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

Dendrimer glucosamine

Soluble low MWt heparan sulphate

Figure 28.3  Branched dendrimers carrying drugs to enhance binding and efficacy.

and deposition of fibronectin, the migration of human corneal fibroblasts, inflammation and deposition of extracellular matrix (ECM) in an in vivo model of subconjunctival scarring after GFS.14

Transglutaminases are calcium-dependent enzymes which cross-link proteins using ε-(γ-glutamyl)-lysine bonds. Transglutaminase (tTgase) and its end product ε-(γ-glutamyl)- lysine were detected in scarred tissue of failed trabeculectomy blebs.15 Since vertebrates lack enzymes capable of hydrolyzing these bonds, the protein cross-linking created by transglutaminases seems to be unbreakable. tTgase cross-links fibronectin and collagen-3; these proteins are produced by human Tenon’s fibroblasts (HTFs) in vitro and have been detected in the scar tissue deposited in the bleb area after GFS. In the same study, TGF-ß2 was shown to stimulate the expression of tTgase and, subsequently, the cross-linking of fibronectin in vitro,15 leading to the conclusion that inhibition of TGF-ß2 activity could extend the success of the surgery as this pathway might lead to enhanced cross-linking of the newly formed scar tissue in vivo.

The main intracellular TGF-ß signaling pathway runs through proteins that activate transcription of the genes that encode the Smad proteins. Of particular relevance is Smad-3, which is essential for TGF-ß-induced production of ECM proteins.16,17 Targeting intracellular signaling downstream of the TGF-ß receptor could be another effective strategy. Inhibiting Smad3 in immediate postoperative applications might prove beneficial.18 Smad-7, acting differently from Smad-3, is another potential therapeutic target. As TGF-ß can suppress its action through the induction of Smad-7 (negativefeedback loop), gene transfer of the Smad-7 gene has been shown in animal models to have a protective effect against the development of lung, liver, and renal fibrosis.19

P38 MAP kinase (MAPK) is believed to trigger the transcription of Smad-2/3, facilitate the phosphorylation and activation of Smad-3 and, subsequently, the formation of Smad-3/4 complex, which is important for the development of the fibrotic reaction. The Smad-3 signaling pathway is

Pathogenesis

important in retinal fibrosis. Inhibition of Smad-3 is associated with a reduction of a cellular fibrotic reaction.20 Adenoviral transfer by intravitreal application of a dominant negative p38MAPK gene demonstrated reduced fibrotic reaction of retinal pigment epithelium cells after retinal detachment.21 In later studies, adenoviral gene transfer of the same gene was applied to in vitro cultured HTFs22 and in an in vivo conjunctival scarring model in mice.23 Reduction of the differentiation of fibroblasts to myofibroblasts and decline of the connective tissue growth factor (CTGF) and of the monocyte chemoattractant protein (MCP-1) expression were the main in vitro findings. Inhibition of conjunctival scarring was observed in vivo. As MCP-1 is a chemoattractant for macrophages, one of the main sources of TGF-ß, the reduction in levels of MCP-1 through inhibition of p38MAPK, seems to reduce the levels of TGF-ß; hence, it plays a favorable role in conjunctival scarring.24–26 Furthermore, the recent finding that the antiglaucoma drug latanoprost, a prostaglandin F2α analog, induces formation of stress fibers in HTFs in vitro as well as contraction of collagen I gels mediated by HTFs in vitro is indicative of the important role of MAPKs in subconjunctival scarring. The contraction of collagen I gels by latanoprost was blocked by inhibitors of MAPKs, Rho-activated kinase, myosin light chain (MLC).27 Moreover, the findings of this in vitro study point out potential induction of scarring by latanoprost in vivo. This conclusion agrees with previous findings that long-term antiglaucoma treatment represents a risk factor in scarring after GFS28 and that eyes treated with latanoprost after surgery were observed to have smaller decrease of IOP compared to the ones that did not receive latanoprost.29

CTGF influences ECM production and subsequent fibrosis. TGF-ß1 triggers the expression of CTGF, which is also necessary for TGF-ß stimulation of myofibroblast differentiation and collagen contraction.30 Inhibition of this factor could be a possible future therapeutic target.31 Lovastatin, a member of the drug class of statins, was shown to inhibit the TGF-ß-induced CTGF transcription, α-smooth-muscle actin (SMA) expression and, subsequently, the HTF differentiation to myofibroblasts as well as collagen contraction in vitro.32

Rho is a small GTPase that has been implicated in the formation of stress fibers and focal adhesions, actin cytoskeleton remodeling, and cell contractility. TGF-ß increases cell tension in HTF cultures and contraction in HTF collagen I gels by triggering the activation of Rho. Rho activates the serine-threonine Rho-associated kinase (ROCK), which enhances cytoskeletal tension and results in actomyosinmediated contraction. ROCK inhibitors reduce cell tension and inhibit the TGF-ß-mediated p-38 activation, α-SMA expression, and HTF development of enhanced contractile abilities characteristic of the so-called myofibroblast phenotype.”22 ROCK inhibitor Y-27632 inhibited contraction of HTF-seeded collagen I gels and α-SMA expression by HTFs in vitro. In vivo, application of Y-27632 after GFS significantly increased the survival of the blebs compared to controls. Furthermore, reduction of collagen I deposition and scarring in the treated blebs compared to controls was observed in histological analysis.33 ROCK inhibitors may block TGF-ß-induced scarring by downregulating pathways that are generating mechanical tension and thereby improve the success of GFS.

Myofibroblasts express a platelet-activating factor (PAF) nuclear receptor and tumor necrosis factor-ß (TNF-ß) receptors; PAF and TNF-ß cause time-dependent myofibroblast apoptosis. Future therapeutic approaches may take advantage of the expression of these receptors.34

Platelet-derived growth factor (PDGF) has been found to activate certain ocular fibroblasts. Some ocular fibroblasts express high levels of PDGF receptor beta. When stimulated, these fibroblasts proliferate, migrate, produce ECM molecules and cause contraction, fibrosis, and the development of fibrotic membranes such as those observed in proliferative vitreoretinopathy (PVR).35 Aptamers, nucleic acid-based macromolecules with similar functions as monoclonal antibodies (high affinity and specificity for target proteins), are capable of recognizing, binding, and blocking PDGF-B. Two aptamers, ARC126 and ARC127, have been tested in animal models of PVR,36 and may also be useful in GFS.

Bone morphogenic proteins (BMPs) are growth factors that are vital for cell proliferation, differentiation, apoptosis, angiogenesis, and other biological functions.37 Activins are dimeric proteins that participate in cell differentiation and proliferation, apoptosis, inflammation, and neurogenesis.38 Investigation of the expression of many members of BMPs and activins in normal and scarred conjunctival tissue revealed enhanced mRNA and protein levels of BMP-6 and activin A in scarred compared to normal conjunctiva.39 The use of follistatin, an inhibitor of activin bioactivity, was shown to be effective in decreasing liver and lung fibrosis.40,41 Based on the above findings, the inhibition of BMP-6 and activin A could be a future therapeutic option for the control of scarring after GFS.39

Fibroblast proliferation and vascularization

The antimetabolites 5-FU and MMC are the main agents currently used to inhibit scarring and subsequent IOP increase and blindness after trabeculectomy. Lately, mechanisms of prolonged release of 5-FU and MMC are sought (Box 28.4). We have achieved the formulation of tablets that release 5-FU for more than 8 hours in our lab model, which mimics the bleb. Prolonged release of 5-FU may enhance the success of trabeculectomies.42 Slow-release MMC-loaded hydrogels were shown to inhibit cell proliferation in an in vitro model. In the future, these gels, placed in the bleb, could find an application in GFS in humans.43 It was recently reported that repeated exposure of HTFs in vitro to MMC increases the expression of P-glycoprotein, a protein that creates multidrug resistance by lowering intracellular concentration of various drugs. This finding may explain failure of repeated trabeculectomies despite the application of MMC. 5-FU seems to be a better option for repeated trabeculectomies as it does not increase the expression of P-glycoprotein.44

Paclitaxel, an antineoplasmatic agent that prevents mitosis by blocking the depolymerization of intracellular microtubules, inhibits HTF proliferation and prolongs the success of GFS. But as paclitaxel is hydrophobic, its administration in the subconjunctival area is not easy. Polyanhydride disks45 and carbopol 980 hydrogel46 containing paclitaxel have been tested, with encouraging results comparable to the antiscarring effects of MMC, although the development of severe inflammation, especially in the case of polyanhydride disks, has been reported.45

Beta-irradiation, by inhibiting the proliferation of fibroblasts,47 significantly improved the success of GFS in a large African trial using a dose based on our laboratory studies.48,49 It may also be useful in pediatric GFS.37

Photodynamic therapy with a diffuse blue light coupled with a photosensitizing agent has been used in order to kill fibroblasts.50 Many studies have demonstrated that photodynamic therapy reduces neovascularization and maturation of scar tissue after GFS. Intraoperative photodynamic therapy using preoperative subconjunctival application of ethyl etiopurin51 and BCECF-AM as photosensitizers52 have proven to be safe and effective against scarring after GFS in vivo. Pilot clinical trials of intraoperative photodynamic therapy with locally administered BCECF-AM have shown promising results.53 Furthermore, postoperative photodynamic therapy has been reported to be effective against neovascularization and scarring. Intravenous administration of the photosensitizer verteporfin in the early postoperative period to occlude the newly formed capillaries in the bleb area had favorable results in the modulation of wound healing in rabbits after GFS.54

Additionally, future interesting experimental strategies to modulate proliferation include overexpressing genes that inhibit fibroblast proliferation, such as p21 WAF-1/CIP-1 introduced via an adenovirus system,55 antagonizing inte­ grins and their receptors,56 or altering intracellular gene transcription.57

It has recently been demonstrated that bevacizumab (Avastin), a humanized monoclonal antibody that is used in the eye for the treatment of proliferative (neovascular) diseases, could potentially inhibit scarring after GFS. Subconjunctival injections of Avastin administered in failed blebs of patients with primary open-angle glaucoma, nor- mal-tension glaucoma, or exfoliation syndrome revealed significant decrease of IOP and of vascularity 1 month postinjection.58 Similar findings regarding IOP and vascularity reduction were observed after bleb needling with antivascular endothelial growth factor treatment (ranibizumab) in patients with failed blebs.59 Furthermore, application of bevacizumab injections combined or not with 5-FU application during trabeculectomy extended the survival of the bleb in an in vivo GFS model.60 Moreover, it has been suggested that intravitreal administration of bevacizumab at the same time as trabeculectomy augmented with MMC in patients with neovascular glaucoma may be effective in inhibition of neovascularization and in modulation of scarring.61 It is likely that bevacizumab may control scarring by inhibiting fibroblast proliferation and their contractile ability as well as by inducing fibroblast death, as has been observed after administration of bevacizumab in HTF cultures.62

Figure 28.5  Fibroblast and matrix imaged simultaneously.

Box 28.5  Modulation of matrix deposition and

cell-mediated contraction

Matrix and cell-mediated contraction

Tissue contraction constitutes a critical component of GFS failure, as revealed by bleb analysis using carefully graded masked digital photographs. We have developed a more detailed understanding of the processes that occur during tissue contraction and have recently been able to image cells and matrix simultaneously during the process of contraction (Figure 28.5). The matrix metalloproteinases (MMPs) are the main enzymes responsible for the ECM degradation among all the proteinases that participate in ECM turnover

220

(Box 28.5). Cell-mediated collagen contraction can be reduced using MMP inhibitors.63 In an experimental model of GFS, the repeated administration of MMP inhibitor injections led to a dramatic reduction of scarring with retention of normal tissue morphology. This action is equivalent to MMC, but without the deleterious side-effects.64,65 MMP inhibition also results in a reduction of collagen synthesis in vitro,63 which may help to explain the dramatic reduction in scar tissue formation in vivo.64 Recently, our group has

formulated a novel prolonged-release MMP inhibitor tablet that was placed at the subconjunctival space after GFS in our in vivo model. It was surprisingly shown that the prolonged release of MMP inhibitor resulted in significantly extended survival of the bleb and lower IOP compared to both the negative (water sponge) and the positive control (MMC 0.2 mg/ml group). Histology revealed decreased collagen deposition and number of fibroblasts at the blebs treated with the MMP inhibitor tablet compared to the positive and negative control blebs.66

Other agents such us Taxol and etoposide (microtubulestabilizing agents) have been used in models of GFS and they prolong bleb survival.67 ß-aminopropionitrile and d-penicillamine interfere with molecular cross-linking of collagen, and there is experimental and clinical evidence that they may work in GFS.67

Figure 28.6  Changes in surgical technique leading to better outcomes.

Using surgical and anatomical principles to modify therapy

Minimizing tissue damage during surgery is of obvious relevance to the outcome of GFS, and we have shown that simple changes in surgical and antimetabolite application technique can radically reduce side-effects even when the same concentrations of antimetabolites are used68 (Figure 28.6). Amniotic membrane, used as a physical spacer, may increase the success of GFS, as it appears to have antiangiogenic, anti-inflammatory, and antifibrotic characteristics. Amniotic membrane has been tested in both animal models of GFS69 and in humans,70,71 with encouraging results. Lately, two pieces of amniotic membrane soaked in MMC were sutured, one under the scleral flap and one into the subconjunctival space, in a study performed in trabeculectomies of high-risk patients (who had had two or more trabeculectomies with MMC). After 6–18 months, IOP was found to be significantly reduced.72 A bioequivalent gel may, in future, perform the function of amniotic membranes. Gas, such as perfluoropropane or sodium hyaluronate 2,3%, may improve subconjunctival drainage spaces with resultant creation of more diffuse blebs (Figure 28.7).73,74 Creation of a subscleral aqueous outflow channel with femtosecond laser in an in vivo study was shown to decrease IOP significantly.75 Devices made of relatively inert materials already used in other spaces, such as the suprachoroidal space, may also facilitate aqueous outflow by keeping the surgical field free of scar tissue (Box 28.6). However, in many cases the continuous inflammatory reaction due to the presence of the biomaterial leads to excessive scarring and poor postoperative results.

Conclusions and future directions

New treatments and refining existing treatments to prevent scarring after disease, trauma, or surgical intervention represent the aim of many scientific groups worldwide. More effective drug delivery methods are sought for post-GFS management because it is clearly vital for the prevention of blindness. The long-term requirement of treatment and the narrow therapeutic window of drugs in current use still limit the control of scarring. Sustained-release delivery systems,

Figure 28.7  Dramatic change in bleb appearance with change in MMC treatment area.

including liposome encapsulation,76 microspheres,77 scleral plugs,78 and biodegradable implant polymers, may have a significant future role. With our ability to combine agents will come better efficacy. An example is the combination of 5-FU and heparin to prevent PVR.79

The ability to control fibrotic processes fully in the eye offers the tantalizing prospect of 100% success of glaucoma surgery with pressure around 10 mmHg associated with minimal progression over a decade. For that reason, in addition to traditional chemical drugs, the development of new technologies such as dendrimers, antibodies, aptamers, ribozymes, gene therapy with viral vectors, and RNA interference is necessary and opens the door to achieve this aim. Finally, most exciting is the prospect that neutralizing the fibrotic response to disease and injury will allow us to revert to the “fetal” mode when regeneration is the “normal” process, such as shown in a recent report which demonstrated that induction of bcl-2 gene expression together with downregulation of gliosis results in axonal regeneration in mice.80 Modifying matrix and cell conditions allows intrinsic stem cells to differentiate into different cells of the retina like lower species, which can regenerate a severely damaged complex retina and possibly the optic nerve.81

Acknowledgments

The authors acknowledge the support of the Medical Research Council, Moorfields Trustees, the Haymans Trust, Ron and

Liora Moskovitz Foundation, the Michael and Ilse Katz Foundation, the Helen Hamlyn Trust in memory of Paul Hamlyn, Fight for Sight (UK), School of Pharmacy University of London, and the AG Levendis Foundation. This research has received a proportion of its funding from the

Department of Health’s National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital and the UCL Institute of Ophthalmology. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health.

4.Shaunak S, Thomas S, Gianasi E, et al. Polyvalent dendrimer glucosamine conjugates prevent scar tissue formation. Nat Biotechnol 2004;22:977–984.

7.Chang L, Crowston JG, Cordeiro MF, et al. The role of the immune system in conjunctival wound healing after glaucoma surgery. Surv Ophthalmol 2000;45(1):49–68.

12.Khaw PT, Grehn F, Hollo G, et al.

A phase III study of sub-conjunctival human anti-transforming growth factor beta(2) monoclonal antibody (CAT-152) to prevent scarring after first-time trabeculectomy. Ophthalmology 2007;114(10):1822–1830.

13.Mead AL, Wong TTL, Cordiero MF, et al. Anti-Transforming growth factor–β2 antibody: a new post operative antiscarring agent in glaucoma surgery. Invest Ophthalmol Vis Sci 2003;44: 3394–3401.

14.Nakamura H, Siddiqui SS, Shen X, et al. RNA interference targeting transforming growth factor-beta type II receptor suppresses ocular inflammation and fibrosis. Mol Vis 2004;4:703–711.

17.Massague J. Wounding Smad. Nat Cell Biol 1999;1:E117–E119.

28.Broadway DC, Grierson I, O’Brien C, et al. Adverse effects of topical antiglaucoma medication. II. The outcome of filtration surgery. Arch Ophthalmol 1994;112:1446–

1454.

49.Kirwan JF, Constable PH, Murdoch IE, et al. Beta irradiation: new uses for an old treatment: a review. Eye 2003;17: 207–215.

55.Perkins TW, Faha B, Ni M, et al. Adenovirus-mediated gene therapy using human p21WAF-1/Cip-1 to prevent wound healing in a rabbit model of glaucoma filtration surgery. Arch Ophthalmol 2002;120:941–949.

63.Daniels JT, Cambrey AD, Occleston NL, et al. Matrix metalloproteinase inhibition modulates fibroblast-mediated matrix contraction and collagen production

in vitro. Invest Ophthalmol Vis Sci 2003; 44:1104–1110.

64.Wong TT, Mead AL, Khaw PT. Matrix metalloproteinase inhibition modulates postoperative scarring after experimental

glaucoma filtration surgery. Invest Ophthalmol Vis Sci 2003;44:1097– 1103.

65.Wong TT, Mead AL, Khaw PT. Prolonged antiscarring effects of ilomastat and MMC after experimental glaucoma filtration surgery. Invest Ophthalmol Vis Sci 2005;46:2018–2022.

68.Wells AP, Bunce C, Khaw PT. Flap and suture manipulation after trabeculectomy with adjustable sutures: titration of flow and intraocular pressure in guarded filtration surgery. J Glaucoma 2004;13: 400–406.

79.Asaria RH, Kon CH, Bunce C, et al. Adjuvant 5-fluorouracil and heparin prevents proliferative vitreoretinopathy: results from a randomized, double-blind, controlled clinical trial. Ophthalmology 2001;108:1179–1183.

81.Lawrence JM, Singhal S, Bhatia B, et al. MIO-M1 cells and similar muller glial cell lines derived from adult human retina exhibit neural stem cell characteristics. Stem Cells 2007;25(8):2033–2043.

Clinical background

The idea that factors other than elevated intraocular pressure (IOP) contribute to the pathophysiological processes underlying glaucoma was formulated more than 150 years ago. Von Graefe was the first to recognize that glaucoma can occur despite normal IOP.1 Only 1 year later Jaeger proposed the vascular concept as cause for normal-tension glaucoma (NTG).2 The prevalence of NTG as estimated from different studies differs significantly. On average it is now assumed that 30–40% of all primary open-angle glaucoma (POAG) patients have normal IOP,3 a proportion that rises to 90% in Japan.4

The fact that optic nerve head damage and loss of visual field are not related only to elevated IOP is also seen from other arguments. On the one hand a large number of subjects have elevated IOP without showing signs of glaucoma, a condition known as ocular hypertension. The rate of conversion from ocular hypertension to glaucoma is small. Therefore, a large proportion of ocular hypertensive patients never develop glaucoma. On the other hand several multicenter trials have shown that a large proportion of patients with glaucoma progress despite IOP-lowering therapy.5,6

In this chapter the evidence that reduced blood flow plays a role in the glaucomatous process will be summarized. Unfortunately, measurement of ocular blood flow is difficult and currently available techniques are not suitable for clinical practice. This makes it difficult to discern whether a specific patient shows signs of vascular dysregulation (Box 29.1) in the optic nerve head or retina. Hence, the diagnosis of vascular dysregulation in glaucoma patients largely relies on indirect evidence and a thorough evaluation of medical history plays a key role. Patients with vascular dysregulation often suffer from a history of cold hands. Migraine, a risk factor for the progression of NTG, can also be found in some glaucoma patients with vascular dysregulation. Obviously, measurement of systemic blood pressure is required in patients with potential vascular involvement. Ideally, a 24-hour ambulatory blood pressure profile is recorded together with a 24-hour IOP profile. This allows for identification of periods of nocturnal hypotension and low ocular perfusion pressure (OPP), which are likely associated with ischemic conditions at the level of the eye.

Blood flow changes in glaucoma

Leopold Schmetterer and Mark Lesk

When discussing the potential therapeutic implications of ocular blood flow disturbances in glaucoma one first has to consider that lowering IOP, the hallmark of glaucoma therapy, has a vascular consequence in itself. Any reduction in IOP, whether achieved pharmacologically or surgically, induces an increase in OPP. In addition, a number of drug classes that may induce direct vasodilatation at the posterior pole of the eye have been identified. The best evidence is available for carbonic anhydrase inhibitors and calcium channel blockers. Given that reduced perfusion and vascular dysregulation are risk factors for glaucoma there is a clear rationale behind such treatment. On the other hand, results of large-scale clinical trials showing that improving ocular blood flow is associated with beneficial effects on visual fields are lacking. Is it conceivable to assume that vasodilator treatment is beneficial for glaucoma? At least some studies show that short-term improvements of visual fields in glaucoma are closely related to vasodilatation, particularly in vasospastic subjects. However, vasodilator therapy could also induce negative effects, including disturbance of autoregulatory mechanisms, increase of capillary hydrostatic pressure, or shunting of blood to other vascular beds. Hence, large-scale clinical trials are urgently required. At the moment any attempted vasodilator treatment in glaucoma patients needs to be done under careful monitoring of visual fields and drug-related adverse events, but may be tried in patients who progress despite optimal IOP reduction. It may currently be more fruitful to evaluate patients for nocturnal hypotension and to treat this, if present, in collaboration with other physicians.

Pathology

The specific tissue changes characteristic for glaucoma are covered in other chapters of this book. Clinical findings suggesting that vascular phenomena are important in glaucoma include the common finding of flame hemorrhages of the optic nerve head neuroretinal rim in open-angle glaucoma patients (Figure 29.1).7 A flame hemorrhage is commonly followed by the appearance of a new nerve fiber layer defect and subsequent progressive visual field loss, suggesting that a vascular phenomenon is contributing to disease progression. These hemorrhages are interpreted as a sign of vascular

Figure 29.1  Optic nerve head neuroretinal rim flame hemorrhage and beta-peripapillary atrophy.

Box 29.1  Clinical findings in systemic vasospasm

(vascular dysregulation)

strain in the optic nerve head, but their cause and mechanism are unknown. Arterial narrowing may also be seen overlying the disk in glaucoma.8 Beta-peripapillary atrophy is associated with glaucomatous optic nerve changes and is linked to glaucoma progression9 (Figure 29.1). This atrophy is hypothesized to be vascular in origin, because it is characterized histologically as a loss of choriocapillaris (Box 29.2).

Attempts have been made to characterize specific phenotypes in optic disk appearance associated with the presence of vascular risk factors10 (Box 29.3). According to this work glaucomatous optic nerve head appearance has been divided into four subtypes: (1) focal glaucomatous optic disk; (2) myopic glaucomatous optic disk; (3) senile sclerotic optic disk; and (4) generalized enlargement of the optic disk cup. The vast majority of glaucomatous disks, however, appear to have features of two or more of these disk types. However, some risk factors were associated with a higher prevalence of a specific disk appearance. Ischemic heart disease was more prevalent among patients with senile sclerotic glau-

Box 29.2  Clinical vascular findings in primary

open-angle glaucoma/normal-tension glaucoma

Ocular

Box 29.3  Clinical characteristics of four glaucoma

disk types (data from Broadway et al10)

Focal ischemic

Focal notch or acquired pit of the optic nerve head, some peripapillary atrophy

•  Vasospasm

•  Cold hands and feet •  Migraine

•  Rim flame hemorrhages •  Two-thirds are female

Senile sclerotic

Shallow saucerized cupping, peripapillary atrophy around most of the disk

•  Older age

•  Systemic cardiovascular disease •  Hypertension

•  Reduced blood flow in the ophthalmic artery •  Slower rate of progression

Myopic disk

Tilted disk with a crescent of peripapillary atrophy

•  Younger age

•  Some vasospasm •  Myopia

•  Two-thirds are male

Concentric cupping

Round, concentric cup without localized rim thinning

•  Younger age

•  Markedly elevated intraocular pressure •  Low prevalence of vascular risk factors

coma in comparison with the other groups. A suggestion of a greater prevalence of systemic hypertension in the senile sclerotic group and of migraine and vasospasticity in the focal glaucomatous group was also observed. Larger studies are required to characterize in more detail which risk factors

Diastolic perfusion pressure (mmHg)

Figure 29.2  Systemic vascular findings in glaucoma. There is a sixfold risk of glaucoma for subjects with the lowest ocular perfusion pressure. POAG, primary open-angle glaucoma. (Baltimore Eye Survey: reproduced with permission from Tielsch JM, Katz J, Sommer A, et al. Hypertension, perfusion pressure, and primary open-angle glaucoma. A population-based assessment. Arch Ophthalmol 1995;113:216–221.)

Time (years)

Figure 29.3  Migraine is a risk factor for the progression of normal-tension glaucoma. (Collaborative Normal Tension Glaucoma Study: reproduced with permission from Drance S, Anderson DR, Schulzer M, et al. Risk factors for progression of visual field abnormalities in normal-tension glaucoma. Am J Ophthalmol 2001;131:699–708.)

are associated with specific optic disk appearance and patterns of visual field loss.

Etiology

A number of vascular risk factors for the prevalence, incidence, and progression of POAG have been identified.

Low systemic blood pressure

Systemic blood pressure has been closely linked to prevalence of open-angle glaucoma. Epidemiologic studies indicate a markedly increased prevalence of glaucoma in people with lower diastolic OPP. In the Baltimore Eye Study, there was a sixfold increased risk of OAG in subjects having the lowest diastolic OPPs11 (Figure 29.2). These findings were confirmed in different populations in the Egna-Neumarkt Eye Study12 and the Rotterdam Eye Study.13 The Barbados Study of Eye Disease subsequently observed an elevated incidence of OAG in subjects with low OPP and low blood pressure.14 The Early Manifest Glaucoma Trial demonstrated an increased risk of glaucoma progression in patients with low OPP.15 Low OPP appears to be the most important vascular risk factor for POAG.

High blood pressure

While in general lower blood pressures and OPPs are associated with glaucoma, epidemiological evidence suggests that systemic hypertension may play a role as well,11,12 particularly in older patients. This association is hypothesized to result from a breakdown of vascular autoregulation in longstanding hypertension. One needs, however, to consider that there is a correlation, albeit weak, between IOP and systemic blood pressure.12

Box 29.4  Evidence for vascular etiology of glaucoma from the Collaborative Normal Tension

Glaucoma Study (data from Drance et al17 and Anderson DR and Drance SM, 2003)

Greater rate of progression in:

•  Migraineurs

•  Patients with disk hemorrhages •  Women (vascular mechanism?)

Lesser response to intraocular pressure therapy if:

Vasospasticity and migraine

Vasospasticity or vascular dysregulation is associated with POAG.16 In the Collaborative Normal Tension Glaucoma Study, there was a 2.5-fold risk of visual field progression in patients reporting a history of migraine17 (Figure 29.3 and Box 29.4). Schulzer et al18 defined two populations of glaucoma patients: those with predominantly atherosclerotic workups and those with peripheral vasospasm (Figure 29.4). While there was no correlation between the maximum known IOP and the degree of visual field damage in the atherosclerotic group, there was a strong positive correlation in the vasospastic group. The authors interpreted their findings to suggest that, while in atherosclerotic patients optic nerve damage might be IOP-independent, in vasospastic patients the IOP damage was IOP-dependent. Hafez et al19 subsequently demonstrated that, in OAG, there exists a correlation between the degree of vasospasticity and the amount

MD

A

20

15

10

5

0

IOP

MD

B

20

15

10

5

0

IOP

of change of neuroretinal rim blood flow upon IOP reduction. In other words, neuroretinal rim blood flow may be more sensitive to changes in IOP in vasospastic patients than in nonvasospastic patients.

Anticardiolipin antibodies

Anticardiolipin antibodies (ACA) are present in acquired prothrombotic syndromes and are linked to ischemic stroke, myocardial infarction, and systemic lupus erythematosus, but it is not known if they are causal or merely a sign of ongoing vascular inflammatory disease. A recent prospective clinical trial found a strong association between positive ACA and progression of open-angle glaucoma, although the prevalence of positive ACA was low in the study population.20 This suggests that vascular inflammatory factors may be linked to OAG, although at this time it is impossible to know whether they are causal or secondary to neurovascular damage.

Ocular blood flow and visual field progression

In order to prove definitively that abnormal ocular blood flow contributes to the pathophysiology of glaucoma a prospective large-scale clinical trial is required. Such a trial would test the hypothesis that reduced blood flow is an independent risk factor for glaucoma. There are some smallscale studies that examined this. In a prospective study of 44 newly diagnosed OAG patients, a lower diastolic velocity and higher resistivity index in the ophthalmic artery were associated with markedly greater risk of visual field progression over a 7-year follow-up.21 This is in good agreement with other data showing that reduced diastolic velocity in the central retinal artery is associated with progression of the disease.22 Martinez and Sánchez also studied OAG patients

226

Box 29.5  Vascular phenomena associated with

visual field progression in glaucoma

prospectively and found that patients with subsequent visual field progression had significantly greater resistance indexes in the ophthalmic artery at baseline.23 Another small-scale study suggested that patients with the smallest improvements in optic nerve head blood flow in response to initial IOP reduction had the greatest risk of visual field progression over 4.5 years24 (Box 29.5).

Pathophysiology

Although there is a large body of evidence that glaucoma is associated with reduced blood flow to the posterior pole of the eye in general and the optic nerve head specifically, it is currently assumed that the disease process is more closely linked to vascular dysregulation. Vascular dysregulation refers to an abnormal vasoconstrictor or vasodilator response to stimulations such as changes in perfusion pressure, increase in neural activity, or changes in neural input. The reason for this vascular dysregulation in glaucoma is not