Evaluation of the Anterior Chamber Angle in Glaucoma

Ophthalmic Technology Assessment

Evaluation of the Anterior Chamber Angle in Glaucoma A Report by the American Academy of Ophthalmology Scott D. Smith, MD, MPH,1 Kuldev Singh, MD, MPH,2 Shan C. Lin, MD,3 Philip P. Chen, MD,4 Teresa C. Chen, MD,5 Brian A. Francis, MD,6 Henry D. Jampel, MD, MHS7 Objective: To assess the published literature pertaining to the association between anterior segment imaging and gonioscopy and to determine whether such imaging aids in the diagnosis of primary angle closure (PAC). Methods: Literature searches of the PubMed and Cochrane Library databases were last conducted on July 6, 2011. The searches yielded 371 unique citations. Members of the Ophthalmic Technology Assessment Committee Glaucoma Panel reviewed the titles and abstracts of these articles and selected 134 of possible clinical significance for further review. The panel reviewed the full text of these articles and identified 79 studies meeting the inclusion criteria, for which the panel methodologist assigned a level of evidence based on a standardized grading scheme adopted by the American Academy of Ophthalmology. Three, 70, and 6 studies were rated as providing level I, II, and III evidence, respectively. Results: Quantitative and qualitative parameters defined from ultrasound biomicroscopy (UBM), anterior segment optical coherence tomography (OCT), Scheimpflug photography, and the scanning peripheral anterior chamber depth analyzer (SPAC) demonstrate a strong association with the results of gonioscopy. There is substantial variability in the type of information obtained from each imaging method. Imaging of structures posterior to the iris is possible only with UBM. Direct imaging of the anterior chamber angle (ACA) is possible using UBM and OCT. The ability to acquire OCT images in a completely dark environment allows greater sensitivity in detecting eyes with appositional angle closure. Noncontact imaging using OCT, Scheimpflug photography, or SPAC makes these methods more attractive for large-scale PAC screening than contact imaging using UBM. Conclusions: Although there is evidence suggesting that anterior segment imaging provides useful information in the evaluation of PAC, none of these imaging methods provides sufficient information about the ACA anatomy to be considered a substitute for gonioscopy. Longitudinal studies are needed to validate the diagnostic significance of the parameters measured by these instruments for prospectively identifying individuals at risk for PAC. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2013;120:1985-1997 ª 2013 by the American Academy of Ophthalmology. The American Academy of Ophthalmology prepares Ophthalmic Technology Assessments (OTAs) to evaluate new and existing procedures, drugs, and diagnostic and screening tests. The goal of an assessment is to review the available research systematically for clinical efficacy and safety. After review by members of the Ophthalmic Technology Assessment Committee, other Academy committees, relevant subspecialty societies, and legal counsel, assessments are submitted to the Academy’s Board of Trustees for consideration as official Academy statements. The objective of this assessment was to assess techniques for evaluation of the anterior chamber angle (ACA) and to determine whether such imaging aids in the diagnosis and management of glaucoma.

Background Strategies for the treatment of glaucoma differ according to glaucoma subtype and are based on the identification of the  2013 by the American Academy of Ophthalmology Published by Elsevier Inc.

mechanism of intraocular pressure (IOP) elevation. Initial therapeutic options for primary open-angle glaucoma (POAG) include the use of glaucoma medications, laser trabeculoplasty, or both, whereas primary angle-closure glaucoma (PACG) generally requires initial treatment with laser peripheral iridotomy (LPI). The assessment of the ACA is critical in distinguishing POAG from PACG. This assessment is made clinically by gonioscopy, allowing the observer to visualize directly the anatomic relationships of the iris, cornea, and ACA structures. However, gonioscopy is a subjective technique, and there are no universally accepted gonioscopic criteria for determining the anatomic threshold that justifies treatment to prevent PACG.1,2 The natural history of PACG remains poorly understood. Classification of individuals with narrow angles based on the results of ophthalmic evaluation, including gonioscopy and other clinical findings, is important in the management of their glaucoma. One system classifies individuals as ISSN 0161-6420/13/$ - see front matter http://dx.doi.org/10.1016/j.ophtha.2013.05.034

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Ophthalmology Volume 120, Number 10, October 2013 being a primary angle-closure suspect (PACS) or as having primary angle closure (PAC) or PACG. Classification as a PACS is defined by iridotrabecular contact of 180
or more without the presence of IOP elevation or peripheral anterior synechiae (PAS). Individuals with PAC have, in addition to iridotrabecular contact, IOP elevation, PAS, or both with no secondary cause, whereas those with PACG also have glaucomatous optic neuropathy. This system is the basis for the American Academy of Ophthalmology Primary Angle Closure Preferred Practice Pattern Guideline3 and is consistent with the World Glaucoma Association consensus on angle closure and angle-closure glaucoma.4 Imaging devices have been used to allow a more objective assessment of the ACA. High-frequency ultrasound biomicroscopy (UBM) was the first method that allowed imaging of angle structures with sufficient resolution to permit qualitative and quantitative ACA assessment.5 The essential components of UBM are identical to conventional B-scan ultrasound devices, except that the former uses significantly higher-frequency ultrasound transducers. These highfrequency transducers provide resolution of 20 to 60 mm and a depth of tissue penetration of approximately 4 mm.6 To obtain a reasonable balance between image resolution and depth of tissue penetration, the most widely used commercial versions of UBM have a 50-MHz ultrasound transducer that requires coupling to the eye with a water bath or other coupling device. This requirement makes the examination time consuming and inconvenient to perform in the routine clinical setting. As a result, alternative noncontact optical imaging methods have been developed for ACA assessment, including systems based on optical coherence tomography (OCT), Scheimpflug photography, and the scanning peripheral anterior chamber depth analyzer (SPAC). Optical coherence tomography is a high-resolution optically based imaging system that uses low-coherence interferometry to provide cross-sectional images of ocular tissues. Modifications of OCT to improve the imaging characteristics for anterior segment applications include the use of a 1310-nm infrared light source. This wavelength offers better penetration through tissues that are not transparent to the 830-nm light source used in traditional time-domain OCT devices designed for retinal imaging.7 As a consequence, direct imaging of the ACA is possible. The OCT instrument that has been studied most extensively in anterior segment imaging is the Visante OCT (Carl Zeiss Meditec, Dublin, CA). This time-domain OCT instrument provides resolution of 10 to 20 mm.6 Although direct imaging of the ACA is possible with OCT, this and other optical methods for anterior segment imaging cannot reliably image structures posterior to the iris, including the ciliary body, peripheral lens, and lens zonules. Scheimpflug photography of the anterior segment is based on the Scheimpflug principle, a technique that involves nonparallel orientation of the lens and image planes to correct for perspective distortion. This technique uses light in the visible spectrum and cannot visualize the ACA directly. Standard Scheimpflug photography obtains anterior segment images in a single cross-section. The Pentacam (OCULUS Optikgeräte GmbH, Wetzlar, Germany) represents a variation of Scheimpflug photography that uses a rotating camera that can image the anterior

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segment in 3 dimensions using 25 to 50 cross-sectional images. A second camera captures eye movement to allow improved centration of the images captured by the rotating camera.8 The SPAC developed by Kashiwagi et al9 (Takagi Seiko Co., Ltd., Iwafune, Japan) is an optical system that uses a slit-lamp microscope angled 60
from the optical axis of the eye that moves along an 8-mm track to create a series of 21 images of the cornea and iris, spaced at 0.4-mm intervals. Positioning the scan region to cover the peripheral anterior chamber and the limbus allows SPAC to obtain a series of images that are captured by a digital camera and are analyzed by an integrated computer system. This device, which captures information about the peripheral anterior chamber depth (ACD), essentially constitutes an automated and quantitative van Herick test. As is the case with slitlamp biomicroscopy and Scheimpflug photography, this noncontact optical system uses light in the visible spectrum that cannot penetrate optically opaque tissues and therefore does not allow direct visualization of ACA structures because of total internal reflection. The application of imaging technology to the ACA has led to the definition of a variety of quantitative parameters that describe anterior segment anatomic features. The use of these parameters has made it possible to compare different imaging devices and to assess correlations between the quantitative information available through imaging and the semiquantitative and qualitative information derived from gonioscopy. Common parameters used to describe features of the ACA and other aspects of the anterior segment include the angle opening distance (AOD), the angle recess area (ARA), the trabecular-iris space area (TISA), and the trabecular-ciliary process distance (Fig 1). Parameters specifically describing the ACA can be measured at varying intervals anterior to the scleral spur. Studies reporting these parameters most frequently use a location 500 or 750 mm anterior to the scleral spur, or both, to define AOD (i.e., AOD500, AOD750), ARA, and TISA.

Questions for Assessment The objective of this OTA was to assess anterior segment imaging and gonioscopy in the evaluation of the ACA by answering 2 questions: (1) How does the information provided from anterior segment imaging correlate with gonioscopy? and (2) Does anterior segment imaging provide additional information that can aid in the diagnosis of PAC?

Description of Evidence Searches of the peer-reviewed literature were conducted on June 23, 2009, November 30, 2009, and May 5, 2010, in the PubMed and Cochrane Library databases without date restrictions. The searches yielded 196 unique citations (Fig 2). The search strategy used the following medical subject heading (MeSH) and text terms: glaucoma, anterior chamber, anterior eye segment, optical coherence tomography, ultrasound biomicroscopy, UBM, acoustic

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Evaluation of the Anterior Chamber Angle in Glaucoma microscopy, noncontact scanning peripheral anterior chamber depth analyzer, SPAC, Scheimpflug, photography and clinical trial, meta-analysis, or review. Additional searches used the Cochrane Highly Sensitive Search Strategy10,11 in combination with the clinical terms. Three additional studies12e14 were identified from surveillance of the literature, for a total of 199 retrievals. Additional broader literature searches in PubMed and the Cochrane Library on July 5 and 6, 2011, retrieved an additional 172 unique citations. The PubMed search strategy for these searches was: ((Glaucoma[MeSH Terms]) OR (glaucoma[tiab])) AND ((anterior chamber angle*[tiab]) OR (anterior chamber depth[tiab]) OR (AC angle*[tiab]) OR (AC depth[tiab]) OR (ACA[tiab]) OR (ACD[tiab]) OR (narrow angle*[tiab]) OR (angle width [tiab]) OR (angle opening distance[tiab]) OR (closed angle*[tiab]) OR (angle-closure[tiab]) OR (parameter* [tiab])) AND ((Anterior Eye Segment[MeSH Terms]) OR (anterior segment[tiab]) OR (Anterior Chamber[MeSH Terms]) OR (anterior chamber[tiab])) AND ((Tomography, Optical Coherence[MeSH Terms]) OR (optical coherence tomography[tiab]) OR (OCT[tiab]) OR (Visante [tiab]) OR (anterior segment imag*[tiab]) OR (ultrasound biomicroscopy[tiab]) OR (UBM[tiab]) OR (Microscopy, Acoustic[MeSH Terms]) OR (scanning peripheral anterior chamber depth analyzer[tiab]) OR (SPAC[tiab]) OR (Scheimpflug[tiab])). This search was restricted to clinical trials, meta-analyses, comparative studies, evaluation studies, multicenter studies, follow-up studies, observational studies, cross-sectional studies, population-based studies, and community-based studies. The same search strategy was used in the Cochrane Library but without publication type restrictions. Neither the PubMed search nor the Cochrane Library search was limited by publication date. Members of the Ophthalmic Technology Assessment Committee Glaucoma Panel reviewed the titles and abstracts of these articles and selected 134 of possible clinical relevance for further review. All citations selected for final review were in the English language. Potentially relevant publications in languages other than English were not considered for inclusion, as in prior glaucoma-specific OTAs. Abstracts of meeting presentations were not included in the assessment. The full text of selected citations was divided among the panel members, who

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Figure 1. A, Angle opening distance at 500 mm anterior to the scleral spur (AOD500), defined as the distance from the corneal endothelium to the anterior iris perpendicular to a line drawn along the trabecular meshwork,

at 500 mm from the scleral spur. B, Angle recess area at 500 or 750 mm from the scleral spur (ARA500, ARA750), defined as the area bounded by the corneal endothelium, trabecular meshwork, and anterior iris surface out to a distance of 500 or 750 mm from the scleral spur, including the lake of fluid posterior to the scleral spur. C, Trabecular-iris space area up to 500 or 750 mm from the scleral spur (TISA500, TISA750), defined as the area bounded by the corneal endothelium, trabecular meshwork, and anterior iris surface out to a distance of 500 or 750 mm from the scleral spur, excluding the lake of fluid posterior to the scleral spur. Adapted by permission from BMJ Publishing Group Ltd. See JLS, Chew PTK, Smith SD, et al. Changes in anterior segment morphology in response to illumination and after laser iridotomy in Asian eyes: an anterior segment OCT study. Br J Ophthalmol 2007;91:1485e9.

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Figure 2. Reports evaluated for inclusion in the Evaluation of the Anterior Chamber Angle in Glaucoma Ophthalmic Technology Assessment. OCT ¼ optical coherence tomography; SPAC ¼ scanning peripheral anterior chamber depth analyzer.

reviewed them in a standardized fashion. Panel members applied the following criteria to determine eligibility for inclusion in the assessment: (1) the purpose of the study was to assess techniques for evaluating the ACA for the presence or risk of developing PAC; (2) the study used UBM, anterior segment OCT, Scheimpflug photography, or SPAC for ACA imaging; (3) the study constituted original research; and (4) not all study participants were minors (younger than 18 years). Seventy-nine studies met the inclusion criteria, and the methodologist on the panel (K.S.) reviewed them for evidence quality. The evidence rating scale was modified from one developed by the Oxford Centre for Evidence Based Medicine.15 A level I rating was assigned to studies reporting an independent masked comparison of an adequately sized cohort of consecutive patients with and without glaucoma, all of whom had undergone both the diagnostic test and an appropriate reference standard. A level II rating was assigned to smaller, independent, masked, or objective comparisons; studies performed in a set of nonconsecutive patients; or studies confined to a narrow spectrum of participants, all of whom had received both the diagnostic test and an appropriate reference standard. A level III rating was applied to studies

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in which the reference standard was not objective, masked, or independent. A total of 3 studies provided level I evidence regarding questions raised in this OTA, 70 studies provided level II evidence, and 6 studies level III evidence. In the description of published results below, specific mention is made of the 3 studies that provided level I evidence.

Published Results Ultrasound Biomicroscopy No studies meeting the inclusion criteria for this OTA provided level I evidence related to UBM imaging in patients with or at risk for PACG. All of the studies relating to UBM that were reviewed provided level II evidence, with the exception of 3 studies that provided level III evidence. In a study by Kondo et al,16 individuals with a narrow ACA (Shaffer grade 2) underwent UBM before and after a prone provocation test. In the subset of eyes that demonstrated IOP elevation, UBM images obtained in the supine position demonstrated an open but narrow ACA both before and after the provocation test. No comparison

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of UBM findings was made between eyes with and without IOP elevation. However, these results suggested that in some eyes with narrow angles, IOP elevation occurs before the angle becomes closed. Subsequent studies reported that in some eyes with narrow angles (Shaffer grade 2), appositional angle closure could be identified by UBM. Imaging in several quadrants demonstrated that eyes with PAS have a larger extent of apposition,17 a shorter trabecular-ciliary process distance,18 greater iris convexity,19 a narrower ACA, a smaller iris-zonule distance, and a smaller scleral-ciliary process angle20 than those without PAS. Fellow eyes of patients who had experienced a unilateral attack of acute PAC were found to have more extensive appositional angle closure than normotensive eyes with narrow angles.21 In addition, Friedman et al22 demonstrated that such eyes have significantly shorter axial length, a thicker lens, shallower ACD, and smaller AOD than populationbased control subjects after adjusting for differences in age and sex. They also found that anterior chamber shallowing in response to low-light conditions or treatment with pilocarpine was greater in cases than in control subjects. Marchini et al23 demonstrated biometric differences between eyes with PACG and normal subjects with regard to ACA and other anatomic parameters indicative of a crowded anterior segment. Angle-closure glaucoma eyes had shorter axial length, a shallower ACD, a thicker and more anteriorly located lens, a narrower ACA measurement, a shorter trabecular-ciliary process distance, and a smaller AOD500. The shorter trabecular-ciliary process distance and smaller AOD were also found in PACG patients compared with POAG patients and normal control subjects.24 Comparison of UBM imaging in photopic and scotopic lighting conditions in eyes with gonioscopically narrow angles also has demonstrated that in a subset of eyes, apposition develops in low-light conditions, and that these eyes tend to have a smaller ARA.25 Studies comparing results of UBM imaging and gonioscopy have demonstrated associations between these methods of ACA evaluation, both in terms of the ACA width26e28 and the presence or absence of iridotrabecular apposition, particularly when both gonioscopy and imaging are performed in low-light conditions where light-induced pupil constriction is minimized.17,29,30 Correlation coefficients describing the correlation between AOD500 and gonioscopic grade were reported in 1 study to be between 0.52 and 0.58, depending on the angle being evaluated.28 Another study31 reported the correlation coefficient between the measured ACA by UBM and gonioscopy grade to be 0.90. In addition to demonstrating qualitative and quantitative anatomic differences between eyes at risk for PACG and normal eyes, changes in anterior segment anatomic features have been documented by UBM after treatment. Laser peripheral iridotomy is performed for the treatment or prevention of PACG to eliminate relative pupillary block and thus to relieve any pressure gradient between the anterior and posterior chambers. Changes in iris configuration after LPI have been demonstrated by comparing UBM images in eyes with or suspected of having PAC. Gazzard et al32 demonstrated that in the fellow eyes of Asian patients

who underwent LPI after acute PAC, UBM imaging showed widening of the ACA peripherally without an increase in central ACD. They found that iris morphologic features after laser treatment differed from those seen with angle widening associated with pupil constriction, and observed a reduction in iris convexity occurring after LPI but not after light-induced pupil constriction. Other studies confirmed their findings of an increased AOD250, AOD500, and ARA after LPI33,34 and showed additional findings of an increased trabecular-iris angle35,36 and a smaller trabecular-ciliary process distance.37 Areas of persistent iridotrabecular contact after LPI have been reported in association with smaller ACA dimensions and a thicker iris.34,38 Ramani et al39 evaluated a group of PACS patients prospectively for 2 years after prophylactic LPI. They found that the 28% of patients who progressed to PAC, defined by the development of PAS during followup, had a smaller ARA measured by UBM at baseline. Plateau iris configuration is another anatomic feature seen in some eyes with PAC that has been characterized by specific findings on UBM imaging. These findings include anterior positioning of the ciliary processes with anterior displacement of the adjacent iris, a steep rise in the iris root from its point of insertion, a flat central iris plane, and absence of the ciliary sulcus. These anatomic features, which can contribute to persistence of a narrow ACA after LPI, have been reported to occur in a high proportion of PACS40 and patients with PACG.13,14,41,42 Long ciliary processes with absence of the ciliary sulcus but without the typical plateau iris configuration also have been described in some eyes with appositional angle closure based on UBM images of the anterior segment.43 In addition to demonstrating the natural iris configuration, modifications to the eye cup used as a water bath during UBM imaging have been made to enhance the visualization of certain anatomic characteristics in patients with narrow angles. Matsunaga et al44,45 have described the results of UBM imaging using this modified eye cup, which produces corneal indentation while it is in place. The device creates an angle configuration similar to that seen clinically when performing indentation gonioscopy, with posterior bowing of the peripheral iris.46 This technique was found to enhance particular anatomic features, including PAS and plateau iris configuration. Imaging of the ACA with UBM after cataract surgery in patients with angle-closure glaucoma has also demonstrated changes in anterior segment anatomic features. Reported changes include an increase in ACD and AOD500, as well as a reduction in anterior positioning of the ciliary processes as reflected by an increase in the trabecular-ciliary process distance.47,48 The level II evidence cited above supports the conclusion that quantitative and qualitative interpretations of UBM images of the ACA correlate with gonioscopic findings. In addition, UBM imaging can provide supplemental anatomic and biometric information characterizing the anterior segment that is associated with PACG, including quantitative parameters describing the angle anatomic features, the position of the ciliary body, the trabecular-ciliary process distance, and the presence of

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Ophthalmology Volume 120, Number 10, October 2013 a plateau iris configuration. In addition, changes in anterior segment anatomic features in response to light- or druginduced pupil constriction seem to differ between individuals at risk for PAC and to individuals not at risk for PAC. Furthermore, the results of UBM imaging may be predictive of the subsequent progression from PACS to PAC.39 Finally, anatomic changes after LPI that may confirm the efficacy of treatment in reducing the subsequent risk of acute PAC have been demonstrated by UBM. Level III evidence supported other studies with level II evidence but did not lead to any independent conclusions.

Optical Coherence Tomography Three studies49e51 evaluating anterior segment OCT imaging of the ACA were rated as providing level I evidence. The remaining studies investigating OCT that met the inclusion criteria provided level II evidence, with the exception of 1 study that provided level III evidence. Radhakrishnan et al52 reported a comparative study of OCT and UBM using a prototype anterior segment OCT device (Carl Zeiss Meditec, Dublin, CA) that preceded the availability of a commercial unit. Gonioscopy, UBM, and OCT imaging were performed in 14 eyes of 7 subjects with PAC who had not undergone previous LPI. An additional 17 eyes of 17 normal control subjects underwent the same procedures. They reported that anterior segment anatomic parameters measured by each instrument had a strong correlation to the Shaffer gonioscopic grade. This was demonstrated by a high degree of accuracy of classification of eyes based on the presence of a narrow angle (Shaffer grade 1 in all quadrants). Areas under the receiver operating characteristic curve ranging between 0.96 and 0.98 for AOD, ARA, and TISA were reported for each imaging method. Differences in image characteristics between UBM and OCT were identified in this study. These included better imaging of the ciliary body by UBM; in OCT images, there was shadowing of structures behind the iris but sharper definition of the scleral spur. The results of this study subsequently were confirmed using the commercial device.53 Mansouri et al54 further confirmed that whereas values of ACA parameters measured by UBM and OCT were highly correlated,52 parameters measured by UBM tended to be smaller than those measured by OCT, perhaps related to the positioning necessary for UBM imaging. Wirbelauer et al55 used a slit-lamp-adapted OCT instrument to evaluate the correlation of ACA parameters measured with gonioscopy. They reported a strong correlation between OCT-measured ACA and AOD with gonioscopy, with correlation coefficients of 0.85 and 0.80, respectively. The parameter that they reported as having the best performance in classifying eyes with narrow angles (Shaffer grade 2 in all quadrants) was the ACA, with sensitivity of 0.86 and specificity of 0.95. This was achieved using a cutoff value for ACA of 22
. Using a cutoff value of 0.29 mm, AOD500 demonstrated sensitivity and specificity of 0.85 and 0.90, respectively. This instrument also was used to investigate anterior segment anatomic differences

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between eyes after an episode of acute PAC and fellow eyes that had not experienced such an episode.56 This study demonstrated significant differences in a wide range of parameters, including a smaller ACD, smaller ACA, and more extensive appositional angle closure, in eyes after acute PAC. Another report described OCT imaging of the anterior segment using a commercially available time-domain device typically used for posterior segment imaging.57 This study did not evaluate quantitative parameters of the anterior segment but described the use of this instrument in 3 patients and documented widening of the ACA after LPI and laser iridoplasty. The authors noted that in some images obtained with this device, which uses an 830-nm light source, the ACA apex was obscured because of opaque tissues present at the limbus. Studies have reported the use of anterior segment OCT to assess the effect on anterior segment anatomic features of light-induced changes in pupil size. Investigators have described results similar to those previously reported for UBM, including a substantial reduction in AOD and TISA with increased pupil diameter under low-light conditions.58e60 Eyes with a narrower ACD demonstrated a greater change in these parameters with physiologic mydriasis.59,60 Laser peripheral iridotomy has been shown to result in pupil constriction and significant widening of the ACA, as assessed by OCT.58,61e63 This finding has been demonstrated in both Asian58,63 and white62 individuals. A study investigating potential anatomic differences that may account for the racial variation in PACG prevalence64 enrolled 60 Chinese and 60 white subjects.65 Half of the subjects in each group were classified as having narrow angles (Shaffer grade 2) by gonioscopy. Optical coherence tomography images of the anterior segment were obtained from 1 eye of each subject. A comparison of a wide range of parameters demonstrated no differences between Chinese and white subjects in mean age, axial length, ACA measurements, pupil diameter, or iris convexity. However, in both open-angle and narrow-angle subjects, after adjusting for the potential effects of confounding factors, ACD and anterior chamber width (ACW; defined by the horizontal scleral spur-to-scleral spur distance) were smaller in Chinese eyes. Similar results were seen in a study evaluating a community-based cohort of 2047 individuals older than 50 years and in a hospital-based cohort of 111 PAC or PACG patients in Singapore.66 This study found that eyes with narrow angles (trabecular meshwork not visible on nonindentation gonioscopy for 180
) had smaller ACD and ACW than eyes with open angles. Subjects diagnosed with PAC or PACG had even smaller mean ACW than those classified as PACS. Other factors associated with a smaller ACW included female sex, Chinese ethnicity, and older age. In addition to ACW, other parameters associated with PAC also have been identified. Nongpiur et al67 investigated lens parameters measured by OCT imaging and their relationship to gonioscopic grading of the ACA. They defined lens vault by the perpendicular distance between the anterior pole of the crystalline lens and the horizontal

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line joining the scleral spur on each side of the anterior chamber. In a group of 102 Chinese subjects with PAC or PACG and 176 normal Chinese subjects with open angles categorized by the value of lens vault, the quartile with the largest values showed a 48-fold increased risk of having PAC compared with the lowest quartile. The absence of an association between PAC and lens thickness or ACD indicated that anatomic variation of the lens position relative to the ACA is an important factor in eyes at risk for PAC. A variety of iris parameters also have been quantified by OCT imaging. The cross-sectional area of the iris was measured from OCT images in a clinic-based group of POAG and PACG patients or suspects.68 This parameter was shown to decrease with increasing pupil size. However, in PACG patients, the reduction in iris crosssectional area was less pronounced with pupil dilation compared with POAG patients. Iris volume also has been estimated using OCT imaging and has been shown to be greater in fellow eyes of patients after an episode of acute PAC than in normal control eyes.69 Furthermore, iris volume has been found to increase after pharmacologic dilation of the pupil but is not affected by the presence of a patent LPI.12,49,70 Wang et al49 performed a community-based study in Singapore (level I evidence) that demonstrated significant associations between gonioscopically narrow angles and anatomic features of the iris. This cross-sectional study recruited 2047 individuals 50 years of age or older from a government primary health care clinic. Subjects underwent gonioscopy and anterior segment OCT imaging under scotopic conditions. Among the 1465 eyes with images that could be analyzed, 315 eyes (21.5%) had narrow angles (posterior trabecular meshwork not visible for 180
on nonindentation gonioscopy in the primary position). Multivariate logistic regression analysis adjusting for age, sex, ACD, axial length, and pupil size was used to compare the odds of having a narrow angle among individuals in the first and fourth quartiles of several iris parameters. Larger values of iris curvature, iris cross-sectional area, and iris thickness measured 2 mm anterior to the scleral spur were associated with increased odds of having a narrow angle, with odds ratios of 2.5 (95% confidence interval, 1.3e5.1), 2.7 (95% confidence interval, 1.6e4.8), and 2.7 (95% confidence interval, 1.5e4.7), respectively. Other studies also have confirmed the association between iris thickness and crosssectional area with narrow angles.12,67 The reproducibility of measurements of anterior segment parameters made by OCT in eyes with narrow angles also has been investigated. In a study of both short- and longterm reproducibility, Radhakrishnan et al71 demonstrated excellent reproducibility of anterior segment anatomic parameters with repeated images obtained in the same session. The greatest reproducibility was seen with ACD measurement, with an intraclass correlation coefficient of more than 0.93 under low- and bright-light conditions. Angle parameters measured in the nasal and temporal quadrants also demonstrated very good to excellent reproducibility, with intraclass correlation coefficients ranging from 0.67 to 0.90. Images from the inferior quadrant showed

lower reproducibility, and no images were taken in the superior quadrant because it was not possible to image this quadrant without mechanical elevation of the upper eyelid. Long-term reproducibility from repeated images obtained at least 24 hours apart also was very good to excellent, with ACA parameters demonstrating an intraclass correlation coefficient between 0.56 and 0.93. Console et al72 reported greater variability in eyes with narrow angles and attributed a substantial proportion of this variability to manual identification of the scleral spur, a critical landmark in defining quantitative ACA parameters. Other clinical findings associated with PAC also have been found to correlate with the results of OCT imaging. Wang et al73 performed dark-room provocative testing in 70 subjects with no prior diagnosis of PAC but who were found to have narrow angles by van Herick grading of the peripheral ACD. Four cross-sectional images of the anterior segment were obtained at 45
intervals. In subjects with a rise in IOP of 8 mmHg or more after provocative testing, a significantly greater number of meridians demonstrated appositional angle closure on OCT images. Su et al74 demonstrated that in eyes with PAC, angles that were narrower based on OCT-measured AOD, ARA, and TISA had a greater extent of PAS than eyes with wider angles. Corresponding to the increased prevalence of PAC with increasing age,75 a cross-sectional study found that mean ACA parameters were smaller in older subjects, suggesting an age-related narrowing of the angle.76 The diagnostic accuracy of OCT parameters in identifying individuals with narrow angles has been evaluated in several clinic-based studies. Nolan et al77 recruited 203 subjects from glaucoma clinics in Singapore with a diagnosis of PAC, PACG, POAG, or nuclear sclerosis of the lens without glaucoma. Each angle quadrant was classified as being open or closed on gonioscopy based on the presence of iridotrabecular contact in that quadrant. The corresponding OCT image for each ACA quadrant was used to determine the association between the presence of gonioscopic- and OCT-identified appositional angle closure. Using this method, the investigators found that 44.4% of eyes had gonioscopic evidence of appositional angle closure in 1 or more quadrants, whereas 66.7% of eyes had angle closure identified by OCT. The higher proportion of angle closure identified by OCT was thought to result from the need for slit-lamp illumination of the eye during gonioscopy, leading to pupil constriction, whereas OCT images could be obtained in a completely dark environment. Using a slit-lamp-based OCT instrument and the same definition for angle closure on gonioscopy, similar findings were reported by Wong et al.78 This study also found a higher proportion of eyes demonstrating appositional angle closure by OCT than by gonioscopy. Pekmezci et al79 evaluated the diagnostic performance of OCT in identifying narrow angles in a clinic-based population of 303 eyes of 155 patients, some of whom had a prior diagnosis of PAC or PACG or had previously undergone prophylactic LPI for suspicion of PAC. The results of OCT measurement of ACA parameters using high- and low-magnification scanning protocols were compared with gonioscopic grade, demonstrating a high

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Ophthalmology Volume 120, Number 10, October 2013 correlation for each parameter at each level of magnification. Correlation coefficients for each of these parameters ranged from 0.60 to 0.74. Using optimal cutoff values, the sensitivity and specificity for classifying eyes with narrow angles (Shaffer grade 2) using ARA were 0.70 and 0.87, respectively. The corresponding sensitivity and specificity for AOD500 were 0.72 and 0.85, respectively. Sakata et al80 compared the stand-alone commercial anterior segment OCT device with a slit-lamp-based instrument. Using gonioscopy as a reference standard, this study reported a high sensitivity of both instruments in detecting angle closure, with a greater proportion of closed angles being detected by each OCT instrument than by gonioscopy. The slit-lamp-based system, however, identified fewer eyes with closed angles, which was thought to be because of the need for dim illumination when using this device in contrast to standard OCT. The relative ease of obtaining OCT versus UBM images makes the former more practical than the latter for application on a large scale and has led to the use of OCT in several community- and population-based studies of PAC. Xu et al50 performed a study (level I evidence) that evaluated OCT images obtained from 2985 subjects enrolled in the population-based Beijing Eye Study. Images were obtained using a slit-lamp-based instrument. Gonioscopy was performed in those subjects with a history of glaucoma or in those suspected of having glaucoma after the ophthalmic examination that was performed at the time of enrollment. Based on multivariate statistical modeling of the OCT-measured ACA as a continuous variable, characteristics of subjects associated with a smaller ACA included older age, female sex, hyperopic refractive error, smaller body weight, shorter stature, presence of a larger optic disc, presence of nuclear cataract, and diagnosis of PACG. Lavanya et al51 performed a community-based crosssectional study (level I evidence) that enrolled 2052 subjects 50 years of age and older from a community polyclinic in Singapore. All subjects underwent anterior segment imaging with OCT and SPAC. The results of biometric measurements were compared with gonioscopy, which was performed in all subjects. Of the 2052 subjects evaluated, narrow angles were diagnosed by gonioscopy in at least 1 eye in 20.4% of subjects and were defined by the presence of visible posterior pigmented trabecular meshwork for 180
or less. Appositional angle closure in 2 or more quadrants on OCT imaging was used to define a narrow angle. Using gonioscopy as a reference standard, the presence of OCT-defined iridotrabecular apposition demonstrated sensitivity and specificity of 0.88 and 0.63, respectively. The relatively low specificity of OCT in this study raised concern by the investigators that its usefulness in large-scale screening for PAC may be limited. Concern about low specificity also was noted in another community-based study in Singapore that evaluated different OCT scanning protocols to identify narrow angles.77 The authors reported that images from the inferior quadrant offered the best diagnostic performance and had sensitivity of 0.84 but relatively low specificity of 0.69. However, in each of these studies, the relatively low specificity also may have been a reflection of the failure of gonioscopy to identify all subjects with iridotrabecular apposition.

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Other large, community-based studies evaluating OCT have confirmed the results of earlier studies in clinic-based populations. In a study of 502 consecutive subjects enrolled in a community clinic in Singapore, Sakata et al81 confirmed that a higher proportion of eyes were found to have narrower angles by OCT than by gonioscopy, particularly in the superior and inferior quadrants. The superior quadrant was most likely to demonstrate iridotrabecular apposition. Narayanaswamy et al82 reported that in a community-based cross-sectional study of 2047 Singaporeans, AOD750 offered the best diagnostic performance for classifying gonioscopically narrow angles and that poor definition of the scleral spur was a significant problem that precluded analysis of 25% of OCT images. Sihota et al83 evaluated 398 subjects in northern India by OCT and demonstrated that 38.7% had a measured ACA width of less than 20
, suggesting a high prevalence of narrow angles in this population. Spectral-domain OCT has been used to image the ACA and has been able to identify angle structures not readily seen with time-domain OCT. The improved resolution achieved with spectral-domain OCT allows imaging of structures including Schwalbe’s line and the trabecular meshwork in a high proportion of images.84 However, the shorter wavelengths of laser light used in most spectraldomain OCT does not allow for complete visualization of the angle recess because of blockage of transmission by the sclera. Level I and level II evidence cited above supports the conclusion that OCT imaging, like UBM, provides useful supplemental information to clinical evaluation with gonioscopy. Parameters describing the anterior segment anatomic features correlate well with both gonioscopy and UBM. This evidence also indicates that OCT imaging does not provide reliable imaging of structures posterior to the iris. However, evidence that OCT imaging performed in completely dark conditions identifies a higher number of eyes with appositional angle closure suggests that it may be more sensitive than gonioscopy in detecting eyes at risk of PAC. Level III evidence confirmed the findings of other studies but led to no additional conclusions.

Scheimpflug Photography No studies meeting the inclusion criteria for this OTA provided level I evidence related to Scheimpflug photography imaging of the anterior segment. Each of the studies relating to this technology provided level II evidence, with the exception of 2 that provided level III evidence. In a study comparing UBM, Scheimpflug photography measurements of the ACA width, and gonioscopy, Friedman et al28 found that correlations between gonioscopic grade and ACA measurements obtained by Scheimpflug photography were weaker than those obtained by UBM. Correlation coefficients ranged from 0.34 to 0.36 for Scheimpflug photography compared with 0.52 to 0.58 for UBM, depending on the angle being measured. The authors noted differences between these imaging methods with respect to the quadrant of the angle that was found to be narrowest. For example, the temporal angle was found to be narrowest by Scheimpflug photography and widest by UBM. This

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observation suggests that factors related to patient positioning, the mechanical forces applied to the eye by UBM, or both may alter the measurements. However, they also reported that data from Scheimpflug photography were generally less satisfactory than those from UBM because of greater variability in the measured ACA and relatively poor correlations to other clinical parameters compared with UBM. Several anatomic features of eyes at risk for PAC previously documented by UBM also have been found to show characteristic findings by Scheimpflug photography. In a study evaluating both UBM and Scheimpflug imaging in fellow eyes of acute PAC patients, Friedman et al22 found that Scheimpflug photography, like UBM, was able to demonstrate anatomic differences in these eyes compared with population-based control subjects. The ACA width was significantly narrower in cases than in control subjects. In addition, cases demonstrated greater narrowing of the ACA in response to pilocarpine-induced pupil constriction than did control subjects. A study by Yang and Hung85 evaluated patients with chronic PACG undergoing cataract surgery and posterior chamber intraocular lens placement. Comparison of Scheimpflug photography before and after surgery demonstrated an increase in ACW and ACD after surgery. Studies investigating the results of rotating Scheimpflug photography have demonstrated strong correlations between parameters measured by the Pentacam and gonioscopic grade. Categorizing subjects by Shaffer grade, Kurita et al31 reported correlation coefficients of 0.65, 0.85, and 0.81 for Pentacam-measured ACA, ACD, and anterior chamber volume, respectively. However, the correlation between Shaffer gonioscopy grade and UBM-measured ACA was greater than the correlation with Pentacam-measured ACA. The most efficient distinction between eyes with open angles (grade 3) and eyes with narrow angles (grade 2) was found using a cutoff parameter of 2.58 mm for ACD, which provided a sensitivity of 1.00 and specificity of 0.87. The authors noted that the identification of the ACA apex often was not possible, making measurement of the angle width less reproducible than the measurement of ACD or anterior chamber volume. Two studies reporting changes in anterior segment anatomy after LPI in PACS or PAC patients demonstrated changes in several parameters measured by Pentacam.86,87 Li et al86 reported no change in the central ACD but found an increase in peripheral ACD, ACA, and anterior chamber volume after LPI. Level II evidence cited above supports the conclusion that information obtained by Scheimpflug photography is similar to some of the information that can be obtained by UBM to describe anterior segment anatomic features in eyes with, or at risk for, PACG. However, the nature of Scheimpflug imaging does not allow detailed imaging of angle structures or the ciliary body as can be achieved by UBM. Evidence also suggests that the reproducibility of measurements using Scheimpflug photography and their correlation to gonioscopy may be less than those identified by UBM. Level III evidence supported other studies providing level II evidence but led to no additional conclusions.

Scanning Peripheral Anterior Chamber Depth Analyzer One study meeting the inclusion criteria for this OTA provided level I evidence related to SPAC imaging of the anterior segment. Six of the studies relating to this technology provided level II evidence, and 1 study provided level III evidence. The first report of SPAC being used to investigate anterior segment anatomic features in eyes with PAC confirmed the increase in peripheral ACD and flattening of the iris contour in response to LPI that had been demonstrated previously by UBM.88 These findings were observed in a series of PACS and PAC patients, some of whom had experienced an acute episode of angle closure. Subsequent studies demonstrated statistically significant differences in peripheral ACD at each measurement location when comparing a group of PACG patients with a gonioscopic grade of 2 or less with a group of POAG patients with a gonioscopic grade of 3 or more89 and a strong correlation between SPAC measurements of peripheral ACD and UBM-measured values of AOD500.90 In an effort to understand the ability of SPAC measurements to detect individuals at high risk of developing acute PAC who require prophylactic or therapeutic LPI, Kashiwagi et al91 evaluated 552 phakic patients in a glaucoma clinic setting. Individuals in whom PAC already had developed or who were considered to be at high risk for developing PAC were classified according to the following criteria: (1) gonioscopy grade 1 or less of at least 180
; and (2) rise in IOP 6 mmHg or more after a prone provocation test, presence of PAS, or iridotrabecular apposition; and (3) IOP of 21 mmHg or more, or glaucomatous cupping with a confirmed visual field defect. All subjects underwent SPAC imaging. Using these criteria, the sensitivity and specificity for identifying diseased or high-risk eyes were 0.98 and 0.84, respectively. They reported a high level of accuracy in the classification of subjects, with an area under the receiver operating characteristic curve of 0.98. Kashiwagi and Tsukahara92 reported the results of screening a population-based sample for PAC using SPAC. Although they reported sensitivity and specificity of 0.89 and 0.80, respectively, for identifying PAC patients and suspects in this population, gonioscopy was performed only in a small subset of individuals referred for definitive examination, making a valid assessment of sensitivity impossible. Further investigation of the ability of SPAC to classify individuals at risk for PAC by Baskaran et al93 demonstrated that measurements were correlated strongly with angle assessment by the modified van Herick test. Their study, which enrolled a group of glaucoma patients representing the full spectrum of angle configurations, reported that the sensitivity and specificity of SPAC for identifying narrow angles using optimal cutoff criteria were 0.85 and 0.73, respectively, worse than the van Herick test’s sensitivity of 0.85 and specificity of 0.90. The relatively low specificity of SPAC was an indication of a significantly greater number of individuals being classified as having narrow angles than by either the van Herick test or gonioscopy. Wong et al78 also investigated the diagnostic performance of SPAC and a slit-lamp-based anterior segment OCT

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Ophthalmology Volume 120, Number 10, October 2013 system in identifying individuals at risk for PAC in a hospital-based glaucoma clinic. They reported sensitivity and specificity for SPAC of 0.80 and 0.80, respectively, which were similar to the measures observed for OCT. Lavanya et al51 conducted a population-based study in Singapore (level I evidence, described in detail earlier) that also found similar diagnostic performance between SPAC and anterior segment OCT. This study demonstrated that SPAC showed slightly better agreement with gonioscopy than did OCT, with sensitivity of 0.90 and specificity of 0.77 using an optimal cutoff value. Level I and level II evidence cited above supports the conclusion that information obtained from SPAC correlates well with that obtained by OCT and UBM. The information from SPAC is more limited in that it describes only the peripheral ACD rather than providing the more detailed anatomic information of these other instruments. However, it seems to provide similar diagnostic accuracy in identifying individuals at risk of PACG. Level III evidence supported the same conclusions as those based on level I and level II evidence.

Conclusions The available literature provides evidence that information obtained from anterior segment imaging by UBM, OCT, Scheimpflug photography, and SPAC correlates with information obtained from gonioscopy. In addition, each of these imaging methods can provide an objective assessment and documentation of the angle, as well as quantitative information describing the anterior segment anatomic features that supplements the qualitative information provided by a clinical assessment using gonioscopy. Imaging with UBM provides the greatest range of anatomic information, given the ability of ultrasound to penetrate through ocular tissues that are opaque to light. Scheimpflug photography and SPAC provide more limited information because of their use of light in the visible spectrum that does not allow direct imaging of the ACA. The noncontact nature of OCT, Scheimpflug photography, and SPAC allows greater ease of obtaining images than UBM does, making them more practical for use in large-scale screening programs for PAC. None of these methods in their present form provides sufficient information about the anatomic features of the ACA to be considered as a substitute for gonioscopy. For example, PAS, pigmentation of angle structures, and angle neovascularization cannot be identified reliably by these instruments. Rather, anterior segment imaging may be considered as providing useful supplemental information to gonioscopy. Imaging allows the quantitative and qualitative evaluation of a range of anatomic parameters that correlate with the presence of PAC. In addition, it is possible to demonstrate responses to physiologic and pharmacologic changes in pupil size, as well as changes after LPI that may be indicative of disease risk and efficacy of laser therapy. The current literature indicates that anterior segment imaging demonstrates good correlation with gonioscopy and the presence of PAC. However, there have been few studies that provide level I evidence of its usefulness as a supplement to gonioscopy in the evaluation of patients at risk for

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PACG. There have been no appropriately powered longitudinal clinical studies demonstrating that imaging can be used to predict the future development of PAC and PACG. Because our understanding of the specific anatomic parameters that may be most useful in the diagnosis of PAC and the prospective validation of such parameters remains incomplete, the added benefit of using these devices for clinical care is not clear.

Future Research To understand fully the potential usefulness of anterior segment imaging in the diagnosis of PAC, longitudinal studies investigating the efficacy of LPI in preventing progression from PACS to PAC and PACG are needed. Studies have been initiated to identify anatomic characteristics measured by anterior segment imaging that are most useful in selecting individuals who may benefit from LPI. Such studies also may provide greater insight into the effectiveness of LPI in preventing PACG. In addition, technological advances in ophthalmic imaging are ongoing, particularly with respect to OCT. The proliferation of spectral-domain OCT devices offers additional opportunities to evaluate the ACA with higher resolution. This, in turn, may lead to improved diagnostic accuracy and the identification of better parameters to estimate the risk of PACG development.

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Footnotes and Financial Disclosures Originally received: May 2, 2013. Final revision: May 2, 2013. Accepted: May 6, 2013. Available online: August 27, 2013. 1

7 Glaucoma Center for Excellence, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Manuscript no. 2013-719.

Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates.

2

Department of Ophthalmology, Stanford University School of Medicine, Stanford, California. 3 Department of Ophthalmology, University of California, San Francisco, San Francisco, California. 4

Department of Ophthalmology, University of Washington, Seattle, Washington. 5

Harvard Medical School, Department of Ophthalmology, Massachusetts Eye & Ear Infirmary, Glaucoma Service, Boston, Massachusetts. 6 Doheny Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California.

Prepared by the Ophthalmic Technology Assessment Committee Glaucoma Panel and approved by the American Academy of Ophthalmology’s Board of Trustees February 23, 2013. Financial Disclosure(s): The author(s) have made the following disclosure(s): Kuldev Singh Consultant - iScience. Funded without commercial support by the American Academy of Ophthalmology. Correspondence: Nicholas Emptage, MAE, American Academy of Ophthalmology, Quality Care and Knowledge Base Development, 655 Beach Street, San Francisco, CA 94109-1336, Email: [email protected]

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