has an intermediate binding afÞnity via its heparin-binding sites. VEGF189 and

Fig. 14.1 Vascular endothelial growth factor (VEGF)-A belongs to the VEGF-platelet-derived growth-factor (PDGF-) supergene family and is divided into different subgroups

VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, PIGF

VEGF-A110, VEGF-A121, VEGF-A143, VEGF-A165, VEGF-183, VEGF-A189, VEGF-A206

Fig. 14.2 VEGF-A121, -A165, -A189 and ÐA206 are the four dominant isoforms.

These differ in their dependence on different binding domains inßuencing their solubility

Fig. 14.3 The members of the VEGFPDGF supergene family bind to different receptors

VEGF206 contain heparin and heparan-sulfate binding domains with additional stretches of basic residues, leading to their nearly complete sequestration in the extracellular matrix (Fig. 14.2). Furthermore, proteolytic processing of VEGF splice variants affects their ability to interact with receptor-related structures [1].

The VEGF family members bind with different afÞnities to three related receptor tyrosine kinases (RTK). VEGF binds mainly to VEGFR-1 (Flt-1) and VEGFR-2 (KDR, Flk-1) (Fig. 14.3). Of the two, it is now generally agreed that VEGR-2 is the major mediator of the mitogenic, angiogenic and permeability-enhancing effects of VEGF. It is considered to be a crucial signal transducer in both physiological and pathological angiogenesis. VEGFR-1 is supposed to function at least partially as a

ÔdecoyÕ receptor on endothelial cells sequestering VEGF to prevent it from binding to VEGFR-2 and induction of biological activities. VEGFR-1 also mediates VEGFtriggered migration of inßammatory cells. Additionally, several co-receptors, such as neuropilins and heparansulfate proteoglycans, appear to inßuence activation of VEGFRs [2].

The multitude within the VEGF family and the VEGF-A isoforms as well as their related receptors and intracellular pathways indicates the complexity of actions associated with VEGF. Both, physiological and pathological factors are Þnely tuned. VEGFR is crucially involved in the embryonic vascular development (vasculogenesis) as well as blood-vessel formation (angiogenesis) in the adult. Additionally, it