Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

vSMC induction

Figure 70.3  The role of platelet-derived growth factor (PDGF)-B in the development of vessel walls. Undifferentiated mesenchymal cells (gray) surrounding the newly formed endothelial tube (yellow) are induced to become vascular smooth-muscle cells (vSMC) and to assemble into a vascular wall (red). During vessel growth and sprouting, PDGF is released by the endothelium to drive vSMC proliferation and migration. In mice lacking PDGF-B or PDGFR-ß, there is reduced vSMC proliferation and migration, which results in vSMC hypoplasia of larger vessels and pericyte deficiency in capillaries. (Reproduced with permission from Hellstrom M, Kalen M, Lindahl P, et al. Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 1999;126:3047–3055.)

led to additional reductions. In contrast, blocking PDGF-B had little effect on developing or established neovascularization in a model of CNV, whereas VEGF inhibition significantly reduced the growth of new vessels; the most potent inhibition was again observed when both factors were inhibited. Finally, PDGF-B blockade of established corneal neovascularization between days 10 and 20 postinjury led to detachment of mural cells from corneal neovessels (Figure 70.4A) while PDGR-B blockade immediately following corneal injury did not significantly reduce neovascularization; in contrast, blocking VEGF led to a significant inhibition in the growth of new vessels. In established vessels, the combination led to the regression of pathological vessels. When both factors were blocked there was a significantly greater reduction than with VEGF inhibition alone (Figure 70.4B).11 In these models, inhibition of PDGF-B signaling led to pericyte depletion in retinal and corneal vessels, but not in quiescent adult limbal vessels,11 suggesting that therapies which block both VEGF and PDGF-B are more likely to

Pathophysiology

achieve regression of both established and developing ocular neovascular lesions.

Fibroblast growth factor 2

Experimental models have not clearly defined the role of fibroblast growth factor 2 (FGF2; also known as basic FGF) in ocular neovascular disease. While studies have demonstrated the presence of FGF2 in surgically removed CNV membranes,31 other studies suggest that FGF overexpression is insufficient in itself to provoke CNV in the absence of an additional stimulus such as cell injury.32,33

Tumor necrosis factor-α

The role of tumor necrosis factor-α (TNF-α) in ocular neovascularization is not fully understood; it may contribute to angiogenesis indirectly by promoting leukostasis in neovascular tissues34 and by inducing expression factors such as VEGF, Ang1, and Ang2.35 Although intravitreal administration of infliximab, an anti-TNF-α monoclonal antibody, reduced the formation of laser-induced CNV in a rat model,36 findings with ischemia-induced retinopathy models in knockout mice were inconclusive. In mice lacking TNF-α expression there was no reduction in neovascularization with respect to wild-type mice,34 while mice lacking TNFreceptor p55 had a reduction in ischemia-induced neovascularization.37 These apparent contradictions in results may reflect differences in experimental methodology.

Angiopoietins 1 and 2

Ang1 and Ang2 are factors that act as ligands for Tie2, a receptor tyrosine kinase. Ang1 binds to and induces the phosphorylation of Tie2 whereas Ang2 usually behaves as an antagonist of Ang1 and Tie2 (reviewed by Eklund and Olsen38). Both Ang1 and Ang2 have been found to colocalize with VEGF in neovascular proliferative membranes of patient eyes.39

Ang1 is produced by vascular smooth-muscle cells.40 Experimentally induced elevations in Ang1 in rodents caused reductions in retinal vascular leukocyte adhesion, endothelial cell damage, and blood–retinal barrier breakdown in a diabetic retinopathy model,41 suppressed the development of CNV following laser wounding, and inhibited VEGFmediated breakdown of the blood–retinal barrier in response to ischemia42; however, Ang1 had no effect on established neovascularization.43

Ang 2, which is produced by endothelial cells and is prominently expressed at sites of vascular remodeling,38 is believed to serve primarily as an antagonist to Ang1/Tie2 during angiogenesis.44 Studies suggest that Ang2 functions as a promoter of angiogenesis, mainly in combination with VEGF,45 and induces vascular regression when VEGF levels are low.46 Thus, the bulk of evidence suggests that Ang1 acts largely to inhibit the development of neovascularization whereas Ang2 acts to destabilize the vascular endothelium, making it more responsive to factors such as VEGF (Figure 70.5).47

Notch

Notch (named for a mutant fruit fly with notched wings) is a 300kDa transmembrane receptor that is involved in the development of a wide range of tissues; it is cleaved on activation, releasing an intracellular domain that activates

Notch-targeted genes (reviewed by Lai48). Angiogenesis occurs when specialized endothelial cells known as tip cells lead the migration of vascular sprouts in response to a concentration gradient of VEGF; tip cells express high levels of VEGF receptor-2 (VEGFR-2) and PDGF-B.49 Activation of Notch signaling upon interaction with the delta-like ligand-4 (Dll-4) restricts tip cell formation, thus establishing correct sprouting and branching patterns.50 Consistent with these findings, overexpression of Dll4 in endothelial cells was found to reduce their expression of VEGFR-2 and inhibit their migratory and proliferative responses to VEGF.51 There is little information available at present regarding a potential role for Notch in ocular neovascularization, however.

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Ephrins

The ephrins and their ligands, the Eph receptor kinases, regulate vessel patterning during angiogenesis.52 There are two subclasses, ephrinA/ephrinB, and EphA/EphB, each with many members (reviewed by Zhang and Hughes53). All ephrins are membrane-bound proteins; ephrinBs, but not ephrinAs, possess a cytoplasmic signaling domain that mediates forward or reverse signaling (Figure 70.6) (reviewed by Dodelet and Pasquale54). A role for EphrinA/EphA interactions in ocular neovascularization is unclear at present so this section will focus on the role of EphrinB/EphB interactions in angiogenesis.

Quiescent/resting vasculature

Ang-1 / Ang-2

Activation / WRB release

Ang-1 / Ang-2

Activated/responsive vasculature

Figure 70.5  Ang-Tie functions in the regulation of quiescent and activated vasculature. The quiescent, resting endothelium (upper) has an antithrombotic and antiadhesive luminal cell surface. Ang1 (shown as multimeric: white), is secreted by periendothelial cells at a constitutive low level. By acting on the endothelium to maintain low-level Tie2 phosphorylation, Ang1contributes to maintaining the vascular endothelium in the resting state. Ang2 (dimeric: gray) is stored in endothelial cell Weibel–Palade body (WPB) of the quiescent vasculature. Endothelial cell activation (lower) involves the release of the endothelial cell WPBs, and concomitant liberation of a variety of stored factors, including Ang2. The resultant Ang1/Ang2 ratio is now biased more in favor of Ang2, leading to endothelial destabilization, and making the endothelial cell layer more responsive to other stimuli, including proinflammatory cytokines. (Reproduced with permission from Pfaff D, Fiedler U, Augustin HG. Emerging roles of the Angiopoietin-Tie and the ephrin-Eph systems as regulators of cell trafficking. J Leukoc Biol 2006;80:719–726.)

EphrinB2 is preferentially expressed on arteries,55 whereas the receptor EphB4 is preferentially expressed on veins56; this expression pattern is believed to be a key determinant of venous and arterial identity. Forward signaling following binding of ephrin B2 to EphB4 usually leads to reduced proliferation and migration of EphB4-expressing cells, while reverse signaling promotes increased proliferation and migration of ephrinB2-expressing cells.57 In patients with proliferative diabetic retinopathy or retinopathy of prematurity, ephrinB2, EphB2, and EphB3 were all expressed on fibroproliferative membranes, but not EphB4.58 The lack of EphB4 expression in these tissues may be a factor contributing to the disorganized neovasculature characteristic of proliferative membranes.58

Erythropoietin

Erythropoietin is best known as an inducer of erythropoiesis in response to hypoxia,59 and has been proposed to contribute to ocular neovascular disease based on studies demon-

Pathophysiology

PDZ

P

Figure 70.6  The structure of ephrins and Eph receptors. Both ephrins and Eph receptors are membrane-bound proteins. However, ephrinAs are tethered to the cellular membrane while ephrinBs have transmembrane and cytoplasmic signaling domains. Binding of ephrins to Eph receptors leads to clustering of receptors, which in turn leads to autophosphorylation of multiple tyrosine residues and provides docking sites for src-homology domain-containing downstream effectors. The carboxyl terminus of both Eph receptors contains a sterile alpha motif (SAM) and a PDZ domain (shown here for EphA, but these also apply to EphB), which promote receptor clustering subsequent to ligand binding.

(Reproduced with permission from Dodelet VC, Pasquale EB. Eph receptors and ephrin ligands: embryogenesis to tumorigenesis. Oncogene 2000;19:5614–5619.)

strating elevated vitreous levels of erythropoietin in patients with diabetic retinopathy60,61 and diabetic macular edema (DME).62 In a murine ischemia-induced retinopathy model, blockade of erythropoietin caused a dose-dependent reduction in retinal neovascularization to levels comparable to those obtained with VEGF blockade.60 Recent work suggests that the timing of erythropoietin supplementation versus blockade may also determine if angiogenesis is enhanced or suppressed.63

Integrins

Integrins are a family of heterodimeric transmembrane proteins that mediate adhesion to the extracellular matrix as well as between cells. They have roles in modulating signaling kinases and are involved in cell survival, proliferation,

and migration. Integrins αvß3 and αvß5 are preferentially expressed on proliferating endothelial cells; their binding to matrix proteins such as fibronectin and vitronectin regulates endothelial cell migration, proliferation, and survival.64 Vasculature in neovascular AMD (NV-AMD) expressed only αvß3, whereas αvß3 and αvß5 were expressed in proliferative diabetic retinopathy; mature vasculature expressed neither integrin.64 Inhibition of αvß3 and/or αvß5 was found to inhibit pathological retinal neovascularization in rodent models,65,66 but did not inhibit CNV.67

Integrin α5ß1, the fibronectin receptor, is expressed at low levels on mature vessels but at high levels on angiogenic sprouts67 and is highly upregulated on activated endothelial cells and tumor blood vessels.68 It has been identified in surgical specimens from NV-AMD (KU Loeffler, unpublished data), proliferative vitreoretinopathy, and proliferative diabetic retinopathy.69 Inhibition of α5ß1 suppresses pathological corneal, retinal, and CNV in multiple rodent and primate models.70–72

Matrix metalloproteinases

Matrix metalloproteinases (MMPs) have been shown to contribute to ocular neovascularization in studies with mice lacking expression of MMP-2 and/or MMP-9.73 MMPs may also contribute to angiogenesis by regulating the bioavailability of VEGF by proteolytic release of the receptor-binding domain of VEGF165 from the matrix-binding domain74 and by inducing proteolysis, pigment epithelium-derived factor (PEDF), an inhibitor of angiogenesis.75

Cryptic collagen IV epitope

The cryptic epitope of collagen type IV, a component of the basement membrane of blood vessels, contributes to angiogenesis by mediating a shift in integrin binding from αvß3 to αvß1.79 Blocking this epitope inhibited corneal79 and CNV80 in murine models. MMP-2 localization at the site of the lesion preceded that of the cryptic epitope, suggesting that MMP proteolysis was responsible for exposure of the epitope.80

Other inhibitors

Other endogenous factors for which evidence supports an inhibitory role in angiogenesis include pigment epitheliumderived factor (PEDF), angiostatin, endostatin, plasminogen kringle 5, kallistatin, and thrombospondin-1. It is suggested that readers interested in more information about these factors refer to the excellent recent review by Zhang and Ma.81

Antiangiogenic therapies for ocular neovascular disease

Antiangiogenic therapies for ocular neovascular disease include anti-VEGF agents, the only approved therapies to date, and multiple other agents under investigation (Box 70.3).

Endogenous inhibitors of angiogenesis

A variety of inhibitors of angiogenesis have been proposed to be involved in ocular neovascularization (Box 70.2).

Soluble VEGFR-1

Soluble VEGF receptor-1 (sVEGFR-1) is a secreted form of the receptor that inhibits VEGF.76 Evidence in mice suggests that corneal avascularity is maintained in large measure due to sVEGFR-1 binding to VEGF in the cornea.77 Thus, sVEGFR-1 is a potent, naturally occurring inhibitor of VEGF in the eye.

VEGFxxxb

VEGFxxxb isoforms comprise a family of differentially spliced, potentially antiangiogenic VEGF isoforms that have been found to be underexpressed in eyes with diabetic retinopathy compared to eyes from nondiabetic patients.78 These findings suggest that diabetic retinopathy may be associated with a switch in splicing from antiangiogenic to proangiogenic isoforms.78

Box 70.2  Inhibitors of angiogenesis involved in

ocular neovascularization

•Soluble vascular endothelial growth factor (VEGF) receptor-1

•VEGFxxxb proteins

•Cryptic collagen IV epitope

•Other inhibitors

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Agents targeting VEGF

Pegaptanib sodium

Pegaptanib sodium (Macugen (OSI), Eyetech/Pfizer) is a pegylated oligonucleotide that selectively binds VEGF165 and is administered every 6 weeks by intravitreal injection.82 Pegaptanib was evaluated for treatment of NV-AMD in two randomized, controlled trials (VEGF Inhibition Study In Ocular Neovascularization trials) involving three different doses of pegaptanib and sham.82 In a combined analysis, the 0.3-mg dose of pegaptanib sodium demonstrated efficacy at 2 years resulting in stabilization of vision (59% versus 45% for controls having a ≤3-line loss); subgroup analysis demonstrated similar efficacy for all angiogenic subtypes. The chance of having a 3-line gain was relatively low (10% towards 4% for the control group after 2 years),83 although in a subsequent analysis of patients with early lesions (i.e., >54 letters and lesion size <2 disk areas at baseline), 76% with pegaptanib versus 50% in the usual care group lost ≤3 lines.84 The long-term ocular and systemic safety of pegaptanib in treatment of NV-AMD is excellent.85 Pegaptanib was also effective in diabetic patients with retinal neovascularization.86

Ranibizumab

Ranibizumab (Lucentis, Genentech) is a humanized monoclonal antibody antigen-binding fragment (Fab) that binds all isoforms of VEGF. In a randomized, controlled phase III trial (MARINA), patients with minimally classic or purely occult CNV received monthly injections of 0.3 or 0.5 mg ranibizumab or sham treatment for 24 months; at 12 months, 95% versus 62% of eyes (ranibizumab versus sham)

Box 70.3  Approved and investigational antiangiogenic therapies for ocular neovascular disease

Approved

•Pegaptanib sodium (anti-vascular endothelial growth factor (VEGF))

•Ranibizumab (anti-VEGF)

Investigational (a partial list of compounds in or entering human clinical trials)

•Other anti-VEGF agents

Bevacizumab

VEGF-Trap-Eye

Small interfering RNAs

Bevasiranib

AGN211745

•Corticosteroids

Triamcinolone acetonide

Anecortave acetate

Dexamethasone

Fluocinolone

•Complement antagonists

Anticomplement factor D antibody

ARC1905

Eculizumab

JPE1375

PMX53

POT-4

TA106

TT30

•Integrin antagonists

JNJ-26076713

JSM6427

Volociximab

•Other therapeutic approaches

AdGVPEDF.11D versus pigment epithelium-derived factor

Tumor necrosis factor-α

E10030 versus platelet-derived growth factor

Sirolimus

Mecamylamine

RTP801i-14

iCo-007

Palomid 529

Radiation brachytherapy

Tyrosine kinase inhibitors

TG100801

Pazopanib

Vascular disrupting agents

Combretastatin A4P (Zybrestat)

OC-10X

lost <15 letters and 34% of eyes receiving the 0.5-mg dose had gains of 15 letters. At 24 months, 90% of eyes in the 0.5-mg group lost <15 letters compared to 53% in the control group; the mean gain in the 0.5-mg group was 7 letters.87 Efficacy was independent of baseline vision and

Pathophysiology

lesion size/composition. In the ANCHOR trial, ranibizumab was found to be superior to photodynamic therapy (PDT) with verteporfin for treatment of AMD.88 The drug was well tolerated overall.87

Bevacizumab

Bevacizumab (Avastin, Genentech) is a humanized antiVEGF monoclonal antibody related to ranibizumab that is approved for intravenous administration in the treatment of colorectal cancer89 and is being used off-label as an intravitreal treatment for ocular neovascular disease. Since the safety of intravitreal bevacizumab has not been evaluated in randomized, controlled trials and the long-term effects of intravitreal bevacizumab are unknown, a multicenter trial sponsored by the National Eye Institute to assess the relative safety and efficacy of bevacizumab with respect to ranibizumab is ongoing.90

Other anti-VEGF agents

VEGF-Trap-Eye (Regeneron Pharmaceuticals) is a VEGFR-Fc fusion protein administered via intravitreal injection that prevents the binding of all isoforms of VEGF isoforms and placental growth factor (which is related to VEGF) to their cellular receptors. Results of a phase II, dose-ranging trial involving 157 patients with NV-AMD showed significant reductions in mean retinal thickness and improvements in visual acuity from baseline after 12 weeks of treatment.91 The current phase III trial is comparing every-4 versus every-8- week VEGF Trap dosing versus monthly ranibizumab for NV AMD.92

Bevasiranib (formerly known as Cand5, Okpo Health) is a small interfering RNA that inactivates VEGF messenger RNA (mRNA), inhibiting the production of all isoforms of VEGF. A phase III trial has been terminated in which intravitreal bevasiranib was evaluated as a maintenance agent in NV-AMD every 8 or 12 weeks following monthly induction with ranabizumab.93 AGN211745 (formerly known as Sirna 027, Allergan) is a small interfering RNA that blocks the VEGFR-1 receptor. It is administered by intravitreal injection and was in phase II trials that have been terminated.94

Corticosteroids

Triamcinolone acetonide, dexamethasone, and fluocinolone

Triamcinolone acetonide, a potent anti-inflammatory corticosteroid with prolonged activity, is being used off-label as an intravitreal treatment for ocular neovascular diseases (reviewed by Jonas95). Although triamcinolone may be used in an adjuvant setting (such as with concurrent PDT), there are insufficient data to support the use of triamcinolone as monotherapy for NV-AMD. Triamcinolone is also associated with a high risk of adverse effects such as increased intraocular pressure and cataract development.

Dexamethasone, an even more potent anti-inflammatory corticosteroid, is also being used intravitreally off-label in combination with PDT and anti-VEGF therapy for NV-AMD.96 An extended-release formulation of dexamethasone (Posurdex, Allergan) is being evaluated in phase II clinical trials in combination with ranibizumab for the treatment of NV-AMD.97

Fluocinolone acetonide was studied in high-dose extended-release formulation as monotherapy for non-AMD

CNV, but had high rates of complications.98 It is currently entering phase II clinical trials at a lower dose, administered as an extended-release formulation by the Medidur intravitreal device, in combination with ranibizumab for patients who have reached a plateau after ranibizumab monotherapy for NV-AMD.99

Anecortave acetate

Anecortave acetate (Retaane, Alcon) is an angiostatic corticosteroid that blocks the migration of proliferating endothelial cells by inhibiting MMPs; it is administered every 6 months by posterior juxtascleral injection. A phase III randomized study comparing anecortave acetate with PDT in patients with NV-AMD found comparable efficacy in terms of < 3-line loss between groups at 12 months.100

Complement antagonists

The complement pathway offers numerous potential targets for inhibition of angiogenesis; however, it is too early to know which target or targets will be the most effective. Compstatin, a small peptide inhibitor of C3 convertase currently being evaluated in clinical trials for eye disease, is being tested in phase I trials for treatment of NV-AMD as the intravitreally injected drug POT-4 (Potentia Pharmaceuticals).101 Eculizumab (Soliris, Alexion Pharmaceuticals) is a monoclonal antibody that binds C5 and prevents cleavage into C5a (an inflammatory anaphylotoxin) and C5b (part of the C5b–C9 membrane attack complex). It is the first Food and Drug Administration-approved complement inhibitor, indicated for intravenous administration in paroxysmal nocturnal hemoglobinuria, and is in preclinical development as an intravitreal agent for NV-AMD (JP Springhorn, unpublished data). ARC1905 (Ophthotech), an anti-C5 aptamer, is in phase I clinical trials for NV-AMD alone and in combination with ranibizumab.102

Approaches that target the C5a–C5aR pathway are being investigated (Jerini Ophthalmic; Arana Therapeutics) which may offer the potential for clinical efficacy while allowing the production of the C5b–C9 membrane attack complex; deficiencies in C5, C5b, and C6–9 are known to lead to increased bacterial infections and, in particular, meningococcal disease.103 A monoclonal antibody against complement factor D is in preclinical development for both dry AMD and NV-AMD (J Le Coulter, unpublished data). In addition, Taligen Therapeutics has two agents in preclinical development for treating NV-AMD: TA106, a monoclonal antibody Fab that blocks complement factor B, and TT30, targeting complement factor H.104

Integrin antagonists

JSM6427 (Jerini Ophthalmic), a specific small-molecule inhibitor of α5ß1 that showed antiangiogenic, antifibrotic, antiproliferative, and anti-inflammatory effects in preclinical models,70–72 is currently in phase I safety and pharmacokinetic testing with single and repeat intravitreal injections for advanced NV-AMD.105 Volociximab, a monoclonal antibody against α5ß1 currently in phase II trials for several types of cancer, was recently licensed for ophthalmic use (Ophthotech) and is in phase I clinical trials for NV-AMD.106 Finally, an oral αvß3/αvß5 antagonist is in preclinical development for the treatment of diabetic retinopathy (Johnson and Johnson JNJ-26076713).107

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Other therapeutic approaches based on modulating angiogenic factors

Other therapeutic approaches may prove useful in treating ocular neovascular disease. In one approach, an adenoviral vector expressing PEDF was administered intravitreally to 28 patients with NV-AMD in a phase I study, with most patients experiencing stable vision at 6 months postinjection.108 Another approach is suggested by the previously described preclinical data in which the anti-TNF-α antibody infliximab reduced the formation of CNV36; these findings have gained validation from a small study in which three patients experienced regression of NV-AMD while receiving intravenous infliximab for treatment of arthritis.109 In addition, an intravitreally injected anti-PDGF aptamer (E10030; Ophthotech) that showed potential in inducing regression of established CNV in preclinical studies when used in combination with anti-VEGF therapy has recently entered phase I safety trials in NV-AMD in combination with ranibizumab.110

Sirolimus, an mTOR kinase inhibitor that suppresses cytokine-driven T-cell proliferation, is used systemically for preventing organ transplant rejection and cardiac stent ste­ nosis; it has immunosuppressive, antipermeability, antifibrotic, antiangiogenic, antimigratory, and antiproliferative properties. It is currently in phase I/II clinical trials for NV-AMD and DME as a subconjunctival or intravitreal injection (MacuSight).111 Another agent in phase I clinical trials as an intravitreal injection is RTP801i-14/REDD14NP (Quark Pharmaceuticals), an siRNA against the hypoxia-inducible gene RTP801 that demonstrated anti-inflammatory, antiapoptotic, and antiangiogenic effects in preclinical models.112 Another agent, iCO-007 (iCo Therapeutics), is a secondgeneration antisense inhibitor targeting C-raf kinase mRNA and is thought have utility in the treatment of retinal neovascular diseases such as diabetic retinopathy; it is currently in phase I clinical trials as an intravitreal agent for treatment of diffuse DME.113 Palomid 529 is a small molecule that inhibits bFGFand VEGF-stimulated endothelial cells114 and has been shown to be effective in preclinical models of CNV and retinal neovascularization114,115; it is anticipated to enter human clinical trials at the end of 2009 as an intravitreal injection.116

Since radiation preferentially affects dividing cells, many studies have looked at external-beam radiation for NV-AMD, with inconclusive results. In a slightly different approach, strontium-90 beta irradiation applied directly over the macula during vitrectomy using a brachytherapy device (EpiRad 90, Neovista) is currently in phase III clinical trials for NV-AMD in combination with ranibizumab.117

Several topically administered compounds are in clinical trials for NV-AMD, including TG100801 (TargeGen), a prodrug that inhibits the VEGFR and src tyrosine kinases118; pazopanib (GlaxoSmithKline),119 a small-molecule tyrosine kinase inhibitor against VEGFR-1, -2, and -3, c-kit, and PDGFR, is also under study. Zybrestat (OXiGENE), a smallmolecule endothelium-targeting vascular disrupting agent in phase III clinical trials for oncology, is being formulated for topical delivery after being administered intravenously for myopic CNV.120 Finally, OC-10X (OcuCure Therapeutics), a vascular disruptor that binds the β-tubulin subunit, is in development for topical treatment of NV-AMD and diabetic

retinopathy after animal studies showed suppression and regression of neovascularization.121

Conclusions

A greater understanding of the factors involved in promoting and inhibiting angiogenesis has led to the development of

Key references

new therapies for treating ocular neovascular diseases such as AMD and diabetic retinopathy. While the only approved therapies are those targeting VEGF, there are new investigational agents in development that may provide additional options, either alone or in combination with anti-VEGF therapy, for the treatment of ocular neovascular diseases.

2.Ishida S, Usui T, Yamashiro K, et al. VEGF164-mediated inflammation is required for pathological, but not physiological, ischemia-induced retinal neovascularization. J Exp Med 2003;198: 483–489.

3.Donoso LA, Kim D, Frost A, et al. The role of inflammation in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 2006;51:137–152.

4.Nozaki M, Raisler BJ, Sakurai E, et al. Drusen complement components C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci USA 2006;103:2328–2333.

9.Ishida S, Yamashiro K, Usui T, et al. Leukocytes mediate retinal vascular remodeling during development and vaso-obliteration in disease. Nat Med 2003;9:781–788.

11.Jo N, Mailhos C, Ju M, et al. Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol 2006;168:2036–2053.

14.Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal

disorders. N Engl J Med 1994;331:1480– 1487.

18.Tolentino MJ, McLeod DS, Taomoto M, et al. Pathologic features of vascular endothelial growth factor-induced retinopathy in the nonhuman primate. Am J Ophthalmol 2002;133:373–385.

22.Krzystolik MG, Afshari MA, Adamis AP, et al. Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch Ophthalmol 2002;120:338–346.

23.Adamis AP, Shima DT, Yeo KT, et al. Synthesis and secretion of vascular permeability factor/vascular endothelial growth factor by human retinal pigment epithelial cells. Biochem Biophys Res Commun 1993;193:631–638.

24.Aiello LP, Northrup JM, Keyt BA, et al. Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol 1995;113:1538–1544.

31.Frank RN, Amin RH, Eliott D, et al. Basic fibroblast growth factor and vascular endothelial growth factor are present in epiretinal and choroidal neovascular membranes. Am J Ophthalmol 1996;122: 393–403.

41.Joussen AM, Poulaki V, Tsujikawa A,

et al. Suppression of diabetic retinopathy with angiopoietin-1. Am J Pathol 2002;160:1683–1693.

77.Ambati BK, Nozaki M, Singh N, et al. Corneal avascularity is due to soluble VEGF receptor-1. Nature 2006;443:993– 997.

82.Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med 2004;351:2805–2816.

86.Adamis AP, Altaweel M, Bressler NM, et al. Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology 2006;113: 23–28.

Clinical background

Retinal detachment (RD) is a physical separation of the neural retina from the retinal pigmented epithelium (RPE). An important physiological ramification of the creation of a detachment is an increase in the physical distance between the photoreceptor cells and their blood supply, the choroicapillaris. Detachment recreates a space that disappears during early embryonic development.

Definitions: types of retinal detachment

Detachment occurs in three categories: exudative (or serous), traction, and rhegmatogenous (Box 71.1).

Serous detachment

Serous detachment occurs as fluid accumulates between the neural retina and RPE, but the retina remains physically intact.1 Serous detachments may be idiopathic or occur as part of inflammatory reaction, or as a result of neoplastic ocular tumors (Box 71.2).

Tractional detachment

Tractional detachment occurs as a result of “vitreoretinal adhesions” or the growth of cells in the vitreous that attach to the surface of the retina and contract, mechanically creating an RD.

Rhegmatogenous detachment

This is the commonest form of RD and the focus of this chapter. It results from a tear across the retina, creating a physical continuity between the vitreous and RPE–photore- ceptor interface and thus resulting in the accumulation of “foreign” fluid beneath the retina and a subsequent detachment (Figure 71.1).

Tractional detachments can also be rhegmatogenous, i.e., a complex form of RD (Figure 71.2).2 These often result from fibrotic or scar tissue that forms on either surface of the retina after reattachment. Contraction of this scar tissue can cause traction on the retina with wrinkling and redetachment and often retearing of a previous break or creation of new ones. This is a visually devastating condition and its prevalence has remained discouragingly static over the years.

Retinal detachment

Steven K Fisher and Geoffrey P Lewis

Symptoms, signs of retinal detachment, and diagnostics

All RDs are accompanied by some loss of visual function but this will vary depending upon the type of detachment, its size, and retinal location, making it difficult to ascribe one set of symptoms to the condition (Box 71.3). Diagnosing RD is complex, with many qualifications.

Abnormal vision is the only reliable symptom of RD. But the types of abnormal vision are large and varied: light flashes, floaters, changes in the peripheral visual field, decreased acuity, defective color vision, distorted vision (metamorphopsia), or even unilateral double vision (diplopia). Patients often remain unaware of large peripheral detachments until they approach the macula and begin to produce a visual field defect. Many times they are discovered during an ocular examination. Foveal detachment always involves loss of central visual acuity. Indeed, the duration of a foveal rhegmatogenous RD is based upon the time of patient-observed decrease in visual acuity.3 A macular rhegmatogenous RD will generally produce visual acuity loss that cannot be corrected, while blurred vision produced by a centrally located serous detachment (central serous retinopathy, or CSR) can often be corrected by shifting the focal plane of the image to a more forward location. The book series Retina includes much information relevant to diagnosing detachments.4

History

Greg Joseph Beer provided what is generally described as the earliest description of detachment in the early 18th century3,5; his observations were done without benefit of an ophthalmoscope (an instrument with magnifying lenses that allows examination of the inside of the eye). After Hermann von Helmholtz recognized the importance of the ophthalmoscope in about 1850, detailed descriptions of detachments and accompanying breaks or tears proliferated rapidly.

The first treatment of rhegmatogenous RD by sealing the retinal break with a red-hot probe occurred in 1889, and was revived as a standard treatment by Jules Gonin. Gonin was also the first to suggest a relationship between detachment duration and successful visual recovery. His technique is

Laser beam

Tractional

forces on Tear in retina

retina

History

Blunt needle or glass micropipette

Retina

Retinal hole

Subretinal injection

Retinal detachment

Figure 71.2  Rhegmatogenous detachments can be created in animal models by the injection of fluid between the neural retina and underlying retinal pigmented epithelium. The pipette or needle will leave a hole in the retina that will remain open and even expand, creating the retinal break characteristic of this type of detachment.

Figure 71.1  In a rhegmatogenous detachment a tear or break forms in the retina, allowing fluid from the vitreous cavity to enter, and creating a space between the neural retina and retinal pigmented epithelium (RPE). A laser can be used to “seal” the retinal tear and encircling bands of material (scleral buckle) can be used to indent the wall of the eye so that the retina is reapposed to RPE. Natural adhesion forces will allow reattachment to occur. A rhegmatogenous detachment may detach the whole retina. A serious complication of reattachment is the formation and attachment of scar tissue on the vitreal surface of the retina, which can become contractile and subsequently create a traction detachment.

Box 71.3

A monograph, Retinal Detachment, prepared in 1979 for the American Academy of Ophthalmology,3 is a valuable resource describing much of the history associated with the diagnosis, symptoms, and treatment of detachment. It is referenced here although out of print, because copies exist in libraries and used copies presumably can be found for sale. Much of the historical information presented here is derived from that source

Box 71.1

Rhegma, derived from Greek, refers to a break in continuity

Box 71.2

Central serous retinopathy (CSR) or central serous choreoretinopathy results from serous detachment of the macula. It occurs most commonly in middle-aged males. The mechanisms are poorly understood. These detachments usually, but not always, resolve spontaneously. Even those that do resolve can have lasting effects on vision1

credited with moving an inevitably blinding condition into a treatable one. The next major advance occurred 70 years later when Custodis described the “scleral buckle”6 (Box 71.4).

This technique achieved a success rate of between 75 and 88%.7 In the early 1970s Norton8 described the use of “pneumatic retinopexy,” or injection of an expanding gas bubble into the vitreous cavity (Box 71.5) to reappose the retina and RPE (once these tissues are moved into close physical proximity, natural adhesive forces will usually cause them to

Box 71.4

A scleral buckle consists primarily of a band or bands of material, now usually silicone rubber and/or silicone sponges in a variety of configurations surgically placed to encircle the globe and to indent the wall of the eye in the region of the detachment.6 A scleral buckle is used in conjunction with cyrotherapy or laser treatment to seal the retinal break

Box 71.5

The gases sulfur hexafluoride (SF6) and perfluoropropane (C3F8) are commonly used in pneumatic retinopexy

reattach9). There is still much ongoing discussion on the use of scleral buckling, primary vitrectromy, and pneumatic retinopexy6,7,10–12 to treat rhegmatogenous RD.

The success rate for rhegmatogenous RD after one surgical procedure is now cited as in the range of 80–95%.7 That number rises closer to 95% if a second reattachment procedure is performed.

Surgical success refers to a reapposition of the sensory retina and RPE and does not refer specifically to the return of vision. Redetachment by traction on the retina and imper-

fect vision can both occur after successful reattachment. The goal of experimental detachment in animal models is gaining an understanding of underlying cellular mechanisms that will presumably aid in developing improvements in the treatment of the primary detachment as well as the means for preventing the occurrence of secondary tractional RD.

Epidemiology

The incidence of rhegmatogenous RD is described as anywhere from 1 in 10 000 to 1 in 15 000 in the general population. This translates to a prevalence of about 0.3% or approximately 1 in 300 patients over the course of the average patient lifetime. The risk levels for RD vary slightly among different studies but there is general agreement that if ocular trauma is factored out, the prevalence among men and women is about equivalent.

Prognosis and complications

Rhegmatogenous RD is still the condition most frequently treated by retinal surgeons (H. Heimann, personal communication). About 5% of reattachments fail for unknown reasons. Traction detachment caused by proliferative vitreo­ retinopathy (PVR: the growth of cellular “membranes” on the retinal surface) remains the most common reason for failure, with a rate of 7–10% in primary surgeries and even higher when a second procedure is necessary.2,13,14 Many studies have shown significant effects of rhegmatogenous RD on functional vision after successful repair. Burton15 and Tani et al16 estimated that 30–40% of reattachment patients do not achieve reading ability. A variety of studies estimate that 50% require low-vision aids in order to achieve reading ability (H. Heimann, personal communication). While functional recovery after reattachment is remarkable, it is also true that there is room for improvement.

The development of PVR or subretinal fibrosis (growth of cellular membranes in the subretinal space, i.e., on the photoreceptor surface) is probably the most ominous complication of reattachment. The incidence of PVR is well documented, but that of subretinal fibrosis is not because of the difficulty of resolving these fine cellular membranes by ophthalmic exam. The cellular membranes that form are complex, consisting of at least glial cells, macrophages, and RPE cells. Their attachment to the retina (whether on the vitreal or photoreceptor surface) and contraction can cause wrinkling and redetachment (Figure 71.1). Subretinal fibrosis also effectively blocks the regeneration of outer segments in animal models.17 PVR was named without a clear link to the actual process of cell division. Indeed, this link is suggested by a variety of data, but not proven. Both cell growth (hypertrophy) and actual proliferation probably play a role (see below). The demonstration that detachment stimulates intraretinal proliferation of all nonneuronal cell types,18,19 coupled with the assumption that proliferation is generally a part of scar formation, makes antiproliferative agents attractive prospects for preventing or controlling these conditions. Clinical trials with the common antiproliferative drug, 5-fluorouracil (5-FU), proved disappointing,20 but other antiproliferative agents are providing more encouraging results in animal models.21 Evidence in mice lacking the

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RPE

Figure 71.3  Cell types that have been shown to respond to retinal detachment include the retinal pigmented epithelium, rod and cone photoreceptors, rod bipolar cells, axon-bearing horizontal cells, ganglion cells, Müller cells, and microglia.

expression of glial fibrillary acidic protein (GFAP) and vimentin demonstrates that inhibitors of these intermediate filament proteins may lead to better treatment of the proliferative diseases because subretinal scars do not form in these animals.22 There are currently no such agents available for medical use. The only therapy for PVR or subretinal fibrosis is surgical removal of the cellular membranes, but even successful removal may lead to disappointing results and carries its own risk. PVR is covered at greater length in Chapter 78.

Pathology

For many years the degeneration of photoreceptor outer segments was recognized as the main cellular pathology of RD. The migration of RPE cells from the monolayer and glial cell expansion to form fibrotic lesions or scars on the retina was also recognized in early pathological studies. More detailed studies by electron microscopy and especially the use of immunohistochemical labeling and confocal imaging have revealed many complex cellular responses to detachment extending through all retinal layers (Figure 71.3).

Reattachment was assumed to return the retina to its “normal” state based on early observations of outer-segment regeneration (“After surgical reattachment the receptor cell outer segments regenerate, the discs assume a normal pattern, and the phagosomes again return to the retinal pigment epithelial cells”3). Reattachment instead results in what has been referred to as a “patchwork”17,23 of recovery across the RPE–photoreceptor interface (Figures 12 and 13 in Fisher et al24).

Etiology

Aging, myopia, local retinal atrophy (i.e., lattice degeneration), and cataract surgery are all well-recognized factors that increase risk of detachment. Less common factors