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

Box 24.5  Mechanism of glaucoma and

directed therapy

Blockage of aqeous outflow by a combination of pigment and exfoliation material in the intertrabecular spaces and juxtacanalicular meshwork is believed to be the major cause of elevated intraocular pressure. Therapy designed to prevent this buildup (directed therapy) is a major goal for the future. At the present time, 2% pilocarpine given at bedtime suffices to produce a 3-mm nonreactive pupil throughout the day and limits release of pigment and exfoliation material

Argon laser trabeculoplasty (ALT) is particularly effective, at least early on, in eyes with XFS. Approximately 20% of patients develop sudden, late rises of IOP within 2 years of treatment.26 Continued pigment liberation may overwhelm the restored functional capacity of the trabecular meshwork, and maintenance of miotic therapy (again 2% pilocarpine qhs) to minimize pupillary movement after ALT might counteract this. Selective laser trabeculoplasty needs further evaluation as an effective and safe alternative to ALT in the treatment of XFG.

Trabeculectomy results are comparable to those in POAG. Trabeculotomy is also successful.27 Jacobi et al28 described a procedure termed trabecular aspiration, designed to improve outflow facility by eliminating the trabecular blockage by pigment and XFM. Deep sclerectomy and similar procedures including a deroofing of Schlemm’s canal are becoming popular choices in some centers owing to the reduced risk profile of nonpenetrating surgery. In one series, XFG patients had significantly better success than POAG patients following deep sclerectomy with an implant.29 Moreover, phacoemulsification combined with penetrating and nonpenetrating procedures does not seem to influence success rate adversely.

Etiology

Several lines of evidence, including regional clustering, familial aggregation, and genetic linkage analyses, had previously supported a genetic predisposition to XFS.30 Recently, a genome-wide association study detected two common SNPs in the coding region of the LOXL1 gene on chromosome 15q24 that were specifically associated with XFS and XFG in two Scandinavian populations from Iceland and Sweden, accounting for virtually all XFS cases.31 These diseaseassociated polymorphisms appeared to confer risk of glaucoma mainly through XFS. The combination of alleles formed by the two coding polymorphisms determined the risk of developing XFG, which is increased by a factor of 27 if the high-risk haplotype is present. Individuals carrying two copies of this high-risk haplotype would have a 700-times increased risk of developing XFG. Moreover, these genetic alterations also lead to decreased tissue expression of LOXL1 dependent on the individual haplotype. These genetic findings have been confirmed in populations of European descent in Iowa,32 New York,33 Utah,34 Boston,35 and Australia.36 One different SNP and one common SNP have been reported in a Japanese population.37 The LOXL1 gene

Pathogenesis of exfoliation syndrome and exfoliative glaucoma

variations are not associated with POAG or primary angle closure.38

LOXL1 is a member of the lysyl oxidase family of enzymes, which are essential for the formation, stabilization, maintenance, and remodeling of elastic fibers and prevent agerelated loss of tissue elasticity.39 It is involved in cross-linking tropoelastin to mature elastin using elastic microfibrils as a scaffold,40 thus serving both as a cross-linking enzyme and as a scaffolding element which ensures spatially defined elastin deposition.41 The functional consequences of the LOXL1 gene variants in XFS are not yet known; however, inadequate tissue levels of LOXL1 could predispose to impaired elastin homeostasis and to increased elastosis. Genetic variation in LOXL1 may be a factor in spontaneous cervical artery dissection, a cause of stroke in younger patients.42 Reduced LOXL1 levels are also found in patients with varicose veins and venous insufficiency.43 Overactivity of lysyl oxidase, with localization of the enzyme in blood vessel walls and in plaque-like structures, has been found in Alzheimer’s disease.44 Mice deficient in LOXL1 develop pelvic organ prolapse secondary to a generalized connective tissue defect,45 and women with prolapse have reduced mRNA for LOXL1.46 Marked elastosis with elastic fiber degeneration has been observed in the skin and connective tissue of the lamina cribrosa in XFS eyes.47 Although further studies correlating the genetic variants and tissue alterations associated with XFS are needed, these new findings already provide a basis for both genetic testing and novel treatment approaches.

Various nongenetic factors, including dietary factors, autoimmunity, infectious agents, and trauma, have also been hypothesized to be involved in the pathogenesis of XFS. Reports dealing with sunlight exposure (ultraviolet radiation) are conflicting. Eskimos are the only people reported to have no XFS, but it is common in Lapps living at the same latitude.48 Persons living at lower latitudes develop XFS at younger ages, whereas those living at higher altitudes had a greater prevalence in two series49,50 but not in a third.51 In one series, XFS was detected more frequently in eyes with blue irides versus brown irides.52 Herpes simplex virus type 1 was detected by polymerase chain reaction in 13.8% of iris and anterior capsule specimens of patients with XFS compared to 1.8% of controls.53 Younger patients have developed XFS after penetrating keratoplasty using buttons from elderly donors.54–57 Altogether, it appears that XFS represents a complex, multifactorial, late-onset disease, involving both genetic and nongenetic factors in its pathogenesis.

Pathogenesis of exfoliation syndrome and exfoliative glaucoma

A precise understanding of the pathogenesis of XFS remains elusive. However, the pathologic process in intraand extraocular tissues is characterized by the progressive accumulation of an abnormal fibrillar matrix, which is the result of either an excessive production or an insufficient breakdown or both, and which is regarded as pathognomonic for the disease based on its unique light microscopic and ultrastructural criteria.

Ultrastructure and composition of exfoliation material

Exfoliation fibers are clearly distinguishable from any other known form of extracellular matrix. Light microscopy reveals XFM to be periodic acid–Schiff (PAS)-positive, eosinophilic, bush-like, nodular, or feathery aggregates on the surfaces of anterior-segment tissues. On transmission electron microscopy, the aggregates consist of randomly arranged, fuzzy fibrils, 25–50 nm in diameter, frequently with 20–25 or 45–50 nm cross-banding. These composite fibers are generally associated with 8–10 nm microfibrils, which resemble elastic microfibrils and which aggregate laterally into mature fibers. However, the microfibrillar core of the complex fibers is usually hidden by a coating of electron-dense amorphous material.

The exact chemical composition of XFM remains unknown. Indirect histochemical and immunohistochemical evidence suggests a complex glycoprotein/proteoglycan structure composed of a protein core surrounded by abundant glycoconjugates, including various glycosaminoglycans (heparin sulfate, chondroitin sulfate, hyaluronan) indicating excessive glycosylation.58 The protein components contain epitopes of the elastic fiber system, such as elastin, tropo­ elastin, amyloid-P, and vitronectin.59 Components of elastic microfibrils, such as fibrillin-1, microfibril-associated glycoprotein (MAGP-1), and the latent TGF-ß-binding proteins (LTBP-1 and LTBP-2), are associated with XFM deposits in intraand extraocular locations and co-localize with latent TGF-ß1 on exfoliation fibers.60–63

A recent direct analytical approach using liquid chromatography coupled with tandem mass spectrometry (LC-MS/ MS) showed XFM to consist of the elastic microfibril components fibrillin-1, fibulin-2, and vitronectin, the proteoglycans syndecan and versican, the extracellular chaperone clusterin, the cross-linking enzyme lysyl oxidase, and some other proteins, confirming many of the previously reported immunohistochemical data.63 Together, these findings support the notion that XFM represents an elastotic material arising from abnormal aggregation of elastic microfibril components interacting with multiple ligands.

Origin of exfoliation material

Ocular XFM is closely associated with the nonpigmented ciliary epithelium, pre-equatorial lens epithelium, iris pigment epithelium, trabecular and corneal endothelia, and virtually all cell types in the iris stroma and vasculature, all showing signs of active fibrillogenesis.23,64 Passive distribution of XFM by the aqueous humor may be responsible for abnormal deposits on the central anterior lens capsule, the zonules, the anterior hyaloid surface, vitreous, and intraocular lenses. In extraocular locations, fibers are found in close proximity to connective tissue fibroblasts, vascular wall cells, smooth and striated muscle cells, and cardiomyocytes.65,66

Molecular pathogenesis

Differential gene expression

With gene expression analyses, XFS tissues contained a number of differentially expressed genes, which were mainly

Box 24.6  Other mechanisms and approaches

There is increasing evidence that cellular stress conditions (oxidative stress, ischemia/hypoxia) are involved in the pathobiology of exfoliation syndrome and that a low-grade inflammatory component is present. Homocysteine levels are elevated and vitamins B6, B12, and folate are reduced. Therapies based on these facets of the disease may prove beneficial

involved in extracellular matrix metabolism and in cellular stress.67,68 Onesetofgenesconsistentlyupregulatedinanteriorsegment tissues comprised the elastic microfibril components fibrillin-1, LTBP-1 and LTBP-2, the cross-linking enzyme transglutaminase (TGase)-2, TIMP-2, TGF-ß1, several heat shock proteins (Hsp 27, Hsp 40, Hsp 60), proinflammatory cytokines, apolipoprotein D, and the adenosine receptor (AdoR)-A3. Genes reproducibly downregulated in XFS tissues included TIMP-1, the extracellular chaperone clusterin, the antioxidant defense enzymes glutathione- S-transferases (mGST-1, GST-T1), components of the ubiquitin-proteasome pathway (ubiquitin conjugating enzymes E2A and E2B), several DNA repair proteins (ERCC1, hMLH1, GADD 153), the transcription factor Id-3, and serum amyloid A1.

Together, these findings provide evidence that the underlying pathophysiology of XFS is associated with an excessive production of elastic microfibril components, enzymatic cross-linking processes, overexpression of TGF-ß1, a proteolytic imbalance between MMPs and TIMPs, low-grade inflammatory processes, increased cellular and oxidative stress, and an impaired cellular stress response, as reflected by the downregulation of antioxidative enzymes, ubiquitinconjugating enzymes, clusterin, and DNA repair proteins (Box 24.6).

Pathogenetic factors and key molecules

Factors which might stimulate the synthesis and stable deposition of XFM include growth factors, a dysbalance of MMPs and TIMPs, and increased cellular and oxidative stress conditions (Figure 24.6).

Apart from increased concentrations of various growth factors (basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), connective tissue growth factor (CTGF), in the aqueous humor of XFS patients,69,70 TGF-ß1, a major modulator of matrix formation in many fibrotic diseases, appears to be a key mediator in the XFS process. It is significantly increased in the aqueous humor of XFS patients, in both its latent and active form, it is upregulated and actively produced by anterior-segment tissues, and it regulates most of the genes differentially expressed in XFS eyes, e.g., fibril- lin-1, LTBP-1 and -2, TGase-2, and clusterin.71,72 Binding of TGF-ß1 to XFM via the TGF-ß binding proteins LTBP-1 and -2 may represent a mechanism of regulation of growth factor activity in XFS eyes. Whereas the TGF-ß3 isoform was also reported to be significantly increased in aqueous humor of XFS patients,73 levels of TGF-ß2 were significantly higher in the aqueous humor of POAG patients but not that of XFS patients.

Changes in the local MMP/TIMP balance and reduced MMP activity in aqueous humor and tissues may further

Exfoliative material

Pathogenesis of exfoliation syndrome and exfoliative glaucoma

Figure 24.6  Summary of pathogenetic concept of exfoliation syndrome.

promote abnormal matrix accumulation in XFS. Significantly increased concentrations of MMP-2, MMP-3, TIMP-1, and TIMP-2 were detected in aqueous humor of XFS patients with and without glaucoma compared to controls.74,75 However, levels of endogenously active MMP-2, the major MMP in human aqueous humor, were significantly decreased, as was the ratio of MMP-2 to TIMP-2, resulting in a molar excess of TIMP-2 over MMP-2. An imbalance of MMPs and TIMPs has been also reported in meshwork specimens from XFG patients.76

There is increasing evidence that cellular stress conditions (oxidative stress, ischemia/hypoxia) are involved in the pathobiology of XFS. Significantly reduced levels of antioxidants (ascorbic acid, glutathione) and increased levels of oxidative stress markers (8-isoprostaglandin-F2α, malondialdehyde) in aqueous humor, serum, and tissues indicate a faulty antioxidative defense system and increased oxidative stress in the anterior chamber of XFS eyes.77–81

Development of glaucoma

Friction between the iris and the lens surface leads to disruption of the iris pigment epithelium at the sphincter region and concomitant dispersion of pigment into the anterior chamber. Blockage of aqueous outflow by a combination of pigment and XFM deposited in the intertrabecular spaces, and XFM in the juxtacanalicular meshwork and beneath the endothelium of Schlemm’s canal is believed to be the major cause of elevated IOP.

Increased outflow resistance both in the trabecular meshwork and in the uveoscleral pathways,82 most probably from blockage of the outflow channels by XFM, leads to elevated IOP. Aggregates of XFM are found in the anterior portions of the ciliary muscle, on the inner surface of the trabecular meshwork, beneath the inner and outer wall of Schlemm’s canal, and in the periphery of intrascleral aqueous collector channels and aqueous veins (Figure 24.7).83 Accumulation of XFM in the meshwork may derive from both passive deposition from the aqueous on the surface of the uveal meshwork and local production by trabecular and Schlemm’s canal endothelial cells in the juxtacanalicular tissue and canal wall. Progressive accumulation of XFM in the subendothelial space leads to a marked thickening of the juxtacanalicular tissue, the site of greatest resistance to

aqueous outflow (Figure 24.8). Concomitant disruption and breakdown of the normal elastic fiber network surrounding Schlemm’s canal appear to result in a progressive destabilization and disorganization of the normal tissue architecture. Collapse of aqueous veins due to perivascular accumulation of elastotic material can also occasionally be observed.

The amount of XFM within the juxtacanalicular region correlates with the presence of glaucoma, the average thickness of the juxtacanalicular tissue, and the mean crosssectional area of Schlemm’s canal, and also with the IOP level and the axon count in the optic nerve.83,84 These findings suggest that therapeutic efforts to improve outflow need to address the alterations in the juxtacanalicular area to obtain lasting IOP reduction.

In addition to XFM and pigment obstruction of the meshwork, increased aqueous protein concentrations and cellular dysfunction may also contribute to elevated IOP. Several members of the phospholipase A2 enzyme family, which play a major role in phospholipid metabolism and membrane homeostasis, are significantly decreased in the trabecular meshwork of exfoliative glaucoma patients compared to normal controls or POAG patients.85 These observations may indicate abnormal physiological functions, decreased structural stability and flexibility, and reduced protection against oxidative stress in trabecular meshwork cells of XFG eyes.

Increased trabecular pigmentation is a prominent and early sign of XFS. In patients with clinically unilateral XFG, the pigment is usually denser in the involved eye. Eyes with POAG or eyes without glaucoma tend to have less pigmentation than eyes with XFG. Glaucomatous damage is usually more advanced in the eye with greater pigmentation. Pigment dispersion and deposition in the trabecular meshwork may lead to acute pressure rises after pupillary dilation.

Although XFG is characteristically a high-pressure disease with a predominant mechanical component of optic nerve damage, pressure-independent (e.g., vascular) risk factors, and structural alterations of the lamina cribrosa may further increase the individual risk for glaucomatous damage. In a prospective study of patients with clinically unilateral involvement, in whom IOP was equal throughout the follow-up period, disc changes took place only in the involved eye, suggesting that the exfoliative process itself

may be a risk factor for optic disc changes.86 Marked elastosis in the connective tissue sheets of the lamina cribrosa of XFS eyes may adversely affect tissue elasticity and increase the susceptibility of optic nerve fibers towards mechanical and vascular damage (Figure 24.9).87,88 Moreover, accumulation of XFM in the walls of retrobulbar vessels increased the rigidity of their walls.89 The recently identified sequence variants in the LOXL1 gene and reduced tissue levels of LOXL1, a key enzyme in elastic fiber homeostasis, may predispose to these elastotic matrix processes characterizing XFS and possibly contribute to glaucoma development in XFS patients.

Angle closure is also associated with XFS. Ritch89 found either clinically apparent XFS or XFM on conjunctival biopsy in 17 of 60 (28.3%) consecutive patients with uncomplicated primary angle closure glaucoma or occludable angles. Pupillary block may be caused by a combination of posterior synechiae, increased iris thickness or rigidity, or anterior lens movement secondary to zonular weakness or dialysis.90

Vacular abnormalities in XFS

An emerging clinical spectrum of associations with cardiovascular and cerebrovascular diseases elevates XFS to a condition of general medical importance. XFS is associated

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with ocular ischemia, particularly iris hypoperfusion and anterior-chamber hypoxia,91 and with a reduced ocular and retrobulbar microand macrovascular blood flow ocurring in both patients with and without glaucoma.92 Blood flow of the lamina cribrosa and neural rim decreases with increasing glaucomatous damage.93 In clinically unilateral cases, ipsilateral pulsatile ocular blood flow and carotid blood flow are reduced.94,95 Recently, pathological carotid artery function as well as altered parasympathetic vascular control was reported.96 In a large study, XFS was reported to be an important risk factor for coronary artery disease.97

The vasoactive peptide endothelin-1 is significantly increased in the aqueous of XFS patients,98 while levels of nitric oxide, a potent physiological vasodilator, were decreased in a small number of XFS patients.99 This imbalance may play a role in the obliterative vasculopathy of the iris causing local ischemia early in the disease process. Elevated homocysteine levels in the aqueous humor of patients with XFS100,101 may further contribute to ischemic alterations, such as endothelial dysfunction, oxidative stress, enhancement of platelet aggregation, reduction of nitric oxide bioavailability, and abnormal perivascular matrix metabolism. These findings have been summarized in a recent editorial.102

2.Lindberg JG. Clinical investigations on depigmentation of the pupillary border and the translucency of the iris in cases of senile cataract and in normal eyes in elderly persons (1917) (reprinted). Acta Ophthalmol 1989;67(Suppl 190):1–96.

4.Ritch R. Exfoliation syndrome: the most common identifiable cause of openangle glaucoma. J Glaucoma 1994;3: 176–178.

5.Prince AM, Streeten BW, Ritch R, et al. Preclinical diagnosis of pseudoexfoliation syndrome. Arch Ophthalmol 1987;105:1076–1082.

6.Mitchell P, Wang JJ, Smith W. Association of pseudoexfoliation with increased vascular risk. Am J Ophthalmol 1997;124:685–687.

23.Ritch R, Schlötzer-Schrehardt U. Exfoliation syndrome. Surv Ophthalmol 2001;45:265–315.

31.Thorliefsson G, Magnusson KP, Sulem P, et al. Common sequence variants in the LOXL1 gene confer susceptibility to

exfoliation glaucoma. Science 2007;317: 1397–1400.

47.Netland PA, Ye H, Streeten BW, et al. Elastosis of the lamina cribrosa in pseudoexfoliation syndrome with glaucoma. Ophthalmology 1995;102: 878–886.

64.Naumann GOH, Schlötzer-Schrehardt U, Küchle M. Pseudoexfoliation syndrome for the comprehensive ophthalmologist: Intraocular and systemic manifestations. Ophthalmology 1998;105:951–968.

65.Streeten BW, Li ZY, Wallace RN, et al. Pseudoexfoliative fibrillopathy in visceral organs of a patient with pseudoexfoliation syndrome. Arch Ophthalmol 1992;110:1757–1762.

66.Schlötzer-Schrehardt U, Koca MR, Naumann GOH, et al. Pseudoexfoliation syndrome. Ocular manifestation of a systemic disorder? Arch Ophthalmol 1992;110:1752– 1756.

67.Zenkel M, Poschl E, von der Mark K, et al. Differential gene expression in pseudoexfoliation syndrome. Invest Ophthalmol Vis Sci 2005;46:3742– 3752.

78.Koliakos GG, Konstas AGP, SchlötzerSchrehardt U, et al. 8-Isoprostaglandin F2a and ascorbic acid concentration in the aqueous humour of patients with exfoliation syndrome. Br J Ophthalmol 2003;87:353–356.

82.Gharagozloo NZ, Baker R, Brubaker RF. Aqueous dynamics in exfoliation syndrome. Am J Ophthalmol 1992;114: 473–478.

84.Gottanka J, Flügel-Koch C, Martus P, et al. Correlation of pseudoexfoliation material and optic nerve damage in pseudoexfoliation syndrome. Invest

Ophthalmol Vis Sci 1997;38:2435–2446.

101.Vessani RM, Liebmann JM, Jofe M, et al. Plasma homocysteine is elevated in patients with exfoliation syndrome. Am J Ophthalmol 2003;136:41–46.

Overview

Primary angle closure glaucoma (PACG) is an important cause of glaucoma worldwide, especially in East Asia,1–3 and the leading cause of bilateral glaucoma blindness in countries such as Singapore, India, and China.2–4 Recent population-based surveys have shown that PACG is most commonly an asymptomatic disease, and the visual morbidity of the condition may be related to the finding that the asymptomatic form of the disease is visually destructive.5

Clinical background

Under the International Society for Geographical and Epidemiological Ophthalmology (ISGEO) classification system, there are three stages for angle closure glaucoma (ACG)6 (Box 25.1):

1.Primary angle closure suspect (PACS) is the term for an eye in which contact between the peripheral iris and posterior trabecular meshwork is considered possible, but there are no other abnormalities in the eye.5,7 There has been some debate recently regarding the diagnostic criteria for PACS. While 270° of iridotrabecular contact (where the posterior trabecular meshwork is not visible on gonioscopy) has been used as the minimum criterion for angle closure under the ISGEO system, this has been suggested to be too strict as eyes with lesser extent of closure may still have peripheral anterior synechiae (PAS).8 An alternative definition is one in which 180° is the cutoff for defining angle closure. Such a definition was recently used in population-based surveys in India9 and Singapore.10

2.Primary angle closure (PAC) is present when there are features in the eye indicating that trabecular meshwork obstruction by the peripheral iris has occurred. Such features include PAS, increased intraocular pressure (IOP), iris whorling, glaucomflecken (Figure 25.1), lens opacities, or excessive pigment deposition on the trabecular meshwork. Importantly, the optic disc does not have signs of glaucomatous damage during this stage.

Angle closure glaucoma

Shamira Perera, Nishani Amerasinghe, and Tin Aung

3.PACG is PAC with evidence of glaucomatous optic neuropathy (GON) and visual field loss compatible with glaucoma.

Epidemiology

Age

The risk of angle closure increases with age.11,12 This appears to be due to progressive shallowing of the anterior chamber as the lens grows in thickness and moves forwards.13

Ethnicity

The highest rates of ACG have been found in the Inuits.14,15 High rates of angle closure have also been described in East Asian populations from Mongolia,1 Singapore (Chinese),11 Myanmar16 and Hong Kong,17 and the rate is lower amongst Indians,4,18 Thais,19 and Malays.11 Several population-based studies have shown that the predominant form of ACG in Asia is asymptomatic and not acute angle closure. ACG prevalence is even lower amongst Europeans, with a prevalence of about 0.1% in people over 40 years.20–22 The fact that angle closure is more common among Chinese, even after adjusting for axial length and anterior-chamber depth (ACD), suggests that mechanisms for angle closure may differ across racial/ethnic groups, and that factors such as thicker iris or ciliary body anatomy may have an important role in causing the disease.23

Clinical assessment

Gonioscopy

Gonioscopy is the main clinical method of assessing the angle. It visualizes the angle through a contact lens at the slit lamp. Various grading schemes categorize eyes on the basis of the width of the anterior-chamber angle. For example, the Spaeth classification assesses the insertion of the iris, the angular width of the angle recess, and the configuration of the peripheral iris. The Schaffer classification assesses the possibility of closure depending on which angle structures are visible (Figure 25.2).

Figure 25.1  A slit-lamp photograph of an eye in acute angle closure. The pupil is mid dilated and there is glaucomflecken – ischemic anterior lens cortex fibers.

Figure 25.2  A EyeCam view of a wide-open inferior angle where the ciliary body band can be seen. This eye is extremely unlikely to proceed to primary angle closure.

Box 25.1  International Society for Geographical and Epidemiological Ophthalmology (ISGEO) classification of primary angle closure

unlike the UBM it cannot image the ciliary body. The UBM requires a water bath to be placed on the eye of the supine patient before scanning occurs. Research comparing UBM, AS-OCT, and gonioscopy shows that AS-OCT and UBM are good at identifying narrow angles, but AS-OCT overidentifies subjects as having closed angles compared to gonioscopy.24,25

Scanning peripheral anterior-chamber (SPAC) depth analyzer

The SPAC takes rapid slit measurements of the central and peripheral ACD which are compared to a normative database, and a risk assessment for angle closure is produced.26 SPAC is sensitive, but overestimates the proportion of narrow angles relative to gonioscopy and the modified van Herick grading system for peripheral ACD assessment.27

Peripheral anterior synechiae

PAS are present when the peripheral iris attaches anteriorly in the angle extending over the trabecular meshwork. PAS may be localized or extensive, pinpoint or broad. The ideal method to assess for PAS is dynamic indentation gonioscopy.

Anterior-segment optical coherence tomography (ASOCT) and ultrasound biomicroscopy (UBM)

AS-OCT and UBM are new and promising technologies for angle assessment. AS-OCT images the angle using infrared light in a noncontact fashion. Like the UBM, semiautomated image analyses can be performed. However,

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Provocative testing

Provocation tests consist of placing subjects suspected as having angle closure into situations where there is a high chance of iridotrabecular contact. Examples include a dark room, prone positioning, and after pharmacologic pupil dilatation. However, provocative tests have not been shown to be consistently useful in correctly identifying those who are safe or at risk of angle closure.28

Acute primary angle closure

Acute primary angle closure (APAC) presents with ocular pain, nausea and vomiting, intermittent blurring of vision with haloes noted around lights, and IOP usually much greater than 21 mmHg. Typically, there is marked conjunctival injection, corneal epithelial edema, a mid dilated unreactive pupil, a shallow anterior chamber, and the presence of a closed angle on gonioscopy (Figure 25.3).

Figure 25.3  This slit-lamp photograph depicts an eye in acute primary angle closure. The cornea displays microcystic edema. The iris is mid dilated and there is conjunctival injection.

Box 25.2  Management of angle closure glaucoma

Laser

Laser peripheral iridotomy (PI)

Argon laser peripheral iridoplasty

Medical therapy

Surgery

Trabeculectomy

Lens extraction for angle closure

Combined lens extraction and trabeculectomy surgery

Treatment of angle closure glaucoma   (Box 25.2)

Laser

Laser peripheral iridotomy (LPI)

The aim of an LPI is to eliminate pupil block. The iridotomy is usually placed between 11 and 1 o’clock so as to minimize visual disturbance. In thick brown irides, sequential use of argon laser to photocoagulate and pit the iris, and subsequent use of the Nd:YAG laser to create a patent hole has been described.29 In blue irides where less power is required, Nd:YAG laser may be all that is necessary. Postlaser IOP spikes can be alleviated by brimonidine or apraclonadine perioperatively.30

If LPI fails or is unfeasible, surgical iridectomy may be pursued. No difference in terms of visual acuity or IOP has been observed between LPI and surgical iridectomy in a 3-year randomized controlled trial of unilateral APAC.31

Studies have shown that 58% of APAC subjects need further treatment of some type whilst 32% need surgery after an APAC attack treated with LPI. However, for patients with chronic PACG, 90% of patients need medications or surgery after LPI.32

Complications of LPI include increased IOP; laser burn to cornea, lens, or retina; development of posterior synechiae; and the development of a ghost image in the inferior

Acute primary angle closure

field of vision. Other rare complications include progression of cataract opacity and corneal decompensation.33

Argon laser peripheral iridoplasty

This may be indicated if the angle remains appositionally closed with high IOP. Iridoplasty involves the placement of circumferential low-energy laser burns which pull the adjacent iris out of the angle.

For cases of APAC, iridoplasty lessens the reliance on systemic medications34 which have side-effects, especially in elderly patients with systemic comorbidity. Medical therapy has a relatively slow onset, and 60% of APAC patients treated medically may still develop chronic PACG.35 In a randomized controlled trial from Hong Kong, iridoplasty was found to be better in reducing the IOP in the initial 2 hours after presentation of APAC. It was also found to lead to a low percentage of cases with subsequent PAS.35

Medical therapy

Residual chronic PACG after iridectomy or iridotomy is common in Asian patients and is usually due to lens factors, plateau iris, or trabecular meshwork damage.36

Topical beta-blockers, prostaglandin analogs, carbonic anhydrase inhibitors, and alpha-2-agonists can be used in angle closure patients in the same way as for primary openangle glaucoma (POAG) management.

Latanoprost has been shown to be more effective than timolol in lowering IOP in Asian PACG eyes,37 even in eyes with 360° of PAS.38 Pilocarpine constricts the pupil and pulls the iris away from the trabecular meshwork. However, long-term use can result in posterior synechiae and can make cataract surgery more difficult. Miotic agents have not been shown to prevent progression of angle closure, and should not be used in place of an iridotomy.

Follow-up evaluation of treated PACG/APAC

Patients should have regular IOP checks (to detect asymptomatic rises in IOP) and indentation gonioscopy. Those with residual open angle after laser iridotomy and raised IOP and/or GON are managed similarly to those with POAG.

Plateau iris

Plateau iris is considered when the iris root is rotated forwards and centrally in a particular configuration. The iris surface is relatively flat and the anterior chamber is usually deep. The angle is narrow. Dynamic gonioscopy reveals a double-hump sign where the peripheral iris drapes over the anteriorly rotated ciliary processes. These patients tend to be female and younger and may have a family history of ACG. There is usually some element of pupil block. Cataract extraction may not be so useful in eyes with plateau iris as iridociliary apposition still occurs,39 whereas argon laser peripheral iridoplasty may be effective in opening up the angles.40

Surgery

Trabeculectomy

Trabeculectomy is indicated when there is a failure of medical or laser treatment, or poor compliance or intolerance to medical treatment leading to poorly controlled glaucoma and continuing optic disc and visual field damage.

Lens extraction for angle closure

Lens extraction deepens the anterior chamber, decreases angle crowding, and relieves pupil block.41 Lai et al42 showed that this leads to a decrease in IOP, and a reduced requirement for antiglaucoma medications in PACG. Cataract surgery is technically difficult in PACG eyes because of frequently coexisting shallow anterior-chamber, large bulky lens, iris atrophy secondary to ischemia, and zonular weakness. This surgical option may be particularly useful in the setting of mild optic disc damage in PACG with coexisting cataract, but there is little evidence for its effectiveness in more severe cases of PACG.

Combined lens extraction and trabeculectomy surgery

This has been shown to have similar complication rates in PACG and POAG eyes43 and allows for an improvement in the visual acuity of PACG patients. Combined surgery may also prevent IOP spikes postoperatively and widens the angle.

Goniosynechialysis

This procedure involves stripping PAS from the angle wall, utilizing an instrument to peel PAS gently from the trabecular meshwork. However goniosynechialysis can cause IOP spikes, cataract, and hyphema. Goniosynechialysis can be combined with cataract surgery and has been found to be useful when PAS has been present for less than 1 year.44

Management of acute primary angle closure

The main aims of APAC treatment are to reduce the IOP, reduce inflammation, and reverse the angle closure. The patient is kept supine to allow gravity to aid in posterior movement of the lens and be reassessed regularly. Analgesics and antiemetics are used for symptomatic relief.

Medical therapy includes some of the following agents, based on the patient’s overall medical status:

•Topical beta-adrenergic antagonists

•Topical alpha2-adrenergic agonists

•Topical or systemic carbonic anhydrase inhibitors

•Topical miotics

•Systemic hyperosmotic agents

Hyperosmotic agents such as mannitol 20% (or glycerol orally) can be used if the IOP remains high for too long. Hyperosmotic agents reduce vitreous volume by causing an osmotic diuresis. In one study, 44% of APAC patients required an osmotic agent to reduce IOP,45 sometimes in multiple administrations. Topical steroids should be used to reduce the sometimes marked inflammatory response.

The fellow eye of APAC requires prophylactic treatment with an LPI, since half of these will otherwise suffer an acute attack within 5 years.46

Surgery for acute primary angle closure

Lens extraction for APAC

Lens removal serves to deepen the anterior chamber and open up the drainage angle. There is limited information whether primary cataract extraction as initial treatment is useful in APAC, but it is an option for refractory cases after

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attempting to break the pupillary block.47 The optimum timing of lens extraction in such cases is not known; the risks and technical difficulties of surgery have to be weighed against the need to reduce IOP.48

Long-term prognosis after APAC

In one study, in the long term (4–10 years) following an APAC attack, 18% of eyes were blind, 48% of eyes developed serious GON, and 58% of eyes had vision worse than 20/40.49

Etiology (Box 25.3)

Ocular biometry

Eyes with angle closure tend to share certain biometric characteristics. These include shallow central ACD, thick lens, anterior lens position, small corneal diameter and radius of curvature, and short axial length.13,50 Of these, a shallow ACD is regarded as the most important risk factor in most ethnic groups, and explains the high prevalence of PACG in Inuits, who have the shortest ACDs.51 A shorter ACD is more commonly found in females and those with increasing age,52 explaining their increased risk of angle closure in these groups. The lens is also more anteriorly placed in PACG eyes and is thicker than normal.53 Some, but not all, studies have shown Chinese and Indian populations to have shorter axial lengths21 and, furthermore, eyes with extremely short axial lengths are more affected by APAC than by chronic asymptomatic angle closure.28,54,55 Other studies have shown that a more anterior lens position is responsible for a greater proportion of the differences between angle closure and normal eyes.35

Genetics

A more anterior position of the lens, increased lens thickness, and shallow ACD are seen out of proportion in close relatives of patients with ACG as compared to the general population.56–59

The inheritance of PACG is believed to be polygenic,60–63 although both autosomal-dominant and recessive inheritance patterns have been seen in pedigrees. Sihota et al64 found that the ACD is shallowest, lens is thickest, and axial length shortest in family members having PACG, and these

Box 25.3  Risk factors for angle closure

•Increasing age

•Female gender

•Ethnicity:

Inuit

East Asian

•Biometry and ocular anatomy:

Hyperopia

Shallow anterior-chamber depth

Shorter axial length

•Genetic factors