Advances and Clinical Applications of Anterior Segment Imaging Techniques

Journal of Ophthalmology

Guest Editors: Sang Beom Han, Jodhbir S. Mehta, Yu‑Chi Liu, and Karim Mohamed‑Noriega Advances and Clinical Applications of Anterior Segment Imaging Techniques Journal of Ophthalmology

Advances and Clinical Applications of Anterior Segment Imaging Techniques

This is a special issue published in “Journal of Ophthalmology.” All articles are open access articles distributed under the Creative Com- mons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Editorial Board

Monica L. Acosta, New Zealand Takeshi Ide, Japan Jesús Pintor, Spain Hee B. Ahn, Republic of Korea Vishal Jhanji, Hong Kong Pawan Prasher, India Luis Amselem, Spain Thomas Klink, Germany Antonio Queiros, Portugal Usha P. Andley, USA Naoshi Kondo, Japan Anthony G. Robson, UK Siamak Ansari-Shahrezaei, Austria Ozlem G. Koz, Turkey Mario R. Romano, Italy Taras Ardan, Czech Republic Hiroshi Kunikata, Japan Dirk Sandner, Germany Francisco Arnalich-Montiel, Spain Toshihide Kurihara, Japan Ana Raquel Santiago, Portugal Takayuki Baba, Japan George Kymionis, Greece Patrik Schatz, Sweden Paul Baird, Australia Neil Lagali, Sweden Kin Sheng Lim, UK Antonio Benito, Spain Achim Langenbucher, Germany Wisam A. Shihadeh, USA Mehmet Borazan, Turkey Van C. Lansingh, Mexico Bartosz Sikorski, Poland Francis Carbonaro, Malta Paolo Lanzetta, Italy Katsuyoshi Suzuki, Japan Chi-Chao Chan, USA Theodore Leng, USA Shivalingappa K. Swamynathan, USA Lingyun Cheng, USA Marco Lombardo, Italy Suphi Taneri, Germany Chung-Jung Chiu, USA Tamer A. Macky, Egypt Christoph Tappeiner, Switzerland Daniel C. Chung, USA David Madrid-Costa, Spain S. C. Beng Teoh, Singapore Colin Clement, Australia Edward Manche, USA Panagiotis Theodossiadis, Greece Miguel Cordero-Coma, Spain Flavio Mantelli, USA Biju B. Thomas, USA Ciro Costagliola, Italy E. Mencía-Gutiérrez, Spain Lisa Toto, Italy Vasilios F. Diakonis, USA Marcel Menke, Switzerland Manuel Vidal-Sanz, Spain Priyanka P. Doctor, India Lawrence S Morse, USA Gianmarco Vizzeri, USA Michel E. Farah, Brazil Darius M. Moshfeghi, USA David A. Wilkie, USA Giulio Ferrari, Italy Majid M. Moshirfar, USA Suichien Wong, UK Paolo Fogagnolo, Italy Hermann Mucke, Austria Victoria W Y Wong, Hong Kong Joel Gambrelle, France R. Naranjo-Tackman, Mexico Wai T. Wong, USA M.-A. Gamulescu, Germany Magella M. Neveu, UK Terri L. Young, USA Santiago Garcia-Lazaro, Spain Neville Osborne, UK H. Gon Yu, Republic of Korea Ian Grierson, UK Ji-jing Pang, USA Vicente Zanon-Moreno, Spain V. Grigoropoulos, Greece Enrico Peiretti, Italy Takaaki Hayashi, Japan David P. Piñero, Spain Contents

Advances and Clinical Applications of Anterior Segment Imaging Techniques Sang Beom Han, Jodhbir S. Mehta, Yu-Chi Liu, and Karim Mohamed-Noriega Volume 2016, Article ID 8529406, 2 pages

To Study and Determine the Role of Anterior Segment Optical Coherence Tomography and Ultrasound Biomicroscopy in Corneal and Conjunctival Tumors Katleen Janssens, Michelle Mertens, Noémie Lauwers, Rob J. W. de Keizer, Danny G. P. Mathysen, and Veva De Groot Volume 2016, Article ID 1048760, 11 pages

Applications of Scheimpflug Imaging in Glaucoma Management: Current and Potential Applications Alexander T. Nguyen, Tiffany Liu, and Ji Liu Volume 2016, Article ID 3062381, 9 pages

Accelerated Corneal Collagen Cross-Linking Using Topography-Guided UV-A Energy Emission: Preliminary Clinical and Morphological Outcomes Cosimo Mazzotta, Antonio Moramarco, Claudio Traversi, Stefano Baiocchi, Alfonso Iovieno, and Luigi Fontana Volume 2016, Article ID 2031031, 10 pages

Agreement between Gonioscopic Examination and Swept Source Fourier Domain Anterior Segment Optical Coherence Tomography Imaging Mohammed Rigi, Nicholas P. Bell, David A. Lee, Laura A. Baker, Alice Z. Chuang, Donna Nguyen, Vandana R. Minnal, Robert M. Feldman, and Lauren S. Blieden Volume 2016, Article ID 1727039, 8 pages

Effects of V4c-ICL Implantation on Myopic Patients’ Vision-Related Daily Activities Taixiang Liu, Shaorong Linghu, Le Pan, and Rong Shi Volume 2016, Article ID 5717932, 6 pages

Changes in Anterior Segment Morphology of Iris Bombe before and after Laser Peripheral Iridotomy in Patients with Uveitic Secondary Glaucoma Wakako Ikegawa, Takashi Suzuki, Koji Namiguchi, Shiro Mizoue, Atsushi Shiraishi, and Yuichi Ohashi Volume 2016, Article ID 8496201, 5 pages

Anterior Segment Imaging in Ocular Surface Squamous Neoplasia SallyS.Ong,GargiK.Vora,andPreeyaK.Gupta Volume 2016, Article ID 5435092, 12 pages

Assessment of Anterior Segment Measurements with Swept Source Optical Coherence Tomography before and after Ab Interno Trabeculotomy (Trabectome) Surgery Handan Akil, Ping Huang, Vikas Chopra, and Brian Francis Volume 2016, Article ID 4861837, 7 pages

Applications of Anterior Segment Optical Coherence Tomography in Cornea and Ocular Surface Diseases Sang Beom Han, Yu-Chi Liu, Karim Mohamed Noriega, and Jodhbir S. Mehta Volume 2016, Article ID 4971572, 9 pages Corneal Epithelial Remodeling and Its Effect on Corneal Asphericity after Transepithelial Photorefractive Keratectomy for Myopia Jie Hou, Yan Wang, Yulin Lei, Xiuyun Zheng, and Ying Zhang Volume 2016, Article ID 8582362, 7 pages

Evaluation of Anterior Chamber Volume in Cataract Patients with Swept-Source Optical Coherence Tomography Wenwen He, Xiangjia Zhu, Don Wolff, Zhennan Zhao, Xinghuai Sun, and Yi Lu Volume 2016, Article ID 8656301, 6 pages

Corneal Biomechanical Findings in Contact Lens Induced Corneal Warpage Fateme Alipour, Mojgan Letafatnejad, Amir Hooshang Beheshtnejad, Seyed-Farzad Mohammadi, Seyed Reza Ghaffary, Narges Hassanpoor, and Mehdi Yaseri Volume 2016, Article ID 5603763, 5 pages

Quantitative Analysis of Lens Nuclear Density Using Optical Coherence Tomography (OCT) with a Liquid Optics Interface: Correlation between OCT Images and LOCS III Grading You Na Kim, Jin Hyoung Park, and Hungwon Tchah Volume 2016, Article ID 3025413, 5 pages

Rotating Scheimpflug Imaging Indices in Different Grades of Keratoconus Sherine S. Wahba, Maged M. Roshdy, Rania S. Elkitkat, and Karim M. Naguib Volume 2016, Article ID 6392472, 9 pages

Evaluation of Outflow Structures In Vivo after the Phacocanaloplasty Daiva Paulaviciute-Baikstiene, Renata Vaiciuliene, Vytautas Jasinskas, and Ingrida Januleviciene Volume 2016, Article ID 4519846, 6 pages

Assessment of Corneal Epithelial Thickness in Asymmetric Keratoconic Eyes and Normal Eyes Using Fourier Domain Optical Coherence Tomography S. Catalan, L. Cadarso, F. Esteves, J. Salgado-Borges, M. Lopez, and C. Cadarso Volume 2016, Article ID 5697343, 6 pages

Central Corneal Thickness in Spectral-Domain OCT and Associations with Ocular and Systemic Parameters Alexander Karl-Georg Schuster, Joachim Ernst Fischer, and Urs Vossmerbaeumer Volume 2016, Article ID 2596956, 6 pages

Assessment of Anterior Segment Changes in Pseudophakic Eyes, Using Ultrasonic Biomicroscopic Imaging, after Pars Plana Vitrectomy with Silicone Oil or Gas Tamponade Erkan Ünsal, Kadir Eltutar, Belma Karini, and Osman Kızılay Volume 2016, Article ID 8303792, 8 pages

Ultrasound Biomicroscopy Comparison of Ab Interno and Ab Externo Intraocular Lens Scleral Fixation Lie Horiguchi, Patricia Novita Garcia, Gustavo Ricci Malavazzi, Norma Allemann, and Rachel L. R. Gomes Volume 2016, Article ID 9375091, 5 pages Hindawi Publishing Corporation Journal of Ophthalmology Volume 2016, Article ID 8529406, 2 pages http://dx.doi.org/10.1155/2016/8529406

Editorial Advances and Clinical Applications of Anterior Segment Imaging Techniques

Sang Beom Han,1 Jodhbir S. Mehta,2,3,4 Yu-Chi Liu,2,3,4 and Karim Mohamed-Noriega5

1 Department of Ophthalmology, Kangwon National University Hospital, Seoul, Republic of Korea 2Singapore National Eye Centre, Singapore 3Singapore Eye Research Institute, Singapore 4Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 5Department of Ophthalmology, Autonomous University of Nuevo Leon, Monterrey, NL, Mexico

Correspondence should be addressed to Sang Beom Han; [email protected]

Received 7 November 2016; Accepted 8 November 2016

Copyright © 2016 Sang Beom Han et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

With the rapid development of computer science and tech- changes before and following laser peripheral iridotomy of nologies in recent years, there has been dramatic advance in iris bombe in patients with uveitic secondary glaucoma; anterior segment imaging. (4) anterior segment measurements with swept source OCT As we have mentioned in the call for papers for this special before and after ab interno trabeculotomy; (5) effects of a issue, manuscripts are covering the topics of anterior seg- new type implantable collamer lens implantation on vision- ment imaging techniques including anterior segment optical related daily activities; (6) corneal epithelial remodeling coherence tomography (OCT), specular microscopy, corneal after transepithelial photorefractive keratectomy for myopia; topography, confocal microscopy, and ultrasound biomi- (7) measurement of anterior chamber volume in cataract croscopy (UBM). These techniques have enabled precise patients using swept-source OCT; (8) biomechanical findings visualization and objective assessments of anterior segment in contact lens-induced corneal warpage; (9) quantitative structures; thus, these devices have become essential tools for analysis of lens nuclear density using OCT with a liquid better diagnosis and treatment of anterior segment diseases optics interface; (10) rotating Scheimpflug imaging indices including corneal disorders, cataract, glaucoma, and even in different grades of keratoconus; (11) evaluation of outflow disorders of the lacrimal system. Future development of novel structures in vivo after the phacocanaloplasty; (12) evaluation modalities, that is, en face OCT or ultrahigh-resolution OCT, of corneal epithelial thickness in asymmetric keratoconic eyes is expected to allow more detailed visualization at a micro- and normal eyes using Fourier domain OCT; (13) central scopic level, which would provide even more understanding corneal thickness measured using spectral-domain OCT of anterior segment pathology at a cellular level. In this and associations with ocular and systemic parameters; (14) special issue, the authors contributed 15 original articles and 4 anterior segment changes in pseudophakic eyes after pars review papers regarding technologies of the anterior segment plana vitrectomy with silicone oil or gas tamponade using imaging and clinical application of the imaging devices. UBM imaging; and (15) UBM comparison of ab interno and The authors have contributed the results of their original ab externo intraocular lens scleral fixation. researches on various topics on anterior segment imag- This special issue also includes review articles on the ing: (1) agreement between gonioscopic examination and following topics: (1) application of Scheimpflug imaging swept source OCT imaging; (2) preliminary outcomes of in glaucoma management; (2) anterior segment imaging accelerated corneal collagen cross-linking using topography- in ocular surface squamous neoplasia; (3) applications of guided ultraviolet-A energy emission; (3) anterior segment anterior segment OCT in cornea and ocular surface diseases; 2 Journal of Ophthalmology and(4)theroleofanteriorsegmentOCTandUBMincorneal and conjunctival tumors. We hope these articles will provide readers with useful information on anterior segment imaging and new ideas for researches on related topics.

Acknowledgments This study was supported by 2016 Kangwon National Univer- sity Hospital Grant. Sang Beom Han JodhbirS.Mehta Yu-Chi Liu Karim Mohamed-Noriega Hindawi Publishing Corporation Journal of Ophthalmology Volume 2016, Article ID 1048760, 11 pages http://dx.doi.org/10.1155/2016/1048760

Review Article To Study and Determine the Role of Anterior Segment Optical Coherence Tomography and Ultrasound Biomicroscopy in Corneal and Conjunctival Tumors

Katleen Janssens,1 Michelle Mertens,1 Noémie Lauwers,2 Rob J. W. de Keizer,2,3 Danny G. P. Mathysen,1,2 and Veva De Groot1,2

1 University of Antwerp, Antwerp, Belgium 2Department of Ophthalmology, University Hospital Antwerp, Edegem, Belgium 3Department of Ophthalmology, LUMC, Leiden, Netherlands

Correspondence should be addressed to Michelle Mertens; [email protected]

Received 17 June 2016; Accepted 23 October 2016

Academic Editor: Karim Mohamed-Noriega

Copyright © 2016 Katleen Janssens et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. To analyze and describe corneal and conjunctival tumor thickness and internal characteristics and extension in depth and size and shape measured by two noninvasive techniques, anterior segment optical coherence tomography (AS-OCT) and ultrasound biomicroscopy (UBM). Design.Systematicreview.Methods. This systematic review is based on a comprehensive search of 4 databases (Medline, Embase, Web of Science, and Cochrane Library). Articles published between January 1, 1999, and December 31, 2015, were included. We searched for articles using the following search terms in various combinations: “optical coherence tomography”, “ultrasound biomicroscopy”, “corneal neoplasm”, “conjunctival neoplasm”, “eye”, “tumor” and “anterior segment tumors”. Inclusion criteria were as follows: UBM and/or AS-OCT was used; the study included corneal or conjunctival tumors; and the article was published in English, French, Dutch, or German. Results. There were 14 sources selected. Discussion.Several studies on the quality of AS-OCT and UBM show that these imaging techniques provide useful information about the internal features, extension, size, and shape of tumors. Yet there is no enough evidence on the advantages and disadvantages of UBM and AS-OCT in certain tumor types. Conclusion. More comparative studies are needed to investigate which imaging technique is most suitable for a certain tumor type.

1. Introduction and the quality of AS-OCT or UBM in assessing these tumors. It is still not clear which technique to use in certain tumor Since the early nineties ultrasound biomicroscopy (UBM) types. We therefore conducted a literature search in order has been used for the imaging of the anterior eye segment to find an answer to the following question: how accurate and was soon discovered to be useful in the evaluation are AS-OCT and UBM in determining tumor margins and of superficial tumors. Anterior segment optical coherence tumor depth of conjunctival and corneal tumors and can they tomography (AS-OCT) became available in the 21st century. provide additional information guiding the diagnosis? One of the first series on the use of OCT in the evaluation of conjunctival tumors was published by Buchwald et al., in 2. Material and Methods 2003 [1], followed by De Keizer and Razzaq in 2007 [2]. Corneal and conjunctival tumors can be visualized by 2.1. Anterior Segment Optical Coherence Tomography. AS- AS-OCT and UBM, two noninvasive imaging techniques. OCT is an examination technique that uses reflected light Hereby, tumor thickness and internal characteristics and waves in order to reconstruct a cross section of the examined extension in depth and size and shape can be measured. tissue. Time-domain OCT measures the electromagnetic Several small series have been published, evaluating the use radiation in function of the time. This investigation can 2 Journal of Ophthalmology make up to 400 axial scans per second and has an axial were included. We searched for articles using the following resolution of 8–10 𝜇m. Spectral-domain OCT measures the search terms in various combinations: “optical coherence wavelength of the reflected light and compares the image tomography”, “ultrasound biomicroscopy”, “corneal neo- with a reference point by means of mirrors, which allows plasm”, “conjunctival neoplasm”, “eye”, “tumor”, and “ante- it to measure faster. This imaging technique also measures rior segment tumors”. electromagnetic radiation and can make up to 25.000–50.000 scans per second. It has an axial resolution of 5–7 𝜇m. In Stage 2. Articleswerefirstselectedbasedontitleandsubse- comparison, spectral-domain OCT obtains more data in less quently on abstract and full text. Inclusion criteria were as time and with higher axial resolution [3, 4]. OCT of the follows: UBM and/or AS-OCT was used; the study included anterior segment can achieve a 9-10 𝜇maxialand15𝜇m corneal or conjunctival tumors; the article was published in transverse resolution [5]. This enables it to visualize smaller English, French, Dutch, or German. We could include 14 details compared to those shown on ultrasound or MRI [6, articles. 7]. Ultrahigh Resolution OCT (UHR-OCT) uses a similar Theflowdiagramoftheliteraturesearchisshownin technique to OCT but results in a higher resolution (3 𝜇m Figure 1. axial resolution) [8–10]. 3. Results Advantages and Disadvantages.OCThasmanyimportant advantages. It is a widely available noncontact method with- We analyzed 14 papers: 6 studies on UBM, 6 on OCT, and 2 out ionizing radiation. As a result, there are no risk of eye studies that compared the two imaging techniques. damageandnodiscomfortforthepatient.OCTdirectly All studies are listed in Tables 1, 2, and 3. renders high resolution images while the examination takes less than 5 minutes and can be performed by an optometrist. 3.1. UBM. Lanzl et al. [16], Grant and Azar [17], and Hoops In comparison with other competing imaging techniques, etal.[18]allstudiedtheuseofUBMinlimbaldermoids, AS-OCT has a low penetration depth of 1–3 mm but offers respectively, on 2, 1, and 8 patients. They all found a hyper- ahighaxialresolutionduetotheuseofshortwavelength ± reflective lesion compared to the cornea. They concluded that light ( 830 nm mostly) [3, 5, 11]. AS-OCT is ideal for imaging UBM is a useful preoperative tool in limbal dermoids [16, 17] structures from the surface of the eye to the level of the iris but insufficient in some cases to measure corneal penetration [5].AdisadvantageofAS-OCTisthatitcannotvisualize [17]. structures behind pigmented lesions, like the iris, and cannot 𝜇 Buchwald et al. demonstrated in 28 patients with solid visualize early pathological changes smaller than 5 msuch tumors of the conjunctiva that UBM can be an additional as early dysplasia [5, 7]. diagnostic tool, for example, to determine the margins of the solid tumors or cysts [19]. 2.2. Ultrasound Biomicroscopy. UBM is an examination tech- Similarly to the study of Buchwald et al., Lin et al. niquethatusessoundwavestoanalyzethestructuresasinthe proved in 2 cases that UBM is a useful tool to show cysts in classic ultrasound investigation. However, in UBM a higher conjunctival lesions. This technique could be used for deline- frequency is used which consequently allows more detail but ating the extent of the lesion before excision [20]. less penetration into the tissue [12]. For the anterior segment, Ho et al. studied the assessment of tumor thickness transducers are used with a frequency of 35–50 MHz. UBM 𝜇 in three conjunctival melanomas by means of UBM. They has an axial resolution of 42 m and a tissue penetration of concluded that high frequency UBM is useful for estimating 4-5 mm [5, 13]. tumor thickness in conjunctival melanomas and can be used to determine the tumor depth prior to surgical resection Advantages and Disadvantages. The most important advan- [21]. tageofUBMisthatitcanpenetrateopaquetissue[14]. In contrast, AS-OCT is unable to do this. UBM also has a 3.2. AS-OCT. The study of Shields et al. on 22 conjunctival broadfieldofview[15].UBMisidealforimagingstructures nevi demonstrated that all margins of conjunctival nevi, from the surface of the eye to the anterior vitreous [5]. including the deep borders, could be visualized by AS-OCT. Disadvantages are the limited penetration depth of 4-5 mm AS-OCT images showed a high resolution in 100% of anterior andthelimiteddepthresolution.UBMrequirestopical borders and 82% of posterior borders [22]. Some of the anesthesia and the application of an eyecup filled with fluid images were affected by deep optical shadowing, especially in contact with the eye surface causing mild discomfort for in pigmented nevi (86%). The sensitivity of AS-OCT for the thepatient.UnfortunatelytheaccessibilitytoUBMislimited detection of intrinsic cysts in a conjunctival nevus is 80%, the to the larger centers. specificity is 100%, the positive predictive value is 100%, and 2.3. Methods. We performed a specific literature search of the negative predictive value is 60%. Thus, AS-OCT ensures peer reviewed published journal articles in the following high resolution images of conjunctival nevi, it can delineate stages. the borders of the lesion, and it can demonstrate the presence of intralesional cysts [22]. The main drawback of OCT is Stage 1. Comprehensive search of 4 databases (Medline, the presence of optical shadowing in pigmented nevi. The Embase, Web of Science, and Cochrane Library). Articles thickness of nevi in the study ranged from 0.1 mm to 1.7 mm published between January 1, 1999, and December 31, 2015, measured with AS-OCT [22]. Journal of Ophthalmology 3

Records identified through Additional records identified database searching through other sources (n=1) (n = 27) Identification

Records after duplicates (n=11) removal (n = 17)

Screening Records screened based Records excluded on abstract (n = 17) (n = 0)

Full-text articles assessed Full-text articles excluded, for eligibility with reasons (n = 17) (n = 3) Eligibility (i) No corneal or conjunctival tumors Studies included in included (n = 3) qualitative synthesis (n = 14) Included

Figure 1: Flow diagram of literature search.

Welch et al. studied the difference between the measure- average epithelial thickness in the 17 epithelial squamous cell ments of a pterygium by slit-lamp examination and by AS- carcinomas (SCC) was 346 𝜇m, compared to 101 𝜇minthe17 OCT imaging [23]. When measuring the distance from the pterygia. Using a cut-off value of 142 𝜇m results in a sensitivity apex of the pterygium to the limbus in 13 eyes, AS-OCT of 94% and a specificity of 100% [8] in differentiating SCC gave significantly better reproducible results. Therefore, they from pterygia. concluded that AS-OCT allows us to accurately determine In another study of Shousha et al., the use of UHR- the extension of a pterygium on the cornea [23]. OCT in the diagnosis of 54 ocular surface lesions was Shousha et al. studied the use of UHR-OCT in the studied. It was demonstrated that when the clinical diagnosis diagnosis and follow-up of conjunctival and corneal intraep- of ocular surface lesions was uncertain, UHR-OCT images ithelial neoplasia (CCIN). UHR-OCT images of the 7 lesions provided optical signs indicating more specific diagnosis and discerned a thickened hyperreflective epithelium and abrupt management. They concluded that this imaging technique transition from normal to hyperreflective epithelium. Their canvisualizethestructureandlocationofthelesionandas results demonstrated that macroscopically resolved residual such can aid in guiding the diagnosis and management [10]. tumor nodules can be visualized by UHR-OCT. They con- Nanji et al. studied the use of high resolution, spectral- cluded that UHR-OCT is useful for guiding diagnosis and domain optical coherence tomography (HR-OCT) in the treatment follow-up of CCIN [9]. diagnosis of corneal and conjunctival pathologies, with a The results of the study of Kieval et al. showed that focus on malignant lesions. In this pilot study on 82 lesions, UHR-OCToftheanteriorsegmentcouldbeanaccurate they concluded that HR-OCT was helpful to determine the tool in differentiating ocular squamous cell carcinoma from etiology and to differentiate between multiple ocular surface pterygium [8]. The difference in measured epithelial thick- lesions, including ocular surface squamous neoplasia, ptery- ness allows ophthalmologists to make a distinction. The gium, nevi, and melanoma, as well as to evaluate resolution 4 Journal of Ophthalmology UBM (i) Useful diagnostic adjunct for limbal dermoids (ii) Helpful in delineating the extent of these lesions UBM (i) Improves the preoperative evaluation of limbal dermoids (ii) Subtle examination technique for the depth of corneal penetration is required because of the strong sound attenuationin this tissue, reducing the visibility of deep corneal structures UBM (i) Can assess depth involvement of opaque corneal lesions such as limbal dermoids (ii) Because planning of the surgical approach in these cases is facilitated by preoperative knowledge about the depth of penetration of these opaque lesions, UBM can be regarded as a helpful tool in the clinical management Clinical examination, ultrasound biomicroscopy, biopsy confirmed the diagnosis of limbal dermoid (highly echogenic lesion, 0.78 mm thick) (i) 7/8: UBM showed a more reflective and predominantly homogeneous lesion compared with the unaffected corneal stroma, so that the lateral margins of the lesion could be clearly identified (ii) Penetration of the tumor: 4/8: incomplete stromal penetration of the dermoid was noticed; 1/8 showed a corneal full-thickness dermoid; 1/8 intraocular protrusion; 2/8 remained unclear because of reduced compliance (iii) 7/8: Descemet’s membrane beneath the dermoid could not be visualized because of strong sound attenuation inside the lesion UBM (i) Can distinguish normal cornea from the more sonolucent lesion (ii) Presence or absence of Descemet’s membrane could be identified (iii) Depth of involvement of limbal dermoids could be assessed Limbal dermoid Limbal dermoids Infantile limbal dermoid UBM Aim Tumor type Results Conclusion (UBM) ultrasound ultrasound could improve biomicroscopy biomicroscopy management of limbal dermoid examination for dermoids which of penetration of surgical planning biomicroscopy in use of ultrasound To investigate the the diagnosis and the corneal depth To assess whether (UBM) can detect in limbal dermoids To report the use of planning of surgery Table 1: Articles using UBM in conjunctival and corneal tumors. Imaging (50 MHz) probe not technique mentioned) UBM (type of biomicroscopy High resolution 1 2UBM(50MHz) 8 patients Number of Study The role of ultrasound biomicroscopy in surgical planning for limbal dermoids—study design not given Ultrasound biomicroscopy in the diagnosis and management of limbal dermoid—study design not given Preoperative evaluation of limbal dermoids using high resolution biomicroscopy— retrospective analysis Author, year Lanzl et al., 1998 Grant and Azar, 1999 Hoops et al., 2001 Journal of Ophthalmology 5 (of conjunctival lesions UBM (i) Useful tool for estimationtumor of thickness for conjunctival melanomas (ii) Additional diagnostic tool for estimating tumor thickness before surgical resection of conjunctival melanoma UBM (i) Useful diagnostic to distinguish cysts in conjunctival lesions (ii) May be helpful in delineating the extent of lesions prior to excision UBM caused by a cyst or a(i) solid May tumor) be an additional diagnostic tool (ii) Now not possible to differentiate between different lesions solely by means of ultrasonography Patient 1: UBM thickness = 1.99 mm and Breslow thickness = 1.5 mm Patient 2: UBM thickness = 2.4 mm and Breslow thickness = 2.23 mm Patient 3: both UBMBreslow and thickness = 2.3 mm UBM (i) Multiple areas of cystic tissue, which is compatible with pathologic finding of compound nevus with epithelial inclusion cysts formation (ii) Clear interface between the mass and the underlying sclera was found UBM (i) Cyst of conjunctiva: demonstrating cystic tumor in 21% (ii) Solid tumor of conjunctiva: no definite diagnosis with UBM (iii) Compound nevus: heterogeneous sonographic structure within the tumor (iv) Foreign body: posterior shadowing of the underlying tissue Conjunctival melanoma (3) 2 conjunctival lesions: raised melanocytic lesions localized on the conjunctiva characterised by rapid growth; they were suspected to be inflamed juvenile conjunctival nevi 28 conjunctival lesions: Compound nevus (8/28), cysts (6/28), inflammatory processes (3/28), granulomatous processes (2/28), lymphomas (2/28), foreign bodies (2/28), pterygium (2/28), malignant melanoma (1/28), primary acquired melanosis (1/28), conjunctival amyloidosis (1/28) Table 1: Continued. nevi Aim Tumor type Results Conclusion lesions melanomas thickness of UBM in the conjunctival conjunctival To assess the of pigmented preoperatively high frequency the diagnosis of value of UBM in To determine the clinical diagnosis and management feasibility of using conjunctival cystic UBM in estimating To report the use of Imaging probe not technique mentioned) UBM (type of 3UBM(50MHz) 2 28 UBM (30 MHz) patients Number of Study Ultrasound biomicroscopy of conjunctival lesions— prospective study Ultrasound Biomicroscopy in Pigmented Conjunctival Cystic Nevi—study design not given Ultrasound biomicroscopy for estimation of tumor thickness for conjunctival melanoma— retrospective review Author, year Buchwald et al., 2003 Lin et al., 2004 Ho et al., 2007 6 Journal of Ophthalmology (for OSSN and pterygia) AS-OCT (i) Significantly more reproducible results than the slit-lamp beam for measurements of the distance of a apex pterygium’s the from limbus (ii) May provide more accurate clinical assessment of extension of pterygia ontocornea the and may be useful forpurposes research UHR-OCT (i) Statistically significant difference in epithelial thickness (ii) Significant degree morphologic of correlation with the histopathologic results UHR-OCT (i) Useful to diagnose and manage medically treated CCIN (ii) Could prevent the prematuretermination of topical treatment in the presence of subclinical disease (iii) A larger sample size isfurther needed validation for of its sensitivityspecificity and AS-OCT (i) Provides high resolution imaging of conjunctival nevi (ii) Can demonstrate all margins (iii) Can provide information on the presence of intralesional cysts, for diagnosis (iv) Main drawback: optical shadowing of deeper structures from pigment within nevi of % of cases, % ) ) % of cases (cut-off value of % % % 𝑝 = 0.0256 -test demonstrated a statistically (for differentiating between 𝑡 m) 𝜇 significant difference in these measurements ( AS-OCT (i) All margins of thedeep nevus, margin, including could the be visualizedresolution with high of the anterior margin in 100 Slit lamp versus OCT (i)Slitlamp:themeanofthedifferences was 0.3 and the standard(ii) deviation OCT: was the 0.32 mean of the0.1 and differences the was standard deviation wastwo-tailed 0.12. A cases, posterior margin in 82 (ii) Intrinsic cysts within the nevusdetected were in 17 cases (77 lateralmarginin86 142 UHR-OCT (i) Thickened hyperreflective epithelium and abrupt transition from normalhyperreflectiveepithelium to in all 7 cases (ii) Excellent correlation with histopathologic specimens UHR-OCT OSSN and pterygia) (i) Sensitivity 94 (ii) Specificity 100 AS-OCT Conjunctival nevi (22) Pterygia Conjunctival and corneal intraepithelial neoplasia (CCIN) Conjunctival lesions (34) clinically suspicious for OSSN or pterygia To evaluate conjunctival nevi using AS-OCT To compare standard slit-lamp beam measurements of pterygia to computer caliper measurements of AS-OCT images To reportdiagnostic a technique novel and a case series of CCIN diagnosed and followed up using prototype UHR-OCT To assess the use of an UHR-OCT as an adjuvant diagnostic tool in distinguishing OSSN and pterygia Aim Tumor type Results Conclusion Table 2: Articles using AS-OCT in conjunctival and corneal tumors. not Imaging AS-OCT AS-OCT (870 nm) (840 nm) (1310 nm) technique UHR-OCT UHR-OCT mentioned) (wavelength 7 13 patients 22 eyes of 34 eyes of 21 patients 34 patients Number of Anterior segment optical coherence tomography of conjunctival nevus—retrospective interventional case series Pterygia measurements are more accurate with anterior segment optical coherence tomography (a pilot study)—study design not given Diagnosis and management of conjunctival and corneal intraepithelial neoplasia using ultrahigh resolution optical coherence tomography— prospective, noncomparative, interventional case series Ultrahigh resolution optical coherence tomography for differentiation of ocular surface squamous neoplasia (OSSN) and pterygia—prospective case series Author, year Study Shields et al., 2011 Welch et al.,2011 Shousha et al., 2011 Kieval et al., 2012 Journal of Ophthalmology 7 UHR-OCT (i) Correlations between UHR-OCThistopathologic and findingsconfirm that UHR-OCTisanadjunctivediagnostic method that can provide a noninvasive means to help guide diagnosis and management of ocular surface lesions HR-OCT (i) Useful noninvasive adjunctive tool indiagnosis the of ocular surface lesions UHR-OCT (i)Closecorrelationwiththeobtained histopathologic specimens (ii) When clinical differential diagnosis of ocular surface lesions was broad, UHR-OCT images provided optical signs indicating a more specific diagnosis and management (iii) Amelanotic melanoma, conjunctival amyloidosis, primary histiocytosis and,case in of 1 OSSN, UHR-OCT was instrumental in guiding the diagnosis. InUHR-OCT those suggested cases, that the presumed clinical diagnosis was incorrect andadiagnosisthatlaterwasconfirmedby favored histopathologic examination HR-OCT (i) Useful in differentiating amongvarious lesions based on optical signs(ii) OSSN: epithelial thickening and hyperreflectivity (iii) Pterygia and pinguecula: subepithelial mass under thinner epithelium (iv) Lymphoma: hyporeflective, homogenous subepithelial mass (v) Pigmented lesions: differentiation was more difficult, but certain characteristics could be identified. Eyes with nevimelanoma and displayed both intensely hyperreflective basal epithelial layers and discrete subepithelial lesions but could be differentiated by the presence of cystsnevi in and intense shadowing of sublesional tissue in most melanomas Table 2: Continued. 24 conjunctival lesions, 19 corneoconjunctival lesions, 11 corneal lesions: primary acquired melanosis lesions (8/54), amelanotic melanoma lesions (5/54), nevi (2/54), ocular surface squamous neoplasia lesions (19/54), histiocytosis lesion (1/54), conjunctival lymphoma lesions (6/54), conjunctival amyloidosis lesions (2/54), pterygia lesions (11/54) Location of lesions not mentioned: Normal eyes (10), OSSN (21), pterygium or pingueculum (24), lymphoma (3), pigmented conjunctival lesions (nevus, flat melanosis, or melanoma) (18) and Salzmann nodular degeneration (6) To assess the use of ultrahigh resolution (UHR) optical coherence tomography (OCT) in the diagnosis of ocular surface lesions To evaluateacommercially the useavailable, of high resolution, spectral-domain optical coherence tomography (HR-OCT) device in the diagnosis of corneal and conjunctival pathologies, with a focus on malignant lesions Aim Tumor type Results Conclusion Imaging (830 nm) (840 nm) HR-OCT technique UHR-OCT 82 54 patients Number of Diagnosis of ocular surface lesions using ultrahigh resolution optical coherence tomography— prospective, noncomparative, interventional case series High resolution optical coherence tomography as an adjunctive tool in the diagnosis of corneal and conjunctival pathology— prospective case series Author, year Study Shousha et al., 2013 Nanji et al., 2015 8 Journal of Ophthalmology AS-OCT > (i) Anterior segment tumors: better visualization of the posterior margin and overall better images for entire tumor configuration UBM OCT Show very small cystic structures more distinctly than UBM UBM Better for assessing the margins of the tumor than OCT ; 107 [66%] versus ;23[61%]versus15 𝑛 = 162 𝑛=38 UBM (i) Better overall tumor visualization (138 [69%] versus 62 [31%]) (ii) Better resolution of the posterior margin (147 [74%] versus 53 [27%]) (iii) Better resolution for pigmented tumors ( 55 [34%]) (iv) Better resolution for nonpigmented tumors ( [39%]) AS-OCT (i) Better resolution of the anterior margin (40 [20%] versus 160 [80%]) (ii) Better overall resolution of anterior segment anatomy (41 [21%] versus 159 [80%]) AS-OCT (i) More reliable imaging: small cystic structures of compound nevus (ii) Assessment of the margins of the tumors (particularly in depth) was impossible or uncertain AS-OCT and UBM Solid tumors: the definite diagnosis could not be differentiated by UBM or OCT alone 6conjunctivallesions (diagnosis not mentioned), 0 corneal lesions, 194 other locations: nevus (75/200), melanoma (47/200), cyst (48/200), epithelioma (adenoma) (5/200), metastasis (4/200), melanocytosis (4/200) and melanocytoma (4/200), others (3/200) 13 conjunctival lesions and25eyelidlesions: pterygium (8/38), seborrheic keratosis (7/38), cyst of the eyelid (5/38), basal cell carcinoma of the eyelid (4/38), compound nevus of the conjunctiva (4/38), chalazion (3/38), primary acquired melanosis (1/38), actinic keratosis (1/38), nevus (1/38), cavernous haemangioma (1/38), melanoma in situ (1/38), foreign body (1/38), epidermoid cyst (1/38) of Aim Tumor type Results Conclusion lesions the eye anterior UBM and and eyelid imaging of segment of AS-OCT in the value of To compare To compare conjunctival UBM versus AS-OCT for the diagnosis tumors of the UBM versus AS-OCT Imaging AS-OCT (1310 nm) (1310 nm) technique probe) and and AS-OCT UBM (50 MHz UBM (30 MHz) 200 of 35 patients patients 38 tumors Number of Table 3: Articles describing the use of UBM and AS-OCT in conjunctival and corneal tumors. Study Optical coherence tomography versus ultrasound biomicroscopy of conjunctival and eyelid lesions—prospective study Assessment of anterior segment tumors with ultrasound biomicroscopy versus anterior segment optical coherence tomography in 200 cases—retrospective, noninterventional case series Author, year Buchwald et al., 2003 Bianciotto et al., 2011 Journal of Ophthalmology 9 after treatment. However, this imaging technique was less margins more often than AS-OCT [1, 25]. Therefore UBM is useful in evaluating pigmented lesions. Even though this a useful tool in delineating the margins and measuring the imaging technique cannot replace either clinical evaluation extent of a conjunctival lesion before surgical excision [20]. or histopathologic diagnosis, it can be an important aid in Another advantage of UBM is that tumor shadowing is rarely determiningthediagnosisofocularsurfacepathologyandin seen, while this is much more frequently seen on AS-OCT determining disease resolution [24]. [8, 9, 24, 25]. For this reason, AS-OCT is not preferable for the visualization of large pigmented lesions [25]. In contrast, 3.3. UBM and AS-OCT. Buchwald et al. studied 13 conjunc- AS-OCT provides a better resolution of the anterior margin tival and 25 eyelid lesions. The authors concluded that, in and anterior segment anatomy [25]. solid tumors, the final diagnosis cannot be made based on Forthickerlesionsasalimbal dermoid,UBMisthe UBM or AS-OCT alone [1]. In general, when using AS- preferred technique. UBM has proven to be valuable in OCT it was impossible or uncertain to determine the tumor measuring the depth and extension of dermoids [17, 18] and depth. When comparing AS-OCT and UBM, AS-OCT is the also in establishing a differential diagnosis [17]. Since UBM better imaging technique for small cystic structures. This is can accurately measure depth of invasion, it is therefore very especially useful for nevi as they often contain small cysts. In useful in the preoperative evaluation of a limbal dermoid contrast, UBM is a better technique to determine the tumor [16, 18]. margins [1]. Conjunctival nevi often contain typical small cysts. Lin Bianciotto et al. studied 200 eyes with anterior segment et al. demonstrated that UBM is useful in visualizing these tumors.Eventhoughtheyonlyincluded6conjunctival cysts in pigmented conjunctival lesions [20]. Shields et al. and tumors, their study resulted in interesting conclusions. Com- Buchwald et al. found that AS-OCT can identify these small parisonofUBMandAS-OCTshowedthatUBMhadabetter cystic structures more accurately than UBM, and, therefore, tumor visualization and better resolution of the posterior AS-OCT is a useful tool in investigating these lesions [1, 22]. margin. UBM also had a better resolution for pigmented as AS-OCT also has a high correlation with clinical examination well as for nonpigmented tumors. However, AS-OCT had and histopathology in visualizing these intrinsic cysts [22]. better resolution of the anterior border and better resolution It was also found that AS-OCT can visualize all margins of the anterior segment anatomy. Posterior tumor shadowing of conjunctival nevi, even the deep margins, although deep was rarely found in UBM images and more common in AS- optical shadowing is often seen, especially in pigmented nevi OCT. The image quality was good in UBM but less inAS- [22]. For conjunctival nevi we can conclude that AS-OCT OCT. This study shows that AS-OCT is superior to UBM for seems to be more accurate in assessing the extent of these the imaging of conjunctival lesions, because AS-OCT offers tumors as long as the nevus is not very thick and not heavily a higher resolution and conjunctival lesions are superficial pigmented. and mostly not pigmented. Their findings demonstrate that Ho et al. investigated conjunctival melanomas and found AS-OCT is affected by optical shadowing in large pigmented that UBM is a very good technique for determining the lesions. AS-OCT uses light, which is more comfortable for posterior margin and estimating tumor thickness. Therefore, thepatient,butthelightisblockedbyopaquetissueswhich UBM is useful in determining the excision depth important results in lower penetration depth. This is a crucial factor in the planning of a surgical resection [21]. AS-OCT was not in the evaluation and treatment of anterior segment tumors. compared to UBM in conjunctival melanomas. They conclude that AS-OCT is a useful tool in the evaluation Concerning squamous cell carcinoma (SCC),HR-OCT of superficial nonpigmented lesions of the eye, although AS- was found to be useful in the differentiation between SCC and OCT suffers from poor resolution and shadowing in large or similar lesions like amelanotic melanoma and corneal fibrosis pigmented lesions. In comparison, UBM can penetrate better [10, 24]. Studies which concentrated on the differentiation through the lesion, which results in better visualization of the between SCC and pterygia concluded that AS-OCT is a posterior tumor border and whole tumor configuration [25]. good diagnostic tool to differentiate SCC from pterygia [8, 10, 24]. AS-OCT can differentiate between these two 4. Discussion lesions by measuring the difference in epithelial thickness [8]. Furthermore, the authors found that, for SCC as well as These studies showed that AS-OCT and UBM both have their pterygia, there is a good correlation between the findings on advantages and disadvantages because of their specific char- UHR-OCT and histopathology [8]. Also Nanji et al. found acteristics. None can replace histopathological examination that for SCC HR-OCT correlated well with histopathology for diagnosis but they both give useful information helping [24]. HR-OCT can also be used for the monitoring of the in the differential diagnosis [1, 19]. Both noninvasive imaging resolution of SCC during therapy. In this way, HR-OCT can techniques provide useful information about the thickness detect subtle residual epithelial thickening which is not visible and internal characteristics and extension in depth and size on clinical examination. This prevents premature termination and shape of conjunctival and corneal tumors. of treatment. Although AS-OCT technically has a higher resolution Shousha et al. found that UHR-OCT is a good technique than UBM [9, 10], UBM seems to be superior in accuracy when visualizing conjunctival and corneal intraepithelial neo- of tumor visualization, quality of the image, resolution of the plasia (CCIN). UHR-OCT is particularly useful for the confir- posterior margin, and resolution of pigmented and nonpig- mation of recovery of CCIN. This is important because UHR- mented tumors [1, 24, 25]. UBM is also able to visualize all OCT could in this way replace a biopsy, which is harmful to 10 Journal of Ophthalmology thesurfaceoftheeyeandwhichcanbefalsenegativebecause [4] M. Schneider, O. Szekeres, H. Kiss, M. Kis, A. Papp, and of sampling error. Disadvantages of UHR-OCT concerning J. Nemeth,´ “Comparison of thickness values in nine macu- CCIN are the fact that microinvasion cannot be excluded and lar subfields using time-domain and spectral-domain optical thefactthattheresolutionofUHR-OCTisnothighenough coherence tomography,” Orvosi Hetilap,vol.154,no.52,pp. to assess intracellular characteristics [9]. 2059–2064, 2013. UBM and AS-OCT both have a strong correlation with [5]J.P.S.GarciaJr.andR.B.Rosen,“Anteriorsegmentimag- histopathology and they can both assess the structure and the ing: optical coherence tomography versus ultrasound biomi- extent of lesions in order to guide treatment [8, 10, 24]. When croscopy,” Ophthalmic Surgery Lasers and Imaging,vol.39,no. 6, pp. 476–484, 2008. tumor invasion of the sclera or cornea is documented before resection, the surgeon can prepare and counsel the patient [6] H. Li, V. Jhanji, S. Dorairaj, A. Liu, D. S. C. Lam, and C. 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Conclusion [9]M.A.Shousha,C.L.Karp,V.L.Perezetal.,“Diagnosisand management of conjunctival and corneal intraepithelial neopla- The literature shows that AS-OCT and UBM are both very sia using ultra high-resolution optical coherence tomography,” useful and complementary techniques for the evaluation and Ophthalmology, vol. 118, no. 8, pp. 1531–1537, 2011. follow-up of corneal and conjunctival tumors even though [10] M. A. Shousha, C. L. Karp, A. P. Canto et al., “Diagnosis they cannot replace histopathological analysis for the diag- of ocular surface lesions using ultra-high-resolution optical nosis. Due to their different measuring technique, they have coherence tomography,” Ophthalmology,vol.120,no.5,pp.883– different advantages and disadvantages. The disadvantage of 891, 2013. AS-OCT is that it cannot penetrate deeper than 1–3 mm and [11] J. G. Fujimoto, C. Pitris, S. A. Boppart, and M. E. Brezinski, cannot penetrate through pigmented lesions. But for smaller “Optical coherence tomography: an emerging technology for lesionsAS-OCTisamoreaccuratetechniquethatcangive biomedical imaging and optical biopsy,” Neoplasia,vol.2,no. detailed images of the remaining healthy cornea, can identify 1-2, pp. 9–25, 2000. cysts,ormightbeusefulindetectingtumorrecurrence.For [12] J.-R. Fenolland,´ M. Puech, C. Baudouin, and A. Labbe,´ “Imag- larger or pigmented lesions UBM can better delineate tumor ing of the iridocorneal angle in glaucoma,” Journal Francais margins and tumor thickness. More comparative studies d’Ophtalmologie,vol.36,no.4,pp.378–383,2013. are needed to investigate which imaging technique is most [13] H. Ishikawa and J. S. Schuman, “Anterior segment imaging: suitable for a certain tumor type. ultrasound biomicroscopy,” Ophthalmology Clinics of North America,vol.17,no.1,pp.7–20,2004. Competing Interests [14] S. El-Kady, “Ultrasound biomicroscopy: role in diagnosis of iris and ciliary body tumours,” The Medical Journal of Cairo The authors declare that there is no conflict of interests University,vol.79,no.2,pp.81–86,2011. regarding the publication of this paper. [15] D. Bhatt, “Ultrasound biomicroscopy: an introduction,” Journal of the Bombay Ophthalmologists’ Association,vol.12,no.1,2002. Authors’ Contributions [16] I. M. Lanzl, J. J. Augsburger, R. W. Hertle, C. Rapuano, Z. Correa-Melling, and C. Santa Cruz, “The role of ultrasound Katleen Janssens and Michelle Mertens contributed equally biomicroscopy in surgical planning for limbal dermoids,” to this work. Cornea, vol. 17, no. 6, pp. 604–606, 1998. [17] C. A. Grant and D. Azar, “Ultrasound biomicroscopy in the References diagnosis and management of limbal dermoid,” American Journal of Ophthalmology,vol.128,no.3,pp.365–367,1999. [1] H.-J.Buchwald,A.Muller,¨ J. Kampmeier, and G. K. Lang, “Opti- [18] J. P. Hoops, K. Ludwig, K.-P. 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[21]V.H.Ho,T.C.Prager,H.Diwan,V.Prieto,andB.Esmaeli, “Ultrasound biomicroscopy for estimation of tumor thickness for conjunctival melanoma,” Journal of Clinical Ultrasound,vol. 35,no.9,pp.533–537,2007. [22] C. L. Shields, I. Belinsky, M. Romanelli-Gobbi et al., “Anterior segment optical coherence tomography of conjunctival nevus,” Ophthalmology, vol. 118, no. 5, pp. 915–919, 2011. [23] M. N. Welch, C. D. Reilly, K. Kalwerisky, A. Johnson, and S. G. Waller, “Pterygia measurements are more accurate with anterior segment optical coherence tomography—a pilot study,” Nepalese Journal of Ophthalmology, vol. 3, no. 1, pp. 9–12, 2011. [24] A. A. Nanji, F. E. Sayyad, A. Galor, S. Dubovy, and C. L. Karp, “High-resolution optical coherence tomography as an adjunctive tool in the diagnosis of corneal and conjunctival pathology,” Ocular Surface,vol.13,no.3,pp.226–235,2015. [25] C. Bianciotto, C. L. Shields, J. M. Guzman et al., “Assessment of anterior segment tumors with ultrasound biomicroscopy versus anterior segment optical coherence tomography in 200 cases,” Ophthalmology,vol.118,no.7,pp.1297–1302,2011. Hindawi Publishing Corporation Journal of Ophthalmology Volume 2016, Article ID 3062381, 9 pages http://dx.doi.org/10.1155/2016/3062381

Review Article Applications of Scheimpflug Imaging in Glaucoma Management: Current and Potential Applications

Alexander T. Nguyen, Tiffany Liu, and Ji Liu

Department of Ophthalmology and Visual Science, Yale School of Medicine, New Haven, CT, USA

Correspondence should be addressed to Ji Liu; [email protected]

Received 17 June 2016; Revised 6 September 2016; Accepted 4 October 2016

Academic Editor: Karim Mohamed-Noriega

Copyright © 2016 Alexander T. Nguyen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Scheimpflug photography is the basis for a variety of imaging devices that are highly versatile. The applications of Scheimpflug imaging are wide in scope, spanning from evaluation of corneal ectasia to quantifying density in nuclear sclerotic cataracts. The potential uses for Scheimpflug-based devices are expanding and a number of them are relevant in glaucoma. In particular, they can provide three-dimensional image reconstruction of the anterior segment which includes assessment of the iridocorneal angle. Photographic analyses allow also for a noncontact method of estimating central corneal thickness (CCT) and intraocular pressure (IOP), as well as the study of various corneal biomechanical properties, which may be useful for stratifying glaucoma risk.

1. Introduction their effect on tonometry [6]. The Corvis ST (Corneal Visual- ization Scheimpflug Technology, Oculus, Wetzlar, Germany) The clinical utility of anterior segment imaging continues to is an ultra-high speed Scheimpflug device that offers a highly be refined as newer investigations reveal novel applications reproducible, noncontact method of performing pachymetry, for their use. As a complement to the slit lamp examination, estimating intraocular pressure (IOP), and obtaining corneal anterior segment imaging offers qualitative information as biomechanical data [6, 7]. well as objective, quantifiable data [1]. Scheimpflug photog- raphyisthebasisforanumberofdevicesthatcanimage the anterior segment. The technology is highly versatile, with 2. The Scheimpflug Principle potential applications in the areas of keratorefractive surgery, corneal biomechanics, corneal ectasia evaluation, anterior The Scheimpflug principle refers to a concept in geometric segment imaging, cataract grading, and surgical planning for optics whereby a photograph of an object plane that is femtosecond laser-assisted cataract surgery [2–7]. not parallel to the image plane can be rendered maximally Herein we review Scheimpflug photography and some focused given certain angular relations among the object of its applications that are relevant to the management plane,thelens,andtheimageplane(Figure1)[2].When of glaucoma patients. Like other anterior segment imaging applied to ophthalmic imaging, it allows for photographic technologies, Scheimpflug-based devices can provide three- documentation of the anterior segment with a depth of focus dimensional image representations of the anterior segment, ranging from the anterior cornea to the posterior lens surface which may be useful for screening narrow angles [1–3]. [9,10].Photographicimagesoftheanteriorsegmentmaybe Intraocular pressure (IOP) is a modifiable and independent variably compressed by the capture of light rays exiting the risk factor for predicting glaucomatous progression [8]. Its cornea at unfavorable camera angles. However, this distortion measurement can be affected by corneal parameters like cen- can be minimized by the selection of specific camera angles tral corneal thickness (CCT). Despite this, there is accruing relative to the slit beam where the capture of reflected evidence to suggest that CCT and corneal biomechanical light is approximately perpendicular to the corneal surface properties are associated with glaucoma independently of [1, 11]. This technique is the foundation for the rotational 2 Journal of Ophthalmology

The Orbscan (Bausch & Lomb Surgical, Salt Lake City, Lens Object plane (plane of focus) Image USA) was commercially introduced in 1995. It is based on Lens axis a concept referred to as slit-scan triangulation to obtain topographic data. It projects 40 slit beams (20 nasal and 20 ∘ temporal)attheanteriorsegmentatanangleof45 from the axis of the camera [13]. In order for the cornea, the iris, Lens plane and the lens to be captured in focus, the image plane of the camera is tilted to satisfy the Scheimpflug condition. The measurements obtained by triangulation can then be integrated to provide three-dimensional information regarding Image plane the anterior segment. Relevant to the evaluation of angle Scheimpflug intersection closure, the Orbscan can estimate the iridocorneal angle and the anterior chamber depth (ACD) [14]. In normal Figure 1: Depiction of the Scheimpflug principle as it applies to subjects, these measurements have been shown to be highly photography. When an oblique tangent is extended from the image reproducible [14]. However, studies validating the utility of plane and the lens plane, they intersect at a point that is also the Orbscan in assessing angle closure are still needed. intersected by a line extended from the plane of focus. An object that In contrast, the use of the rotational Scheimpflug cameras lies on this plane can be captured in focus despite not being parallel in evaluating angle closure has been supported with direct with the image plane. comparisons to ultrasound biomicroscopy (UBM) [3] and anterior segment optical coherence tomography (ASOCT) [12]. The Pentacam (Oculus, Wetzlar, Germany) is equipped Table 1: Select Scheimpflug imaging systems. with two cameras: a rotational camera that captures the Scheimpflug image and a front camera that is used to Device Manufacturer Image acquisition evaluate the pupillary opening. Information obtained by the Orbscan II Bausch & Lomb, USA Horizontal cross section frontcameraaidswithmeasurementcorrectionsaswellasthe Pentacam Oculus, Germany Single rotating camera three-dimensional reconstruction (Figure 2) [2]. However, Galilei Ziemer, Switzerland Dual rotational camera all Scheimpflug-based devices share a similar drawback Sirius CSO, Italy Single rotating camera when compared to UBM and ASOCT. Due to total internal TMS-5 Tomey, Japan Single rotating camera reflection, photographs of the innermost aspects of the Precisio Ivis, Italy Single rotating camera iridocorneal angle cannot be obtained and therefore direct visualization of the angle is not possible [1–3]. Scheimpflug devices rely on extrapolated measurements from surrounding structures. On the other hand, ASOCT devices detect the Scheimpflug camera. A select list of Scheimpflug devices is backscatter of reflected infrared light, which allows for high- presented in Table 1. resolution image reconstruction of the angle, and, to a certain extent, the ciliary body and sulcus [12]. 3. Anterior Chamber and Iridocorneal Parameters obtained by the Scheimpflug imaging have Angle Assessment been shown to correlate well with gonioscopy [3, 12, 15]. It is capable of estimating the anterior chamber depth (ACD), Recent investigations have explored the emerging role of anterior chamber volume (ACV), and anterior chamber anterior segment imaging in screening for angle closure [1]. angle (ACA). Kurita et al. [3] compared Pentacam param- Gonioscopyhasservedasthediagnosticstandardforeval- eters with parallel measurements obtained by UBM (UBM uating narrow angles and related entities [9]. However, this model840,HumphreyResearchDivision,CarlZeissInc, technique requires a contact lens and a proficient examiner Thornwood, NY) in ability to identify patients with narrow to provide a confident diagnosis [3]. And even among angles. The UBM measurement of the ACA was found to experienced clinicians, there is variability in angle grading have the highest correlation with Shaffer grade [3]; this due to the subjective nature of the assessment. Anterior was consistent with prior works establishing the utility of segment imaging devices hold the potential for a noncontact UBM in evaluating narrow angles [16]. However, the Pen- method of angle closure screening [1, 12, 13]. It may enable tacam’s ACA measurement was not reliable for evaluating practitioners that are less familiar with gonioscopy to effec- eyes with a Shaffer grade of 2 or less. The correlation between tively screen for angle closure or patients suspected of ACA measurement and gonioscopic grade was also weaker having angle closure. For experienced clinicians, noncontact by Schiempflug photography when compared to UBM [17]. imaging may serve as a useful supplement to gonioscopy. It The unreliability of the Pentacam’s ACA measurement is maybeparticularlyvaluableinsituationswherearoutine likelyduetolimitedanglevisualization.Nonetheless,the examination is difficult, such as with patients who poorly Pentacam’s ACD measurement and ACV measurement were tolerate gonioscopy or who have difficulty with the required showntobeeffectiveatidentifyingprimaryangleclosureeyes positioning [1, 2, 8]. Several technologies have capabilities [3, 15]. One study using both UBM and Scheimpflug imaging that may be useful in the evaluating narrow angles, which are showed that, in patients with acute angle closure, the fellow overviewedinTable2[1,3,12]. eye had findings of narrow ACA width and additional ACA Journal of Ophthalmology 3

Table 2: Comparison of anterior segment imaging modalities for assessing narrow angles.

Correlation with Quantitative Imaging system Advantages Limitations gonioscopy parameters Slit scan Iridocorneal angle No visualization of angle, ciliary N/A Noncontact topography ACD body or sulcus Rotational ACD ∗ No visualization of angle, ciliary Scheimpflug ++ ACV Noncontact body or sulcus camera ACA Noncontact Requires identification of scleral AOD500 Direct angle visualization spur ASOCT +++ TISA500 Some visualization of ciliary Noncontact assessment limited body and sulcus to temporal and nasal angles ACD ACV Excellent visualization of angle, Requires contact, identification UBM +++ ACA ciliary body and sulcus of scleral spur AOD500 TISA500 ACD: anterior chamber depth, ACV: anterior chamber volume, ASOCT: anterior segment OCT, UBM: ultrasound biomicroscopy, AOD: angle opening distance, and TISA: trabecular iris area. N/A: not available, validating studies required. ∗ indicates that it may be as useful as ASOCT for partitioning narrow angles but it does not provide direct angle visualization.

Figure 2: Three-dimensional image representation of the anterior segment obtained by the Pentacam (Oculus, Wetzlar, Germany). Note that visualization of the iridocorneal angle is obscured by total internal reflection. Various parameters obtained by extrapolated measurements may be useful for angle closure screening (red box). These include anterior chamber angle (ACA), anterior chamber depth (ACD), and anterior chamber volume (ACV). narrowinginresponsetoalight-to-darkluminancechange with gonioscopy as the reference standard [12]. Although the and also pilocarpine-induced pupillary constriction [18]. Pentacam cannot directly visualize the angle, it is advantaged Rotational Scheimpflug imaging has also been shown by the breadth of three-dimensional data incorporated in its to be comparable to ASOCT in partitioning patients with analyses. In contrast, noncontact ASOCT assessment limited narrow angles. Grewal et al. [12] matched the Pentacam’s to cross sections of only the nasal and temporal angles may ACD and ACV measurement against parameters obtained exclude representative information regarding the angle. To by spectral domain ASOCT. The RTVue 100 (Optovue Inc, image the superior and inferior angles, contact would be Fremont, CA, USA) ASOCT used in their study was equipped required to move the eyelids obscuring visualization [9]. with a corneal adaptor module that allows for software to Scheimpflug systems such as the Pentacam appear to be calculatetheangleopeningdistanceat500micronsfromthe viable technologies for evaluating angle closure. Although the scleral spur (AOD500). The AOD500 is a parameter previ- Pentacam was better able to predict angle anatomy than the ously defined using UBM [17]. The Pentacam’s estimation of RTVue 100 ASOCT in one study [12], further investigations the ACV and ACD outperformed the parameters obtained are needed to discern how rotational Scheimpflug imaging by the RTVue 100 ASOCT in the detection of narrow angles measures up against ASOCT. Presently, both technologies 4 Journal of Ophthalmology appear comparable in their ability to deliver a noncontact measurements can be obtained by the Pentacam, Sirius, methodforscreeningangleclosure.Thevalueofhaving Galilei, and Corvis ST. Of these devices, the Galilei has the reproducible, quantifiable parameters is desirable for screen- highest reported intraoperator repeatability. This may be in ing as well as monitoring treatment effect. The Pentacam, part attributable to its dual-rotational camera design, which for instance, is capable of demonstrating a posttreatment can average the CCT estimate from two different Scheimpflug increase in ACV following laser iridotomy [17, 19–23]. How- cameras [32]. However, studies vary widely in reporting ever, one clear advantage held by ASOCT and UBM imaging how similar CCT measurements are between the different is direct visualization of the angle, ciliary body, and sulcus. devices. A study comparing CCT measurements obtained by This is of particular importance for evaluating mass lesions Scheimpflug systems with ultrasound pachymetry has been or conditions such as plateau iris where visualization of ciliary published previously [32]. Some investigations have noted body anatomy is essential to the diagnosis [9, 24]. no difference in mean CCT obtained by either ultrasound pachymetry or with the Pentacam [31, 37]. In contrast, 4. Central Corneal Thickness several other studies have noted a significant difference in the mean CCT measured by Pentacam and by ultrasound Goldmann applanation tonometry (GAT) is often regarded pachymetry [38–41]. Similarly, the Sirius-CCT measurement as reference standard for measurement of intraocular pres- is comparable but significantly different from the ultrasound sure (IOP). When Goldmann and Schmidt introduced their pachymetry CCT [42, 43]. Despite sharing a common imag- tonometer in 1957, they acknowledged sources of possible ing technology, the various Scheimpflug devices appear to error including CCT. The Imbert-Fick law serves as the basis obtain CCT measurements that are statistically different from for GAT. The concept assumes a perfectly thin cornea that each other. Even though these differences may be small, behaves like a membrane where the IOP is equal to the caution is generally advised in comparing CCT values across applanating pressure. In actuality, the cornea is variably thick different measurement platforms. It remains to be clarified rather than perfectly thin, and the tear film contributes a whether these differences may be sufficiently small for them confounding force from surface tension [25, 26]. to be negligible in clinical contexts. One of the strongest independent risk factors for developing primary open-angle glaucoma (POAG) is CCT [27– 5. Corneal Biomechanics and IOP 29]. Another independent risk factor is IOP, a measurement which can be influenced by CCT. For this reason, it is believed CCT is but one dimension of a multifaceted area of study by some that the CCT is a risk factor for developing POAG that comprises corneal biomechanics. Interest in the biome- only by virtue of its influence on IOP measurement [29]. chanical properties of the cornea parallels our interest in If this is correct, then we would not expect CCT to be an CCT: it may help explain the source of measurement error independent risk factor for developing glaucoma if predictive in tonometry and how structural features of the cornea can models corrected for the IOP measurement error attributed predict the risk of glaucomatous progression independent of to CCT [29]. However, the evidence to date suggests that their effect on IOP. However, the mechanisms underpinning a thin CCT is associated with an increased risk of POAG how CCT and corneal properties confer a risk towards beyond its artefactual effect on tonometry [27–30]. For developing glaucoma remain unclear. this reason, an interest in corneal properties like CCT will Theoretical models predict that optic nerve head biome- remain relevant regardless of the error it confers towards IOP chanics can be influenced by the structure of the adjacent measurement. sclera [44, 45]. The optic nerve head is a site of discontinuity Although ultrasound pachymetry is widely used to mea- within the cornealscleral shell [45] and is the location of sure CCT, it is disadvantaged in several ways [31, 32]. retinal ganglion cell injury due to glaucoma [45]. From Measurement accuracy and repeatability depend on accurate theoretical models, the lamina cribrosa is predicted to expe- placement of the probe onto the cornea, which is done man- rience an increase in tensile strain with increasing eye radius ually. Corneal indentation can occur with contact between [44, 46]. These models also predict, though, that scleral the cornea and the probe, which may falsely underestimate stiffness may mitigate this increase in strain expected from the actual CCT. And because this technique relies on the having a longer eye [44, 46]. It has been hypothesized that assumption that the speed of sound is similar through corneal parameters like CCT may serve as surrogate measures healthy and diseased corneal tissue, the measurement may be forsomebiomechanicalpropertyofthesclera[44,46]. inaccurate in certain pathologic disease states. For these rea- Lanzagorta-Aresti et al. [47] showed that changes in the sons, noncontact methods for estimating CCT are desirable. displacement of the lamina cribrosa after medical treatment Devices capable of measuring CCT in this fashion include of IOP was significantly correlated corneal hysteresis. Fur- Scheimpflug imaging devices such as the Pentacam, Galilei thermore, Wells et al. [48] demonstrated that low corneal (Ziemer, Port, Switzerland), Sirius (Costruzione Strumenti hysteresis, but not CCT, was associated with reduced optic Oftalmici, Florence, Italy), TMS-5 (Tomey, Nagoya, Japan), nerve head compliance. However, efforts to correlate CCT and the Corvis ST. with lamina cribrosa thickness have yielded no significant Scheimpflug devices are able to provide highly repeatable association between the two [49]. CCT measurements that are comparable to, but not likely The two devices capable of quantifying biomechanical interchangeable with, ultrasound pachymetry CCT [32–36]. features of the cornea include the Ocular Response Ana- Prior studies have shown that highly reproducible CCT lyzer or ORA (Richert Ophthalmic Instruments, Depew, Journal of Ophthalmology 5

New York, USA) and the Scheimpflug-based noncontact is growing evidence, though, that corneal biomechanical tonometer Corvis ST [7, 50]. To date, most of the studies properties, such as corneal hysteresis, may better explain the investigating corneal biomechanics have utilized the ORA, source of measurement error in tonometry than CCT [56]. which was released in 2005; the Corvis ST was made available The corneal deformation amplitude measured by the in 2012. The ORA can measure corneal hysteresis, which may Corvis ST has been implicated as source of measurement be an indicator of the cornea’s viscoelasticity [51]. Patients error of GAT. In a study population containing normal with POAG and normal tension glaucoma have been shown and glaucomatous eyes, Leung et al. [7] compared IOP to have lower-than-average corneal hysteresis values [52]. measurements obtained by GAT with dynamic contour Furthermore, low corneal hysteresis has also been implicated tonometry (DCT, Pascal, Swiss Microtechnology AG, Port, in glaucomatous field progression [53, 54]. Switzerland). IOP measurement by DCT is theoretically less The Corvis ST provides a noncontact method for eval- dependent on corneal biomechanical properties and by this uating IOP, CCT, and the cornea’s biomechanical response virtue it may better approximate the “true” IOP. Indeed, IOP to a collimated puff of air. It is equipped with an ultrahigh- measurements obtained by DCT are highly concordant with speed Scheimpflug camera that is capable of recording 4330 intracameral measurements [57]. To evaluate factors that may frames/second. The air puff is delivered with a fixed pressure explain the difference in IOP measurements obtained by DCT at the corneal surface over 31 ms, allowing for the digital and GAT, Leung et al. [7] also studied the biomechanical captureof140images.Thecornealresponsetotheairpuff properties obtained by the ORA and the Corvis ST. Mea- is initially marked by an inward conformational change in surement of the corneal deformation amplitude was shown the corneal curvature. This initial flattening of the cornea is to be dependent on IOP and CCT (measured by ultrasound referred to as the first applanation (Figure 3) [50, 55]. The pachymetry). From their univariate analysis, the difference cornea eventually deforms to a point where it is maximally in DCT and GAT measurements was associated with CCT concave prior to returning to its original shape. This event and corneal deformation amplitude after adjusting for the defines the corneal deformation amplitude at the highest effect of IOP. But with the multivariate analysis, the only concavity(Figure3).Thecorneathennaturallyreturnstoits parameter significantly associated with this measurement original shape, which is referred to as the second applanation difference was corneal deformation amplitude. The authors [50, 55]. Various aspects of the corneal deformation response comment that the influence of CCT on GAT likely stems totheair-puffcanbequantified,whicharereviewedindetail from the effect of CCT on corneal deformation amplitude [7]. elsewhere [55]. Of note, the corneal hysteresis and corneal resistance factor Recently, Lee et al. [50] published a cross-sectional study measurements obtained by the ORA were not significantly demonstrating a parameter obtained by the Corvis ST that associated with the measurement discrepancy between DCT appeared to be independently associated with glaucoma risk. and GAT in this investigation [7]. The ORA functions in a They identified three Corvis ST parameters that could parti- very different way from the Corvis ST; while the air puff of tion patients with either POAG or normal tension glaucoma the Corvis ST is applied with a fixed force, the ORA air puff is from normal controls: (1) outward applanation velocity, (2) delivered with a variable force. Although both instruments time to highest concavity, and (3) peak distance. However, assess corneal biomechanics, it is difficult to compare the two of these parameters, namely, outward applanation veloc- metrics obtained by these two devices [55, 58]. ity and peak distance, were associated with Corvis-IOP [50]. Although the Corvis ST is capable of providing an On the other hand, the highest concavity time was associated estimate of IOP,Leung et al. [7] did not compare the accuracy with the glaucomatous group and not dependent on other of this measurement with DCT. The IOP estimate by the established risk factors for glaucoma such as CCT or IOP. It Corvis ST has been shown to be highly reproducible [59] should be noted, though, that their results contrast with those and comparable to GAT [60, 61]. It should be noted, though, of Leung et al. [7] in that the latter study group did not find that the degree of correlation between Corvis-IOP [59] and any of the Corvis ST parameters to be capable of partitioning GAT was relatively weak compared to other techniques such glaucomatous patients from normal subjects. as DCT [62] and iCare rebound tonometry [62, 63]. The sig- While various corneal parameters may be associated nificance of this finding is unclear absent data validating with glaucomatous risk independently of their effect on IOP the accuracy of Corvis-IOP measurements [59, 61]. Future measurement, the study of corneal biomechanics may aid in investigations comparing intracameral IOP measurements to better understanding sources of measurement error. IOP is the Corvis ST would be helpful for this end [60]. There is no a modifiable risk factor associated with glaucomatous pro- consensus agreement among studies on whether the Corvis- gression [27–30]. A coveted goal in glaucoma management IOP tends to be higher [60, 63] or lower [61, 64] than the IOP is approximating IOP, as close as possible, to the “true” estimated by GAT. IOP. An intracameral measurement of IOP may be the most accuratemethodforachievingthisend,butitisclinically 6. Cataract Evaluation impractical [56]. Because of this, various approaches have been developed and described to help correct for the effects A brief section on cataract evaluation is reviewed given that biomechanical features of the cornea have on IOP its relevance in glaucoma management and especially in measurement. Regression analyses have been proposed with light of the rising interest in combining cataract extraction formulaic corrections for values obtained by applanation with minimally invasive glaucoma surgery (MIGS). MIGS tonometry, taking into account the effects of CCT. There procedures offer the potential for modest reductions in IOP 6 Journal of Ophthalmology

Applanation length1 Applanation length2 D

T1 T2

Figure 3: Diagramatic representation of the biomechanical response of the cornea to the metered air puff delivered by the Cornea Visual Scheimpflug Technology (Corvis ST). The first phase (left) is marked by corneal surface flattening and the initiation of aninward conformational change in the corneal curvature (referred to as the first applanation 𝑇1). Further deformation produces a concave corneal surface. The moment it reaches the maximally deformed state (middle) is referred to as the time of highest concavity. The distance, 𝐷,isthe peak distance or corneal deformation amplitude. After reaching its maximally concave shape, the cornea recoils into its original shape. When the surface is similarly flattened compared to 𝑇1, this moment marks the second applanation or 𝑇2 (right).

in patients with mild-moderate glaucoma. They are not may help guide the selection of phacoemulsification tech- always performed as standalone procedures given that their nique or use of a femtosecond laser for lens fragmentation. IOP-lowering effect cannot rival that of traditional filtering It should be mentioned, however, that lens densitometry surgeries. Because of this, it is often preferable for MIGS measurements are currently less precise for higher-grade procedures to be done conveniently at the time of cataract nuclear cataracts [67]. Scheimpflug imaging has been shown surgery [65]. to be helpful for evaluating intraocular lens tilt and decen- Traditionally, the appraisal of a visually significant tration following cataract extraction [68, 69]. The LENSAR cataract involves two main factors: (1) a functional deficit, (LENSAR Inc., Winter Park, USA) is a femtosecond laser suchasSnellenacuity,and(2)theclinician’sassessmentof that is equipped with Scheimpflug imaging capabilities [70]. lens opacification. There are shortcomings associated with Similar to the Pentacam, the device can automatically grade both arms of the traditional approach. Patients with relatively lens density on a scale of 1–5. It special features an imaging good Snellen acuity may actually have poor vision quality system that enables the detection of any tilt that may be and the subjective grading of lens opacification is subject exhibited by the native crystalline lens; this is important for to interrater variability. The most widely recognized lens- maximizing the likelihood of a producing a precise, free- grading schema is the Lens Opacification Classification III floating capsulotomy [70]. (LOCS III), which was last updated in 1993 [66]. Scheimpflug systems such as the Pentacam may be able to enhance our assessment of cataractogenesis. The Penta- 7. Summary cam can measure lens densitometry with specific metrics The Scheimpflug principle is the basis for a number of devices that include average density and maximum density. Based and imaging systems. The technology is extraordinarily on these measurements, the Pentacam can be equipped versatile, with applications spanning from laser keratore- with software that then assigns a grade of nuclear sclerosis on a scale of 1–5 (Pentacam Nuclear Staging or PNS). fractive surgery to quantifying cataractogenesis. Scheimpflug The PNS score has been shown to correlate well with devices have several relevant applications for glaucoma Snellen acuity and LOCS III grade, validating the Pentacam’s management. Currently, Scheimpflug-based imaging systems automated assessment of nuclear sclerosis [67]. Furthermore, have formidable capabilities to ASOCT for predicting angle the Pentacam’s densitometric parameters have been positively closure, despite their inability to visualize the iridocorneal correlated with higher-order aberrations (HOAs) obtained angle. Noncontact methods of assessment have multiple from wavefront analyses [67]. A consideration of HOAs advantages including sanitary considerations, patient com- may enable clinicians to better appreciate why patients with fort, and in some cases, less operator-dependent. Because of relatively good Snellen acuity may complain of poor vision this,technologieslikeScheimpflug-baseddevicesarelikely quality. Similar such innovations are likely to increase our to be increasingly used as they become more accessible. sensitivity in identifying visually significant lens opacities, The clinician should heed caution, though, in interchanging thereby potentially expanding our indications for cataract measurements obtained by different technologies as they can extraction. be slightly different. With the introduction of the Corvis ST, The use of Scheimpflug systems as surgical planning tools investigators have 2 available devices for the study of corneal has also been suggested. Measurements of lens densitometry biomechanics. Relevant investigations with these devices are enable a quantitative evaluation of a nuclear sclerosis; this needed to provide unanswered questions for how corneal Journal of Ophthalmology 7

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Clinical Study Accelerated Corneal Collagen Cross-Linking Using Topography-Guided UV-A Energy Emission: Preliminary Clinical and Morphological Outcomes

Cosimo Mazzotta,1,2 Antonio Moramarco,3 Claudio Traversi,2 Stefano Baiocchi,2 Alfonso Iovieno,3 and Luigi Fontana3

1 SienaInt.Cross-LinkingCenter,Siena,Italy 2Department of Medical, Surgical and Neurosciences, Ophthalmology Unit, Siena University, Siena, Italy 3Ophthalmology Unit, Arcispedale Santa Maria Nuova Hospital-IRCCS, Reggio Emilia, Italy

Correspondence should be addressed to Antonio Moramarco; [email protected]

Received 17 June 2016; Revised 10 October 2016; Accepted 3 November 2016

Academic Editor: Yu-Chi Liu

Copyright © 2016 Cosimo Mazzotta et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. To assess the clinical and morphological outcomes of topography-guided accelerated corneal cross-linking. Design. Retrospectivecaseseries.Methods. 21 eyes of 20 patients with progressive keratoconus were enrolled. All patients underwent 2 2 accelerated cross-linking using an ultraviolet-A (UVA) exposure with an energy release varying from 7.2J/cm up to 15 J/cm , according to the topographic corneal curvature. Uncorrected (UDVA) and corrected (CDVA) distance visual acuity, topography, in vivo confocal microscopy (IVCM), and anterior segment optic coherence tomography (AS-OCT) were evaluated preoperatively and at the 1, 3, 6, and 12 months postoperatively. Results. 12 months after surgery UDVA and CDVA did not significantly vary from preoperative values. The average topographic astigmatism decreased from −4.61 ± 0.74 diopters (D) to −3.20 ± 0.81 D and coma aberration improved from 0.95 ± 0.03 𝜇m to 0.88 ± 0.04 𝜇m after surgery. AS-OCT and IVCM documented differential effects on the treated areas using different energies doses. The depths of demarcation line and keratocyte apoptosis were assessed. Conclusions. Preliminary results show correspondence between the energy dose applied and the microstructural stromal changes induced by the cross-linking at various depths in different areas of treated cornea. One year after surgery a significant reduction in the topographic astigmatism and comatic aberration was detected. None of the patients developed significant complications.

1. Introduction Conventional CXL with epithelium removal (epithelium- off) represents an evidence based and scientifically well- Conventional riboflavin UVA corneal cross-linking (CXL) supported treatment, with documented long-term efficacy represents an evolving therapy for the conservative treatment in stabilizing progressive keratoconus and secondary ectasia of progressive keratoconus (KC) [1, 2] and secondary corneal as reported in a series of nonrandomized and randomized ectasia [3, 4] due to its capacity to increase the corneal clinical trials [7, 8]. Since conventional CXL procedure biomechanical resistance and the intrinsic anticollagenase requires long treatment time (1 hour approximately), [9] activity. The physiochemical basis of conventional CXL accelerated cross-linking (ACXL) treatment protocols have lies in the photodynamic types I-II reactions induced by been proposed with the purpose of shortening treatment the interaction between riboflavin molecules, absorbed in 2 time, improving patient’s comfort and reducing hospital corneal tissue, and UVA rays delivered at 3 mW/cm for waiting lists. 2 30 minutes (5.4 J/cm energy dose), which releases reactive Recent studies have shed light on the chain of chemical oxygen species able to mediate cross-link formation between events occurring during the photochemical activation of andwithincollagenfibersandwithinproteoglycancore riboflavin with ultraviolet light, emphasizing the impor- proteins in the interfibrillary space [5, 6]. tance of corneal oxygenation during treatment. With pulsed 2 Journal of Ophthalmology fractionation of ultraviolet-A (UVA) radiation, cross-linking Topography-guided ACXL were carried out with the KXL efficiency may be improved by allowing rediffusion of oxygen II6 UVA illuminator (Avedro Inc., Waltham, MA, USA) 2 during UVA light exposure pauses. using a 30 mW/cm UV-A power with pulsed-light emission Topography-guided ACXL was first proposed as a poten- (1 second on/1 second off). Treatments were individually tial approach to improve optical predictability of CXL and planned by using a dedicated software (Avedro Mosaic Sys- maximizing corneal regularization in a patient-specific com- tem version 1.0, Avedro Inc., Waltham, MA, USA), according 2 putational modeling study of keratoconus progression and to the preoperative topography data. The 30 mW/cm cus- differential responses to CXL [10]. In simulations comparing tomized, topography based, ACXL treatments consisted in a broad-zone CXL treatments to focal, cone-localized treat- differentiated energy dose release according to the different ment, much greater reductions in cone curvature and higher cornealcurvaturesshowedbyeachkeratoconus.Theentry 2 order aberrations (HOA) were observed with cone-localized levelenergydoseof7.2J/cm was delivered in the flattest patterns for a variety of patient tomographies [10]. Given peripheral cone area under 48 diopters (D) of maximum 2 that corneal ectasia is driven by focal rather than general- corneal curvature (𝐾max), by using 30 mW/cm (1 sec on/1 sec ized weakness [11], focal stiffening of the cone region may off) pulsed (or fractionated) light illumination for 8 minutes promote a more favorable material property redistribution of UV-A exposure time. Ectatic areas with corneal curvature with compensatory steepening of surrounding areas, thereby over 48 D and under 52 D were treated with an energy dose 2 2 enhancing topographic normalization [10]. of 10 J/cm maintaining the same UV-A power of 30 mW/cm Here we present the 1-year functional and morphological prolonging the exposure time of 3 minutes in order to reach 2 results of the first topography-guided ACXL study performed the programmed dose of 10 J/cm (11 min of total exposure in Italy. time). If present, the steepest areas of corneal curvature over 52 D were treated by extending further the exposure 2 2. Materials and Methods time, until reaching the maximum energy dose of 15 J/cm with a total UV-A treatment time of 16 min on balance. The The study was conducted at the Siena International Cross- treatment planning was established by using semimeridians Linking Center and at the Ophthalmic Unit of the Arcisped- K values on Pentacam maps. Total treatment time was 8 min ale Santa Maria Nuova of Reggio Emilia. The high-irradiance for keratoconus under or equal to 48 D of maximum K values, corneal collagen ACXL with topography-guided UVAenergy 11 min for keratoconus including simulated K values over 48 release treatment protocol was approved by the Institutional and under 52 D in the steepest areas, extending the exposure Review Board. All patients gave informed consent and the time to 16 min for keratoconus showing curvatures over 52 D study was conducted according to the ethical principles in the steepest areas. The treatment starts from a baseline for medical research stated in the Helsinki Declaration as broad-beam illumination including the flattest peripheral 2 renewed in 2013. areas(48Dandunder)at7.2J/cm ; then after the first 8 min, Preoperatively and postoperatively at 1, 3, 6, and 12 these areas are masked and the steepest zones illumination months, patients underwent a full ophthalmologic examina- is further extended until the final energy dose of 10 J or 2 tion including uncorrected distance visual acuity (UDVA) 15 J/cm is delivered according to maximum curvature values. logMAR, corrected distance visual acuity (CDVA) logMAR, The thinnest point and the area of major posterior elevation refraction, slit lamp evaluation, tonometry, and fundoscopy. were included within the highest dose treatment zone. The At the same time intervals patients were investigated by using irradiation patterns shapes included arc, circular, oval, and Scheimpflug corneal tomography (Pentacam6 HR, Oculus, combined patterns according to keratoconus tomography Arlington, WA, USA), in vivo confocal microscopy (IVCM) andshape.Theirradiationpatternwasalignedbyusinga with the Heidelberg Retina Tomograph II (HRTII) (Rostock direct real time visualization of the cornea, maintaining a Cornea Module, Heidelberg, Germany), and anterior seg- perfect centration by the eye-tracking system provided by the ment optical coherence tomography (AS-OCT) (Zeiss, Jena, machine. Germany). All patients included for this analysis completed After UV-A irradiation, the cornea was washed with ster- the 1-year follow-up visit. ile balanced salt solution (BSS), medicated with antibiotics (moxifloxacin), cyclopentolate eye drops, and dressed with a therapeutic soft contact lens that was removed after four days. 3. Surgical Technique Inclusion criteria and treatment protocol are listed in Table 1. Topography-guided ACXL procedures were carried out Statistical analysis was performed using the Wilcoxon test. All analyses were performed using the IBM SPSS under sterile operating conditions and topical anesthesia ≤ with the application of 4% lidocaine and 0.2% oxybupro- Statistics version 16.0 (Armonk, USA). A p value of 0.05 was caine hydrochloride anesthetic drops. Topical pilocarpine considered statistically significant. 2% was administered 10 minutes before treatment. After application of a lid speculum, the corneal epithelium was 4. Results removed by a blunt metal spatula in the central 9 mm area. Corneal stroma was soaked for 10 minutes with a riboflavin Twenty-one eyes of 20 patients, 16 males and 4 females, 0.1% Hydroxyl-Propyl Methyl-Cellulose (HPMC) dextran- mean age 28.9 ± 5.8 years (range 22–34 years) with progres- free solution (VibeX Rapid Avedro Inc., Waltham, MA, USA). sive keratoconus, were included in the study. One patient Journal of Ophthalmology 3

Table 1: Inclusion criteria and treatment protocol.

Keratoconus progression criteria Increased sim 𝐾max ≥ 1D;pachymetryreduction≥ 10 𝜇m Epithelium removal, 10-minute soaking with VibeX Rapid 0.1 riboflavin, saline, HPMC Procedure solution applied every 90 seconds 2 Irradiance 30 mW/cm pulsed or fractionated UVA light exposure (1 second on/1 second off) 2 2 Energy From 7.2 J/cm up to 15 J/cm total energy dose Arc patterns for “peripheral cones” (apex distance ≥3mmfromthepupillarycenter); Patterns circular patterns for “central cones” Thickness Minimum stromal thickness 400 𝜇m

underwent a bilateral treatment. Mean UDVA and CDVA, UCVA (logMAR) respectively, changed from preoperative 0.55 ± 0.2 logMAR 1.00 and 0.21 ± 0.1 logMAR to 0.36 ± 0.1 logMAR (𝑝 = 0.65) 0.90 and 0.10 ± 0.1 logMAR at 12 months (𝑝 = 0.10).Themean 0.80 0.70 − 0.55 preoperative topographic astigmatism improved from 4.61 0.60 0.52 ± 0.74 diopters (D) to −3.20 ± 0.81 Dat12-monthfollow-up 0.50 0.42 0.38 0.36 (𝑝 = 0.048). The 12th month difference from preoperative 0.40 topographic astigmatism was −1.41 D. Visual acuity and 0.30 topographic astigmatism are reported for each time interval 0.20 0.10 in Figure 1. 0.00 𝐾 𝐾 𝐾 Mean preoperative max, min and average values out- Preop 1 month 3 months 6 months 12 months 47.50 ± 1 45.21 ± 0 47.44 ± lined at 3 mm were .14 D, .67 D, and (a) 0.99 D, respectively; values changed to 46.50 ± 1.81 D (𝑝= CDVA (logMAR) 0.088), 45.70 ± 0.7 D (𝑝 = 0.055), and 47.98 ± 1.42 D (𝑝= 0.077) at 12 months' follow-up, respectively. Topography K 0.50 0.45 values are reported for each time interval in Figure 2. 0.40 Mean preoperative coma, RMS, and spherical aberration 0.35 0.95 ± 0.03 𝜇 2.09 ± 0.01 𝜇 0.30 values were, respectively, m, m, and 0.21 0.02 ± 0.01 𝜇m; values changed to 0.88 ± 0.04 𝜇m(𝑝 = 0.049), 0.25 0.19 0.20 1.89 ± 0.03 𝜇m(𝑝 = 0.058), and 0.00 ± 0.01 (0.068) 𝜇mat 0.12 0.15 0.09 0.10 the 12 months’ follow-up. The 1-year change from baseline in 0.10 coma was statistically significant𝑝 ( = 0.049). High order 0.05 aberrations values are reported for each time interval in 0.00 Figure 3. Preop 1 month 3 months 6 months 12 months Mean preoperative minimum pachymetry values varied (b) from 462.20±10 𝜇matbaselineto466.29±8.2 𝜇m(𝑝 = 0.087) Cylinder (D) at 6 months and to 460.01±12.1 𝜇m(𝑝 = 0.079)at12months Preop 1 month 3 months 6 months 12 months follow-up. Mean endothelial cell density changed from 2490± −0.50 2 2 −1.00 17 cells/mm at baseline to 2469 ± 31 cells/mm at 1 month 2 −1.50 (𝑝 = 0.66), to 2475 ± 28 cells/mm at 3 months (𝑝 = 0.65), to −2.00 2 2482 ± 23 cells/mm at 6 months (𝑝 = 0.65), and to 2488 ± −2.50 2 𝑝 = 0.67 −3.00 37 cells/mm at 12 month follow-up ( ). −3.50 −4.00 −3.21 −3.20 −3.66 5. Anterior Segment OCT Analysis −4.50 −4.06 −5.00 −4.61 −5.50 Corneal OCT scan (Figure 4(a)) showed a double demarcation line according to the different energy doses delivered (c) in the corneal tissue and different exposure times. Treat- Figure 1: LogMAR average UDVA (a), CDVA (b), and topographic ment irradiation patterns combined a peripheral single arc astigmatism (c) values after high-irradiance topography-guided illumination (7.2J) followed by a central circular irradiation CXL. 1-year follow-up mean topographic astigmatism value signifi- pattern (10 J), Figure 4(b). The corresponding treatment plan- cantly improved from −4.61 diopters (D) to −3.20 D (𝑝 < 0.05). ning is showed in Figure 4(c) based on corneal curvatures. 2 After 8 min of UV-A exposure time at 30 mW/cm power with pulsed-light illumination (1 sec on/1 sec off) to deliver demarcation line, measured from epithelial surface, was 150 2 7. 2 J / c m in the peripheral flattest area, the average depth of ± 18 𝜇mSDintheflattercornealareaand 300 ± 37 𝜇mSD 4 Journal of Ophthalmology

K max Coma (𝜇m) 55.00 1.00 0.98 0.95 50.00 47.50 48.52 49.36 46.60 46.50 0.96 0.94 0.92 0.92 0.90 0.89 45.00 0.90 0.88 0.88 40.00 0.86 Preop 1 month 3 months 6 months 12 months 0.84 0.82 K min 0.80 50.00 Preop 1 month 3 months 6 months 12 months 48.00 RMS (𝜇m) 45.21 46.04 46.30 45.81 45.77 3 46.00 2.8 2.6 44.00 2.4 2.2 2.09 42.00 2.04 1.94 2.02 2 1.89 Preop 1 month 3 months 6 months 12 months 1.8 K 1.6 avg 50 1.4 49.5 1.2 49 1 47.44 48.2 48.17 48.00 47.98 Preop 1 month 3 months 6 months 12 months 48.5 48 Spherical aberration (𝜇m) 47.5 0.5 47 0.45 46.5 0.4 46 0.35 Preop 1 month 3 months 6 months 12 months 0.3 0.25 𝐾 𝐾 𝐾 0.2 Figure 2: max, min,and average after high-irradiance topography- guided CXL. 1-year follow-up of simulated K readings tangential 0.15 0.1 0.07 algorithm values data showed that 𝐾max changed from 47.50±1.14 D 0.05 0.02 0.01 0.01 to 46.50±1.81 D (𝑝 > 0.05),while𝐾min value increased from 45.21± 0 0.67 47.7 ± 0.91 (𝑝 < 0.05) 𝐾 0 Dto D . average values passed from Preop 1month 3months 6months 12 months 47.44 ± 0.99 Dto47.98 ± 1.42 D (𝑝 > 0.05). Figure 3: Coma, RMS, and spherical aberration values after high- irradiance topography-guided CXL. 1-year follow-up aberrometry data showed a statistically significant coma value reduction (𝑝 < 2 0.05). No statistically significant changes were recorded for RMS and in the steeper corneal area treated at 10 J/cm as shown spherical aberrations. in Figure 4(a) by the deeper demarcation line. The greater depth of the demarcation line in the paracentral area was correlated with the prolonged exposure time (11 min) and higher energy dose delivered in the central steepest zone (10 J). The hyperreflectivity of the stroma corresponded to the 𝜇 central area treated with the highest energy dose. Differential by the red arrows (depth 310 m). Figure 5(c) shows a 2-Zone topography-guided ACXL treatment with 7.2 (green arrows) corneal topography between preoperative (Figure 4(e)) and 2 postoperative acquisition, Figure 4(d), at 6 months shows and 10 J/cm (blue arrows) E doses treatment planning. OCT a clear improvement with flattening of the steepest inferior scan performed one month after treatment, Figure 5(d), area (−1.9 D) and a compensatory steepening (+0.9 D) of the revealed a double demarcation line according to different superior flatter zone, Figure 4(f). exposure times and doses delivered according to the corneal 𝜇 There are two different treatment programs according curvature reaching a demarcation line depth of 164 minthe to the different KC severity (Figure 5). Figure 5(a) shows peripheral area treated with 7.2J for 8 min of UVA exposure 𝜇 a 3-Zone topography-guided ACXL treatment planning (green arrow) and 311 m in the steeper paracentral area according to corneal curvatures. Postoperative OCT scans treated with 10 J (blue arrow). one month after treatment, Figure 5(b), revealed a triple demarcation line according to the three different exposure 2 6. IVCM Outcomes times and energy doses used: 7.2 J/cm in the peripheral KC flattest area 48 D and under (depth 151 𝜇m), green arrows; Different demarcation lines were also documented with 2 10 J/cm in the intermediate area between 48 and 52 D (depth IVCM at 150 𝜇m ± 28 𝜇m SD depth in the flattest areas 2 2 215 𝜇m), blue arrows; 15 J/cm in the steepest area indicated (48 D and under), irradiated at 7.2 J/cm (Figures 6(a), Journal of Ophthalmology 5

(a) (b) (c) 90∘ 90∘ 90∘ ∘ 120∘ 60 OD 120∘ 60∘ OD 120120∘ 6060∘ 8 9 mm 8 9 mm 8 9 mm

150∘ 30∘ 150∘ 30∘ 150150∘ 3030∘ 40.2 4 40.0 4 4 42.9 42.6 40.5 40.5 44.0 41.9 ∘ ∘ 45.8 40.1 45.0 40.6 ∘ ∘ ∘ ∘ 0 0 0 0 0 0

180 44.1 180 43.4 180 45.9 43.4 42.5 48.0 43.7 45.5 4 42.6 44.9 4 4 210∘ 330∘ ∘ 330∘ 210∘ 33033 ∘ 42.7 210 43.0

8 ∘ 300∘ 8 ∘ ∘ 8 ∘ ∘ TNT 240 N TNT 240 300 N 240240 300300 270∘ 270∘ 270∘ 8 4 0 4 8 8 4 084 8 4 084 (d) (e) (f) Figure 4: Corneal OCT following high-irradiance topography-guided CXL. At 3rd postoperative month (a), multiple demarcation lines due to the different energy doses delivered according to the topography-guided CXL protocol were evident. (b) illustrates the topography-guided 2 treatment in progress. (c) shows the topo-guided treatment planning with programmed double energy dose: 7.2 J/cm in the flattest area under 2 48 D (yellow arrow) with arc-step pattern, and 10 J/cm in the steepest central area over 48 D (red arrow) with circular pattern. (d) shows the 12th month postoperative flattening compared with preoperative tomography (e), followed by compensatory steepening of the flattest superior cornea documented in differential corneal tomography (f).

6(b), and 6(c)), at 250 𝜇m ± 22 𝜇m SD depth in the areas reappeared (Figures 7(a) and 7(b)). The hyperreflectivity 2 (>48 D and ≤52 D) irradiated at 10 J/cm energy dose, (Fig- of extracellular tissue was progressively reduced; lacunar ure 6(d)), and 300 𝜇m ± 31 𝜇m SD depth in the steepest edema gradually disappeared with keratocytes repopulation, 2 corneal areas (>52 D) irradiated at 15 J/cm energy dose similar to all conventional and accelerated epi-off CXL (Figure 6(e)). IVCM scans were performed in the central procedures (Figures 7(c), 7(d), and 7(e)). Twelve months after corneal areas, paracentral areas, and peripheral one by a treatment IVCM analysis showed diffuse keratocytes repop- direct real time control view of the acquisition zone by the ulation with no endothelial micromorphological alterations same operator and controlled by a second expert observer. (Figure 7(f)). An average of repeated measurements was reported. IVCM scans performed in the first postoperative 3 months showed 7. Discussion hyperreflectivity of corneal tissue and keratocytes loss was associated with marked stromal lacunar edema and nerve dis- This study documented that topography-guided ACXL is appearance in the treated areas (Figures 7(a), 7(b), and 7(c)). safe and effective in halting keratoconus progression and The intensity of stromal reflectivity and the depth of kera- improving to corneal topography at 12 months. Interestingly, tocytes apoptosis were correlated with the increasing energy regional effects on keratocyte stromal reflectivity and corneal dose delivered in the tissue. The higher the dose, the higher nerves, as well as multiple stromal demarcation lines, indi- the reflectivity detected in the first 3 months. The depth of rectly demonstrated the effectiveness of topography-guided keratocytes apoptosis well correlated with exposure times treatment planning according to different E doses and UV-A and energy doses delivered to the different areas of corneal exposure time. tissue analyzed by IVCM. No endothelial damage was doc- Recently, accelerated cross-linking protocols have been umented (Figure 7(f)). After the 3rd postoperative month, investigated in several studies. Bunsen-Roscoe’s law [12] epithelium appeared healthy and subepithelial plexus fibers established that photochemical reactions, including CXL, 6 Journal of Ophthalmology

A C

B D

Figure 5: Topography-guided ACXL treatment programs according to different KC severity. (a) shows a 3-Zone topography-guided ACXL treatment planning according to corneal curvatures. Postoperative OCT scans one month after treatment (b) revealed a triple demarcation line 2 according to the three different exposure times and energy doses: 7.2J/cm in the peripheral KC flattest area 48 D and under (depth 151 𝜇m), 2 green arrows (8 min UV-A exposure); 10 J/cm in the intermediate area between 48 and 52 D (depth 215 𝜇m), blue arrows (11 min UV-A 2 exposure); 15 J/cm in the steepest area (depth 310 𝜇m), red arrows (16 min UV-A exposure). (c) shows a 2-Zone topography-guided ACXL 2 treatment with 7.2 (green arrows) and 10 J/cm (blue arrows) E doses treatment planning. OCT scan performed one month after treatment (d) revealed a double demarcation line according to the different exposure times and doses delivered according to corneal curvatures, reaching 2 ademarcationlinedepthof164𝜇m in the peripheral area treated with 7.2 J/cm for 8 min of UVA exposure (green arrow) and 311 𝜇minthe 2 steeper paracentral area treated with 10 J/cm for 11 min of UV-A exposure (blue arrow).

depend on the absorbed UVA energy (E)andtheirbiological conventional broad-beam CXL and ACXL protocols induce effectisproportionaltothetotalenergydosedeliveredto improvements in visual acuity and topographic and aberro- the tissue [13, 14]. According to the so-called “equal-dose” metric parameters in many patients, these optical outcomes 2 2 physical principle, 9 mW/cm for 10 min, 18 mW/cm for vary from case to case due to patient-specific factors and 2 2 5min, 30mW/cm for 3 min, or 45 mW/cm for 2 min at inhomogeneous responses to the intrinsic photodynamic 2 constant energy dose (E) of 5.4 J/cm may have the same reaction and its stiffening effects [24, 25]. 2 photochemical impact of conventional CXL with 3 mW/cm In order to improve patient’s quality of vision, while for 30 minutes [8, 9]. The clinical results of high-irradiance maintaining keratoconus stability, we have investigated this 2 30 mW/cm ACXL protocol with continuous and fraction- novel topography-guided accelerated CXL protocol with cus- 2 ated UV-A light exposure [15, 16] and 18 mW/cm demon- tomized energy dose release according to corneal curvatures. strated keratoconus stability and endothelial safety, but less In this pilot study we have observed a statistically significant anterior corneal flattening effect compared to conventional reduction of the mean topographic cylinder magnitude along CXL [17]. On the other hand, a recent review [18] on with a decrease in coma aberration. Patients corneal topogra- laser scanning in vivo confocal microscopy (IVCM) of the phies were characterized by the flattening of the steeper cornea after conventional and accelerated CXL protocol KC areas associated with a compensatory steepening on the 2 documented less intrastromal penetration using 30 mW/cm flattest areas resulting in an improved corneal symmetry. All 2 𝐾 𝐾 UVA irradiance compared with standard 3 mW/cm CXL [19, functional parameters (UDVAand CDVA, max,and average) 20]. The safety of conventional CXL and ACXL riboflavin tended to improve, and we recorded a flattening of the central UVA-induced corneal collagen cross-linking in the conserva- cone area as showed in Figure 4(d) compared with preoper- tive treatment of keratoconus was evaluated and confirmed ative tomography (Figure 4(e)), followed by compensatory in vivo in humans by laser scanning in vivo confocal steepening of the flattest superior cornea documented in microscopy (IVCM) of the cornea [21, 22]. IVCM allowed for differential corneal tomography map (Figure 4(f)). a detailed, high magnification in vivo micromorphological The microstructural corneal analysis performed by IVCM showed that in the topography-guided ACXL protocol using analysis of corneal layers, enabling the assessment of early 2 energy doses higher than conventional 5.4 J/cm (from 7.2up and late corneal changes induced by these treatments with 2 much greater axial resolution (1 𝜇m) than traditional biomi- to 15 J/cm ), keratocytes apoptosis was detected between 250 2 2 croscopy and corneal optical coherence tomography (OCT), (10 J/cm )and300𝜇m (15 J/cm ). As showed by corneal OCT in both progressive keratoconus and secondary corneal scans we revealed multiple demarcation lines underlying ectasias [21, 23]. the different energy doses and UV-A exposure times used CXL is known to be an effective mean for stabilizing according to the topography-guided ACXL principle, Figures keratoconus over extended follow-up periods. Even though 5(b) and 5(d). Journal of Ophthalmology 7

(a) (b) (c)

(d) (e) (f)

Figure 6: IVCM scans in the first month after high-irradiance topography-guided CXL. Different demarcation lines were documented 2 at 150 𝜇m depth in the flattest areas (48 D and under) irradiated at 7.2 J/cm ((a), (b), and (c)); at 250 𝜇m depth in the area (>48 D and 2 2 ≤52 D) irradiated at 10 J/cm E dose (d); at 300 𝜇m depth in the steepest cone area (>52 D) irradiated at 15 J/cm E dose (e). IVCM also showed hyperreflectivity of corneal tissue and keratocytes apoptosis associated with dense trabecular patterned lacunar edema and nerve disappearance ((a), (b), and (c)). No endothelial damage was documented (f).

2 2 2 These preliminary observations allow us to formulate the 7. 2 J / c m (10 J/cm and 15 J/cm )wecanachievehigherpen- hypothesis that CXL induced biodynamic interaction and etration (i.e., cell apoptosis) with reduced exposure time and CXL treatment volume is related not only to the UV-A power increased UV power compared to conventional epithelium- and relative exposure time, but also to energy dose delivered off CXL. 2 to the corneal tissue. In conventional 5.4 J/cm energy dose The possibility to have a topography-guided ACXL treat- CXL, we demonstrated with IVCM analysis that CXL stromal ment capable of improving patient’s quality of vision, with penetration (i.e., cell apoptosis) appeared to be inversely reduced corneal aberrations and astigmatism, by mean of a proportional to UV-A power and directly proportional to nonablative, nonincisional surgery, should be highly desir- exposure time. The same basic concepts were applicable 2 able in reducing the need of combined procedures for CXL to 7.2 J/cm energy dose. After high-irradiance, fractionated refractive empowerment [26–28]. 2 ACXL with 7.2 J/cm our previously published IVCM data Current study addresses the potentiality of CXL cus- showed an increased hyperreflectivity of stromal tissue sur- tomization based on corneal curvatures, differentiated energy 2 rounding keratocytes compared to 5.4 J/cm energy dose doses,andirradiationtimes(atthesameirradiance,which [18, 20]. After topography-guided high-irradiance pulsed- also implies a higher energy dose). Mazzotta et al. [15] and light CXL, IVCM showed that by using energy doses over morerecentlyPeyman et al.[29] haveshown that pulsed-light 8 Journal of Ophthalmology

(a) (b) (c)

(d) (e) (f)

Figure 7: IVCM scans 6 months after high-irradiance topography-guided CXL. Regular epithelium (a) and regenerated subepithelial plexus nerves (b) were evident at 6 months. The hyperreflectivity of extracellular matrix and the lacunar edema gradually disappeared with progressive keratocytes repopulation ((c), (d), and (e)). Oblique dark microstriations are visible (scans 7(d) and 6(e)) in absence of endothelial micromorphological alterations (f).

CXL induces a deeper demarcation line than continuous- Topography-guided ACXL results, in our preliminary light CXL maintaining the same irradiance and the same experience, reduced some degree of corneal aberrations and energy, potentially because pulsed-light CXL has a longer topographic cylinder value with improvement in patient’s overall irradiation time. In the same line, Kling et al. [30] quality of vision that was recorded since the first postop- have shown that the biomechanical effect of continuous and erative month. However, the overall 1-year results of this pulsed-light CXL (different energies and irradiances, but pilot study showed no better clinical outcomes compared same overall irradiation time) is equivalent. Therefore, the with literature data reported in conventional broad-beam deeper demarcation line in the “high energy” zone and the epithelium-off CXL [1, 2, 7, 31]. Of interest, all treated patients observedreductionofastigmatismmayresultfromthelonger reported a faster improvement in their quality of vision irradiation time. However, considering that the depth of con- without the typical glare disability reported in the first 1 to 2 ventional CXL (C-CXL) with 5.4 J/cm E dose and 30 minutes 3 months after conventional epithelium-off treatment. of total UV-A exposure time reached 300 𝜇m of depth on Conventional broad-beam epithelium-off CXL and average [19], the topography-guided accelerated CXL reaches ACXL remain a safe and efficient solution to delay or halt a comparable treatment penetration in 18 minutes instead corneal ectasia progression in progressive keratoconus, of 30 minutes and in this contest the higher dose may be a for which the primary aim is to stabilize the disease. possible explanation of the increased treatment penetration Topography-guided ACXL may represent an adjunctive beyond the exposure time. option for visual rehabilitation, both for patients with early Journal of Ophthalmology 9

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Research Article Agreement between Gonioscopic Examination and Swept Source Fourier Domain Anterior Segment Optical Coherence Tomography Imaging

Mohammed Rigi,1 Nicholas P. Bell,1,2 David A. Lee,1,2 Laura A. Baker,1 Alice Z. Chuang,2 Donna Nguyen,1,2 Vandana R. Minnal,1,2 Robert M. Feldman,1,2 and Lauren S. Blieden1,2

1 RobertCizikEyeClinic,6400FanninSt.,Suite1800,Houston,TX77030,USA 2Ruiz Department of Ophthalmology and Visual Science, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth), 6431 Fannin St., MSB 7.024, Houston, TX 77030, USA

Correspondence should be addressed to Lauren S. Blieden; [email protected]

Received 17 June 2016; Revised 12 October 2016; Accepted 25 October 2016

Academic Editor: Yu-Chi Liu

Copyright © 2016 Mohammed Rigi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. To evaluate interobserver, intervisit, and interinstrument agreements for gonioscopy and Fourier domain anterior segment optical coherence tomography (FD ASOCT) for classifying open and narrow angle eyes. Methods. Eighty-six eyes with open or narrow anterior chamber angles were included. The superior angle was classified open or narrow by 2 of 5 glaucoma specialists using gonioscopy and imaged by FD ASOCT in the dark. The superior angle of each FD ASOCT image was graded as open or narrow by 2 masked readers. The same procedures were repeated within 6 months. Kappas for interobserver and intervisit agreements for each instrument and interinstrument agreements were calculated. Results. The mean age was 50.9 (±18.4) years. Interobserver agreements were moderate to good for both gonioscopy (0.57 and 0.69) and FD ASOCT (0.58 and 0.75). Intervisit agreements were moderate to excellent for both gonioscopy (0.53 to 0.86) and FD ASOCT (0.57 and 0.85). Interinstrument agreements were fair to good (0.34 to 0.63), with FD ASOCT classifying more angles as narrow than gonioscopy. Conclusions. Both gonioscopy and FD ASOCT examiners were internally consistent with similar interobserver and intervisit agreements for angle classification. Agreement between instruments was fair to good, with FD ASOCT classifying more angles as narrow than gonioscopy.

1. Introduction reproducible images of the angle, and image acquisition can be performed by a technician with minimal training [1–5]. A crucial part of any evaluation for the primary angle closure However, most ASOCT instruments measure only horizontal (PAC) spectrum of diseases is an examination of anterior and vertical meridians, with up to 80% of superior angles not chamber angle (ACA) anatomy. Gonioscopy is the current adequately visible [6]. This may limit the clinical application clinical gold standard for evaluating ACA anatomy, allowing of ASOCT, because, on gonioscopy, the narrowest angle, assessment of the angle over 360 degrees as well as iden- which is considered as the most important clinically, is the tification of other angle characteristics, such as peripheral superior angle [7]. anterior synechiae (PAS) and pigmentation level. However, While there have been several published studies compar- gonioscopy is difficult to perform and subjective, limiting its ing angle classification using ASOCT to clinical gonioscopy use in clinical research. [6–12], the agreements are widely variable, in large part due A variety of imaging technologies have been developed to the image quality and difficulty imaging the superior angle. to evaluate ACA anatomy in a more quantitative manner. The CASIA SS-1000 ASOCT (Tomey Corporation, Nagoya, Anterior segment optical coherence tomography (ASOCT) is Japan) uses Fourier domain (FD) swept source technology widely used because it is quick and noncontact and provides to provide high-resolution images (10 𝜇maxiallyand30𝜇m 2 Journal of Ophthalmology

(a) (b)

Figure 1: Comparison of a narrow angle and wide-open angle. (a) Gonioscopy image of a narrow angle. (b) Gonioscopy image of a wide-open angle. (c) 2D anterior segment optical coherence tomography (ASOCT) image (vertical) from the CASIA SS-1000 of a narrow angle. (d) 2D ASOCT image (vertical) of a wide-open angle. (a, c) Images from the same eye; (b, d) Images from the same eye.

transversally for 2D images) for both horizontal and vertical eye was randomly selected by a coin flip (heads: right eye, meridians in 1.2 seconds. From our prior studies, we have tails: left eye). found that this device provides high-quality images of the After obtaining informed consent, demographics, ocular superior angle that can be reliably analyzed using customized history, and present ocular medications were recorded, and software [3–5, 13]. slit lamp examination was performed to screen for eligibility. Thepurposeofthisstudywastoevaluatetheinterob- Cataracts were graded without dilation to avoid angle closure server, intraobserver (intervisit), and interinstrument agree- in narrow angle participants. Eligible participants underwent ments for both gonioscopy and the CASIA SS-1000 FD a gonioscopy examination and FD ASOCT imaging (first ASOCT for evaluation of the superior angle in both open and visit). At the second visit, within 6 months of the first narrow angle eyes. one,gonioscopywiththesameexaminersandFDASOCT imaging were repeated (Figure 1). 2. Participants and Methods This prospective cohort study was conducted at the Robert 2.2. Gonioscopy. The study eye was examined by gonioscopy Cizik Eye Clinic of the Ruiz Department of Ophthalmology on 2 separate visits by 2 of 5 glaucoma specialists (NPB, LSB, and Visual Science at the McGovern Medical School at DAL, VRM, and RMF) on the same day. Gonioscopy was The University of Texas Health Science Center at Hous- performed using a Posner 4-mirror lens at high magnification ton (UTHealth). Institutional Review Board approval was (10x), with the eye in the primary position of gaze under the obtained from The University of Texas Committee for the lowest possible ambient lighting conditions by turning off Protection of Human Subjects before study commencement. all ambient light sources and closing the door of the exam All research adhered to the tenets of the Declaration of room. Gonioscopic examination was first performed without Helsinki and was HIPAA compliant. Informed consent was indentation, with care taken to minimize light from the slit obtained from all study participants before initiation of study lamp beam from entering the pupil. The superior quadrant data collection and procedures. was graded for iris insertion using the Spaeth grading system (gradingthedeepestvisibleACAstructure,A:anteriorto 2.1. Participants. Consecutive adult participants (at least Schwalbe’s line; B: between Schwalbe’s line and scleral spur; 18 years old) who visited the Robert Cizik Eye Clinic C: scleral spur; D: ciliary body; and E: beyond 0.1 mm of were recruited. Participants were excluded if they used any ciliary body) [14, 15]. Gonioscopy was then performed with medication that may have affected angle anatomy within a indentation for grading presence or absence of PAS at 12 month before imaging (e.g., pilocarpine or atropine). Eyes o’clock, 3 o’clock, 6 o’clock, and 9 o’clock. During the second were excluded if there was a history of penetrating trauma, visit, the gonioscopic examinations were performed by the any intraocular procedures within 90 days before imaging, same 2 examiners from the initial visit in the same order (1st anticipated intraocular procedures before completion of the or 2nd examiner). Examiners were masked to the grading second study visit, or any anterior segment abnormalities of the other examiners. Spaeth grading from the gonioscopy affecting visualization of the angle (e.g., significant corneal exam without indentation was used for the agreement opacity). When both eyes of the participant were eligible, one study. Journal of Ophthalmology 3

2.3. FD ASOCT Instrument and Acquisition of FD ASOCT 3. Results Images. Details of the CASIA SS-1000 FD ASOCT and procedures for image acquisition have been previously described A total of 88 eyes of 88 participants were recruited. Two [4]. Eyes were scanned in 2D mode in the dark (lighting in eyes were excluded, one participant withdrew consent, and the room was measured at 0 lux) using the angle analysis scan images could not be obtained from the other participant, type with the autoalignment function. leaving a total of 86 eyes enrolled in the study. Seventy-two participants (84%) returned in a mean of 1.2 months (SD = 1.1 2.4. FD ASOCT Image Reading. All raw study images were months, range 1 day to 4 months) for the second visit, which exported from the FD ASOCT after data collection was was more than the anticipated 80% returning for the second complete and imported to customized software, Anterior visit. Demographics and baseline ocular characteristics are Chamber Angle and Interpretation (ACAI, Houston, TX), as summarized in Table 1. One participant’s FD ASOCT image described in previous publications [3–5]. Two experienced (visit 1) was not analyzed due to poor image quality; another FD ASOCT readers (AZC, LAB) identified scleral spur participant was imaged by FD ASOCT at visit 2 but did landmarks (SSLs) on superior angles (12 o’clock) and graded not undergo gonioscopy. All sequential gonioscopy was iris insertion using Spaeth definitions (A, B, C, D, or E). performed with at least 3 minutes to 480 minutes between Magnification and contrast adjustment of the image were exams. Any sequential gonioscopy and then ASOCT imaging allowedtoclarifythepositionoftheSSLsandSchwalbe’s was performed with at least 5 minutes between exam and line. When Schwalbe’s line was not visible, the measurement testing. rings that mark 250, 500, and 750 𝜇mfromtheSSLwere turnedon.Ananglewasgradedas“A”iftheirisinsertion 3.1. Gonioscopy Agreement. Table 2 shows “pooled” inter- was 500 𝜇m anterior to the SSL, as the length of the trabecular observer agreements for gonioscopy among examiners. The meshwork is approximately 500 𝜇m [16, 17]. Both readers agreement was good (kappa = 0.66 and 0.69 at visits 1 examined all study images independently and were masked and 2, resp.). Pairs of gonioscopy examiners agreed on to the gonioscopy evaluation and FD ASOCT results from the angle classification in 85% and 89% of eyes for visits 1and other reader. 2, respectively. Intraobserver (intervisit) agreements ranged from moderate (kappa = 0.53) to excellent (kappa = 0.86) 2.5. Sample Size and Power Calculation. Inanefforttohave for individual examiners and good (kappa = 0.74) for all sufficient participants representing the whole spectrum of examiners combined. Ninety percent (79 eyes) were classified angle grades, the study recruited 15% A, 15% B, 20% C, 30% D, into the same group (open or narrow) on both visits (Table 3). and 20% E angles, as determined using the grading from the first examiner at the first visit. A minimum of 70 participants 3.2. ASOCT Agreement. The FD ASOCT readers had moder- was required for kappa = 0.4 agreement, with a precision of ate to good interobserver agreement (kappa = 0.73 and 0.58 0.15 on each side of the agreement. With an estimated 80% at visits 1 and 2, resp.) (Table 4). Both readers agreed on of participants expected to return for the second visit, 88 angle classification in 74 (87%) eyes at the first visit and 58 participants needed to be recruited. of 72 (81%) eyes in the second visit. FD ASOCT reader 1 had moderate intraobserver agreement (kappa = 0.57) while 2.6. Data Analysis. Demographics were summarized by FDASOCTreader2hadexcellent intraobserver agreement mean and standard deviation (SD) for continuous variables or (kappa = 0.83). Of the 14 angle disagreements between visits by frequency (%) for discrete variables. Angles were classified by reader 1, 4 eyes were graded as “C” in visit 1 and “B” in visit using grading from both examinations (gonioscopy and FD 2,while6eyesweregradedas“C”invisit1and“B”invisit2. ASOCT) as “narrow” if graded A or B and as “open” if graded C, D, or E. 3.3. Gonioscopy and FD ASOCT Agreement. The interinstru- Kappastatisticswerecalculatedfortheangleclassification ment agreements between the “pooled” gonioscopy examin- to evaluate interobserver agreement between gonioscopic ers and FD ASOCT readers ranged from moderate to good examiners and agreement between FD ASOCT readers at (kappa ranged from 0.42 to 0.63, Table 5). The percentage of each visit. The agreement between gonioscopic examiners agreement for angle classification between each examiners- at each visit was calculated by pooling all 1st examiners reader pair ranged from 71% to 82%. In general, more eyes versus pooling all 2nd examiners, as the sample size was too were classified as “narrow” by the FD ASOCT readers than small to evaluate the interobserver agreement for each of by the gonioscopy examiners. the 10 different pairs of gonioscopy examiners. Intraobserver (intervisit) agreement was calculated between visits for each 4. Discussion pair of gonioscopy examiners (5 of them) and combining all 5 examiners for each ASOCT reader; interinstrument Gonioscopy is the current clinical gold standard for eval- agreement was determined for each examiner-reader pair uation of the ACA, but it is difficult to perform and a (with examiner pooled 1st or 2nd) at each visit. subjective method for examining the angle. Angle grad- All statistical analyses were performed using SAS for ing depends on examiner interpretation, which limits the Windows version 9.4 (SAS, Inc., Cary, NC). The kappa criteria potential for repeatable quantitative measurements using were <0.2 poor; 0.21 to 0.40 fair; 0.41 to 0.60 moderate; 0.61 gonioscopy alone. Our study found that, 10% of the time, to 0.80 good; and >0.80 excellent [18]. the same examiner disagreed with their original gonioscopic 4 Journal of Ophthalmology

Table 1: Demographics and baseline ocular characteristics. Table 1: Continued.

Statistics Statistics Variable Variable 𝑁=86 (𝑁=86) ( ) Age, years (SD) 50.9 (18.4) C: scleral spur visible 19 (22%) Sex, n male (%) 27 (31%) D: ciliary body 26 (30%) Race, n (%) E: beyond 0.1 mm of ciliary body 17 (20%) Presence of PASa (%) 11 (13%) White 34 (40%) SD: standard deviation; IOP: intraocular pressure; PAS: peripheral anterior Black 19 (22%) synechiae. a Hispanic 20 (23%) Missing 2datapoints. Asian 13 (15%) Study eye, n right (%) 46 (53%) Table 2: Gonioscopy “pooled” interobserver agreement for angle classification (kappa [95% confidence interval]). Iris color, n (%) Brown 68 (79%) Agree Kappa N Disagree Blue 16 (19%) [95% CI] Overall Narrow Open n (%) n (%) n n Green/hazel 2 (2%) Visit 1 Type of glaucoma, n (%) 0.66 Normal 40 (47%) [0.50, 0.83] 86 73 (85%) 22 51 13 (15%) Primary open angle glaucoma 11 (13%) Visit 2 Primary open angle glaucoma suspect 9 (10%) 0.69 [0.50, 0.89] 71 63 (89%) 13 50 8 (11%) Acuteprimaryangleclosureglaucoma 2(2%) CI: confidence interval. Primary angle closure glaucoma 8 (9%) The kappa criteria were <0.2 poor; 0.21 to 0.40 fair; 0.41 to 0.60 moderate; > Primary angle closure 7 (8%) 0.61 to 0.80 good; and 0.80 excellent. Primary angle closure suspect 9 (10%) Average IOP, mm Hg (SD) 14.8 (3.2) classification for the same patient seen at the second visit Number of IOP-lowering medications, n (%) (intervisit). Having a reproducible, objective, and quantitative 0 69 (80%) method for measuring the angle could advance clinical 110(12%)research and ultimately improve patient care. ASOCT has been used to evaluate angle anatomy quanti- 24(5%)tatively [19] and holds the potential to be useful for longitu- 33(3%)dinal angle evaluations. Prior studies have shown moderate Previous ocular surgery, n (%) or worse agreements between ASOCT and gonioscopy [6– Argon laser trabeculoplasty 1 (1%) 8, 11, 12, 20]. However, a big limitation of those studies hasbeentheabilitytoimagethesuperiorangle,which Cataract extraction 3 (3%) is the narrowest quadrant and typically used clinically (by Laser peripheral iridotomy 6 (7%) gonioscopy) to determine whether a patient has open or Laser-assisted keratomileusis 4 (5%) narrow angles. Often, the methodology in the published literature on ASOCT and gonioscopy does not indicate which Conjunctival abnormality, n (%) 7 (8%) angle specifically was used for the gonioscopic classification. Corneal abnormality, n (%) When indicated, most published studies compared superior Punctate epithelial erosions 5 (6%) quadrant gonioscopy with nasal/temporal meridian ASOCT Punctate epithelial keratopathy 3 (3%) images, which cannot be assumed to be equivalent, especially in eyes with PAC [8, 10, 11]. A few studies have compared Superficial punctate keratitis 31 (36%) gonioscopy to superior/inferior angles with visible scleral Others 7 (8%) spurbuthaveexcluded20–95%ofimagedeyes[6,7,9,12,20]. Lens abnormality, n (%) In our study, we compared the classification agreements of the superior angles using both gonioscopy and FD ASOCT Cataract 53 (62%) and found that interobserver agreements were moderate to Posterior chamber intraocular lens 3 (3%) good for both gonioscopy and FD ASOCT, and intraob- Spaeth grading by the 1st gonioscopic examiner, n (%) server (intervisit) agreements were moderate to excellent A: anterior to Schwalbe’s line 12 (14%) for both instruments. The agreements between instruments (gonioscopy versus FD ASOCT) for both parameters were B: between Schwalbe’s line and scleral spur 12 (14%) fair to good. Journal of Ophthalmology 5

Table 3: Gonioscopic intraobserver (intervisit) agreement for angle classification by examiner (kappa [95% confidence interval]).

Agree 𝑁 Disagree Examiner Kappa [95% CI] Overall Narrow Open 𝑛 n (%) n n 0.67 V [0.10, 1.00] 6 5 (83%) 3 2 1 (17%) 0.72 W [0.43, 1.00] 27 24 (89%) 6 18 3 (11%) 0.86 X [0.68, 1.00] 32 30 (94%) 10 20 2 (6%) 0.68 Y [0.43, 0.94] 36 31 (86%) 9 22 5 (14%) 0.53 Z [0.07, 1.00] 41 38 (93%) 2 36 3 (7%) 0.74 Combined 142 128 (90%)309814(10%) [0.62, 0.87] CI: confidence interval. The kappa criteria were <0.2 poor; 0.21 to 0.40 fair; 0.41 to 0.60 moderate; 0.61 to 0.80 good; and >0.80 excellent.

Table 4: Fourier domain anterior segment optical coherence tomography agreement for angle classification (kappa [95% confidence interval]).

Agree Kappa Disagree [95% CI] 𝑁 Overall Narrow Open 𝑛 (%) 𝑛 (%) 𝑛 𝑛 Interobserver, visit 1 0.73 [0.59, 0.88] 85 74 (87%) 30 44 11 (13%) Interobserver, visit 2 0.58 [0.39, 0.77] 72 58 (81%) 19 39 14 (19%) Intraobserver (intervisit), reader 1 0.57 [0.37, 0.77] 71 57 (80%) 18 39 14 (20%) Intraobserver (intervisit), reader 2 0.83 [0.69, 0.96] 71 65 (92%) 26 39 6 (8%) CI: confidence interval. Kappa criteria: <0.2 poor; 0.21 to 0.40 fair; 0.41 to 0.60 moderate; 0.61 to 0.80 good; and >0.80 excellent.

4.1. Gonioscopy: Interobserver and Intraobserver Agreement. parameter to evaluate the consistency of the individual The interobserver agreement for gonioscopy was good (kappa examiner on different visits with the same patient, which was =0.66and0.69).Theseresultsaresimilartoresultspublished higher than the agreement reported by Campbell et al. (kappa byHuetal.onangleclassificationasopenorclosedby3 = 0.29), the only reference we found for a study evaluating different gonioscopy examiners (kappa = 0.65 for superior intraobserveragreementforgonioscopy[10].Giventhe quadrant). Hu et al. also reported a near perfect agreement coordination it took to evaluate intraobserver agreement, we (Kendall W = 0.83) using clinical assessment for angle closure can understand why there is a paucity of existing literature. risk [6], which takes into account not only angle classification The less-than-perfect agreement not only points out the butalsootheranglefeaturesassessedbygonioscopy(e.g., potential limitations of gonioscopic interpretation but also level of pigmentation, presence of PAS). This indicates that may represent the dynamic anatomic variation that may there is likely a complex multifactorial relationship between occur in the individual patient. angle classification and angle closure risk. This relationship deserves further study. 4.2. FD ASOCT: Interobserver and Intraobserver Agreement. Combined intraobserver (intervisit) agreement was good The interobserver agreements between FD ASOCT readers (kappa = 0.74) in our study. With the technical limitations were moderate (kappa = 0.58) to good (kappa = 0.73). Our of gonioscopy, we thought this might be an interesting definition of open or narrow angles on FD ASOCT is based on 6 Journal of Ophthalmology

Table 5: Agreement (%) between pairs of gonioscopic examiners and Fourier domain anterior segment optical coherence tomography readers at each visit. Agree Disagree Kappa G: narrow G: open Examiner-reader pair Overall Narrow Open [95%CI] A: open A: narrow 𝑛 (%) 𝑛 𝑛 𝑛 (%) 𝑛 (%) Visit 1 (𝑁=85) 0.48 1st examiner versus reader 1 [0.28, 0.67] 65 (76%) 47 18 5 (6%) 15 (18%) 0.43 1st examiner versus reader 2 [0.25, 0.61] 62 (73%) 43 19 4 (5%) 19 (22%) 0.63 2nd examiner versus reader 1 [0.46, 0.80] 70 (82%) 45 25 7 (8%) 8 (9%) 0.57 2nd examiner versus reader 2 [0.39, 0.74] 67 (79%) 41 26 6 (7%) 12 (14%) Visit 2 (𝑁=71) 0.46 1st examiner versus reader 1 [0.23, 0.69] 56 (78%) 45 11 4 (6%) 11 (15%) 0.45 1st examiner versus reader 2 [0.25, 0.66] 54 (71%) 41 13 2 (3%) 15 (21%) 0.42 2nd examiner versus reader 1 [0.19, 0.65] 54 (71%) 42 12 7 (10%) 10 (14%) 0.53 2nd examiner versus reader 2 [0.33, 0.73] 56 (78%) 40 16 3 (4%) 12 (17%) CI: confidence interval. G: gonioscopic examination; A: anterior segment optical coherence tomography. Kappa criteria: <0.2 poor; 0.21 to 0.40 fair; 0.41 to 0.60 moderate; 0.61 to 0.80 good; and >0.80 excellent. the level of iris apposition relative to the scleral spur landmark Given this methodology, one would expect our study to have [4], which approximates the location of the scleral spur. A less intraobserver (intervisit) agreement. previous study by Quek et al. evaluated the interobserver We believe that our FD ASOCT agreements are better agreement on identifying angle structures, including scleral than the previously published literature because the CASIA spur, using the Cirrus (Carl Zeiss Meditec, Dublin, CA) SS-1000 FD ASOCT produces images with less artifact that andiVueOCTs(OptovueCorporation,Fremont,CA).In could be enhanced using customized ACAI software. Fur- that study, the agreement for identifying scleral spur on thermore, we took a closer look at intraobserver agreement the superior angle was poor (kappa = 0.04) for Cirrus and by reader 1 and found 10 of 14 disagreed angles were graded moderate (kappa = 0.44) for iVue [12]. In another study, Tay as“C”inoneofthevisitsand“B”intheothervisit.Wesuspect et al. reported that the interobserver kappa was 0.51 using that this is due to the difficulty in evaluating C angles on the the temporal/nasal angle images obtained from the Visante images, which may be represented by only 1-2 pixels on the ASOCT instrument (Carl Zeiss Meditec, Dublin, CA) [8]. screen. The inherent variability between the image, device, Compared to these prior studies using Cirrus, Visante, and and observer judgment is unknown and may represent more iVue OCTs, our agreements (kappa = 0.58 and 0.73) are better. than 1-2 pixels. Intraobserver (intervisit) kappas were 0.57 and 0.83 for readers 1 and 2, respectively, in our study, which was better 4.3. Interinstrument Agreement: Gonioscopy versus FD than previously published results (kappa = 0.47) using the ASOCT. In our study, the majority of interinstrument agree- spectral domain Topcon OCT (Topcon Europe Medical ments between FD ASOCT and gonioscopy were moderate BV, Netherlands) in the anterior segment mode (840 nm (kappa between 0.41 and 0.60). Previous studies have wavelength) [10]. published inconsistent results when evaluating interinstru- Queketal.usedasetof20imagesfromtheCirrusand ment agreement of gonioscopy and anterior segment imaging 20 from iVue OCTs and evaluated angle structure visibility devices. The agreements ranged from poor (kappa < 0.20) (i.e., scleral spurs, trabecular meshwork) on the same images [6, 8, 11] to fair (kappa = 0.21 to 0.40) [6–8, 12] to moderate twice, resulting in good to excellent agreement for the Cirrus (kappa = 0.41 to 0.60) [7, 9, 12, 20]. We believe that the OCT and excellent agreement for the iVue OCT on the reason why prior studies have shown variable agreements visibility of each structure [12]. This study evaluated only between ASOCT and gonioscopy is because they were unable reader variability while our study evaluated a combination of to identify angle landmarks sufficiently for classification, reader, device, and imaging session variabilities, because we especially in the superior angle. Many studies reported only lookedatimagesofthesamepatienttakenonseparatevisits. being able to identify a portion of landmarks in images Journal of Ophthalmology 7 necessary to classify the angle, resulting in those images (80 in the same order for both visits. Our sample size was too superior angles) being eliminated from the analysis [6]. Our small to analyze agreements between the 10 potential pairs FD ASCOT readers could visualize and identify SSL in 99% of examiners. of superior angles, regardless of angle configuration. Possible In conclusion, our study demonstrates the expected explanations for the observed differences in SSL visualization agreements between ASOCT imaging and gonioscopy classi- between ASOCT technologies include (1) the higher scan ficationofthesuperiorangleinopenandnarrowangleeyes. speeds and resolution of FD ASOCT, allowing visualization Previously, published studies have included limited data from of the peripheral angle with less artifact, or (2) use of the the superior angle. For angle classification, ASOCT of the custom-designed ACAI software to enhance the visibility superior angle performs similarly to gonioscopy; however, of the angle structures by manipulating image contrast. It is other parameters that determine angle closure risk need important to note that our FD ASOCT readers also found the further evaluation. SSL more challenging to identify in the superior and inferior angles compared to the nasal/temporal angles, consistent Competing Interests with other reports using ASOCT [6, 7]. No authors declare any relevant conflict of interests. 4.4. Limitations. There are a few limitations to consider. Despite standardized dark background conditions, slit lamp illumination required for gonioscopy may induce pupillary Acknowledgments constriction, resulting in the apparent opening of the angle Supported in part by National Eye Institute Vision Core or dynamic changes in iris configuration [7, 20]. Similarly, Grant P30EY010608, a Challenge Grant from Research to accidental indentation resulting from gonioscopy artificially Prevent Blindness to the McGovern Medical School, and the opens the drainage angle [7]. In such cases, appositional HermannEyeFund.TheCASIASS-1000wasloanedtoDr. closure may go undetected by gonioscopy. In fact, our FD Feldman by the Tomey Corporation. ASOCT readers classified more angles as narrow than did our gonioscopy examiners. This is consistent with the reported literature [7, 21]. Although gonioscopy has traditionally been References the gold standard for grading ACAs, given the intraobserver [1]K.Mansouri,N.D.Burgener,M.Bagnoud,andT.Shaarawy, (intervisit) agreements found in our study and those pub- “Aprospective ultrasound biomicroscopy evaluation of changes lished by Campbell et al. [10], it is not clear that it is a more in anterior segment morphology following laser iridotomy in reliable representation of the true angle status as open or European eyes,” Eye,vol.23,no.11,pp.2046–2051,2009. narrow when compared to ASOCT, which may be the result [2] L. M. Sakata, R. Lavanya, D. S. Friedman et al., “Assessment of examiner technique or dynamic anatomic variation in the of the scleral spur in anterior segment optical coherence individual. tomography images,” Archives of Ophthalmology, vol. 126, no. 2, Another explanation for differences found between pp.181–185,2008. gonioscopy and FD ASOCT is related to the actual locations [3]L.S.Blieden,A.Z.Chuang,L.A.Bakeretal.,“Optimalnumber of measurement. Gonioscopy does not grade at a single axis, of angle images for calculating anterior angle volume and iris but as an area, which may be a clock hour or a quadrant, volume measurements,” Investigative Ophthalmology and Visual while with the FD ASOCT, measurement is taken in a single Science,vol.56,no.5,pp.2842–2847,2015. meridian. It might be appropriate in a future study to compare [4] R.J.Cumba,S.Radhakrishnan,N.P.Belletal.,“Reproducibility a quadrantric measurement, such as a quadrant of trabecular- of scleral spur identification and angle measurements using iris circumference volume (TICV [5]), to gonioscopy rather fourier domain anterior segment optical coherence tomogra- than a single plane measurement. Unfortunately, that was phy,” Journal of Ophthalmology, vol. 2012, Article ID 487309, 14 beyond the scope of the current study as FD ASOCT pages, 2012. measurements were taken with 2D images, which cannot be [5] M. Rigi, L. S. Blieden, D. Nguyen et al., “Trabecular-iris used for TICV. circumference volume in open angle eyes using swept-source ACA grading based on FD ASOCT imaging is not fourier domain anterior segment optical coherence tomography,” Journal of Ophthalmology, vol. 2014, Article ID 590978, 6 yet entirely automated; hence, readers’ subjectivity might pages, 2014. have influenced the results, especially with adjudicating the [6]C.X.Hu,A.Mantravadi,C.Zangallietal.,“Comparing location of the scleral spur landmark. However, we previously gonioscopy with visante and cirrus optical coherence tomog- reported good reproducibility in identifying SSL location on raphy for anterior chamber angle assessment in glaucoma FD ASOCT imaging at the superior angle by 2 observers; that patients,” Journal of Glaucoma,vol.25,no.2,pp.177–183,2016. is, mean differences were 20 𝜇mand7𝜇mforthe𝑥-axis and 𝑦 [7] L. M. Sakata, R. Lavanya, D. S. Friedman et al., “Comparison of -axis, respectively [4]. In addition, eyelid manipulation is gonioscopy and anterior segment ocular coherence tomography necessary for superior angle imaging and may have led to in detecting angle closure in different quadrants of the anterior inadvertent changes in angle configuration. A standardized chamber angle,” Ophthalmology,vol.115,no.5,pp.769–774, imaging protocol is in place to reduce the image variability. 2008. Finally, for practical reasons, we did not use fixed pairs [8]E.L.T.Tay,V.K.Y.Yong,B.A.Lim,S.Sia,E.P.Y.Wong,and of gonioscopy examiners for all participants; however, each L. W. L. Yip, “Agreement of angle closure assessments between participant was examined by the same pair of examiners gonioscopy, anterior segment optical coherence tomography 8 Journal of Ophthalmology

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Clinical Study Effects of V4c-ICL Implantation on Myopic Patients’ Vision-Related Daily Activities

Taixiang Liu, Shaorong Linghu, Le Pan, and Rong Shi

Guizhou Ophthalmic Hospital, The Affiliated Hospital of Zunyi Medical College, Zunyi 563003, China

Correspondence should be addressed to Taixiang Liu; [email protected]

Received 10 May 2016; Revised 13 August 2016; Accepted 27 September 2016

Academic Editor: Yu-Chi Liu

Copyright © 2016 Taixiang Liu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The new type implantable Collamer lens with a central hole (V4c-ICL) is widely used to treat myopia. However, halos occur insome patients after surgery. The aim is to evaluate the effect of V4c-ICL implantation on vision-related daily activities. This retrospective study included 42 patients. Uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), intraocular pressure (IOP), endothelial cell density (ECD), and vault were recorded and vision-related daily activities were evaluated at 3 months after operation. The average spherical equivalent was −0.12 ± 0.33 D at 3 months after operation. UCVA equal to or better than preoperative BCVA occurred in 98% of eyes. The average BCVA at 3 months after operation was −0.03 ± 0.07 LogMAR, which was significantly better than preoperative BCVA (0.08 ± 0.10 LogMAR) (𝑃 = 0.029). Apart from one patient (2.4%) who had difficulty reading computer screens, all patients had satisfactory or very satisfactory results. During the early postoperation, halos occurred in 23 patients (54.8%). However there were no significant differences in the scores of visual functions between patients with and without halos (𝑃 > 0.05). Patients were very satisfied with their vision-related daily activities at 3 months after operation. The central holeof V4c-ICL does not affect patients’ vision-related daily activities.

1. Introduction High intraocular pressure is a major concern after ICL implantation, particularly for early ICL models [5–8]. Posterior chamber phakic intraocular lens (pIOL) implan- To avoid postoperative elevation of intraocular pressure, tation is generally accepted as an effective and reversible peripheral iridectomy should be performed before or during treatment method for high myopia with preservation of ICL implantation. However, iridectomy may lead to pain and lens-regulating capability. In the ophthalmology clinic, the intraoperative bleeding and increase difficulty performing implantable Collamer lens (ICL, STAAR Surgical, Nidau, the operation. Switzerland) is the main posterior chamber pIOLs; it is Toavoid peripheral iridectomy, the V4c-ICL model with a designed to be placed between the iris and the anterior 0.36mmcentralholehasbeendesignedbasedontheV4-ICL surfaceofthelensandisfixedtotheciliarysulcusbyfour model. Because the central hole of the V4c-ICL facilitates haptics, thus preventing its contact with the lens [1]. the outflow of the aqueous humor, peripheral iridectomy Although pIOL implantation has a good clinical efficacy is not required. In addition, compared with the traditional in the correction of high myopia, some short-term and V4-ICL model, the V4c-ICL model exhibits similar low-, long-term complications have been reported. Cataract is the middle-, and high-frequency contrast sensitivity and higher- most common complication after ICL implantation. This order aberrations under the conditions of various pupil sizes, complication may be caused by direct contact of the ICL and the subjective symptoms such as glare or halo were withthelensduetoalowvaultorinsufficientcirculation also essentially equivalent, thus suggesting that the V4c-ICL of the aqueous humor. The incidence of cataract after ICL model has good safety and efficacy [9, 10]. implantation ranges between 0.61% and 2.7%, depending on Although studies have investigated the effect of V4c-ICL different follow-up periods in different studies [2–4]. implantation on patients’ visual function status, to our 2 Journal of Ophthalmology knowledge, the effect of V4c-ICL implantation on visual the manufacturer (STAAR Surgical). Fifteen minutes before activity in the complex environment of the patients’ daily operation, compound tropicamide eye drops were applied to lives has not been studied. Furthermore, some patients dilate the pupils, followed by topical anesthesia with 0.4% complain of halos after V4c-ICL implantation. It remains to oxybuprocaine hydrochloride. For patients implanted with be determined whether this subjective symptom can affect V4c-ICL for astigmatism, the astigmatic axis was marked the patient’s daily visual activity. Therefore, in this study, we usingaslitlamp.Themainincisionsitewascreatedatthe ∘ conducted a questionnaire to investigate the effects of V4c- position of 135 and an auxiliary incision site was made at the ∘ ICL implantation on myopic patients’ vision-related daily position of 45 . activities. After introduction of viscoelastic materials to maintain the anterior chamber, the V4c-ICL was slowly pushed into 2. Material and Methods the anterior chamber using an injector cartridge. Then, the haptics of the ICL was enclaved into the anterior chamber via 2.1. Patients. This retrospective study collected data from 42 the main and auxiliary incision sites using the manipulator. consecutive patients (82 eyes) with complete clinical data who After the axis was adjusted, the remaining viscoelastic mate- underwent V4C-ICL implantation at the Affiliated Hospital rials were replaced. The use of miotics was dependent on the of Zunyi Medical College (Zunyi, China) between November pupil size. Anti-inflammatory treatment was applied after the 2014 and November 2015. All patients were followed up for operation. morethan3months(range,3to6months;mean,4.62± 1.23 months). Fourteen patients were male and 28 patients were female. In 2 cases, V4c-ICL implantation was performed in 2.3. Statistical Analysis. Numerical data are presented as ± 1 eye. In 40 cases, V4c-ICL implantation was performed in mean SD. Analyses were performed using SPSS v17.0 both eyes. software. Repeated analysis of variance was used to analyze The patients’ average age was 24.04 ± 4.75 years (range, the differences in intraocular pressure as well as ECD at dif- 18–35 years). The average preoperative sphere power was ferent timepoints before and after the operation. Independent −10.21 ± 3.02 diopter (D) (range, −4.0 D to −15.0 D), and the Student’s 𝑡-test was used to analyze the differences in the average cylinder power was −2.48 ± 0.91 D (range, −1.25 D central vault and peripheral vault and the score of visual to −4.5 D). The average spherical equivalent (SE) was −11.55 analog scale between different groups. Probability values less ± 3.52 D (range, −5.75 D to −16.25 D). The preoperative and than 0.05 were considered statistically significant. postoperative uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA) of the patients were recorded 3. Results using the decimal method and converted into the LogMAR (logarithm of the minimal angle of resolution) equivalence. 3.1. Refractive Status and Vision. The average preoperative Preoperative and postoperative intraocular pressure and spherical equivalent was −11.55 ± 3.52 D (range, −5.75 D ECD were measured. UBM was used to detect the central and to −16.25 D). The average spherical equivalent was −0.12 ± peripheral vault at 3 months after operation. Three months 0.33 D (range, −1.00 to −0.50 D) and the residual astigmatism after operation, all patients were asked by the same doctor to was −0.18 ± 0.32 D (range, 0.25 to −1.25 D) at 3 months after evaluate the visual function. The questionnaire was designed patients operations, excluding those patients with preexisting based on the visual function evaluation questionnaire used astigmatismwhodidnotreceivetheimplantedastigmatic by the Corneal Diseases and Excimer Laser Research Unit, V4c-ICL model and required preservation of astigmatic University of Dundee, Scotland [11], with slight modifica- power. tions. Since some patients complained of halos after V4c- The average preoperative UCVA was 1.47 ± 0.23 LogMAR ICL implantation, we also investigated the effect on the (range,1.15to2.0).TheaverageUCVAwas−0.03 ± visual functions of the presence of a halo in patients during 0.08 LogMAR (range, −0.18 to 0.30) at 3 months after oper- the follow-up. This study was performed according to the ation. The uncorrected visual acuity had increased signif- Declaration of Helsinki, and all patients gave their informed icantly at 3 months after operation compared with before consent after a comprehensive explanation of the possible risk operation (𝑝 < 0.001). At 3 months after operation, UCVA in of V4c-ICL implantation. 80 eyes (98%) was equal to or better than preoperative BCVA. Inclusion criteria were BCVA of 0.5 or above and refrac- The efficacy index (= postoperative UCVA/preoperative tive stability for more than 2 years. Exclusion criteria were BCVA) was 1.27. age < 18 years; anterior chamber depth < 2.8 mm, ECD < 2 The average BCVA at 3 months after operation was 2000/mm ; corneal diseases; and a history of eye diseases −0.03 ± 0.07 LogMAR (range, −0.18 to 0.22), which was affecting visual function such as glaucoma, cataract, retinal significantly better than preoperative BCVA (average, 0.08 diseases, uveitis, and ocular trauma. ± 0.10 LogMAR; range, −0.08 to 0.40) (𝑝 = 0.029). No patients had postoperative BCVA worse than preoperative 2.2. Surgical Procedure. The size of the V4c-ICL was deter- values. Thirty eyes (36%) had postoperative BCVA equal to mined by the horizontal white-to-white corneal diameter preoperative values. Postoperative BCVA increased by one and anterior chamber depth of the patients. The power line in 26 eyes (32%). Postoperative BCVA increased by two of V4c-ICL was calculated using the software provided by lines in 18 eyes (22%). Postoperative BCVA increased by Journal of Ophthalmology 3

20 3500

15 3000

IOP (mmHg) IOP 2500 10 cells Endothelial

2000 5 Pre-operation Pre-operation day post-operation day month post-operation month 1 months post-operation months month post-operation month 1 months post-operation months 3 1 3 Figure 2: The ECD before and at 1 month and 3 months after V4c- Figure 1: The IOP before and at 1 day, 1 month, and 3 months after ICL implantation. V4c-ICL implantation. three lines in 8 eyes (10%). The safety index (= preoperative vault was 0.42 ± 0.22 mm (range, 0.13 to 0.90 mm), which was BCVA/postoperative BCVA) was 1.28. significantly higher than the peripheral vaults𝑝 ( = 0.000, 0.003, 0.000, and 0.000, resp.). 3.2. Intraocular Pressure. The average preoperative intraoc- In one eye, the peripheral vault at 2 o’clock and 4 o’clock ular pressure (IOP) was 13.35 ± 2.34 mmHg (range, 9.7 wasashighas0.92mm,andtheperipheralvaultat8o’clock to 18.0 mmHg). One day after operation, the IOP was and10o’clockwas0.46mmand0.44mm,respectively.The slightly increased (average, 14.26 ± 3.20 mmHg; range, 10.0 central vault was 0.9 mm. The high vault value may be due to25.0mmHg).OnlyoneeyehadanIOP> 21 mmHg, and to ICL tilt after implantation. During the 6-month follow- up,thepatientshadvisualacuityof−0.08, normal IOP (11– the IOP returned to the normal level (14 mmHg) without 16 mmHg), no endothelial damage, and normal daily visual any special treatment at the second day after surgery. At 1 activities. Therefore, we did not exchange or reposition the month after operation, the IOP was stable (average, 13.46 tilt ICL. ± 1.74 mmHg; range, 10.0 to 17.2mmHg). At 3 months after operation, the average IOP was 13.42 ± 2.19 mmHg (range, 10.0 to 17.0mmHg), which was not significantly different from 3.5. Visual Function. The patients were required to fill out that before (and at 1 month) and after operation (Figure 1). a questionnaire about visual functions at 3 months after operation. Complete questionnaires were returned by 42 ± patientsandallofthesepatientsansweredthequestionnaire 3.3. Corneal Endothelial Cell Density. ECD was 2857.76 satisfactorily. 295.60 before operation, 2745.59 ± 384.11 at 1 month after ± In Table 1, items 1-2 evaluated near vision, items 3–5 operation, and 2719.30 363.02 at 3 months after operation. evaluated far vision, item 6 was for night vision, and items Compared with the preoperative value, ECD at 1 month and 7–11wereformiddle-distancevision.Weevaluatedthedaily 𝑝 = 0.144 3 months after operation decreased by 3.92% ( )and activities associated with near vision, far vision, and middle- 𝑝 = 0.065 4.83% ( ), respectively (Figure 2). distance vision. Apart from one patient who had a difficulty reading computer screens, all patients had satisfactory or very 3.4. Vault. We investigated the peripheral vault (the perpen- satisfactory results. We also investigated whether the patients dicular line between the end of suspensory ligament and the had a halo after operation. During the early postoperative ICL) and the central vault (the perpendicular line between follow-up period, halos occurred in 23 patients (54.8%). With thesurfaceoftheanteriorlenscapsuleandtheICLsurface) time, halos gradually disappeared at 3 months after operation at 3 months after ICL implantation (Figure 3). The peripheral without any treatments. The patients were categorized into vault was 0.25 ± 0.17 mm (range, 0.03 to 0.92 mm) at 2 o’clock, two groups: patients with halos and patients without halos. 0.29 ± 0.21 mm (range, 0.05 to 0.92 mm) at 4 o’clock, 0.23 The average age in patients with halos was 25.5 ± 4.3 years, ± 0.12 mm (range, 0.06 to 0.64 mm) at 8 o’clock, and 0.22 ± whichwasnotsignificantlydifferentfromthosewithouthalos 0.13 mm (range, 0.01 to 0.80 mm) at 10 o’clock. The central (23.2 ± 5.0 years) (𝑝 = 0.702). There were no significant 4 Journal of Ophthalmology

alleyeshadBCVAequaltoorbetterthanpreoperativeBCVA by one line or more. The postoperative UCVA and BCVA were −0.03 ± 0.08 LogMAR and −0.03 ± 0.07 LogMAR, respectively. The efficacy index and safety index were 1.27and 1.28, respectively, which were consistent with previous studies [9, 12–14]. These findings suggest that V4c-ICL is a safe and effective treatment for high myopia, and it significantly sim- plifies the ICL implantation procedure. During postoperative follow-up periods, intraocular pressure was stable and only slightly increased on postoperative day 1. Due to the presence of the central hole, V4c-ICL implantation avoids preoperative or intraoperative peripheral iridectomy, thus reducing IOP elevation caused by surgical stimulation, depigmentation, and pupillary block. This may explain the similar IOP before and after V4C-ICL implantation. In the present study, we found that the ECD at 1 month and 3 months after operation were reduced by 3.92% and 4.83%, respectively. Compared with the preoperative value, postoperative ECD was not significantly decreased, which was consistent with the results reported by Shimizu et al. [13]. Although we found that V4c-ICL implantation did not produce a short-term effect on ECD, it remains to be 0.8 determined whether aqueous outflow through the central hole of the V4c-ICL has a long-term effect on ECD. Further studies with long-term follow-ups and large sample sizes 0.6 should be performed. Vault is one of the most important indices for evaluating 0.4 thepostoperativeeffectoftheICLimplantation.Inthe

Vault present study, we performed UBM to observe the relative position between the V4c-ICL and the lens and found that no 0.2 V4c-ICL was in direct contact with the lens. The peripheral vaultateachmeasuredsitewassignificantlylowerthanthe central vault. This may occur because the center of the V4c- 0.0 ICL is designed to be thinner than the periphery. 2 o’clock 4 o’clock Center 8 o’clock 10 o’clock Evaluation of visual quality is a comprehensive method to evaluate the effect of refractive surgery and has been Figure 3: The peripheral vault and central vault at 3 months after V4c-ICL implantation. widely used. It has been reported that there is no significant difference in visual outcome between V4c-ICL and V4-ICL implantation [9, 10]. However, these studies only investigated the effect of V4c-ICL and C4-ICL implantation differences in the scores of visual functions between the two on contrast sensitivity and higher-order aberration. There 𝑝 > 0.05 groups ( ,Table2). were no reports about whether it affects the daily visual functions after implantation of V4c-ICL. In the present 4. Discussion study, we investigated the effect of V4c-ICL implantation on vision-related daily activities during follow-up. We found Posterior chamber pIOL implantation is an effective refrac- that apart from one patient (2.4%) who had a difficulty in tive surgery that has been widely accepted. However, elevated reading computer screen, all patients had satisfactory or very intraocular pressure is a common postoperative complication satisfactory results. In addition, we found that there were after pIOL implantation, even in patients with preoperative or tilt ICL in one eye of another patient. During the 6-month intraoperative iridectomy [5]. follow-up, the patients with tilt ICL had visual acuity of −0.08, To simplify the ICL implantation procedure and improve normal IOP (11–16 mmHg), no endothelial damage, and postoperative aqueous circulation, V4c-ICL with a 0.36 mm normaldailyvisualactivities.Inourshort-termfollow-up, central hole was developed. Clinical studies have shown even the tilt of the V4c-ICL could not bring a serious impact that V4c-ICL implantation is effective in the treatment of onthepatient.Ofcourseitwasnecessarytoobservethe moderate and high myopia [9, 12, 13]. patient for a long term. During the early postoperative follow- In the present study, we found that (after V4c-ICL up period, halos occurred in more than 50% (54.8%, 23 implantation) UCVAwas equal to or better than preoperative patients) of patients. With time, halos gradually disappeared BCVA in 80 eyes (98%) with high myopia. No patients had after operation without treatment. There were no significant postoperative BCVA worse than preoperative BCVA. Almost differences in the scores of visual functions between patients Journal of Ophthalmology 5

Table 1: Visual functions of patients after V4c-ICL implantation (𝑛 = 42).

Very Very positive% Positive% Negative% negative% Visual functions Mean score ± SD (number of (number of (number of (number of patients) patients) patients) patients) Reading in daylight 8.3 ± 0.9 83.3 (35) 16.7 (7) 0 (0) 0 (0) Reading in artificial light 8.0 ± 1.1 71.4 (30) 28.6 (12) 0 (0) 0 (0) Watching TV 8.0 ± 1.1 71.4 (30) 28.6 (2) 0 (0) 0 (0) Watching movie at cinema 8.0 ± 1.1 71.4 (30) 28.6 (12) 0 (0) 0 (0) Driving in daylight 8.3 ± 1.0 81.0(34) 19.0(8) 0(0) 0(0) Driving at night 7.8 ± 1.2 61.9 (26) 38.1 (16) 0 (0) 0 (0) Reading computer screen 7.5 ± 1.4 52.4 (22) 45.2 (19) 2.4 (1) 0 (0) Playing sports 8.2 ± 1.0 78.6 (33) 21.4 (9) 0 (0) 0 (0) Swimming 8.1 ± 1.1 73.8 (31) 26.2 (11) 0 (0) 0 (0) Shaving/makeup 8.0 ± 1.1 71.4 (30) 28.6 (12) 0 (0) 0 (0) Shopping 8.3 ± 1.0 81.0(34) 19.0(8) 0(0) 0(0)

Table 2: Visual functions after 4c-IC implantation in patients with (+) or without (–) halo.

Halo − Visual functions + 𝑝 𝑛=19 𝑛=23 Reading in daylight 8.8 ± 0.0 8.4 ± 1.0 0.165 Reading in artificial light 8.3 ± 1.0 8.2 ± 1.1 0.780 Watching TV 7.8 ± 1.3 8.2 ± 1.1 0.497 Watching movie at cinema 8.3 ± 1.0 7.6 ± 1.3 0.152 Driving in daylight 8.8 ± 0.0 8.2 ± 1.1 0.082 Driving at night 8.1 ± 1.2 8.0 ± 1.2 0.859 Reading computer screen 7.8 ± 1.3 7.0 ± 1.6 0.178 Playing sports 8.8 ± 0.0 8.2 ± 1.1 0.082 Swimming 8.5 ± 0.8 8.0 ± 1.2 0.194 Shaving/makeup 8.3 ± 1.0 8.0 ± 1.2 0.500 Shopping 8.8 ± 0.0 8.4 ± 1.0 0.082

with or without halos. These findings suggest that halos do Authors’ Contributions not affect postoperative vision-related daily activities. In conclusion, we investigated the vision-related daily Taixiang Liu and Shaorong Linghu contributed equally to this activities at 3 months after V4c-ICL implantation. We found study. that the patients were satisfied with their vision-related daily life activities, and the presence of central hole of References V4c-ICL did not affect vision-associated daily activities. Postoperative intraocular pressure was stable, and no vision- [1] C. F. Lovisolo and D. Z. Reinstein, “Phakic intraocular lenses,” associated complications were found during the follow-up Survey of Ophthalmology, vol. 50, no. 6, pp. 549–587, 2005. period. However, because V4c-ICL implantation alters aque- [2]J.F.Alfonso,C.Lisa,L.Fernandez-Vega,´ D. Almanzar, C. ous circulation, it remains to be determined whether V4c- Perez-Vives,´ and R. Montes-Mic´ o,´ “Prevalence of cataract after ICL implantation produces long-term effect on intraocular collagen copolymer phakic intraocular lens implantation for pressure and ECD. myopia, hyperopia, and astigmatism,” Journal of Cataract and Refractive Surgery,vol.41,no.4,pp.800–805,2015. Competing Interests [3] D. R. Sanders, J. A. Vukich, K. Doney et al., “U.S. food and drug administration clinical trial of the implantable contact lens for The authors declare that there is no conflict of interests moderate to high myopia,” Ophthalmology,vol.110,no.2,pp. regarding the publication of this article. 255–266, 2003. 6 Journal of Ophthalmology

[4]D.R.Sanders,K.Doney,andM.Poco,“UnitedStatesFoodand Drug Administration clinical trial of the Implantable Collamer Lens (ICL) for moderate to high myopia: three-year follow-up,” Ophthalmology, vol. 111, no. 9, pp. 1683–1692, 2004. [5]P.Fernandes,J.M.Gonzalez-M´ eijome,´ D. Madrid-Costa, T. Ferrer-Blasco, J. Jorge, and R. Montes-Mic´ o,´ “Implantable collamer posterior chamber intraocular lenses: a review of potential complications,” Journal of Refractive Surgery,vol.27, no. 10, pp. 765–776, 2011. [6] J. S. Lee, Y. H. Kim, S. K. Park et al., “Long-term clinical results of posterior chamber phakic intraocular lens implantation to correct myopia,” Clinical and Experimental Ophthalmology,vol. 44, no. 6, pp. 481–487, 2016. [7] C. A. Sanchez-Galeana,R.J.Smith,D.R.Sandersetal.,´ “Lens opacities after posterior chamber phakic intraocular lens implantation,” Ophthalmology,vol.110,no.4,pp.781–785,2003. [8]S.Almalki,A.Abubaker,N.A.Alsabaani,andD.P.Edward, “Causes of elevated intraocular pressure following implantation of phakic intraocular lenses for myopia,” International Ophthal- mology,vol.36,no.2,pp.259–265,2016. [9] K. Shimizu, K. Kamiya, A. Igarashi, and T. Shiratani, “Intrain- dividual comparison of visual performance after posterior chamber phakic intraocular lens with and without a central hole implantation for moderate to high myopia,” American Journal of Ophthalmology,vol.154,no.3,pp.486–494.e1,2012. [10] C. Pe´rez-Vives, T. Ferrer-Blasco, D. Madrid-Costa, S. Garcia-´ Lazaro,´ and R. Monte´s-Mico,´ “Visual quality comparison of conventional and Hole-Visian implantable collamer lens at different degrees of decentering,” British Journal of Ophthalmology, vol. 98, no. 1, pp. 59–64, 2014. [11] C. N. J. McGhee, J. P. Craig, N. Sachdev, K. H. Weed, and A. D. Brown, “Functional, psychological, and satisfaction outcomes of laser in situ keratomileusis for high myopia,” Journal of Cataract & Refractive Surgery,vol.26,no.4,pp.497–509,2000. [12] K. Shimizu, K. Kamiya, A. Igarashi, and H. Kobashi, “Long- term comparison of posterior chamber phakic intraocular lens with and without a centralhole (Hole ICL and Conventional ICL) implantation for moderate to high myopia and myopic astigmatism: consort-compliant article,” Medicine,vol.95,no. 14, p. e3270, 2016. [13] K. Shimizu, K. Kamiya, A. Igarashi, and T. Shiratani, “Early clinical outcomes of implantation of posterior chamber phakic intraocular lens with a central hole (Hole ICL) for moderate to high myopia,” British Journal of Ophthalmology,vol.96,no.3, pp.409–412,2012. [14]C.Lisa,M.Naveiras,B.Alfonso-Bartolozzi,L.Belda-Salmeron,´ R. Montes-Mic´ o,´ and J. F. Alfonso, “Posterior chamber collagen copolymer phakic intraocular lens with a central hole to correct myopia: one-year follow-up,” Journal of Cataract and Refractive Surgery, vol. 41, no. 6, pp. 1153–1159, 2016. Hindawi Publishing Corporation Journal of Ophthalmology Volume 2016, Article ID 8496201, 5 pages http://dx.doi.org/10.1155/2016/8496201

Clinical Study Changes in Anterior Segment Morphology of Iris Bombe before and after Laser Peripheral Iridotomy in Patients with Uveitic Secondary Glaucoma

Wakako Ikegawa, Takashi Suzuki, Koji Namiguchi, Shiro Mizoue, Atsushi Shiraishi, and Yuichi Ohashi Department of Ophthalmology, Graduate School of Medicine, Ehime University, Toon, Ehime 791-0295, Japan

Correspondence should be addressed to Takashi Suzuki; [email protected]

Received 12 May 2016; Revised 8 September 2016; Accepted 13 October 2016

Academic Editor: Karim Mohamed-Noriega

Copyright © 2016 Wakako Ikegawa et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. To quantify changes in anterior segment (AS) parameters after laser peripheral iridotomy (LPI) using AS-optical coherence tomography (OCT) of iris bombe. Method.ASimagesofeighteyeswerecapturedbeforeandafteririsbombeandmorethan2 weeks after LPI (post-LPI) using AS-OCT. We compared the following AS parameters: anterior chamber depth (ACD), anterior chamber volume (ACV), iris curvature (IC), iris thickness at 500 𝜇m from the scleral spur (IT-1) in the middle between the iris root and pupillary margin (IT-2) and 500 𝜇m from the pupillary margin (IT-3) to the anterior chamber angle (ACA) (angle opening distance [AOD750]), and trabecular iris space area. Results. Mean IT-1 and IT-3, but not IT-2, were lower after iris bombe (IT-1, 𝑃 = 0.001;IT-2,𝑃 = 0.081; and IT-3, 𝑃 = 0.001). There were no significant differences between ACD at pre-LPI and before iris bombe (𝑃 = 0.096). The mean ACV and AOD750 of iris bombe increased at post-LPI (ACV, 𝑃 < 0.01,andAOD750,𝑃 < 0.05). The mean IT-1, IT-2, and IT-3 increased at post-LPI (all, 𝑃 ≤ 0.01). IC decreased at post-LPI (𝑃 < 0.001), and ACD at post-LPI did not change. Conclusions. The iris extends and becomes thinner during iris bombe. LPI during bombe decreases the IC and increases the ACV and ACA.

1. Introduction AS-optical coherence tomography (AS-OCT) has recently been used to visualize AS structures [4]. During Uveitis causes glaucoma, cataract, and retinal damage, result- this process, customized software measures AS structures ing in severe visual loss. Uveitic glaucoma includes iris bombe including the angles, iris, anterior chamber, and lens. Several that is an uncommon severe complication of uveitis [1]. Iris studies have described the morphology of the AS in primary bombe is induced by formation of the posterior synechiae and angle closure glaucoma [5–8]. Xu et al. reported that there pupillary block. Because intraocular pressure (IOP) elevation was a significant association between shallow anterior during iris bombe is caused by angle closure, iridotomy is chamber depth (ACD) and the presence of angle closure a treatment option for the reduction of IOP. However, laser glaucoma [8]. Miki et al. reported AS-OCT images in two iridotomy has a high failure rate as a result of continuous cases of iris bombe before and after laser iridotomy [9]. inflammation [2, 3], and little is known about the appropriate However, little is known about the changes that occur in treatment for iris bombe. Therefore, to treat this condition, AS-OCT parameters in iris bombe before and after laser it is necessary to more comprehensively understand the iridotomy. morphology of the iris and anterior segment (AS), to better Therefore,theaimofthepresentstudywastoanalyzeAS- facilitate bypass of the aqueous outflow. OCT parameters during iris bombe to better understand the 2 Journal of Ophthalmology morphology of the angles, iris, anterior chamber, and lens determined using AS-OCT images that were acquired in the during this disorder. horizontal meridian only. The AOD750, TISA750, IT (IT-1, IT-2, and IT-3), and IC were determined as the average of 2. Materials and Methods temporal and nasal values. AS-OCT analysis in each eye was performed with angle closure (attack) just after LPI (LPI) 2.1. Study Participants. Eighteyeswithirisbombefromseven and >2 weeks after LPI (post-LPI). Six of seven patients were patients were enrolled in this study. Patient information is imaged before iris bombe (preattack). shown in Table 1. The mean age was 59 ± 18.6 years. All seven participants were female and were treated with topical 2.3. Statistical Analyses. All of the data are expressed as the steroids before iris bombe. The diagnosis of iris bombe was mean ± standard deviation (SD). Comparisons of parameters made in eyes with angle closure, posterior synechiae, and an were evaluated by paired 𝑡-tests. A 𝑃 value < 0.05 was IOP elevation ≥ 5 mmHg. Laser peripheral iridotomy (LPI) considered statistically significant. Data were analyzed with was performed in the superior region of the iris (from the StatMate IV software (ATMS, Tokyo, Japan). 10 o’clock to the 2 o’clock position) using topical anesthesia 𝜇 with sequential argon (800–1,000 mW, 50 millis, 50 m, and 3. Results 10–50 shots) and a Nd:Yag laser at 1–3 mJ (2–10 pulses). Dexamethasone (0.1%) eye drops were administered 4–6 All of the subjects had a bypass of aqueous outflow after times a day after LPI. IOP was measured in eyes with iris LPI and resolved angle closure. Although all of the cases did bombe, before iris bombe, and >2 weeks after LPI. This study not show a recurrence of iris bombe due to reclosure of the was approved by the Ehime University Review Board and iridotomy window until 2 weeks, two eyes needed cataract adhered to the tenets of the Declaration of Helsinki. Written surgery due to reclosure of the iridotomy window by fibrin informed consent was obtained from each study participant. formation after 2 weeks. AS-OCT imaging showed marked iris elevation in the horizontal image and angle closure. 2.2. AS-OCT Imaging. Each eye was imaged using AS-OCT Flattening of the iris and opening of the angle were observed (swept-source 1000 Casia AS-OCT; Tomey, Nagoya, Japan) immediately after LPI. Representative images are shown in by an experienced operator who was masked to the results Figure 2. We compared the IOP and AS-OCT parameters of the ophthalmic examinations. This AS-OCT system used a at the preattack, attack, immediately after post-LPI, and 1,310 nm wavelength coupled with high resolution to deliver post-LPI (Table 2). Mean ACV, AOD750, IT-1, and IT-3 30,000Ascanspersecondwithanaxialresolution<10 𝜇m significantly decreased when assessed at attack. Moreover, that could scan the entire AS in one frame [10]. Imaging by IC significantly increased at attack. However, there was no AS-OCT was performed for all of the subjects under room significant change in ACD, IT-2, or IV. Mean ACV, AOD750, light conditions of 990 lux. Images of the anterior chamber TISA750, IT-1, IT-2, IT-3, and IV significantly increased, angle (ACA) were obtained using AS-OCT at the temporal and IC significantly decreased immediately after post-LPI. and nasal angles of the anterior chamber in the horizontal ACV, AOD750, and IT (IT-1, IT-2, and IT-3) significantly meridian.Alloftheimageswereprocessedandanalyzedby increased at post-LPI. IOP significantly increased at attack two graders (Wakako Ikegawa and Takashi Suzuki) who were and decreased at post-LPI. masked to the demographics of the subjects. The two graders agreed on their evaluations of study parameters. The instru- 4. Discussion ment software in the SS-1000 Casia instrument analyzed the following parameters: anterior chamber depth (ACD; 3 Iris bombe in uveitic eyes is a unique pathology of acute angle mm), anterior chamber volume (ACV; mm ), ACA (angle closure. Pupillary block induced by inflammation in the AS opening distance [AOD750; mm] and trabecular iris space is a trigger for this disorder. However, little is known about 2 area [TISA750; mm ]), iris thickness (IT; mm), iris volume the morphological changes in the AS during iris bombe. 3 (IV; mm ), and iris curvature (IC; mm) [11]. The AOD750 was In the present study, AS-OCT showed that AS parameters defined as the distance from the corneal endothelium to the including ACV, AOD750, IT-1, and IT-3 decreased during anterior iris surface, perpendicular to a line drawn 750 𝜇m iris bombe, compared to preattack, but recovered after LPI. anterior to the scleral spur. The TISA750 was defined as the These changes are similar to previous studies of acute angle trapezoidalareawiththefollowingboundaries:anteriorly, closure crisis (ACCC) [5, 12]. Lee et al. reported that eyes the AOD750; posteriorly, a line drawn from the scleral withACCChadashallowerACDandsmallerACAcompared spur perpendicular to the plane of the inner scleral wall to fellow eyes [5]. Moreover, acute attack-affected eyes had opposing the iris; superiorly, the inner corneoscleral wall; a greater lens vault (LV). Acute phacomorphic angle closure andinferiorly,theirissurface.TheICwasdefinedasthe is a secondary type of angle closure disorder. Compared to maximum distance from the posterior boundary of the iris ACCC, Mansouri et al. recently reported that phacomorphic and iris root. The IT was measured at 500 𝜇mfromthescleral angle closure resulted in a shallower ACD and greater spur (IT-1), in the middle between the iris root and pupillary LV,axiallength,andACA[12].IncontrasttoACCCor margin (IT-2), and 500 𝜇m from the pupillary margin (IT-3; phacomorphic angle closure, iris bombe does not involve a mm) (Figure 1). The ACD, ACV, AOD750, TISA750, and IV shallow ACD. Furthermore, the IC during iris bombe was were automatically calculated by the internal software of the larger compared to previous studies of ACCC [5]. Although instrument. The ACD, AOD750, TISA750, IT, and IC were ACCC and phacomorphic angle closure could be related to Journal of Ophthalmology 3

ACD ACV

AOD750 IT-2 IT-3 750 𝜇m IT-1 SS IC TISA750

Figure 1: Anterior segment optical coherence tomography (AS-OCT) of iris bombe showing where the study variables were measured. SS: scleral spur.

(a)

(b)

(c)

Figure 2: Representative anterior segment optical coherence tomography (AS-OCT) images (left) and slit-lamp images (right) showing (a) preattack, (b) attack, and (c) post-LPI.

Table 1: Summary of data on seven patients with iris bombe.

Age at onset Eye(s) with Causative agent of uveitis Case Gender Recurrence of iris bombe (+/−) (years) iris bombe (systematic disease) 1 F 36 OS Idiopathic uveitis − 2 F 68 OU Systemic lupus erythematosus OD+ OS− 3 F 30 OD Idiopathic uveitis − 4 F 66 OD Idiopathic uveitis − 5 F 80 OS Rheumatoid arthritis + 6 F 70 OD Exogenous endophthalmitis − 7 F 63 OD Rheumatoid arthritis − 4 Journal of Ophthalmology post-LPI Preattack versus 0.001 0.233 < post-LPI Attack versus values 𝑃 0.001 0.02 0.053 0.168 0.012 0.029 0.107 0.002 0.004 0.141 < d post-LPI evaluations. Attack versus immed-post-LPI 0.001 0.01 0.02 0.081 0.029 0.006 0.652 0.016 0.265 0.035 0.749 0.001 0.003 0.009 0.854 0.001 0.012 0.01 0.089 0.793 0.015 0.211 0.329 0.057 0.096 0.139 0.112 0.296 attack < Preattack versus attack, immed-post-LPI, an 16 ± 9 Post-LPI 0.33 ± 0.19 0.37 ± 0.07 0.69 ± 0.34 2.52 ± 1.07 0.18 ± 0.09 0.39 ± 0.05 0.33 ± 0.14 35.44 ± 20.26 126.46 ± 28.27 Table 2: Comparison of AS parameters among preattack, Preattack Attack Immed-post-LPI 0.19 ± 0.06 0.070.39 ± ± 0.09 0.07 0.25 ± 0.04 0.17 ± 0.09 0.32 ± 0.04 2.37 ± 0.22 2.17 ± 0.30 2.28 ± 0.22 0.23 ± 0.17 0.72 ± 0.17 0.22 ± 0.14 0.43 ± 0.15 0.32 ± 0.06 0.38 ± 0.07 0.33 ± 0.11 0.10 ± 0.14 0.35 ± 0.19 0.35 ± 0.22 0.29 ± 0.04 0.34 ± 0.05 33.58 ± 22.19 27.34 ± 7.71 42.73 ± 20.27 15.33 ± 14.75 26.50 ± 14.76 21.38 ± 11.30 106.77 ± 27.80 59.66 ± 16.53 110.17 ± 28.47 ) 2 ) 3 ) 3 IT-1 (mm) IT-2 (mm) AOD750 (mm) TISA750 (mm IT-3 (mm) IT ACV (mm ACD (mm) IC (mm) IOP (mmHg) ACA IV (mm Journal of Ophthalmology 5 lens parameters, iris bombe is not influenced by the lens. IC is [2]D.J.Forster,N.A.Rao,R.A.Hill,Q.H.Nguyen,andG. usuallyusedtoevaluaterelativepupillaryblock[6,13].Thus, Baerveldt, “Incidence and management of glaucoma in Vogt- iris bombe could be associated with a relative pupillary block Koyanagi-Harada syndrome,” Ophthalmology,vol.100,no.5, without a large anterior movement or swelling of the lens. The pp.613–618,1993. iris could be extended by pressure of the posterior chamber, [3]N.A.Spencer,A.J.H.Hall,andR.J.Stawell,“Nd:YAGlaser resulting in angle closure. Evaluation of the IC could therefore iridotomy in uveitic glaucoma,” Clinical and Experimental Oph- be used to estimate the relative pupillary block during iris thalmology,vol.29,no.4,pp.217–219,2001. bombeandcouldalsobeusedasanindicatorforLPI. [4]S.Radhakrishnan,A.M.Rollins,J.E.Rothetal.,“Real- The root of the iris (IT-1) and the papillary margin (IT- time optical coherence tomography of the anterior segment at 3), but not the middle of the iris (IT-2), were significantly 1310 nm,” Archives of Ophthalmology,vol.119,no.8,pp.1179– thinner, compared to values before attack, suggesting that the 1185, 2001. posterior chamber pressure could extend the iris root and [5]J.R.Lee,K.R.Sung,andS.Han,“Comparisonofanteriorseg- papillary margin, compared to the middle iris. Matsuki et al. ment parameters between the acute primary angle closure eye and the fellow eye,” Investigative Ophthalmology and Visual Sci- reported that there was a negative association between the IT ence,vol.55,no.6,pp.3646–3650,2014. and IC during angle closure [6]. Thus, extension of the iris [6] T. Matsuki, F. Hirose, S.-I. Ito, M. Hata, Y. Hirami, and Y. rootandirisbulgecouldeasilyinduceangleclosure. Kurimoto, “Influence of anterior segment biometric parameters Type I collagen is present in the basement membrane of on the anterior chamber angle width in eyes with angle closure,” iris vessels [14]. A thinner iris with low amounts of type I Journal of Glaucoma,vol.24,no.2,pp.144–148,2015. collagen may be more elastic. Uveitis induces inflammation [7] S. Radhakrishnan and D. Yarovoy, “Development in anterior and damage of the iris that may reduce collagen levels and segment imaging for glaucoma,” Current Opinion in Ophthal- facilitate iris extension. mology,vol.25,no.2,pp.98–103,2014. The present study showed that iris morphology could [8]L.Xu,W.F.Cao,Y.X.Wang,C.X.Chen,andJ.B.Jonas, recover after LPI, with increasing TISA and AOD, decreasing “Anterior chamber depth and chamber angle and their associa- IC, and a reduction of IOP in all of the patients. As previously tions with ocular and general parameters: the Beijing Eye Study,” noted, iris bombe may not be related to any lens parameters. American Journal of Ophthalmology,vol.145,no.5,pp.929– A previous study reported that iris thickness was associated 936.e1, 2008. with a greater decrease in IC and an increase in TISA after [9] A. Miki, Y. Saishin, R. Kuwamura, N. Ohguro, and Y. Tano, LPI [15]. Thus, LPI can release pupillary block. However, two “Anterior segment optical coherence tomography assessment eyes needed cataract surgery due to reclosure of the iridotomy of iris bombe´ before and after laser iridotomy in patients with window by fibrin formation. To prevent recurrence of iris uveitic secondary glaucoma,” Acta Ophthalmologica,vol.88,no. bombe, anti-inflammatory treatments should therefore be 2, pp. e26–e27, 2010. continued after LPI. [10] C. K.-S. Leung and R. N. Weinreb, “Anterior chamber angle Statistical comparisons of small samples using the 𝑡-test imaging with optical coherence tomography,” Eye,vol.25,no. may be associated with type 1 errors. Therefore, studies with 3,pp.261–267,2011. larger sample sizes are needed. [11] T. Furuya, F. Mabuchi, T. Chiba, S. Kogure, S. Tsukahara, and K. Kashiwagi, “Comparison of the anterior ocular segment mea- 5. Conclusions surements using swept-source optical coherent tomography and a scanning peripheral anterior chamber depth analyzer,” Iris bombe disorder results in angle closure without a shal- Japanese Journal of Ophthalmology,vol.55,no.5,pp.472–479, lower ACD, which may be related to a relative pupillary 2011. block. The increased IC in iris bombe may be associated with [12] M. Mansouri, F.Ramezani, S. Moghimi et al., “Anterior segment reversibility of AS changes after LPI. optical coherence tomography parameters in phacomorphic angle closure and mature cataracts,” Investigative Ophthalmol- ogy and Visual Science,vol.55,no.11,pp.7403–7409,2014. Disclosure [13] A. Nonaka, T. Iwawaki, M. Kikuchi, M. Fujihara, A. Nishida, The English in this document has been checked by at least and Y. Kurimoto, “Quantitative evaluation of iris convexity in two professional editors, both native speakers of English. primary angle closure,” American Journal of Ophthalmology,vol. 143, no. 4, pp. 695–697, 2007. For a certificate, please see http://www.textcheck.com/certificate/iWoBkc. [14] A. G. Konstas, G. E. Marshall, and W. R. Lee, “Immunocyto- chemical localisation of collagens (I–V) in the human iris,” Graefe’s Archive for Clinical and Experimental Ophthalmology, Competing Interests vol. 228, no. 1, pp. 180–186, 1990. The authors have no competing commercial or financial [15]R.Y.Lee,T.Kasuga,Q.N.Cuietal.,“Associationbetweenbase- line iris thickness and prophylactic laser peripheral iridotomy interests associated with the article. outcomes in primary angle-closure suspects,” Ophthalmology, vol. 121, no. 6, pp. 1194–1202, 2014. References

[1] R. S. Moorthy, A. Mermoud, G. Baerveldt, D. S. Minckler, P. P. Lee, and N. A. Rao, “Glaucoma associated with uveitis,” Survey of Ophthalmology,vol.41,no.5,pp.361–394,1997. Hindawi Publishing Corporation Journal of Ophthalmology Volume 2016, Article ID 5435092, 12 pages http://dx.doi.org/10.1155/2016/5435092

Review Article Anterior Segment Imaging in Ocular Surface Squamous Neoplasia

Sally S. Ong, Gargi K. Vora, and Preeya K. Gupta

Duke University Department of Ophthalmology, Durham, NC, USA

Correspondence should be addressed to Preeya K. Gupta; [email protected]

Received 18 June 2016; Accepted 15 August 2016

Academic Editor: Karim Mohamed-Noriega

Copyright © 2016 Sally S. Ong et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Recent advances in anterior segment imaging have transformed the way ocular surface squamous neoplasia (OSSN) is diagnosed andmonitored.Ultrasoundbiomicroscopy(UBM)hasbeenreportedtobeusefulprimarilyintheassessmentofintraocular invasion and metastasis. In vivo confocal microscopy (IVCM) shows enlarged and irregular nuclei with hyperreflective cells in OSSN lesions and this has been found to correlate with histopathology findings. Anterior segment optical coherence tomography (AS-OCT) demonstrates thickened hyperreflective epithelium with an abrupt transition between abnormal and normal epithelium in OSSN lesions and this has also been shown to mimic histopathology findings. Although there are limitations to each of these imaging modalities, they can be useful adjunctive tools in the diagnosis of OSSN and could greatly assist the clinician in the management of OSSN patients. Nevertheless, anterior segment imaging has not replaced histopathology’s role as the gold standard in confirming diagnosis.

1. Introduction solar ultraviolet radiation as well as human immunod- eficiency virus (HIV) and human papillomavirus (HPV) Ocular surface squamous neoplasia (OSSN) is the most com- infections [7, 8]. OSSN lesions are usually located within the mon tumor affecting the ocular surface in adults [1]. OSSN interpalpebral fissure at the limbus in the nasal quadrant, was a term suggested by Lee and Hirst to describe all primary which receives the highest intensity of sunlight [7]. Clinically, dysplastic and carcinomatous lesions that originate from the OSSN has been described as elevated gelatinous, papilliform, epithelium of the cornea or conjunctiva [2]. Histologically, or leukoplakic limbal lesions that move freely over the sclera OSSN includes epithelial dysplasia, carcinoma in situ, and with adjacent feeder vessels (Figure 1) [4, 9]. Diagnosis can be invasive squamous cell carcinoma [3]. In conjunctival and made by clinical examination with slit lamp biomicroscopy. corneal intraepithelial neoplasia (CCIN), epithelial cells are However,overlapinclinicalfeaturesinOSSNandmasquer- thickened, dysplastic, and irregular with increased cell proliferation. These changes affect less than the full thickness of aders like pterygium, dyskeratosis, papilloma, scar tissue, the epithelium. When the entire epithelium is involved but corneal pannus, pyogenic granuloma, amelanotic melanoma, tumor cells have not yet invaded the substantia propria, the and sebaceous cell carcinoma can occasionally make diagno- lesion is categorized as carcinoma in situ.Invasivesquamous sis by clinical examination alone difficult. Accuracy of clinical cell carcinoma is defined as when the lesion has affected the diagnosis has been reported to range between 40% and 86% epithelial basement membrane and substantia propria [4, 5]. when compared to histopathology results [2, 10]. It can locally invade the sclera, uvea, eyelids, and orbit and The gold standard for confirming diagnosis of OSSN is has the ability to metastasize to distant sites thus potentially excisional biopsy for histopathology. This technique, how- becoming life threatening [6]. ever, is not without its limitations. Biopsy for histopathology OSSN occurs worldwide but has the highest incidence may miss lesions that are not included in the excised tissue as rates in Africa [7]. Risk factors for developing OSSN include diffuse lesions can be difficult to excise with clear margins. 2 Journal of Ophthalmology

modality since a high proportion of benign lesions also stained positive [22]. Given the limitations of IC and vital dye staining, there is now increased interest in the use of anterior segment imaging techniques to assist in the diagnosis of OSSN. This is becoming especially pertinent since current management options for OSSN include not only surgical excision with cryotherapy but also primary medical therapy with the use of topicalchemotherapysuchasmitomycin-C,5-fluorouracil, and interferon alfa-2b. In this review, we will discuss the use of ultrasound biomicroscopy (UBM), in vivo confocal Figure 1: Slit lamp photograph of a corneal-conjunctival intraep- microscopy (IVCM), and anterior segment optical coherence ithelial neoplasia with gelatinous and papilliform features as well as tomography (AS-OCT) in the diagnosis and monitoring feeder vessels. of OSSN. We performed a comprehensive review within the peer reviewed literature using http://pubmed.gov/. The following search terms were used: ocular surface squamous Additionally, since OSSN can recur even after successful neoplasia, conjunctival intraepithelial neoplasia, corneal treatment, repeated excisional biopsies may cause conjunc- intraepithelial neoplasia, carcinoma in situ squamous cell tivalscarringandlimbalstemcelldeficiency[13].Adjunctive carcinoma, impression cytology, toluidine blue, methylene methods such as impression cytology (IC) and vital dye blue, ultrasound biomicroscopy, in vivo confocal microscopy, staining have therefore been used to assist in the diagnosis and anterior segment optical coherence tomography. and follow-up of OSSN. Althoughnowrarelydone,ICcanbeusefulindiagnosis andhasbeenshowntocorrelatecloselywithhistopathology 2. Ultrasound Biomicroscopy [14, 15]. In IC, superficial epithelial cells are collected by applying collecting devices (either cellulose acetate filter Ultrasound biomicroscopy (UBM), which was first developed papers or Biopore membrane device [Millipore Corp, Bed- by Pavlin et al. in 1990, provides cross-sectional visualization ford,MA])suchthatthecellsadheretothesurfaceandare of the anterior segment in an intact globe at microscopic removed from the eye to be fixed, stained, and then mounted resolution [30]. UBM uses high frequency ultrasonography on a slide for analysis [29]. Nolan et al. found that 55% of ranging from 20 to 50 MHz. In the 50 MHz mode, images intraepithelial OSSN cases diagnosed by IC had keratinized toadepthof5to6mmataresolutionof25microns dysplastic cells often accompanied by hyperkeratosis, 35% canbeproduced[31].Pavlinetal.suggestedtheuseof had large syncytial-like groups, and 10% had nonkeratinized UBM to measure and determine the extent of invasion dysplastic cells as a predominant feature [16]. Importantly, of anterior segment tumors, which had been difficult with however, it was not possible to differentiate intraepithelial conventional ultrasound [32, 33]. Today it is widely used to lesions from invasive squamous cell carcinoma given the image anterior segment tumors although limitations exist. superficial sampling of cells, thus limiting the utility of IC in These include requiring an eyebath in the reclined position diagnosing invasive disease [16]. The inability of IC to reach and a technician familiar with its use to obtain the best deep atypical cells even with repeated imprints of the same images. area of the lesion has also been noted in other studies [17, 18]. Studies on the use of UBM in diagnosing OSSN have Another diagnostic test that is inexpensive and helpful shown that UBM is most useful in assessing intraocular in identifying OSSN is dye staining. Diagnostic dyes like tumor extension and metastasis [11, 23]. Char et al. examined lissamine green and rose bengal are routinely used to stain four patients with possibly highly invasive squamous cell and delineate the extent of OSSN lesions but since these carcinoma of the conjunctiva who underwent 20 MHz high dyes are nonspecific and stain many other ocular surface frequency ultrasound [23]. In all four cases, UBM was useful conditions, it is not possible to diagnose OSSN with the use as an adjunct to clinical examination in determining the pres- of these dyes alone. Other vital dyes that have been studied ence of deep invasion. For example, one patient was referred in the diagnosis of OSSN include toluidine blue (ToB) and for possible deep invasion from a conjunctival squamous methylene blue. ToB and methylene blue are acidophilic dyes cell carcinoma. There was no evidence for invasion on high that stain abnormal tissue dark royal blue. They have an frequency ultrasound, which correlated with biopsy findings affinity for nucleic acids and, given the increased nuclear of tumor confined to the conjunctiva. Another patient had material from high rates of mitoses and poor cell-to-cell atypical scleritis with a large superficial tumor and clinical adhesion in malignancy, these tissues stain more frequently evidence of intraocular invasion, which was confirmed by than benign tissues [22]. Several studies have shown that high frequency UBM showing invasion into the ciliary body ToB and methylene blue staining have a high sensitivity but with thickening [23]. low to moderate specificity in diagnosing OSSN compared Finger et al. described general ultrasonographic charac- to histopathology [20–22]. This makes ToB and methylene teristics of conjunctival intraepithelial neoplasia and squa- blue a good initial screening tool since very few OSSN lesions mous cell carcinoma in addition to UBM findings in intraoc- did not stain with these dyes but an insufficient diagnostic ular tumor extension in 11 patients [11]. Using 20 and 50 MHz Journal of Ophthalmology 3

(a) (b) (c)

Figure 2: 20 MHz transverse (a) and longitudinal (b) ultrasound biomicroscopy sections of conjunctival intraepithelial neoplasia demonstrate hyperechoic tumor surface (arrows) and hypoechoic stroma. (c) 20 MHz UBM image taken from a patient with squamous cell carcinoma demonstrates blunting of the anterior chamber angle (arrow) which correlated to anterior chamber angle invasion on histopathology [11]. high frequency ultrasound, the tumor surface was found with bright hyperreflective nuclei in conjunctival and corneal to be hyperechoic while the tumor stroma was generally intraepithelial neoplasia [36, 37]. Meanwhile, Falke et al. hypoechoic in all patients (Figures 2(a) and 2(b)). The presented a case of carcinoma in situ with IVCM findings of authors also reported two UBM findings suggestive of ocular regular conjunctival epithelium interspersed with complexes tumor extension: (1) blunting of the anterior chamber angle of enlarged cells with polymorphic nuclei [38]. (Figure 2(c)) and (2) uveal thickening, which correlated with Balestrazzi et al. described an atypical case of OSSN in histopathology findings. In patients where the tumor had a patient one month after clear corneal phacoemulsification covered a functioning filtering bleb or obscured the corneal with papillomatous invasion in the area of the side port surface, the authors were able to determine that there was no incision. IVCM demonstrated typical characteristics of the evidence of intraocular extension by using UBM. In patients limbal portion of OSSN with very bright intracellular bodies, with orbital extension, the authors differentiated the relatively while the corneal lesion demonstrated large hyperreflective hypoechoic tumor from the more hyperechoic orbital tissues roundtoovalshapedcellswithperipherallydisplacednucleus usingUBM.However,imagingoftheposteriormarginsof and stromal invasion of neoplasia across an interrupted Bow- the tumor was limited by the maximum penetration of 20 man layer [39]. The authors hypothesized that the Bowman and 50 MHz UBM. Additionally, while 50 MHz images had layer was interrupted by the side port incision made during better resolution, 20 MHz ultrasonography provided a deeper cataract surgery. and wider field of view. The authors concluded that UBM Gentile et al. presented a case report of how IVCM was enabled the preoperative assessment of conjunctival tumors performed to determine the involvement of corneal incisions for intraocular invasion [11]. from previous refractive surgery [40]. The patient had a history of radial keratotomy (RK) and laser in situ keratomileusis 3. In Vivo Confocal Microscopy (LASIK), and she presented with biopsy proven limbal and conjunctival OSSN. IVCM showed that atypical cells had In vivo confocal microscopy (IVCM) is a noninvasive imaging extended just below the level of basement membrane and technique that allows in vivo microscopic examination of all Bowman layer along the scars of RK incisions. Because of layers of the ocular surface. In brief, it utilizes a point light these findings, the patient underwent surgical excision with source that scans the ocular surface and a point detector a lamellar keratectomy and cryotherapy, followed by topical to increase the resolution [34]. Using conjugate pinholes, chemotherapy a few weeks later. the point light source and the detector work in tandem to Larger case series by Alomar et al., Parrozzani et al., amplify the optical resolution, thus allowing the sectioning and Xu et al. also demonstrated correlation between IVCM of the ocular surface at the cellular level [34]. Duchateau and histopathology findings [12, 24, 25]. Alomar et al. et al. were the first to examine conjunctival intraepithelial studied 4 patients with corneal/conjunctival intraepithe- neoplasia using IVCM [35]. lial neoplasia (CCIN) and reported that, in these lesions, Several other reports in the literature have suggested bright prominent nucleoli produced a starry night sky pat- that IVCM may be helpful in establishing the diagnosis of tern [12]. These lesions also consisted of hyperreflective OSSN. Single case reports by Malandrini et al. and Wakuta pleomorphic cells, which resulted in a contrast between et al. described IVCM findings of enlarged, irregular cells the edge of the darker normal cells and the lesions with 4 Journal of Ophthalmology

(a) (b) (c)

Figure 3: In vivo confocal microscopy findings of a patient with corneal/conjunctival intraepithelial neoplasia (CCIN). (a) demonstrates multinucleated bizarre-shaped cells in the mid-epithelial layer. In (b), a starry-sky pattern (ill-defined borders with tiny bright spots 2 to 4 𝜇m in size within dark spaces) is seen in the basal cells. (c) demonstrates the fimbriated advancing border of CCIN at the mid-epithelial layer. There is higher reflectivity and cell density as well as pleomorphism in CCIN compared to the adjacent normal epithelium [12]. hyperreflective cells (Figure 3). Additionally, the authors 4. Anterior Segment Optical noted that subbasal corneal nerves were absent in areas Coherence Tomography of CCIN. Parrozzani et al. examined 10 cases of OSSN First introduced by Izatt et al. in 1994, anterior segment and reported that IVCM demonstrated dysplastic cells in optical coherence tomography (AS-OCT) is a noncontact and each case and morphologic agreement with ex vivo scraping noninvasive imaging technique that captures high resolution cytology and histology in 100% of cases [24]. Xu et al. cross-sectional images of the anterior segment [41]. In AS- examined five patients with OSSN and demonstrated high OCT, the Michelson interferometer is used to produce a concordance between the morphological features and extent reference beam of infrared light [42, 43]. The reference beam of invasion shown in IVCM and histopathologic analysis of light is then collected along with light reflected from [25]. thetissuesampletocreateaninterferencepattern.Multiple ThelargeststudythusfarontheutilityofIVCMin interference patterns are created over the surface of the differentiating OSSN from benign lesions was conducted by samplebeingimaged[42].Thedelayoftissuereflections Nguena et al. in Moshi, Tanzania [10]. The study recruited against the reference beam of light is compared to create a 60 cases and 60 age matched controls. IVCM was attempted series of axial scans (A-scans), which are then combined into on all participants, and final analysis of IVCM scans was acompositeimage[44]. performed on 44 cases (with both histopathology and ade- In the original time-domain OCT (TD-OCT), axial quatescans)and57controls.Ofthe44cases,18were resolution was limited at 18 𝜇m. In a study comparing TD- benign lesions and 26 were OSSN lesions as determined by OCT with UBM, Bianciotto reported that while TD-OCT histopathology. All scans were graded in a masked manner was useful for the assessment of superficial nonpigmented and were examined for hyperreflective cells, variation of lesions such as conjunctival tumors, UBM was in general cell size, mitotic cells, and starry night appearance of the superior for the visualization of all tumor margins and had basal layer. In each of these graded features, there was a fewer problems with posterior tumor shadowing [31]. UBM statistically significant difference between the normal con- provided superior overall image quality and tumor visual- trols and cases (benign and OSSN combined) but there ization, improved resolution of the posterior margin, and much better resolution of pigmented tumors, iris pigment was no difference between the benign and OSSN cases. epithelium cysts, and ciliary body lesions [31]. Therefore, this study showed that it was not possible to With the development of spectral domain OCT (SD- reliably differentiate benign from OSSN lesions because of OCT), higher resolution imaging has become available. High anoverlapinIVCMfeaturesinthevariousocularlesions resolution OCT (HR-OCT) is capable of providing axial [10]. resolution of 5–10 𝜇m, while ultra-high resolution OCT Other limitations of IVCM include its ability to provide (UHR-OCT) can provide axial resolution better than 5 𝜇m only en face images in contrast to cross-sectional images [42]. Vajzovic et al. demonstrated that a custom built UHR- obtained in tissue histology [12]. Additionally, it is difficult OCT with axial resolution of 2 𝜇mallowedthedelineation to obtain IVCM images and biopsy specimens from the of individual cornea layers [45]. The authors also reported exact same site where the tissue is being examined [10]. that UHR-OCT of an OSSN lesion showed epithelial thick- Moreover, because it provides images at a cellular level, IVCM ening and increased reflectivity of the epithelium with is unable to provide a comprehensive scan of the entire ocular an obvious delineation from tumor to nonaffected tissue surface. [45]. Journal of Ophthalmology 5

(a) (b)

Figure 4: High resolution anterior segment optical coherence tomography of a corneal intraepithelial neoplasia demonstrates (a) a sharp delineation between normal and abnormal epithelium and (b) a thickened and hyperreflective epithelium.

Several subsequent studies have further demonstrated 16 weeks, with the longest delay being approximately 29 weeks that thickened hyperreflective epithelium, abrupt transition [42]. The authors therefore suggested continuing treatment from normal to abnormal epithelium, and a sharp plane of for 16 weeks after clinical resolution of disease if UHR- cleavage between the lesion and underlying tissue (Figure 4) OCT was not available to monitor for presence of subclinical were all features that were both seen in UHR-OCT images disease. and histopathologic specimens of OSSN lesions [13, 26, Other scenarios where UHR-OCT can be useful include 27]. Shousha et al. examined a case series of 7 eyes with ruling out OSSN in the setting of complex ocular pathol- corneal/conjunctival intraepithelial neoplasia (CCIN) and ogy and in clinically indeterminate lesions. Thomas et al. found that UHR-OCT images taken before initiation of described a patient with a past medical history of HIV,vernal treatment were well correlated with histopathologic speci- keratoconjunctivitis, limbal stem cell deficiency (LSCD), and mens in the 4 cases that underwent incisional biopsies [13]. previously treated OSSN who presented with a change in Another study by Shousha et al. of 54 eyes with biopsy proven appearance in the limbal conjunctiva [42]. UHR-OCT imag- ocularsurfacelesions,ofwhich19wereOSSNlesions,also ing revealed epithelial thickening and hyperreflectivity. After confirmed these observations [27]. the patient completed treatment, UHR-OCT was also used to Kieval et al. compared UHR-OCT of pterygia with OSSN confirm resolution. UHR-OCT has also been used to show [26].Pterygiahavenormalthinconjunctivalepitheliumwith foci of OSSN in pterygia, Salzmann’s nodular degeneration, underlying subepithelial hyperreflective tissue. Using UHR- HSV keratopathy, and atypical peripheral corneal infiltrates OCT at a resolution of 2 𝜇m, Kieval et al. showed that an when the clinical diagnosis was unclear [42]. epithelial thickness value greater than 140 𝜇mprovided94% Additional advantages of OCT over other forms of sensitivity and 100% specificity for differentiating CCIN from anterior segment imaging include its noncontact method pterygia [26]. In contrast, using HR-OCT with a resolution of of obtaining images, patients being imaged sitting in an 5–7 𝜇m, Nanji et al. demonstrated that an epithelial thickness upright and comfortable position, and user friendliness for cutoff at greater than 120 𝜇m provided 100% sensitivity and theoperator[31].However,duetothecostofthemachine, specificity for differentiating OSSN from pterygia [28]. In high resolution OCT may not be readily available in resource fact, normal epithelium overlying subepithelial lesion con- poor settings, thus limiting its widespread use. fidently rules out OSSN [27]. UHR-OCT can also be used to diagnose pigmented CCIN, as demonstrated in the study 5. Conclusion by Shousha et al., where UHR-OCT demonstrated thickened andhyperreflectiveepitheliuminapigmentedconjunctival There are several adjunctive diagnostic modalities available lesion that had been referred for conjunctival melanoma. that can assist in the diagnosis and monitoring of OSSN Histopathology confirmed the diagnosis of pigmented CCIN lesions. These include IC, vital dye staining, ultrasound [27]. biomicroscopy, IVCM, and AS-OCT. A summary of main UHR-OCT can also be used to monitor disease resolution findings from major studies on these diagnostic modali- and detect residual subclinical disease. For lesions treated ties is presented in Table 1 and a summary of advantages successfully with topical agents, posttreatment UHR-OCT and disadvantages of each diagnostic modality is shown in showed normalization of epithelial architecture at the site Table 2. of the treated lesions. However, in lesions resistant to med- Given the limitations of IC and vital dye staining, there ical treatment, UHR-OCT will show persistently thickened has been a shift in interest to anterior segment imaging epithelium with retained abrupt transition between normal modalities such as UBM, IVCM, and AS-OCT. As discussed and diseased epithelium [13, 42]. Continuation of topical in this review, anterior segment imaging can provide the treatment in patients with residual subclinical disease in clinician with microscopic lesion detail to make an accurate the study by Shousha et al. resulted in complete resolution diagnosis but is equally as important to guide therapeutic of the otherwise subclinical lesion [13]. Therefore, UHR- decisions. Each device has its limitations, but when combined OCT prevented what could have been premature cessation with clinical examination, anterior segment imaging can oftopicaltreatment,whichcouldhaveincreasedtherisk greatly aid the clinician. Nevertheless, it is important to of recurrent disease. Thomas et al. reported that, in their note that none of these imaging modalities has replaced early experience of these cases, there was a median delay histopathology’s role as the gold standard for diagnosing between clinical and UHR-OCT resolution of approximately OSSN. More research over time and advances in technology 6 Journal of Ophthalmology NPV 94%). 4.25, sensitivity was 95%, specificity was 93%, ≥ There were no false positives. There were no false positives. was invasive by histopathology. cases, and not correlated in 8% of cases. to diagnose disease affecting deeper tissue. IC is less sensitive for keratotic lesions and invasive disease. hyperkeratosis (55%), (2) syncytial-like groupings (35%), and (3) Compared with histologic findings, IC had a high positive predictive reports in the moderate dysplasia to microinvasive carcinoma group. nonkeratinized dysplastic (10%) cells. Meanwhile, invasive cases had a with histological findings was accurate in 80% of cases, poor 12% of in With an index score of preinvasive lesions (one AK lesion and one CCIN lesion), IC sampling PPV was 95%, and NPV was 93% for predicting SCC. However, in two tendency to be more highly keratinized and to have a greater degree of The cytomorphology of OSSN is described in detail.For intraepithelial diagnosing OSSN was 78% overall but was lower (70%) when the lesion was not sufficiently deepreach to atypical cells and presents a limitation Cytological features related to malignancy were applied to determine an inflammation than the keratinized high grade intraepithelial cases it but IC can be used to demonstrate the morphology of normal and abnormal conjunctival cells. Cytology report was positive in 77% of histopathology making it a good screening tool but inadequate gold standard. Moreover, IC is accurate in predicting the diagnosis of OSSN. Correlation rate of IC IC showed high agreement with histopathology in detecting unsuspected index score that best differentiatesinvasive SCC from preinvasive lesions. value (PPV) of 97.4% and a fair negative predictive value (NPV) of 52.9%, was not possible to confidently predict invasion on IC. Sensitivity of IC in OSSN in pterygia patients (sensitivity 92%, specificity 94%, PPV 92%, and lesions, these include (1) keratinized dysplastic cells often accompanied by gnostic modalities in ocular surface squamous neoplasia (OSSN). (2) (a) in situ SCC (20) Impression cytology (IC) Pterygium (1) No OSSN (21) neoplasia (142) Carcinoma neoplasia (CCIN) (9) Intraepithelial OSSN or Actinic keratosis (AK) (9) Keratinizing dysplasia (15) Invasive OSSN or SCC (23) and malignant melanoma (1) Nonkeratinizing dysplasia (7) Pterygia without atypical cells (19) (20), squamous papilloma (4), and Pterygia with associated OSSN (13) corneal/conjunctival intraepithelial Squamous cell carcinoma (SCC) (1) Corneal/conjunctival intraepithelial Invasive squamous cell carcinoma (6) OSSN (50) including SCC (20), dysplasia nondysplastic changes of the epithelia (6) Pigmented lesions (5) including nevus (4) Conjunctival intraepithelial neoplasia (49) series case series Transverse, Transverse, prospective, Study design Number of eyes Main findings observational observational observational Retrospective Retrospective Observational Prospective case Year 2014 2001 2001 1994 2008 2009 Table 1: Summary of main findings frommajor studies adjunctive of dia Brazil Brazil Thailand Australia Australia Australia Nolan et al. [14] Tole et al. [15] Nolan et al. [16] Tananuvat et al. [17] de Nadai Barros et al. [18] de Nadai Barros et al. [19] Study Location Journal of Ophthalmology 7 extension. NPV 100%). 60%, and NPV 95%). 31%, PPV 41%, and NPV 88%). Toluidine blue 1% is a good tool for the diagnosis of OSSN and 20 and/or 50 MHz high frequency ultrasound helps delineate tumor Methylene blue 1% can exclude malignant lesions but cannot replace determining if the tumor has extended into the sclera, eye, and orbit. thickness, shape, and internal reflectivity and is particularly helpful in deep invasion. It is of otherwise limited utility in tumors without deep 20 MHz high frequency ultrasound demonstrates deep involvement of Toluidine blue 0.05% is a good screening tool but not a good diagnostic tumorintothesclera,globe,ororbitandisausefultoolfortumorswith premalignant lesions but the intensity of staining does not correlate with tool due to a high frequency of false positives (sensitivity 92%, specificity histopathology as the gold standard (sensitivity 97%, specificity 50%, PPV the degree of malignancy (sensitivity 100%, specificity 50%, PPV 73%, and (c) (b) Vital dye staining SCC (4) SCC (11) OSSN (143) Ultrasound biomicroscopy Pterygia (10) Non-OSSN (276) Actinic keratosis (10) conjunctival SCC (27) (16) and severe dysplasia (17) Benign or premalignant lesions (42) Malignant lesions including invasive SCC Conjunctival intraepithelial neoplasia and Conjunctival intraepithelial neoplasia and series series validation case series diagnostic multicenter Prospective Study design Number of eyes Major findings Study design Number of eyes Major findings Retrospective Cross-sectional, Prospective case Prospective case Year Year 2013 2015 2014 2003 2002 Brazil Kenya South Africa United States United States Romero et al. [20] Steffen et al. [21] Gichuhi et al. [22] Char et al. [23] Finger et al. [11] Study Location Study Location 8 Journal of Ophthalmology and in situ borders. similar to histopathologic findings. cytomorphologic findings included cellular anisocytosis, distinguishing OSSN from benign conjunctival lesions. In vivo This study defined featuresIVCM CCIN, of which included (1) IVCM was able to reliably distinguish normal conjunctiva from perpendicular to the tumor surface. Marginal findings included included large areas of superficial cell debris and/or keratin debris OSSN from benign conjunctival lesions due to an overlap in IVCM subepithelial (pre-Bowman) space involvement in 4 cases, irregular IVCM findings of OSSN lesions were described. Structural findings actively mitotic dysmorphic epithelial cells in carcinoma findings were found to be highly correlated with histologic features. nests were partially formed by isolated keratinized, binucleated, and ocular surface squamous carcinoma. TheIVCM characteristicswere pleocytosis, and anisonucleosis, enlarged nuclei with high nuclear to the conjunctival epithelium and/or the corneal basal epithelium layer, cases. prominent nucleoli, and (4) absence of subbasal corneal nerves within features between the two conditions (kappa = 0.44, 95% CI 0.32–0.57). of hyperreflective CCIN lesion contrasting with darker the and smaller healthy tissue infiltration atthe lateral edge the of lesion incases,2 and cytoplasmic ratio, high reflective cytoplasm, and indistinct cytoplasmic areas involved by CCIN compared to nonaffected regions. These IVCM IVCM demonstrated cellular anisocytosis and enlarged nuclei with high IVCM has a low sensitivity (38.5%) and moderate specificity (66.7%) for conjunctival lesions. However, IVCM was unable to reliably differentiate accompanied by syncytial-like groupings, loss of the normal structure of abrupt demarcation between neoplastic cells and normal epithelium in 8 normal cells, (3) “starry night sky” pattern of the basal layer produced by hyperreflective pleomorphic cells varying of shapes and sizes, (2) edge the papillomatous organization, large fibrovascular structures, and fine vessels nuclear to cytoplasmic ratio in conjunctival intraepithelial neoplasia while (1) (d) in situ confocal microscopy (IVCM) OSSN (26) neoplasia (8) proliferation) conjunctiva (57) Carcinoma neoplasia (CCIN) (4) In vivo with diffuse keratoconjunctival Benign conjunctival lesions (18) Control (4; 2 with limbal stem cell Corneoconjunctival intraepithelial Age matched controls with normal Corneal/conjunctival intraepithelial Ocular surface squamous carcinoma (1) Conjunctival intraepithelial neoplasia (3) Conjunctival intraepithelial neoplasia (2) deficiency, 1 with suspicious limbal lesion, 1 series case series case series Study design Number of eyes Major findings Case-control Retrospective Observational Prospective case 2011 2011 Year 2012 2014 Italy Italy China United Tanzania Kingdom and Parrozzani et al. [24] Alomar et al. [12] Xu et al. [25] Nguena et al. [10] Study Location Journal of Ophthalmology 9 m) was significantly higherthan 𝜇 ). UHR-OCT had a high sensitivity (94%) 𝑝 < 0.001 residual lesions on UHR-OCT. m) ( 𝜇 epithelial thickening and hyperreflectivity. subepithelial layer was uninvolved in OSSN. Ultra-high resolution (UHR) OCT demonstrated a thickened and specificity (100%) for differentiating OSSN from pterygia. hyperreflectiveepithelium may obscure inferior the border. The hyperreflective epithelium and abrupt transition from normal to UHR-OCT findings of OSSN and pterygia were correlated well to normal and affectedepithelium. large In lesions,shadow a the from abrupt transition from normal to neoplastic tissue. Meanwhile, both lesions based on optical signs. Specifically OSSN,in HR-OCT shows of OSSN demonstrated a thickened layer of epithelium, oftenwith an invisible. Continuation of treatment resulted in complete resolution of examined ocular lesions. Specifically for OSSN, the epithelial layer was on UHR-OCT while 3 cases showed residual disease that was clinically clinical resolution, 4 cases demonstrated normal epithelial configuration diagnostic modalities for pterygia showed a normal thin epithelium with severely thickened and hyperreflective with anabrupt transition between histopathologic findings. Both UHR-OCT and histopathologic specimens Commercially available HR-OCT is also capable of differentiating various thickness on UHR-OCT for OSSN (346 for pterygia (101 hyperreflectiveepithelium in all CCIN cases. After treatment medical and underlying thickening of the subepithelial mucosal layers. Mean epithelial UHR-OCT and histopathologic findings were closely correlated for all the (e) Nevi (2) OSSN (21) OSSN (19) Pterygia (7) Normal (10) Pterygia (11) Pterygia (17) Lymphoma (3) Histiocytosis (1) neoplasia (CCIN) (7) Amelanotic melanoma (5) Pterygia or pinguecula (24) Conjunctival lymphoma (6) Conjunctival amyloidosis (2) Primary acquired melanosis (8) Pigmentedconjunctivallesions(18) Salzmann nodular degeneration (6) Corneal/conjunctival intraepithelial Ocular surface squamous neoplasia (17) Anterior segment optical coherence tomography (AS-OCT) series series series series Study design Number of eyes Major findings Prospective case Prospective case Prospective case Prospective case 2011 Year 2013 2015 2012 United States United States United States United States Shousha et al. [13] Kieval et al. [26] Shousha et al. [27] Nanji et al. [28] Study Location 10 Journal of Ophthalmology

Table 2: Summary of advantages and disadvantages of adjunctive diagnostic modalities in OSSN.

Imaging modality Advantages Disadvantages (1) Inexpensive (1) Assesses only superficial cells and is unable to Impression cytology (2) Easy to perform sample deep lesions or invasive disease (3) Good correlation with histopathology (2) Requires skilled professional to interpret results (1) Inexpensive (2) Easy to use (1) Low to moderate specificity so a large number of Vital dye staining (3) High sensitivity compared to histopathology benign lesions would also test positive making it a good screening tool (1) Lower resolution images compared to OCT (1)Goodwidthanddepthofpenetrationallowing (2) Requires skilled technician or provider to Ultrasound the detection of invasive disease and metastasis perform imaging biomicroscopy (2) Can be used for pigmented and thick lesions (3) Need for eyebath and reclined position (4) Limited utility in noninvasive disease (1) Requires skilled technician or provider to performtestandinterpretresults (2) Unable to obtain cross-sectional images and thus may miss deep disease (1) Allows microscopic and cellular examination of (3) Cannot obtain comprehensive scan of entire In vivo confocal lesion ocular surface microscopy (IVCM) (2) Images are en face (4) Difficult to obtain IVCM and pathology specimens from the same site (5) Overlap in features with benign ocular surface lesions limiting its use in differentiating OSSN from benign lesions (1) High resolution images (2) Easy to use, noncontact (3) High specificity and sensitivity for (1) Limitation in width and depth of penetration, differentiating OSSN from pterygia High resolution anterior especially in commercial models (4) HR-OCT morphologic features of OSSN are segment optical (2) Shadowing in pigmented lesions and thick well defined, allowing the differentiation of OSSN coherence tomography lesions, therefore limiting the ability to determine from benign and other malignant ocular lesions the posterior limit of lesions (5) Ability to image the same site as before and therefore can be used to monitor disease resolution after treatment will likely provide us with further improved imaging modali- [6] Y. A. Yousef and P. T. Finger, “Squamous carcinoma and ties, but to date these devices warrant integration into clinical dysplasia of the conjunctiva and cornea: an analysis of 101 cases,” practice. Ophthalmology,vol.119,no.2,pp.233–240,2012. [7]S.Gichuhi,M.S.Sagoo,H.A.Weiss,andM.J.Burton, Competing Interests “Epidemiology of ocular surface squamous neoplasia in Africa,” Tropical Medicine and International Health,vol.18,no.12,pp. The authors declare that they have no competing interests. 1424–1443, 2013. [8]H.Carreira,F.Coutinho,C.Carrilho,andN.Lunet,“HIV and HPV infections and ocular surface squamous neoplasia: References systematic review and meta-analysis,” British Journal of Cancer, [1]H.E.Grossniklaus,W.R.Green,M.Luckenbach,andC. vol. 109, no. 7, pp. 1981–1988, 2013. C. Chan, “Conjunctival lesions in adults. A clinical and [9] L. D. Pizzarello and F. A. Jakobiec, “Bowen’s disease of the histopathologic review,” Cornea,vol.6,no.2,pp.78–116,1987. conjunctiva: a misnomer,” in Ocular and Adnexal Tumors,F.A. [2] G. A. Lee and L. W.Hirst, “Ocular surface squamous neoplasia,” Jakobiec, Ed., vol. 18, Aesculapius, Birmingham, Ala, USA, 1978. Survey of Ophthalmology,vol.39,no.6,pp.429–450,1995. [10]M.B.Nguena,J.G.VanDenTweel,W.Makupaetal., [3] C. W.Spraul and H. E. Grossniklaus, “Tumors of the cornea and “Diagnosing ocular surface squamous neoplasia in east africa: conjunctiva,” Current Opinion in Ophthalmology,vol.7,no.4, case-control study of clinical and in vivo confocal microscopy pp.28–34,1996. assessment,” Ophthalmology,vol.121,no.2,pp.484–491,2014. [4] J. C. Erie, R. J. Campbell, and T. J. Liesegang, “Conjunctival and [11] P. T. Finger, H. V. Tran, R. E. Turbin et al., “High-frequency corneal intraepithelial and invasive neoplasia,” Ophthalmology, ultrasonographic evaluation of conjunctival intraepithelial neo- vol.93,no.2,pp.176–183,1986. plasia and squamous cell carcinoma,” Archives of Ophthalmol- [5] R. Hamam, P. Bhat, and C. S. Foster, “Conjunctival/corneal ogy,vol.121,no.2,pp.168–172,2003. intraepithelial neoplasia,” International Ophthalmology Clinics, [12] T. S. Alomar, M. Nubile, J. Lowe, and H. S. Dua, “Corneal vol.49,no.1,pp.63–70,2009. intraepithelial neoplasia: in vivo confocal microscopic study Journal of Ophthalmology 11

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Clinical Study Assessment of Anterior Segment Measurements with Swept Source Optical Coherence Tomography before and after Ab Interno Trabeculotomy (Trabectome) Surgery

Handan Akil,1 Ping Huang,1 Vikas Chopra,1,2 and Brian Francis1,2

1 Doheny Eye Institute, Doheny Image Reading Center, Los Angeles, CA, USA 2Department of Ophthalmology, David Geffen School of Medicine, Los Angeles, CA, USA

Correspondence should be addressed to Handan Akil; [email protected]

Received 17 June 2016; Accepted 1 September 2016

Academic Editor: Yu-Chi Liu

Copyright © 2016 Handan Akil et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. To compare the changes of anterior segment parameters, assessed by swept source anterior segment optical coherence tomography (AS-OCT) after combined Trabectome-cataract surgery and Trabectome-only surgery in open angle glaucoma patients. Methods. Thirty-eight eyes of 24 patients with open angle glaucoma were scanned with swept source AS-OCT before and 4 weeks after combined Trabectome-cataract or Trabectome-only surgery. Intraocular pressure, number of medications, and AS-OCT parameters, such as angle opening distance at 500 and 750 𝜇mfromthescleralspur(AOD500andAOD750),trabecular- 2 2 iris space area at 500 and 750 mm (TISA500, TISA750), angle recess area at 500 and 750 mm (ARA500, ARA750), trabecular iris angle (TIA), anterior chamber depth (ACD), anterior chamber width (ACW), and anterior chamber volume (ACV), were obtained before the surgery. These parameters were compared to evaluate whether the outcome of the surgery differed among the patients after the surgery. The width of the trabecular cleft was also measured for both groups. Results. The reduction of IOP and number of medications was found to be statistically significant in both groups (𝑝 < 0.001). ACD, ACV, and angle parameters such as AOD 500/750, TISA 500/750, ARA 500/750, and TIA500 showed significantly greater changes from the preoperative values to postoperative 1st month values in combined Trabectome-cataract surgery group (𝑝 < 0.05), whereas Trabectome-only group did not show statistically significant difference (𝑝 > 0.05). There was no statistically significant difference between two groups forthe width of the trabecular cleft (𝑝 = 0.7). Conclusion. Anterior chamber angle parameters measured with swept source AS-OCT may be useful for evaluating glaucoma patients before and after Trabectome surgery with or without cataract surgery.

1. Introduction external filtration bleb, as it enhances the traditional trabecular outflow pathway [3]. It has been previously reported that Glaucoma is one of the leading causes for irreversible blind- trabeculotomy by internal approach (Trabectome: NeoMedix ness worldwide [1]. To date, lowering the intraocular pressure Corporation, Tustin, CA, USA) surgery performed with or (IOP) has been known to be the only proven therapy to without cataract surgery can lower intraocular pressure and slow the progression of optic nerve damage. Classic glaucoma dependence on glaucoma medications while maintaining an filtration surgery by means of trabeculectomy or glaucoma excellent safety profile [3, 4]. The surgical procedure involves aqueous shunt implants is the most effective way of lowering the selective removal of the inner wall of Schlemm’s canal and intraocular pressure in the long term. Although both sur- the juxtacanalicular trabecular meshwork, which is theorized gical procedures are well established, potentially dangerous tobethesourceofthemostresistancetoaqueoushumor intraoperative and postoperative complications are known to outflow [5]. Ablation of these areas using the Trabectome occur [2]. This has led to the development of the concept without damaging the collector channels facilitates aqueous of minimally invasive glaucoma surgery (MIGS). This sur- outflow and reduces IOP. This surgical method can be gicalapproachdoesnotaltertheconjunctivaorinvolvean performed through a clear corneal incision, and the primary 2 Journal of Ophthalmology sites of abnormal flow resistance can be removed without The same surgeon (BF) performed trabeculotomy using damaging the conjunctiva [4]. Trabectome first and then phacoemulsification, if indicated, Optical coherence tomography (OCT) has become an according to the surgical technique as described in previous essential tool in ophthalmic imaging, which provides objec- studies [3, 5]. tive documentation of the angle [6, 7], as opposed to the All eyes were imaged without dilation (nonmydriasis) in subjective evaluation using gonioscopy. OCT technology has the room light (light intensity, 368 lux) by a trained glaucoma been improved from time-domain to spectral-domain sys- research fellow (HA) using the “3D-angle high definition tems, with enhanced image acquisition speed and resolution (HD)” protocol, which was composed of a volumetric scan [8]. Spectral-domain systems yield A-scan rates from 20 kHz (dimension, 8 mm × 4 mm and 64 B scans) and this allowed [9] to 400 kHz (swept source) [10] and are capable of 3- 360-degree imaging of the whole anterior segment in 2.4 dimensional imaging of biological structures. There are only a seconds. The seated subject fixated at an internal fixation few commercially available spectral-domain OCT (SD-OCT) target during the imaging. To avoid lid artifact, participants devices that are able to image the anterior segment. Swept wereinstructedtopulldownthelowerlidagainstthelower source AS-OCT (SS-OCT, CASIA SS-1000, Tomey Corpora- orbital rim to expose the lower limbus while the imager tion, Nagoya, Japan) is a variation of spectral-domain OCT elevated the upper lid against the upper orbital rim to that is specifically designed for anterior segment imaging expose the upper limbus. All images obtained were free using 1,310 nm wave width with a scan speed of 30,000 A- from lid artifacts. A total of 128 cross-sectional images of scans per second and an axial resolution of less than 10 𝜇m. the anterior chamber were collected. The semiautomated In the high-definition scan mode, both scleral spur (SS) and software of the CASIA can be used to measure the anterior Schwalbe’s line (SL) can be identified [11–13]. chamber angle parameters. For the quantitative assessment Therefore, because of the ability of SS-OCT to accurately of the anterior segment parameters, prior identification of a and reproducibly characterize anterior chamber structures, landmark, scleral spur (SS), is necessary. The SS is identified the aim of this prospective study was to evaluate the changes asthepointwherethereisachangeincurvatureofthe of the anterior chamber parameters before and after com- corneoscleral interface in two-dimension analysis of software bined Trabectome-cataract and Trabectome-only surgery on the chosen horizontal frame. After the scleral spur and using swept source AS-OCT. trabecular cleft were identified manually on nasal sample slices, the customized analytic software exported the values of anterior chamber parameters of that slice. 2. Methods The anterior chamber parameters given automatically This prospective comparison study was approved by the bysweptsourceAS-OCT,angleopeningdistanceat500– local ethics committee and followed the regulations of the 750 mm (AOD 500/750), trabecular-iris space area at 500– Declaration of Helsinki. After written informed consent, a 750 mm (TISA 500/750), angle recess area at 500–750 mm totalof38eyesof24patients(18eyesinTrabectome-only (ARA500/750), trabecular iris angle (TIA 500/750) at surgical surgery group, 20 eyes in combined Trabectome-cataract quadrants, anterior chamber volume (ACV), anterior cham- surgery group) with primary open angle glaucoma (POAG) ber width (ACW: from spur to spur), and trabecular cleft were included in the study in a consecutive manner from width, were incorporated for analysis [14–17]. August 2015 to February 2016 at the Doheny Eye Institute, Images were analyzed with the Angle Assessment Pro- UCLA. gram (CASIA software). After the scleral spurs are identified, All subjects underwent comprehensive ophthalmic exam- the software calculates various parameters of the iris, cornea, inations, including measurement of the best-corrected visual and lens using automated identification of the anterior and acuity, Goldmann applanation tonometry, slit-lamp biomi- posterior surfaces of the cornea, iris, and the anterior surface croscopy,gonioscopy,dilatedfundusexamination,OCT,and of the lens. We were also able to measure the width of the standard automated perimetry, using the Humphrey Visual trabecular cleft with the same software in manual mode. Field Analyzer (Carl Zeiss, Inc., Dublin, CA, USA) and Good quality images of the angle area provided assessment integrated 24-2 Swedish Interactive Threshold Algorithm ofthesurgicalsiteandotheranteriorchamberparameters (SITA) software program. (Figure 1). Ten eyes underwent scanning two times for image Primary open angle glaucoma was defined as the presence acquisition reproducibility analysis. All images were analyzed of glaucomatous optic nerve damage (localized or diffuse by 2 research fellows (HA and PH) for intra- and intergrader neuroretinal rim thinning and/or retinal nerve fiber layer repeatability analysis. Intraclass correlation coefficient (ICC) defect) and an associated visual field defect, with an open was calculated for all the repeatability. angleconfirmedongonioscopyintheabsenceofother known causes of glaucomatous disease. Mean Cup/Disk ratio 3. Statistical Analysis was 0.7 ± 0.2, visual field mean deviation (MD) was −5.6 ± 4.9 dB, and visual field pattern standard deviation (PSD) was Statistical analysis was performed using SPSS software ver- 4.3 ± 4.7 dB. sion 18 (SPSS, Inc., Chicago, IL, USA). The mean and SD were Swept source AS-OCT (SS-1000 CASIA; Tomey Co. Ltd. calculated for the anterior segment variables. Continuous Nagoya, Japan) was performed before and 1 month after com- variables were analyzed using Wilcoxon signed rank test. The bined Trabectome-cataract and Trabectome-only surgery. anterior segment parameters were compared before and after Journal of Ophthalmology 3

parameters (𝑝 > 0.05). ACD, ACV, and all the angle parameters such as AOD 500/750, TISA 500/750, ARA 500/750, and TIA500 of the combined Trabectome-cataract surgery group were significantly different from the preoperative values (𝑝 < 0.05). ACD and TIA500 values showed significantly greater changes from the preoperative values to postoperative 1st month values in combined Trabectome-cataract surgery AOD750 group compared to the Trabectome-only group (𝑝 < 0.001), AOD500 whereastheACWvaluewasnotsignificantlydifferent.The mean differences of ACW, ACD, and ACV were 0.24 ± 0.2, Trabecular cleft 0.5 ± 0.11,and26.65 ± 8.8,respectively(𝑝 = 0.25, 𝑝< 0.001,and𝑝 = 0.05) in the combined Trabectome-cataract surgery group (Table 1) and 0.26 ± 0.12, 0.12 ± 0.05,and SS 2.26 ± 1.8 (𝑝 = 0.2, 𝑝 = 0.11,and𝑝=0.8)inTrabectome- TIA TISA750 TISA500 only group (Table 2). The width of the trabecular cleft was0. 358 ± 0.13 mm in the combined Trabectome-cataract group and was 0. 342±0.1 mm in the Trabectome-only group. There Figure 1: A cross-sectional OCT image of the nasal angle showing was no statistically significant difference between two groups the anterior chamber angle parameters of a patient in combined forthewidthofthetrabecularcleft(𝑝 = 0.7). ICC values for Trabectome group postoperatively. intragrader reproducibility, intergrader reproducibility, and repeatability measures were found excellent (Table 3). the surgery. For comparison between the 2 groups, repeated 5. Discussion measure ANOVA was used. A 𝑝 value less than 0.005 was considered statistically significant. Ab interno trabeculectomy using the Trabectome is a relatively new option for reducing the IOP and the number of glaucoma medications in selected patients with primary 4. Results andsecondaryopenangleglaucoma[5].Thepresentstudy showed that there is a statistically significant decrease in the The mean age was 76.32 ± 9.9 years in the combined IOP and number of medications after both stand-alone and Trabectome-cataract surgery group (men: 11 eyes, women: combined surgeries comparable to previous studies [3, 5, 6]. 9eyes)and72.5 ± 7 years in the Trabectome-only group Surgical intervention is an important aspect of glaucoma (men: 8 eyes, women: 10 eyes). There were no significant management. Pre- and postoperative angle imaging are intraoperative or postoperative complications. Mean age did useful for documenting and evaluating surgery outcomes. not differ significantly between the groups (𝑝 > 0.05). Gonioscopy as a traditional method is used in the visual- The interobserver agreement for assessment of visibility ization of anterior chamber angle; however, it is a contact of the angle structures of two groups was high with agreement method and has certain limitations such as high interobserver coefficients ranging between 0.82 and 0.987. variability and difficulty in quantification of the angle [7– For the Trabectome-only group, the mean preoperative 10]. AS-OCT can be used for noncontact measurement even IOP of 24.2 ± 4.7 mm Hg was reduced by 40% to 14.6 ± immediately following surgery without the risk of infection 3.2 mm Hg at the 1st month. For combined Trabectome- or wound dehiscence. Thus, early postoperative analysis is cataract group, the mean preoperative IOP of 25.3 ± possible by measuring data starting on the day after surgery. 6.4 mm Hg was reduced by 44% to 14.2 ± 2.8 mm Hg at the In the present study, there were no cases in which identifying 1st month. the SS was difficult (Figure 1). In addition, we were able to Medications decreased from 2.6 ± 1.2 to 1.7 ± 1.2 with a evaluate the trabecular cleft and measure the width easily 32% reduction in combined Trabectome-cataract group and after both of the surgeries. from 2.9±1.2 to 2.1±1.5 witha28%reductioninTrabectome- An advantage of using swept source AS-OCT for postop- only group. erative assessment is its short scan time. Less than 3 seconds There is statistically significant decrease of IOP and is required to image the angle morphology in high resolution number of medications in both groups after the surgery (𝑝< circumferentially in 360 degrees (Figure 2). Another advan- 0.001). But no statistically significant difference was found tage of swept source AS-OCT imaging is its ability to discern between the two groups in amount of IOP reduction and the patency of trabecular cleft, which sometimes is difficult to number of medications (𝑝 > 0.05). be visualized with gonioscopy. There was no significant difference for the preoperative The swept source AS-OCT device is useful for detailed baseline anterior segment anatomy values of both groups angle evaluation and the imaging procedure is convenient, (𝑝 > 0.05). Trabectome-only group did not show a statis- imposing fewer difficulties on the patients, and can be tically significant difference between preoperative and post- performed in a shorter time [18]. However, although the operative measurements of anterior chamber angle (ACA) interobserver variability is small [19], identifying the scleral 4 Journal of Ophthalmology

Table 1: Comparison of the angle measurements with swept source OCT before and after Trabectome-only surgery.

∗ Variables Preoperative Postoperative Mean difference 𝑝 value AOD 500 [mm] 0.51 ± 0.34 0.62 ± 0.289 0.11 ± 0.1 0.3 AOD 750 [mm] 0.68 ± 0.37 0.7 ± 0.23 0.02 ± 0.01 0.8 2 TISA 500 [mm ] 0.186 ± 0.04 0.21 ± 0.03 0.02 ± 0.05 0.09 2 TISA 750 [mm ] 0.334 ± 0.2 0.332 ± 0.15 −0.002 ± 0.11 0.9 ∘ TIA 500 [ ]45.6± 2.27 46.12 ± 3.16 1.06 ± 0.32 0.6 2 ARA 500 [mm ] 0.26 ± 0.02 0.28 ± 0.04 0.02 ± 0.003 0.06 2 ARA 750 [mm ] 0.44 ± 0.15 0.48 ± 0.2 0.04 ± 0.05 0.5 ACW [mm] 11.95 ± 0.63 12.21 ± 0.51 0.26 ± 0.12 0.2 ACD [mm] 2.96 ± 0.26 3.08 ± 0.16 0.12 ± 0.05 0.11 3 ACV [mm ] 168.64 ± 45.63 170.9 ± 15.68 2.26 ± 1.8 0.8 Mean ± standard deviation. ∗ Wilcoxon signed rank test, 𝑝 < 0.005 statistically significant.

Table 2: Comparison of the angle measurements with swept source OCT before and after combined Trabectome-cataract surgery.

∗ Variables Preoperative Postoperative Mean difference 𝑝 value AOD 500 [mm] 0.504 ± 0.254 0.71 ± 0.26 0.21 ± 0.12 0.015 AOD 750 [mm] 0.72 ± 0.263 0.88 ± 0.24 0.16 ± 0.02 0.05 2 TISA 500 [mm ] 0.196 ± 0.112 0.296 ± 0.143 0.09 ± 0.03 0.03 2 TISA 750 [mm ] 0.349 ± 0.17 0.478 ± 0.22 0.13 ± 0.06 0.04 ∘ TIA 500 [ ]43.4± 4.65 51.2 ± 5.32 7.8 ± 1.58 <0.001 2 ARA 500 [mm ] 0.2 ± 0.1 0.29 ± 0.15 0.09 ± 0.04 0.03 2 ARA 750 [mm ] 0.43 ± 0.25 0.58 ± 0.24 0.15 ± 0.07 0.04 ACW [mm] 11.73 ± 0.58 11.97 ± 0.72 0.24 ± 0.2 0.25 ACD [mm] 3.1 ± 0.38 3.62 ± 0.31 0.5 ± 0.11 <0.001 3 ACV [mm ]159.634± 36.77 186.29 ± 14.3 26.65 ± 8.8 0.005 Mean ± standard deviation. ∗ Wilcoxon signed rank test, 𝑝 < 0.005 statistically significant.

Table 3: Intraobserver and interobserver reproducibility and repeatability measurement of angle parameters with the swept source OCT.

Intergrader ICC (95% CI) Intragrader ICC (95% CI) Repeatability ICC (95% CI) SS-AOD 500 0.927 (0.896–0.949) 0.958 (0.930–0.975) 0.977 (0.966–0.984) SS-AOD 750 0.936 (0.909–0.956) 0.931 (0.885–0.959) 0.970 (0.957–0.979) SS-TISA 500 0.915 (0.875–0.933) 0.912 (0.856–0.947) 0.964 (0.948–0.975) SS-TISA 750 0.869 (0.833–0.945) 0.843 (0.749–0.904) 0.957 (0.938–0.970) Trabecular cleft width 0.960 (0.938–0.975) 0.940 (0.920–0.950) 0.946 (0.940–0.960) SS: scleral spur, AOD: angle opening distance, TISA: trabecular-iris space area, ICC: intraclass correlation coefficient, and CI: confidence interval. spur (SS) can be difficult with other spectral-domain OCT showed statistically significant increases in AOD, TISA, TIA, devices. ACD, and ACV measurements. The angle parameters of the Many studies have shown that distance-based measure- Trabectome-only group did not increase to the same extent ments made 500 𝜇m and/or 750 𝜇mfromthescleralspur as the angle parameters in combined Trabectome-cataract are clinically valid for the evaluation of the ACAs [20–22]. group. AOD 500 measurement might be affected by the cleft These distance-based parameters, such as AOD, are usually depth and therefore ARA and TISA metrics may be clinically based on the assumption that the iris surface conforms to a more reliable for postoperative evaluation. Additionally, the straight line, but irregularity of iris contour and curvature current study suggests that combined Trabectome-cataract are commonplace. To overcome this limitation, researchers surgery affects the angle parameters more with lens extrac- have devised alternative area-related parameters, such as tion by means of increasing the space between the iris and angle recess area (ARA) and TISA. Both parameters have cornea (Figures 3 and 4). shown good discrimination between open and narrow ACAs Liu et al. showed that swept source AS-OCT provides when compared to grading using gonioscopy [20–22]. Our reproducible measurement of AOD, TISA, and TIA at dif- patients who had combined Trabectome-cataract surgery ferent meridians, suggesting that it is useful for measuring Journal of Ophthalmology 5

Figure 2: A nasal quadrant screenshot of the video gonioscopy of the post-Trabectome patient which gives information about the trabecular cleft of the angle morphology in high resolution circumferentially in 360 degrees. Red arrows show the Trabectome surgical site. Figure 4: A cross-sectional OCT image of the nasal angle following Trabectome-only surgery. This frame-averaged image shows that the posterior trabecular meshwork has been removed.

significance of comparing the changes of anterior angle parameters after Trabectome surgery in narrow angle glaucoma would be expected easily, so we only recruited patients with open angle glaucoma. Importantly, our data suggest that evaluation and fol- lowupofTrabectomesurgicalsiteswithsweptsourceOCT imaging may help us understand the reason for the success and failure of the surgery with the evidence for excellent repeatability and intra- and intergrader reproducibility. The Figure 3: A cross-sectional OCT image of the nasal angle following combined Trabectome-cataract surgery. This frame-averaged image relation between the structural change of the trabecular shows that the posterior trabecular meshwork has been removed, cleftandsuccessrateoftheTrabectomesurgerymaybea leaving a wide trabecular cleft. hypothesis for future research. Several limitations of our study warrant mention. First of all, in the current study, the number of patients is low. Secondly, it would be better to have a control group which the angle for risk assessment and for evaluating longitudinal undergoes only cataract surgery. One may argue that angle changes before and after therapeutic intervention in patients. measurements using Schwalbe line would help clinicians They found an association between the angle width and the more but the device does not have software based on that. variances of AOD and TISA [23]. Another limitation could be related to lightning condition Lee et al. also studied the angle parameters before and ofthestudy.Theimagingprocedurewasperformedin after cataract surgery in an Asian population and found that room light (without dilation) to evaluate the changes of the swept source OCT is useful for the evaluation of the changes angle structures precisely after the surgery but swept source in angle parameters before and after the cataract surgery [24]. OCT is usually done in complete dark room to maintain Therearealsosomestudieswhichhavefocusedonthe standard light conditions. This can lead to variations and changes of the anterior chamber angle in glaucomatous and may not be comparable to other similar studies in which healthy eyes using various technologies. Zou et al. showed no imaging procedures were done in complete dark conditions. statistically significant difference of ACV, ACD, and ACA by Additionally, the current study evaluated short-term effects Pentacam Scheimpflug system between open angle patients of Trabectome on the angle structures of open angle patients and age-matched healthy controls [25]. Cataract extraction but follow-up assessment with swept source OCT in longer and IOL implantation can significantly deepen the ACD, terms might be more helpful for both open and closed angle widen the anterior chamber drainage angle, and lower IOP in patients. It should be noted that the success of the surgical narrow angle and open angle eyes [26]. Although ACA, ACD, procedures is not the subject of this report. and ACV were found to be increased a little less in open angle Over the past years, the technology of OCT has evolved glaucoma than in narrow angle glaucoma, the difference very rapidly. Commercially available SD-OCT devices use was still found statistically significant after uncomplicated a shorter wavelength and allow higher scanning speed and phacoemulsification [27, 28]. increasedaxialandtransverseresolution.Despitethefactthat To the best of our knowledge, this is the first study that shadowing artifacts and decreased ability to image the scleral shows how to evaluate anterior chamber parameters with a spur can still occur with this technology, the improvement trabecular cleft by swept source AS-OCT after the combined in image resolution has provided a more detailed analysis of Trabectome-cataract and Trabectome-only surgery. Clinical angle structures. The present study showed that scleral spur 6 Journal of Ophthalmology visibility was excellent and placement of measurement tools [10] B. Potsaid, B. Baumann, D. Huang et al., “Ultrahigh speed was reproducible with swept source OCT technology. But this 1050 nm swept source/Fourier domain OCT retinal and ante- might also result from the fact that images were acquired rior segment imaging at 100,000 to 400,000 axial scans per by an ophthalmologist who checked image quality after the second,” Optics Express,vol.18,no.19,pp.20029–20048,2003. acquisition. [11] W. Y. Oh, S. H. Yun, B. J. Vakoc et al., “High-speed polarization In conclusion, imaging the anterior chamber angle with sensitive optical frequency domain imaging with frequency swept source OCT may provide an efficient approach to multiplexing,” Optics Express,vol.16,no.2,pp.1096–1103,2008. visualize the anterior chamber before and after Trabectome [12] S. H. Yun, G. J. Tearney, J. F. De Boer, N. Iftimia, and B. surgery. Measurement of the angle parameters and cleft width E. Bouma, “High-speed optical frequency-domain imaging,” longitudinally with success rates may be useful to detect angle Optics Express, vol. 11, no. 22, pp. 2953–2963, 2003. and cleft pathology in relation to IOP increase and glaucoma [13] C. K.-S. Leung and R. N. Weinreb, “Anterior chamber angle progression. imaging with optical coherence tomography,” Eye,vol.25,no. 3,pp.261–267,2011. [14] Y. Eslami, G. Latifi, S. Moghimi et al., “Effect of adjunctive Competing Interests viscogonioplasty on drainage angle status in cataract surgery: a randomized clinical trial,” Clinical and Experimental Ophthal- Dr. Brian Francis is a surgical consultant for NeoMedix mology,vol.41,no.4,pp.368–378,2013. Corporation, makers of the Trabectome. 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Review Article Applications of Anterior Segment Optical Coherence Tomography in Cornea and Ocular Surface Diseases

Sang Beom Han,1 Yu-Chi Liu,2,3,4 Karim Mohamed Noriega,5 and Jodhbir S. Mehta2,3,4

Correspondence should be addressed to Jodhbir S. Mehta; [email protected]

Received 16 June 2016; Accepted 31 July 2016

Academic Editor: Tamer A. Macky

Optical coherence tomography (OCT) is a noncontact technology that produces high-resolution cross-sectional images of ocular tissues. Anterior segment OCT (AS-OCT) enables the precise visualization of anterior segment structure; thus, it can be used in various corneal and ocular surface disorders. In this review, the authors will discuss the application of AS-OCT for diagnosis and management of various corneal and ocular surface disorders. Use of AS-OCT for anterior segment surgery and postoperative management will also be discussed. In addition, application of the device for research using human data and animal models will be introduced.

1. Introduction light instead of sound, although its principle is similar to that of ultrasound or radar imaging [4]. Optical coherence tomography (OCT), first developed by Based on low-coherence interferometry, OCT compares Huang et al. [1], is a noncontact imaging technology that the time-delay and intensity of infrared light reflected from produces detailed cross-sectional images (tomography) using the tissue structures against a reference beam [5], and this low-coherence interferometry in biological tissues [1]. The interference pattern leads to a cross-sectional image of the use of anterior segment OCT (AS-OCT) imaging was first tissue of interest [4]. To obtain an OCT image, multiple scans introduced in 1994 [2], and AS-OCT became commercially are performed at a series of lateral locations to create a series available in 2001 [3]. With dramatic development of imaging of axial scans (A-scans), and these A-scans are combined techniques, AS-OCT is currently used for analysis of anterior into a composite two-dimensional image, a B-scan, or cross- segment structures worldwide. sectional tomography [4, 6]. In this review, we aimed to provide information on the Currently, two different OCT platforms are currently clinical and research applications of AS-OCT in corneal and available: time domain (TD-OCT) and spectral domain (SD- ocular surface disorders. OCT). In TD-OCT, cross-sectional images are produced by varying the position of the reference mirror [4]. The TD-OCT includes Visante OCT (Carl Zeiss Meditec, Oberkochen, 2. Principles and Devices Germany) and slit-lamp OCT (Heidelberg Engineering GmbH, Heidelberg, Germany) [7]. Both devices use a longer The cross-sectional imaging capability of OCT is analogous to wavelength (1310 nm) light compared with that used for ultrasound biomicroscopy (UBM), but OCT has differences retinal imaging (830 nm), which result in reduced scattering as follows: (1) It requires no contact, which prevents patient andlesssignallossinopaquemedia[3].Thisallowsdeeper discomfort and image distortion. (2) Higher uses infrared penetration through sclera and limbus for the visualization 2 Journal of Ophthalmology of the scleral spur and iridocorneal angle, with a 15–20 𝜇m prolapsingintothetearmeniscusinpatientswithconjunc- resolution [8]. Another advantage of TD-OCT is a wider area tivochalasis, which can also evaluate the effect of thermore- of capture in a single image, whereas SD-OCT processes only duction therapy [28]. a small component of the anterior segment [4, 6]. Visante In pterygium and pinguecula, SD-OCT shows subepithe- OCT has 16 mm scan width and almost 6 mm scan depth lial hyperreflective wedge-shaped mass with a thin overlying in tissue, which are sufficient for anterior chamber biometry epithelium [29, 30]. In UHR-OCT, thin or normal epithe- [9]. lium overlying dense, hyperreflective, subepithelial lesion is SD-OCT, also known as Fourier-domain OCT (FD- observed [27]. In pseudopterygium, SD-OCT images demon- OCT), uses a stationary reference mirror [4, 10]. The interfer- strate that the overgrowing membrane is not really attached ence between the sample and reference reflection is detected to the underlying cornea [30]. as a spectrum [4, 10]. A spectrometer is used to detect the In conjunctival lymphoma, a hyporeflective subepithelial signal by varying the wavelength of the light source with time lesion with a thin, slightly hyperreflective layer of uninvolved [11]. Mathematical calculation using Fourier transformation subepithelial around the lesion is observed in SD-OCT of the spectral interferogram produces the cross-sectional images [29]. images [4, 10]. In melanoma or nevi, SD-OCT displays epithelial hyper- SD-OCT devices include the Spectralis (Heidelberg Engi- reflectivity,mostintenseinthebasallayerwithslighthyper- neering GmbH, Heidelberg, Germany), RTVue (Optovue, reflectivity throughout the epithelium with discrete subep- Inc., CA, USA), and Cirrus OCT (Carl Zeiss Meditec, ithelial lesions [29]. UHR-OCT shows normal thickness or Oberkochen, Germany) [7]. In TD-OCT, the speed of image slightly thicker overlying epithelium with variable hyper- captureislimitedbythevelocityofmechanicalmovementof reflectivity [27]. Intralesional cystic space can be observed the reference mirror. By contrast, SD-OCT is freed from the in nevi, although this does not exclude malignancy [23, 26]. limitations of a moving reference mirror [12], and the source Intense shadowing of sublesional tissue is visible in most A-scans are all captured simultaneously, leading to 10 to 100 melanomas [27, 29]. Thick lesions may exhibit significant times higher speed of image acquisition [4]. By employing optical shadowing of deeper structures due to pigment in the shorter wavelengths (830 nm) compared to TD-OCT, SD- mass [27, 31]. OCT devices are capable of improved axial resolutions of 4– 7 𝜇m[12,13].However,SD-OCTdeviceshaveadisadvantage 3.2. Anterior Segment Tumors. In OSSN, SD-OCT and UHR- that horizontal scan width is limited to 3–6 mm and scan OCT show hyperreflective, thickened epithelium with abrupt depth is shorter compared to TD-OCT [5]. Swept-source transitions from normal to abnormal epithelium [27, 29]. OCT (SS-OCT), a slightly different form of SD-OCT, such as UHR-OCT can also be used for the monitoring of treatment Casia SS-1000 OCT (Tomey, Nagoya, Japan), uses a light with response in OSSN [27]. With resolution of OSSN, UHR- a1310nmwavelengthandhorizontalscanwidthof16mmbut OCT images demonstrate progression toward epithelial nor- carried an axial resolution of only 10 𝜇m[14]. malization: reduced thickness and hyperreflectivity with less Ultrahigh-resolution OCT (UHR-OCT) is capable of ax- distinct transition zone [27]. Complete resolution of OSSN ial resolution of 1–4 𝜇m, with scan width of 5–12 mm [5, 15– can be confirmed by UHR-OCT, which shows normalization 17]. Improved axial resolution was attained by using a light of epithelial appearance [27]. source with a broad bandwidth of more than 100 𝜇manda In Salzmann nodular degeneration, SD-OCT and UHR- spectrometer that can detect the fringes reflected from both OCT images display dense, hyperreflective subepithelial reference and sample arms [5]. lesion overlying Bowman’s layer with normal surrounding Development of UHR-OCT enables the precise imaging epithelium [27, 29]. of the individual corneal and conjunctiva layers [4, 5, 15, 18, In most iris and ciliary tumors, UBM has superior ability 19], tear film and meniscus [16, 17], and contact lens interfaces to penetrate large or highly pigmented iris tumors and [16, 17, 20–22]. UHR-OCT can also be used for differentia- ciliary body tumors; thus, it can provide superior imaging tion among various corneal and ocular surface pathologies, quality and reproducible measurements of the lesions [32, including ocular surface squamous neoplasia (OSSN), lym- 33]. However, as a noncontact technique, SD-OCT can be phoma, pterygium, melanosis, and Salzmann nodular degen- a reliable alternative in small nonpigmented anterior iris eration [23–26]. Although most articles regarding UHR-OCT tumors [32, 34]. arebasedonthedatafromcustom-builtmachines,commercially available UHR-OCT devices exist, that is, the Bioptigen Envisu (Bioptigen Inc., Research Triangle Park, NC, USA) 3.3. Corneal Diseases. SD-OCT is an accurate method of pre- and the SOCT Copernicus HR (Optopol Technologies SA, dicting the depth of phototherapeutic keratectomy required Zawiercie, Poland) [27]. to remove visually significant stromal haze in patients with granular corneal dystrophy (Figure 1) [35]. In patients with Fuchs’ dystrophy, UHR-OCT is a valuable tool for in vivo 3. AS-OCT for Diagnosis of Corneal and imaging of Descemet’s membrane (DM) [15]. UHR-OCT Anterior Segment Diseases showed that DM in patients with Fuchs’ dystrophy appears as a thickened band of 2 opaque lines: smooth anterior 3.1. Conjunctival Diseases. AS-OCT is a reliable tool for line and wavy and irregular posterior line with areas of measurement of the cross-sectional area of conjunctiva localized thickening [15]. The DM thickness measured using Journal of Ophthalmology 3

the sequential changes of tear meniscus after artificial tear instillation with SD-OCT. Recently, Hwang et al. [50] introduced a method of producing three-dimensional images of meibomian glands by reconstructing tomograms of these glands captured with high speed SD-OCT, suggesting that AS-OCT also can be used in meibomian gland disorders.

Figure 1: An AS-OCT image of a patient with granular dystrophy. AS-OCT can accurately show the location and depth of the visually 3.5. Anterior Segment Trauma. AS-OCT can be a useful tool significant stromal haze. in ocular injuries [10]. Its high resolution is optimal for evaluating depth of injury to the cornea or sclera and the type, size, and location of the foreign body [51, 52]. Noncontact scanning capability is also ideal for prevention of further UHR-OCT also correlated significantly with that measured tissue damage in fragile eyes and reducing discomfort of by light microscopy [15]. patients. It can also adequately assess the extent and depth of In patients with microbial keratitis, corneal infiltration corneoscleral injuries in the setting of media opacity, which imaged as a hyperreflective area in the corneal stroma, retro- is critical for the diagnosis and follow-up of corneoscle- corneal pathologic feature, and AC inflammatory cells can be ral injuries, that is, monitoring of corneal healing process observed using AS-OCT [36]. Serial AS-OCT evaluation with after amniotic membrane transplantation for a corneal burn measurement of infiltrate thickness and corneal thickness [10, 51]. can be a tool for monitoring of treatment response [36]. Fuentes et al. [37] investigated the cornea of the patients 3.6. En Face OCT. En face OCT can visualize ocular sur- with keratoconus using SD-OCT and showed that increased face changes that are not detectable using conventional B- epithelial thickness, stromal thinning at the cone, anterior scan OCT in patients with corneal dystrophies, keratitis, hyperreflection at the Bowman’s layer, and the absence of pterygium, conjunctivochalasis, or OSSN [53]. Although its stromal scarring are associated with increased risk of corneal resolution is lower than that of in vivo confocal microscopy, hydrops [37]. AS-OCT can be helpful for the visualization it allows overall visualization of the lesions due to the larger of cornea and anterior chamber (AC) in cases of acute scan width [53]. Compared with in vivo confocal microscopy, hydrops. Vanathi et al. [38] used AS-OCT for evaluation enfaceOCTisalsoadvantageousbecauseitisanoncontact and monitoring of acute hydrops in a patient with pellucid method that allows easy and rapid image capture [53]. marginal corneal degeneration, in which AS-OCT visualized intrastromal clefts with DM detachment and their resolution after treatment with intracameral6 SF [38]. AS-OCT can 4. Use of AS-OCT in Anterior Segment Surgery generate consistent pachymetry mapping in the presence of 4.1. AS-OCT in Cataract Surgery. Use of AS-OCT for precorneal scars [39]. It is also useful for the measurement of scar operative planning includes calculation of intraocular lens depth [39]. (IOL) power, evaluation of lens, AC, and angle structures, AC inflammation can also be evaluated using AS-OCT. and assessment of risk factors for postoperative complica- Igbre et al. [40] showed that AS-OCT is a useful technique for tions [54]. Wong et al. [55] demonstrated that lens density grading AC cells [40]. In particular, AS-OCT can be used as measurement using AS-OCT was reliable and correlated an imaging modality in detecting AC inflammation in uveitis with the Lens Opacity Classification System Version III in eyes with decreased corneal clarity and compromised AC grading scores. Measurement of corneal power using SD- visualization due to corneal edema [41]. OCTshowedhighrepeatabilityandreproducibility[56].In particular, AS-OCT can be an innovative tool for measure- 3.4. Dry Eye Disease. Studies have shown that AS-OCT is a ment of the corneal power for IOL power calculation in reliable tool for quantitative evaluation of tear film thickness patients with prior keratorefractive surgery [57]. Tang et and tear film meniscus, suggesting the possibility of AS-OCT al. [57] showed that IOL power calculation based on SD- as a tool of diagnosis and follow-up of dry eye disease (DED) OCT data in patients with previous myopic laser vision [42–46]. The remarkable finding is that AS-OCT findings correction has equal or better predictive accuracy compared showed good agreement with patient-reported subjective with current standards. symptoms [44]. Qiu et al. [47] reported the diagnostic Successful intraoperative use of AS-OCT has been accuracy of AS-OCT in patients with Sjogren¨ syndrome described for in vivo assessment of clear cornea wound archi- is higher than that in those with aqueous or lipid tear tecture and OCT-guided femtosecond laser-assisted cataract deficiency. surgery [54]. Das et al. [58] recently showed that microscope AS-OCT can also be an innovative clinical tool for mon- integrated intraoperative real-time OCT using the RESCAN itoring of treatment responses in DED. Ibrahim et al. [48] 700 (Carl Zeiss Meditec, Oberkochen, Germany) was helpful revealed that measurement of tear meniscus height using AS- during all the critical steps of cataract surgery, that is, evalu- OCT might be effective in monitoring tear meniscus changes ation of corneal wound architecture, position of IOL, wound after punctal occlusion. Bujak et al. [49] also demonstrated gaping at the end of surgery, and the adequacy of stromal 4 Journal of Ophthalmology

Figure 2: A TD AS-OCT image demonstrating localized Descemet’s membrane detachment (white arrow) adjacent to the wound and internal wound gaping (black arrow) that was not detected in slit- Figure 4: An intraoperative AS-OCT image taken during deep lamp examination. anterior lamellar keratoplasty (DALK) that confirms an optimal descemetic or predescemetic dissection.

Figure 3: An AS-OCT image of precut donor cornea for Descemet’s stripping automated endothelial keratoplasty (DSAEK) taken for (a) evaluation of thickness of graft donor tissue. hydration [58]. It was also helpful for determining the adequate depth of trenching and differentiation of true posterior polar cataracts from suspected cases intraoperatively [58]. Most commercially available laser systems, such as LenSx (Alcon LenSx Lasers Inc., Aliso Viejo, CA, USA), Catalys (b) (Optimedica, Sunnyvale, CA USA), and VICTUS (Technolas Perfect Vision GmbH, Munich, Germany), utilize SD-OCT Figure 5: AS-OCT images demonstrating detachment of the for three-dimensional high-resolution reconstruction of the Descemet’s membrane (DM; white arrow) after DALK (a) and anterior segment structures to improve safety and precision reattachment of the DM after intracameral air injection (b). of laser cataract surgery [54]. AS-OCT is also used in postoperative management after cataract surgery. AS-OCT is a reliable option for evaluation of predescemetic dissection (Figure 4) [69]. When attempting corneal incisions after cataract surgery [10, 58–61]. It can be big-bubble technique, AS-OCT images allow precise eval- used for the assessment of corneal epithelial remodeling fol- uation of the depth reached by the cannula tip used for lowing cataract surgery [62]. It is also useful in the detection pneumatic dissection and can confirm the decision to proof postoperative gape of small-incision clear cornea wounds ceed with air injection, which may improve the success rate or localized DM detachment in the immediate postoperative of big-bubble formation [70]. Lim et al. [71] demonstrated period that cannot be observed with slit-lamp microscopy that AS-OCT can provide valuable information on donor (Figure 2) [63]. AS-OCT is also useful for evaluation of the apposition and DM detachment after DALK (Figure 5). They location and stability of IOL [64]. Use of AS-OCT for the also showed that AS-OCT is useful for visualization of the diagnosis of capsular block syndrome after cataract surgery complications of Descemet’s stripping automated endothelial was also introduced [65]. keratoplasty (DSAEK), such as graft dislocation, primary In addition, AS-OCT is reliable tool for measurement of graft failure, AC crowding with consequent chamber angle AC depth, cornea to IOL distances, IOL to crystalline lens encroachment, and pupillary block [71]. Hand-held AS-OCT distance, and iridocorneal angles in patients with phakic IOL canbeaninnovativetoolforassessmentofthehost-donor [9, 66]. interfaceinDASEK[72].AfterDSAEKorDescemet’smem- brane endothelial keratoplasty (DMEK), DM detachment is 4.2. Corneal Transplantation. AS-OCT is a valuable tool often difficult to detect with slit-lamp evaluation in cases of in corneal transplantation surgery, particularly in lamellar persistent corneal edema. In this situation, AS-OCT can be transplantation [10]. Preoperatively, AS-OCT can be used a useful option for visualization of graft detachment [73– for evaluation of graft donor tissue for thickness and tissue 76]. Yeh et al. [77] revealed that AS-OCT scan at 1 hour preservation (Figure 3) [67, 68]. after DMEK showed the best predictive value on 6-month In deep anterior lamellar keratoplasty (DALK), intraoper- graft adherence status. Shih et al. [78] also demonstrated ative AS-OCT helps the surgeon’s decision making in several that corneal thickness measured with AS-OCT at 1 week steps of the surgery and to achieve an optimal descemetic or postoperatively was an important predictor of DSAEK failure Journal of Ophthalmology 5

[78]. Both studies suggest that AS-OCT findings at early changes in corneal epithelial and stromal thickness after CXL postoperativeperiodmaybehelpfulfordecisionmakingon [89]. reintervention after posterior lamellar keratoplasty [77, 78]. AS-OCT is also able to show the presence of residual DM in the recipient cornea in a patient with a failed DSAEK, 5. Assessment of Anterior Segment Biometry supporting the assumption that inadequate DM stripping OCT does not require direct probe contact to the eye or water maybethecauseofgraftfailure[79]. immersion; thus, it eliminates the risk of image distortion and In patients with Keratoprosthesis (KPro) implantation, provides higher resolution images than UBM [90]. Studies there is no standardized method for evaluation of the demonstrated that AS-OCT is more accurate and repeatable implanted KPro and adjacent tissues [80]. Due to limited compared with UBM or slit-lamp photography in anterior visualization, it is often difficult to detect serious complica- segment biometry [4, 8, 91, 92]. tions such as retroprosthetic membrane, wound gape, and AS-OCT can generate various pachymetric maps of angle closure. In these cases, AS-OCT may play an important the cornea, which is helpful for detecting keratoconus or role. AS-OCT can show the presence of retrokeratoprosthetic keratectasia after refractive surgery [9]. Because it does not membranes and a gape in the interface and lack of epithelial require contact lens removal, it is an ideal tool for monitoring sealing around the KPro edge [81, 82]. Qian et al. [80] also of corneal thickness changes caused by contact lens wear [93]. suggested that AS-OCT can demonstrate anatomic changes Temstet et al. [94] reported that the thickness and location including angle closure, peripheral anterior synechiae, iris- of the thinnest corneal zone determined by the SD-OCT KPro backplate touch, and graft-host interface changes that epithelial mapping might be useful for the early diagnosis cannot be detected otherwise. of Forme fruste keratoconus.InastudybyRochaetal.[95], SD-OCT demonstrated significant differences in central and 4.3. Refractive Surgery. SD-OCT and UHR-OCT enable the regional epithelial thickness profile between keratoconus, precise measurement laser in situ keratomileusis (LASIK) ectasia, and normal eyes, with significant variability and flap thickness and the residual stromal bed thickness unpredictability in ectatic eyes. Development of UHR-OCT before LASIK enhancement to avoid a post-LASIK ectasia also enables the evaluation of each layer of the cornea [83, 84]. [96]. Intraoperative examination using hand-held SD-OCT Evaluation of the AC dimensions, including the AC depth system (Bioptigen Inc., Morrisville, NC, USA) allows more [97], AC angle [7], the angle-to-angle width [4], or the lens accurate evaluation of the flap characteristic before flap thickness and density, is also enabled with the development edema and stromal bed hydration changes accuracy [85]. SD- of AS-OCT [55]. OCT is also used for evaluation of the flap and stromal bed Changes of the biometry of anterior segment dimensions after femtosecond lenticule extraction [86]. during accommodation can also be evaluated using AS- AS-OCT is also useful for the diagnosis and management OCT [98]. Using extended scan depth OCT, Li et al. [98] of the complications after keratorefractive surgery. Interface demonstrated that pupil diameter, AC depth, and anterior fluid syndrome (IFS) is a flap-related complication of LASIK andposteriorsurfacecurvaturesoflensbecamesignifi- surgery characterized interface haze, fluid collection, and cantly smaller during accommodation, and lens thickness flap edema [87]. Han et al. [87] reported that SD-OCT is significantly increased with accommodation. Decrease in the a valuable tool for visualization of these findings and can anterior and posterior surface curvatures were also found in also be used for confirmation of resolution of interface fluid another study using SS-OCT [99]. collectionandhazeaftertreatment.SD-OCTisalsoused for quantitative assessment of the infiltration in the eye with post-LASIK corneal inflammation [88]. 6. Use of AS-OCT in Animal Experiment Experiments using animal models are useful for elucidation 4.4. Surgeries for Keratoconus and Keratectasia. Efficacy of ofthepathophysiologyanddevelopmentoftreatmentmodal- AS-OCT in the management of keratoconus and post- ities of corneal and ocular surface disorders. For precise operative keratectasia has also been reported. AS-OCT evaluation of changes in anterior segment structures in allows the determination of the precise depth and posi- animal experiments, AS-OCT is advantageous due to its tion of the intrastromal corneal ring segments when plac- noncontact nature and ability to produce high-resolution ing the implants in patients with keratoconus and helps images in a short period of time [4]. Han et al. [100] developed to avoid depth-related complications including epithelial- a mouse model of corneal endothelial decompensation using stromal breakdown or perforation into the AC [4, 6]. Corneal transcorneal cryoinjury and proved the persisted corneal collagen crosslinking (CXL) is also used for the stabilization edema with AS-OCT. AS-OCT was also useful for visual- of the corneal stroma by increasing its rigidity in patients ization of the complications of cryoinjury, including irido- with keratoconus or postoperative keratectasia [6]. During corneal adhesion, AC inflammation, and cataract [100]. They the CXL procedure, AS-OCT can localize the demarcation also established an animal model of congenital hereditary line that indicates the transition zone between the treated endothelial dystrophy using Slc4a11 knockout (KO) mice and the untreated stromal tissue and measure the depth of and showed the progressive thickening of the cornea of theline[6].AS-OCTcanalsobeusedfortheevaluationof the KO mice using AS-OCT [101]. Using rat penetrating 6 Journal of Ophthalmology

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Hindawi Publishing Corporation Journal of Ophthalmology Volume 2016, Article ID 8582362, 7 pages http://dx.doi.org/10.1155/2016/8582362

Clinical Study Corneal Epithelial Remodeling and Its Effect on Corneal Asphericity after Transepithelial Photorefractive Keratectomy for Myopia

Jie Hou,1,2,3,4,5 Yan Wang,1,2,3,4 Yulin Lei,5 Xiuyun Zheng,5 and Ying Zhang5

1 Clinical College of Ophthalmology, Tianjin Medical University, Tianjin 300020, China 2Tianjin Eye Hospital, Tianjin 300020, China 3Tianjin Key Lab of Ophthalmology and Visual Science, Tianjin 300020, China 4Tianjin Eye Institute, Tianjin 300020, China 5Jinan Mingshui Eye Hospital, Zhangqiu, Shandong 250200, China

Correspondence should be addressed to Yan Wang; [email protected]

Received 22 April 2016; Accepted 28 July 2016

Academic Editor: Karim Mohamed-Noriega

Copyright © 2016 Jie Hou et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. To evaluate the changes in epithelial thickness profile following transepithelial photorefractive keratectomy (T-PRK) for myopia and to investigate the effect of epithelial remodeling on corneal asphericity. Methods. Forty-four patients (44 right eyes) who underwent T-PRK were retrospectively evaluated. Epithelial thickness was measured using spectral-domain optical coherence tomography at different corneal zones (central, 2 mm; paracentral, 2–5 mm; and mid-peripheral, 5-6 mm) preoperatively andat 1 week and 1, 3, and 6 months postoperatively. The correlation between the changes in corneal epithelial thickness (ΔCET) and postoperative 𝑄-value changes (ΔQ) was analyzed 6 months postoperatively. Results. Epithelial thickness at 6 months showed a negative meniscus-like lenticular pattern with less central thickening, which increased progressively toward the mid-periphery (3.69 ± 4.2, 5.19 ± 3.8,and6.23 ± 3.9 𝜇m at the center, paracenter, and mid-periphery, resp., 𝑃 < 0.01). A significant positive relationship was observed between epithelial thickening and ΔQ6monthspostoperatively(𝑟 = 0.438, 0.580, and 0.504, resp., 𝑃 < 0.01). Conclusions. Significant epithelial thickening was observed after T-PRK and showed a lenticular change with more thickening mid-peripherally, resulting in increased oblateness postoperatively. Epithelial remodeling may modify the epithelial thickness profile after surface ablation refractive surgery for myopia.

1. Introduction more corneal biomechanical properties than LASIK [9, 10]. However, associated pain, irregular epithelial healing, and In recent years, owing to refractive accuracy and stability of corneal haze are the drawbacks of this procedure. New excimer laser ablation concerns, research on epithelial thick- advanced surface ablation techniques, such as transepithelial ness profile changes after myopic surgery has gained general photorefractive keratectomy (T-PRK) [11], have been devel- interest [1, 2]. The majority of studies have noted that epithe- oped to reduce these complications. lial thickness increased after myopic procedures; however, Until now, changes in the full-corneal epithelial thickness these studies were only based on central epithelial thickness profile after T-PRK and the effect of epithelial remodeling measurements. The thickness distribution in normal eyes is on corneal asphericity in accordance with clinical data are uneven from the center of the cornea to the periphery [3– not well described. In this study, we evaluate the postoper- 5]. Nonuniformity in the thickness of corneal epithelium has ative changes in epithelial thickness centrally, paracentrally, also been observed after laser in situ keratomileusis (LASIK) and mid-peripherally after T-PRK by using high-resolution [6, 7] and photorefractive keratectomy (PRK) [8]. spectral-domain optical coherence tomography (SD-OCT) Corneal surface ablation such as PRK has been the and to investigate the potential association of these changes better choice for eyes with thin corneas because it preserves with 𝑄-value change. 2 Journal of Ophthalmology

2. Materials and Methods not used in those patients whose average SE refraction of the subjects was ≤−6.00 D. 2.1. Patients. Forty-fourmyopicpatients(righteyes)whohad After photoablation, the cornea was irrigated with a received treatment for T-PRK were enrolled from August cool balanced salt solution. A soft bandage contact lens was 2014 to March 2015 in this retrospective study. The study applied for 3 to 4 days. All patients were instructed to use protocol was approved by the ethics committee and adhered 0.5% levofloxacin (Cravit; Santen, Inc.) four times a day for 1 to the tenets of the Declaration of Helsinki. The inclusion week, and 0.1% fluorometholone (Allergan, Inc.) drops were ≥ criteria were age 18 years, no ocular disease or systemic initiated four times a day after epithelial closure and contact disease, no epithelial defects, no dry eye disorder, spherical lens removal; the drops were tapered progressively over the ≤− equivalent (SE) refraction 6.00 diopters (D), refractive following 4 months. diopter maintained stable for more than 2 years, preoperative corneal central thickness (CCT) >460 𝜇masmeasuredby OCT, and discontinuation of soft contact lens wear or rigid 2.4. Statistical Analysis. Statistical analyses were performed gas-permeable contact lens (RGP) at least 2 weeks or more using IBM SPSS Statistics, version 20 (IBM Corp., Armonk, than 1 month before surgery, respectively. NY, USA). The average value of the eight octants within All patients underwent preoperative and postopera- the different annulus between the circles was calculated as the paracentral or mid-peripheral thickness. All changes tive examinations including uncorrected visual acuity, best- − corrected visual acuity, manifest and cycloplegic refractions, were calculated as follows: 6-month postoperative preoperative value; in this paper, changes are preceded by the noncontact intraocular pressure, anterior segment slit-lamp Δ microscopy, and corneal topography with the Scheimpflug symbol. The distributions of variables were determined tomography system (Pentacam; Oculus GmbH, Wetzlar, Ger- using Kolmogorov-Smirnov tests. The mean and standard many). The 𝑄-value of the cornea within the 6 mm corneal deviation were used for descriptive statistics. Mean epithelial diameter was assessed using the Pentacam before surgery and thicknesses at different examination points and different 6 months postoperatively. Patients were followed up at 1 week measurement zones were compared by repeated-measures and1,3,and6monthspostoperatively. analysis of variance. Postoperative changes in corneal epithelial thickness (ΔCET) superiorly versus inferiorly and nasally versus temporally were calculated using the paired 𝑡-test. The Pearson correlation coefficient (𝑟) was used to evaluate cor- 2.2. Epithelial Thickness Measurements. The RTVue Fourier- relations between variables while multiple linear regression domain OCT system (v. 6.11.0.12, Optovue Inc., Fremont, CA, analysis was used to explore factors influencing ΔCET. A 𝑃 USA) was used to measure epithelial thickness and corneal value less than 0.05 was considered statistically significant. thickness. The device has a scan speed of 26000 axial scans per second using a wavelength of 830 nm. A “Pachymetry + Cpwr” scan pattern (6 mm scan diameter, eight radials, 3. Results 1024 axial scans each, repeated five times) centered on the 21.70± pupilwasusedtomapthecornea.Theepithelialthickness The mean age of all patients at the time of surgery was 5.1 −3.96 ± 1.3 mapwasgeneratedbyanautomaticalgorithmanddivided years. The mean SE refraction was Dand into a total of 17 sectors: (1) a central 2 mm diameter zone, the mean preoperative central corneal thickness measured by 482.16±40.7 𝜇 6.52± (2) eight paracentral octants between 2- and 5 mm diameter OCT was m. The mean OZ diameter was 0.2 rings, and (3) eight mid-peripheral octants between 5- and mm, while the ablation depth, including the epithelium, 117.67 ± 19.9 𝜇 6 mm diameter rings (Figure 2(a)). For each of these sectors, was m.Meancornealepithelialthicknessat 52.78 ± 3.3 average thickness was displayed over the corresponding area. the center, paracenter, and mid-periphery was , 52.83 ± 3.0 52.47 ± 2.7 𝜇 Each eye was scanned three times and the average value was ,and m, respectively. used for further analysis. 3.1. Changes in Postoperative Epithelial Thickness. Table 1 shows the epithelial thickness at increasing radial distances 2.3. Surgical Technique. The same surgeon performed all from the corneal vertex over time. A slight increase in central surgeries (Jie Hou). Preoperatively, each eye received one epithelial thickness was observed at 1 week and a slight drop of proparacaine (Alcaine), a sterile drape was applied, decrease at 1 month postoperatively. However, no significant and a lid speculum was inserted. differences were found between the two follow-up points (𝑃= The epithelium and stroma were ablated in a single 0.261 and 𝑃 = 0.297, resp.). The epithelium was significantly step using the aberration-free transepithelial PRK mode of thickerat3and6monthspostoperativelycomparedwith the Schwind Amaris 750 Hz (Schwind Eye-tech-solutions preoperative measurements (𝑃 = 0.027 and 𝑃 < 0.001, GmbH, Kleinostheim, Germany). The module integrates resp.) (Figure 1). After annular averaging, this trend was aspheric ablation profiles that compensate for the peripheral also observed at the paracentral and mid-peripheral zones loss of energy caused by an increased angle of incidence (Table 1). on the cornea. For each treatment, the optical zone (OZ) At 6 months postoperatively, the epithelial thickness diameter varied between 6.30 and 7.10 mm based on the pupil showed a thickening of 3.69 ± 4.2, 5.19 ± 3.8,and6.23 ± diameter and the type of refractive error. In consideration of 3.9 𝜇m at the central, paracentral, and mid-peripheral zones, the potential toxic influence on corneal tissue, mitomycin was respectively (𝑃 < 0.001).Asignificantchangeinepithelial Journal of Ophthalmology 3

Table 1: Epithelial thickness profile at 1 week, 1 month, 3 months, and 6 months after T-PRK.

1week 1month CET (𝜇m) Central Para Mid Central Para Mid Mean ± SD 53.97 ± 4.3 53.50 ± 4.3 51.94 ± 5.5 51.03 ± 4.1 52.96 ± 3.6 53.68 ± 3.4 𝑃𝑃= 0.261 𝑃 = 0.487 𝑃 = 0.192 𝑃 = 0.297 𝑃 = 0.894 P = 0.192 3months 6months CET (𝜇m) Central Para Mid Central Para Mid Mean ± SD 55.14 ± 5.5 56.61 ± 4.8 57.18 ± 4.1 56.68 ± 5.1 58.03 ± 4.6 58.70 ± 3.7 𝑃𝑃= 0.027 𝑃<0.001 𝑃<0.001 𝑃<0.001 𝑃<0.001 P < 0.001 𝑃 value in comparison with preoperative measurements; SD: standard deviation.

Table 2: The correlation between ΔCET and Δ𝑄-value, SE, and AD 6 months postoperatively.

𝑟-value (𝑃 value) Parameter Δ𝑄-value SE AD OZ Central 0.438 (0.007) 0.380 (0.020) 0.216 (0.199) −0.427 (0.008) Para 0.580 (<0.001) 0.492 (0.002) 0.380 (0.020) −0.554 (<0.001) Mid 0.504 (0.001) 0.423 (0.009) 0.383 (0.019) −0.557 (<0.001)

∗∗ 75 corneal surfaces showed an oblate shift within the ablation ∗ 𝑄 0.73±0.39 70 zone. The -value increased to in eyes undergoing T-PRK. Figure 4 shows that the epithelial thickening at each 65 Δ 𝑃 < 0.01

m) zone was positively correlated with Q( ). There was 𝜇 60 also a statistically significant correlation between ΔCET and 55 SE. Epithelial thickening was correlated with ablation depth paracentrally and mid-peripherally (𝑟 = 0.380 and 0.383; 50 𝑃 < 0.05). Epithelial thickening at each zone was negatively 45 correlated with OZ diameter (𝑃 < 0.01). 40 Multiple linear regression models were constructed to Epithelial thickness ( Epithelial Δ 35 explore factors influencing CET 6 months postoperatively. Optical zone diameter and Δ𝑄 were enrolled into regression equations. The regression equations were as follows: Pre-op After 1w After 1m After 3m After 6m 2 ΔCET0−2 mm = 0.278 + 4.844Δ𝑄 (𝑅 = 0.185, 𝐹 = 7.933, Time 2 𝑃 = 0.008); ΔCET2−5 mm = 42.349+3.775Δ𝑄−6.134OZ (𝑅 = Figure 1: Change in central corneal epithelial thickness over time 0.408, 𝐹 = 11.719, 𝑃 = 0.000); and ΔCET5 6 mm = 62.122 + 2 - after T-PRK. The epithelium was significantly thicker at 3and6 3.739Δ𝑄 − 9.019OZ (𝑅 = 0.426, 𝐹 = 5.940, 𝑃 = 0.001). months after surgery compared with preoperative measurements. ∗∗ ∗ 𝑃 < 0.001, 𝑃 < 0.05. 4. Discussion The corneal epithelium has the ability to alter its thickness thickness was detected among the three zones (𝑃 = 0.030), profile to reduce surface irregularities and to reestablish and the most pronounced change was observed at the mid- a smooth optical surface [12]. Histological studies have periphery zone (𝑃 = 0.008).Afterthesamesectoraveraging, shown that these epithelial changes include elongation of the the epithelium was 1.67 ± 2.07 𝜇mthinnersuperiorlythan basal epithelial cell layer and an increase in the number of inferiorly (𝑃 < 0.001)and1.00±1.00 𝜇mthinnernasallythan superficial cell layers [2]. Such compensatory changes in the temporally (𝑃 = 0.002). The maximum amount of epithelial corneal epithelium after myopic excimer laser ablation have thickening was 8.37 ± 5.4 𝜇m at the temporal zone (Figures 2 been demonstrated using Artemis very high frequency digital and 3). ultrasound [6], confocal microscopy [2], and OCT [4, 5] in several previous studies. All of these studies showed that 3.2. Correlation and Regression Analysis. Table2showsthe increased epithelial thickness after excimer laser surgery is 𝑟-values and associated 𝑃 values for the analysis of the rela- caused by epithelial hyperplasia. The hyperplasia not only is tionship between ΔCET and Δ𝑄-value, between ΔCET and a response to epithelial removal during PRK but also occurs SE, between ΔCET and ablation depth, and between ΔCET after LASIK, during which the central epithelium remains and OZ diameter at 6 months postoperatively. The anterior intact [1, 2]. Furthermore, a previous study speculated that 4 Journal of Ophthalmology

Epithelium map 6 mm ×6mm 80 Epithelium map 6 mm ×6mm 80 75 75 70 70 65 65 60 60 55 55 m) 50 m) 50 𝜇 𝜇 ( 45 ( 45 40 40 35 35 30 30 25 25 20 20 (a) (b) Epithelium map 6 mm ×6mm 80 Epithelium map 6 mm ×6mm 80 75 75 70 70 65 65 60 60 55 55 50 m) 50 m) 𝜇 𝜇 ( 45 45 ( 40 40 35 35 30 30 25 25 20 20 (c) (d) Epithelium map 6 mm ×6mm 80 75 70 65 60 55 50 m) 𝜇 45 ( 40 35 30 25 20 (e)

Figure 2: Epithelial thickness profile mapping seen preoperatively (a) and 1 week (b), 1 month (c), 3 months (d), and 6 months (e) postoperatively in a T-PRK examination. The patient (right eye) received treatment for −4.75 D. thechangeinanteriorcornealcontourafterlaserablation thickening in central corneal epithelium 1 week postoper- stimulates epithelial thickening [2]. atively, and then epithelial thickness was reduced after 1 The reliability, reproducibility, and axial resolution of month, followed by a gradual epithelial thickening over the cornealepithelialthicknessmeasurementsbySDOCThave following 6 months. The mechanism underlying the thinning already been reported [3, 13, 14]. Rocha et al. [5] and Chen of the corneal epithelium at 1 month postoperatively is not et al. [8] applied this technique to acquire epithelial thickness well understood. However the sensory nerves transection and profiles after LASIK and PRK. To the best of our knowledge, reduction of trophic modulator secretion after laser ablation no previous study has used SD-OCT to evaluate the role of may explain the thinning of the corneal epithelium [15, 16]. the epithelial remodeling on the anterior corneal asphericity The regeneration of subepithelial corneal nerves is usually after corneal refractive surgery. active 3 months postoperatively [17]. In our study, increased In the present study, the epithelial debridement in the thickening of the corneal epithelium was observed in the surface ablation caused an initial edema and nonuniform third postoperative month, further indicating that the corneal Journal of Ophthalmology 5

5.29 ± 5.7 10

5.14 ± 4.7

6.91 ± 3.8 4.21 ± 4.9 8 5.65 ± 4.6 4.12 ± 4.1

.0± 7.20 6 T 3.69 ± 4.2 N 7.41 ± 5.8 5.00 ± 5.1 5.1

8.37 ± 5.4 4

6.76 ± 5.0 5.21 ± 4.2

7.14 ± 4.2 6.06 ± 4.4 2 ± 4.6

5.94

5.43 ± 4.5 0

Corneal epithelium

Figure 3: Epithelial thickening at each sector 6 months postoperatively (mean ± standard deviation, 𝜇m).

15 with the maximum amount of epithelial thickening observed 10 temporally, in accordance with the findings of Chen et al. on 5 PRK [8]. m) 𝜇 0 Furthermore, a negative meniscus-like lenticular change in the epithelial thickness profile, with less thickening cen-

CET ( −5 Δ trally and a progressively increasing thickening toward the −10 periphery, was observed after T-PRK in the current study. −15 0 0.25 0.5 0.75 1 1.25 1.5 1.75 2 The epithelial thickness at the central, paracentral, and mid- peripheral zones was 3.69 ± 4.2, 5.19 ± 3.8,and6.23 ± ΔQ-value 3.9 𝜇m, respectively, at 6 months postoperatively, with a 2.5- Center 𝜇m thicker epithelium mid-peripherally than centrally. This Paracenter pattern is consistent with the post-PRK epithelial thickness Mid-periphery profile changes noted by Chen et al. [8] using the same Δ Δ𝑄 measurement technology but in contrast to the post-LASIK Figure 4: Correlation between CET and -value 6 months epithelial thickening detected using Artemis, which showed postoperatively. more thickening centrally and progressively less thickening toward the periphery [6]. This might be explained by the aspheric ablation profile in the Amaris results, with increased nerve regeneration may play an important role in post- peripheraltissueablationcomparedwiththecenterofthe operative epithelial remodeling. The duration of epithelial cornea. Therefore, the corneal epithelium may compensate thickening was longer than that reported in a previous study for this transition zone by having a reduced thickness on LASIK (1 week) [1, 18], possibly owing to differences in centrally. This was confirmed by the statistical relationship initialepithelialwoundhealingbetweenlasersurfaceablation between ablation depth and paracentral epithelial thickening and LASIK. after surgery in the present study. The nonuniform preoperative epithelial thickness profile It is widely acknowledged that myopic laser ablation has been reported to be thicker inferiorly and nasally in changes the cornea from prolate to oblate shape [19–21]. normaleyes[2,4,8].Wealsofoundthattheepithelium Kwon and Bott [22] and Huang et al. [23] applied a math- thickening was characterized by a thicker epithelium inferi- ematical model to explain the origin of changes in corneal orly than superiorly and temporally than nasally after T-PRK, asphericity after laser refractive surgery. They showed that 6 Journal of Ophthalmology corneal remodeling changes the corneal shape after surgery by anterior-segment optical coherence tomography: a clinical by making the center of the cornea flatter and the periphery reference study,” Cornea,vol.32,no.11,pp.1493–1498,2013. steeper, resulting in a more oblate cornea. [4] Y. Li, O. Tan, R. Brass, J. L. Weiss, and D. Huang, “Corneal An additional finding of our study was that the lenticular epithelial thickness mapping by fourier-domain optical coher- epithelial thickening had a significant positive effect on the ence tomography in normal and keratoconic eyes,” Ophthalmol- corneal asphericity, indicating that the differential increase ogy,vol.119,no.12,pp.2425–2433,2012. in epithelial thickness profile could account for the observed [5] K. M. Rocha, C. E. Perez-Straziota, R. D. Stulting, and J. B. clinical trend to oblateness. The thicker the epithelial thick- Randleman, “SD-OCT analysis of regional epithelial thickness ness, the more pronounced the shift. In addition, we explored profiles in keratoconus, postoperative corneal ectasia, and the positive correlation between ΔCET and SE and between normal eyes,” Journal of Refractive Surgery,vol.29,no.3,pp. ΔCET and ablation depth. This emphasizes that greater 173–179, 2013. attentionshouldbepaidtoepithelialremodelingaftercorneal [6] D. Z. Reinstein, T. J. Archer, and M. Gobbe, “Change in refractive surgery, especially for high myopic patients with epithelial thickness profile 24ours h and longitudinally for 1 year after myopic LASIK: three-dimensional display with artemis aspheric profiles of ablation in the correction of spherical very high-frequency digital ultrasound,” Journal of Refractive aberration. We also found a significant negative correlation Surgery,vol.28,no.3,pp.195–201,2012. between postoperative epithelial thickening and OZ diam- [7]K.M.RochaandR.R.Krueger,“Spectral-domainoptical eter, indicating that epithelial hyperplasia was greater with coherence tomography epithelial and flap thickness mapping smaller zone sizes. This is in agreement with previous findings in femtosecond laser-assisted in situ keratomileusis,” American [6, 8]. Journal of Ophthalmology,vol.158,no.2,pp.293–301.e1,2014. One limitation of the current study is that the results [8]X.Chen,A.Stojanovic,Y.Liu,Y.Chen,Y.Zhou,andT. are not representative of the general myopic eye population P. Utheim, “Postoperative changes in corneal epithelial and becausesomeofourpatientshadcorneasthatwereslightly stromal thickness profiles after photorefractive keratectomy in thinner than the average. Another limitation is the inability treatment of myopia,” Journal of Refractive Surgery,vol.31,no. of SD-OCT to measure epithelial thickness outside the 6 mm 7,pp.446–453,2015. diameter of the cornea. [9] F. W.Fraunfelder and S. E. Wilson, “Laser in situ keratomileusis In summary, the present study demonstrated that a versus photorefractive keratectomy in the correction of myopic specific remodeling occurred from the center to the periphery astigmatism,” Cornea,vol.20,no.4,pp.385–387,2001. of the cornea after T-PRK for myopia. The lenticular change [10] K. Kamiya, K. Shimizu, and F. Ohmoto, “Comparison of the in the epithelial thickness profile after T-PRK may be caused changes in corneal biomechanical properties after photorefrac- by more peripheral tissue ablation. This change results in tive keratectomy and laser in situ keratomileusis,” Cornea,vol. increased oblateness and may counterbalance the positive 28, no. 7, pp. 765–769, 2009. effectofrestoringtheprolateshapeofthecentralcornea. [11] A. Fadlallah, D. Fahed, K. Khalil et al., “Transepithelial photore- Further investigations are required to evaluate the long-term fractive keratectomy: clinical results,” Journal of Cataract and effect of corneal epithelial changes and the potential effect on Refractive Surgery,vol.37,no.10,pp.1852–1857,2011. visual quality. [12] A. Vogt, Textbook and Atlas of Slit Lamp Microscopy of the Living Eye, Wayenborgh, Bonn, Germany, 1981. [13]P.A.Keane,R.A.Bhatti,J.W.Brubaker,S.Liakopoulos,S. Competing Interests R. Sadda, and A. C. Walsh, “Comparison of clinically relevant None of the authors have financial or proprietary interest in findings from high-speed fourier-domain and conventional time-domain optical coherence tomography,” American Journal any material or method mentioned in this study. of Ophthalmology,vol.148,no.2,pp.242–248,2009. [14] X. J. Ma, L. Wang, and D. D. Koch, “Repeatability of corneal Acknowledgments epithelial thickness measurements using fourier-domain optical coherence tomography in normal and post-LASIK eyes,” This study was supported by research grants from the Cornea,vol.32,no.12,pp.1544–1548,2013. National and Science Program Grant (no. 81470658), China. [15] R. Ambrosio´ Jr., T. Tervo, and S. E. Wilson, “LASIK-associated dry eye and neurotrophic epitheliopathy: pathophysiology and References strategies for prevention and treatment,” Journal of Refractive Surgery,vol.24,no.4,pp.396–407,2008. [1] A. Ivarsen, W.Fledelius, and J. Ø. Hjortdal, “Three-year changes [16] S. E. Wilson, “Laser in situ keratomileusis-induced (presumed) in epithelial and stromal thickness after prk or lasik for high neurotrophic epitheliopathy,” Ophthalmology,vol.108,no.6,pp. myopia,” Investigative Ophthalmology and Visual Science,vol. 1082–1087, 2001. 50, no. 5, pp. 2061–2066, 2009. [17] J. Tomas-Juan,´ A. Murueta-Goyena Larranaga,˜ and L. Han- [2]S.V.Patel,J.C.Erie,J.W.McLaren,andW.M.Bourne,“Con- neken, “Corneal regeneration after photorefractive keratec- focal microscopy changes in epithelial and stromal thickness tomy: a review,” Journal of Optometry,vol.8,no.3,pp.149–169, up to 7 years after LASIK and photorefractive keratectomy for 2015. myopia,” Journal of Refractive Surgery,vol.23,no.4,pp.385– [18]M.Tang,Y.Li,andD.Huang,“Cornealepithelialremodeling 392, 2007. after LASIK measured by fourier-domain optical coherence [3] A. J. Kanellopoulos and G. 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[19] R. G. Anera, J. R. Jimenez,L.J.DelBarco,J.Berm´ udez,´ and E. Hita, “Changes in corneal asphericity after laser in situ keratomileusis,” Journal of Cataract and Refractive Surgery,vol. 29,no.4,pp.762–768,2003. [20] D. Gatinel, J. Malet, T. Hoang-Xuan, and D. T. Azar, “Anal- ysis of customized corneal ablations: theoretical limitations of increasing negative asphericity,” Investigative Ophthalmology and Visual Science,vol.43,no.4,pp.941–948,2002. [21] D. Gatinel, L. Racine, and T. Hoang-Xuan, “Contribution of the corneal epithelium to anterior corneal topography in patients having myopic photorefractive keratectomy,” Journal of Cataract and Refractive Surgery, vol. 33, no. 11, pp. 1860–1865, 2007. [22] Y. Kwon and S. Bott, “Postsurgery corneal asphericity and spherical aberration due to ablation efficiency reduction and corneal remodelling in refractive surgeries,” Eye,vol.23,no.9, pp.1845–1850,2009. [23] D. Huang, M. Tang, and R. Shekhar, “Mathematical model of corneal surface smoothing after laser refractive surgery,” American Journal of Ophthalmology,vol.135,no.3,pp.267–278, 2003. Hindawi Publishing Corporation Journal of Ophthalmology Volume 2016, Article ID 8656301, 6 pages http://dx.doi.org/10.1155/2016/8656301

Research Article Evaluation of Anterior Chamber Volume in Cataract Patients with Swept-Source Optical Coherence Tomography

Wenwen He,1,2,3 Xiangjia Zhu,1,2,3 Don Wolff,4 Zhennan Zhao,1,2,3 Xinghuai Sun,1,2,3 and Yi Lu1,2,3

1 Department of Ophthalmology, Eye and Ear, Nose, and Throat Hospital, Fudan University, 83 Fenyang Road, Shanghai 200031, China 2Key Laboratory of Myopia, Ministry of Health, Shanghai 200031, China 3Shanghai Key Laboratory of Visual Impairment and Restoration, Fudan University, Shanghai 200031, China 4Parkway Health Hongqiao Medical Center, 2258 Hongqiao Road, Shanghai 200335, China

Correspondence should be addressed to Yi Lu; [email protected]

Received 29 April 2016; Accepted 20 July 2016

Academic Editor: Yu-Chi Liu

Copyright © 2016 Wenwen He et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. To evaluate the anterior chamber volume in cataract patients with Swept-Source Optical Coherence Tomography (SS- OCT) and its influencing factors. Methods. Anterior chamber volume of 92 cataract patients was evaluated with SS-OCT in this cross-sectional study. Univariate analyses and multiple linear regression were used to investigate gender, age, operated eye, posterior vitreous detachment, lens opacity grading, and axial length (AXL) related variables capable of influencing the ACV. Results. The 3 3 average ACV was 139.80 ± 38.21 mm (range 59.41 to 254.09 mm ). The average ACV was significantly larger in male patients than in female patients (𝑃 = 0.001). ACV was negatively correlated with age and LOCS III cortical (C) grading of the lens (Pearson’s correlation analysis, 𝑟 = −0.443, 𝑃 < 0.001, and Spearman’s correlation analysis, 𝜌 = −0.450, 𝑃 < 0.001). ACV was also increased with AXL (Pearson’s correlation analysis, 𝑟 = 0.552, 𝑃 < 0.001). Multiple linear regression showed that, with all of the covariates entered into the model, gender (𝑃 = 0.002), age (𝑃 = 0.015), LOCS III C grade (𝑃 = 0.043), and AXL (𝑃 = 0.001) 2 were still associated with ACV (𝐹 = 10.252 𝑃 < 0.001 𝑅 = 0.498). Conclusion. With SS-OCT, we found that, in healthy cataract patients, ACV varied significantly among different subjects. Influencing factors that contribute to reduced ACV were female gender, increased age, LOCS III C grade, and shorter AXL.

1. Introduction in spectral-domain OCT (SD-OCT) [5]. Thus, with 30,000 A- scans per second, SS-OCT allows rapid and precise anterior Precisemeasurementoftheanteriorchamberisimportantin chamber measurement. As a variation of FD-OCT, SS-OCT many aspects of ophthalmology, such as assessing glaucoma hasadvantagesofmeasurementspeedandsensitivityover risk [1, 2] and surgical planning and intraocular lens (IOL) time-domain OCT [6]. Besides, SS-OCT also has advantages power calculation [3, 4]. Previous studies have focused on over SD-OCT, such as higher robustness [7] and capability of the measurement of anterior chamber depth (ACD) or the separating the real OCT image from its mirror image [8, 9]. anterior chamber angle (ACA). Accurate measurement of Previous studies comparing SS-OCT and SD-OCT in poste- anterior chamber volume (ACV) has been difficult histori- rior segment measurements have proved these advantages. cally due to technology limitations. It has been shown to have higher resolution, resulting in Recent development of Swept-Source Optical Coherence more measureable images [10]. SS-OCT is also superior in Tomography (SS-OCT CASIA SS-1000 OCT, Tomey Corpo- detecting details of choroid-scleral interface and choroidal ration, Nagoya, Japan) is a form of Fourier-domain OCT (FD- sublayer [11, 12]. Studies comparing SS-OCT to other OCTs in OCT), which uses a monochromatic tunable fast scanning observations of anterior segment were rare, yet SS-OCT has laser source and a photodetector to detect wavelength- been widely used in the measurement of anterior chamber resolved interference signal instead of using a spectrometer as [13–16]. 2 Journal of Ophthalmology

Anterior chamber anatomy may vary with aging, thickening of the lens, liquefaction of the vitreous, corneal changes, gender differences [17], and elongation of the axial length (AXL)inhighmyopia[18,19].Cataracttypesalsohave different impact on anterior chamber characteristics [20]. However, few studies have evaluated the effects of all these 180 0 (N) (T) factors on the volume of the anterior chamber in normal cataract patients. In this study, we used the SS-OCT, to investigate ACV in normal cataract patients and to better understand factors that impact ACV measurement. Figure 1: SS-OCT automatically detects the boundaries of cornea, iris and lens. SS-OCT= Swept-Source Optical Coherence Tomogra- 2. Methods phy. The Institutional Review Board of the Eye and ENT Hospital of Fudan University approved this prospective Table 1: Demographic data. study. All procedures adhered to the tenets of the Dec- Parameter Data (range) laration of Helsinki and were conducted in accordance Age (year) 66.48 ± 10.57 (44–90) with the approved research protocol. Informed consent was obtained from each patient. The study was registered at Gender (male/female) 33/59 https://www.clinicaltrials.gov/; the clinical trial accession Operated eye (right/left) 43/49 number is NCT02182921. AXL (mm) 25.09 ± 2.96 (20.76–33.88) High myopia (<−6.00) (%) 29.35 (27/92) LOCS III NC grade 3.27 ± 0.97 (1.8–5.7) 2.1. Subjects. Ninety-two eyes of consecutive cataract patients LOCS III NO grade 3.14 ± 0.94 (1.5–5.5) attheEyeandENTHospitalofFudanUniversity,between LOCS III C grade 2.83 ± 0.67 (1.8–4.9) May 2015 and August 2015, were enrolled. Exclusion criteria 1.41 ± 0.58 included zonular weakness, corneal disease, glaucoma, previ- LOCS III P grade (1.0–3.0) ± 𝑛 ous trauma, or any ocular surgical history. Valuesarepresentedasthemean standard deviation (range) or . AXL = axial length; LOCS III = Lens Opacities Classification System III; NC = nuclear color; NO = nuclear opalescence; C = cortical cataract; P = posterior subcapsular cataract. 2.2. Examinations. Complete anterior and dilated fundus- copic exams were done. Posterior vitreous detachment (PVD) was evaluated by B-scan by the same senior technician. 500 (AOD 500), the trabecular iris space area 500 (TISA 500), AXL was measured with an IOL Master (Carl Zeiss AG, the angle recess area 500 (ARA 500), and the trabecular iris Oberkochen, Germany). The lens opacity was assessed angle 500 (TIA 500), which were determined as previously according to the Lens Opacities Classification System III described for the superior, inferior, nasal, and temporal (LOCS III developed by Dr. Leo Chylack, Mass Eye and angles [21]. Ear) under slit lamp examination by one investigator. LOCS III System has 4 categories: NC = nuclear color, NO = nuclear opalescence, C = cortical cataract, and P = posterior 2.3. Statistical Analysis. All data were expressed as the mean ± 𝑡 subcapsular cataract. According to the previous study, NC standard deviation. Student’s -test was used to compare and NO were graded from 0.1 to 6.9 and C was graded from differences in mean measurements between men and woman 0.1 to 5.9 [20]. P was graded from 1 to 5. after normality tests and homogeneity of variance tests. SS-OCT anterior segment scan mode was used with 128 Pearson and Spearman’s correlation analyses were used to radial scans, with a depth of 6 mm and a length of 16 mm. investigate the relationships between ACV and demographic Patients were instructed to fixate on the internal target and data (Pearson for continuous variables and Spearman for pull down the lower lid while the technician elevated the categorical variables). Determinants of ACV were further 𝑃 < upper lid to expose the limbus. The total scan time was less evaluated using multiple liner regression. values 0.05 than 0.3 seconds. All images with eyelids or motion artifact were considered statistically significant. All analyses were wereexcluded.Thecornealmapscantypewasusedfor performed using SPSS version 11.0 (SPSS Inc., Chicago, IL, measurement of posterior corneal curvature. All eyes were USA). imaged in room light (336 lux) without pupil dilation. A total of 64 B-scans taken from the anterior segment scan mode 3. Results were analyzed for measurement of ACV. The instrument software automatically detected the boundaries of cornea, 3.1. Patient Characteristics. The demographic data of the iris, and lens for each image, as shown in Figure 1. Manual patients are shown in Table 1. The average age of the patients adjustmentwasmadeifthesoftwarefailedtodetectthe was 66.48 ± 10.57 years old. There were 29.35% (27/92) high boundaries at the correct location. Angle width parameters myopic (<−6.0 D) patients and the average AXL was 25.09 ± derived from SS-OCT included the angle opening distance 2.96 mm. Journal of Ophthalmology 3

Table 2: Biometry measurements of anterior segment. Table 3: Multiple linear regression analysis of ACV.

Parameter Data (range) 𝛽𝑃 3 ∗ ACV (mm ) 139.80 ± 38.21 (59.41–254.09) Gender 0.301 0.002 ∗ ACD (mm) 2.71 ± 0.42 (1.76–3.86) Age −0.263 0.015 AOD 500 (mm) 0.61 ± 0.28 (0.19–1.67) Operated eye −0.087 0.325 2 ARA 500 (mm ) 0.35 ± 0.18 (0.11–1.25) PVD 0.053 0.597 2 TISA 500 (mm ) 0.24 ± 0.12 (0.07–0.74) LOCS III NC grade −0.254 0.393 ∘ TIA 500 ( ) 32.72 ± 11.62 (9.53–61.55) LOCS III NO grade 0.208 0.477 ∗ Posterior corneal curvature (D) 6.40 ± 0.26 (−5.80–−6.95) LOCS III C grade −0.183 0.043 Values are presented as the mean ± standard deviation (range). LOCS III P grade −0.029 0.733 ∗ ACV = anterior chamber volume; ACD = anterior chamber depth; AOD 500 AXL 0.358 0.001 = angle opening distance 500; ARA 500 = angle recess area 500; TISA 500 = 𝐹 = 10.252 𝑃 < 0.0012 𝑅 = 0.498 trabecular iris space area 500; TIA 500 = trabecular iris angle 500. Model . PVD = posterior vitreous detachment; LOCS III = Lens Opacities Classifica- tion System III; NC = nuclear color; NO = nuclear opalescence; C = cortical cataract; P = posterior subcapsular cataract; AXL = axial length. ∗ 3.2. Biometry Measurements of ACV Related Anterior Segment These parameters were significantly correlated with𝑃 ACV( < 0.05). Parameters. Table 2 shows the biometry measurements of 3 anterior segment. The average ACV was 139.80 ± 38.21 mm , 3 range 59.41 to 254.09 mm .TheaverageACDwas2.71± chamber [23], resulting in an inaccurate assessment of ACV 0.42 mm. which also lacks reproducibility. CASIA SS-1000 OCT used a swept laser source, which could show high-resolution 3- 3.3. Influencing Factors of ACV. We performed univariate dimensional images of anterior chamber by a very high- analysis for influencing factors of ACV and multivariable speed scanning system. Previous studies reported variable analysis to adjust for independent covariates. The average influencing factors on ACV, including gender [17], ACD, ACV was significantly larger in male patients than in female and age [20]. However, it remains unclear whether these patients (Figure 2(a), 𝑃 = 0.001). ACV was negatively factors remain significant after adjusting for independent correlated with age and LOCS III C grade of the lens covariates. In the study, we reported SS-OCT data in healthy (Figures 2(b) and 2(c), Pearson’s correlation analysis, cataract patients and found that ACV varied significantly 𝑟 = −0.443, 𝑃 < 0.001, and Spearman’s correlation analysis, among different subjects. Influencing factors that contributed 𝜌 = −0.450, 𝑃 < 0.001). LOCS III NC, NO, and P grades were to reduced ACV were female gender, increased age, LOCS III not correlated with ACV narrowing (Spearman’s correlation C grade, and lower AXL. analysis, 𝜌 = 0.127, 𝑃 = 0.246, 𝜌 = 0.146, 𝑃 = 0.180, The female gender was related to decreased ACV possibly 𝜌 = −0.024,and𝑃 = 0.819, resp.). ACV was also increased because generally females have shorter AXL, smaller body with increased AXL (Figure 2(d), Pearson’s correlation habitus, eyes, and therefore a narrower anterior chamber analysis, 𝑟 = 0.552, 𝑃 < 0.001). than males [17]. However, there were almost twice as many Table 3 presents the result from the multiple linear femalesasmalesinourstudy,whichmightbeabias.This regression.Withallofthecovariatesenteredintothemodel, was a limitation and we will verify the result in a population female gender (𝑃 = 0.002), greater age (𝑃 = 0.015), higher with similar percentages of men and women in the future. Besides, the anterior chamber became shallower over time LOCS III C grade (𝑃 = 0.043), and less myopia AXL (𝑃= with thickening of the crystalline lens, which partly explained 0.001) were all correlated with decreased ACV (𝐹 = 10.252 2 the negative correlation between increased age and ACV. 𝑃 < 0.001 𝑅 = 0.498). Cortical lens changes impact lens thickness more significantly than nuclear sclerosis. Consequently, LOCS III C grade 4. Discussion was also negatively correlated with ACV. After adjusting for independent covariates, gender, age, LOCS III C grade, and Objective,precisemeasurementoftheanteriorchamber AXLwerestillrelatedtothevolumeofanteriorchamberby volume has importantsignificance as a predictor of nar- multiple linear regression analysis. row angle glaucoma risk, assessment of pupil block, in These factors, along with SS-OCT evaluation, are impor- addition to surgical planning in AC IOL and Phakic IOL tant for assessing risk in glaucoma patients and may impact placement. Previous reports of anterior chamber volume the timing of therapeutic cataract surgery in patients with measurements relied on the Scheimpflug system [22], which anatomic narrow angles or those with cataract-induced nar- requires protracted cooperation of patients during testing. By row angles. Moreover, patients needing AC IOL or Phakic using Scheimpflug system, previous studies found that, with IOL placement can benefit from SS-OCT assessment as a increasing age, ACD and ACV diminished and no correlation preoperative tool to assess risk and aid surgical planning. was found between ACV and anterior chamber angle [22]. Further studies can examine if these risk factors are also However, the Scheimpflug system could only provide an found in patients before senile cataracts develop, in patients estimation rather than a direct visualization of the anterior with open or narrow angle glaucoma, and how cataract 4 Journal of Ophthalmology

250 300

Pearson’s r=−0.443, P < 0.001 250 200

200 ) ) 3 3 150 150

100 (mm ACV ACV (mm ACV 100

50 50

0 0 Female Male 40 50 60 70 80 90 100 Age (year) (a) (b) 300 300 Pearson’s r = −0.552, P < 0.001 Spearman’s 𝜌 = −0.450, P < 0.001 250 250

200 200 ) ) 3 3

150 150 ACV (mm ACV ACV (mm ACV 100 100

50 50

0 0 123456 20 22 24 26 28 30 32 34 36 LOCS III C grade AXL (mm) (c) (d)

Figure 2: Univariant analysis. (a) The average ACV was significantly greater in males compared to females𝑃 ( = 0.001). (b) ACV was negatively correlated with age (Pearson’s correlation analysis, 𝑟 = −0.443, 𝑃 < 0.001). (c) ACV was negatively correlated with LOCS III C grade of the lens (Spearman’s correlation analysis, 𝜌 = −0.450, 𝑃 < 0.001). (d) ACV was also increased with AXL (Pearson’s correlation analysis, 𝑟 = 0.552, 𝑃 < 0.001). ACV = anterior chamber volume; AXL = axial length. LOCS III = Lens Opacities Classification System III; C = cortical opacity. surgery impacts the postoperative ACV in patients at risk of angle visualization and generates an ACV which is more narrow angles. preciseandobjectivethantheScheimpflugsystemofangle In addition, several anterior segment imaging modalities, estimation. Besides, this SS-OCT could automatically show such as Scheimpflug system, anterior segment OCT, and accurate measurements of anterior chamber angle, which has ultrasound biomicroscopy (UBM), can be used to evaluate advantages over UBM [14]. However, other methods still have the volume of the anterior chamber. All devices promise their value in clinical ophthalmology. For instance, in cases of quantitative information and qualitative imaging of anterior corneal scaring, UBM could still evaluate anterior chamber segment. However, compared to other instruments, the SS- parameters while OCTs could not. OCT used in the current study has several advantages: (1) To conclude, SS-OCT could provide faster, objective, and It is a noncontact optical system compared to UBM, which more precise measurement of anterior segment than other avoids distortion of the eye anatomy and angle and reduces methods in some conditions, which may have advantages contagion[24].(2)ItisfasterthantheScheimpflugsystem in evaluation of ACV but still need further confirmation or UBM because of the swept laser source and captures in the future study. With SS-OCT, we found female gen- data of ACV in less than 1 second. Thus, patients could der, increased age, higher LOCS III cortical grading, and cooperate with this test easier than the Scheimpflug system decreased AXL to be important predictors for smaller ACV or UBM. (3) Similarly to UBM, SS-OCT provides direct in normal cataract patients. Journal of Ophthalmology 5

Competing Interests [9]J.Zhang,J.S.Nelson,andZ.Chen,“Removalofamirror image and enhancement of the signal-to-noise ratio in Fourier- The authors declare that there is no conflict of interests domain optical coherence tomography using an electro-optic regarding the publication of this paper. phase modulator,” Optics Letters,vol.30,no.2,pp.147–149,2005. [10] S.-P.Chee, S.-W.N. Chan, and A. Jap, “Comparison of enhanced depth imaging and swept source optical coherence tomography Authors’ Contributions in assessment of choroidal thickness in Vogt-Koyanagi-Harada Wenwen He, Xiangjia Zhu, and Zhennan Zhao contributed disease,” Ocular Immunology and Inflammation,2016. equally to this work. Xiangjia Zhu designed the study; [11] D. S. W. Ting, G. C. M. Cheung, L. S. Lim, and I. Y. S. Wenwen He and Zhennan Zhao conducted the experiment; Yeo, “Comparison of swept source optical coherence tomog- Wenwen He and Zhennan Zhao collected the data; Wenwen raphy and spectral domain optical coherence tomography in He and Don Wolff analyzed and interpreted the data; Xiangjia polypoidal choroidal vasculopathy,” Clinical and Experimental Ophthalmology,vol.43,no.9,pp.815–819,2015. Zhu, Xinghuai Sun, and Yi Lu prepared, reviewed, and approved the paper. [12] G. Barteselli, D.-U. Bartsch, R. N. Weinreb et al., “Real-time full- depth visualization of posterior ocular structures: comparison between full-depth imaging spectral domain optical coherence Acknowledgments tomography and swept-source optical coherence tomography,” Retina,vol.36,no.6,pp.1153–1161,2016. This study has been supported by the National Natural Sci- [13] S. N. Ni, J. Tian, P. Marziliano, and H.-T. 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Research Article Corneal Biomechanical Findings in Contact Lens Induced Corneal Warpage

Fateme Alipour,1 Mojgan Letafatnejad,2 Amir Hooshang Beheshtnejad,1 Seyed-Farzad Mohammadi,1 Seyed Reza Ghaffary,1 Narges Hassanpoor,1 and Mehdi Yaseri3

1 Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran 2Tehran University of Medical Sciences, Tehran, Iran 3Eye Research Center and Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran

Correspondence should be addressed to Fateme Alipour; [email protected]

Received 1 April 2016; Accepted 31 July 2016

Academic Editor: Karim Mohamed-Noriega

Copyright © 2016 Fateme Alipour et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. To evaluate the difference in biomechanical properties between contact lens induced corneal warpage and normal and keratoconic eyes. Method. Prospective observational case control study, where 94 eyes of 47 warpage suspicious and 46 eyes of 23 keratoconic patients were included. Warpage suspected cases were followed until a definite diagnosis was made (warpage, normal, or keratoconus). Results. 44 eyes of 22 patients had contact lens related corneal warpage. 46 eyes of 23 people were diagnosed as nonwarpage normal eyes. 46 eyes of 23 known keratoconus patients were included for comparison. The mean age of the participants was 23.8 ± 3.8 years, and 66.2% of the subjects were female. The demographic and refractive data were not different between warpage and normal groups but were different in the keratoconus group. The biomechanical properties (corneal hysteresis or CH and corneal resistance factor or CRF) were different with the highest value in the warpage group followed by normal and keratoconus groups. CRF was 10.08 ± 1.75, 9.23 ± 1.22, and 7.38 ± 2.14 and CH was 10.21 ± 1.57, 9.59 ± 1.21, and 8.69 ± 2.34 in the warpage, normal, and keratoconus groups, respectively. Conclusion. Corneal biomechanics may be different in people who develop contact lens induced warpage.

1. Introduction Apart from serial examinations and follow-ups which are the definite way to differentiate contact lens induced corneal Contact lens induced corneal warpage is occasionally seen in warpage [7, 8], other features like the corneal topography people who regularly wear contact lenses [1, 2]. Considering andcornealthicknesspattern[9]havebeenproposedtohelp the high prevalence of the contact lens use among refractive with the differentiation of this condition from keratoconus. surgery candidates, the clinical picture could be especially Considering the major role of corneal biomechanical prop- confusing in the setting of refractive surgery when the erties in the pathogenesis of keratoconus, there may be a condition can mimic pathologies like keratoconus which is difference in the corneal biomechanical parameters between commonly considered an absolute contraindication to refrac- true keratoconic and corneal warpage in contact lens using tive surgery [3]. The usual suggested “off contact lens” waiting patients in theory. period in most refractive surgery clinics is about 2 weeks [4], In this study, we evaluated the biomechanical changes whichisnotnecessarilyenoughforresolvingthewarpage (using the Ocular Response Analyzer) in patients presenting induced by the long-term use of contact lenses. This waiting with corneal warpage and compared these changes with period (which may be even more than 2 months) [1, 5, 6] is biomechanical findings in patients with keratoconus. The not acceptable for many of the people who are accustomed to corneal biomechanical parameters, corneal hysteresis (CH) a spectacle-free lifestyle and have planned to have refractive and corneal resistance factor (CRF), are commonly used for surgery at a specific time. this purpose. 2 Journal of Ophthalmology

The corneal biomechanical parameters (CH and CRF) follow-up visit. To reduce variability due to diurnal variations canbeassessedbytheOcularResponseAnalyzer(ORA, in the corneal thickness [15] and CH [10], all evaluations were Reichert, Corp., Buffalo, NY). ORA measures the corneal performed between 11:00 and 14:00 pm. At least three accept- response to a rapid air pulse. Two measurements of the able ORA measurements were recorded for each patient and intraocular pressure at the first applanation (𝑃1)andthe themeanvaluewasconsideredfordataentry. second applanation (𝑃2) when the cornea flattens again as the The final categories were based on the consensus of3 air pressure falls are made. It has been found that the second cornea subspecialists (AH.B., F.A., and SF.M.), reviewing all applanation occurs at a lower pressure than the first appla- the records as nation. The difference between the two pressures has been termed CH and represents a function related to the viscoelas- (1) Contact lens induced corneal warpage. tic properties of the cornea [10]. In addition to CH, the ORA (2) Nonwarpage normal. (𝑃1−𝑘𝑃2) measures CRF, which is derived from the formula , (3) Keratoconus. where 𝑘 is a constant empirically determined so that CRF is more strongly associated with the central corneal thickness Diagnosis of keratoconus was made based on a combi- (CCT) than CH [11, 12]. nation of clinical signs like the presence of the scissor reflex on retinoscopy and biomicroscopic findings such as stromal thinning, conical protrusion, Fleischer’s ring, Vogt’s striae, 2. Methods and enlarged corneal nerves and topographic findings con- 2.1. Prospective Observational Case/Control Study. From the sistent with keratoconus like an asymmetric bow tie pattern refractive surgery candidates of the Farabi Eye Hospital (AB) or skewed radial axes (SRAX). Nonwarpage normal was Refractive Surgery Clinic, 94 eyes of 47 people who were defined as a stable pattern and refraction not compatible with suspicious for corneal warpage, based on the corneal topo- keratoconus, and contact lens induced corneal warpage was graphic pattern, were included in the study in the case group. defined as a refraction and topographic pattern compatible For the control group, 46 eyes of 23 known keratoconic with warpage returning to normal. patients who never wore contact lenses were included. These The demographic data, final CRF, and final CHwere control patients were selected from the Cornea Clinic of compared between these groups. Changes in CH and CRF Farabi Eye Hospital. were also evaluated in the case group. Patients with any form of corneal scarring were excluded The protocol of the study adhered to the tenets of the from the study. Abnormal topography in the corneal warpage Declaration of Helsinki and informed consent was obtained group was defined as central irregular astigmatism, loss of from all participants. radial symmetry, and reversal of the normal topographic pattern of progressive flattening of the corneal contour from 3. Statistical Analysis the center to the periphery [13]. The Pentacam (Oculus Optikgerate¨ GmbH, Wetzlar, Germany) or Orbscan (Bausch Descriptive statistics were used to evaluate the distribution & Lomb, Rochester, NY) were used for topographic measure- of the data. The normality of the data was tested with ments. The corneal biomechanical parameters (CH and CRF) Kolmogorov-Smirnov/Shapiro-Wilk test. We used the paired were assessed by Ocular Response Analyzer (ORA, Reichert, 𝑡-test to assess the changes within groups (corneal warpage). Corp., Buffalo, NY). As for the difference in the baseline pachymetry, Analysis of In the case group, the patients were asked not to wear Covariance (ANOVA) with adjustment for corneal thickness their contact lenses for 2 to 4 more weeks and return to was used to evaluate the difference between the groups. the clinic for examinations. Refraction, corneal imaging Considering the possible correlation of the results in two eyes, (Orbscan II or Pentacam), and ORA measurements (CH and we applied the GEE analysis. We used Bonferroni method to CRF) were repeated. At this stage, based on the changes in the adjust for multiple comparisons. 𝑃 values less than 0.05 were topographic pattern, the patients were diagnosed as follows: considered statistically significant. All statistical analyses were performed with SPSS software (IBM SPSS Statistics for (1) Contact lens induced corneal warpage—complete Windows, Version 22.0., Armonk, NY: IBM Corp.). 𝑃 values resolution. less than 0.05 were considered significant. (2) Possible contact lens induced corneal warpage— Finally, 44 eyes of 22 patients were found to have contact incomplete resolution. lens related corneal warpage. Frothy-six eyes of 23 patients (3) Keratoconus. were diagnosed as nonwarpage normal eyes. Two patients had warpage in only one eye and a nonwarpage normal stable The criteria for stabilization were defined as (1) manifest pattern in the other eye. Frothy-six eyes of 23 known kerato- refraction changes within 0.50 D, (2) keratometry changes conus patients were included for comparison (Figure 1). within 0.50 D, and (3) a normal corneal topography pattern Demographic and refractive data are shown in Table 1. [14]. There was a significant difference between the final diagnosis Those with suspicious incomplete warpage resolution categories regarding the age (𝑃 < 0.001), sex (𝑃 < 0.001), were requested to wait for 2–4 more weeks and all astigmatism (𝑃 < 0.001), and the thinnest point (𝑃 = 0.004). the abovementioned examinations were repeated at each According to the post hoc analysis (adjusted for multiple follow-up visit. The ORA measures were repeated in each comparisons by the Bonferroni method), the keratoconus Journal of Ophthalmology 3

Table 1: Demographic data according to the final diagnosis.

Group Parameter Total 𝑃 Keratoconus Normal Warpage † Age Mean ± SD 23.8 ± 3.8 21.3 ± 2.9 25.5 ± 4.3 25 ± 2.8 <0.001 Female 43 (66.2%) 8 (34.8%) 16 (80.0%) 19 (86.4%) ∗ Sex <0.001 Male 22 (33.8%) 15 (65.2%) 4 (20.0%) 3 (13.6%) Sphere Mean ± SD −3.39 ± 2.47 −2.98 ± 3.83 −3.55 ± 1.35 −3.55 ± 1.99 0.521§ Astigmatism Mean ± SD −1.4 ± 2.31 −3.42 ± 3.14 −0.58 ± 1.35 −0.66 ± 1.13 <0.001§ Spherical equivalent Mean ± SD −4.11 ± 2.73 −4.79 ± 4.31 −3.84 ± 1.33 −3.88 ± 2.19 0.847§ BCVA (decimal) Mean ± SD 0.95 ± 0.6 0.86 ± 1.11 0.99 ± 0.05 0.99 ± 0.04 0.775§ Thinnest Mean ± SD 534 ± 51 469 ± 60 535 ± 27 552 ± 50 0.004§ † Based on analysis of variance (ANOVA). ∗ Based on chi-square test. §Based on GEE analysis.

Table 2: Differences in the corneal biomechanical indexes according to the baseline diagnosis.

Group 95% CI Total Diff 𝑃§ Warpage Keratoconus Lower Upper Mean ± SD 9.06 ± 1.96 9.57 ± 1.59 7.38 ± 2.14 CRF 2.03 0.95 3.11 <0.001 Median (range) 9 (3.75 to 14.13) 9.25 (6.4 to 14.13) 7.39 (3.75 to 13.3) Mean ± SD 9.55 ± 1.76 9.81 ± 1.46 8.69 ± 2.34 CH 1.01 0.02 2.03 0.056 Median (range) 9.25 (4.05 to 15.56) 9.6 (6.6 to 13.65) 8.49 (4.05 to 15.56) Mean ± SD 542 ± 47 551 ± 39 480 ± 60 CCT 75 29 121 0.001 Median (range) 548 (423 to 639) 549 (453 to 639) 463 (423 to 600) §Based on GEE analysis.

group (𝑃 > 0.99). Gender difference was significant between Start of study keratoconus group and the two other groups (the warpage and the normal nonwarpage groups) with higher male to femaleratiointhekeratoconusgroup,(both𝑃 < 0.001) 94 eyes of 47 46 eyes of 23 known patients suspicious keratoconic patients but there was no difference between the nonwarpage normal to corneal warpage (Control) and warpage group (𝑃 = 0.868). The same was true for the difference in astigmatism (𝑃 < 0.001 for both keratoconus Detecting the group and nonwarpage normal and warpage and 𝑃 > 0.99 for status based on corneal imaging thenormalgroupversusthewarpagegroup)andthethinnest point (𝑃 = 0.003 for keratoconus versus nonwarpage normal, 𝑃 = 0.004 𝑃 > 0.99 Nonwarpage normal: for keratoconus versus warpage, and for 46 eyes of 23 patients normal versus warpage). Corneal biomechanical indices are shown in Tables 2 and 3. CH, CRF, and CCT were significantly different between Contact lens related corneal warpage: groups. The Bonferroni method was used for multiple com- 44 eyes of 22 patients parisons. Significant values are bolded in Table 3.

2 patients with lens related corneal warpsge in one eye and normal stable pattern in the other eye 4. Discussion (2 warpage eyes + 2 normal eyes) Analysis of the demographic data showed no significant Figure 1: Study subjects. differences in age, sex, and refraction between patients who suffered from warpage and normal participants without warpage. However, the participants in the keratoconus group group had a significant difference in age with nonwarpage were younger with a higher male to female ratio, thinner normal and warpage groups (both 𝑃 < 0.001)buttherewas corneas, higher refractive errors, and lower best corrected no difference between the nonwarpage normal and warpage visual acuity. Although this finding could be predicted 4 Journal of Ophthalmology

Table 3: Corneal biomechanical indexes according to the final diagnosis.

Keratoconus Nonwarpage normal Warpage 𝑃§ 𝑃1 𝑃2 𝑃3 Mean ± SD 7.38 ± 2.14 9.23 ± 1.22 10.08 ± 1.75 CRF <0.001 0.002 <0.001 0.066 Median (range) 7.39 (3.75 to 13.3) 9.15 (6.4 to 13) 9.63 (7.3 to 14.13) Mean ± SD 8.69 ± 2.34 9.59 ± 1.21 10.21 ± 1.57 CH 0.028 0.158 0.013 0.069 Median (range) 8.49 (4.05 to 15.56) 9.5 (6.6 to 13.2) 10.14 (7.65 to 13.65) Mean ± SD 480 ± 60 542 ± 26 562 ± 48 CCT 0.005 0.002 0.001 0.83 Median (range) 463 (423 to 600) 548 (489 to 593) 556 (453 to 639) Significant values are shown bolded. §Based on GEE analysis. 𝑃1: Comparison of keratoconus versus normal adjusted for multiple comparison based on Bonferroni method. 𝑃2: Comparison of keratoconus versus warpage adjusted for multiple comparison based on Bonferroni method. 𝑃3: Comparison of normal versus warpage adjusted for multiple comparison based on Bonferroni method. because of our selection method which was to include use more advanced methods for the measurement of corneal documented keratoconus patients who never used contact biomechanical properties. lenses in our control group, it might have resulted in some biases in our findings [16]. Competing Interests In our study, the mean CH and CRF were 9.59 ± 1.21 9.23 ± 1.22 and in the normal group, respectively, which was None of the authors has any related financial or intellectual lowerthantheresultsofastudybySedaghatetal.thatwas conflict of interests to disclose. conducted on a normal population from the north eastern part of Iran without considering the history of the contact lensuse(themeanCHandCRFforalleyeswere9.9 ± 1.4 Acknowledgments and 10.1 ± 1.6 mmHg, resp.) [17]. This may be either due This study was supported by a grant from Tehran University to changes induced by the long-time contact lens wearing of Medical Sciences. in our population, even those who had stable topographic and refractive results after discontinuation of the contact lens use, or due to different study populations. Other studies have References reported even higher CH and CRF values in the normal population [18, 19]. [1]X.Wang,J.P.McCulley,R.W.Bowman,andH.D.Cavanagh, “Time to resolution of contact lens-induced corneal warpage Interestingly, despite the fact that our first theory was prior to refractive surgery,” The CLAO Journal,vol.28,no.4,pp. “those who develop warpage are possibly more similar to 169–171, 2002. keratoconus patients,” we found a significant difference in [2] M. Schornack, “Hydrogel contact lens-induced corneal war- CH and CRF between participants with documented corneal page,” Contact Lens & Anterior Eye,vol.26,no.3,pp.153–159, warpage, normal participants (no warpage), and keratoconus 2003. patients; the highest values were seen in the warpage group. [3] S. S.-Y. Tseng, J. C.-J. Hsiao, and D. C.-K. Chang, “Mistaken Thesefindingsshowthattheremightbeastructuraldif- diagnosis of keratoconus because of corneal warpage induced ferenceinthecorneaofthepeoplewhodevelopcorneal by hydrogel lens wear,” Cornea,vol.26,no.9,pp.1153–1155,2007. warpage. Clinicians may be able to use this difference for [4] H. Hashemi, M. R. Firoozabadi, S. Mehravaran, and F. Gorouhi, predicting the development of corneal warpage in those “Corneal stability after discontinued soft contact lens wear,” who wish to use contact lenses. Another possible clinical Contact Lens & Anterior Eye,vol.31,no.3,pp.122–125,2008. implication of these findings is shortening the waiting time [5] F. Alba-Bueno, A.` Beltran-Masgoret, C. Sanjuan, M. Biarnes,´ for the resolution of possible corneal warpage. and J. Mar´ın, “Corneal shape changes induced by first and A study on changes in the corneal biomechanical indexes second generation silicone hydrogel contact lenses in daily after wearing orthokeratology contact lenses reported a wear,” Contact Lens and Anterior Eye,vol.32,no.2,pp.88–92, decrease in CRF that correlated with the duration of the 2009. contact lens use [20]. [6]L.T.Ng,E.M.Lee,andA.L.Nguyen,“Preoperativeassessment The idea of evaluating corneal biomechanical properties of corneal and refractive stability in soft contact lens wearing for differentiating contact lens induced corneal warpage from photorefractive candidates,” Optometry and Vision Science,vol. keratoconus is a novel idea. The results of this study showed 84,no.5,pp.401–409,2007. that there might be a potential application for detecting [7]K.A.LebowandR.M.Grohe,“Differentiatingcontactlens the subjects who are prone to warpage. Further studies are induced warpage from true keratoconus using corneal topog- required on the corneal structure and histology of these three raphy,” The CLAO Journal,vol.25,no.2,pp.114–122,1999. groups, with including one normal group with no history of [8] J. T. Holladay, “Keratoconus detection using corneal topogra- the contact lens use, to prove our findings and find biological phy,” JournalofRefractiveSurgery,vol.25,no.10,pp.S958–S962, explanations for these differences. It is also recommended to 2009. Journal of Ophthalmology 5

[9] S. C. Pflugfelder, Z. Liu, W.Feuer, and A. Verm, “Corneal thickness indices discriminate between keratoconus and contact lens-induced corneal thinning,” Ophthalmology,vol.109,no. 12, pp. 2336–2341, 2002. [10] D. A. Luce, “Determining in vivo biomechanical properties of thecorneawithanocularresponseanalyzer,”Journal of Cataract &RefractiveSurgery,vol.31,no.1,pp.156–162,2005. [11] D. Luce, “Methodology for cornea compensated IOP and corneal resistance factor for the Reichert Ocular Response Analyzer,” Investigative Ophthalmology & Visual Science,vol.47, no.13,p.2266,2006. [12] A. Kotecha, A. Elsheikh, C. R. Roberts, H. Zhu, and D. F. Garway-Heath, “Corneal thickness- and age-related biomechanical properties of the cornea measured with the ocular response analyzer,” Investigative Ophthalmology & Visual Sci- ence,vol.47,no.12,pp.5337–5347,2006. [13] S. E. Wilson, D. T. C. Lin, S. D. Klyce, J. J. Reidy, and M. S. Insler, “Topographic changes in contact lens-induced corneal warpage,” Ophthalmology,vol.97,no.6,pp.734–744,1990. [14]X.Wang,J.P.McCulley,R.W.Bowman,andH.D.Cavanagh, “Time to resolution of contact lens-induced corneal warpage prior to refractive surgery,” The CLAO Journal,vol.28,no.4, pp. 169–171, 2002. [15] C. L. Harper, M. E. Boulton, D. Bennett et al., “Diurnal variations in human corneal thickness,” British Journal of Ophthalmology,vol.80,no.12,pp.1068–1072,1996. [16] N. Terai, F. Raiskup, M. Haustein, L. E. Pillunat, and E. Spoerl, “Identification of biomechanical properties of the cornea: the ocular response analyzer,” Current Eye Research,vol.37,no.7, pp. 553–562, 2012. [17] M. R. Sedaghat, M. Sharepoor, S. Hassanzadeh, and M. Abr- ishami, “The corneal volume and biomechanical corneal factors: is there any orrelation?” Journal of Research in Medical Sci- ences,vol.17,no.1,pp.32–39,2012. [18]D.S.Ryan,C.D.Coe,R.S.Howard,J.D.Edwards,andK.S. Bower, “Corneal biomechanics following epi-LASIK,” Journal of Refractive Surgery,vol.27,no.6,pp.458–464,2011. [19] N. M. Yenerel, R. B. Kucumen, and E. Gorgun, “Changes in corneal biomechanics in patients with keratoconus after penetrating keratoplasty,” Cornea, vol. 29, no. 11, pp. 1247–1251, 2010. [20] D. L. A. Chen and P. Cho, “A pilot study on the corneal biomechanical changes in short-term orthokeratology,” Ophthalmic and Physiological Optics,vol.29,no.4,pp.464–471,2009. Hindawi Publishing Corporation Journal of Ophthalmology Volume 2016, Article ID 3025413, 5 pages http://dx.doi.org/10.1155/2016/3025413

Clinical Study Quantitative Analysis of Lens Nuclear Density Using Optical Coherence Tomography (OCT) with a Liquid Optics Interface: Correlation between OCT Images and LOCS III Grading

You Na Kim,1 Jin Hyoung Park,2,3 and Hungwon Tchah1,3

1 Department of Ophthalmology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea 2NUNEMISO Eye Center, Seoul, Republic of Korea 3Research Institute for Biomacromolecules, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea

Correspondence should be addressed to Hungwon Tchah; [email protected]

Received 17 June 2016; Accepted 9 August 2016

Academic Editor: Sang Beom Han

Copyright © 2016 You Na Kim et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. To quantify whole lens and nuclear lens densities using anterior-segment optical coherence tomography (OCT) with a liquid optics interface and evaluate their correlation with Lens Opacities Classification System III (LOCS III) lens grading and corrected distance visual acuity (BCVA). Methods. OCT images of the whole lens and lens nucleus of eyes with age-related nuclear cataract were analyzed using ImageJ software. The lens grade and nuclear density were represented in pixel intensity units (PIU) and correlations between PIU, BCVA, and LOCS III were assessed. Results. Forty-seven eyes were analyzed. The mean whole lens and lens nuclear densities were 26.99 ± 5.23 and 19.43 ± 6.15 PIU, respectively. A positive linear correlation was observed between lens 2 2 opacities (𝑅 = 0.187, 𝑝 < 0.01)andnucleardensity(𝑅 = 0.316, 𝑝 < 0.01) obtained from OCT images and LOCS III. Preoperative 2 BCVA and LOCS III were also positively correlated (𝑅 = 0.454, 𝑝 < 0.01). Conclusions. Whole lens and lens nuclear densities obtained from OCT correlated with LOCS III. Nuclear density showed a higher positive correlation with LOCS III than whole lens density. OCT with a liquid optics interface is a potential quantitative method for lens grading and can aid in monitoring and managing age-related cataracts.

1. Introduction densitometry in eyes with and without cataract. Although the magnitude of the density was higher in the cataract group, The Lens Opacities Classification System III (LOCS III) is the cataract group displayed marginally less repeatability than routinely used in most clinics to quantify cataract density. did the noncataract group [10]. CATALYS5 precision laser Since this assessment is based on a slit-lamp evaluation system is a newly developed equipment for femtosecond by ophthalmologists, it is limited by the observer bias laser-assisted cataract surgery, and this system comprises and reproducibility [1–3]. Although previous studies have a high quality spectral domain OCT using a liquid optics attempted quantitative lens grading using lens densitometry, interface (<11 𝜇m depth resolution, >12 mm image depth). such as the Scheimpflug system [4–6], there were several Conventional time-domain anterior segment OCT can only limitations, including the potential influence of the cornea [7] capture either the anterior or the posterior half of the lens at or the anterior lens surface on the assessment of the internal each time and integrate two disjointed images into a whole structure of the lens [8]. Also other studies have pointed image [11]. In contrast to the time-domain OCT, this spectral out some parameters of Scheimpflug system should be inter- OCT system can visualize entire lens anatomy, including pretated with caution [2], because the scattering effects of the posterior capsules, and can be used to measure cataract theposteriorcortexandposteriorcapsuleareinducedby density objectively [12, 13]. To the best of our knowledge, the lens position [9]. Kirkwood et al. described the repeata- commercialized technical equipment that can measure poste- bility and reproducibility of Scheimpflug imaging for lens rior capsule and the objective lens densities for the assessment 2 Journal of Ophthalmology of age-related nuclear cataract is not available at this time. Table 1: Patient demographic data. Therefore, the aim of the current study is to quantify lens ± density using OCT with a liquid optics interface and to Parameter Range Mean SD evaluate the correlation between lens density (obtained using Eyes (𝑛)47 OCT images), BCVA, and LOCS III lens opalescence grading Patients (𝑛)47 score system. Sex (male : female) 23 : 24 Age (years) 61.00–87.00 73.13 ± 6.35 2. Materials and Methods LOCS III grade 3.00–6.00 4.41 ± 1.03 Preop. BCVA (logMAR) 0.00–3.00 0.61 ± 0.78 2.1. Patients. The medical records of patients who underwent Preop. SE (diopters) −11.00–+3.13 −0.72 ± 2.55 femtosecond laser-assisted cataract surgery at the Asan Med- Whole lens density (PIU) 17.49–38.06 26.99 ± 5.23 ical Center (Seoul, Republic of Korea) between December ± 2013andJune2015werereviewed.Patientsaged≥60 years Lens nuclear density (PIU) 9.69–31.65 19.43 6.15 ± and with an LOCS III lens opalescence grading system score Lens thickness (pixels) 90.00–163.00 110.32 11.95 >3 were included in the study. Exclusion criteria included any ocular pathology that could influence quantitative OCT imaging and any other specified type of cataract. This study calculated automatically and scored in the range 0–50 in pixel was approved by the institutional review board of the Asan intensity units (PIU) (Figure 1). Medical Center (Seoul, Republic of Korea) (IRB no. 2016- 0645) and adhered to the tenets of the Declaration of 2.4. Statistical Analysis. To identify the correlations between Helsinki. LOCS III, BCVA, and nuclear density from OCT images, Spearman correlation coefficient analysis was carried out 2.2. Patient Assessment. Baseline examinations included using SPSS software (version 21, IBM, USA) anda 𝑝 < 0.05 measurement of uncorrected distance visual acuity (UDVA) was considered statistically significant. and corrected distance visual acuity (BCVA), manifest refraction using the fogging technique, slit-lamp examination of 3. Results the anterior segment, and dilated fundoscopy. Intraocular pressure (IOP) was measured using a noncontact tonome- 3.1. Patient Characteristics. A total of 47 eyes from 47 patients ter (Canon TX-20, Canon, NY, USA). Other measure- were included in the study (23 male, 24 female) and their ments included specular microscopy (CELLCHECK SL, mean age was 73.13 ± 6.35 years (range 61–87). The mean Konan medical, USA), optical biometry (IOLMaster, Zeiss, preoperative BCVA was 0.61 ± 0.78 logMAR units and the Germany), slit scanning corneal tomography (ORBSCAN, mean spherical equivalent was −0.72 ± 2.55 diopters. The BAUSCH & LOMB, USA), and macular and optic disc optical mean nuclear opalescence obtained from LOCS III was 4.41 ± coherence tomography (OCTIII, Heidelberg Engineering, 1.03 (range 3.00–6.00). From OCT images analysis, the mean Germany). All baseline examinations were performed by whole lens and nuclear densities were found to be 26.99 ± 5.23 specially trained optometrists. Prior to the surgery, the and 19.43 ± 6.15 PIU, respectively (Table 1). Among 47 eyes, purpose, as well as possible complications, was explained to subgroups of nuclear, cortical, and posterior subcapsular each patient, after which an informed written consent was cataract were analyzed by their age, preoperative BCVA, and obtained. LOCS III. Comparing three cataract groups with Kruskall Wallis test, only LOCS III grade showed significant difference 2.3. Lens Density Quantification. Using a traditional method, between each cataract group (𝑝 = 0.000,Table2). cataract density was measured based on LOCS III grading score following a slit lamp examination under mydriasis with 3.2. Lens Density and Inter Measurement Correlation. The tropicamide 0.5% and phenylephrine HCl 0.5%. To control lens opacity, measured using OCT, positively correlated with observer bias, only one specially trained ophthalmologist 2 LOCS III score (𝑅 =0.187,𝑝 < 0.01)(Figure2).Thenuclear (Hungwon Tchah) performed every slit lamp examination. 2 density showed a higher positive correlation (𝑅 =0.316,𝑝< The LOCS III grading score was assigned a numeric scale to 0.01 reflect the degree of nuclear opacity (3.0–6.0) in increments )(Figure3).Theanalysisoflensthicknessandpreoper- 𝑅2 of 0.50 and the eyes with a score >6.0 were excluded due to ative SE revealed no specific correlation between them ( = 𝑝 < 0.05 the limited resolution of posterior capsule in OCT images. 0.064, ). In addition, the relationship between preop- In this study, the OCT images from CATALYS precision erative BCVA and LOCS III and OCT-measured grading was lasersystemwereacquiredonthedayofcataractsurgeryand compared and positive correlation was observed only with 𝑅2 𝑝 < 0.01 femtosecond laser-assisted nuclear phacoemulsification was LOCS III score ( =0.264, ). performed in all cases. Although OCT images offer sagittal and axial views simultaneously, only sagittal view images were 4. Discussion analyzed to increase correlation with slit lamp examinations. Using the ImageJ program, the contours of the entire lens, Though age-related cataract is one of the major causes of nucleus, and lens thickness were measured manually by one blindness worldwide, the absence of an objective grading independent observer (You Na Kim). The mean density was system continues to be a challenge [14]. Phacoemulsification Journal of Ophthalmology 3

(a) (b)

(left) (right)

(c)

Area Mean Min Max Angle Length 1 14851 27.843 0 120 0 0 2 5245 22.418 0 103 0 0 3 95 35.042 0 114−90 94

(d)

Figure 1: The procedure for measuring lens opacity, lens nuclear density, and lens thickness using ImageJ program. (a) A CATALYS OCT image of anterior segment including entire lens. (b) The procedure for measuring lens thickness from the image. (c) The procedure for measuring whole lens density (left) and nuclear density (right). (d) Lens density and lens thickness values measured using ImageJ (pixel intensity unit).

Table 2: Demographic data and Lens Opacities Classification System (LOCS) III cataract grading.

Cataract Parameter Nuclear Cortical PSC 𝑝 value Eyes (𝑛)241214 Age (years) 72.96 ± 6.75 73.75 ± 6.45 72.36 ± 5.96 0.800 Preop. BCVA (logMAR) 0.69 ± 0.90 0.31 ± 0.27 0.69 ± 0.78 0.322 ∗ LOCS III grade 4.85 ± 0.99 3.50 ± 0.64 4.32 ± 0.82 0.000 Statistical significance between the three study groups analyzed by Kruskall Wallis test (∗: 𝑝 < 0.05). has been used as a definite treatment modality for age-related of camera based lens densitometry, such as Scheimpflug cataract. However, its irreversibility draws our attention while camera, there were trials evaluating the correlation between making an objective grading of cataract density and in lens image density and cataract opalescence [15]. Cabot et al. predicting phacodynamics during cataract surgery. Several described that the parameters, Objective Scatter Index (OSI) clinical classifications, including LOCS III, have been used and Modulation Transfer Function (MTF), from Optical to quantify lens density. However, their use has been limited Quality Analysis System (Visiometrics, Terrasa, Spain) are due to a lack of reproducibility and intraobserver variations correlated with the severity of the cataract according to the [2, 3]. In this respect, there have been numerous trials to LOCS III grade and with visual acuity in nuclear, cortical, standardize cataract grading systems. With the development posterior subcapsular cataract subgroups. In consequence 4 Journal of Ophthalmology

40.00 R2 = 0.187 very successful and to get constant result regardless of its lens magnification [3]. Furthermore, newly developed OCT with a liquid optics interface can visualize posterior capsule and 35.00 facilitates the analysis of lens density with greater objectivity. In this study, the correlations between LOCS III and lens 30.00 density, obtained from OCT with liquid optics interface imaging, and BCVAwere evaluated. Particularly, lens nuclear y = 17.28 + 2.2 ∗ x density and the LOCS III grading revealed a higher positive 2 2 Lens_PIU 25.00 correlationthanwholelensdensity(𝑅 =0.316,𝑅 =0.187,𝑝< 0.01, resp.). It seems that it reflects that nuclear opalescence 20.00 of LOCS III grading was classified as the color of nucleus of cataract. To our knowledge, this is the first study, which confirms the correlation between LOCS III and AS OCT 15.00 images, acquired using a liquid optics interface, including 3.00 3.50 4.00 4.50 5.00 5.50 6.00 entire posterior capsule of lens as a visual pathway. LOCS III Although OCT with liquid optics interface imaging can image the entire lens, as opposed to other anterior-segment Figure 2: The relationship between whole lens opacity density measured using optical coherence tomography (OCT) and LOCS OCT techniques, it has several limitations associated with the III. evaluation of lens anatomy [12, 13, 23]. Even when pupils were fully dilated, the posterior shadowing of pupils concealed the margin of the lens cortex. This imposed a restriction on iden- 35.00 R2 = 0.316 tifying the margins covering the entire lens capsule and could be the reason behind the observed higher correlation between 30.00 lens nuclear density and LOCS III score compared to whole lens opacity. Since a thick nucleus inhibits media penetration, 25.00 theposteriorcortexandposteriorcapsuleliningswerehardly visible in a lens densitometry system, in advanced cataract 20.00 y = 4.58 + 3.36 ∗ x [23]. In addition, other types of cataract, except age-related cataract, could not be evaluated in this study, which is one Nu_PIU of the limitations. Apart from these technical limitations, the 15.00 small number of cases is another limitation of this study to verify its repeatability and reproducibility. In this respect, fur- 10.00 ther study should be designed with bigger sample size to make up for the limitation of reproducibility in this study. 5.00 Concerning quantifying cataract grading, OCT-based 3.00 3.50 4.00 4.50 5.00 5.50 6.00 measurement of lens density is more objective and repro- LOCS III ducible compared with LOCS III grading. Therefore, these results imply that the lens densitometry using OCT with Figure 3: The relationship between lens nuclear densities measured liquid optics interface imaging can be one of the options using optical coherence tomography (OCT) and LOCS III. for cataract grading. Like OCT with liquid optics interface imaging, the advent of objective cataract grading imaging tools enables the evaluation of cataract progression in long- of these results, the study determined that OSI and MTF term follow-up patients and providing consistent medical could be useful parameters to discriminate objective cataract consultation [15, 24, 25]. grading of crystalline lens [16]. In addition, ocular wavefront aberration was applied from ray tracing system to evaluate 5. Conclusion visual quality distortion related to nuclear sclerosis [17, 18]. Although these are developed as reproducible methods for The development of anterior-segment imaging modalities cataract grading, Scheimpflug camera imaging was limited enables the visualization of lens density for cataract surgery by the use of a single peak value of lens density to compare [26]. Among these modalities, CATALYS precision laser the average nuclear densities [19, 20] and it cannot visualize system providing OCT images can capture an image of the posterior cortex and capsule appropriately. In addition, OSI entirelensatonego[12,13].Inconclusion,PIUofwhole or wavefront aberration analysis cannot provide direct infor- lens and nuclear densities obtained from OCT with a liquid mation of the lens opacification but only reflects information optics interface correlated with LOCS III score and BCVA. affected by scattering [21, 22]. Contrary to the methods The nuclear density showed a higher positive correlation with mentioned above, anterior segment OCT can reveal the LOCS III than the whole lens density and BCVA. In other complete lens anatomy directly. In the recent study directed words, CATALYS OCT-based measurement of lens density by Skiadaresi et al., images of anterior and posterior segment wasanalyzedtoestablishanobjectivecataractgradingsystem from spectral or Fourier-domain OCT have proven to be and the correlation with LOCS III was confirmed. Although Journal of Ophthalmology 5

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Research Article Rotating Scheimpflug Imaging Indices in Different Grades of Keratoconus

Sherine S. Wahba,1,2 Maged M. Roshdy,1,2 Rania S. Elkitkat,1,2 and Karim M. Naguib1,2

1 Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt 2Al Watany Eye Hospitals, 211 Alhegaz Street, Alhegaz Square, Heliopolis, Cairo 11361, Egypt

Correspondence should be addressed to Rania S. Elkitkat; [email protected]

Received 9 March 2016; Revised 26 June 2016; Accepted 10 July 2016

Academic Editor: Sang Beom Han

Copyright © 2016 Sherine S. Wahba et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. To evaluate accuracy of various Keratoconus (KC) screening indices, in relation to Topographic Keratoconus (TKC) grading. Setting.AlWatanyEyeHospital,Cairo,Egypt.Methods. Data of 103 normal (group 1)and73KCeyes(group 2), imaged by Pentacam (branded as Allegro Oculyzer), were analysed. Group 2 was divided into 2a: 14 eyes (TKC = 1, early KC), 2b:25eyes (TKC = 1 to 2 or 2, moderate KC), and 2c:34eyes(TKC=2to3upto4,severeKC).Participantswerefollowedupforsixyears to confirm diagnosis. Area under the receiver operating characteristic curve (AUROC) was calculated for evaluated curvature, elevation, and pachymetry indices with various reference shapes at different diameters. Results. When comparing normal to KC eyes, ten indices had significantly higher AUROC. Only five of them had significantly higher AUROC in early KC compared to normal corneas: Pachymetry Progression Index- (PPI-) Maximum (Max), Ambrosio’s´ Relational Thickness- (ART-) Max, PPI-Max minus PPI-Minimum (Min), central corneal thickness (CCT), and diagonal decentration of thinnest point from the apex (AUROC = 0.690, 0.690, 0.687, 0.683, and 0.674, resp.). Conclusion. Generally, ten pachymetry and elevation-based indices had significantly higher AUROC. Five indices had statistically significant high AUROC when comparing early KC to normal corneas.

1. Introduction authors believe that elevation maps are better than axial curvature maps for KC screening [3]. Others claim that The hallmark characteristic of Keratoconus (KC) is the devel- curvatureisstillthemostsensitive[4]. opment of localized, cone-shaped ectasia accompanied by The rotating Scheimpflug camera “Pentacam” (Oculus corneal thinning in the area of the cone. This leads to irregular GmbH, Wetzlar, Germany) can generate various indices astigmatism and steeper corneal curvature over the area of within each of the three indices subgroups. the cone [1]. The early detection of these changes is usually Pentacam allows for measuring local elevation points by based on Placido-based corneal topography and rotating fitting the corneal shape to a best-fit sphere (BFS) reference Scheimpflug camera corneal tomography. However, there surface with variable diameters or to a best-fit toric ellipsoid are confounding conditions that can imply topographic and surface (BFTE), which simulates more the corneal shape than tomographic corneal changes resembling KC, such as corneal the BFS [5]. The guidelines differ between authorities. For scarring, hyperopic refractive surgery, contact lens-induced instance, some prefer using BFS based on the analysis of 8 mm warpage [2], and even normal variants of topographic curva- zone around the corneal apex, especially for refractive surgery ture patterns. screening [6, 7], others keep the device default at 9 mm zone, There are several tomographic criteria for KC diagnosis. although there are some concerns about it; that is, it is more They can be divided into three main subgroups: curvature- difficult to get reliable scans without wide palpebral fissure. based, elevation-based, and pachymetry-based. Unfortu- On the contrary, BFTE has been recommended for use by nately, none of them is 100% sensitive and specific. Some other studies, as they concluded that toric ellipsoid reference 2 Journal of Ophthalmology surface is the most sensitive reference body to compare KC to (b) radii of curvature of the 7,8, and 9 mm posterior normal corneas [8–10]. BFS (in mm). More recently, there have been other proposed indices; oneofthemostvaluableKCindicesistheAmbrosio’s´ (iv) Determinants of posterior BFTE: Relational Thickness (ART) [11]. This study aims at comparing the accuracy of each of the (a) eccentricity of the 7, 8, and 9 mm posterior tested indices at various best-fit reference surfaces, in cohorts BFTE, of KC and normal corneal cases who were followed up for (b) flattest and steepest radii of curvature of the 7, 8, six years, and to evaluate the accuracy of various indices in and 9 mm posterior BFTE (in mm). relation to Topographic KC (TKC) grading. To the best of our knowledge, our study is innovative Elevation indices are as follows: in evaluating the accuracy of KC indices using different reference surfaces of various diameters when applicable. (i) Elevation of the thinnest point from the 7 mm poste- Moreover, novelty lies in comparing the tested indices against rior (PE) BFS (in 𝜇m). time evidence, through our six-year follow-up interval (stability even after LASIK surgeries of normal corneas and (ii) Elevation of the thinnest point from the 8 and 9 mm spontaneous progression over years in KC cases). Time anterior (AE) and posterior (PE) BFS and difference between corresponding anterior and posterior values evidence is a definite proof of diagnosis not relying on 𝜇 subjective assessment. (in m). (iii) Elevation of the thinnest point from the 7,8, and 9 mm 2. Patients and Methods posterior (PE) BFTE (in 𝜇m). A retrospective study was conducted using the data from (iv) Maximum elevation, minimum elevation, and the 𝜇 consecutive patients’ files that were imaged in the time difference between them (in m) from the 8 and interval between June 2008 and December 2009, using the 9mmanteriorBFS. Pentacam branded as Allegro Oculyzer (WaveLight, GmbH, (v) Maximum elevation, minimum elevation, and the Erlangen, Germany) [12] with software version 1.16r12 at Al difference between them (in 𝜇m) from the 7, 8 and Watany (National) Eye Hospital, Cairo, Egypt. Patients with 9mmposteriorBFS. any detected corneal pathology other than KC and patients with history of ocular surgery, contact lens wear during the (vi) Maximum elevation, minimum elevation, and the previous two weeks, or narrow palpebral fissure impeding difference between them (in 𝜇m)fromthe7,8,and reliable imaging were excluded from the study. Any patient 9 mm posterior BFTE. with questionable diagnosis at the time of initial Pentacam imaging was also excluded. Moreover, the patients were Pachymetry indices are as follows: followed up until December 2015 to confirm the diagnosis andhencetoconfirmandevaluatetheresults. (i) Pachymetry at corneal apex, corneal center, and 𝜇 Every eye was scanned at least thrice by the Allegro thinnest point (in m). Oculyzer, in a dark room and according to the recommen- (ii) Pachymetry Progression Index-Average (PPI-Avg), dationsstatedinthedevicemanual.Eachscanincluded25 Minimum (PPI-Min), and Maximum (PPI-Max) and Scheimpflug images. Despite good repeatability, data were the difference between PPI-Max and PPI-Min (PPI- collected from the most reliable scan as stated by the “QS” Max minus PPI-Min). pop-up box (i.e., largest analysed area, valid data percent, andgoodalignment).Thedatawerecollectedfromthe (iii) Ambrosio’s´ Relational Thickness-Average (ART-Avg), automatically calculated indices or generated by manually Minimum (ART-Min), and Maximum (ART-Max). changing the reference surface shape (BFS or BFTE) and (iv) Horizontal and vertical decentration of the thinnest calculation area (7, 8, or 9 mm) and getting the elevation point from the apex and the resultant diagonal values on mouse click. The investigated indices were as decentration [=√(squared horizontal decentration + follows. squared vertical decentration) (in mm)]. Curvature indices are as follows: Patients were classified into two groups according to TKC (i) Mean eccentricity of the anterior corneal surface in staging adopted by the device software; group 1 included 103 the central 3 mm. normal eyes, while group 2 is comprised of 73 eyes with KC. (ii) Mean radii of curvature of anterior and posterior Group 2 was furtherly divided into subgroups: group 2a:14 corneal surfaces in the central 3 mm (in mm). eyes (TKC = 1, early KC), group 2b:25eyes(TKC=1to2or (iii) Determinants of BFS: 2, moderate KC), and group 2c: 34 eyes (TKC = 2 to 3, 3, 3 to 4, or 4, severe KC). (a)radiiofcurvatureofthe8and9mmanterior The study adhered to the Tenets of the Declaration of BFS (in mm), Helsinkiandtothelocalethicsstandards. Journal of Ophthalmology 3

Table 1: The mean, SD, and 95% confidence interval (CI) of all tested KC detecting parameters. Radii of curvature are in mm, elevations in 𝜇m, pachymetry in 𝜇m, and decentration in mm.

Normal Keratoconusstages1to4 Indices Mean SD 95%CI Mean SD 95%CI Curvature indices Central 3 mm Mean radius of curvature of anterior 3 mm corneal surface 7.725 0.2305 7.323–8.149 6.954 0.6640 5.296–8.124 Mean radius of curvature of posterior 3 mm corneal surface 6.425 0.256 6.040–6.809 5.624 0.685 4.145–6.777 Mean eccentricity of the anterior corneal surface 0.519 0.132 0.210–0.730 0.799 0.3312 −0.034–1.310 Determinants of BFS Radius of curvature of the 8 mm anterior BFS 7.786 0.2252 7.413–8.200 7.350 0.445 6.191–8.230 Radius of curvature of the 9 mm anterior BFS 7.833 0.2225 7.462–8.269 7.488 0.398 6.535–8.284 Radius of curvature of the 7 mm posterior BFS 6.390 0.2147 5.991–6.758 5.935 0.4148 5.109–6.700 Radius of curvature of the 8 mm posterior BFS 6.464 0.3544 6.031–6.790 6.125 0.3842 5.465–7.022 Radius of curvature of the 9 mm posterior BFS 6.548 0.3426 6.101–6.899 6.280 0.3041 5.765–6.981 Determinants of BFTE Flattest radius of curvature of the 7 mm posterior BFTE 6.644 0.2495 6.143–7.152 5.972 0.7057 4.312–6.947 Steepest radius of curvature of the 7 mm posterior BFTE 6.175 0.2317 5.741–6.609 5.273 0.6972 3.971–6.630 Eccentricity of the 7 mm posterior BFTE 0.181 0.3173 −0.441–0.765 0.618 0.5282 −0.447–1.350 Flattest radius of curvature of the 8 mm posterior BFTE 6.655 0.2507 6.143–7.169 5.972 0.7057 4.312–6.947 Steepest radius of curvature of the 8 mm posterior BFTE 6.175 0.2317 5.741–6.609 5.278 0.6936 3.971–6.630 Eccentricity of the 8 mm posterior BFTE 0.181 0.3173 −0.441–0.765 0.618 0.5282 −0.447–1.350 Flattest radius of curvature of the 9 mm posterior BFTE 6.658 0.2665 6.143–7.169 5.972 0.7057 4.312–6.947 Steepest radius of curvature of the 9 mm posterior BFTE 6.175 0.2317 5.741–6.609 5.287 0.7092 3.971–6.630 Eccentricity of the 9 mm posterior BFTE 0.181 0.3173 −0.441–0.765 0.618 0.5282 −0.447–1.350 Elevation indices Using BFS Elevation of the thinnest point from the 7 mm posterior BFS 1.5 3.13 −4.0–9.9 46.2 32.7 2.3–115.4 Maximum elevation from the 7 mm posterior BFS 32.8 15.12 17.1–72.6 79.9 34.3 27.7–153.7 Minimum elevation from the 7 mm posterior BFS −34.4 15.4 −75.0–−14.1 −76.5 33.5 −160.9–−29.3 Maximum minus minimum elevation from the 7 mm posterior 67.2 29.2 34.0–142.8 156.48 64.2 60.6–296.0 BFS Elevation of the thinnest point from the 8 mm anterior BFS 2.6 1.5 0.0–6.0 26.7 17.7 2.0–68.7 Elevation of the thinnest point from the 8 mm posterior BFS 4.1 4.7 −2.0–17.8 58.4 39.0 6.3–143.4 Elevation of the thinnest point from the 8 mm posterior BFS 1.5 4.5 −5.0–14.0 31.8 22.5 1.0–77.0 minus that of anterior BFS Maximum elevation from the 8 mm posterior BFS 51.4 23.3 21.0–107.9 89.6 33.3 35.0–159.4 Minimum elevation from the 8 mm posterior BFS −43.0 18.3 −93.9–−22.1 −90.9 41.1 −198.9–−32.0 Maximum minus minimum elevation from the 8 mm posterior 94.5 37.9 49.2–188.6 180.5 71.4 67.6–351.8 BFS Elevation of the thinnest point from the 9 mm anterior BFS 4.5 2.0 1.0–9.0 34.0 21.5 6.0–90.7 Elevation of the thinnest point from the 9 mm posterior BFS 9.9 6.8 2.0–31.9 72.7 43.9 11.0–171.8 Elevation of the thinnest point from the 9 mm posterior BFS 5.3 6.2 −2.0–24.9 38.7 24.0 2.3–89.0 minus that of anterior BFS Maximum elevation from the 9 mm posterior BFS 76.5 28.16 43.1–145.9 112.836 41.9722 48.7–212.7 Minimum elevation from the 9 mm posterior BFS −57.2 21.2 −124.0–−33.2 −104.8 61.0 −248.4–−40.3 Maximum minus minimum elevation from the 9 mm posterior 133.7 45.7 77.6–284.5 217.6 89.23 87.3–428.0 BFS 4 Journal of Ophthalmology

Table 1: Continued. Normal Keratoconus stages 1 to 4 Indices Mean SD 95%CI Mean SD 95%CI Using BFTE Elevation of the thinnest point from the 7 mm posterior BFTE 3.5 2.8 −1.0–10.0 37.6 24.9 0.0–97.01 Maximum elevation from the 7 mm posterior BFTE 18.0 10.7 6.1–40.0 71.3 54.8 17.7–225.6 Minimum elevation from the 7 mm posterior BFTE −25.8 8.6 −47.8–−12.1 −72.8 39.6 −187.4–−18.3 Maximum minus minimum elevation from the 7 mm posterior 43.8 16.3 23.0–80.3 144.1 88.3 39.3–393.1 BFTE Elevation of the thinnest point from the 8 mm posterior BFTE 4.3 3.9 −2.0–13.0 39.5 26.45 −3.0–104.0 Maximum elevation from the 8 mm posterior BFTE 43.9 22.2 11.1–114.8 103.1 84.1 23.0–360.0 Minimum elevation from the 8 mm posterior BFTE −33.4 11.7 −62.9–−16.1 −89.9 40.9 −185.1–−29.0 Maximum minus minimum elevation from the 8 mm posterior 77.3 28.2 32.1–141.7 192.9 114.2 68.0–557.4 BFTE Elevation of the thinnest point from the 9 mm posterior BFTE 3.6 5.6 −5.0–16.9 38.7 30.8 −18.34–111.8 Maximum elevation from the 9 mm posterior BFTE 89.9 39.5 35.2–174.6 170.8 152.9 39.6–665.5 Minimum elevation from the 9 mm posterior BFTE −42.1 15.5 −88.3–−21.1 −114.5 50.2 −217.5–−32.7 Maximum minus minimum elevation from the 9 mm posterior 132.0 43.3 65.2–231.4 285.2 177.1 107.3–859.2 BFTE Pachymetry indices Apex thickness 545.3 35.4 471.7–624.3 482.5 39.4 384.3–573.4 Central corneal thickness 545. 5 35.5 471.7–623.4 491.4 35.3 408.9–573.4 Thinnest point thickness 543.5 35.7 471.7–622.3 465.1 68.1 361.8–566.7 PPI-Min 0.543 0.1512 0.300–0.800 1.504 0.8265 0.500–3.570 PPI-Avg 0.826 0.1365 0.600–1.100 2.104 1.0454 0.900–4.967 PPI-Max 1.077 0.1716 0.800–1.400 2.800 1.3960 1.232–6.705 PPI-Max minus PPI-Min 0.534 0.189 0.300–0.992 1.296 0.763 0.400–3.835 ART-Min 1109.9 430.9 613.0–2044.2 423.3 272.5 94.0–1045.4 ART-Avg 677.6 131.4 395.7–975.2 276.6 138.2 75.7–616.9 ART-Max 517.8 90.6 326.6–697.0 207.1 100.6 54.6–427.5 Horizontal decentration of the thinnest point from the apex 0.026 0.569 −0.948–1.019 −0.087 0.574 −0.940–0.827 Vertical decentration of the thinnest point from the apex −0.273 0.208 −0.639–0.214 −0.519 0.347 −1.394–0.110 Diagonal decentration of the thinnest point from the apex 0.618 0.240 0.202–1.088 0.799 0.288 0.366–1.525 SD:standarddeviation,95% CI: 95% confidence interval, BFS: best-fit sphere, BFTE: best-fitc tori ellipsoid, PPI-Min: Pachymetry Progression Index-Minimum, PPI-Avg: Pachymetry Progression Index-Average, PPI-Max: Pachymetry Progression Index-Maximum, ART-Min: Ambrosio’s´ Relational Thickness-Minimum, ART-Avg: Ambrosio’s´ Relational Thickness-Average, and ART-Max: Ambrosio’s´ Relational Thickness-Maximum.

2.1. Statistical Analysis. Data were collected and verified, and to 53.2) and 27.8 ± 7.3 years (range 14 to 44.4) in normal and the compound indices were calculated using Microsoft Excel KC groups, respectively. There was no statistically significant 2010 (Redmond, Washington, USA). Statistical analyses were difference between the two groups (𝑃 = 0.253). The ratios performed using IBM SPSS Statistics (v19; Armonk, NY, betweenrightandlefteyeswere53:50and40:33innormal USA) and Medcalc v11.1.1.0 (MedCalc, Belgium). and KC groups, respectively (𝑃 = 0.777). The following tests were performed: calculation of the mean,standarddeviation(SD),unpaired𝑡-test, sensitiv- The mean, SD, and 95% confidence interval (CI) of each ity, specificity at different cut-off values, likelihood ratios, parameter are listed in Table 1. and area under the receiver operating characteristic curve Table 2 represents the AUROC of all tested indices when (AUROC). AUROCs are compared using the DeLong comparing normal corneas to all other grades of KC collec- method [13]. Values were considered statistically significant tively, and Table 3 represents the ten indices with the highest 𝑃 if value was less than 0.05. AUROC. The AUROCs of these ten indices were statistically 𝑃 > 0.05 3. Results noninferior to each other ( ). Meanwhile, all other indices had statistically inferior AUROC to that of at least one 3.1. Cases Characteristics. Average patients’ age at the time of of these ten indices. It is worth mentioning that none of the the initial Pentacam imaging was 29.2 ± 8.8 years (range 17.4 curvature indices was among these ten indices. Journal of Ophthalmology 5

Table 2: AUROC of all indices when differentiating all grades of KC collectively from normal corneas.

Indices AUROC SEM 95% CI Curvature indices Central 3 mm Mean radius of curvature of anterior 3 mm 0.885 0.03 0.828 to 0.928 Mean radius of curvature of posterior 3 mm 0.882 0.0307 0.824 to 0.925 Mean eccentricity of the anterior surface 0.811 0.039 0.745 to 0.866 Using BFS Radius of curvature of the 8 mm anterior BFS 0.812 0.035 0.747 to 0.867 Radius of curvature of the 9 mm anterior BFS 0.776 0.0374 0.707 to 0.835 Radius of curvature of the 7 mm posterior BFS 0.841 0.0323 0.779 to 0.892 Radius of curvature of the 8 mm posterior BFS 0.784 0.037 0.712 to 0.856 Radius of curvature of the 9 mm posterior BFS 0.746 0.038 0.671 to 0.821 Using BFTE Flattest radius of curvature of the 7 mm posterior BFTE 0.829 0.0344 0.765 to 0.882 Steepest radius of curvature of the 7 mm posterior BFTE 0.895 0.0298 0.840 to 0.936 Eccentricity of the 7 mm posterior BFTE 0.757 0.0402 0.687 to 0.818 Flattest radius of curvature of the 8 mm posterior BFTE 0.834 0.034 0.770 to 0.885 Steepest radius of curvature of the 8 mm posterior BFTE 0.895 0.0298 0.840 to 0.936 Eccentricity of the 8 mm posterior BFTE 0.757 0.0402 0.687 to 0.818 Flattest radius of curvature of the 9 mm posterior BFTE 0.833 0.034 0.769 to 0.885 Steepest radius of curvature of the 9 mm posterior BFTE 0.884 0.0313 0.827 to 0.927 Eccentricity of the 9 mm posterior BFTE 0.757 0.0402 0.687 to 0.818 Elevation indices Elevation of the thinnest point from the 7 mm posterior BFS 0.971 0.0137 0.934 to 0.990 Maximum elevation from the 7 mm posterior BFS 0.916 0.0202 0.865 to 0.953 Minimum elevation from the 7 mm posterior BFS 0.908 0.0219 0.855 to 0.946 Maximum minus minimum elevation from the 7 mm posterior BFS 0.923 0.0193 0.873 to 0.957 Elevation of the thinnest point from the 7 mm posterior BFTE 0.953 0.0214 0.910 to 0.979 Maximum elevation from the 7 mm posterior BFTE 0.944 0.0161 0.899 to 0.973 Minimum elevation from the 7 mm posterior BFTE 0.91 0.0264 0.858 to 0.948 Maximum minus minimum elevation from the 7 mm posterior BFTE 0.949 0.0174 0.905 to 0.976 Elevation of the thinnest point from the 8 mm anterior BFS 0.968 0.018 0.930 to 0.989 Elevation of the thinnest point from the 8 mm posterior BFS 0.979 0.00837 0.945 to 0.995 Maximum elevation from the 8 mm posterior BFS 0.837 0.0304 0.775 to 0.889 Minimum elevation from the 8 mm posterior BFS 0.89 0.0255 0.834 to 0.932 Maximum minus minimum elevation from the 8 mm posterior BFS 0.875 0.0272 0.817 to 0.920 Elevation of the thinnest point from the 8 mm anterior BFS minus that of posterior BFS 0.961 0.0139 0.920 to 0.984 Elevation of the thinnest point from the 8 mm posterior BFTE 0.933 0.0264 0.885 to 0.965 Maximum elevation from the 8 mm posterior BFTE 0.806 0.0342 0.739 to 0.861 Minimum elevation from the 8 mm posterior BFTE 0.923 0.022 0.873 to 0.958 Maximum minus Minimum elevation from the 8 mm posterior BFTE 0.912 0.0225 0.861 to 0.950 Elevation of the thinnest point from the 9 mm anterior BFS 0.979 0.0118 0.945 to 0.995 Elevation of the thinnest point from the 9 mm posterior BFS 0.977 0.0098 0.942 to 0.994 Maximum elevation from the 9 mm posterior BFS 0.772 0.0364 0.703 to 0.832 Minimum elevation from the 9 mm posterior BFS 0.865 0.0294 0.805 to 0.912 Maximum minus minimum elevation from the 9 mm posterior BFS 0.832 0.0324 0.768 to 0.884 Elevation of the thinnest point from the 9 mm anterior BFS minus that of posterior BFS 0.952 0.0171 0.909 to 0.979 Elevation of the thinnest point from the 9 mm posterior BFTE 0.904 0.0309 0.851 to 0.943 Maximum elevation from the 9 mm posterior BFTE 0.671 0.0451 0.597 to 0.740 Minimum elevation from the 9 mm posterior BFTE 0.934 0.0204 0.886 to 0.966 Maximum minus minimum elevation from the 9 mm posterior BFTE 0.887 0.0264 0.831 to 0.930 6 Journal of Ophthalmology

Table 2: Continued. Indices AUROC SEM 95% CI Pachymetry indices Apex thickness 0.897 0.0268 0.842 to 0.938 Central corneal thickness 0.878 0.0288 0.820 to 0.922 Thinnest point thickness 0.915 0.0241 0.863 to 0.952 PPI-Min 0.939 0.0208 0.893 to 0.969 PPI-Avg 0.978 0.00973 0.944 to 0.994 PPI-Max 0.987 0.00563 0.958 to 0.998 PPI-Max minus PPI-Min 0.903 0.0246 0.850 to 0.943 ART-Min 0.949 0.0183 0.905 to 0.976 ART-Avg 0.976 0.0101 0.942 to 0.993 ART-Max 0.987 0.00605 0.957 to 0.998 Horizontal decentration of the thinnest point from the apex 0.558 0.0444 0.481 to 0.633 Vertical decentration of the thinnest point from the apex 0.737 0.0397 0.666 to 0.801 Diagonal decentration of the thinnest point from the apex 0.686 0.0403 0.612 to 0.754 AUROC: area under the receiver operating characteristic curve. SEM: standard error of the mean. 95% CI: 95% confidence interval of the AUROC. BFS: best-fit sphere, BFTE: best-fit toric ellipsoid, PPI-Min: Pachymetry Progression Index-Minimum, PPI-Avg: Pachymetry Progression Index-Average, PPI-Max: Pachymetry Progression Index-Maximum, ART-Min: Ambrosio’s´ Relational Thickness-Minimum, ART-Avg: Ambrosio’s´ Relational Thickness-Average, and ART-Max: Ambrosio’s´ Relational Thickness-Maximum.

Table 3: The indices with highest AUROC.

AUROC Indices AUROC 95% CI Criterion Sensitivity Specificity LR+ LR− compared to that of PPI-Max PPI-Max 0.987 0.958 to 0.998 >1.4 91.78 98.06 47.27 0.084 ART-Max 0.987 0.957 to 0.998 ≤412 97.26 93.2 14.31 0.029 𝑃 = 0.880 Elevation of the thinnest point from 0.979 0.945 to 0.995 >7 95.89 92.23 12.35 0.045 𝑃 = 0.501 the 9 mm anterior BFS Elevation of the thinnest point from 0.968 0.930 to 0.989 >5 91.78 96.12 23.63 0.086 𝑃 = 0.288 the 8 mm anterior BFS Elevation of the thinnest point from 0.979 0.945 to 0.995 >20 86.3 100 N/A 0.14 𝑃 = 0.229 the 8 mm posterior BFS Elevation of the thinnest point from 0.971 0.934 to 0.990 >10 87.67 100 N/A 0.12 𝑃 = 0.217 the 7 mm posterior BFS Elevation of the thinnest point from 0.977 0.942 to 0.994 >22 89.04 96.12 22.93 0.11 𝑃 = 0.199 the 9 mm posterior BFS PPI-Avg 0.978 0.944 to 0.994 >1.1 87.67 98.06 45.15 0.13 𝑃 = 0.147 Elevation of the thinnest point from 0.953 0.910 to 0.979 >10 87.67 99.03 90.3 0.12 𝑃 = 0.104 the 7 mm posterior BFTE ART-Avg 0.976 0.942 to 0.993 ≤496 94.52 94.17 16.23 0.058 𝑃 = 0.089 All other tested indices 𝑃<0.05 AUROC: area under the receiver operating characteristic curve. 95% CI: 95% confidence interval of the AUROC. LR+: likelihood ratio of positive results. LR−: likelihood ratio of negative results. 𝑃 from PPI-Max: probability of chance that the AUROC is less than that of PPI-Max. PPI-Max: Pachymetry Progression Index-Maximum, ART-Max: Ambrosio’s´ Relational Thickness-Maximum, BFS: best-fit sphere,-Avg: PPI Pachymetry Progression Index-Average, BFTE: best- fit toric ellipsoid, and ART-Avg: Ambrosio’s´ Relational Thickness-Average.

Among the examined patients of both groups, pachym- ART-Max was (≤412 with sensitivity 97.26% and specificity etry progression indices showed the highest AUROC accu- 93.2%). racy among the evaluated parameters, where the Pachymetry The further analysis of the indices according to patients’ Progression Index-Maximum (PPI-Max) and Ambrosio’s´ grouping (based on TKC grading) showed that the mean Relational Thickness-Maximum (ART-Max) had the same values of all indices were significantly different when com- highest AUROC (0.987). The best cut-off for PPI-Max was paring group 2c corneas and normal corneas (𝑃 < 0.05), (>1.4 with sensitivity 91.78% and specificity 98.06%) and for with the only exception of horizontal decentration of the Journal of Ophthalmology 7

Table 4: Scheimpflug imaging indices differentiating between GROUP 2a KC and normal corneas.

Indices AUROC SEM 95% CI 𝑃 value PPI-Max 0.690 0.038 0.615 to 0.765 0.018 ART-Max 0.690 0.038 0.615 to 0.764 0.019 PPI-Max minus PPI-Min 0.687 0.055 0.579 to 0.796 0.020 Central corneal thickness 0.683 0.048 0.590 to 0.776 0.023 Diagonal decentration of the thinnest 0.674 0.062 0.552 to 0.795 0.031 point from the apex AUROC: area under the receiver operating characteristic curve, SEM: standard error of the mean, 95% CI: 95% confidence interval of the AUROC, PPI-Max: Pachymetry Progression Index-Maximum, ART-Max: Ambrosio’s´ Relational Thickness-Maximum, and PPI-Min: Pachymetry Progression Index-Minimum. thinnest point from the apex (𝑃 = 0.292). Meanwhile, only be significant. On evaluating BFTE and smaller best-fit three indices were statistically insignificant when comparing surface (7 mm), we focused on the posterior rather than the their values in group 2b keratoconic corneas against group 1 anterior corneal surface, being the site for primary subclinical normal corneas (radius of curvature of the 9 mm posterior tomographic changes, preceding the anterior surface [16–19]. BFS (𝑃 = 0.061) and maximum elevated point of the 9mm Curvature-based indices derived from both anterior and posterior BFTE (𝑃 = 0.361), in addition to horizontal decen- posterior surfaces were evaluated and analysed. According tration of the thinnest point from the apex (𝑃 = 0.150). Con- to the ROC curves, all evaluated curvature indices had trarily, only five indices’ values were statistically significant in statistically significant less AUROC for diagnosing KC than discriminating group 2a KC corneas from normal corneas, as most of elevation and pachymetry indices. Previous reports shown in Table 4. demonstrated similar results [20–22]. Despite being the least significant in diagnosing KC, they have been considered as important criteria in KC and after LASIK ectasia follow-up 4. Discussion [23, 24]. Placido-based systems rely on the analysis of a reflected Inthisstudy,whereweonlyanalyseddatafromgood image. This cannot provide data from the posterior corneal quality scans with corneal surface area more than 9 mm, surface [6]. Additionally, without information about the analysis of elevation indices showed that posterior surface posterior corneal surface, complete pachymetric evaluation elevation (PE) from 8 mm BFS and anterior surface elevation is not possible [14]. Ultrasonic central pachymetry measures (AE) from 9 mm BFS had the highest accuracy, with AUROC one point, which is not necessarily the thinnest point, and (0.979) for both, followed by PE from 7 and 9 mm BFS does not reflect the overall thickness profile [15]. Moreover, (AUROC = 0.977 and 0.971, resp.). AE and PE from reference the posterior corneal surface is appreciated as a sensitive best-fit surfaces did not differ in their accuracy with various indicatorofcornealectasiaandcanoftenbeabnormalinspite diameters (7, 8, and 9 mm). Correia et al. reported that PE of a still normal anterior corneal surface. While the corneal from both 8 mm BFS and BFTE had highest AUROC (0.983 refractive power is largely determined by the anterior surface, and 0.986, resp.) [20]. de Sanctis et al. [25] evaluated the sen- the evaluation of anatomical properties of the cornea is at sitivity and specificity of PE from 9 mm BFS in discriminating least equally dependent upon both surfaces [14]. Therefore, normal corneas from KC. The AUROC analyses showed high corneal tomography parameters assessment appeared to be overall predictive accuracy of PE for KC (AUROC 0.99). They essential in detecting KC. concluded that PE very effectively discriminates KC from With the appearance of many KC indices and suggestion normal corneas, but its efficacy is lower for subclinical KC, of various best-fit reference surfaces [6], the goal of our and thus data concerning PE should not be used alone to study was to evaluate the accuracy (including both sensitivity stratify patients with this condition. and specificity) of such indices with the use of different We enrolled in our work the elevation indices of the reference surfaces, at different diameters, and correlate these thinnest point from both BFS and BFTE. The latter was parameters to TKC grading. Some previous studies used evaluatedinliteratureandshowedhigherpredictiveaccuracy cyclic evidence that stated that a certain index was accurate in diagnosing KC and forme fruste KC compared to BFS, basedondifferentiatingKCfromnormalcorneausingcertain especially with a fixed eccentricity. A possible explanation criteria closely related to this same index. Our study adds for its diagnostic superiority in ectatic corneas is that its the long follow-up (6 years) as a more robust evidence. If central vaulting can determine whether the corneal pattern is a cornea was falsely diagnosed as normal and underwent associated with an atypical condition, a true corneal disease, LASIK, it would develop ectasia in such a long follow-up or an artifact of alignment or processing [16, 20]. period. On the other side, a KC diagnosis can be confirmed if According to our study results, parameters that had the it spontaneously progressed over time. highest AUROC for diagnosing KC were the PPI-Max at cut- The inclusion of every single possible index is out of the off value of >1.4 and the ART-Max at cut-off value of ≤412 scopeofthisstudy.Theincludedindicesarethosementioned (0.987 for both). These results were comparable to those of individually in other studies or those we thought they might Ambrosio´ Jr. et al. [1] who reported that the most sensitive 8 Journal of Ophthalmology parameters were ART-Avg and ART-Max (AUROC = 0.987 pachymetry and elevation-based indices were significantly and 0.983, resp.). more accurate than other indices, having higher AUROC. Our study investigated the accuracy of various tomo- Five of them had statistically significant high AUROC when graphic indices in relation to TKC grading [26]. We found comparing early KC to normal corneas. that most of the tested indices had significantly different values between each of grades 2 to 4 (moderate and/or severe) Competing Interests KC and normal corneas. In 2012, Ishii and his coworkers [27] investigated the severity of KC in terms of corneal ele- There are no competing interests of any of the authors with vation differences, and they correlated the data with Amsler- any establishment having a relation to this present work. Krumeich classification of KC. They observed that cases of higher elevation differences in the anterior and posterior Acknowledgments corneal surfaces were staged higher in Amsler-Krumeich classification (𝑃 < 0.001) and concluded that anterior and SherineS.WahbaandMagedM.Roshdyreceivedtravel posterior corneal surface height data obtained by elevation- support by Alcon Laboratories Inc., USA, to attend ESCRS based tomography provide useful information in improving Congress. KC diagnostic accuracy and in grading the severity of KC. Their results are comparable to ours in the accuracy of elevation indices; however, they did not furtherly investigate References other indices. [1] R. Ambrosio´ Jr., A. L. C. Caiado, F. 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Clinical Study Evaluation of Outflow Structures In Vivo after the Phacocanaloplasty

Daiva Paulaviciute-Baikstiene, Renata Vaiciuliene, Vytautas Jasinskas, and Ingrida Januleviciene Department of Ophthalmology, Lithuanian University of Health Sciences, Eiveniu Street 2, LT-50009 Kaunas, Lithuania

Correspondence should be addressed to Daiva Paulaviciute-Baikstiene; daiva [email protected]

Received 29 March 2016; Revised 17 May 2016; Accepted 16 June 2016

Academic Editor: Karim Mohamed-Noriega

Copyright © 2016 Daiva Paulaviciute-Baikstiene et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose.Toevaluatethein vivo changes in Schlemm’s canal (SC) and the trabecular meshwork (TM) in patients with primary open- angle glaucoma (POAG) after phacocanaloplasty using anterior segment optical coherence tomography (AS-OCT). Methods.Ten eyes of nine patients with POAG (6 men and 3 women) who underwent phacocanaloplasty. Preoperative and postoperative visual acuity (VA), intraocular pressure (IOP), and use of glaucoma medications were evaluated. The main outcome measures were the area of SC and TM thickness assessed using AS-OCT before and 12 months after surgery. Results. We found statistically significant reduction in IOP (from 26.4 (8.6) mmHg to 12.9 (2.5) (𝑝 < 0.05) mmHg), increase in VA from 0.7 (0.4) to 0.9 (0.2), and decrease in glaucoma medication from 2.6 (1.2) to 1.1 (1.3) at 12 months postoperatively. There was a significant increase in the SC area (3081.7 2 2 (842.8) 𝜇m versus 5098.8 (1190.5) 𝜇m , 𝑝 < 0.001) and a decrease in mean TM thickness (91.2 (18.6) 𝜇m versus 81.3 (15.1) 𝜇m, 𝑝 = 0.001) after surgery. We found negative correlations between SC area and IOP before surgery (𝑟 = −0.67, 𝑝 = 0.03)andalso between SC area before and IOP reduction 12 months after the phacocanaloplasty𝑟 ( = −0.80, 𝑝 = 0.005). Conclusions. Our results showed statistically significant dilation of SC area and reduction of TM thickness after phacocanaloplasty in POAG patients. The degree of SC expansion was related to the IOP decrease.

1. Introduction the natural outflow pathway and to be independent of filtering blebs [7]. The point of canaloplasty effect is circum- Elevated intraocular pressure (IOP) is the only modifiable ferential dilation and suture tensioning of SC inner wall, after risk factor for the presence and progression of glaucoma [1]. which SC is permanently enlarged and better access to the The conventional drainage route of aqueous humor occurs collector channels is achieved [8]. via the trabecular meshwork (TM), Schlemm’s canal (SC), In a small number of eyes, this surgery could be unsuc- collector channels, and aqueous veins and then streams cessful because of a nonreversible disruption of collector into episcleral venous circulation. Appropriate secretion and channels or other outflow pathways that cannot be expanded regulation of aqueous humor are essential for normal eye due to anatomical factors [9]. Technological advances like function [2]. anterior segment optical coherence tomography (AS-OCT) SC plays an important role in regulating IOP in the with high axial resolution allow us to observe in vivo human eye [3, 4]. Dimensions of SC may correlate with structural and pathophysiological changes in SC and the TM theIOPfluctuations[5].Whentopicalglaucomamedication thickness [10]. Only a few studies assessed the anatomical treatment is ineffective Schlemm’s canal based nonperforated changes of SC and TM before and after a nonpenetrating glaucoma surgery is considered to be the most effective surgical procedure. The purpose of the current study was to method to lower IOP [6]. Canaloplasty is an advanced evaluate and to compare SC and TM parameters before and interventional glaucoma treatment. It has gained increasing one year after phacocanaloplasty in patients with primary popularity as a surgical procedure by attempting to stimulate open-angle glaucoma (POAG) using AS-OCT.Main outcome 2 Journal of Ophthalmology measurements included SC area and TM thickness with respect to IOP as a secondary variable.

2. Materials and Methods All study procedures were carried out according to the Declaration of Helsinki, and the study protocol was approved SC by the Lithuanian University of Health Sciences Review TM Board. Study objectives and methods were explained to all the subjects prior to the examination. Written informed consent was obtained from all the patients. Figure 1: Visualization of outflow structures (SC, TM) with AS- The inclusion criteria for surgical cataract and glaucoma OCT. The image was adjusted to maximize visualization with ImageJ treatment were POAG patients over 18 years with medically program. uncontrolled IOP, progressing glaucoma with diffuse and/or subcortical and/or nuclear lens opacities that influenced visual acuity or visual function that no longer met patients’ was tightened under tension on a soft eye and tied in order to needs. One patient had an allergy to all IOP-lowering med- stretch the TM circumferentially and to open the SC when ications. Pregnant or nursing women, patients with uncon- IOP returned to normal. The superficial flap was closed and trolled systemic diseases, previous ocular surgery, secondary sutured watertight with 10-0 vicryl sutures. glaucoma, and congenital glaucoma, and patients with a All surgical procedures were performed by the same history of other eye diseases or trauma were excluded from surgeon V. J. the study. Ophthalmic examination consisted of Snellen best-cor- 2.2. SC and TM Measurements Using Optical Coherence rected visual acuity (BCVA), IOP (Goldmann tonometer— Tomography. For SC and TM scanning, all subjects under- an average of 3 separate IOP measurements was taken), went spectral-domain AS-OCT imaging (Nidek, RS-3000, slit-lamp biomicroscopy, gonioscopy (VOLK, Three-Mirror Advance, Japan). Cross-sectional images are captured with Lens), fundus examination measurements, visual field testing the optical interferometer using an infrared light source with (24-2 SITA-Standard strategy; Humphrey Standard Achro- a wavelength of 880 nm. Scans centered on the pupil and matic Perimetry), and AS-OCT (Nidek, RS-3000, Advance, were obtained using the standard anterior segment single- Japan)beforeand12monthsafterthephacocanaloplasty. scan protocol in the horizontal meridian, at the 3 and 9 o’clock Patients were examined at the same time of the day to avoid position. Baseline SC scanning was performed one day before fluctuations. phacocanaloplasty. Follow-up angle scanning was carried out twelve months after surgery. The SC was observable in all ten 2.1. Surgical Procedure. Phacocanaloplasty is a relatively new eyes which were included in the study. Based on image quality nonpenetrating surgical procedure [9]. The conjunctiva was threeimageswerechosenforfinalanalysis. dissected at the limbus in the superior medial segment. × A5.0 5.0 mm parabolic shape superficial scleral flap 2.3. Image Analysis. The AS-OCT images of SC were im- was created including about one-third of superficial scleral ported in ImageJ (ImageJ v1.50b, NIH, https://imagej.nih thickness. The second scleral flap was of the same shape .gov/ij/) for analysis after they were enhanced with the adap- but slightly smaller than the superficial one and involved tive compensation algorithm. Contrast and magnification almost all remaining scleral thickness. The flap was dissected were adjusted to maximize visualization. Scans with poor to the limbal area until SC was localized. Later continuous resolution and/or nonvisible SC were excluded. According to curvilinear capsulorhexis, standard phacoemulsification, and the previous studies, SC was defined as observable when the endocapsular foldable intraocular lens (IOL) implantation thin, black, lucent space was found outside of the TM on the were performed. After cataract surgery, SC was unroofed and AS-OCT images [11]. remnants of corneal stroma were striped from the Descemet The SC area was drawn freehand and represented the area membrane (DM) about 0.5 mm towards the center of the surrounded by the outline of SC and then was measured man- cornea. Created flap was excised performing a window of 5 ually by a masked operator (Figure 1). The area of SC in each DM. Ostia of SC were dilated with Healon GV with a micro site was recorded as the arithmetic mean of measurements cannula. A flexible microcatheter (iTrack-250A, iScience) ∘ from three images. TM thickness was measured below the SC was introduced into the ostia of SC. After complete 360 5 from the anterior to the posterior end point of SC. The mean passing of the iTrack a Prolene Suture (10-0) was fixed to ofthenasalandtemporalSCandTMwasusedintheanalysis. the distal tip of the microcatheter and looped through the canal. At the same time, SC was filled and dilated with Healon GV.ThesuturewastightenedtostretchtheinnerwallofSC 2.4. Statistical Analysis. Statistical analysis was performed and the TM circumferentially. The distension of the canal was using SPSS version 20.0 for Windows (IBM Corporation, observed clinically by the inward movement of the suture and Armonk, NY, USA). The level of significance 𝑝 ≤ 0.05 was inner wall of exposed SC at the surgical access area. The suture considered significant. Preoperative and postoperative data Journal of Ophthalmology 3

100 𝜇m 100 𝜇m

(a) (b)

2 2 3081.7 𝜇m 5098.8 𝜇m

Figure 2: Anatomical changes of SC before ((a), (c)) and after ((b), (d)) phacocanaloplasty. Visualization was maximized by adjusting contrast and magnification using ImageJ program ((c), before surgery, and (d), after surgery).

Table 1: Comparison between preoperative and postoperative 5000 ) parameters. 2 4500 m 𝜇 Preoperative Postoperative 4000 BCVA 0.7 (0.4) 0.9 (0.2) 3500 ∗ IOP, mmHg 26.4 (8.6) 12.9 (2.5) 3000 MD, dB −9.6 (10.9) −10.53 (10.4) 2500 ∗ Number of IOP-lowering drugs 2.6 (1.2) 1.1 (1.3) 2000 BCVA: best corrected visual acuity; IOP: intraocular pressure; MD: mean 1500 deviation. surgery ( before SC area ∗𝑝 1000 Values are shown in mean (SD), <0.05, based on Wilcoxon test. 0 5 10 15 20 25 30 35 Δ of IOP (mmHg) were analysed with the Wilcoxon test. Relations between data r = −0.80, p = 0.005 were analysed using Spearman’s correlation. Figure 3: Scattergram showing the relationship between the SC area 3. Results before surgery and the reduction of IOP. 2 The mean age of participants was 51.3 (14.7) years; 3 patients versus 5098.8 (1190.5) 𝜇m , 𝑝 < 0.001) (Figure 2). Inter- were women and 6 were men (totally 10 eyes). Mean glaucoma estingly, the mean TM thickness decreased statistically sig- duration was 7 (5.1) years (min 1 and max 18). The visual field nificantly after surgical treatment (91.2 (18.6) 𝜇mversus81.3 mean deviation was −9.6 (10.9) dB and we found no statisti- (15.1) 𝜇m, 𝑝 = 0.001). callysignificantchangesoneyearaftersurgery.Preoperative We found a negative correlation between reduction in and postoperative data are shown in Table 1. IOPat12monthsafterbaselineandtheSCareabeforesurgery After phacocanaloplasty surgery IOP decreased statisti- (𝑟 = −0.80, 𝑝 = 0.005) (Figure 3). Also, mean SC area cally significantly to 12.9 (2.5)𝑝 ( < 0.05) mmHg (or 51.1% negatively correlated with IOP before surgery (𝑟=−0.67, from preoperative value). Nine eyes were under medical 𝑝 = 0.03) (Figure 4). We found a significant correlation treatment before surgery (min 0 and max 4) and four eyes between a preoperative number of glaucoma medications and after surgery (min 0 and max 3) (𝑝 < 0.05). SC area after surgery (𝑟 = −0.82, 𝑝 = 0.004) (Figure 5).

3.1. Changes in Anterior Chamber Angle Morphology after 4. Discussion the Phacocanaloplasty. There was a statistically significant increase in the SC area at the follow-up examination com- The current study investigated changes in SC and TM as 2 paredwiththebaselinevalue(SCarea:3081.7(842.8)𝜇m two main structures of the conventional outflow tract after 4 Journal of Ophthalmology

5000 glaucomatous eyes [14]. In the present study, we evaluated ) 2

m 4500 SC area; compared to Fuest different AS-OCT system was 𝜇 4000 used.Wewerefocusedonthelatepostoperativedata.Our results demonstrated the distension of the SC area one 3500 year postoperatively with sufficiently low IOP. Fuest et al. 3000 identifiedthatdilationofSCnegativelycorrelatedwiththe 2500 IOP after surgery. We found a strong negative correlation between the SC area before surgery and the reduction of 2000 IOP. Studies carried out by other authors reported that a SC area before surgery ( before SC area 1500 strong correlation exists between the outflow capacity and SC 15 20 25 30 35 40 45 dimensions [5, 10, 15, 17]. IOP before surgery (mmHg) Studies of single point SC measurements from healthy r = −0.67, p = 0.03 and POAG patients have established that SC area in healthy patientswassignificantlylargerthaninPOAGpatients[5, Figure 4: Scattergram showing the relationship between the SC area 10, 15, 18, 19]. Kagemann et al. in their study made by high- and IOP before surgery. density OCT showed that acute IOP elevations in healthy eyes with open angles resulted in a reduced SC cross-sectional 8000 area [20]. They subjectively explained that compression of

) SCispossiblyduetoamovementoftheinnerwalltowards

2 7000

m theouterandmightbearesultofelevatedIOP.Irshad 𝜇 6000 et al. established that the diameter of SC was smaller in 5000 eyes with previous glaucoma surgery compared with eyes without glaucoma surgery [21]. Furthermore, Kagemann and 4000 colleagues obtained that SC area varies between 4064 and 2 3000 7164 𝜇m [11, 20, 22–24]. Our results analysed and estimated 2000 with enough new ImageJ program showed that average of SC

SC area after surgery after ( SC area 2 2 area was 3081.7 (842.8) 𝜇m before and 5098.8 (1190.5) 𝜇m 1000 0 12345 after surgery. It is important to mention that the results Number of preoperative IOP-lowering drugs of anterior segment structures performed with different visualization methods (UBM or AS-OST) or systems from r = −0.82, p = 0.004 different manufacturers may vary. Figure 5: Scattergram showing the relationship between the SC area According to the previous studies, TM also could be after surgery and glaucoma medication before surgery. visualized and measured in vivo. Filla with colleagues in a prospectivestudyfoundthatincreasedextracellularmatrix expression and deposits in the TM resulted in an increase the phacocanaloplasty. It is believed that IOP reduction after in IOP [25]. Johnstone and Grant reported that elevated canaloplasty is achieved by opening previously nonfunctional IOP may induce the TM compression [26]. TM thickness areas of the outflow system and alleviating the natural aque- measurements were performed with UBM in Yan et al. study. ous drainage system through collector channels and aqueous Authors noticed that TM thickness was smaller in POAG veins [12]. The decrease of IOP after effective canaloplasty is patients compared to healthy controls (103.9 (11.1) versus usually assigned to the successful plasticity of the SC [13, 14]. 88.3 (13.2) 𝜇m). They also found a negative correlation with However, earlier conclusions about SC and the TM were IOP [15]. In the present study, we measured TM thickness made in vitro. Technological advances (AS-OCT, UBM) with AS-OCT below the SC and compared preoperative let us in vivo evaluate outflow structures associated with and postoperative results. We revealed that TM thickness phacocanaloplasty [14, 15]. AS-OCT offers a high-resolution decreased after expansion of the SC area when compared to imaging of superficial conjunctival areas, SC, and TM after presurgical values. To the best of our knowledge, this is the nonpenetrating glaucoma surgery, whereas with UBM it is first report of the measurement of TM thickness in living easier to detect deeper structures such as intracanal sutures human individuals after phacocanaloplasty. and scleral lakes [14]. Recent studies revealed a significant decrease in IOP by To our knowledge, only a few original studies aimed to approximately 40% with a reduction of medications from assess the anatomical changes of SC after the canaloplasty. 2.3 to 1.0 [4, 27–29] and less surgical complications in Usui et al. reported that SC area was enlarged after the canaloplasty than in trabeculectomy [30–34]. A number of pseudo viscocanalostomy in enucleated human eye. These retrospective and prospective studies found better results results were supported by histologic sections [16]. Fuest and concerning IOP reduction in combined surgical (phaco- colleagues examined a total of twelve POAG patients with canaloplasty) cases compared with canaloplasty [32, 33]. spectral-domain AS-OCT and UBM and found enlargement The present study results demonstrated a significant cor- oftheSCheightandwidththreemonthsafterthenonpen- relation between a number of preoperative IOP-lowering etrating glaucoma surgery. They reported that the collapse drugs and SC area after surgery. Our results suggest that in SC occurred mainly because of a reduction in height in phacocanaloplasty surgery has been shown to be an effective Journal of Ophthalmology 5 andsafemethodtoreduceIOP(51.1%frompreoperative [5] R. R. Allingham, A. W. De Kater, and C. R. Ethier, “Schlemm’s value) and a number of medications (from 2.6 to 1.1) in POAG canal and primary open angle glaucoma: correlation between patients. Schlemm’s canal dimensions and outflow facility,” Experimental Our study has some limitations: relatively small sample Eye Research,vol.62,no.1,pp.101–109,1996. size which made it difficult to investigate SC and TM mor- [6] M. A. Khaimi, “Canaloplasty: a minimally invasive and maxi- phologyatdifferentstagesofPOAG.OurAS-OCTsystemdid mallyeffectiveglaucomatreatment,”Journal of Ophthalmology, not have a tracking system for the exact location finding. We vol. 2015, Article ID 485065, 5 pages, 2015. have followed a constant AS-OCT imaging protocol which [7] T. Klink, E. Panidou, B. Kanzow-Terai, J. Klink, G. Schlunck, contained scanning of specific sites (at 3 and 9 o’clock). and F. J. Grehn, “Are there filtering blebs after canaloplasty?” The arithmetic mean of SC area was obtained from three Journal of Glaucoma,vol.21,no.2,pp.89–94,2012. images of the best quality. We have scanned anterior segment [8] M. C. Grieshaber, “Ab externo Schlemm’s canal surgery: visco- horizontally leaving the superior and inferior limbus zones canalostomy and canaloplasty,” Developments in Ophthalmol- not evaluated. This was done to prevent interference from ogy,vol.50,pp.109–124,2012. the eyelids. For that reason, data may not represent overall [9] P. Brusini, “Canaloplasty in open-angle glaucoma surgery: a circumferential changes in these outflow structures (SC and four-year follow-up,” The Scientific World Journal,vol.2014, TM). Future studies with longer follow-up periods and a ArticleID469609,7pages,2014. larger group of patients could help to understand the long- [10] J. Hong, J. Xu, A. 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Research Article Assessment of Corneal Epithelial Thickness in Asymmetric Keratoconic Eyes and Normal Eyes Using Fourier Domain Optical Coherence Tomography

S. Catalan,1 L. Cadarso,2 F. Esteves,3 J. Salgado-Borges,4 M. Lopez,5 and C. Cadarso5

1 Department of Ophthalmology, University Hospital of Vigo, 36200 Vigo, Spain 2Cl´ınicaCadarso,36203Vigo,Spain 3Department of Ophthalmology, Hospital da Boa Nova, 4455-421 Matosinhos, Portugal 4Cl´ınica Salgado-Borges, 4000-422 Porto, Portugal 5Department of Statistics and Operations Research, School of Medicine, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain

Correspondence should be addressed to S. Catalan; [email protected]

Received 11 April 2016; Accepted 10 May 2016

Academic Editor: Sang Beom Han

Copyright © 2016 S. Catalan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. To compare the characteristics of asymmetric keratoconic eyes and normal eyes by Fourier domain optical coherence tomography (OCT) corneal mapping. Methods. Retrospective corneal and epithelial thickness OCT data for 74 patients were compared in three groups of eyes: keratoconic (𝑛=22) and normal fellow eyes (𝑛=22)inpatientswithasymmetrickeratoconus and normal eyes (𝑛 = 104) in healthy subjects. Areas under the curve (AUC) of receiver operator characteristic (ROC) curves for each variable were compared across groups to indicate their discrimination capacity. Results. Three variables were found to differ significantly between fellow eyes and normal eyes (all 𝑝 < 0.05): minimum corneal thickness, thinnest corneal point, and central corneal thickness. These variables combined showed a high discrimination power to differentiate fellow eyes from normal eyes indicated by an AUC of 0.840 (95% CI: 0.762–0.918). Conclusions. Our findings indicate that topographically normal fellow eyes in patients with very asymmetric keratoconus differ from the eyes of healthy individuals in terms of their corneal epithelial and pachymetry maps. This type of information could be useful for an early diagnosis of keratoconus in topographically normal eyes.

1. Introduction In contrast, the diagnosis of subclinical keratoconus is a challenge and this can have dire consequences. For example, Keratoconus is a bilateral, noninflammatory corneal ectasia an undetected incipient ectasia could be worsened by a refrac- in which the cornea assumes a conical shape due to progres- tive procedure such as LASIK, whereby the already reduced sive thinning and steepening of the corneal stroma. With a mechanical strength of the cornea is further weakened by prevalence of 54 per 100 000, it is the most common primary surgery possibly causing rapid progression of the ectasia [5]. corneal ectasia [1]. Recently, it has been noted that the cornea of keratoconic Moderate forms of keratoconus are easy to detect using eyes may show early thickness changes involving both the several devices [2] to examine anterior corneal topography. stroma and epithelium. Such observations include progres- These range from simple inexpensive devices, such as hand- sive thinning of the stroma and a localized area of thinner held keratoscopes (Placido’s disks), to sophisticated devices epithelium over the cone surrounded by an annulus of thicker such as computer-assisted videokeratoscopes. In clinical epithelium [6]. Several methods have been used to map the practice, the Pentacam corneal tomographer [3] or Orbscan corneal epithelium [6–8]. topography system [4] is widely used to detect subtle changes The present study sought to detect subtle changes in early and control disease progression. stages of keratoconus. Corneal epithelial thickness and total 2 Journal of Ophthalmology corneal thickness measurements were made in healthy eyes 2.3. Fourier Domain OCT and Image Analysis. The instru- and in the eyes of patients with highly asymmetric kerato- ment used was Fourier domain OCT system (RTVue; conus. We propose that in these patients the topographically Optovue, Inc., Fremont, CA) which was fitted with a corneal normal eye is a good model to assess early changes, since the adaptor module for the corneal epithelial maps. This is a vast majority of these fellow eyes will develop keratoconus 26000 Hz Fourier domain OCT system with 5 microns of [9]. Although other authors have also used this model to axial resolution. The corneal mapping scan pattern includes detect subclinical changes in keratoconus, these studies have 6 mm lines on 8 meridians centered at the pupil and each examined other corneal properties [10, 11]. line scans 1024 axial points in 0.04 seconds. The set of eight meridians is acquired in 0.31 seconds and the exam is repeated 2. Materials and Methods five times in 1.55 seconds. The software then generates the epithelium boundaries and the thickness map. 2.1. Subjects. Participants were recruited among the adult Each eye was scanned 3 times within a single visit. Maps patients (>18 years) of two European healthcare centers: reproducibility was assessed analyzing 3 acquisitions for each Cl´ınica Cadarso (Vigo, Spain) and the Hospital of Santa eye of each patient without finding major changes. Maria da Feira (Portugal). The study protocol adhered to the A computer algorithm automatically maps corneal thick- principles of the Declaration of Helsinki and received institu- ness (across the central 5 mm of the corneal surface divided tional review board approval. into three zones: central 2 mm, superior 2 to 5 mm, and All adult patients for which complete OCT corneal thick- inferior 2 to 5 mm) and calculates the following variables on ness and corneal epithelial thickness data were available were the pachymetry and epithelial maps. identified in the databases of the two participating centers. Normal subjects were recruited from patients seeking 2.4. Pachymetry Map refractive surgery and cataract surgery consultation. Of the 160 eyes of 80 patients identified, two eyes with Superonasal − inferotemporal (SN − IT): difference corneal scarring, seven eyes subjected to ocular surgery, and between superonasal and inferotemporal corneal two eyes giving rise to segmentation errors (the OCT is not thickness (2 to 5 mm from the center). able to detect the corneal layers and their boundaries) were excluded.Thisleftuswithafinalstudysampleof148eyesof Minimum pachymetry (Min): thickness of the thin- 74 patients. nest corneal point. Corneal topography was obtained using a Placido-topog- Minimum − median (Min − Med): difference between raphy and an elevation-based Scheimpflug imaging device thethicknessofthethinnestpointandthemedianof (Pentacam, Oculus). all points. The 148 eyes were divided into three groups according to − − slit-lamp findings and the topographical criteria for kerato- Superior inferior (S I): difference between mean conus (Placido disc-based indices) [12] described below: superior and mean inferior corneal thickness (2 to 5mmfromthecenter). (1) Normal eyes (𝑛 = 104): eyes showing normal slit- Y location: location of the thinnest point in the ver- lamp findings and no topographical signs of kerato- tical meridian (positive values for locations superior conus. to the corneal vertex; negative values for locations (2) Keratoconic eyes (𝑛=22): eyes of patients with diag- inferior to the corneal vertex). nosed asymmetric keratoconus showing clinical and Minimum − maximum (Min − Max): difference topographical findings compatible with keratoconus. between the thickest and thinnest point. (3) Fellow eyes (𝑛=22): contralateral eyes of the patients with asymmetric keratoconus showing normal slit- Central pachymetry (CCT): corneal thickness at the lamp findings and no signs of topographic kerato- central point. conus. 2.5. Epithelial Map 2.2. Topographical Criteria for Keratoconus Superior epithelium (Sup): mean of thickness values (1) Inferior-superior power asymmetry: difference recorded in the superior epithelium (2 to 5 mm from between the average surface power of 5 inferior points the center). and 5 superior points, 3 mm from the center of the Inferior epithelium (Inf ep): mean of thickness values ∘ ≥ cornea at 30 intervals ( 1.4). recorded in the inferior epithelium (2 to 5 mm from (2) Central corneal power: ≥47.2 diopters. the center). (3) KISA% index: product of four indices in the topogra- Minimum epithelium (Min ep): thinnest point of the phy (≥100%). epithelium. (4) Keratoconus predictability index: linear discriminant Maximum epithelium (Max): thickest point of the analysis of 8 quantitative topographic indices (≥0.23). epithelium. Journal of Ophthalmology 3

− − Minimum maximum (Min Max ep): difference m) 600 between minimum and maximum epithelial thick- 𝜇 ness. 500 400 Standard deviation (SD): standard deviation of all Minimum

pachymetry ( pachymetry Normal Fellow Keratoconic epithelial thicknesses recorded in the central 5 mm of the cornea. 500 −500 Central epithelial thickness (CET): thickness of the m) 𝜇 ( epithelium at the central point. location −2000 Y Normal Fellow Keratoconic 2.6. Statistical Analysis. Statistical analysis was performed

on both qualitative variables (provided as frequencies and m) 𝜇 percentages) and quantitative variables (provided as the mean 550 ± standard deviation and ranges). The Kolmogorov-Smirnov testwasusedtocheckthenormalityofthedata.Differences Central 450 in the diagnostic variables among the three groups of eyes

pachymetry ( pachymetry Normal Fellow Keratoconic weredeterminedinpairwisecomparisonsconductedusing the Kruskal-Wallis test and post hoc analysis (normal versus Figure 1: Values recorded for the variables Min, Y location, and keratoconic eyes, normal versus fellow eyes, and keratoconic CCT in the three study groups. versus fellow eyes). An association was considered significant when 𝑝 < 0.05. The receiver operating characteristic (ROC) curve method was used to assess the diagnostic accuracy of each for the patients with asymmetric keratoconus (𝑛=22,44 variable [13–16]. As a measure of the capacity of each variable eyes). to discriminate between normal and keratoconic eyes, the The OCT mapping data obtained for the three groups of areaundertheROCcurve(AUC)wascomputedusingcluster eyes (keratoconic, fellow, and normal) are provided in Table 1. data, considering the eye (left or right) as a cluster (taking Pairwise comparisons among the three groups of eyes into account the possible correlation between both eyes of the revealed the following significant differences: keratoconic same patient). When the relationship between the diagnostic versus normal eyes, all variables (𝑝 < 0.01); keratoconic ver- variable and the presence of keratoconus was not monotonic sus fellow eyes, all variables except Sup (𝑝 = 0.101), Y loca- (increasing or decreasing), a new transformed diagnostic tion (𝑝 = 0.067), and Inf ep (𝑝 = 0.05); and normal versus variable was obtained by estimating the probability that the fellow eyes, Min, Y location, and central pachymetry (𝑝< patient has keratoconus by means of Generalized Additive 0.001) (Figure 1). Models (GAMs) [17, 18] for binary data. A GAM is a flexible AUC for all variables were 0.742 to 0.964 for keratoconic regression model used to express the nonlinear (smooth) versus normal eyes indicating their good discrimination effect of a continuous covariate on the response. In our case, capacity (CI > 0.5) and 0.690 to 0.935 for keratoconic the response is a binary variable that indicates whether the versus fellow eyes also indicating their good discrimination patient has keratoconus (=1) or not (=0), and the continuous capacity (CI >0.5). In the comparisons of fellow eyes versus covariate is the corresponding diagnostic variable for normal eyes, the three variables showing the greater AUC keratoconus. To assess improvements in discrimination were Min (AUC: 0.780; CI: 0.698–0.862), Y location (AUC: capacity, a combination of several variables was also 0.725; CI: 0.474–0.976), and CCT (AUC: 0.765; CI: 0.713– considered using Generalized Linear Models (GLMs) [19]. 0.816). The variables Min and CCT were able to discriminate A GLM is a particular case of a GAM, in which the effect of well between the two sets of eyes whereas Y location showed the covariate on the presence of keratoconus is linear. All a poor discrimination power (CI <0.5). statistical tests were conducted with R 3.0.1 (R Development Finally, combinations of selected variables showing good CoreTeam,2013[20]).ROCcurveswereconstructedwith discrimination capacity were tested, avoiding the introduc- theRpackageROCR[21].LogisticGAMswerefittedwiththe tion of correlated data in the same model. The following gam function of the R package mgcv [22]. To compute AUC AUC were obtained for the different combinations of vari- with cluster data, considering the eye (left/right) as a cluster, ables included in the models: keratoconic versus normal a specific function in R was used (packages freely available at eyes, AUC = 0.974 (95% IC: 0.909–1.038) for Min − Med, https://www.R-project.org/). superior − inferior, and Min ep; keratoconic versus fellow eyes, AUC = 0.938 (95% CI: 0.928–0.948) for SD and CCT; 3. Results andnormalversusfelloweyes,AUC=0.840(95%CI:0.762– 0.918) for all variables. This last model including all variables Demographic data were mean age 37.96 ± 11.32 (18 to 61 emerged as showing the best discrimination power when years), 34 women (65.38%) and 18 men (34.62%) for the 52 compared with the AUC of each of the three variables found subjects without keratoconus (104 eyes), and mean age 34.91± to vary significantly between normal eyes and fellow eyes 11.96 (18 to 63 years), 6 women (27.27%) and 16 men (72.73%) (Min, Y location, and central pachymetry) (Figure 2). 4 Journal of Ophthalmology

ROC curves Table 1: Data obtained for the three groups of eyes. 1.0 Normal eyes Variable Mean SD Median Range 0.8 SN − IT 17.39 12.92 17 −24 to 54 Min 531.7 30.17 532 454 to 592 Min − Med −20.50 5.06 −20 −47 to −8 0.6 S − I 8.519 12.70 9 −40 to 48 𝑌 location −155.9 398.43 −141 −137 to 607 0.4 Min − Max −53.42 11.81 −52 −97 to −26 CCT 537.6 30.66 538 459 to 598 Sup 52.03 3.27 52 37 to 60 0.2 Inf ep 53.38 3.10 53 46 to 62 Min ep 49.52 3.73 50 33 to 57 0.0 Max 56 3.55 56 48 to 69 Min − Max ep −6.423 3.04 −6 −25 to −2 0.0 0.2 0.4 0.6 0.8 1.0 SD 1.549 0.75 1.40 0.6 to 4.9 Fellow eyes/normal eyes CET 52.90 3.09 53 42 to 61 Minimum pachymetry (AUC = 0.780; CI 95%: 0.698–0.862) Fellow eyes Y location (AUC = 0.725; CI 95%: 0.474–0.976) Central pachymetry (AUC = 0.765; CI 95%: 0.713–0.816) Variable Mean SD Median Range Combination (AUC = 0.840; CI 95%: 0.762–0.918) SN − IT 24.50 20.05 20 −1to68 Min 503.2 32.71 499.5 447 to 597 Figure 2: ROC curves and AUC for the three variables showing Min − Med −22.36 9.42 −20.5 −48 to −13 significant differences between normal and fellow eyes and for the S − I15.95017.3515−19 to 48 model combining these three variables. 𝑌 location −558.6 591.70 −610 −1809 to 513 Min − Max −57.50 18.80 −52.5 −103 to −37 4. Discussion CCT 513.1 31.90 512.5 453 to 605 Sup 53.27 4.25 52 48 to 67 Our study was designed to identify possible subtle changes Inf ep 53.14 4.50 52.5 47 to 70 in the corneal epithelial thickness maps of patients with Min ep 49.09 4.74 49 37 to 64 very early stage keratoconus. To assess this incipient stage of Max 56.86 4.52 56.5 52 to 73 disease, we compared several corneal and epithelial variables Min − Max ep −7. 8 1 8 3 . 8 9 −6 −20 to −3 in normal eyes and both the keratoconic eyes of patients with SD 1.891 0.99 1.50 0.7 to 4.7 asymmetric keratoconus and their fellow eyes with no topo- CET 52 4.07 53.23 49 to 68 graphical signs of keratoconus. Epithelial thickness profiles may increase the sensitivity Keratoconic eyes and specificity of screening for keratoconus compared to Variable Mean SD Median Range corneal topography alone and may be useful in clinical prac- SN − IT 56.95 28.49 55 12 to 114 tice. Epithelial information may allow for an earlier diagnosis Min 458.0 45.14 451.5 380 to 589 of keratoconus, as epithelial changes will precede any changes Min − Med −54.27 23.72 −51 −101 to −14 producedonthefrontsurfaceofthecornea[23].Suchepithe- S − I 44.770 35.25 41 −38 to 115 lial thickness changes in keratoconus have been examined by 𝑌 location −947.5 549.53 −834 −2369 to −206 other authors [6, 7]. Today, corneal epithelial and pachymetry Min − Max −114.60 51.96 −99 −227 to −44 profiles can be assessed through OCT, an accurate, rapid CCT 482.9 30.62 479 416 to 536 noninvasive tool [8]. Sup 55.55 6.36 55 40 to 67 In this study, we compared several epithelial and corneal variables extracted from Fourier domain OCT maps in the Inf ep 50.82 5.86 49.5 41 to 64 three groups of eyes described above. Significant differences Min ep 41.18 6.45 42 33 to 56 were observed in all these variables between normal and ker- Max 63.36 8.45 62 47 to 80 atoconic eyes, while when keratoconic and fellow eyes were Min − Max ep −22.090 10.80 −20 −44 to −7 compared, significant differences emerged for all variables SD 5.918 3.19 5.55 1.7 to 13.8 except three (Y location,Sup,andInfep). In contrast, when CET 48.59 5.71 47.5 39 to 61 fellow and normal eyes were compared, differences were only observed in Min (𝑝 < 0.001;normaleyes531.7 ± 30.17 𝜇m, fellow eyes 503.2 ± 32.71 𝜇m), Y location (𝑝 < 0.001;normal 513.1 ± 31.90 𝜇m).Thevaluesobtainedforeachvariableand eyes −155.9 ± 398.43 𝜇m, fellow eyes −558.6 ± 591.70 𝜇m), differences observed between keratoconic and normal eyes and CCT (𝑝 < 0.001;normaleyes:537.6 ± 30.66, fellow eyes are similar to those reported by Li et al. [8]. Journal of Ophthalmology 5

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Research Article Central Corneal Thickness in Spectral-Domain OCT and Associations with Ocular and Systemic Parameters

Alexander Karl-Georg Schuster,1,2 Joachim Ernst Fischer,1 and Urs Vossmerbaeumer1,2

1 Mannheim Institute of Public Health, Social and Preventive Medicine, Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Straße 7-9, 68167 Mannheim, Germany 2Department of Ophthalmology, Medical Faculty Mannheim, Heidelberg University, Langenbeckstraße 1, 55131 Mainz, Germany

Correspondence should be addressed to Alexander Karl-Georg Schuster; [email protected]

Received 8 February 2016; Revised 22 April 2016; Accepted 16 May 2016

Academic Editor: Sang Beom Han

Copyright © 2016 Alexander Karl-Georg Schuster et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. Optical coherence tomography (OCT) allows quantitative analysis of the anterior segment of the eye with a noncontact examination. The aim of this study is to analyze associations of central corneal thickness (CCT) as measured by OCT with ocular and systemic cardiovascular parameters. Methods. A cross-sectional study of 734 persons was performed in a working age population. Only healthy eyes were included. A comprehensive ophthalmological examination including refraction, noncontact tonometry, and imaging of the anterior segment by SD-OCT was performed. In parallel, a broad range of systemic cardiovascular parameters were measured. Associations were analyzed using a generalized estimating equations’ model. Results. CCT measurements showed a significant association with corneal curvature and intraocular pressure: a thinner CCT was associated with a flatter cornea andwith lower intraocular pressure (𝑝 < 0.001). Age was positively associated with CCT (𝑝 < 0.001); all other cardiovascular parameters were not associated. Conclusion. A thinner cornea is associated with a flatter surface and with lower intraocular pressure readings, while there are no independent associations with refraction and systemic cardiovascular parameters. Our findings highlight the value of SD-OCT CCT measurements as a standard tool in anterior segment analysis.

1. Introduction corneal thickness readings as determined by spectral-domain OCT (SD-OCT) imaging should be further investigated. For Optical coherence tomography (OCT) enables high- clinical evaluation of central corneal thickness as determined resolution imaging of the anterior segment of the human eye. by SD-OCT, it is essential to know physiological factors that In a noncontact examination it is possible to analyze layers are associated with the dimensions of the tissue. and shape of cornea in cross-sectional images. This includes Based on this background, this study aimed to inves- the option to determine central corneal thickness. tigate the associations of distinct central corneal thickness Central corneal thickness itself affects the accuracy of measurements determined by SD-OCT with ocular and intraocular pressure measurements [1]. In the last decades, systemic cardiovascular parameters in a Caucasian cohort. correlations between central corneal thickness and intraoc- Our hypothesis is that higher central corneal thickness may ular pressure readings have been evaluated in many stud- be associated with a flatter corneal curvature and with ies establishing the correlation between these two ocular higher intraocular pressure, while systemic cardiovascular parameters [2–12]. Many of these studies have used optical or parameters are not associated. ultrasonic pachymetry for corneal thickness measurements and applanation tonometry for intraocular pressure measure- 2. Materials and Methods ment. Nowadays, noncontact tonometry is widely used in clinical daily routine for screening purposes [13]. Therefore, The study was designed as a cross-sectional, observational the relationship of this measurement technique with central study conducted within the scope of a health promotion 2 Journal of Ophthalmology

Table 1: Characteristics of the study sample (𝑛 = 734 participants). OD: right eyes, OS: left eyes; myopic, emmetropic, and hyperopic eyes classified according to spherical equivalent measurements.

Mean Standard deviation Minimum Maximum Age (years) 40.4 11.2 17 64 2 Body mass index (kg/m ) 22.9 4.0 15.2 49.3 Mean arterial pressure (mmHg) 98 11 70 148 HbA1c (%) 5.62 0.40 4.60 9.60 High density lipoproteins (mg/dL) 59 13 28 113 Low density lipoproteins (mg/dL) 126 32 54 258 Triglycerides (mg/dL) 126 78 30 741 Manifest refraction (diopters): Sphere OD −1.61 2.70 −9.75 6.50 Cylinder OD −0.68 0.74 −6.00 0.00 Sphere OS −1.59 2.82 −11.00 8.50 Cylinder OS −0.73 0.81 −6.25 0.00 Tonometry (mmHg): OD 16.01 3.23 9 26 OS 16.21 3.22 9 26 Central corneal thickness (𝜇m) OD 560.1 31.9 468 672 OS 562.2 32.9 463 660 Anterior corneal curvature (mean radius in mm) OD 7.43 0.26 6.68 8.31 OS 7.43 0.28 6.58 8.38 Manifest refraction: grouped Frequency Percentage Right eyes: Myopic eyes (<−0.5 D) 𝑛 = 430 59% Emmetropic eyes 𝑛 = 232 32% Hyperopic eyes (>0.5 D) 𝑛=68 9% Left eyes: Myopic eyes (<−0.5 D) 𝑛 = 441 60% Emmetropic eyes 𝑛 = 218 30% Hyperopic eyes (>0.5 D) 𝑛=71 10% project conducted within a major industry company. The were drawn to determine triglycerides (TRI), low density study population consists of working age subjects (age range lipoproteins (LDL), high density lipoproteins (HDL), and from 17 to 64 years) of the MIPH Eye & Health Study. glycosylated hemoglobin (HbA1c) using routine laboratory Exclusion criteria were any manifest eye disease, either self- analyzers. reported or detected on fundus photographs, and insufficient The cornea was imaged with the anterior segment mode OCT scan quality of the anterior segment OCT. 1460 healthy of the 3D OCT-2000 (Topcon Corp., Tokyo, Japan). Auto- eyes of 734 subjects (730 right eyes, 730 left eyes; 514 men, 220 mated calculation of corneal curvature and central corneal women) were included in the analysis. The characteristics of thickness (CCT) with the integrated software was performed thesamplearegiveninTable1. and all OCT images were checked for correct identification The study was conducted according to the tenets of of the corneal surface. Quality of OCT scans were graded the Declaration of Helsinki and fully approved by both the in a four categories: “high,” “medium,” “acceptable,” and ethics approval committee of the University of Heidelberg “insufficient.” Mean curvature of the corneal radius was (institutional review board), the company’s advisory board, computed. Automated objective refractometry was obtained and the board of employees. Written informed consent as to using a KR-8900 (Topcon Corp., Tokyo, Japan) and noncon- the scientific objectives of the study was obtained from each tact tonometry was performed (CT-80 Tonometer, Topcon participant. Corp., Tokyo, Japan). Three averaged measurements were Blood pressure was recorded from the dominant arm in obtained per eye. the seated position after a standardized 20 min rest period Fundus photographs of the macula and optic nerve by sphygmomanometry. Body weight and height were mea- head were obtained from all participants and images were sured and body mass index was calculated. Blood samples evaluated by two independent ophthalmologists. Eyes with Journal of Ophthalmology 3 previous intraocular or refractive surgery were excluded from 675 thestudy,aswereeyeswithknownandconfirmedocular 650 m) disease. Subjects wearing contact lenses were excluded as this 𝜇 625 might affect corneal thickness. All other eyes were included. 600 Raw data results were processed by statistical analysis 575 software (SPSS 21.0, Chicago, IL) and plots were performed with STATA software (version 13.1 SE, College Station, TX: 550 StataCorp LP). Associations with central corneal thickness 525 were analyzed by multivariable linear regression algorithms 500 with parameter estimation performed with generalized esti-

Central corneal thickness ( 475 mation equations. This statistical model takes the relationship 450 between the right and left eye into account by linking the 8 10 12 14 16 18 20 22 24 26 individual pair of eyes. As dependent variable central corneal Intraocular pressure (mmHg) thickness was included in the statistical model, mean corneal radius, intraocular pressure, refraction, age, gender, body GEE regression mass index, mean arterial blood pressure, HbA1c, HDL, LDL, 95% CI and triglyceride values were evaluated as associated factors. Figure 1: Association of central corneal thickness (CCT) as Association analysis between central corneal thickness determined with SD-OCT and intraocular pressure (IOP). The and intraocular pressure, respectively, means corneal curva- correlation coefficient is 𝑟 = 0.45 (𝑝 < 0.001) and the regression ture was performed with univariate linear regression as well equation is CCT (in 𝜇m) = 509 + [3.29 ∗ IOP (in mmHg)]. to determine comparable parameter estimates with literature reports. In addition, a reverse analysis with intraocular pres- 675 sure as dependent and central corneal thickness as explana- 650 tory variable was computed. Spearman correlation coefficient m) was computed to determine the relationship between central 𝜇 625 corneal thickness readings and OCT image quality. 600 A 𝑝 value of 0.05 was regarded as statistically significant. 575 Due to multiple testing, we corrected this parameter to 0.004 550 using the Bonferroni method. For further interpretation of 525 the results, all 𝑝 values above 0.001 are exactly reported. 500

Central corneal thickness ( 475 3. Results 450 6.6 6.8 7 7.2 7.4 7.6 7.8 8 8.2 8.4 Considering all eyes together, mean CCT was 561.1 ± 32.3 𝜇m Corneal curvature (mm) ± ± 𝜇 (mean standard deviation; right eyes: 560.1 31.8 m; GEE regression and left eyes: 562.2 ± 32.8 𝜇m). Association analysis of CCT 95% CI measurements found a statistically significant relationship between corneal curvature and intraocular pressure: CCT Figure 2: Relationship of central corneal thickness as determined with SD-OCT and corneal curvature: an increase of central corneal was found to be negatively associated with intraocular thickness (CCT) is associated with a flatter corneal curvature (CC). pressure readings (𝑝 < 0.001;Figure1)andpositively 𝑟 = 0.20 𝑝 < 0.001 𝑝 < 0.001 The correlation coefficient is ( ) and the regression associated with a flatter corneal curvature ( ; equation is CCT (in 𝜇m) = 354 + [27.9 ∗ CC (in mm)]. Figure 2). Reversely, univariable analysis between intraocular pressure as dependent variable and central corneal thickness as explanatory variable revealed that an increase of 22 𝜇min central corneal thickness is linked to an increased measure- LDL and triglycerides) was significantly associated with CCT 𝑝 < 0.004 ment of intraocular pressure of 1 mmHg. after Bonferroni correction for multiple testing ( ) Inthemultivariablemodel,anincreaseof10 𝜇mincentral (Table 2). corneal thickness was associated with an increase of 3 mmHg Aweakassociationbetweenlowerscanqualityand in intraocular pressure reading. Refraction of the eye did not thinner central corneal thickness measurement was deter- 𝜌=−0.09𝑝< show a significant association with CCT (Table 2). Regard- mined (Spearman correlation coefficient , 0.001 ing anthropometric characteristics of the study sample, ). Nevertheless, upon incorporating this parameter as age was independently associated with CCT: older subjects sensitivity analysis in the multivariable model, our findings had a higher central corneal thickness (Table 2). Central remained unaltered. corneal thickness values from OCT measurements increase by 0.34 𝜇mperyearofage. 4. Discussion Regarding cardiovascular parameters, none of the investigated parameters (gender and BMI and mean arterial blood Our study in a Caucasian cohort demonstrates that central pressure and biochemical parameters: HbA1c and HDL and corneal thickness readings as measured with the Topcon 4 Journal of Ophthalmology

Table 2: Association analysis of SD-OCT based central corneal andcoworkersfoundassociationsofcentralcornealthickness thickness on ocular and systemic parameters using a generalized with male gender, younger age, and higher body mass index estimating equations model. Regression coefficient Beta (Reg 𝛽), in an Indian population [8]. 𝑝 95% confidential interval (95% CI), and value. In Chinese people, central corneal thickness is associated Central corneal thickness Associations with male gender and urban region, while it is not associated with age, body mass index, and body height [7]. A study in a Multivariable linear regression Reg 𝛽 95% CI 𝑝 value [ ] Japanese population found similar findings for Asian people Mean corneal radius [mm] 25.19 19.25; 31.12 0.000 reporting an association of central corneal thickness with [ ] Intraocular pressure [mmHg] 3.33 2.75; 3.92 0.000 male gender but none for age, body weight, and body height Refraction [SE in diopters] 0.31 [−0.28; 0.91] 0.30 [11]. The ambiguities to our study results may arise from Age [years] 0.34 [0.15; 0.53] 0.001 the use of different CCT assessment methods and variations Gender [female] 1.95 [−3.52; 7.41] 0.49 in age, body measurements, and genetic background of the 2 Body mass index [kg/m ] 0.23 [−0.42; 0.87] 0.49 study populations. Mean blood pressure [mmHg] −0.31 [−0.52; −0.09] 0.005 In our study population consisting of a cohort of Cau- HbA1c [in %] 3.24 [−3.77; 10.25] 0.37 casianswithanagerangefrom17to64years,centralcorneal High density lipoproteins [mg/dL] −0.23 [−0.42; −0.05] 0.012 thickness was associated with age: each decade of age went alongwithanincreaseof3.4𝜇mincentralcornealthickness Low density lipoproteins [mg/dL] −0.06 [−0.13; 0.02] 0.13 [− ] over the entire age span. Upon comparing our findings to Triglycerides [mg/dL] 0.01 0.02; 0.04 0.44 those published by other groups, it must be considered that our age range corresponds to the working age and that we have only included healthy eyes with the purpose of 3D OCT-2000 are independently associated with corneal reporting physiological conditions. This means that our study curvature and with intraocular pressure readings. Previ- group starts at a juvenile age and terminates at retirement, ously published studies have yielded congruent findings whereas many other studies have appeared with a much older using optical or ultrasound pachymetry and association with starting age reaching into senility. There are some studies intraocular pressure [2–4, 7, 8, 10]. However, we used SD- in European cohorts with different age ranges that did not OCT for determining central corneal thickness which makes find an association between central corneal thickness and a technical difference to other studies where analyses were age[9,10,20].Incontrast,wefoundanassociationwith basedonultrasoundpachymetryorScheimpflugimaging. age: central corneal thickness increased slightly up to the age SD-OCT accurately measures central corneal thickness as of 64 years. In other ethnicities and especially in persons reported by prior publications within the physical limitations aged 70 years and older, Chua et al. reported a decrease of of the method itself as determined by wavelength, optical central corneal thickness with age [21]; similar results were system, and sensor characteristics [14]. Furthermore, our reported by other research groups [22–24]. This indicates finding of a relationship of corneal curvature with central that central corneal thickness may gradually increase in the corneal thickness as measured by OCT is new. Nevertheless, decades covered by our cohort, while over 70 years a decrease there are several studies reporting such a relationship using may be observed. other methods [15–18]. Also, our study may contribute In contrast to earlier studies, gender and body mass index to deepening the understanding of associations between were not related to central corneal thickness, nor was any CCT readings obtained from OCT and intraocular pressure other cardiovascular parameter. Interestingly, mean arterial readings obtained from noncontact tonometry and add to blood pressure showed some association with CCT. However, knowledge being generated with different methods [12]. In this association was only small and failed to reach the level of the range between 11 and 21 mmHg intraocular pressure significance after Bonferroni correction. Sensitivity analysis and 500 to 625 𝜇m central corneal thickness, we found revealed that systolic blood pressure is rather associated an approximately linear relationship between these two with central corneal thickness compared to diastolic blood parameters, but this relationship cannot be extrapolated to pressure. Based on these negative findings for associations higher or lower values as measurements were not sufficiently between central corneal thickness and cardiovascular param- available there. With an increase of 22 𝜇minCCT,intraocular eters, the underlying hypothesis seems to be true that central pressure (as dependent variable) increased by 1 mmHg, and corneal thickness itself is independent of cardiovascular this magnitude is similar to that reported in literature [12]. changes. There are few studies about systemic influencing factors Our study has several limitations: first, we did not exam- on central corneal thickness. Elflein et al. reported associa- ineaxiallengthandconsequentlycouldnotcontrolforitas tions of central corneal thickness with male gender, higher influencing factor, as previously reported by Nangia et al. [8]. body height, and body mass index in a German population Asrefractivepowerofthecorneaisknowntobeassociated [19]. The differences with our study might be explained bythe with central corneal thickness [8], we included both corneal underlying study population: we included far more male than curvature and overall manifest refraction into our analysis female participants, a different age span (17 to 64 years versus model: we found an association of central corneal thickness 35 to 74 years by Elflein et al.), and a different mean body mass with corneal curvature, but not with refraction after having index (22.9 versus 27.2), while both studies included mainly corrected for corneal curvature. Though not expected, this Caucasians. In a similar age span to Elflein et al., Nangia finding is similar to the study report by Zhang et al. [7], who Journal of Ophthalmology 5 also did not find an association of central corneal thickness [2] E. M. Hoffmann, J. Lamparter, A. Mirshahi et al., “Distribution with refraction. In addition, due to the fact that our study of central corneal thickness and its association with ocular cohort is a cross section of a working population, this may not parameters in a large central european cohort: the gutenberg strictly reflect the entire Caucasian population. Nevertheless, health study,” PLoS ONE,vol.8,no.8,ArticleIDe66158,2013. we examined a cohort of over 700 subjects with a broad range [3]M.Kohlhaas,A.G.Boehm,E.Spoerl,A.Pursten,¨ H. J. Grein, of age (from 17 to 64 years) and refraction (from −11.75 D to and L. E. Pillunat, “Effect of central corneal thickness, corneal +7.625 D) which may come close to this criterion. OCT scan curvature, and axial length on applanation tonometry,” Archives quality is a critical issue for further data processing [25, 26]. of Ophthalmology,vol.124,no.4,pp.471–476,2006. 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Association with ocular and general corneal thickness as determined by SD-OCT should also be parameters. The Beijing eye study,” Graefe’s Archive for Clinical performed with respect to individual corneal curvature and and Experimental Ophthalmology,vol.246,no.4,pp.587–592, intraocular pressure interpretation merits the knowledge of 2008. central corneal thickness. [8] V. Nangia, J. B. Jonas, A. Sinha, A. Matin, and M. Kulkarni, “Central corneal thickness and its association with ocular and general parameters in Indians: the Central India Eye and Ethical Approval Medical Study,” Ophthalmology,vol.117,no.4,pp.705–710,2010. [9]R.C.W.Wolfs,C.C.W.Klaver,J.R.Vingerling,D.E.Grobbee, All procedures performed in studies involving human partic- A. Hofman, and P. T. V. M. 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Clinical Study Assessment of Anterior Segment Changes in Pseudophakic Eyes, Using Ultrasonic Biomicroscopic Imaging, after Pars Plana Vitrectomy with Silicone Oil or Gas Tamponade

Erkan Ünsal, Kadir Eltutar, Belma Karini, and Osman KJzJlay

Istanbul Research and Training Hospital, 34098 Istanbul, Turkey

Correspondence should be addressed to Erkan Unsal;¨ [email protected]

Received 30 March 2016; Revised 19 April 2016; Accepted 24 April 2016

Academic Editor: Sang Beom Han

Copyright © 2016 Erkan Unsal¨ et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objective. To evaluate the morphological changes of the anterior segment using ultrasonic biomicroscopy (UBM) imaging in pseudophakic patients who underwent pars plana vitrectomy (PPV) with silicone oil or gas (C3F8) internal tamponade agent injection. Method. This prospective study included pseudophakic patients with planned PPV,divided into two groups according to internal tamponade agent: those in which silicone oil was used (𝑛=27, Group 1) and those in which gas (C3F8)wasused(𝑛=24, Group 2). UBM measurements were performed in the supine position before and one week after surgery. Results. In patients of Group 1, postoperative trabecular meshwork-ciliary process distance (T-CPD) and iris-ciliary process distance (I-CPD), according to preoperative values, were found to be statistically significantly reduced, and postoperative mean value of scleral thickness (ST) and intraocular pressure (IOP), according to preoperative value, was found to be statistically significantly increased. In patients of Group 2, postoperative mean values of anterior chamber depth (ACD), ciliary body thickness (CBT), T-CPD, I-CPD, and IOP, according to preoperative values, were found to be statistically significantly reduced. Preoperatively, in Group 2 patients, according to Group 1 patients, TIA and IOP were found to be statistically significantly increased. Preoperative and postoperative IOP between the measured parameters with UBM showed no statistically significant correlation. Conclusions.Gasescausemoremorphological changes in the anterior segment structures. It is thought that complications such as increased intraocular pressure can be seen more frequently for this reason.

1. Introduction of the received image. In addition, the variability in the measurement analysis should not be underestimated. The Ultrasound biomicroscopy (UBM) technology uses high- main reasons underlying this variability are the differences in frequency ultrasound to produce images of the anterior theselectionoftheframetobemeasuredandthedetection segment in high resolution. Anterior segment structures, ofthelocationofthescleralspur.Therefore,thecomparison including the crystalline lens, ciliary body, and lens zonules, of the measurements before and after any attempt should be canbemorphologicallyassessedandquantitativelymeasured performed by the same observer. Thus, in our study, pre- by using this in vivo noninvasive imaging technique. The and postoperative UBM measurements were performed and reported repeatability of UBM measurements is good if compared by a single observer. the measurements are performed by the same experienced In many vitreoretinal diseases, PPV is considered the observer [1–4]. UBM has been investigated regarding the standard surgical approach. Gases and silicone oil are used repeatability of measurements, accuracy, and precision [5– frequently as internal tamponade agents. Following PPV 7]. Several publications have reported that intraobserver surgery, many complications can be encountered, a number reproducibility is high for all the measurements performed of which are related to the anterior segment. UBM can reveal using this technique, but interobserver reproducibility is poor changes in the anterior segment due to complications in [3, 7, 8]. The main reason for this variability is the quality the postoperative period [9–16]. Among these changes are 2 Journal of Ophthalmology shallowing of the anterior chamber [9], narrowing of the photocoagulation were done prophylactically. Silicone oil anterior chamber angle, and ciliary body detachment [9, 11– (1000cs) was used as a long-acting internal tamponade agent; 13]. As a result of such changes, complications including glau- 14% C3F8 was used as short-acting internal tamponade agent. coma or hypotonia may occur [11]. In all patients treated with silicone oil, sclerectomies were The purpose of our study was to use UBM imaging sutured. In cases treated with gas, sclerotomies were sutured techniques to analyze changes in the anterior segment mor- only when needed. After the operation all patients were phology in the postoperative period of pseudophakic patients prescribed 1% prednisolone acetate and lomefloxacin drops who had either PPV with silicone oil or PPV with gas (C3F8) in the form of one drop every two hours for a month. injection. UBM examinations were performed by the same surgeon, using the same device (SONOMED VuMAX II5)witha 2. Methods 35 mHz transducer. These examinations were performed before (24–48 hours) surgery and at one week (5–10 days) Examination of the subjects’ eyes was performed from Octo- (7±3days) after surgery. In order to avoid the effects of drugs ber 2012 to March 2015, and 51 pseudophakic eyes of 51 used such as paralysis of accommodation after atropine, patients with planned PPV were included in this prospective cyclopentolate, or tropicamide use or mydriasis after phenyle- study. Patients were categorized as those who had silicone oil phrine use, all UBM measurements were performed after as an internal tamponade agent (Group 1) and those who had the effects of these drugs. Scanning was performed with gas (C3F8) as an internal tamponade agent (Group 2). the patient in the supine position. In order to use natural The study was conducted in accordance with the tenets pupil dilation, scanning was performed in a room with low of the World Medical Association’s Declaration of Helsinki. illumination. Accommodation was kept constant by asking Approval of the local ethics of the study protocol was obtained thepatienttostareataredtargetontheceiling. from the Ethics Committee of the Istanbul Education and After introducing topical 0.5% proparacaine HCL Research Hospital. All patients included in the study were (Alcaine5, Alcon), a soft silicone eyecup of the appropriate informed about the details of the surgical procedure and diameter (18, 20, or 22 mm) was inserted between the upper signed an informed consent form. lid and the fornix conjunctiva of the lower lid. Scanning One or two days before the surgery, all eyes underwent of every patient before and after surgery was performed a complete ophthalmologic examination. A detailed history using the same eyecup. In order to prevent corneal contact, including age, gender, systemic diseases, and drugs used was the focus distance of the transducer was set at 12 mm. For recorded. The patients best-corrected vision acuity (BCVA) thepurposeofimmersion,theeyecupwasfilledwithan was measured using the Snellen chart. Goldmann Applana- adequate amount of sterile physiological saline. tion Tonometry was used to measure intraocular pressure Axial images of the anterior chamber and radial section of (IOP). The Goldmann three-mirror lens was used to evaluate the angle images from the temporal quadrant were scanned. the anterior chamber angle. In order to obtain an ideal image and to have consistent pre- The following situations were excluded: patients with pre- andpostoperativemeasurements,wetookcaretohavestable vious intraocular surgery (except cataract surgery); patients scanned axial images of the anterior segment (theoretically with ocular trauma history; cases of PPV that required asso- aligned with the central horizontal line and symmetrically ciated surgical procedures, such as scleral buckling; previous toit)aswellasstableimagesintheverticalalignment anterior segment laser therapy; history of uveitis or glaucoma; (cornea, lens, and anterior and posterior capsule should be useofanytopicalorsystemicdrugthatmightaffectpupilor balanced with the referenced vertical central line). When accommodation; and patients with postoperative intraocular taking radial cross-sectional images of the angle, we made pressure above 22 mmHg. sure that the probe was perpendicular to the limbus of the Indications for PPV included pseudophakic rhegmatoge- scanned quadrant, and we chose the images with the best nous retinal detachments (RRD), pseudophakic diabetic reflectivity of the iris [17]. In terms of accuracy and ease, retinopathy (DR) with persistent vitreous hemorrhage, pseu- localization of the scleral spur was given close attention in dophakic fibrovascular proliferation, and pseudophakic trac- order to choose the images that best showed the ciliary body, tional retinal detachment involving the macula, pseudopha- the iris, and the reflectance of the interface between the ciliary kic epiretinal membrane (ERM), and macular hole (MH). body and the sclera. Each patient underwent a 23-gauge pars plana vitrectomy The anterior chamber depth and lens thickness were by a single surgeon (EU). PPV was performed with a BIOM measured from the axial images of the anterior segment, noncontact wide-angle viewing system. In patients with a using the methods previously recommended by Pavlin et al. retinal tear, we performed three to four rows of endolaser and the scales provided in the user’s guide for the device photocoagulation around the retinal tear using an endolaser [18, 19]: probe. As a standard aspect of the surgery, we used twin light. After injection of triamcinolone acetonide, all cases (1) Axial ACD measurement: detected by measuring the were controlled for the presence of the posterior hyaloid distance between the posterior surface of the central membrane. In cases of an attached posterior hyaloid mem- cornea and the anterior surface of the IOL in the brane, this was separated using the tip of a vitrectomy probe midline of the pupil (Figure 1(a)). with vacuum, and, after that, it was surgically excised. In the (2) Trabecular meshwork-iris angle (TIA): measured appropriate cases, three to four rows of 360-degree endolaser withtheapexintheirisrecessandthearmsof Journal of Ophthalmology 3

(a) (b) (c)

(d) (e)

Figure 1: Views of axial images of the anterior chamber and radial section of the angle images from the temporal quadrant. (a) An UBM image of anterior chamber depth (ACT) and trabecular meshwork-iris angle (TIA). (b) An UBM image of ciliary body thicknesses 1 and 2 (CBT 1 and 2). (c) An UBM image of ciliary body thickness 3 (CBT 3) and the maximum ciliary body thickness (CBT Max). (d) An UBM image of scleral thickness (ST) and trabecular-ciliary process distance (T-CPD). (e) An UBM image of iris-ciliary process distance (I-CPD).

the angle passing through a point on the trabecular ciliary body to the border perpendicular to the meshwork 500 𝜇mfromthescleralspurandapoint surface of the sclera (Figure 1(c)). on the iris perpendicularly opposite (Figure 1(a)). (3) Ciliary body thickness (CBT) measured in four re- (4) Scleral thickness (ST): the distance of the episcleral gions: surface measured perpendicular to the scleral spur (Figure 1(d)). (a) the distance 1 mm from the scleral spur (CBT 1), (5) Trabecular meshwork-ciliary process distance (T- detected by measuring the distance between the CPD): measured as a line extending from a point posterior surface of the sclera and ciliary body 500 𝜇m anterior to the scleral spur along the corneal to the border perpendicular to the surface of the endothelium and dropped perpendicularly through sclera (Figure 1(b)); the iris to the most anterior ciliary process seen (b)thedistance2mmfromthescleralspur(CBT2), during scanning in that meridian (Figure 1(d)). detected by measuring the distance between the (6) Iris-ciliary process distance (I-CPD): the distance posterior surface of the sclera and ciliary body measured between the iris pigment epithelium and to the border perpendicular to the surface of the ciliary processes (Figure 1(e)). sclera (Figure 1(b)); (c)thedistance3mmfromthescleralspur(CBT3), Oneweek(5–10days)afterthesurgery,IOPwasmea- detected by measuring the distance between the sured and we repeated at the same meridian (temporal quad- posterior surface of the sclera and ciliary body rant) all the UBM examinations. We compared the values to the border perpendicular to the surface of the determined before and after the surgery. We used SPSS 15.00 sclera (Figure 1(c)); for Windows software (SPSS Inc., Chicago, Illinois, USA) (d) the thickest location of the ciliary body (CBT to evaluate the findings of this study. Comparison of the Max), detected by measuring the distance parameters of the same group was done using the paired between the posterior surface of the sclera and 𝑡-test. The comparison of independent groups was done 4 Journal of Ophthalmology

Table 1: Demographic and clinical characteristics of the groups.

Group 1 (𝑛=27)Group2(𝑛=24) Mean age ± SD (range) 60.3 ± 11.3 (41–77) 69.25 ± 9.8 (56–84) Male/female 15/12 6/18 Eyes affected, 𝑛 (right/left) 15/12 6/18 IOP (preoperative) mmHg, mean ± SD (range) 11.68 ± 2.86 (7–18) 14.10 ± 2.30 (10–18) IOP (postoperative) mmHg, mean ± SD (range) 18.92 ± 2.23 (14–22) 12.81 ± 2.74 (9–19) IOP: intraocular pressure; SD: standard deviation.

Table 2: Distribution of the patients diagnoses. Comparison of the between-groups preoperative and 𝑛=27 𝑛=24 postoperative parameters of the anterior segment and the Group 1 ( )Group2()Totalangle of the temporal quadrant and IOP are shown, respec- PDR 6 3 9 tively, in Table 4. Preoperatively, in Group 2 patients, accord- RRD 18 3 31 ing to Group 1 patients, TIA and IOP were found to ERM No 13 13 bestatisticallysignificantlyincreased.Postoperatively,in MH No 2 2 Group 2 patients, according to Group 1 patients, TIA was IVH 3 3 6 found to be statistically significantly increased, and CBT 2, PDR: proliferative diabetic retinopathy; RRD: rhegmatogenous retinal CBT3,andIOPwerefoundtobestatisticallysignificantly detachment; ERM: epiretinal membrane; MH: macular hole; IVH: intravit- decreased (Table 4, Figure 2). Preoperative and postoper- real hemorrhage. ative IOP between the measured parameters with UBM were not statistically significantly correlated𝑃 ( > 0.005, 𝑟 < 0.25). using the independent samples 𝑡-test. Pearson’s correlation analysis was used to compare IOP and measured parameters 4. Discussion with UBM. The 𝑃 values of <0.05 were accepted as being statistically significant. ST was found to be increased in the group of patients in which silicone oil was used as an internal tamponade agent. 3. Results In Group 2 patients of our study, postoperative mean values of ciliary body thickness, T-CPD, and I-CPD, according to Despite postoperative antiglaucomatous drugs, five patients preoperative values, were found to be statistically significantly with IOP more than 22 mmHg were excluded due to the fact reduced. that the initiative surgery of lowering IOP may have been Marigo et al. [20] in a study of 20 patients reported needed. no statistically significant differences in the morphology of This prospective study included pseudophakic patients the anterior segment measurements performed with UBM with planned PPV, divided into two groups according to preoperatively and one month after vitrectomy. In contrast internal tamponade agent: those in which silicone oil was to our study, Marigo did not use an internal tamponade. used (𝑛=27, Group 1) and those in which gas (C3F8)was Our study consists of two groups: a group in which silicone used (𝑛=24,Group2). oilwasusedandanothergroupinwhichgas(C3F8)was Patient characteristics by group are included in Table 1. used as internal tamponade agents. In addition, our study Distribution of the patients diagnoses is shown in Table 2. aimed to show early postoperative morphological changes In our study, it appears that there are marked differences of the anterior segment, so we performed the postoperative in the diagnosis distribution between the groups. Group 1 measurements one week after the surgery in order to show patients are mainly composed of RRD and PD patients, while the effects of gas as an internal agent. Group 2 consists primarily of ERM patients. C¸ alik et al. [21] evaluated anterior segment changes with The comparisons of the preoperative and postoperative Pentacam Scheimpflug camera pre- and postoperatively in parameters of the anterior segment and the angles of the tem- patients who underwent pars plana vitrectomy (PPV) and poral quadrant and IOP are shown, respectively, in Table 3. silicone oil injection. They reported that there was no change In patients of Group 1, postoperative T-CPD and I- in TIA values of PPV patients with or without internal tam- CPD, according to preoperative values, were found to be ponade of silicone. Similarly, in our study, there was no statisticallysignificantlyreduced,andthepostoperativemean change in TIA values of PPV patients with internal tampon- value of Stand IOP according to preoperative value was found ade of both silicone oil (Group 1) and gas (Group 2). to be statistically significantly increased (Table 3). Kim and Yu [22] evaluated the ciliary body thickness In patients of Group 2, postoperative mean values of using UBM pre- and postoperatively in patients who under- ACD, CBT 1, CBT 2, CBT 3, CBT Max, T-CPD, I-CPD, went PPV for diffuse DME. They reported that the average and IOP according to preoperative values were found to be preoperative value of CBT in DME patients was found to statistically significantly reduced (Table 3). be thicker than the control groups. The CBT decreased Journal of Ophthalmology 5

Table 3: Comparison of the preoperative and postoperative parameters of the anterior segment and the angle of the temporal quadrant.

Group 1 (𝑛=27)Group2(𝑛=24) ∗ ∗ Pre Post 𝑃 Pre Post 𝑃 ACD, mean ± SD (mm) 3.37 ± 0.76 3.36 ± 0.67 0.914 3.55 ± 0.39 3.29 ± 0.40 0.000 ∘ TIA ( ), mean ± SD 24.77 ± 9.6 27.44 ± 7.2 0.156 33.12 ± 8.74 31.37 ± 5.99 0.124 CBT 1, mean ± SD (mm) 1.11 ± 0.23 1.07 ± 0.18 0.076 1.13 ± 0.21 1.05 ± 0.25 0.000 CBT 2, mean ± SD (mm) 0.72 ± 0.22 0.71 ± 0.23 0.654 0.67 ± 0.23 0.59 ± 0.17 0.000 CBT 3, mean ± SD (mm) 0.55 ± 0.19 0.58 ± 0.24 0.251 0.50 ± 0.14 0.35 ± 0.09 0.047 CBT Max, mean ± SD (mm) 1.28 ± 0.19 1.23 ± 0.21 0.077 1.23 ± 0.24 1.13 ± 0.22 0.000 ST, mean ± SD (mm) 0,94 ± 0.08 1.02 ± 0.09 0.004 0.94 ± 0.07 0.97 ± 0.14 0.113 T-CPD, mean ± SD (mm) 1.43 ± 0.19 1.34 ± 0.12 0.014 1.41 ± 0.14 1.31 ± 0.11 0.000 I-CPD, mean ± SD (mm) 0.95 ± 0.17 0.87 ± 0.16 0.002 0.96 ± 0.19 0.84 ± 0.12 0.030 IOP, mean ± SD (range) (mmHg) 11.68 ± 2.86 (7–18) 18.92 ± 2.23 (14–22) 0.000 14.10 ± 2.30 (10–18) 12.81 ± 2.74 (9–19) 0.002 ACD: anterior chamber depth; LT: lens thickness; TIA: trabecular meshwork-iris angle; CBT 1, 2, and 3: ciliary body thicknesses 1, 2, and 3 mm, CBT Max: maximum ciliary body thickness; ST: sclera thickness; T-CPD: trabecular meshwork-ciliary process distance; I-CPD: iris-ciliary process distance; SD: standard ∗ deviation; paired 𝑡-test.

Table 4: Comparison of the between-groups preoperative and postoperative parameters of the anterior segment and the angle of the temporal quadrant and IOP.

Pre Post ∗ ∗ Group 1 Group 2 𝑃 Group 1 Group 2 𝑃 ACD, mean ± SD (mm) 3.37 ± 0.76 3.55 ± 0.39 0.310 3.36 ± 0.67 3.29 ± 0.40 0.681 ∘ TIA ( ), mean ± SD 24.77 ± 9.6 33.12 ± 8.74 0.002 27.44 ± 7. 2 31 . 3 7 ± 5.99 0.041 CBT 1, mean ± SD (mm) 1.11 ± 0.23 1.13 ± 0.21 0.695 1.07 ± 0.18 1.05 ± 0.25 0.767 CBT 2, mean ± SD (mm) 0.72 ± 0.22 0.67 ± 0.23 0.481 0.71 ± 0.23 0.59 ± 0.17 0.039 CBT 3, mean ± SD (mm) 0.55 ± 0.19 0.50 ± 0.14 0.106 0.58 ± 0.24 0.35 ± 0.09 0.000 CBT Max, mean ± SD (mm) 1.28 ± 0.19 1.23 ± 0.24 0.482 1.23 ± 0.21 1.13 ± 0.22 0.126 ST, mean ± SD (mm) 0,94 ± 0.08 0.94 ± 0.07 0.948 1.02 ± 0.09 0.97 ± 0.14 0.094 T-CPD, mean ± SD (mm) 1.43 ± 0.19 1.41 ± 0.14 0.762 1.34 ± 0.12 1.31 ± 0.11 0.349 I-CPD, mean ± SD (mm) 0.95 ± 0.17 0.96 ± 0.19 0.862 0.87 ± 0.16 0.84 ± 0.12 0.528 IOP, mean ± SD (range) (mmHg) 11.68 ± 2.86 (7–18) 14.10 ± 2.30 (10–18) 0.002 18.92 ± 2.23 (14–22) 12.81 ± 2.74 (9–19) 0.000 ACD: anterior chamber depth; LT: lens thickness; TIA: trabecular meshwork-iris angle; CBT 1, 2, and 3: ciliary body thicknesses 1, 2, and 3 mm, CBT Max: maximum ciliary body thickness; ST: sclera thickness; T-CPD: trabecular meshwork-ciliary process distance; I-CPD: iris-ciliary process distance; SD: standard ∗ deviation; independent samples 𝑡-test.

significantly after PPV in DME group. This decrease in CBT decrease in ACD in the eyes of patients who had undergone correlates with the decrease of ciliary body edema. In our gas tamponade (Group 2). However, we did not find a study, the decrease in CBT in patients with gas tampon- significant decrease in ACD in the eyes of patients who had ade unlike those with silicone tamponade was considered undergone silicone oil tamponade (Group 1). In the same aresultofthepressurethatgasesexertonciliarybody study [14] no correlation was found in increase of IOP and because of surface tension rather than the ciliary body edema ACD. In our study, cases with IOP above 22 mmHg after the reduction. operation were not considered because they were excluded Neudorfer et al. [14] evaluated the short-term changes from the study. induced by PPV on anterior segment morphology by means In patients in Group 2, postoperative mean values of of high-frequency UBM. In the study patients were classi- ACD, CBT 1, CBT 2, CBT 3, CBT Max, T-CPD, and I- fied according to the gas tamponade usage. They found a CPD, according to preoperative values, were found to be significant decrease in ACD in the eyes of patients who had statistically significantly reduced. We concluded that there undergone gas tamponade but not in those who had not was much more pressure on the ciliary body in patients undergone gas tamponade. Similarly, we found a significant who were given gas in the supine position compared to the 6 Journal of Ophthalmology

(a) (b)

Figure 2: Views of radial section of the angle images from the temporal quadrant. (a) UBM image of an eye with silicone oil used as internal tamponade agent. (b) UBM image of an eye with gas (C3F8)usedasaninternaltamponadeagent.

silicone-treated patients. This may be due to the fact that the five patients (9.8%) with IOP more than 22 mmHg after the surface tension of gases is higher than the surface tension of operation were excluded. silicone oil and may be related to the spherical structure of In terms of the shortcomings of our study, besides the silicone oil inside the eye which exerts less pressure on the earlypostoperative(oneweek)UBMmeasurements,late ciliary body. postoperative measurements were not performed. However, The mean value of ST of Group 1 patients was statistically the reduction of the amount of intraocular gas used as significantly higher than the mean value of ST of Group an internal tamponade agent (C3F8)combinedwiththe 2 patients because, in patients treated with silicone oil, all advancing time causes postoperative decreased activity. This access sites were closed by scleral sutures, which may result departs from the aim of the study. Although no significant in episcleral edema. But the access sites of patients treated correlation exists between IOP and the measured parameters with gas tamponade (Group 2) were sutured only when with UBM, another limitation is the exclusion of eyes with needed. postoperative IOP above 22 mmHg. In addition our study After the first week of operations changes in the anterior only includes a small sample size of each disorder, which segment have been described in the posterior segment, such may have influenced morphological changes of the ante- as vitrectomy and scleral buckling [9–12, 23–25]. However, rior segment among vitreoretinal disorders. Intraobserver there is limited information on the effects of vitrectomy on reproducibilityishighforallthemeasurementsperformed the morphology of the anterior segment. If we could detect using this technique, but interobserver reproducibility is the effects of vitrectomy on the morphology of the anterior poor [27]. Therefore, UBM examinations were performed segment, we would be able to prevent complications in the bythesamesurgeon.Ontheotherhand,thiscondition predisposing eyes. mayhavecausedbiaswhichcanbeoneofthelimitations PPV with silicone oil and with gas as an internal of our study. Besides the quality of the image acquisition tamponade agent causes changes in the parameters of the and the analysis differences, UBM evaluation of the anterior anterior segment. It seems that a significant number of chamber may be affected and influenced by physiological and postoperative complications arise due to the changes of these environmental variables. Factors such as room illumination, parameters. A better understanding of the changes in these fixation, and accommodative efforts of the patient can cause parameters can be important to prevent such complica- several changes in the anterior segment anatomy. Thus, tions. these factors should remain constant when dealing with Hasegawa et al. compared IOP elevations in the imme- quantitative measurements. In our study all measurements diate postoperative period after vitrectomy for various vit- where performed according to a protocol with standard reoretinal disorders and to determine the incidence of and environment and conditions. risk factor for IOP elevation [26]. They found that the IOP Gases do cause more morphological changes in the five hours after surgery was significantly lower in patients anterior segment structures (Figure 3). It is thought that with MH than in those with DME, PDR, PVR, or RRD. complications such as increased intraocular pressure can be The IOP one day after surgery was significantly lower in seen more frequently for this reason. Future studies with patients with MH and ERM than in those with DME, PDR, a large sample size and using more advanced devices will or RRD. In the same study, IOP elevation (>25 mmHg) was further facilitate our understanding of the morphological found in approximately one-quarter of cases within one day. changes of the anterior segment in patients undergoing In our study, despite postoperative antiglaucomatous drugs, vitrectomy. Journal of Ophthalmology 7

Silicone oil Gas (C3F8)

(a) (b)

Figure 3: Views of demonstrative image: (a) silicone oil internal tamponade; (b) gas (C3F8) internal tamponade.

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Clinical Study Ultrasound Biomicroscopy Comparison of Ab Interno and Ab Externo Intraocular Lens Scleral Fixation

Lie Horiguchi,1 Patricia Novita Garcia,1,2 Gustavo Ricci Malavazzi,1,2 Norma Allemann,2 and Rachel L. R. Gomes2,3

1 Department of Ophthalmology, Irmandade da Santa Casa de Misericordia´ de Sao˜ Paulo, Sao˜ Paulo, SP, Brazil 2Department of Ophthalmology, Federal University of Sao˜ Paulo, Sao˜ Paulo, SP, Brazil 3Hospital de Olhos Paulista, Rua Ab´ılio Soares 218, 04005-000 Sao˜ Paulo, SP, Brazil

Correspondence should be addressed to Rachel L. R. Gomes; [email protected]

Received 22 March 2016; Revised 1 May 2016; Accepted 4 May 2016

Academic Editor: Sang Beom Han

Copyright © 2016 Lie Horiguchi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose.Tocompareab interno and ab externo scleral fixation of posterior chamber intraocular lenses (PCIOL) using ultrasound biomicroscopy (UBM). Methods. Randomized patients underwent ab externo or ab interno scleral fixation of a PCIOL. Ultrasound biomicroscopy was performed 3 to 6 months postoperatively, to determine PCIOL centration, IOL distance to the iris at 12, 3, 6, and 9 hours, and haptics placement in relation to the ciliary sulcus. Results. Fifteen patients were enrolled in the study. The ab externo technique was used in 7 eyes (46.6%) and the ab interno in 8 eyes (53.3%). In the ab externo technique, 14 haptics were located: 4 (28.57%) in the ciliary sulcus; 2 (14.28%) anterior to the sulcus; and 8 (57.14%) posterior to the sulcus, 6 in the ciliary body and 2 posterior to the ciliary body. In the ab interno group, 4 haptics (25.0%) were in the ciliary sulcus, 2 (12.50%) anterior to the sulcus, and 10 (75.0%) posterior to the sulcus, 4 in the ciliary body and 6 posterior to the ciliary body. Conclusions. Ab externo and ab interno scleral fixation techniques presented similar results in haptic placement. Ab externo technique presented higher vertical tilt when compared to the ab interno.

1. Introduction Ultrasound biomicroscopy (UBM) is an effective method to study the anterior segment and haptics placement behind Capsular bag is the standard of care for posterior chamber theiris[9].Inthisstudywecomparedab interno and intraocular lens (IOL) placement. However, if the capsular ab externo techniques to evaluate both haptics position in support is absent, many techniques can be used to fixate the relation to ciliary sulcus and the IOL distance from iris plane lens. Ab interno and ab externo are trans scleral suture tech- determining vertical and horizontal tilt using UBM. niques described to fixate a posterior chamber intraocular lens (PCIOL) [1–3]. Nevertheless, other techniques to fixate 2. Methods an IOL have been described, such as the no-suture technique that places the IOL haptic inside a scleral tunnel [4–6]. This study was approved by the Santa Casa de Sao˜ Paulo The aim of fixation is to position the haptics in the ciliary Ethics Committee. Patients scheduled for IOL implantation sulcus; however, these procedures are performed without were randomly assigned to participate in one of the groups. direct visualization of the path of the needle. Scleral fixation was performed after a complete ophthalmic Direct view techniques, guided by endoscopic probe, examination. Surgery was scheduled according to patient’s have greater rate of success in lens centration and correct intraocular inflammation status. Patients with any sign of haptic position [7, 8]. This technique is considered the active inflammation or best-corrected visual acuity worse gold standard; however, it requires particular equipment and than 20/40 during the recruitment timeframe were excluded specific training. from this study. In one group, the IOL was fixated using 2 Journal of Ophthalmology

0.33 mm 0.41 mm 0.10 mm 0.85 mm

(a) (b)

Figure 1: Ultrasound biomicroscopy of the left eye submitted to intraocular lens fixation using ab externo technique. (a) Horizontal plane showing good lens positioning; (b) vertical tilt of the IOL, lens placed more posteriorly in the superior meridian compared to the inferior meridian. ab interno technique and in the other group, it was fixated represented a centered IOL. Positive values represented an using ab externo. All patients did not present adequate anterior displacement of the IOL portion in relation to the capsule support and were candidates for scleral IOL fixation perfect position, and negative values represented a posterior surgery. Block randomization method was used to allocate displacement of the IOL portion in relation to the null patients in the treatment groups. All surgeries were per- position. A 𝑝 value less than 0.05 was considered statistically formedbythesamesurgeon(RLRG). significant. In the ab externo surgical technique, two triangular scleral flaps were created at the 2 and 8 o’clock positions in the right 3. Results eyesandat4and10o’clockpositionsinthelefteyes.Next,a 26-gauge needle was used to penetrate the bed of the scleral A total of nineteen eyes of 19 patients were included in the flap at 2 or 4o’clock position perpendicular to the sclera and study. Four patients were excluded for lost follow-up. Surgery 1.5 mm posterior to the limbus. At the same time, a straight was performed in 8 right eyes (OD) and 7 left eyes (OS). The needle attached to a 10-0 polypropylene suture was used to mean age was 63.53 ± 20.8 years. penetrate the bed of the opposite scleral flap perpendicular The ab externo technique was used in 7 eyes (57.8 ± 28.4 to the sclera. The suture was threaded into the barrel ofa years, 3 females) and the ab interno in 8 eyes (68.5 ± 10.7 years, 26-gauge needle. An uninterrupted intersulcus suture was 5 females). Sixteen eyes were aphakic, 2 had subluxated lens, placed, extending across the posterior chamber. The anterior and1haddislocatedIOL.Patientdemographicsandaphakia chamber was then opened and filled with 2% methylcellulose etiology are listed in Table 1. Figures 1 and 2 demonstrate the solution.Thesuturewaspulledoutsidetheeye,divided,and UBM images. tied to the haptics of a single-piece (polymethylmethacrylate) In the ab externo technique, 14 haptics were located using IOL. The IOL was then placed in the posterior chamber. UBM: 4 (28.57%) in the ciliary sulcus, 2 (14.28%) anterior In the ab interno technique, 2 scleral flaps were created to the sulcus, and 8 (57.14%) posterior to the sulcus (6 were using the same criteria as in the ab externo technique, and 2 in the ciliary body and 2 were posterior to the ciliary body). straight needles with 10-0 polypropylene sutures were passed In the ab interno group, 16 haptics were located using UBM: through a scleral incision parallel to the undersurface of the 4 (25.0%) in the ciliary sulcus, 2 (12.50%) anterior to the iris. Further steps were as in the ab externo technique. sulcus, and 10 (75.0%) posterior to the sulcus (4 were in Ultrasound biomicroscopy (UBM Vumax II, Sonomed theciliarybodyand6wereposteriortotheciliarybody). Inc., NY, USA) was performed by the same examiner (PNG) Table 1 summarizes the demographics of the sample and the under immersion technique (anesthetic drop instillation position of the haptics after the surgical intervention in each prior to the insertion of an immersion cup between the group (ab externo and ab interno) based on information from eyelids, filled with 10 mL saline solution) from 3 to 6 months ultrasound biomicroscopy evaluation. postoperatively to detect the position of both haptics in Tables 2 and 3 compare the findings of intraocular lens relation to the ciliary sulcus and the position of the optics in position (“tilt”) considering each surgical technique, utilizing relation to the iris, in different positions: 3, 6, 9, and 12 o’clock ultrasound biomicroscopy. hours. Statistical analysis was performed using Stata 14 software 4. Discussion (StataCorp 2015, Stata Statistical Software, Version 23, Col- lege Station, Texas, USA). IOL tilt in vertical and horizontal The aim of scleral fixation techniques is to place the IOL planes was compared using variance analysis. IOL tilt was haptics in the sulcus. The results of our study demonstrate defined as the difference in millimeters in the position that the ab interno technique is similar to the ab externo between measurements obtained in the vertical plane (12 to assure the ciliary sulcus placement of the haptics. Four and 6 hours) and the horizontal plane (3 and 9 hours). Null (28.57%) haptics of the ab externo technique patients were Journal of Ophthalmology 3

Table 1: Demographics of the sample and cause and technique used for intraocular lens fixation and postoperative IOL positioning evaluated using ultrasound biomicroscopy.

Age (yrs) Gender Cause of inadequate capsular support IOL fixation surgical technique Postoperative UBM haptics position in relation to sulcus 1 77 F After Phaco aphakia Ab interno ( )Posterior-parsplana (2)Sulcus 1 80 M Decentered IOL Ab interno ( )Posterior-parsplana (2) Anterior 1 58 M Unknown aphakia Ab interno ( ) Posterior-ciliary body (2) Anterior 1 55 F After Phaco aphakia Ab interno ( )Posterior-parsplana (2)Sulcus 1 82 F After ICE aphakia Ab interno ( ) Posterior-ciliary body (2) Posterior-ciliary body 1 73 F After Phaco aphakia Ab interno ( )Posterior-parsplana (2)Posterior-parsplana 1 60 F After Phaco aphakia Ab interno ( )Posterior-parsplana (2)Sulcus 1 63 M Subluxated cataract Ab interno ( )Sulcus (2) Posterior-ciliary body 1 18 M Subluxated cataract Ab externo ( ) Posterior-ciliary body (2) Anterior 1 43 F Subluxated cataract Ab externo ( )Sulcus (2)Sulcus 1 69 M After ECE aphakia Ab externo ( )Sulcus (2) Posterior-ciliary body 1 82 F After Phaco aphakia Ab externo ( )Sulcus (2)Posterior-parsplana 1 93 M After Phaco aphakia Ab externo ( ) Posterior-ciliary body (2) Posterior-ciliary body 1 72 M After Phaco aphakia Ab externo ( )Posterior-ciliaryBody (2) Anterior 1 28 F Unknown aphakia Ab externo ( ) Posterior-ciliary body (2)Posterior-parsplana F: female; M: male; IOL: intraocular lens; ECE: extracapsular extraction; Phaco: phacoemulsification; ICE: intracapsular extraction;1 ( ): haptic 1; (2): haptic 2.

Table 2: Intraocular lens position in relation to the iris (IOL tilt) in Table 3: Intraocular lens position in relation to the iris (IOL tilt) in the horizontal plane (3 and 9 h), considering UBM findings. the vertical plane (12 and 6 h), considering UBM findings.

95% confidence 95% confidence 𝑁 Mean (mm) SD interval 𝑁 Mean (mm) SD interval Inferior Superior Inferior Superior Ab externo 7 −0.12 0.1603 −0.4356 0.927 Ab externo 7 −0.36 0.1261 −0.6058 −0.1113 Ab interno 8 −0.04 0.1138 −0.2668 0.1793 Ab interno 8 −0.2 0.1059 −0.4101 0.0051 Total 15 −0.08 0.0933 −0.2628 0.1028 Total 15 −0.28 0.0813 −0.4347 −0.116 SD:standarddeviation;IOL:intraocularlens. SD:standarddeviation;IOL:intraocularlens. in the sulcus, compared to 4 haptics (25%) in the ab interno group. Using UBM, Kamal et al. reported that 29% of the and 50%, respectively, versus 55%, 27.5%, and 17.5% reported hapticswereintheciliarysulcuswiththeab interno technique by Sewelam et al. [12]. de Camargo Vianna Filho et al. [13] and 31% with the ab externo, with no statistical significance observed that there was a tendency of the haptics to be placed [2]. out of the sulcus in the ab externo technique (75%), and this The results may vary between studies. Pavlin et al. [10] was more evident at one side of the fixation. The current study found 38.24% of the haptics in the sulcus, 38.24% anterior presented similar results. In the ab externo group, 75.0% of the to the sulcus, and 23.53% posterior to the sulcus after ab haptics were out of sulcus, and in the ab interno group, 71.42% externo scleral fixation. Steiner et al. [11] reported 33%, 17%, ofthehapticswereoutofsulcus. 4 Journal of Ophthalmology

(a) (b)

Figure 2: Ultrasound biomicroscopy of eyes submitted to intraocular lens fixation using UBM images. Arrows show the ciliary body, and arrowheadsshowthehaptic.(a)Ab externo, haptic placed in the ciliary body; (b) ab interno,hapticinthesulcus;(c)ab interno,haptic posterior to the ciliary body; (d) haptic in the sulcus.

Ultrasound biomicroscopy was performed from 3 to Hayashietal.observedsignificantlygreatertiltintheeyesthat 6monthspostoperatively.Aftersurgery,allcaseshada underwent suture scleral fixation when compared to other centered and stable IOL positioned with no IOL-related iris techniques [20]. complication. The IOL remained stable during the study Ab externo and ab interno scleral fixation techniques follow-up period. In the literature, it is observed that the presented similar results in haptic placement in the group haptic position after a sutured scleral fixation does not change examined. Ab externo technique resulted in a higher vertical over time unless suture breakage occurs. The polypropylene IOLtiltwhencomparedtotheab interno technique. suture showed stability for more than 4 years in the long-term evaluation [14, 15]. Price et al. observed late postoperative Disclosure dislocation of PCIOL, 7 to 14 years after fixation. More studies will be important to determine the long-term results [16]. This research was done in Santa Casa deSao˜ Paulo and The variability of the results and haptic placement may Federal University of Sao˜ Paulo. berelatedtothesurgeonpersonaltechniqueandspecific anatomic difficulties of each operated eye. We observed more Competing Interests surgical difficulties in the aphakic patients after phacoemulsi- RachelL.R.GomesisaresearchersupportedbytheCAPES fication. Probably, the anatomy and the orbital conformation Foundation, Ministry of Health, Brazil. The other authors did could have compromised the result of the primary surgery not receive any grant or funding support for this work. and might also have influenced the secondary IOL implantation. Rau et al. [17] evaluated the PCIOL tilt in reference to References theirisplaneusingUBM.Theyobserved18.1%tiltedPCIOL [1] E. Can, M. Res¸at Bas¸aran, and A. Gul,¨ “Scleral fixation of a intentionally implanted in the ciliary sulcus. The evaluation of single-piece multifocal intraocular lens,” European Journal of IOL tilt was different in studies. Vasavada et al. [18] and Loya Ophthalmology,vol.23,no.2,pp.249–251,2013. et al. [19] also studied tilt with the same imaging method. [2] A. M. Kamal, M. Hanafy, A. Ehsan, and R. H. Tomerak, We observed that there was a significant vertical tilt in the ab “Ultrasound biomicroscopy comparison of ab interno and ab externo group and there was no horizontal tilt in our sample. externo scleral fixation of posterior chamber intraocular lenses,” Journal of Ophthalmology 5

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