Glaucoma

Essentials in Ophthalmology

Glaucoma F. Grehn R. Stamper Editors

Essentials in Ophthalmology

Glaucoma

G. K. Krieglstein R. N. Weinreb Series Editors

Cataract and Refractive Surgery Uveitis and Immunological Disorders Vitreo-retinal Surgery Medical Retina Oculoplastics and Orbit Pediatric Ophthalmology, Neuro-Ophthalmology, Genetics Cornea and External Eye Disease Vitreo-retinal Surgery

Editors Franz Grehn Robert Stamper

Glaucoma With 67 Figures, Mostly in Colour and 8 Tables

123

Series Editors

Volume Editors

Günter K. Krieglstein, MD Professor and Chairman Department of Ophthalmology University of Cologne Kerpener Straße 62 50924 Cologne Germany

Franz Grehn, MD Professor and Chairman Department of Ophthalmology University of Wuerzburg Josef-Schneider-Straße 11 97080 Wuerzburg Germany

Robert N. Weinreb, MD Professor and Director Hamilton Glaucoma Center Department of Ophthalmology University of California at San Diego 9500 Gilman Drive La Jolla, CA 92093-0946 USA

Robert Stamper, MD Director of Glaucoma Service Department of Ophthalmology University of California 10 Kirkham Street, Rm K301 San Francisco CA 94143 USA

ISBN 978-3-540-69472-4

e-ISBN 978-3-540-69475-5

ISSN 1612-3212 Library of Congress Control Number: 2008932232 © 2009 Springer-Verlag Berlin Heidelberg This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover Design: WMXDesign GmbH, Heidelberg, Germany Printed on acid-free paper 9 8 7 6 5 4 3 2 1 springer.com

Foreword

The Essentials in Ophthalmology series represents an unique updating publication on the progress in all subspecialties of ophthalmology. In a quarterly rhythm, eight issues are published covering clinically relevant achievements in the whole field of ophthalmology. This timely transfer of advancements for the best possible care of our eye patients has proven to be effective. The initial working hypothesis of providing new knowledge immediately following publication in the peer-reviewed journal and not waiting for the textbook appears to be highly workable. We are now entering the third cycle of the Essentials in Ophthalmology series, having been encouraged by

readership acceptance of the first two series, each of eight volumes. This is a success that was made possible predominantly by the numerous opinion-leading authors and the outstanding section editors, as well as with the constructive support of the publisher. There are many good reasons to continue and still improve the dissemination of this didactic and clinically relevant information. G.K. Krieglstein R.N. Weinreb

Series Editors September 2008

Preface

This third volume in the series, Essentials of Ophthalmology, just like the first, seeks to bring the ophthalmic practitioner up to date in the important new advances or changes in glaucoma diagnosis or management that have occurred over the last ten years. The last decade has seen significant changes in our understanding of the pathophysiology of some glaucomas, in our diagnostic approaches and in our management of them. Toward the goal of providing the most up-to-date information in a readable fashion, we have asked some of the world’s experts to discuss areas to which they have contributed in a way that will be useful for the practicing doctor. For example, one of the pioneers in the imaging of live ganglion cells is Dr. Francesca Cordeiro. Her studies could lead to a potentially significant breakthrough as, in the future, clinicians may be able to determine the health and number of ganglion cells in the retina as both a diagnostic and monitoring test. As the prevalence of glaucoma increases in our aging population, epidemiology has become more important as a methodology to identify risk factors; Drs. Giangiacomo and Coleman discuss what we have recently learned that is relevant to our clinical understanding of glaucoma. Drs. Doshi, Weinreb and colleagues describe the diurnal fluctuation of intraocular pressure, how those fluctuations impact on glaucoma, the relationship of postural change to that fluctuation, and what it means for managing glaucoma. Detecting progression of glaucoma can be tricky. Imaging techniques may be

helpful. Strouthidis and Garway-Heath tell us how. Our concepts of and terminology for angle-closure glaucoma have undergone major changes over the last few years. Sharma, Low and Foster describe these changes and introduce the new—now internationally agreed upon—terminology. The association of uveitis and glaucoma has been known and has frustrated those caring for patients with these two concurrent conditions for many years; Drs. Nagpal and Acharya discuss the interrelationship between uveitis and glaucoma, what the doctor should look for, and how to manage these difficult patients. New approaches to glaucoma surgery have been described recently. Drs. Mendrinos and Shaarawy describe the techniques and results of nonpenetrating glaucoma surgery. Drs. Tam and Ahmed describe and discuss several new approaches to glaucoma surgery using special shunts that have appeared in the past few years. As electronic medical record systems gain popularity around the world, Drs. Schargus and Grehn describe the European Glaucoma Society’s electronic glaucoma record and their agreement on what is important to include in such a system. We hope that all the topics and authors that we have selected are helpful in improving the understanding of the many faces of glaucoma and, ultimately, will contribute to reduced visual loss and better care for our patients. Franz Grehn Robert L. Stamper

Contents

Chapter 3 Circadian Changes in Intraocular Pressure

Chapter 1 Imaging Individual Ganglion Cells in the Human Retina

Amish B. Doshi, John H.K. Liu, Robert N. Weinreb

Nicholas E.H. Wood, Li Guo, M. Francesca Cordeiro 1.1 1.2 1.3 1.3.1 1.3.2 1.3.3 1.3.4 1.3.5 1.4 1.4.1 1.4.2 1.4.3 1.5

Introduction ................................................. 1 Description of the Imaging Techniques .................................................... 1 The Imaging Techniques .......................... 2 Scanning Laser Polarimetry .................... 2 High-Resolution Reflectance Imaging .......................................................... 2 Optical Coherence Tomography ........... 3 Confocal Scanning Laser Ophthalmoscopy ........................................ 5 Adaptive Optics ........................................... 6 Applications to RGC Imaging ................. 7 Retrograde Labelling................................. 7 RGC-Specific Fluorescent Protein Expression ..................................................... 7 The Detection of Apoptosing Retinal Cells (DARC) .................................................. 8 The Future ..................................................... 9 References ..................................................... 10

Introduction ................................................. Primary Open-Angle Glaucoma ............ Increased IOP ............................................... Age ................................................................... Family History .............................................. Sex.................................................................... Ethnicity ......................................................... Myopia ............................................................ Other Risk Factors....................................... Primary Angle-Closure Glaucoma ........ Risk Factors ................................................... Prevalence ..................................................... References .....................................................

13 13 14 14 15 15 15 16 17 17 18 18 19

23 23 24 25 26 27

Nicholas G. Strouthidis, David F. Garway-Heath 4.1 4.1.1 4.1.2 4.1.3

4.2.2

Annette Giangiacomo, Anne Louise Coleman

Introduction ................................................. Normal IOP Curve ....................................... Sources of Circadian Control .................. Glaucoma and 24-Hour IOP .................... Medical Management of 24-Hour IOP .................................................. References .....................................................

Chapter 4 Detecting Glaucoma Progression by Imaging

4.2 4.2.1

Chapter 2 The Epidemiology of Glaucoma

2.1 2.2 2.2.1 2.2.2 2.2.3 2.2.4 2.2.5 2.2.6 2.2.7 2.3 2.3.1 2.3.2

3.1 3.2 3.3 3.4 3.5

4.2.3 4.2.4 4.2.5 4.3 4.4 4.5 4.6

Introduction ................................................. The Principles of Progression ................. Historical Perspective: Optic Nerve Head Photography ........................ The Potential of Optic Nerve Head Imaging Devices .............................. HRT................................................................... HRT Progression: Available Techniques .................................................... HRT Progression: Stereometric Parameter vs. Pixel-Based Techniques .................................................... HRT Progression: Stereometric Parameter Event Analyses ....................... HRT Progression: Stereometric Parameter Trend Analyses ....................... HRT Progression: Pixel-Based Technique ...................................................... Detecting Progression by GDx-VCC......................................................... Detecting Progression by OCT .............. Frequency of Testing ................................. Lack of Concordance ................................. References .....................................................

29 29 30 30 31 31

31 34 34 35 35 37 37 38 39

x

Contents

Chapter 5 The Classification of Primary Angle-Closure Glaucoma

Tarun Sharma, Sancy Low, Paul J. Foster 5.1 5.2 5.3

5.4 5.5 5.6

5.7 5.8 5.9 5.9.1 5.9.2 5.9.3 5.9.4 5.10

Background .................................................. The Purposes of Disease Classification ................................................ The Evolution of Classification Schemes for Angle-Closure Glaucoma ...................................................... Definition of an “Occludable” or Narrow Angle ............................................... Primary Open-Angle Glaucoma is a Diagnosis of Exclusion .............................. Classification of Angle Closure in Epidemiological Research (ISGEO Scheme) .......................................... Trabecular Meshwork Damage in Angle Closure ............................................... An Anatomical Basis for the Primary Angle Closure Mechanism ...................... Classification System for Angle-Closure Glaucomas ....................... Level I: Iris and Pupil .................................. Level II: Ciliary Body ................................... Level III: Lens-Induced Angle Closure............................................................ Level IV: Ciliolenticular Block/Aqueous Misdirection/“Malignant Glaucoma” ... Gonioscopy ................................................... References .....................................................

42 42

6.4.3 6.4.4 6.4.5 6.4.6 6.4.7 6.4.8 6.5 6.5.1 6.5.2 6.6

43

44

Chapter 7 Nonpenetrating Glaucoma Surgery

Efstratios Mendrinos, Tarek Shaarawy 44 45

7.1 7.2 7.2.1 7.2.2

45 45 45 46 46 46 47 47

7.3 7.4 7.5 7.6 7.6.1 7.6.2 7.7 7.8 7.9 7.9.1 7.9.2 7.9.3

Agnieszka G. Nagpal, Nisha R. Acharya

6.3 6.3.1 6.3.2 6.3.3 6.4

6.4.1 6.4.2

Introduction ................................................. The Epidemiology of Uveitis-Related Ocular Hypertension (OHT) and Secondary Glaucoma ................................ Pathogenesis of Uveitic Glaucoma....... Aqueous Dynamics in Uveitic Glaucoma ...................................................... Mechanical Causes of Uveitic Glaucoma ...................................................... Steroid-Induced Glaucoma ..................... Common Uveitic Entities Associated with OHT and Secondary Glaucoma ...................................................... Glaucomatocyclitic Crisis: Posner– Schlossman Syndrome ............................. Fuchs’ Heterochromic Iridocyclitis ....................................................

53 53 53 54 54 54 55 55 55 56 56

43

Chapter 6 Uveitic Glaucoma

6.1 6.2

Herpetic Disease ......................................... Juvenile Inflammatory Arthritis (JIA) ... Pars Planitis ................................................... Toxoplasmosis.............................................. Sarcoidosis .................................................... Syphilis ........................................................... Treatment of Uveitic Glaucoma............. Medical Treatment ..................................... Surgical Treatment ..................................... Conclusion .................................................... References .....................................................

49

7.9.4 7.9.5 7.9.6

49 50

7.9.7 7.10

50

7.10.1 7.10.2 7.11

50 51

51

7.11.1 7.11.2 7.11.3 7.12

51 52

7.12.1

Introduction ................................................. Deep Sclerectomy ...................................... Superficial Scleral Flaps ............................ Deep Sclerectomy and Exposure of Trabeculo-Descemet’s Membrane..................................................... Deep Sclerectomy Technique ................ The Use of Implants ................................... Viscocanalostomy....................................... Mechanisms of Filtration ......................... Flow Through the TDM ............................. Aqueous Humor Resorption................... Nd:Yag Goniopuncture ............................. Technique ...................................................... Indications for Nonpenetrating Glaucoma Surgery...................................... Primary Open Angle Glaucoma............. Glaucoma in High Myopia ....................... Pseudoexfoliation and Pigmentary Glaucoma ...................................................... Uveitic Glaucoma ....................................... Congenital and Juvenile Glaucoma ..... Glaucoma Associated with Sturge– Weber Syndrome ........................................ Glaucoma in Aphakia ................................ Contraindications for Nonpenetrating Glaucoma Surgery...................................... Relative Contraindications ...................... Absolute Contraindications .................... Complications of Nonpenetrating Glaucoma Surgery...................................... Intraoperative Complications ................ Early Postoperative Complications ...... Late Postoperative Complications........ Clinical Experience with Nonpenetrating Glaucoma Surgery ........................................................... Viscocanalostomy.......................................

59 59 59

60 60 61 61 62 62 62 63 64 64 64 64 64 64 64 65 65 65 65 66 66 66 67 69

70 70

Contents

7.12.2 7.12.3

Deep Sclerectomy ...................................... Studies Comparing Trabeculectomy and Nonpenetrating Glaucoma Surgery ........................................................... References .....................................................

70

8.6

71 72

Chapter 9 Digital Glaucoma Patient Record and Teleconsultation Systems for Glaucoma Specialists: The European Glaucoma Society Glaucocard Project

Chapter 8 New Glaucoma Surgical Devices

8.2.1 8.2.2 8.3 8.4

8.4.1

8.4.2 8.4.3 8.5

Introduction ................................................. Basic Review of the Anatomy and Physiology of Aqueous Outflow and Drainage Devices ........................................ Subconjunctival Filtration ....................... Schlemm’s Canal Outflow ........................ Subconjunctival Filtration Device: the Ex-PRESS Shunt.................................... Schlemm’s Canal Devices: Canaloplasty/ iScience, Glaukos Trabecular Micro-Bypass Stent, and the Trabectome .................................. Ab Externo Schlemm’s Canal Approaches: Nonpenetrating Schlemm’s Canaloplasty .......................... Trabecular Micro-Bypass Stent .............. Trabectome................................................... Suprachoroidal Filtration Device: The SOLX Gold Microshunt .....................

94 96

Marc Schargus, Franz Grehn, The Glaucocard Workgroup

Diamond Y. Tam, Iqbal Ike K. Ahmed 8.1 8.2

Conclusion .................................................... References .....................................................

75

9.1 9.2

76 77 77

9.3

79

9.3.1 9.3.2

81

81 86 89 91

9.4 9.5 9.6

Index

Introduction ................................................. History of Telemedicine in Ophthalmology ........................................... The Concept of an Electronic Glaucoma Patient Health Record System ............................................. General Issues for Implementation .......................................... Important Classifications for Electronic Glaucoma Medical Record Systems ........................................... The EGS Glaucocard Project ................... Future Prospects ......................................... Conclusion .................................................... Acknowledgments ..................................... References .....................................................

99

104 106 109 109 110 110

............................................................................

113

100

101 101

xi

Contributors

Nisha R. Acharya Francis I. Proctor Foundation University of California San Francisco 95 Kirkham St., San Francisco CA 94143, USA

Annette Giangiacomo CB 7040, 5109 Bioinformatics Building Department of Ophthalmology University of North Carolina-Chapel Hill Chapel Hill, NC 27599-7040 USA

Iqbal Ike K. Ahmed University of Toronto Toronto Ontario, Canada

Franz Grehn University Eye Hospital Wuerzburg Josef Schneider Str. 11 97080 Wuerzburg Germany

Anne Louise Coleman Jules Stein Eye Institute/UCLA 100 Stein Plaza Los Angeles, CA 90095 USA M. Francesca Cordeiro Glaucoma & Retinal Degeneration Research Group UCL Institute of Ophthalmology Bath Street London EC1V 9EL, UK Amish B. Doshi Hamilton Glaucoma Center Department of Ophthalmology University of California San Diego, CA USA Paul Foster Department of Epidemiology & International Eye Health UCL Institute of Ophthalmology 11-43 Bath Street London EC1V 9EL, UK David F. Garway-Heath Moorfields Eye Hospital and UCL Institute of Ophthalmology NIHR Biomedical Research Centre 162 City Road London, UK

Li Guo Glaucoma & Retinal Degeneration Research Group, UCL Institute of Ophthalmology Bath Street London EC1V 9EL, UK

John H.K. Liu Hamilton Glaucoma Center Department of Ophthalmology University of California San Diego CA, USA

Sancy Low Glaucoma Service Moorfields Eye Hospital London, UK Department of Epidemiology and International Eye Health UCL Institute of Ophthalmology Bath Street, EC1V 9EL London, UK

Efstratios Mendrinos Department of Ophthalmology Glaucoma Unit Geneva University Hospitals 1211 Geneva 14 Switzerland

xiv

Contributors

Agnieszka G. Nagpal Francis I. Proctor Foundation University of California, San Francisco 95 Kirkham St. San Francisco, CA 94143 USA

Nicholas G. Strouthidis Moorfields Eye Hospital and UCL Institute of Ophthalmology NIHR Biomedical Research Centre 162 City Road London, UK

Marc Schargus University Eye Hospital Wuerzburg Josef Schneider Str. 11 97080 Wuerzburg Germany

Diamond Y. Tam University of Toronto Toronto Ontario, Canada

Tarek Shaarawy Glaucoma Unit Department of Ophthalmology Geneva University Hospitals Alcide-Jentzer 22 1211 Geneva 14 Switzerland

Robert N. Weinreb Department of Ophthalmology University of California 9500 Gilman Drive La Jolla, CA 92093 USA

Tarun Sharma Glaucoma Service Moorfields Eye Hospital London, UK

Nick Wood Glaucoma & Retinal Degeneration Research Group UCL Institute of Ophthalmology Bath Street EC1V 9EL London, UK

Chapter 1

Imaging Individual Ganglion Cells in the Human Retina

1

Nicholas E.H. Nick Wood, Li Guo, M. Francesca Cordeiro

Core Messages ■

■

■

■

Retinal ganglion cells (RGCs) are the key cells implicated in glaucoma, and their assessment could lead to effective treatment and monitoring regimens Scanning laser polarimety (SLP) gives a good measure of RNFL thickness and RGC axonal loss but cannot provide focussed information about RGCs High-resolution reflectance imaging uses highquality CCDs(charge-coupled device), which can use much more information from simple funduscopic observa-tions but again provide little information on RGCs Optical coherence tomography (OCT) is a rapidly developing technology which is now enabling

1.1

Introduction

Glaucoma is a leading cause of blindness worldwide [1] and it is expected that the number of people with the disease will rise dramatically by 2020 [2]. Diagnosis is traditionally from changes in the optic nerve head (ONH) and visual field loss, but these can only detect the disease after significant (25–40%) loss of retinal ganglion cells (RGCs), the key cell implicated in this process [3, 4]. The inner retinal layers, being optical media that are therefore transparent to visible-frequency light, are inherently low contrast. This presents a significant challenge for traditional imaging such as fundus imaging. Modern technologies now use many different properties of light to differentiate between the retinal structures and these technologies are enabling us to observe fine detail, such as the photoreceptor layers, in vivo [5]. Combined with other techniques, they allow the examination of individual RGCs [3, 5–7]. In vivo imaging also enables longitudinal studies [3, 5], which brings great possibilities for elucidating disease pathways and developing new treatments [8, 9].

■

■

■

■

retinal cellular, functional and 3D imaging, but its role in RGC imaging is still uncertain Most promising technologies use the established confocal scanning laser ophthalmoscope (cSLO) combined with other methodologies to improve RGC visualization Imaging in experimental research has permitted the direct assessment and successful evaluation of RGCs in disease models Some safe techniques developed in animal models are beginning to make the crossover into clinical glaucoma detection Ideally, methodologies enabling the visualization of healthy and “sick” RGCs would provide a comprehensive assessment of glaucomatous changes and disease states

Recent advances have allowed unprecedented access to the retinal layers, creating the possibility of potentially visualizing ganglion cells in order to provide a new and early clinical parameter for glaucomatous injury. This chapter aims to cover the current research achievements in RGC imaging and the promising directions they are taking visual science.

1.2 ■

■

■

Description of the Imaging Techniques

Scanning laser polarimetry (SLP): A confocal imaging system with a polarimeter to measure the birefringence caused by the retinal nerve fibre layer (RNFL) High-resolution reflectance imaging: Based around a fundus camera with a high-quality CCD camera, this system can take a sequence of rapid images which can measure wavelength-dependent reflectance changes with very high temporal resolution Optical coherence tomography (OCT): A low-coherence interferometry-based imaging system where changes in reflectivity are measured in a volume of the retina with very high axial resolution

2 ■

1

■

■

■

■

1 Imaging Individual Ganglion Cells in the Human Retina

Confocal scanning laser ophthalmoscopy (cSLO): A confocal imaging system which uses a fine confocal aperture to limit the light detected to that from the focal plane, and therefore achieves high lateral resolutions Adaptive optics (AO): An adaption which uses a patterned guide laser to sense errors in the optics of the eye and a deformable mirror to correct for them in real time Retrograde labelling of RGCs via direct application of dyes has enabled the analysis of ganglion cell number and morphology in numerous studies with animal models RGC-specific fluorescent protein expression has been developed in a number of mouse lines to enable RGC identification and subtype study The detection of apoptosing retinal cells (DARC) uses an injection of fluorescently labelled annexin-5 which binds to the membrane of apoptosing cells to act as a marker for RGC disease

Summary for the Clinician ■

■

Glaucoma is the leading cause of irreversible blindness if left untreated, and current methods will only detect it when significant damage has already been done RGCs are the key cells implicated, and observing them could lead to effective treatment and monitoring regimens

1.3.1

Scanning Laser Polarimetry

First reported by Weinreb et al. in 1990 [11], the basic layout of this can be seen in Fig. 1.1. This is based on the linear relationship between the birefringence and thickness of the RNFL. Birefringence is a quality of highly ordered optical media such that they exhibit polarising properties and refractive indices that are dependent on the polarisation of the incident light. This can be detected by a system with polarisation-sensitive detectors. The parallel microtubule structures in the RNFL cause birefringence and the degree of birefringence is dependent on the tissue thickness. This measure has been shown to be sensitive and specific and, unlike the cSLO technology (Heidelberg Retinal Tomography (HRTIII), Heidelberg Engineering Vista, CA, USA), it has the advantage of not requiring the operator to provide reference points [12]. The cornea had previously been a problem in SLP imaging, as it also has a degree of birefringence. The current incarnations of the commercially available machine (the GDx, Carl Zeiss Meditec, Inc., Dublin, CA, USA) have overcome this [13] with a variable corneal compensator (VCC-SLP) which uses the macular as a reference point non-birefringent to gain a measure of the corneal birefringence. This was followed by the enhanced variable compensator (ECCSLP), which avoids problems with low-quality images [14] by using software correction. The machine is still limited to measuring the RNFL thickness though, and is therefore not as versatile as the other devices in terms of RGC cell body assessment.

1.3 The Imaging Techniques The imaging of cells in living systems poses numerous problems, as (unlike histology) it involves direct exposure of living tissue, and even relatively innocuous staining compounds bind to cell constituents and therefore may interfere with cellular function. Intrinsic cellular properties are therefore sought that allow them to be resolved from the surroundings. The RGCs in particular have proven a challenge to image, but modern techniques taken from other fields such as cell biology and cosmology are beginning to yield some insight into their morphology and behaviour in vivo. Many techniques have recently been developed to assess the RNFL thickness, as its thinning is associated with glaucomatous progression [10]. In real terms, this thinning process represents the large-scale loss of the RGC axons. However, higher resolutions are needed to gain access to individual cell bodies, and here we discuss the most current methods and some of the promising directions the research is taking.

Summary for the Clinician ■ ■ ■

SLP uses the polarisation change imparted on incident light by the RNFL to measure its thickness VCC and ECC have been developed to counter problems with corneal birefringence The machine is limited to RNFL thickness analysis

1.3.2

High-Resolution Reflectance Imaging

This uses a high-quality, high-speed CCD attached to a fundus camera with a method for the illumination of the retina in time with image detection. The sensitivity of the camera allows for very accurate measurement of reflectivity changes. The stimulation of nervous tissue has been shown to cause reflectivity changes [15–17]. Such changes are most likely due to changes in membrane reflective index or morphology and can be detected with the sensitive camera to give an indication

1.3 The Imaging Techniques

3

Perpendicular detector

Parallel detector

Rotating half-wave plate Light Source

Polarizer

Fig. 1.1 A diagram showing the basic form of a scanning laser polarimeter. Light from the laser light source passes through a confocal system incorporating a linear polariser prior to a rotating half-wave plate. This provides a series of polarisation states directed into the eye. These are then passed back through the optics to detectors that can measure two polarisation states. The images produced can then be analysed to give the degree of phase retardation imparted by the RNFL

of the function of the cells. When used in the eye, imaging the inner layers can give reflectivity changes representing the activation of RGCs [15], and may be able to give a measure of their functional health. However, the absolute quantification of RGCs is not possible. A commercial version, the Retinal Functional Imager (RFI, Optical Imaging, Rehovot, Israel), promises to allow blood flow velocity calculations using ratio comparison of images, and will be able to rapidly change a filter wheel in time with the image acquisition to gain high temporal resolution data on wavelength-dependent reflectivity changes [18].

Summary for the Clinician ■

■

Reflectivity changes can be measured with high acuity and temporal accuracy using a fundus camera with a high-quality CCD and light source These machines are capable of detecting functional reflectance changes and measuring blood velocity

1.3.3

Optical Coherence Tomography

Based on a technique long established in other fields, OCT was developed to visualise the retina in 1991 [19]. In the last few years, OCT has become an increasingly accepted method for assessing the thickness of the RNFL [20] due to its reproducibility and accuracy [21]. This has fuelled a series of rapid advances, and current research is demonstrating submicron resolutions [22, 23], functional imaging [16, 17] and 3D imaging [24]. Imaging of the RGC layer however, is difficult due to its weakly backscattering nature and low-contrast edges, and the technology has some way to go before individual cells become accessible in vivo. The basic form is shown diagrammatically in Fig. 1.2. This system is based on low-coherence interferometry, the principle that light split from one beam into two different paths which are then recombined will create interference patterns that depend on the phase difference introduced by the variance in the path length. When the beams are recombined in phase they will do so constructively, but they destructively combine when they are half a coherence length out of phase. The coherence length is the distance

4

1 Imaging Individual Ganglion Cells in the Human Retina

Out of phase

In phase Detector

1 Beam Splitter

X-Y Scanning Mirror

Light Source

Reference Arm

Fig. 1.2 A diagrammatic representation of a basic OCT setup. Components will vary with specific OCT machines. For a full description see the main text

over which a wave can combine to form interference patterns. Therefore, the smaller the coherence length, the more certain the distance measured by interference will be. The coherence length is inversely proportional to the coherence of the light source. Images can be constructed from a number of ultrasound-like A scans to give a 2D reflectivity profile, or B scan. A 3D image is possible if sufficient B scans can be taken before involuntary movement affects slice alignment. The scanning time in any particular axis is a major time and complexity limitation of the devices, so a number of ingenious methods have been adopted to reduce total imaging time and increase resolution. The first OCT incarnations used a moving reference arm to obtain axial information. These are called time domain OCTs (TD-OCT), as the axial information is obtained over the time taken to move the reference arm. Scanning speed is thus limited by the movement of the motors controlling the reference mirror. The time taken to make a series of scans sufficient to construct a 3D image is preclusive, as involuntary eye movement will mar the results. There are a number of clinically available machines, such as the Stratus (Carl Zeiss), which have proven efficient at disease detection [21, 25–28], but with maximum resolutions of 10 microns they are unable to clearly resolve the RGC layer.

Ultrahigh resolution OCT (UHR-OCT) is a time domain system that uses a wide-band light source which gives a much smaller coherence length than conventional OCT. This improves the axial resolution and has given three-micron resolutions in the retina [29]. The increase in resolving power has enabled the imaging in vivo of many retinal layers, including the RGC layer (although not individual RGCs), which is impossible to image with conventional TD-OCT [29–33]. While their expense has traditionally been preclusive, as they rely on costly broadband lasers, developments in optical technology have now begun to offer alternatives, such as super luminescent diodes (SLDs) [30, 34] or xenon arc lamps [22]. The resulting reduction in cost is bringing UHR-OCTs to the clinic. Ultrahigh-speed spectral domain OCT (SD-OCT) is a faster, more sensitive method for obtaining axial information which measures the interference for each wavelength in a broadband light source in order to obtain full axial scans without moving the reference or sample arm [35–37]. This is because the distance at which interference occurs will vary with wavelength. The detector can be replaced by a spectrophotometer to measure all the broadband spectra at the same time. Alternatively, the light source can be replaced with a swept source, and the same photometer as used in TC-OCT can be used.

1.3 The Imaging Techniques

Because the system is not limited by the rate of sample mirror movement, the scans take less time and 3D imaging as well as video-rate 2D sectioning becomes possible [30, 36]. The system is also called Fourier domain OCT (FD-OCT), as the signals obtained are related to those of TD-OCT by the Fourier transform. Devices using FDOCT have recently been made commercially available, and are taking full advantage of the high image capture rates [40,000 A-scan/s with the Spectralis (Heidelberg Engineering) and Cirrus (Carl Zeiss)] to make 3D images of the diseased eye available in the clinic [38, 39]. En face OCT has been used in a number of studies to attempt to overcome the imaging speed limitations of TDOCT. Two different methods have been developed to provide an en face image in real time. Full-face methods have been used to create three-dimensional reflectivity images at resolutions approaching those of confocal machines [22, 23, 34, 40–42]. These machines use high numerical aperture (NA) lenses on the reference and sample arm and a charge-coupled device (CCD) to capture full-face (x–y) images. As there is no lateral scanning, transverse cross-sections can be captured in real time, and because of the high-NA lenses, the submicron resolution is sufficient to access cellular detail. There are limitations to the systems though, and many modifications need to be made before they can be used for disease detection. The small imaging volume and requirement for the sample to be moved for axial scanning make it unsuitable for in vivo studies. Additionally, the use of high-NA lenses causes aberrations when attempting deep tissue penetration [22]. Flying spot systems use a fast transverse raster scanning technique combined with slower axial scanning. This allows the construction of en face scans in real time [34]. The main advantage of this system is the ease with which it can be combined with an SLO [34, 41, 42]. This overcomes the axial resolution limitation of SLO as well as the lateral limitation of traditional OCT. The scanning speed is still limited by the slowest moving part though (the axial movement systems in this case). The OCT has also been shown capable of birefringence measurements if a polarimeter is combined with the light path [35]. This should allow yet more accurate measurements of RNFL thickness, and even allows a measure of birefringence with depth, which SLP is unable to achieve. This may give an indicator of disease-induced structural losses in specific regions of the nerve fibre layer. One advantage of the OCT polarimeter over the SLP is that it can use the surface of the RNFL as a reference point and is therefore not susceptible to variations in the corneal birefringence. Functional OCT (fOCT) is becoming a reality as more studies are being made of the changes in reflectivity

5

profiles of nervous tissue with stimulation [15–17]. The fOCT can enable the examination of functional reflectivity changes through all layers of the retina over time [17], and has shown changes in the RGC layer after light stimulation. As the frame rate of the OCT becomes greater, it may become possible to image 3D volumes with sufficient temporal resolution to form maps of retinal function in vivo. A full review of OCT is beyond the scope of this book chapter, but we would recommend [41] for further reading.

Summary for the Clinician ■ ■ ■ ■ ■

■ ■

■

OCT has been around for over a decade and is increasingly used for RNFL analysis It is based on low-coherence interferometry Time domain OCT uses a moving reference arm for image acquisition Ultrahigh resolution OCT uses a broadband light source to increase resolution Spectral domain and Fourier domain OCT uses the spectrally varying coherence length of light to drastically increase scan rates En face OCT uses different methods to obtain full-face images in real time OCT machines can also be made to measure function dependent reflectivity changes and birefringence As yet, due to the weakly backscattering nature and low-contrast edges of cells, individual RGCs are not able to be seen with this technology

1.3.4

Confocal Scanning Laser Ophthalmoscopy

Currently the most popular and well tested of the imaging modalities discussed, the cSLO, has survived the fastmoving field well due to its versatility. It is based on the principle of confocal microscopy (Fig. 1.3): namely that if light is focussed onto a spot in the focal plane by passing it through a fine pinhole, and the returning light is passed back through the same pinhole, then the action of the fine aperture is to exclude scattered light and light reflected from planes above or below the focal plane. This allows much higher axial and lateral resolution than achieved with conventional light microscopy, such as with a fundus camera. Because they are based on confocal systems, cSLO are inherently suited to viewing excited fluorophores. This capability has been used to detect the

6

1 Imaging Individual Ganglion Cells in the Human Retina

Detector

1

Light Source

Fig. 1.3 A diagrammatic representation of a confocal imaging system. See text for details

apoptosis of individual RGCs [3, 8, 9, 43] as well as to longitudinally view fluorescent markers expressed in the ganglion cells of mice in vivo [44]. Their ability to create 3D topographies, a long-established technique in the clinical assessment of eye disease, can even be used to make indirect assessments of the RNFL thickness [12]. Machines that combine FD-OCT and SLO may overcome the axial limitations of SLO and the lateral limitations of OCT, so this technology may allow the accurate positioning of fluorescent markers in both axial and lateral space. There are now commercially available combination machines, such as the Cirrus and the Spectralis.

Summary for the Clinician ■ ■ ■

cSLO uses fine apertures to limit the light detected to that from the focal plane Clinical machines can indirectly measure RNFL thickness Modern machines combine cSLO with OCT to overcome the axial resolution limitations of cSLO and the transverse resolution limitations of OCT

1.3.5

Adaptive Optics

Many changes have been made to the current imaging systems over the years, producing a number of improvements in the optics and cameras, and a technique learned from a branch of physics is proving very useful in both OCT and SLO.

AO was originally developed for cosmologists to eliminate the speckle produced by the passage of light through the atmosphere when viewing astronomical objects from the Earth. It is based on the idea that if a reference beam consisting of a 2D array of equidistant spots is passed along the same light path as the measurement beam but does not collect information from the object measured, then deformations from the reference pattern must be due to interference in the optical media. These deformations can then be corrected in real time by reflecting both the reference and measured beams off a computer-controlled deformable mirror before passing the measurement beam to the detector and the corrected reference beam to the Hartman–Shack wavefront sensor for further corrections to the mirror. When imaging the eye, the pattern beam is reflected from a point on the retina to prevent the retinal surface scattering the grid pattern. AO was introduced in ophthalmology to reduce the effect of aberrations in the optical media of the eye and so increase the signal-to-noise ratio (SNR) at high resolutions. This has improved acuity to the extent where direct observation of the cone cells has been performed using AO-SLO via their intrinsic autofluorescence alone. It has also been applied to OCT [30, 45], where the use of AO has improved the transverse resolution to the extent that individual nerve fibre bundles have been observed with a FD-OCT in humans in vivo [38]. Recently, AO has been used to improve in vivo imaging quality in mouse eye, where AO was incorporated into a biomicroscope to overcome the presence of aberrations in the rodent eye [46]. With improved resolution, it is possible to image fluorescently labelled capillary vessels and dendrites of microglial cells in mice.

1.4 Applications to RGC Imaging

Summary for the Clinician ■ ■ ■

AO uses a patterned reference beam to detect aberrations in the optical medium Imperfections can be corrected in real time using a deformable mirror This improves the SNR, allowing fine detail to be seen

7

All methods have strong limitations though, as they have the distinct potential to cause damage to the cells and are very invasive. It is because of this that this method cannot be used to examine human cells in vivo. It has produced a huge number of studies in animal models though, and a similar, safer technique in humans would be a very powerful tool.

Summary for the Clinician ■

1.4 Applications to RGC Imaging Until imaging technology achieves higher resolutions, RGC-specific contrast-enhancing agents will have to be used. Intrinsic methods may never be able to detect subtle specific gene expression changes in subtypes of RGCs without using extrinsic agents, which can overcome the resolution limitations by marking features with obvious fluorescent cues. Because of this, the development of a number of contrast-enhancing agents has proven invaluable in glaucoma research.

1.4.1

Retrograde Labelling

Carbocyanine dyes such as DiAsp (4-[4-didecylaminostyryl]-N-methyl-pyridinium iodide), DiI (1,1′-dioctadecyl-3,3,3′,3′-tetramethyl-indocarbocyanine perchlorate), DiO (3,3′-dioctadecyloxacarbocyanine perchlorate) and Fluorogold are lipophilic dyes. Following application, they are inserted into the outer leaflet of the cell membrane and then, as part of lipid turnover, are transported within the cells [47]. Alternatively, hydrophilic dyes such as rhodamine dextran, which are actively transported throughout the cell, can be used. If applied high up in the visual pathway, these fluorescent dyes will pass down the length of the RGC axons into the cell bodies in the retina. This method has been the traditional way of labelling the RGC population of the model organism retina [47, 48, 48–50], and has been used in numerous studies of glaucoma [5, 51–53]. The majority of experiments performed with retrograde dyes have been ex vivo, but retrograde labelling is also showing results with in vivo applications [5, 51, 52]. There are a number of techniques for application, such as direct injection into the axonal innervating centres of the brain (the superior colliculi), or placement of crystals onto the optic nerve. A very recent demonstration has shown that it is possible in primate retina to view the characteristics and morphology of rhodamine-labelled RGCs (Gray, IOVS 2008). Figure 1.4 shows how this is made possible by applying AO techniques to a cSLO image.

■

■

Retrograde labelling uses lipophilic dyes applied in the visual pathway to label RGCs It has traditionally been used with histological studies, but in vivo research is now producing good results It cannot be used in humans because of the application methods, but it can be used with animal models to produce clinically relevant data

1.4.2

RGC-Specific Fluorescent Protein Expression

Modern genetic techniques allow us great control over gene expression in a number of model species and provide us with tools such as green fluorescent protein (GFP) expression systems for identifying cells manufacturing particular proteins. The study of RGCs has produced a number of specific markers, such as Thy1, c-kit and Brn3b in rodents, which are specifically expressed in RGCs over other neurons in the retina [5, 6, 45]. A combination of a Thy1 promoter with introns specific to RGCs and a GFP marker has been used to contrast-enhance RGCs and even distinguish between subtypes in mice [7]. This may prove a good resource to test for RGC subtype-specific disease susceptibilities, as with advances in imaging technology the mouse eye is becoming available for noninvasive studies [43] which allow the longitudinal assessment of disease models [54]. However, this technique is limited to animal studies, as gene insertion is not a viable technique for human studies. Much transferable data can be gained though, which will greatly aid human studies.

Summary for the Clinician ■ ■

Genetic techniques have produced animals which specifically express fluorescent markers in RGCs These animal models can be used to assess the affects of disease on RGCs and even subpopulations of ganglion cells

8

1 Imaging Individual Ganglion Cells in the Human Retina

1

Fig. 1.4 A very recent demonstration has shown that it is possible in primate retina to view characteristics and morphology of rhodamine-labelled RGCs (Gray, IOVS 2008). This shows how this is made possible by applying AO (b, d) techniques to a cSLO image (a, c)

1.4.3 The Detection of Apoptosing Retinal Cells (DARC) In moving towards clinical applications, disease detection methods must be refined from the corresponding research techniques. The reflective response to light would give a general intrinsic signal of RGC function, but variability must be reduced and the RGC layer assessed separately from the rest of the retina before it specifically indicates ganglion cell health. Good extrinsic markers for retinal health are therefore needed to make up for shortcomings in the imaging techniques. DARC has recently been developed as a novel, noninvasive real-time imaging technique for the visualisation of individual RGC apoptosis in the living animal [3]. Apoptosis is the process by which cells undergo controlled destruction following an injury. The technique involves the application of fluorescently labelled annexin-5 to detect apoptosing cells using a fluorescence cSLO such

as the HRA. All of the fluorescent spots across a large section of the retina can then be counted to give a quantitative measure of the level of RGC health. Annexin-5 preferentially binds to phosphatidylserine (PS) that translocates from the inner to the outer plasma membrane during apoptosis. This step occurs much earlier than latestage markers such as DNA fragmentation, which can be detected by methods such as TUNEL, as the PS is used by the cell to indicate the start of the apoptosis cascade. DARC promises to deliver a method for monitoring glaucomatous disease progression and detecting glaucoma at an early stage before large-scale RGC loss has occurred. Using DARC, it has become possible to image changes occurring in RGC apoptosis over hours, days, and months in glaucoma-related animal models in vivo for the first time. Currently, there is no adequate method for assessing neuroprotection in glaucoma. This drawback is reflected in the expensive six-year period of follow-up for the only

1.5 The Future

neuroprotective drug that has undergone a large-scale clinical trial in glaucoma, memantine, which relied on visual field status as a defined end-point. DARC imaging technology is a major advance in this area, as supported by a number of experimental studies where it has been demonstrated to be a useful tool in screening neuroprotective strategies in glaucoma models [8, 9]. Additionally, it has been used to examine the link between Alzheimer’s disease and glaucoma [8]. Figure 1.5 shows DARC in a rat model of glaucoma, where treatment with drugs targeting the Alzheimer protein amyloid beta was given [8]. The number of RGCs apoptosing appears to have been dramatically reduced by the treatment. Clinical trials of DARC are due to start in 2009, and results are eagerly awaited.

Summary for the Clinician ■ ■

■

DARC uses a fluorescent indicator of apoptosis to label dying RGCs The number of fluorescent spots can be measured using a cSLO to give a quantitative indicator of RGC health It has been used so far to elucidate glaucomatous disease pathways and treatments in animal models, but clinical trials are due to start in 2009 in glaucoma patients

1.5 The Future Many changes are taking place in ophthalmological imaging techniques, and the detection and management

9

of glaucoma in particular are undergoing a minor revolution! Studies have concluded that the measurement of IOP is not a reliable indicator of glaucoma [55], and management via IOP-lowering methods are an inadequate solution on their own [56]. It is because of this and the late-stage detection associated with visual field measurements and fundus camera observations that more objective assessments of RNFL layer thickness are being developed. These go some way towards the direct RGC observations needed to make an early reliable diagnosis, but more acuity is needed before characteristics of individual RGCs can be observed in patients using intrinsic signals. Extrinsic methods have long been used in research to overcome the shortcomings of the imaging systems. Retrograde labelling and GFP expression methods cannot be used in a clinical environment, though some safer techniques must be developed before extrinsic methods can be made available in a clinical setting. The DARC protocol promises a novel method of ascertaining the state of RGC health, and uses a marker already tested in human safety trials [57–59]. A clinical trial of this technology is due to start shortly. The rate of advancement of in vivo imaging is now producing live observations of structures that previously required detailed histological assessment [29]. Combining the different imaging modalities may also allow the parallel measurement of a range of the properties of light, such as reflectance, polarisation, fluorescence and phase. Light-based non-invasive methods have the advantage of allowing longitudinal studies, which greatly improves research speeds and accuracy. Research interest from fields such as developmental neurobiology [60] has also been attracted by the ease of accessibility of nervous tissue in the eye. The retina is the

Fig. 1.5 DARC in vivo images show the effect of anti-amyloid-ß (Aß) antibody on reducing RGC apoptosis in a rat model of glaucoma. The white spots represent apoptotic RGCs. Aß antibody treatment (B) significantly reduces RGC apoptosis at three weeks after IOP elevation compared to non-treatment control (A)

10

1

1 Imaging Individual Ganglion Cells in the Human Retina

only part of the brain that can be viewed without invasive procedures, and it therefore provides a perfect model of neuronal systems in vivo. Such research interest is aiding the understanding of RGCs and is enabling the development of new techniques that will hopefully cross over to the clinic. With modern OCT resolutions, it will not be long before individual RGCs can be imaged in humans, and with disease detection methods such as DARC, the early diagnosis of glaucoma and assessment of treatment efficiency should soon become a reality.

Summary for the Clinician ■

■ ■

■

Objective RNFL thickness assessment paves the way to a good indicator of RGC health needed for early glaucoma detection Ophthalmological imaging is beginning to allow cellular detail to be observed in vivo Technologies enabling the visualization of healthy (possibly with AO) and “sick” RGCs (DARC) would provide a comprehensive assessment of glaucomatous changes and disease states in patients Progress in imaging is attracting more research interest in the eye, which in turn is producing techniques that are applicable in the clinic

References 1. Resnikoff S, Pascolini D, Etya’ale D et al. (2004) Global data on visual impairment in the year 2002. Bull World Health Organ 82:844–851 2. Quigley HA, Broman AT (2006) The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90:262–267 3. Cordeiro MF, Guo L, Luong V et al. (2004) Real-time imaging of single nerve cell apoptosis in retinal neurodegeneration. Proc Natl Acad Sci USA 101:13352–13356 4. Harwerth R, Carter-Dawson L, Shen F et al. (1999) Ganglion cell losses underlying visual field defects from experimental glaucoma. Invest Ophthalmol Vis Sci 40:2242–2250 5. Gray D, Merrigan W, Wolfing J et al. (2006) In vivo fluorescence imaging of primate retinal ganglion cells and retinal epithelial cells. Opt Express 14:7144–7158 6. Kerrison JB, Duh EJ, Yu Y et al. (2005) A system for inducible gene expression in retinal ganglion cells. Invest Ophthalmol Vis Sci 46:2932–2939 7. Feng G, Mellor RH, Bernstein M et al. (2000) Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28:41–51

8. Guo L, Salt TE, Luong V et al. (2007) Targeting amyloid-beta in glaucoma treatment. Proc Natl Acad Sci USA 104:13444– 13449 9. Guo L, Salt TE, Maass A et al. (2006) Assessment of neuroprotective effects of glutamate modulation on glaucoma-related retinal ganglion cell apoptosis in vivo. Invest Ophthalmol Vis Sci 47:626–633 10. Harwerth RS, Vilupuru AS, Rangaswamy NV et al. (2007) The relationship between nerve fiber layer and perimetry measurements. Invest Ophthalmol Vis Sci 48:763–773 11. Weinreb RN, Dreher AW, Coleman A et al. (1990) Histopathologic validation of Fourier-ellipsometry measurements of retinal nerve fiber layer thickness. Arch Ophthalmol 108:557–560 12. Zangwill LM, Bowd C (2006) Retinal nerve fiber layer analysis in the diagnosis of glaucoma. Curr Opin Ophthalmol 17:120–131 13. Sehi M, Ume S, Greenfield DS (2007) Scanning laser polarimetry with enhanced corneal compensation and optical coherence tomography in normal and glaucomatous eyes. Invest Ophthalmol Vis Sci 48:2099–2104 14. Medeiros FA, Bowd C, Zangwill LM et al. (2007) Detection of glaucoma using scanning laser polarimetry with enhanced corneal compensation. Invest Ophthalmol Vis Sci 48:3146–3153 15. Okawa Y, Fujikado T, Miyoshi T et al. (2007) Optical imaging to evaluate retinal activation by electrical currents using suprachoroidal-transretinal stimulation. Invest Ophthalmol Vis Sci 48:4777–4784 16. Lazebnik M, Marks DL, Potgieter K et al. (2003) Functional optical coherence tomography for detecting neural activity through scattering changes. Opt Lett 28:1218–1220 17. Bizheva K, Pflug R, Hermann B et al. (2006) Optophysiology: depth-resolved probing of retinal physiology with functional ultrahigh-resolution optical coherence tomography. Proc Natl Acad Sci USA 103:5066–5071 18. Nelson DA, Krupsky S, Pollack A et al. (2005) Special report: Noninvasive multi-parameter functional optical imaging of the eye. Ophthalmic Surg Lasers Imaging 36:57–66 19. Huang D, Swanson EA, Lin CP et al. (1991) Optical coherence tomography. Science 254:1178–1181 20. Schuman JS, Pedut-Kloizman T, Pakter H et al. (2007) Optical coherence tomography and histologic measurements of nerve fiber layer thickness in normal and glaucomatous monkey eyes. Invest Ophthalmol Vis Sci 48:3645–3654 21. Soliman MA, Van Den Berg TJ, Ismaeil AA et al. (2002) Retinal nerve fiber layer analysis: relationship between optical coherence tomography and red-free photography. Am J Ophthalmol 133:187–195 22. Moneron G, Boccara AC, Dubois A (2005) Stroboscopic ultrahigh-resolution full-field optical coherence tomography. Opt Lett 30:1351–1353 23. Dubois A, Grieve K, Moneron G et al. (2004) Ultrahighresolution full-field optical coherence tomography. Appl Opt 43:2874–2883

References 24. Srinivasan VJ, Ko TH, Wojtkowski M et al. (2006) Noninvasive volumetric imaging and morphometry of the rodent retina with high-speed, ultrahigh-resolution optical coherence tomography. Invest Ophthalmol Vis Sci 47:5522–5528 25. Miglior S, Riva I, Guareschi M et al. (2007) Retinal sensitivity and retinal nerve fiber layer thickness measured by optical coherence tomography in glaucoma. Am J Ophthalmol 144:733–740 26. Parikh RS, Parikh SR, Sekhar GC et al. (2007) Normal agerelated decay of retinal nerve fiber layer thickness. Ophthalmology 114:921–926 27. Kim TW, Park UC, Park KH et al. (2007) Ability of Stratus OCT to identify localized retinal nerve fiber layer defects in patients with normal standard automated perimetry results. Invest Ophthalmol Vis Sci 48:1635–1641 28. Huang ML, Chen HY (2005) Development and comparison of automated classifiers for glaucoma diagnosis using Stratus optical coherence tomography. Invest Ophthalmol Vis Sci 46:4121–4129 29. Drexler W, Morgner U, Ghanta RK et al. (2001) Ultrahighresolution ophthalmic optical coherence tomography. Nat Med 7:502–507 30. Chen TC, Cense B, Pierce MC et al. (2005) Spectral domain optical coherence tomography: ultra-high speed, ultrahigh resolution ophthalmic imaging. Arch Ophthalmol 123:1715–1720 31. Wojtkowski M, Srinivasan V, Fujimoto JG et al. (2005) Three-dimensional retinal imaging with high-speed ultrahigh-resolution optical coherence tomography. Ophthalmology 112:1734–1746 32. Mumcuoglu T, Wollstein G, Wojtkowski M (2007) Improved visualization of glaucomatous retinal damage using high-speed ultrahigh-resolution optical coherence tomography. Ophthalmology 115:782–789 33. Povazay B, Hofer B, Hermann B (2007) Minimum distance mapping using three-dimensional optical coherence tomography for glaucoma diagnosis. J Biomed Opt 12:041204 34. Cucu RG, Podoleanu AG, Rogers JA (2006) Combined confocal/en face T-scan-based ultrahigh-resolution optical coherence tomography in vivo retinal imaging. Opt Lett 31:1684–1686 35. Nassif N, Cense B, Park BH (2004) In vivo human retinal imaging by ultrahigh-speed spectral domain optical coherence tomography. Opt Lett 29:480–482 36. Ruggeri M, Wehbe H, Jiao S (2007) In vivo three-dimensional high-resolution imaging of rodent retina with spectraldomain optical coherence tomography. Invest Ophthalmol Vis Sci 48:1808–1814 37. Mujat M, Park BH, Cense B (2007) Autocalibration of spectral-domain optical coherence tomography spectrometers for in vivo quantitative retinal nerve fiber layer birefringence determination. J Biomed Opt 12:041205 38. Truong SN, Alam S, Zawadzki RJ (2007) High resolution Fourier-domain optical coherence tomography of retinal angiomatous proliferation. Retina 27:915–925

11

39. Huber R, Adler DC, Srinivasan VJ (2007) Fourier domain mode locking at 1050 nm for ultra-high-speed optical coherence tomography of the human retina at 236,000 axial scans per second. Opt Lett 32:2049–2051 40. Dubois A, Moneron G, Grieve K (2004) Three-dimensional cellular-level imaging using full-field optical coherence tomography. Phys Med Biol 49:1227–1234 41. van Velthoven ME, Verbraak FD, Yannuzzi LA (2006) Imaging the retina by en face optical coherence tomography. Retina 26:129–136 42. Podoleanu AG (2006) Combining SLO and OCT technology. Bull Soc Belge Ophtalmol 301:133–151 43. Maass A, von Leithner PL, Luong V (2007) Assessment of rat and mouse RGC apoptosis imaging in Vivo with different scanning laser ophthalmoscopes. Curr Eye Res 32:851–861 44. Leung CKS, Lindsey JD, Weinreb RN (2007) Abstract 78–9. In: World Glaucoma Congress, Singapore, 18–21 July 2007, pp. P091 45. Hermann B, Fernandez EJ, Unterhuber A (2004) Adaptiveoptics ultrahigh-resolution optical coherence tomography. Opt Lett 29:2142–2144 46. Biss DP, Sumorok D, Burns SA (2007) In vivo fluorescent imaging of the mouse retina using adaptive optics. Opt Lett 32:659–661 47. Thanos S, Fischer D, Pavlidis M (2000) Glioanatomy assessed by cell–cell interactions and phagocytotic labelling. J Neurosci Methods 103:39–50 48. Thanos S, Naskar R, Heiduschka P (1997) Regenerating ganglion cell axons in the adult rat establish retinofugal topography and restore visual function. Exp Brain Res 114:483–491 49. Thanos S, Indorf L, Naskar R (2002) In vivo FM: using conventional fluorescence microscopy to monitor retinal neuronal death in vivo. Trends Neurosci 25:441–444 50. Thanos S, Naskar R (2004) Correlation between retinal ganglion cell death and chronically developing inherited glaucoma in a new rat mutant. Exp Eye Res 79:119–129 51. Naskar R, Wissing M, Thanos S (2002) Detection of early neuron degeneration and accompanying microglial responses in the retina of a rat model of glaucoma. Invest Ophthalmol Vis Sci 43:2962–2968 52. Higashide T, Kawaguchi I, Ohkubo S (2006) In vivo imaging and counting of rat retinal ganglion cells using a scanning laser ophthalmoscope. Invest Ophthalmol Vis Sci 47:2943–2950 53. Leak RK, Moore RY (1997) Identification of retinal ganglion cells projecting to the lateral hypothalamic area of the rat. Brain Res 770:105–114 54. Aihara M, Murata H, Chen Y (2007) Abstract 80. In: World Glaucoma Congress, Singapore, 18–21 July 2007, pp. P094 55. Rotchford A (2005) What is practical in glaucoma management? Eye 19:1125–1132 56. Collaborative Normal-Tension Glaucoma Study Group (1998) Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and

12

1

1 Imaging Individual Ganglion Cells in the Human Retina

patients with therapeutically reduced intraocular pressures. Collaborative Normal-Tension Glaucoma Study Group. Am J Ophthalmol 126:487–497 57. Kemerink GJ, Liu X, Kieffer D (2003) Safety, biodistribution, and dosimetry of 99mTc-HYNIC-annexin V, a novel human recombinant annexin V for human application. J Nucl Med 44:947–952 58. Belhocine T, Steinmetz N, Hustinx R (2002) Increased uptake of the apoptosis-imaging agent (99 m)Tc recombinant

human Annexin V in human tumors after one course of chemotherapy as a predictor of tumor response and patient prognosis. Clin Cancer Res 8:2766–2774 59. Narula J, Acio ER, Narula N (2001) Annexin-V imaging for noninvasive detection of cardiac allograft rejection. Nat Med 7:1347–1352 60. Mumm JS, Williams PR, Godinho L (2006) In vivo imaging reveals dendritic targeting of laminated afferents by zebrafish retinal ganglion cells. Neuron 52:609–621

Chapter 2

The Epidemiology of Glaucoma Annette Giangiacomo, Anne Louise Coleman

2

Core Messages ■

■

■

■

Glaucoma is second to cataract as a leading cause of global blindness and is the leading cause of irreversible visual loss. In 2002, 37 million individuals were blind worldwide, with glaucoma accounting for 12.3% of these individuals. By the year 2020 it is estimated that there will be almost 80 million people in the world with openangle glaucoma and angle-closure glaucoma. The majority of these individuals will have open-angle glaucoma. Of those with ACG, it is predicted that 70% will be women and 87% will be Asian. Bilateral blindness from glaucoma is projected to affect 8.4 million individuals worldwide by

2.1

Introduction

Glaucoma is second only to cataract as a leading cause of global blindness [46], and is the leading cause of irreversible visual loss, largely due to primary open-angle glaucoma (POAG). In 2002, it was estimated that 161 million individuals worldwide had visual impairment and 37 million were blind. Glaucoma accounted for 12.3% of global blindness, while cataract accounted for 47.8% (see Fig. 2.1). Visual impairment from glaucoma weighs a heavier burden in the least developed regions, and affects adults more than children and women more than men [46]. By the year 2010 it is estimated that there will be 60.5 million people in the world with open-angle glaucoma (OAG) and angle-closure glaucoma (ACG). By the year 2020 this number is predicted to increase to 79.6 million. The majority (74%) of these individuals will have OAG. Of the group with ACG, 70% will be women and 87% will be Asian. Bilateral blindness from glaucoma is projected to affect 8.4 million individuals worldwide by 2010 and greater than 11 million by 2020. Globally, glaucoma is a significant cause of vision loss that disproportionately affects women and Asians [42].

■

■

2010 and greater than 11 million by 2020. Globally, glaucoma is a significant cause of vision loss that disproportionately affects women and Asians. Risk factors for open-angle glaucoma include increased age, African ethnicity, family history, increased intraocular pressure, myopia, and decreased corneal thickness. Risk factors for angle closure glaucoma include Inuit and Asian ethnicity, hyperopia, female sex, shallow anterior chamber, short axial length, small corneal diameter, steep corneal curvature, shallow limbal chamber depth, and thick, relatively anteriorly positioned lens.

In the United States, more than three million Americans are projected to have glaucoma by the year 2020. Glaucoma blindness is almost three times higher in African Americans than white Americans, and POAG is the leading cause of blindness in African Americans [14]. There is no doubt that as the economic burden of all healthcare rises, there will be new challenges regarding the distribution and delivery of healthcare, and the burden of glaucoma is no exception. It was recently estimated that 17.8% of direct medical costs of major eye diseases in the United States were attributable to patients with glaucoma, representing a substantial portion given that the annual total direct medical costs for these disorders was estimated to be $16.2 billion [45]. As the US population ages and as medical care for glaucoma increases, the challenge involved in meeting these costs will undoubtedly increase.

2.2

Primary Open-Angle Glaucoma

It has been estimated that by 2010, almost 45 million people will have OAG worldwide, and by 2020 this number is expected to increase to 58.5 million. Almost

14

2 The Epidemiology of Glaucoma 13 0.8 3.6 3.9

2

4.8 5.1 47.8 8.7 12.3 Cataract

Chilhood blindness

Glaucoma

Trachoma

AMD3

Onchocerciasis

Corneal opacities

Others

Diabetic retinopathy 3AMD

= Age-related macular degeneration,

WHO 04, 138

Fig. 2.1 Global causes of blindness as a percentage of total blindness in 2002 Reprinted with permission from [46]

half (47%) of these people will reside in Asia while 24% will be European. The mean prevalence is estimated to be 1.96%. Women are expected to comprise >55% of those with OAG because of their increased longevity compared to men [42]. In the United States, the overall prevalence of OAG in individuals ³40 years old is 1.86%, affecting 1.57 million whites and 398,000 black individuals. In 2020, due to the rapidly aging population, it is estimated that this number will grow to 3.36 million [14].

2.2.1

In the past decade, two studies have provided insight about risk factors for developing glaucoma among patients with OHT. The Ocular Hypertension Treatment Study (OHTS) and the European Glaucoma Prevention Study (EGPS) each studied a large population of individuals with elevated IOP but normal visual fields and normal optic discs. The OHTS showed that the progression to glaucoma was reduced from 9.4 to 4.4% over five years if the IOP was reduced at least 20%. The EGPS found that during follow-up, a higher IOP was associated with an increased risk of developing OAG (9% per mm Hg over a five-year period) [35]. Both EGPS and OHTS reported that among patients with OHT, thin central cornea thickness was a risk factor for the development of glaucoma. The etiology for this increased risk is uncertain [13, 19]. They also reported that older baseline age, increased vertical cup-to-disc ratios, and greater pattern standard deviations on the Humphrey automated perimeter were predictive factors for OAG [7, 19, 35]. At this time, the risk associated with long-term fluctuation of IOP over months to years remains controversial. The EGPS and Early Manifest Glaucoma Treatment Trial found that long-term IOP fluctuations were not associated with progression of glaucoma [35], while the AGIS study found an increased risk of glaucoma progression with increased long-term IOP fluctuation, especially in patients with low IOP [5, 39]. While increased IOP is a strong risk factor for the development of glaucoma, it must be remembered that many people with glaucoma have untreated IOPs of 21 mm Hg or less. In general, it is estimated that approximately 50% of POAG is of the normal tension variety. However, studies have found a wide range in the prevalence of normal tension glaucoma among individuals with OAG. For example, normal tension glaucoma was diagnosed in 1/3 of the OAG patients in the Barbados Eye Studies, and 85% of the individuals with OAG in a Chinese population [20, 31].

Increased IOP

Elevated intraocular pressure (IOP) is the most important known risk factor for the development of POAG, and its reduction remains the only clearly proven treatment. Several studies have confirmed that reduction of IOP at any point along the spectrum of disease severity reduces progression (Early Manifest Glaucoma Treatment Trial to Advanced Glaucoma Intervention Study). Also, IOP reduction reduces the development of POAG in patients with ocular hypertension (OHT) and reduces progression in patients with glaucoma despite normal IOP, as seen in the Collaborative Normal Tension Glaucoma Study.

2.2.2

Age

Studies consistently agree that increasing age is a risk factor for the development of glaucoma in general and for patients with OHT. In a population of white individuals in Wisconsin, the prevalence of OAG in the group aged 43–54 years was 0.9%, while it was significantly greater in individuals 75 years of age or older, at 4.7% [24]. In the Barbados Eye Studies, the incidence of POAG was 2.2% for those aged 40–49 years at baseline and 7.9% for those greater than 70 years of age, with a relative risk of developing glaucoma of 3.8 for the older age group [31].

2.2 Primary Open-Angle Glaucoma

A

BES Barbados KEP Proyecto VER

25

BDES BMES Melbourne VIP RS

20 Prevalence, %

20 Prevalence, %

B

BES

25

15 10 5

15

15 10 5

0 40-49

50-54

55-59

60-64

65-69

70-74

75-79

≥80

0 40-49

50-54

Age, y

55-59

60-64

65-69

70-74

75-79

≥80

Age, y

Fig. 2.2 Prevalence of glaucoma in white (A) and black and Hispanic (B) subjects. BES, Baltimore Eye Survey, Baltimore, MD; BDES, Beaver Dam Eye Study, Beaver Dam, WI; BMES, Blue Mountains Eye Study, Sydney, NSW; Melbourne VIP, Melbourne Visual Impairment Project, Melbourne, VIC; RS, Rotterdam Study, Rotterdam, the Netherlands; Barbados, Barbados Eye Study, Barbados, West Indies; KEP, Kongwa Eye Project, Tanzania; and Proyecto VER, Vision Evaluation Research, Nogales and Tucson, AZ. Reprinted with permission from The Eye Diseases Prevalence Research Group [14]

Figure 2.2 shows that the prevalence of OAG increases with age in all depicted ethnicities [14]. The results of a recent meta-analysis to predict prevalence of OAG in adults confirmed that the prevalence of OAG increases with age (see Table 2.1) [14]. Increasing age is considered to be a surrogate risk factor for currently unknown factors such as increased deterioration of tissue or ganglion cells, increased duration of exposure to other risk factors, or poorer adherence to therapy or decreased ability to afford therapy [2].

2.2.3

Family History

Family history has consistently been shown to be a risk factor for glaucoma [27]. In the Barbados Family Study of Open-Angle Glaucoma, 40% of probands had at least one affected family member, one in five siblings had OAG, and a quarter of the family members had definite or suspected glaucoma [30]. Also, in the Rotterdam Glaucoma Study and the Baltimore Eye Survey, the risk of OAG was much higher for first-degree relatives [50]. Family history may reflect similarity in genes directly related to the development of glaucoma, or may reflect genetic similarity related to IOP or optic nerve anatomy that may influence the development of glaucoma. Alternatively, family history may be a reflection of increased access to healthcare and eye exams, and therefore associated with an increased chance of being detected, or a shared environmental exposure.

2.2.4

Sex

Whether sex is associated with an increased risk of glaucoma is a controversial issue. In the Barbados Eye Studies and the Beaver Dam Eye Study there was no statistically significant increased risk with sex [24, 31]. In the Melbourne and Rotterdam studies there was a trend towards increased risk for OAG in males; however, this difference did not reach statistical significance, possibly due to small sample sizes [10, 38]. The Eye Disease Prevalence Research group found no difference between the prevalence of glaucoma between men and women for the white, black and Hispanic populations [14].

2.2.5 Ethnicity Ethnicity is imperfectly defined, given the inconsistent application of variables that are sometimes used to define ethnicity, including language, skin color, and geographic residence, as well as the variability that exists within populations that are classically defined as one ethnicity (i.e., variability exists among “the Chinese”). Nonetheless, ethnicity is used as a gross representation of genetic or other unknown differences between populations, and trends regarding the relationship between ethnicity and glaucoma have been established. It is clear that African descent is associated with a higher risk of developing glaucoma compared with individuals of

16

2 The Epidemiology of Glaucoma

Table 2.1 Prevalence of open-angle glaucoma in adults in the United States

2

Age (years)

European-derived (%)

Blacks (%)

50–54 70–74

F: 0.89 F: 2.16

F: 2.24 F: 5.89

≥80

F: 6.94

F: 9.82

Notes: F = female There were no statistically significant differences in prevalence between males or females in European-derived, black or Hispanic ethnicities. The prevalence rates in Hispanics were not significantly different from those for European-derived adults, but had lower prevalence compared to blacks, with an odds ratio of 0.41. Overall, the black subjects had almost three times the prevalence rates of European-derived individuals. Data from the Eye Diseases Prevalence Research Group [14].

European descent [14, 29, 42, 49], as seen in Fig. 2.2. The estimated incidence of OAG is 2–5 times higher for individuals of African descent compared to their Europeanderived counterparts. Recently, results from nine years of follow-up from the Barbados Eye Studies showed that the nine-year incidence of POAG was 4.4% in this population of individuals predominantly of African descent. When including cases of probable and definite POAG, the incidence rose to 9.4% [31]. Studies of European-derived populations show the five-year incidence of definite glaucoma to be 0.5–0.6% and 1.1–1.8% for definite and probable cases of OAG [10, 38]. The Eye Disease Prevalence Research Group [14] conducted a meta-analysis of several studies on the prevalence of OAG in the world, and extrapolated that data to the United States census population to estimate the prevalence in the United States. They approximated that 1.57 million whites and 398,000 individuals of African descent have glaucoma in the United States, and in 2020 approximately 3.36 million Americans will have glaucoma, due to the rapidly aging population. The overall prevalence of OAG is 1.86%. In every age group, there was a higher prevalence of OAG in individuals of African descent compared with European-derived individuals (See Table 2.1). It is uncertain why there is an increased risk of developing glaucoma among individuals of African descent, although genetic [12] or environmental factors have been suggested. The prevalence of OAG in African Americans in the Baltimore Eye Survey was 4.2%, while it was 7%

in the Africans of the Barbados Eye study, and for the participants in the Barbados Eye Study with a mixed ancestry it was 3.3%, suggesting an influence of ancestral factors. Among the subpopulations of people of African descent, the prevalence is variable: highest in St. Lucia and Ghana (8.8% and 7.7%, respectively) and lower in Tanzania and South Africa (4.2% and 2.9%, respectively) [4, 34, 40, 47]. Several factors could be involved with the higher risk conferred to Africans. Physiologic differences in the optic disc or thinner corneas compared with their peers may be involved. Social differences including less access to health care may also be influential [2]. Asians have a lower risk of OAG compared to individuals of African descent, and show a prevalence similar to those of European descent. The prevalence of POAG in a Chinese population in the Liwan District was 2.1%, similar to the prevalence seen in Chinese Singaporeans [16, 20]. The prevalence of OAG in Latinos appears to be higher than in European-derived individuals. In the Los Angeles Latino Eye Study (LALES), the prevalence of glaucoma in predominantly Mexican-derived Latinos was 4.74%. Prevalence increased with age, with those 40–49 years of age having a prevalence of 1.32%, whereas for those greater than 80 years old it was 21.76%. An astounding 75% of individuals with OAG or OHT were previously undiagnosed [53]. Another study of Latinos found the overall prevalence of OAG to be 1.97%, with an increased prevalence with age (0.50% for those 41–49 years old to 12.63% for those ³ 80 years old). Also, in this study, similar to LALES, 62% of individuals were previously not diagnosed with OAG [43]. Native Americans have not been studied as extensively as other US populations, but one study of Northwest American Indians showed some surprising results. Individuals from three tribes from Oregon, Washington and Idaho had a prevalence of glaucoma of 6.2%, and all of the affected individuals had normal-tension glaucoma [33].

2.2.6

Myopia

Although myopia is not classically included as a risk factor for glaucoma because of concerns over selection bias, prior clinic-based studies have identified myopia as a risk factor. The Blue Mountains Eye Study, a population-based study of white Australians, showed that moderate-to-high myopia (spherical equivalent of −3.00 D or greater) was associated with a two- to threefold increased risk of having glaucoma. The risk was higher (OR, 3.3) for moderate-to-high myopia than for low myopia (OR, 2.3) [36]. A similar association was found in a Europeanderived population in the US [56]. There also appears

2.3 Primary Angle-Closure Glaucoma

to be an increased risk of glaucoma in myopic Chinese individuals. In another population-based study, Chinese with high myopia (greater than −6 D refractive error) were at higher risk of being diagnosed with glaucoma compared to the group consisting of all other refractive errors (odds ratio 2.28) [54]. The increased risk conferred by myopia does not appear to be related to IOP. Mechanisms for the relationship between myopia and glaucoma have been postulated and include (1) increased susceptibility of myopic nerves to glaucomatous damage, (2) shearing forces across the lamina cribrosa by the sclera, (3) other connective tissue changes, or (4) a genetic link [54].

2.2.7

Other Risk Factors

Several studies have suggested a relationship between migraine and glaucoma, including the Blue Mountain Eye Study [41, 55]. In the Collaborative Normal Tension Glaucoma Study, the risk ratios for migraine, disk hemorrhage and female gender were 2.58, 2.72, and 1.85, respectively [11]. Vasospasm in the region of the optic nerve is considered to be the likely cause. However, other studies have not found evidence of a relationship between OAG and migraine headache [25]. Studies have been conflicting regarding the relationship of diabetes and risk of glaucoma. The Baltimore Eye Study found that diabetics had an increased IOP compared to nondiabetics, but that they had a lower risk for OAG [2]. However, this finding may be secondary to selection bias, since diabetics are more likely to be evaluated by an eye doctor and then diagnosed with glaucoma than nondiabetics. Alternatively, the Beaver Dam Eye Study found an increased risk of glaucoma in individuals with adult-onset diabetes [26]. The influence of blood pressure on the optic nerve is complex, and whether hypertension (HTN) increases the risk of OAG remains undetermined. Blood pressure influences optic nerve perfusion; however, the specific parameters that may be related to the development of glaucoma are unknown. While some studies have shown no clear association between blood pressure and OAG [23, 51], others have shown a positive relationship [3, 28, 37], while another has shown a reduced risk of OAG with HTN [32]. Elevated systemic blood pressure has been associated with higher IOP [3]. In the Beaver Dam Eye Study, elevated IOP was associated with increased systolic and diastolic blood pressures. They found a 0.21 mm Hg increase in IOP for a 10 mm Hg increase in systolic and 0.43 mm Hg increase in IOP for a 10 mm Hg increase in diastolic blood pressure [28]. However, the Blue Mountains Eye Study showed a 50% increased risk of OAG with HTN independent of IOP, especially in individuals with

17

poorly controlled, treated HTN [37]. The mechanism by which HTN may cause OAG is unclear. It may be that sustained HTN causes microvascular damage, or impaired autoregulation, or that treatment of HTN causes nocturnal hypotensive episodes [37]. Another parameter of interest is pulse pressure, which is defined as the difference between systolic and diastolic blood pressure. Some studies have shown that a higher pulse pressure is associated with a higher prevalence of OAG [23]. Low diastolic blood pressure is not uncommon in the elderly, and this may result in a higher pulse pressure in the setting of arterial stiffness, which may also be present in the elderly. High pulse pressure may impair ocular autoregulation. With impaired autoregulation, vessels may not be able to respond to a low diastolic blood pressure in order to maintain perfusion, which then may result in ischemia and optic nerve damage [23]. Diastolic perfusion pressure is defined as the difference between diastolic blood pressure and IOP. Several studies have shown an increased risk of OAG with low diastolic perfusion pressure [3, 32, 51]. The Rotterdam study showed that for a population of individuals treated for HTN, a low diastolic perfusion pressure was associated with a lower risk of normal-tension OAG [23] and higher risk of high-tension OAG [23, 51]. In the setting of elevated IOP, higher blood pressure may be needed to maintain perfusion to protect the disc [23]. Treated HTN may be related to subtle changes in the optic disc, since individuals without glaucoma in the Thessaloniki Eye Study had increased cup area, increased cup-to-disc ratio and decreased rim areas compared with individuals with elevated diastolic blood pressure or normal, untreated diastolic blood pressure. Similar findings were also seen for individuals with low pulse pressure. These findings suggest that low diastolic blood pressure secondary to the treatment of HTN may be associated with optic nerve fiber loss and changes in the optic disc structure [52].

2.3

Primary Angle-Closure Glaucoma

In the year 2010, it is estimated that ACG will account for 26% of glaucoma worldwide, with a mean prevalence of 0.69%. By 2020 there will be 21 million people with ACG and 87% of them will reside in Asia. Due to the greater longevity of women and the higher prevalence of ACG in women, women are expected to comprise 70% of individuals with ACG [42]. Narrow angles are more prevalent in Asians than Europeans, and by 2010 it is estimated that primary angleclosure glaucoma will be responsible for about 50% of the global burden of blindness due to glaucoma [42], and the majority of these individuals will be in Asia [42, 46].

18

2

2 The Epidemiology of Glaucoma

Whether evolution, genetics, migration patterns, or environmental factors are responsible for the higher prevalence of narrow angles in Asians remains uncertain. While primary angle closure glaucoma (PACG) tends to be more common in Asians compared to Europeans, [42] POAG remains more common than PACG in most Asian populations. However, PACG is responsible for a disproportionate amount of blindness caused by glaucoma [16, 20].

2.3.1

Risk Factors

Female gender, older age, shallow anterior chamber, short axial length, small corneal diameter, steep corneal curvature, shallow limbal chamber depth, and thick relatively anteriorly positioned lens are risk factors for developing primary angle closure (PAC) [6, 17, 18, 21]. One of the most easily measured variables is the anterior chamber depth, and many studies have shown that shorter anterior chamber depth is related to a higher prevalence of PAC [21]. The most recent study regarding these anatomical differences compared contralateral eyes of patients who had an acute angle closure attack with controls. The contralateral eyes had shorter axial lengths, thicker lenses, shallower anterior chambers, steeper radii of corneal curvature and smaller anterior chamber volumes compared to controls. Despite these differences, there was not adequate predictive power to identify which contralateral eyes would develop ACG [18, 43]. Gonioscopy is the mainstay for diagnosing primary angle closure suspects (PACS), and PAC. The Framingham study, which predominantly included individuals of European descent, reported that 3.8% of eyes had angles with Shaffer grade £2 by gonioscopy, while 47.8% of a Vietnamese population in the US had similar Shaffer grading. In a Burmese population, the prevalence of anatomically narrow angles (as defined by ≤ 90° of visible posterior trabecular meshwork) was 5.7%. Individuals with anatomically narrow angles were more likely to be older than 50 years and female [6]. In Mongolia and Singapore, occludable angles were found in 6.4 and 6.3%, respectively, while [21] in a group of adult Chinese in the Liwan Eye Study, 11% had narrow angles. Twenty percent of these had peripheral anterior synechiae, indicating PAC [22]. The reasons for the higher prevalence of ACG in Asians are thought to be secondary to anatomical characteristics such as shorter axial lengths in Asians; however, all studies have not confirmed such racial anatomic differences [8, 21]. The increased prevalence of ACG in

Asians may be explained by multiple risk factors or possible physiological differences [18, 44].

2.3.2 Prevalence In Asian populations, the prevalence of PACS has been reported to be 1.4–10.1%, while that of PAC has ranged from 1.4 to 3.1%. Although PACG is approximately three times more common in Asian populations compared to European-derived populations [21], this prevalence varies by region within Asia. Mongolian and Chinese populations tend to be affected more, while variable prevalence is seen in Southeast Asia and India. In a population in northern Mongolia, the prevalence of PACG was 1.4%, while the prevalence of gonioscopically occludable angles was 6.4% and the prevalence of POAG was 0.5% [15]. In a Burmese population, the prevalence of PAC (defined as anatomically narrow angle associated with peripheral anterior synechiae or elevated IOP) was 1.5%, and the risk of PAC was significantly greater in women [6]. In a population of Chinese 50 years of age and older in the Liwan district, the prevalence of PAC—based on (1) posterior trabecular meshwork not being visible for ³270° and (2) IOP > 95th percentile of the normal population and/or presence of peripheral anterior synechiae or evidence of anterior segment ischemia after increased IOP—was 2.4% overall; however, it was three times higher in women (3.3%) than men (1.1%) and increased with age [20]. The prevalence of PACG in this population was 1.5%, with women again being affected significantly more than men (1.6% vs. 1.3%, respectively) [20]. In a Southern Indian population, for individuals 40 years of age or older, the prevalence of PACG was 1.08%, while the prevalence of occludable angles without ACG was 2.21% [9]. Most eyes had chronic ACG and 42% of individuals with PACG had blindness in one or both eyes. To more fully understand the health burden of PACS and PAC, Thomas et al. calculated the number needed to treat (NNT) to prevent progression from PACS to PAC or from PAC to PACG. The NNT to prevent one person with PACS from progressing to PAC is six over five years, and the NNT to prevent one person with PAC from progressing to PACG is five over five years [48]. Given the potentially blinding consequences associated with untreated PACS or PAC, these relatively low NNTs reflect the real potential benefit of screening. However, in developing countries, population-based screening is challenging. Alaska’s northwestern Eskimos were shown to have a prevalence of glaucoma of 0.65%, with 10 of the 11 cases being PACG. In Eskimos older than 40 years of

References

age, PACG occurred at a rate of 2.65%, but women were affected almost four times as often as men, and there was a high prevalence of occludable angles (17%) [1]. The prevalence of PACG in European-derived people appears to be much lower compared to Asians, and has been reported to be 0.04% in the Beaver Dam study, 0.06% in Melbourne, 0.09% in Wales, 0.4% in Baltimore, 0.6% in North Italy [21].

Summary for the Clinician ■

■

■

■

Glaucoma is the second leading cause of preventable blindness and is the leading cause of irreversible visual loss. By the year 2020 it is estimated that there will be almost 80 million people in the world with glaucoma. The majority of these individuals will have OAG. Of those with ACG, 70% will be women and 87% will be Asian. Bilateral blindness from glaucoma is projected to affect 11 million individuals worldwide by 2020. Risk factors for open-angle glaucoma include increased age, African or Latino ethnicity, family history, increased IOP, myopia, and decreased corneal thickness. Possible risk factors for OAG include diurnal intraocular pressure variation, long-term intraocular pressure variation, sleep apnea, Hispanic or Indian ethnicity, and migraine. Risk factors for angle-closure glaucoma include increased age, female gender, Asian ethnicity, shallow anterior chamber, short axial length, small corneal diameter, steep corneal curvature, shallow limbal chamber depth, and a thick or anteriorly positioned lens. Because 50% or more of those individuals with glaucoma are unaware of their diagnosis; more effort is needed to effectively screen high-risk groups and to educate society about the preventability and consequences of glaucoma.

References 1. Arkell SM, Lightman DA, Sommer A (1987) The prevalence of glaucoma among Eskimos of northwest Alaska. Arch Ophthalmol 105:482–485 2. Boland MV, Quigley HA (2007) Risk factors and openangle glaucoma: classification and application. J Glaucoma 16:406–418

19

3. Bonomi L, Marchini G, Marraffa M et al. (2000) Vascular risk factors for primary open angle glaucoma. The Egna– Neumarkt study. Ophthalmology 107:1287–1293 4. Buhrmann RR, Quigley HA, Barroy Y et al. (2000) Prevalence of glaucoma in a rural East African population. Invest Ophthalmol Vis Sci 41:40–48 5. Caprioli J, Coleman AL (2008) Intraocular pressure fluctuation: a risk factor for visual field progression at low intraocular pressures in the Advanced Glaucoma Intervention Study. Ophthalmology 115(7):1123–1129 6. Casson RJ, Newland HS, Muecke J et al. (2007) Gonioscopy findings and prevalence of occludable angles in a Burmese population: the Meiktila eye study. Br J Ophthalmol 91:856–859 7. Coleman AL, Gordon MO, Beiser JA et al. (2004) Baseline risk factors for the development of primary open-angle glaucoma in the Ocular Hypertension Treatment Study. Ophthalmology 138:684–685 8. Congdon NC, Qi Y, Quigley HA et al. (1997) Biometry and primary angle-closure glaucoma among Chinese, white and black populations. Ophthalmology 104:1489–1495 9. Dandona L, Dandona R, Mandal P et al. (2000) Angle-closure glaucoma in an urban population in Southern India. Ophthalmology 107:1710–1716 10. de Voogd S, Ikram MK, Wolfs RC et al. (2005) Incidence of open-angle glaucoma in a general elderly population. The Rotterdam Study. Ophthalmology 112:1487–1493 11. Drance S, Anderson DR, Schulzer M et al. (2001) Risk factors for progression of visual field abnormalities in normal-tension glaucoma. Am J Ophthalmol 131:699–708 12. Duggal P, Klein AP, Lee KE et al. (2007) Identification of novel genetic loci for intraocular pressure: a genomewide scan of the Beaver Dam Eye Study. Arch Ophthalmol 125:74–79 13. European Glaucoma Prevention Study Group (2007) Predictive factors for open-angle glaucoma among patients with ocular hypertension in the European Glaucoma Prevention Study. Ophthalmology 113:3–9 14. Eye Diseases Prevalence Research Group (2004) Prevalence of open-angle glaucoma among adults in the United States. Arch Ophthalmol 122:532–538 15. Foster PJ, Baasanhu J, Alsbirk PH et al. (1996) Glaucoma in Mongolia. A population-based survey in Hovsgol province, northern Mongolia. Arch Ophthalmol 114:1235–1241 16. Foster PJ, Oen FT, Machin D et al. (2000) The prevalence of glaucoma in Chinese residents of Singapore: a crosssectional population survey of the Tanjong Pagar district. Arch Ophthalmol 118:1105–1111 17. Foster PJ, Johnson GJ (2001) Glaucoma in China: how big is the problem? Br J Ophthalmol 85:1277–1282 18. Friedman DS, Gazzard G, Foster P et al. (2003) Ultrasonographic biomicroscopy, Scheimpflug photography, and novel provocative tests in contralateral eyes of Chinese patients initially seen with acute angle closure. Arch Ophthalmol 121:633–642 19. Gordon MO, Beiser JA, Bandt JD et al. (2002) The ocular hypertension treatment study. Baseline factors that predict

20

20.

2 21. 22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

2 The Epidemiology of Glaucoma

the onset of primary open-angle glaucoma. Arch Ophthalmol 120:714–720 He M, Foster PJ, Ge J et al. (2006) Prevalence and clinical characteristics of glaucoma in adult Chinese: a populationbased study in Liwan District, Guangzhou. Invest Ophthalmol Vis Sci 47:2782–2788 He M, Foster PJ, Johnson GJ et al. (2006) Angle-closure in East Asian and European people. Different diseases? Eye 20:3–12 He M, Foster PJ, Ge J et al. (2006) Gonioscopy in adult Chinese: the Liwan Eye Study. Invest Ophthalmol Vis Sci 47:4772–4779 Hulsman CA, Vingerling JR, Hofman A et al. (2007) Blood pressure, arterial stiffness, and open-angle glaucoma. The Rotterdam Study. Arch Ophthalmol 125:805–812 Klein BE, Klein R, Sponsel WE et al. (1992) Prevalence of glaucoma. The Beaver Dam Eye Study. Ophthalmology 99:1499–1504 Klein BE, Klein R, Meuer SM et al. (1993) Migraine headache and its association with open-angle glaucoma: the Beaver Dam Eye Study. Invest Ophthalmol Vis Sci 34:3024–3027 Klein BD, Klein R, Jensen SC (1994) Open-angle glaucoma and older-onset diabetes. The Beaver Dam Eye Study. Ophthalmology 101:1173–1177 Klein BE, Klein R, Lee KE (2004) Heritability of risk factors for primary open-angle glaucoma: the Beaver Dam Eye study. Invest Ophthalmol Vis Sci 45:59–62 Klein BE, Klein R, Knudtson MD (2005) Intraocular pressure and systemic blood pressure: longitudinal perspective: the Beaver Dam Eye Study. Br J Ophthalmol 89:284–287 Leske MC, Connell AM, Schachat AP et al. (1994) The Barbados Eye Study: prevalence of open angle glaucoma. Arch Ophthalmol 112:821–829 Leske MC, Nemesure B, He Q et al. (2001) Patterns of open-angle glaucoma in the Barbados Family Study. Ophthalmology 108:1015–1022 Leske MC, Wu SY, Honkanen R et al. (2007) Nine-year incidence of open-angle glaucoma in the Barbados Eye Studies. Ophthalmology 114:1058–1064 Leske M, Wu SY, Hennis A et al. (2008) Risk factors for incident open-angle glaucoma: the Barbados Eye Studies. Ophthalmology 115:85–93 Mansberger SL, Romero FC, Smith NH et al. (2005) Causes of visual impairment and common eye problems in Northwest American Indians and Alaska Natives. Am J Public Health 95:881–886 Mason RP, Kosoko O, Wilson MR et al. (1989) National survey of the prevalence and risk factors of glaucoma in St. Lucia, West Indies. Part I. Prevalence findings. Ophthalmology 96:1363–1368 Miglior S, Torri V, Zeyen T et al. (2007) Intercurrent factors associated with the development of open-angle glaucoma in the european glaucoma prevention study. Am J Ophthalmol 144:266–275

36. Mitchell P, Hourihan F, Sandbach J et al. (1999) The relationship between glaucoma and myopia. Ophthalmology 106:2010–2015 37. Mitchell P, Lee AJ, Rochtchina E et al. (2004) Open-angle glaucoma and systemic hypertension. The Blue Mountains Eye Study. J Glaucoma 3:319–326 38. Mukesh BN, McCarty CA, Rait JL et al. (2002) Five-year incidence of open-angle glaucoma: the Vision Impairment Project. Ophthalmology 109:1047–5 39. Nouri-Mahdavi K, Hoffman D, Coleman AL et al. (2004) Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study. Ophthalmology 111:1627–1635 40. Ntim-Amponsah CT, Amoaku WM, Ofosu-Amaah S et al. (2004) Prevalence of glaucoma in an African population. Eye 18:491–497 41. Phelps CD, Corbett JJ (1985) Migraine and low-tension glaucoma. A case-control study. Invest Ophthalmol Vis Sci 26:1105–1108 42. Quigley HA, Broman AT (2006) The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90:262–267 43. Quigley HA, Wesk SK, Rodrigues J et al. (2001) The prevalence of glaucoma in a population-based study of Hispanic subjects. Proyecto VER. Arch Ophthalmol 119:1819–1826 44. Quigley HA, Friedman DS, Congdon NG (2003) Possible mechanisms of primary angle-closure and malignant glaucoma. J Glaucoma 12:167–180 45. Rein DB, Zhang P, Wirth KE et al. (2006) The economic burden of major adult visual disorders in the United States. Arch Ophthalmol 124:1754–1760 46. Resnikoff S, Pascolini D, Etya’ale D et al. (2004) Global data on visual impairment in the year 2002. Bull World Health Organ 82:844–851 47. Rotchford AP, Johnson GJ (2002) Glaucoma in Zulus: a population-based cross-sectional survey in a rural district in South Africa. Arch Ophthalmol 120:471–478 48. Thomas R, Sekhar GC, Parikh R (2007) Primary angle closure glaucoma: a developing world perspective. Clin Exp Ophthalmol 35:374–378 49. Tielsch JM, Sommer A, Katz J et al. (1991) Racial variations in the prevalence of primary open-angle glaucoma: the Baltimore eye survery. JAMA 266:369–374 50. Tielsch JM, Katz J, Sommer A, Quigley HA, Javitt JC (1994) Family history and risk of primary open angle glaucoma. The Baltimore eye survey. Arch Ophthalmol 112:69–73 51. Tielsch JM, Katz J, Sommer A et al. (1995) Hypertension, perfusion pressure, and primary open-angle glaucoma. A population-based assessment. Arch Ophthalmol 113:216–221 52. Topouzis F, Coleman AL, Harris A et al. (2006) Association of blood pressure status with the optic disk structure in non-glaucoma subjects: the Thessaloniki Eye Study. Ophthalmology 142:60–67

References 53. Varma R, Ying-Lai M, Francis BA et al. (2004) Prevalence of open-angle glaucoma and ocular hypertension in Latinos. The Los Angeles Latino Eye Study. Ophthalmology 111:1439–1448 54. Xu L, Want Y, Want S et al. (2007) High myopia and glaucoma susceptibility. The Beijing Eye Study. Ophthalmology 114:216–220

21

55. Wang JJ, Mitchell P, Smith W (1997) Is there an association between migraine headache and open angle glaucoma? Findings from the Blue Mountains Eye Study. Ophthalmology 104:1714–1719 56. Wong TY, Klein BE, Klein R et al. (2003) Refractive errors, intraocular pressure, and glaucoma in a white population. Ophthalmology 110:211–217

Chapter 3

Circadian Changes in Intraocular Pressure

3

Amish B. Doshi, John H.K. Liu, Robert N. Weinreb

Core Messages ■ ■

■

Intraocular pressure (IOP) follows a circadian rhythm While the suprachiasmatic nucleus controls these rhythms, an intrinsic oscillator may be present within the eye Dysregulation of 24-hour IOP may be responsible for some cases of glaucomatous optic neuropathy

3.1

Introduction

Circadian rhythms explain a variety of physiologic processes, including sleep, body temperature, hormone secretion, and cell regeneration. These rhythms maintain a periodicity of approximately 24 hours (24H) in light or dark, are relatively independent of external temperature, and can be reset by external stimuli. The patterns of a number of processes undergoing circadian rhythm have been linked to melatonin secretion, which peaks in the early morning, and body temperature, which is at its trough at 5 a.m. Extensive clinical evidence indicates that intraocular pressure (IOP) follows a 24H pattern of peaks (in the morning) and troughs (in the evening). The sinusoidal 24H IOP curve suggests a dynamic regulation of the variables in the Goldmann equation (aqueous production, outflow facility, and episcleral venous pressure). Indeed, it has been well recognized that aqueous production follows a circadian cycle [1–3], peaking during the diurnal period and with sleep deprivation [4, 5]. The stimulus for these rhythms likely comes from the hypothalamus and the photic-sensitive suprachiasmatic nucleus (SCN). Neuroendocrine signaling molecules such as norepinephrine and dopamine may regulate these rhythms. Still, the persistence of these rhythms in patients with Horner syndrome may indicate an additional source of biochemical regulation of aqueous flow.

■ ■

IOP is highest in the habitual positions during the nocturnal period Prostaglandin analogs and carbonic anhydrase inhibitors more effectively lower IOP during the nocturnal period than beta-adrenergic antagonists

The importance of 24H IOP, particularly the nocturnal (sleep) values, has not yet been elucidated. Nevertheless, IOP remains the only clinically modifiable risk factor for glaucoma. Moreover, a number of patients with statistically average or low IOPs show progression of glaucomatous optic neuropathy. Twenty-four-hour IOP studies have demonstrated a distinct difference in IOP curves in glaucoma relative to normal subjects [5, 6]. These studies suggest the possibility that a dysregulation of circadian rhythms that may control 24H IOP contribute to the development and worsening of glaucomatous optic neuropathy. Further, peak values of IOP achieved during the nocturnal period may have to be lowered to optimally prevent worsening glaucoma.

3.2

Normal IOP Curve

IOP is typically determined in an office setting using Goldmann applanation tonometry (GAT). The limitations of GAT, including the underestimation of IOP in patients with thin or less rigid corneas, have long been recognized. Only recently, however, has the importance of habitual positioning on the clinical measurement of IOP been quantified [7]. GAT is measured in a seated position. However, up to one-third of the day is spent in a recumbent position. Episcleral venous pressure (EVP) rises when recumbent, though autoregulatory

24

3

3 Circadian Changes in Intraocular Pressure

mechanisms may modify IOP changes related to body position. In a study of normal patients conducted at the Hamilton Glaucoma Center, University of California, San Diego, a sustained rise in IOP was noted during the nocturnal period (an 8 h period during sleep), which was partially explained by the change in body position from seated to supine (Fig. 3.1) [5, 7]. When IOPs were measured while subjects were in a supine position throughout the 24H study, the nocturnal rise in IOP, though present, fitted within a biphasic IOP curve with two peaks within 24H. The relationship of aqueous flow dynamics to 24H IOP remains unclear. Aqueous production is known to decrease by 50–60% at night [8]. However, IOP rises during the nocturnal period, partly due to positional changes [5, 7]. An increase in EVP may contribute to this rise [9]. However, when data is collected in a supine position over 24H, fluctuations in IOP are still present [5]. This underlying fluctuation in IOP suggests circadian control of IOP. This control is independent of ambient lighting and changes in corneal biomechanical properties [10, 11]. Animal studies also suggest that the nocturnal rise in IOP can be entrained by using light and dark stimuli [12]. One possible explanation for the 24H IOP measurements is that an IOP rise during the diurnal period is

related to an increase in aqueous production, while a rise in the nocturnal period is due to a decrease in outflow facility. Yet, the biochemical basis of a circadian rhythm in normal subjects remains unclear. In a rabbit study, aqueous norepinephrine (but not plasma melatonin) concentrations were correlated to rises in IOP during the nocturnal period [13]. Central control of circadian changes in IOP, however, can be altered. Lesions in the SCN significantly blunt the nocturnal IOP rise, suggesting that the hypothalamus regulates daily fluctuations in IOP [14]. Furthermore, mice that lack the expression of circadian clock genes no longer show circadian changes in IOP [15]. Yet, while the SCN may modulate 24H IOP fluctuation, animals recover a circadian pattern of IOP several weeks after SCN lesions, which may indicate compensatory sources of circadian control.

3.3 Sources of Circadian Control The primary regulator of circadian rhythms is the SCN, a paired nucleus located above the optic chiasm in the anterior hypothalamus. The SCN is entrained by photic stimuli detected by photoreceptors and transmitted as neural signals via the retinohypothalamic tract (Fig. 3.2).

Fig. 3.1 24H intraocular pressure (IOP) patterns in normal (open symbols) and glaucoma (filled symbols) patients. Untreated patients with glaucoma have a higher IOP in the seated (circles) and supine (triangles) positions than age-matched controls. A phase delay is present in glaucoma patients, with peak IOP occurring around 7:30 a.m. versus around 5:30 a.m. in normal subjects. Nocturnal IOP is higher than diurnal IOP, when seated, in both normal and glaucoma patients, due partially to a change in body position from seated to supine

3.4 Glaucoma and 24-Hour IOP

These neural signals activate the expression of clock-controlled genes that regulate the release of endocrine and paracrine factors. Recent evidence suggests that circadian clocks also exist in several peripheral tissues and cells [16, 17]. These peripheral oscillators are kept in phase by the SCN. Circadian control of IOP, however, can continue after superior cervical ganglionectomy [18] and ablation of the SCN [14], suggesting an additional source of circadian control of aqueous flow. Aqueous secretion is primarily controlled by the nonpigmented ciliary body epithelium, which shows some neuroendocrine activity. This has led some to believe that the ciliary body is a peripheral oscillator with endocrine and paracrine secretions that may produce circadian variations in aqueous production as well as changes in trabecular outflow facility [16]. According to this hypothesis, the function of trabecular meshwork cells is regulated in part by factors secreted by ciliary processes into the aqueous humor. If ciliary body epithelial cells release hormones and neuropeptides under circadian control, the aqueous concentrations of specific biomolecules would vary based on time of day. Indeed, overall protein concentration in

25

12H light/12H dark entrained rabbits increases during the entrained diurnal period, even when kept in constant darkness [19]. Aqueous concentrations of melatonin and norepinephrine, however, increase with IOP at night [13]. In rabbits, the IOP increase at the onset of dark is due to the activity of ocular sympathetic nerves [20]. This IOP elevation can be modulated by short-wavelength light [21]. Laboratory evidence thereby indicates that at least a component of IOP is under central control, oscillates over approximately 24H, can be entrained with light stimuli, and is correlated with changes in aqueous concentration of neuroendocrine products. Sources of circadian control of outflow facility, however, are yet to be determined.

3.4

Glaucoma and 24-Hour IOP

Several changes occur in the 24H IOP curve in normal relative to untreated glaucoma (OAG) patients [6]. Nocturnal IOP remains higher than diurnal IOP, as in normal subjects, but the magnitude of this change is diminished. A peak IOP delay is present in the OAG group as well,

Fig. 3.2 Putative pathway for circadian IOP control. (1) External light is detected by retinal photoreceptors and a signal is transmitted to retinal ganglion cells. (2) These signals are transmitted to the suprachiasmatic nucleus (SCN), which is entrained to a 24H light/dark cycle. Clock-controlled gene expression is adjusted within the SCN, which regulates the expression of endocrine and paracrine secretions. Sympathetics then transmit this signal to end-organs. (3) Ocular sympathetics are stimulated via the superior cervical ganglion to the long posterior ciliary nerve. (4) The long posterior ciliary nerve may regulate the function of the ciliary body, including control of aqueous flow and the release of neuroendocrine factors, which may affect trabecular outflow facility. Circadian changes in aqueous flow and outflow facility lead to fluctuations in IOP

26

3

3 Circadian Changes in Intraocular Pressure

with peak supine IOP at 7:30 a.m. in OAG. Normal subjects experience a peak approximately 2 h earlier, followed by a net IOP decline (Fig. 3.1). The net effect is a 4-h phase delay in the 24H IOP curve in OAG relative to normal. While the cause of this phase delay remains unclear, alterations in 24H IOP regulation may be related to early pathogenesis of glaucoma. The prevailing explanations for differences in early morning IOP curves in normal versus OAG patients involve either a decrease in outflow facility or an increase in aqueous production in the latter group [22]. Aqueous flow dynamics are altered in OAG, with a relatively higher flow rate at night versus normal based on fluorophotometry studies [23]. While this relative increased flow rate alone probably does not account for an increase in IOP, a decrease in outflow facility in conjunction with this change may account for experimental 24H IOP data. Several pathophysiologic responses may account for changes in outflow facility and trabecular function [24]. Trabecular meshwork cells are known to be steroid-sensitive [25] and therefore susceptible to increases in plasma glucocorticoid activity prior to awakening. The MYOC gene, which accounts for 3–4% of OAG cases, is particularly steroid-sensitive [26]. Circadian control of specific genes and cell products that may affect outflow facility is actively being investigated. Targeted modification of trabecular function based on these findings may be a promising area of future therapy [27]. Still, a recent study suggests that nocturnal changes in EVP or uveoscleral flow may also have to be altered to account for absolute changes in IOP [28].

3.5

Medical Management of 24-Hour IOP

Current treatment standards may need to be re-evaluated based on 24H IOP studies. Despite clear evidence for a nocturnal elevation in IOP in many individuals, it is not clear how such short-term fluctuations in IOP (changes over a 24H period) may impact the pathogenesis of glaucoma. While mean IOP and peak IOP are known risk factors for glaucoma progression, short-term fluctuation of IOP plays an unclear role [29, 30]. Several physiologic parameters apart from IOP change during the 24H period, including ocular blood flow. As optic nerve perfusion pressure is directly correlated with blood flow (which decreases at night) and IOP (which increases at night), glaucoma pathogenesis may be related to a dysregulation of one or both of these variables [31]. The correlation of short-term fluctuation in IOP and disease progression in patients with statistically low IOPs may be coincident to changes in ocular blood flow.

Loss of autoregulatory mechanisms that maintain optic nerve perfusion pressure may also account for worsening of glaucoma. Further study is needed to determine the exact role of elevated nocturnal IOP in glaucoma pathogenesis. The 24H efficacies of several different topical medications have now been evaluated prospectively. 24H data indicate that beta-adrenergic antagonists have a minimal nocturnal effect, while prostaglandin analogs such as latanoprost and travoprost have both a nocturnal and a diurnal effect in habitual positions (Fig. 3.3) [32–34]. The limited nocturnal effect of beta-blockers is related to the low aqueous humor flow rate at night. Prostaglandin analogs may be effective over 24H because uveoscleral outflow is IOP-independent. The IOP-reducing effect of prostaglandin analogs is also sustained over 48 h [34]. Carbonic anhydrase inhibitors are also effective during the nocturnal period [35], though the basis of a 24H effect is unclear. These medication studies suggest that nocturnal IOP reduction may require a change in outflow facility. Indeed, the ability of laser trabeculoplasty to lower nocturnal IOP is consistent with the hypothesis that nocturnal IOP increases due to an increase in outflow resistance [36]. Optimal dosing of medications as well as the choice of IOP-lowering therapy may in the future account for their 24H effect. Nighttime dosing of beta-blockers, for example, may be unnecessary, while a carbonic anhydrase inhibitor may be a reasonable second-line treatment to improve 24H IOP control. Prostaglandin analogs, when tolerated, have the strongest evidence for a 24H IOPlowering effect. Until routine clinical measurement of 24H IOP is practical, the importance of 24H IOP reduction remains unclear for each individual patient. A clinician should, however, understand how well clinical measurements of IOP correlate with IOP in habitual positions. It recently has been suggested that peak nocturnal IOP can be estimated using office measurements [37]. This calculation requires measurement of a diurnal IOP curve, which can be time-consuming. Interestingly, single IOP measurements alone correlate only moderately well with peak nocturnal IOP in the same eye and poorly with between-eye IOP. Accurate monocular drug trials may therefore require calculation of, at the minimum, a diurnal IOP curve [38]. A recent study has also shown that the transient elevation of IOP during the waterdrinking test [39] may correlate with peak 24H IOP and may serve as a more practical method of estimating peak IOP [40]. Further study is needed to determine the true value of the water-drinking test in predicting circadian variability in IOP.

DIURNAL / WAKE

NOCTURNAL/ SLEEP

3:30 PM

11:30 PM

References

27

DIURNAL / WAKE

28

Supine IOP (mmHg)

26 24 22 20 18 16

1:30 PM

11:30 AM

9:30 AM

7:30 AM

5:30 AM

3:30 AM

1:30 AM

9:30 PM

7:30 PM

5:30 PM

14

Clock Time Fig. 3.3 24H supine IOP patterns on glaucoma monotherapy. Topical latanoprost (filled squares) causes a uniform decrease in IOP during the diurnal and nocturnal periods relative to untreated controls (open circles). Timolol (filled triangles) causes a significant decrease in diurnal IOP, with no significant nocturnal effect

Summary for the Clinician ■ ■

■

■

Circadian rhythms control aqueous production and may control outflow resistance. Aqueous production peaks in the diurnal period, while IOP rises at night. This rise in IOP during the nocturnal period may be associated with a decrease in trabecular outflow facility, though the predominant cause of a rise in nocturnal IOP is supine positioning. Certain IOP-lowering therapies, such as prostaglandin analogs, carbonic anhydrase inhibitors and laser trabeculoplasty, may be more effective at lowering 24H IOP than beta-adrenergic antagonists. Diurnal IOP curves allow for an estimation of peak IOP at night. However, as short-term fluctuations in 24H IOP as well as peak IOP have not been clearly correlated to worsening of disease, the importance of 24H IOP in glaucoma progression remains unclear.

References 1. Reiss GR, Lee DA, Topper JE, Brubaker RF (1984) Aqueous humor flow during sleep. Invest Ophthalmol Vis Sci 25(6):776–778

2. Smith SD, Gregory DS (1989) A circadian rhythm of aqueous flow underlies the circadian rhythm of IOP in NZW rabbits. Invest Ophthalmol Vis Sci 30(4):775–778 3. Maus TL, Young WF, Jr., Brubaker RF (1994) Aqueous flow in humans after adrenalectomy. Invest Ophthalmol Vis Sci 35(8):3325–3331 4. Gherghel D, Hosking SL, Orgul S (2004) Autonomic nervous system, circadian rhythms, and primary open-angle glaucoma. Surv Ophthalmol 49(5):491–508 5. Liu JH, Kripke DF, Twa MD, et al. (1999) Twenty-four- hour pattern of intraocular pressure in the aging population. Invest Ophthalmol Vis Sci 40(12):2912–2917 6. Liu JH, Zhang X, Kripke DF, Weinreb RN (2003) Twentyfour-hour intraocular pressure pattern associated with early glaucomatous changes. Invest Ophthalmol Vis Sci 44(4):1586–1590 7. Liu JH, Kripke DF, Hoffman RE, et al. (1998) Nocturnal elevation of intraocular pressure in young adults. Invest Ophthalmol Vis Sci 39(13):2707–2712 8. Brubaker RF (1998) Clinical measurement of aqueous dynamics: implications for addressing glaucoma. In Civan MM ed. The Eye ’s Aqueous Humor from Secretion to Glaucoma. Current Topics in Membranes, 45:233–284, Academic Press, New York 9. Friberg TR, Sanborn G, Weinreb RN (1987) Intraocular and episcleral venous pressure increase during inverted posture. Am J Ophthalmol 103(4):523–526 10. Kida T, Liu JH, Weinreb RN (2006) Effect of 24-hour corneal biomechanical changes on intraocular pressure measurement. Invest Ophthalmol Vis Sci 47(10):4422– 4426

28

3

3 Circadian Changes in Intraocular Pressure

11. Liu JH, Kripke DF, Hoffman RE, et al (1999) Elevation of human intraocular pressure at night under moderate illumination. Invest Ophthalmol Vis Sci 40(10):2439–2442 12. Liu JH (1998) Circadian rhythm of intraocular pressure. J Glaucoma 7(2):141–147 13. Liu JH, Dacus AC (1991) Endogenous hormonal changes and circadian elevation of intraocular pressure. Invest Ophthalmol Vis Sci 32(3):496–500 14. Liu JH, Shieh BE (1995) Suprachiasmatic nucleus in the neural circuitry for the circadian elevation of intraocular pressure in rabbits. J Ocul Pharmacol Ther 11(3):379–88 15. Maeda A, Tsujiya S, Higashide T, et al. (2006) Circadian intraocular pressure rhythm is generated by clock genes. Invest Ophthalmol Vis Sci 47(9):4050–4052 16. Coca-Prados M, Escribano J (2007) New perspectives in aqueous humor secretion and in glaucoma: the ciliary body as a multifunctional neuroendocrine gland. Prog Retin Eye Res 26(3):239–262 17. Zylka MJ, Shearman LP, Weaver DR, Reppert SM (1998) Three period homologs in mammals: differential light responses in the suprachiasmatic circadian clock and oscillating transcripts outside of brain. Neuron 20(6):1103–1110 18. Braslow RA, Gregory DS (1987) Adrenergic decentralization modifies the circadian rhythm of intraocular pressure. Invest Ophthalmol Vis Sci 28(10):1730–1732 19. Liu JH, Lindsey JD, Weinreb RN (1998) Physiological factors in the circadian rhythm of protein concentration in aqueous humor. Invest Ophthalmol Vis Sci 39(3):553– 558 20. Gallar J, Liu JH (1993) Stimulation of the cervical sympathetic nerves increases intraocular pressure. Invest Ophthalmol Vis Sci 34(3):596–605 21. Liu JH, Shieh BE, Alston CS (1994) Short-wavelength light reduces circadian elevation of intraocular pressure in rabbits. Neurosci Lett 180(2):96–100 22. Linner E (1957) The effect of prednisolone on aqueous humor dynamics. Acta Soc Med Upsaliensis LXII:186 23. Larsson LI, Rettig ES, Brubaker RF (1995) Aqueous flow in open-angle glaucoma. Arch Ophthalmol 113(3):283– 286 24. Caballero M, Rowlette LL, Borras T (2000) Altered secretion of a TIGR/MYOC mutant lacking the olfactomedin domain. Biochim Biophys Acta 1502(3):447–460 25. Weinreb RN, Bloom E, Baxter JD, et al. (1981) Detection of glucocorticoid receptors in cultured human trabecular cells. Invest Ophthalmol Vis Sci 21(3):403–407 26. Rozsa FW, Reed DM, Scott KM, et al. (2006) Gene expression profile of human trabecular meshwork cells in response to long-term dexamethasone exposure. Mol Vis 12:125–141 27. Ferrer E (2006) Trabecular meshwork as a new target for the treatment of glaucoma. Drug News Perspect 19(3): 151–158

28. Sit AJ, Nau CB, McLaren JW, et al. (2008) Circadian variation of aqueous dynamics in young healthy adults. Invest Ophthalmol Vis Sci 49(4):1473–1479 29. Bengtsson B, Heijl A (2005) Diurnal IOP fluctuation: not an independent risk factor for glaucomatous visual field loss in high-risk ocular hypertension. Graefes Arch Clin Exp Ophthalmol 243(6):513–518 30. Asrani S, Zeimer R, Wilensky J, et al. (2000) Large diurnal fluctuations in intraocular pressure are an independent risk factor in patients with glaucoma. J Glaucoma 9(2):134–142 31. Choi J, Kim KH, Jeong J, et al. (2007) Circadian fluctuation of mean ocular perfusion pressure is a consistent risk factor for normal-tension glaucoma. Invest Ophthalmol Vis Sci 48(1):104–111 32. Liu JH, Kripke DF, Weinreb RN (2004) Comparison of the nocturnal effects of once-daily timolol and latanoprost on intraocular pressure. Am J Ophthalmol 138(3):389–395 33. Mishima HK, Kiuchi Y, Takamatsu M, et al. (1997) Circadian intraocular pressure management with latanoprost: diurnal and nocturnal intraocular pressure reduction and increased uveoscleral outflow. Surv Ophthalmol 41(Suppl 2):S139–144 34. Sit AJ, Weinreb RN, Crowston JG, et al. (2006) Sustained effect of travoprost on diurnal and nocturnal intraocular pressure. Am J Ophthalmol 141(6):1131–1133 35. Orzalesi N, Rossetti L, Invernizzi T, et al. (2000) Effect of timolol, latanoprost, and dorzolamide on circadian IOP in glaucoma or ocular hypertension. Invest Ophthalmol Vis Sci 41(9):2566–2573 36. Lee AC, Mosaed S, Weinreb RN, et al. (2007) Effect of laser trabeculoplasty on nocturnal intraocular pressure in medically treated glaucoma patients. Ophthalmology 114(4):666–670 37. Mosaed S, Liu JH, Weinreb RN (2005) Correlation between office and peak nocturnal intraocular pressures in healthy subjects and glaucoma patients. Am J Ophthalmol 139(2):320–324 38. Sit AJ, Liu JH, Weinreb RN (2006) Asymmetry of right versus left intraocular pressures over 24 hours in glaucoma patients. Ophthalmology 113(3):425–430 39. Susanna R, Medeiros FA, Vessani RM (2001) Correlation between intraocular pressure peaks in the diurnal tension curve and in the water-drinking test. Invest Ophthalmol Vis Sci 42:S558 40. Hu WD, Medeiros FA, Alencar LM, et al. (2008) The correlation between the water drinking test and 24-hour intraocular pressure measurements in glaucomatous eyes (Abstract 1273). In: Program and Abstracts of the Association for Research in Vision and Ophthalmology 2007 Meeting, Fort Lauderdale, FL, USA, 6–10 May 2007

Chapter 4

Detecting Glaucoma Progression by Imaging

4

Nicholas G. Strouthidis, David F. Garway-Heath

Core Messages ■

■

■

■

Measuring disease progression is vital in the management of patients with glaucoma and ocular hypertension. Progression may be assessed by structure (optic disc photography or semi-automated imaging devices) and function (perimetry). Progression strategies may be subdivided into “event analyses” (progression requires a predetermined threshold to be exceeded) and “trend analyses” (the behaviour of the parameter over time is monitored). Stereophotographic examination is prone to high inter-observer variability.

4.1

Introduction

4.1.1 The Principles of Progression The ability to monitor disease progression is central to the management of the patient with established glaucoma or who is perceived to be at risk of glaucoma, particularly the ocular hypertensive. Such monitoring affords the clinician the potential to assess the patient’s immediate and long-term risk of functionally significant visual loss, as well as the effectiveness of any treatment intervention. As glaucoma is an optic neuropathy associated with characteristic visual field deficits, one can monitor disease progression according to both functional changes and structural changes at the optic nerve head and retinal nerve fibre layer. In current clinical practice, functional progression is monitored by static automated perimetry. The characteristic features of glaucomatous optic neuropathy are discernible by careful examination using indirect ophthalmoscopy, as are nerve fibre layer changes, assisted by red-free illumination. However, clinical examination is prone to wide inter-observer variation, even amongst experienced observers, and does not allow quantitative

■

■

■

■

Amongst imaging devices, the HRT has the most published longitudinal data, as it has been commercially available for the longest time and its software is “backward compatible”. Two progression algorithms are currently available in the HRT software: “trend analysis” and “topographical change analysis”. To date there are no statistically supported progression algorithms in the OCT or GDx-VCC operational software. There is poor concordance between HRT and visual field progression. The reasons for this remain unclear.

comparison [20]. Such a subjective method is suboptimal for longitudinal disease assessment. A degree of objectivity and the potential to quantify change are possible by using optic nerve head photography and, more recently, automated optic nerve head imaging devices. As yet, no consensus exists regarding the best method of assessing structural changes in glaucoma (as is the case for visual field changes). The ideal method will utilise a technology that can reliably discriminate true change secondary to disease progression from observer and measurement variability. As with measuring visual field progression, there are two broad strategies for monitoring change over time— event analyses and trend analyses. Event analyses classify change as occurring when the measurement exceeds a predetermined threshold. Visual field strategies of this type have been utilised in a number of clinical trials of glaucoma [1, 15, 23]; they are particularly useful for clinical trials as they give a binary outcome—either “change” or “no change”. A major disadvantage of event analyses is that they do not allow a measurement of “rate of change”, which is possible using trend analyses. Trend analyses monitor the behaviour of a test parameter over time; the

30

4 Detecting Glaucoma Progression by Imaging

best-known application of this technique in the milieu of visual fields is pointwise linear regression of sensitivity over time [14].

4 4.1.2

Historical Perspective: Optic Nerve Head Photography

Optic nerve head photography is the longest established and most widely available imaging technology. It relies on the observer’s subjective interpretation of the photograph, without recourse to analysis software (unlike the newer imaging devices). It is the only full-colour imaging technology, and allows a number of glaucomatous features (such as peripapillary atrophy and disc haemorrhages) to be detected that are not readily detected by automated imaging technologies. Optic nerve head photographs may be monoscopic or stereoscopic; the latter is preferred, as it achieves better inter-observer agreement [22]. Stereoscopic images may be acquired simultaneously or sequentially. Simultaneous stereophotographs are preferred as they are associated with more reliable determinations of rim loss and cup depth than sequential acquisitions [4, 22]. The assessment of progression from photographs is subjective, although in trained hands the sensitivity and agreement is fair. In OHTS, the independent optic disc reading centre was used to grade glaucomatous change in stereophotographs over time. The inter-observer agreement for detecting glaucomatous disc change by masked graders in that study has been reported as “good to excellent”, with kappa values in the range of 0.65–0.83, specificity from 98 to 100%, and sensitivity from 64 to 81% [26], comparing favourably with other masked grading studies [3, 6, 11, 37]. However the sensitivity of the masked graders—estimated from the number of stereophotographs correctly “regraded” as not demonstrating deterioration in OHTS—was poor: as low as 64% after the first year of the study [26]. This highlights the marked difficulties encountered in trying to consistently detect the small optic disc changes that occur at the earliest stages of glaucoma and ocular hypertension, despite having experienced graders and a robust protocol. Optic nerve head photography is limited by its reliance on the judgements of expert observers or trained graders. This is not the case with the newer, automated, optic nerve head imaging devices; in an animal model of glaucoma, confocal scanning laser tomography had greater sensitivity (with high specificity) for detecting surface change than expert clinicians viewing stereophotographs [12]. There are no reports of the ability of non-expert observers to identify progression using optic nerve photographs.

The greatest barrier to the routine use of optic nerve head photographs in clinical practice is the lack of appropriate viewing systems. New technology is becoming available that permits the viewing of stereoscopic photographs in three dimensions on the computer screen [22]. Retinal nerve fibre layer photographs may also be used to detect progression [6, 29]; however, this technique is perhaps too technically difficult and time-consuming to be used in routine clinical practice.

4.1.3 The Potential of Optic Nerve Head Imaging Devices Given the variability between observers in stereophotograph evaluation, automated imaging devices present an attractive proposition, with the potential for high intertest repeatability and the capacity to generate quantification data, both of which would be advantageous in the detection of structural progression. At the time of writing, three devices, each of which employs a different technology, are pre-eminent. These devices are: the Heidelberg retina tomograph (HRT, Heidelberg Engineering, GmbH, Heidelberg, Germany), which employs confocal scanning laser ophthalmoscopy; the GDx-VCC (Carl Zeiss Meditec, Dublin, CA, USA), which employs scanning laser polarimetry; and the optical coherence tomography scanner (OCT, Carl Zeiss Meditec, Dublin, CA, USA), which employs low-coherence interferometry. A detailed description of each technology is beyond the scope of this chapter. As the HRT has been available in the clinical setting for approximately 15 years, more longitudinal patient data are available for it than for the other two devices. As such, the HRT’s role in the identification of disease progression is established, with algorithms being available in the operational software and a number of other progression techniques proposed in the literature.

Summary for the Clinician ■

■

■

Documentation of the clinical examination of the disc in the patient’s records is not sufficient to monitor structural progression reliably Stereophotographic disc photographs have a proven track record in clinical trials, although their use in clinical practice is very much experiencedependent Semi-automated optic nerve head imaging devices such as the HRT, OCT and GDx-VCC have great potential in the monitoring of glaucomatous progression

4.2 HRT

4.2 4.2.1

HRT HRT Progression: Available Techniques

There are two progression algorithms native to the HRT3 software, “trend analysis” and “topographical change analysis” (TCA) [16]. The trend analysis compares the values at follow-up to those at baseline for global and stereometric summary indices. This is illustrated graphically as the normalised change from baseline over time. Normalisation is performed to enable the same scaling of change for each parameter from +1 (maximum improvement) to −1 (maximum deterioration). Normalisation is achieved by using the ratio of the difference between a given value and baseline to the difference between the average value in a normal eye and in an eye with advanced glaucoma [7]. The trend analysis is therefore interpreted in terms of empirical values; a formal regression analysis giving a quantified rate of change over time is not performed. It is also interesting to note that, to date, there are no studies in the literature that have used this technique. TCA examines changes in the topographical height of the HRT image at the superpixel level [8], the height of a pixel being measured from the mean height of the peripheral reference ring (Fig. 4.2). Superpixels are discrete areas of the ONH image measuring 4 × 4 pixels; there are 64 × 64 superpixels within a topography image. TCA quantifies the change within the disc margin contour. The key determinant in TCA is the variability in topographical height values within the superpixel over the two sets of three images (single topography images) taken at baseline and at follow-up. The statistical method estimates the probability of the value of the difference in height between images occurring by chance alone. Where p < 0.05, the probability is low and the change is therefore unlikely to be due to chance and is ascribed to glaucoma. Where the variability is high between images, which typically occurs at the edge of the cup and along blood vessels, a much greater difference in height values needs to be identified to reach significance. TCA generates a “change probability map”—the reflectivity map is overlaid with colour-coded pixels, red pixels representing significant height depression and green pixels representing significant elevation. In the current software, for two followup images, superpixels will be flagged as significant in the second follow-up if the change occurs in both images. For three follow-up images, superpixels are flagged as significant if the change occurs in all three follow-ups. Finally, for more than three follow-ups, the change needs to be observed in at least three of the last four images. In two longitudinal studies, the criterion

31

for progression by TCA was based on empirical data from normal subjects, whereby less than 5% of normal controls have greater than 20 significantly depressed superpixels within the optic disc margin [9, 24]. Progression was therefore identified when clusters of 20 or more significantly depressed superpixels within the disc margin were observed in three consecutive images. In a later study, the same group defined criteria for change by expressing the size of the largest cluster of depressed superpixels within the disc as a percentage of the total number of superpixels within the contour line, thereby accounting for variability in optic disc size [2]. In the HRT-3 software, the TCA report (an example of which is shown in Fig. 4.1) shows a “trend analysis of the cluster defect”. This enables the change of area and volume of a selected cluster to be monitored over time, allowing some scope to quantify the change over time observed using TCA. A recent study has compared the ability of TCA (HRT-II software) to identify disease progression with expert assessment of optic disc stereophotographs [19]. A 65% concordance was observed between TCA and stereophotographic assessment; 30% of subjects progressed by TCA alone and 6% progressed by photographs alone. It is likely that the discrepancy between techniques is a reflection of the fact that both techniques are examining different aspects of structural progression. Stereophotographic assessments examine a number of features, such as rim loss, presence or absence of splinter haemorrhages and nerve fibre layer defects, which are not specifically picked up by TCA. The TCA, on the other hand, is looking for surface changes or deformation, which is not easy to identify in stereophotographic examination. It is therefore plausible that some of the subjects identified as progressing by TCA and not by photographs demonstrated genuine disease progression—suggesting that the two techniques should be used in a complementary fashion.

4.2.2

HRT Progression: Stereometric Parameter vs. Pixel-Based Techniques

A number of different progression algorithms have been proposed in the literature for the HRT which are yet to be incorporated into the operational software. The majority of these strategies have focussed— unlike TCA, which assesses topographical height change—on the assessment of stereometric parameter change. TCA has the advantage of being able to identify surface height changes across the entire ONH

32

4 Detecting Glaucoma Progression by Imaging

HEIDELBErG ENGINEERING

Heidelberg Retina Tomograph TCA Overview Patient: Sex: male DOB: 05/Jan/1953 Pat-ID: 362628 Ethnicity: (Caucasian) Examination:

OS

Baseline: 29/Nov/1994 Last Follow-Up: 13/Aug/2007 Elapsed: 152 months

400 4x

3.0

300

2.0

200

1.0

100

0.0

01/98 01/99 Total Size Change

01/00

01/01

01/02 01/03 01/04 Examination Date

01/05

01/06

[1/1000 mm3]

4.0 2x

[mm2]

4

0

01/07 01/08 Total Volume Change

Baseline: 29/Nov/1994

Follow-Up: #11, 23/Jul/2001

Follow-Up: #12, 21/Jul/2003

Follow-Up: #13, 02/Feb/2004

Follow-Up: #14, 09/Aug/2004

Follow-Up: #15, 07/Feb/2005

Follow-Up: #16, 08/Aug/2005

Follow-Up: #17, 10/Jan/2006

Follow-Up: #18, 28/Mar/2006

Follow-Up: #19, 17/Jul/2006

Fig. 4.1 Topographical change analysis output demonstrating progressive superpixel height depression (red superpixels) within the left optic disc of an ocular hypertensive subject

4.2 HRT

Elschnig’s ring

33

Elschnig’s ring

Reference ring

Retinal surface

320 microns Reference plane

The standard reference plane is set 50 microns below the temporal disc edge

Neuroretinal rim

Fig. 4.2 Position of the HRT standard reference plane. The 320 reference plane is located 320 µm posterior to the reference ring, which is located in the image periphery (top right inset)

and parapapillary surface. However, it is difficult to quantify change in a way that translates into a clinically understandable phenomenon, such as neural rim narrowing or notching. Stereometric parameters, on the other hand, give numerical values to clinically recognisable features. The majority of stereometric parameters—particularly those relating to cup and rim dimension—are easily comprehensible to the glaucoma clinician. In two separate assessments of HRT test-retest variability [30, 35], rim area has been found to be the most repeatable and reliable parameter, and may therefore be a suitable metric for monitoring disease progression. A criticism of the use of stereometric parameters is that their magnitude and variability are dependent on the position of the disc margin contour line (which is operator-dependent) and the position of the reference plane (which is not the case for TCA, which instead depends on the height of the more stable peripheral reference ring). The reference plane is located parallel to and below the retinal surface within the threedimensional optic nerve image, and is used to delineate structures within the disc margin above as neuroretinal rim and below as cup (Fig. 4.2). Most stereometric parameter values are dependent on the position of the reference plane; a deeply placed plane generates a smaller cup and a greater rim, whereas a superficially placed plane generates a greater cup and a smaller rim. Disc area, height variation contour and cup shape

measure are parameters which are independent of reference plane. The standard reference plane is the default plane in the Heidelberg software. It is located 50 µm below the contour line at the temporal disc margin, between −10 and −4°. The choice of location was based on the mean surface inclination angle of the optic nerve head and because it coincides with the papillomacular bundle [5]. It was assumed that the papillomacular bundle maintains a stable thickness, as central visual acuity is not affected until the latter stages of glaucoma. This has not been supported by OCT studies, which demonstrate reduced bundle thickness in glaucoma despite maintenance of good visual acuity [10]; it is therefore likely that the reference plane height changes as glaucoma progresses. An alternative reference plane, at 320 µm, has been shown to generate less variable rim area measurements than the standard reference plane [31]; it may therefore be a more appropriate option for discriminating true structural change from measurement “noise”. This plane has a fixed offset situated 320 µm posterior to the reference ring located in the image periphery. This reference plane has the advantage of greater stability, but it may not be appropriate for use in discs with oblique insertions, where the difference between the retinal height and the cup level may exceed 320 µm. Also, disease processes occurring outside the disc margin, such as peripapillary atrophy, may influence measurements.

34 4.2.3

4

4 Detecting Glaucoma Progression by Imaging

HRT Progression: Stereometric Parameter Event Analyses

The first indication that the HRT could be used to identify glaucomatous changes utilised stereometric parameters [17]. This study was the first to demonstrate that the HRT could identify structural changes prior to the identification of repeatable glaucomatous field loss, thereby highlighting the great clinical potential of ONH imaging devices in the monitoring of glaucomatous progression. The investigators compared sequential HRT images acquired one year apart from two cohorts: a cohort of 13 eyes of 11 normal control subjects and a cohort of 13 eyes from 13 ocular hypertensive subjects who developed repeatable glaucomatous VF loss at a date subsequent to their second HRT image. The Wilcoxon signed-rank statistical test was used to identify whether a significant change in stereometric parameters had occurred between the first and second image acquisitions. No significant global or segmental parameter changes were identified in the control cohort. In the ocular hypertensive cohort, significant (p < 0.05) changes were identified in global and superior sector rim area. The technique was subsequently refined by estimating 95% confidence limits for change in sequential HRT images acquired from normal control eyes, which was used as an estimate of normal measurement variability [18]. The 95% normal variability limits were used to define thresholds for glaucomatous change within stereometric parameters, whereby any change exceeding the limits was ascribed to glaucomatous damage and within the limits as measurement noise. A potential shortcoming of this approach is that the limits of variability to identify change were based on the test-retest variability of a cohort of normal subjects. As some individuals may have greater measurement variability than others, limits of variability derived from a population may not be suitable for all individuals. In this context, it may be more appropriate to identify variability limits for each individual subject. Tan and Hitchings derived limits for change for individual ONHs based on the RA variability between each of the single topography images used to construct the mean topography image [33]. Limits of variability were calculated for 30° disc sectors from the standard deviation of all possible permutations of paired intra-visit (between single topographies) rim area differences. In the initial description of this technique, limits of variability were defined at p < 0.05, equivalent to a 95% confidence limit. In a longitudinal HRT image series, when the rim area value for a particular 30° sector exceeds the sector’s variability limits for that series, this was defined as “tentative progression”.

“Definite progression” required confirmation in at least two out of three consecutive tests, thereby accounting for spurious change or potential reversal on subsequent testing. This approach yielded a sensitivity of 85% and specificity (1 – false positive rate) of 95% when performed using HRT series acquired from 20 ocular hypertensive subjects demonstrating glaucomatous field conversion and 20 normal control subjects. The 95% statistical limit and two-of-three confirmatory criterion were subsequently shown to be optimal in terms of sensitivity and false-positive rate compared to alternative statistical limits (80%, 90%, 99%) and different confirmatory permutations (single test, two-of-two consecutive tests, three-of-three consecutive tests, two adjacent sectors in a single test, two adjacent sectors in two-of-three consecutive tests) yielding a sensitivity of 83.3% and a false positive rate of 3.1% [34]. More recently, Fayers et al. have defined criteria for rim area change according to ONH sector rim area repeatability coefficients for images acquired on different occasions by different individuals [13]. These repeatability coefficients were calculated using data derived from a test-retest study of HRT imaging [30]. Ninety-five percent of repeated measurement differences are within the value of the repeatability coefficient; larger differences are likely to be outside expected measurement error. As with the technique proposed by Tan previously [34], the specificity of this technique was improved by incorporating confirmatory testing, in particular a “two-ofthree” strategy. Estimated specificity was also improved by requiring change to be confirmed in more than one HRT ONH sector. A unique feature of this event analysis is that image quality (as measured by mean pixel height standard deviation) is taken into consideration, with different repeatability coefficients applied to each sector according to the level of image quality (good, medium and poor quality).

4.2.4

HRT Progression: Stereometric Parameter Trend Analyses

Artes and Chauhan have described a trend analysis in which a Spearman rank correlation is performed on a longitudinal series of ONH sector rim area values [2]. The statistical rationale for this approach is that the Spearman rank correlation identifies the likelihood that the slope generated from the sequence of observed sector rim area values over time occurred by chance in a random sequence. The significance values for the four HRT sectors were graded according to level of significance and

4.3 Detecting Progression by GDx-VCC

were summated to give an overall “evidence of change” score. In that particular study, the evidence of change score was used to allow an objective comparison between different tests: HRT, static automated perimetry and high-pass resolution perimetry. A similar statistical approach (with similar results) was employed by Strouthidis et al., who assessed rim area change by performing a linear regression analysis of rim area over time [32]. The progression criteria (p-value of slope of rim area/time) were tailored according to the variability of the image series such that highly variable series required tighter criteria than less variable series. The technique is somewhat limited by the fact that the definition of image variability was based on the range of variability of the tested population—a cut-off at the 50th centile defined high or low variability. It is uncertain whether these cut-offs would be valid for a different population, and the technique has yet to be validated in an independent patient group. Linear regression of rim area over time is, however, easily applied and well understood, given that it parallels the technique of pointwise linear regression of visual field sensitivity over time.

4.2.5

HRT Progression: Pixel-Based Technique

Statistical image mapping (SIM) is an established technique in the radiology milieu, being used for the analysis of three-dimensional images of the brain acquired using positron emission tomography and magnetic resonance imaging. The methodology has been applied to HRT image series, with promising results [27]. SIM estimates topographic change by the linear regression of the topographical height of each pixel within the disc over time. This generates a test statistic summarising the amount of change at each pixel. The sequence of images is then shuffled in a permutation analysis, and the test statistic is recalculated for each pixel; this step is repeated a number of times, using a unique reordering sequence on each occasion. A distribution of test statistics is therefore generated for each pixel. Significant change is identified by comparing the observed test statistic to the test statistical distribution for that pixel. A pixel is flagged as “active” if it exceeds the 95th percentile (p < 0.05). A global probability value for the entire image series is derived by comparing the largest cluster of active pixels in the observed image series to the permuted distribution of largest clusters. When applied to simulated and real longitudinal HRT data, SIM performed favourably compared to TCA in detecting change.

35

Summary for the Clinician ■

■

■

As the HRT has been available for over a decade, and its hardware and software are backward compatible, it is possible to assess long temporal series of HRT images Assessment of HRT images over time has been shown to identify progression prior to visual field progression in some patients, although visual field progression may occur in the absence of detectable change in HRT images A number of HRT event and trend analyses have been described, although there is no clear consensus as to which technique is optimal for the detection of progression

4.3 Detecting Progression by GDx-VCC As previously stated, the majority of published data relating to longitudinal imaging in glaucoma has been obtained using the HRT. There is currently a paucity of longitudinal data for the GDx because of major alterations in the image acquisition technology (with the introduction of variable corneal compensation) and upgrades to the analysis software. As a consequence, historical images acquired prior to the introduction of variable corneal compensation cannot be analysed meaningfully using the most recent software editions. However, it is clear that the GDx-VCC has the potential to be a useful tool in the monitoring of structural progression because it has been proven to be a highly reproducible device, and the structural correlates assessed (principally nerve fibre layer polarizing properties) are known to alter in progressive glaucoma. In a recent study, long- and short-term variability of GDx-VCC measurements were assessed in a cohort of glaucoma “suspects” known to have stable visual fields over a nine-year follow-up [21]. Long-term variability was slightly higher than short-term variability, but the long-term variability estimates for RNFL thickness parameters ranged from 3.21 to 4.97 µm and are sufficiently low for the nerve fibre indicator (4.93) to support the use of the GDx-VCC for the longitudinal assessment of disease progression. The current software does not have statistically guided glaucoma progression algorithm. Despite this, it is possible to identify progressive nerve fibre layer loss “empirically” in serial GDx-VCC imaging (Fig. 4.3). At the time of writing, however, the introduction of a glaucoma progression analysis tool into the GDx-VCC software is planned

36

4 Detecting Glaucoma Progression by Imaging

4

Fig. 4.3 An example of progressive nerve fibre loss identified by serial GDx-VCC examination. (Courtesy of Dr P. Schlottmann and Mr E. White, Moorfields Eye Hospital)

(personal communication, Dr Zhou, Carl Zeiss Meditec). The progression algorithm is intended to achieve an estimated specificity of at least 95% using either a “fast mode” algorithm or an “extended mode” algorithm. In the fast mode, a single scan per visit is required, and change is detected according to whether population-based

short- term test-retest variability is exceeded. A “change from baseline” approach equivalent to that used in HRT TCA is used, whereby the difference between follow-up visit measurements and two baseline visit measurements are compared to test-retest variability. This is performed for RNFL parameters, the TSNIT (RNFL thickness in the

4.5 Frequency of Testing

parapapillary measurement annulus) plot and for the RNFL image. In the extended mode, three repeat scans per visit are required and change is defined according to the individual’s own test-retest variability (estimated from the three scans at each imaging session). In addition to the “change from baseline” approach, which is applied to RNFL image data, the SIM technique (previously adapted for use with HRT images [27]) is applied to the RNFL parameters and to the TSNIT plot. By requiring change to be detected in at least one of the three structural correlates, it is hoped that both diffuse and focal structural change will be identified.

Summary for the Clinician ■

■

■

In theory, the GDx-VCC should be a useful tool for monitoring progression as it generates repeatable and clinically meaningful measurements As the device has been subject to extensive redevelopment, there is minimal longitudinal data compared to the HRT At the time of writing, a statistically supported progression algorithm is due to be incorporated into the GDx-VCC software

Progression algorithms will be developed and tested as the newer technologies become more established. OCT is poised to become the pre-eminent ocular imaging technology; not least because of its versatility in imaging multiple anatomical sites: the macula, the optic nerve, the peripapillary nerve fibre layer and anterior segment structures (using a different wavelength source). In recent months, a new generation of OCT device, “spectral-domain” OCT, has become commercially available. Spectral-domain OCT allows much faster image acquisition, which enables the measurement (in addition to RNFL parameters) of true optic nerve topography and optic disc cupping, although some movement artefact from axial motion is still a feature.

Summary for the Clinician ■

As with the GDx-VCC, there is a paucity of longitudinal OCT data compared to the HRT

4.5

4.4

Detecting Progression by OCT

As with the GDx, the OCT is potentially useful for monitoring disease progression. However, there are currently few published longitudinal OCT studies, and a statistically guided progression algorithm has not yet been incorporated into the operational software. At present, it is possible to assess change by performing a serial RNFL analysis (Fig. 4.4), which allows the RNFL thinning over time to be evaluated. Wollstein et al. have defined OCT progression as a reproducible thinning of the mean RNFL thickness of at least 20 µm, a value chosen on the basis of the known reproducibility error of the OCT [36]. It should be noted that this study utilised older OCT technology, which is known to have poorer test-retest variability than the newer STRATUSOCT. As with the GDx-VCC, the lack of available longitudinal data for the OCT prevents any detailed discussion relating to its ability to monitor progression. In many respects, great potential in terms of the monitoring of progression may be expected given the excellent reproducibility and discriminatory power of the STRATUSOCT. However, it is the HRT, with its older and more slowly evolving technology, as well as backward-compatible software, which has the longevity necessary for researchers to be able to examine long series of ONH images over time.

37

Frequency of Testing

As with visual field testing in glaucoma, there is no consensus about the most appropriate frequency of testing that is required to enable optimal detection of progression. Owen and coworkers have performed a detailed examination of HRT rim area variability and identified that it was best characterised by a hyperbolic distribution, whereby the majority of rim area measurements are highly repeatable but with a few extreme deviations [25]. The estimates of rim area variability were used to construct computer simulations of disease progression. These computer simulations were used to try to identify the optimal frequency of testing required to identify realistic rates of progression. Detection of progression improved with increased frequency of testing, albeit at the cost of a steep decline in specificity. This latter shortcoming will only be addressed by identifying methods that can limit the number of false-positive tests. This may be best achieved by ensuring that only the highest quality image acquisitions are used. However, in practical terms, this may not always be possible. Glaucoma is largely prevalent in the elderly population, in whom lens opacity often coexists. In such patients it may be more appropriate to apply some form of post hoc image processing to ameliorate image variability. One such technique, “maximum likelihood deconvolution”, has been shown to improve the repeatability of topographical height measures, particularly in poor-quality images [28].

38

4 Detecting Glaucoma Progression by Imaging

4

Fig. 4.4 An example of progressive retinal nerve fibre thinning identified by serial OCT examination (Courtesy of Dr P. Schlottmann and Mr E. White, Moorfields Eye Hospital)

Summary for the Clinician ■

■

Improved detection of progression occurs with increased frequency of testing, although this may be at the cost of declining specificity (higher false-positive rates) Post hoc techniques for improving image quality may improve specificity

4.6

Lack of Concordance

A universal finding in the admittedly small number of published longitudinal imaging studies in glaucoma has been the surprising lack of concordance between identified structural and functional progression. A comparison of event- and trend-based progression techniques was performed in 84 glaucoma subjects and 41 normal

controls followed longitudinally using the HRT, standard achromatic perimetry and high-pass resolution perimetry. A poor agreement between the three test modalities as regards progression was identified regardless of the stringency of the progression criteria applied, with agreement varying from 4 to 19% in the glaucoma group [2]. A similar poor agreement was found by Strouthidis et al., who applied linear regression techniques to HRT rim area and visual field data acquired from ocular hypertensive subjects [32]. Agreement between subjects progressing by structure and function varied between 3 and 12%. More recently, the same group compared agreement between an HRT rim area trend analysis, an HRT rim area event analysis, a visual field trend analysis and a visual field event analysis applied to a cohort of 198 ocular hypertensive subjects followed longitudinally [13]. Agreement as regards progression across all four techniques was only 2%. This poor level of concordance has also been observed using the OCT, with only 3% of 64

References

glaucoma or glaucoma suspect eyes progressing by both OCT and by visual field [36]. In summary, measures of structural change and of functional change appear to identify similar numbers of progressing patients, but not necessarily the same patients. If one assumes that the tests have a high level of specificity, as reported in all of these published studies, then both tests are identifying genuine “progressors”. One should therefore use both tests in a complementary fashion to have the best chance of identifying progression. The reasons for the discrepancy between structural and functional progression are uncertain. One may speculate that the causes relate to the test methodology, to physiology or to both. We are not yet at a stage when either imaging or functional testing in glaucoma has reached their apogee. One should therefore apply the caveat that there is poor concordance between structural and functional progression using currently available techniques. Both visual field testing and optic nerve imaging are prone to differing levels of measurement error, even within the same subject. It is therefore plausible that some of the disagreements may be explained by differences in measurement error between the two testing modalities. It is clear that some structural changes in glaucoma, such as laminar bowing and connective tissue remodelling, do not necessarily result in functional loss. Likewise, IOP-dependent ganglion cell dysfunction may occur in the absence of structural change. Perhaps a more simple explanation relates to the fact that the published studies are relatively short in duration, being less than ten years. It is likely that the level of agreement between structure and function will increase as the length of follow-up increases.

Summary for the Clinician ■

■

A poor agreement has been observed when comparing HRT and OCT progression with visual field progression In order to have the best chance of identifying progression in clinical practice, one needs to continue to monitor both visual field and structural changes

References 1. AGIS Investigators (1994) Advanced glaucoma intervention study. 2. Visual field test scoring and reliability. Ophthalmology 101(8):1445–1455 2. Artes PH, Chauhan BC (2005) Longitudinal changes in the visual field and optic disc in glaucoma. Prog Retin Eye Res 24(3):333–354

39

3. Azuara-Blanco A, Katz LJ, Spaeth GL et al. (2003) Clinical agreement among glaucoma experts in the detection of glaucomatous changes of the optic disk using simultaneous stereoscopic photographs. Am J Ophthalmol 136(5):949–950 4. Boes DA, Spaeth GL, Mills RP et al. (1996) Relative optic cup depth assessments using three stereo photograph viewing methods. J Glaucoma 5(1):9–14 5. Burk RO, Vihanninjoki K, Bartke T et al. (2000) Development of the standard reference plane for the Heidelberg retina tomograph. Graefes Arch Clin Exp Ophthalmol 238(5):375–384 6. Caprioli J, Prum B, Zeyen T (1996) Comparison of methods to evaluate the optic nerve head and nerve fiber layer for glaucomatous change. Am J Ophthalmol 121(6):659–667 7. Chauhan BC (2005) Detection of glaucomatous changes in the optic disc. In: Fingeret M, Flanagan JG, Liebmann JM (eds) The essential HRT primer. Jocoto Advertising, San Ramon, CA 8. Chauhan BC, Blanchard JW, Hamilton DC et al. (2000) Technique for detecting serial topographic changes in the optic disc and peripapillary retina using scanning laser tomography. Invest Ophthalmol Vis Sci 41(3):775–782 9. Chauhan BC, McCormick TA, Nicolela MT et al. (2001) Optic disc and visual field changes in a prospective longitudinal study of patients with glaucoma: comparison of scanning laser tomography with conventional perimetry and optic disc photography. Arch Ophthalmol 119(10):1492–1499 10. Chen E, Gedda U, Landau I (2001) Thinning of the papillomacular bundle in the glaucomatous eye and its influence on the reference plane of the Heidelberg retinal tomography. J Glaucoma 10(5):386–389 11. Coleman AL, Sommer A, Enger C et al. (1996) Interobserver and intraobserver variability in the detection of glaucomatous progression of the optic disc. J Glaucoma 5(6):384–389 12. Ervin JC, Lemij HG, Mills RP et al. (2002) Clinician change detection viewing longitudinal stereophotographs compared to confocal scanning laser tomography in the LSU Experimental Glaucoma (LEG) Study. Ophthalmology 109(3):467–481 13. Fayers T, Strouthidis NG, Garway-Heath DF (2007) Monitoring glaucomatous progression using a novel Heidelberg Retina Tomograph event analysis. Ophthalmology 114(11):1973–1980 14. Fitzke FW, Hitchings RA, Poinoosawmy D et al. (1996) Analysis of visual field progression in glaucoma. Br J Ophthalmol 80(1):40–48 15. Heijl A, Leske MC, Bengtsson B et al. (2003) Measuring visual field progression in the Early Manifest Glaucoma Trial. Acta Ophthalmol Scand 81(3):286–293 16. Heidelberg Engineering (2006) Heidelberg retina tomograph glaucoma module. Operating instructions software version 3.0. Heidelberg Engineering, Heidelberg, Germany 17. Kamal DS, Viswanathan AC, Garway-Heath DF et al. (1999) Detection of optic disc change with the Heidelberg retina tomograph before confirmed visual field change in ocular hypertensives converting to early glaucoma. Br J Ophthalmol 83(3):290–294

40

4

4 Detecting Glaucoma Progression by Imaging

18. Kamal DS, Garway-Heath DF, Hitchings RA et al. (2000) Use of sequential Heidelberg retina tomograph images to identify changes at the optic disc in ocular hypertensive patients at risk of developing glaucoma. Br J Ophthalmol 84(9):993–998 19. Kourkoutas D, Buys YM, Flanagan JG et al. (2007) Comparison of glaucoma progression evaluated with Heidelberg retina tomograph II versus optic nerve head stereophotographs. Can J Ophthalmol 42(1):82–88 20. Lichter PR (1977) Variability of expert observers in evaluating the optic disc. Trans Am Ophthalmol Soc 74: 532–572 21. Medeiros FA, Doshi R, Zangwill LM et al. (2007) Longterm variability of GDx VCC retinal nerve fiber layer thickness measurements. J Glaucoma 16(3):277–281 22. Morgan JE, Sheen NJ, North RV et al. (2005) Digital imaging of the optic nerve head: monoscopic and stereoscopic analysis. Br J Ophthalmol 89(7):879–884 23. Musch DC, Lichter PR, Guire KE et al. (1999) The Collaborative Initial Glaucoma Treatment Study: study design, methods, and baseline characteristics of enrolled patients. Ophthalmology 106(4):653–662 24. Nicolela MT, McCormick TA, Drance SM et al. (2003) Visual field and optic disc progression in patients with different types of optic disc damage: a longitudinal prospective study. Ophthalmology 110(11):2178–2184 25. Owen MF, Strouthidis NG, Garway-Heath DF et al. (2006) Measurement variability in Heidelberg Retina Tomograph imaging of neuroretinal rim area. Invest Ophthalmol Vis Sci 47(12):5322–5330 26. Parrish RK, Schiffman JC, Feuer WJ et al. (2005) Test-retest reproducibility of optic disk deterioration detected from stereophotographs by masked graders. Am J Ophthalmol 140(4):762–764 27. Patterson AJ, Garway-Heath DF, Strouthidis NG et al. (2005) A new statistical approach for quantifying change in series of retinal and optic nerve head topography images. Invest Ophthalmol Vis Sci 46(5):1659–1667

28. Patterson AJ, Garway-Heath DF, Crabb DP (2006) Improving the repeatability of topographic height measurements in confocal scanning laser imaging using maximum-likelihood deconvolution. Invest Ophthalmol Vis Sci 47(10): 4415–4421 29. Quigley HA, Katz J, Derick RJ et al. (1992) An evaluation of optic disc and nerve fiber layer examinations in monitoring progression of early glaucoma damage. Ophthalmology 99(1):19–28 30. Strouthidis NG, White ET, Owen VM et al. (2005) Factors affecting the test-retest variability of Heidelberg retina tomograph and Heidelberg retina tomograph II measurements. Br J Ophthalmol 89(11):1427–1432 31. Strouthidis NG, White ET, Owen VM et al. (2005) Improving the repeatability of Heidelberg retina tomograph and Heidelberg retina tomograph II rim area measurements. Br J Ophthalmol 89(11):1433–1437 32. Strouthidis NG, Scott A, Peter NM et al. (2006) Optic disc and visual field progression in ocular hypertensive subjects: detection rates, specificity, and agreement. Invest Ophthalmol Vis Sci 47(7):2904–2910 33. Tan JC, Hitchings RA (2003) Approach for identifying glaucomatous optic nerve progression by scanning laser tomography. Invest Ophthalmol Vis Sci 44(6):2621–2626 34. Tan JC, Hitchings RA (2004) Optimizing and validating an approach for identifying glaucomatous change in optic nerve topography. Invest Ophthalmol Vis Sci 45(5): 1396–1403 35. Tan JC, Garway-Heath DF, Hitchings RA (2003) Variability across the optic nerve head in scanning laser tomography. Br J Ophthalmol 87(5):557–559 36. Wollstein G, Schuman JS, Price LL et al. (2005) Optical coherence tomography longitudinal evaluation of retinal nerve fiber layer thickness in glaucoma. Arch Ophthalmol 123(4):464–470 37. Zeyen T, Miglior S, Pfeiffer N et al. (2003) Reproducibility of evaluation of optic disc change for glaucoma with stereo optic disc photographs. Ophthalmology 110(2):340–344

Chapter 5

The Classification of Primary Angle-Closure Glaucoma

5

Tarun Sharma, Sancy Low, Paul J. Foster

Core Messages ■

■

■

■

■

The most familiar classification of angle-closure glaucoma is based on the presence of symptoms. This approach fails to recognise the large number of asymptomatic patients and people at risk. Classification based on symptoms does not guide the ophthalmologist in devising a logical management plan and predicting prognosis. The term “glaucoma” is currently used indiscriminately, regardless of the presence or absence of optic neuropathy. Its use should be restricted to cases in which there is evidence of glaucomatous optic neuropathy. The terms anatomically narrow angle and occludable angle are used interchangeably to indicate an anatomical predisposition to pathological angleclosure. These terms have found widespread usage in epidemiological research, and are generally taken to indicate the presence of iridotrabecular contact (ITC)—the defining feature of angleclosure. ITC is now thought to be significant if the posterior (usually pigmented) trabecular meshwork is obstructed by the peripheral iris for half of its circumference or more. However, this is a conservative approach to the assessment of risk, and may underrepresent the “at risk” population and thus be revised in future. International expert consensus is that the classification of angle closure should describe the conceptual stage in the natural history of angle closure, ranging from iridotrabecular contact (ITC) (primary angle closure suspect), to anterior segment signs of disease, specifically raised intraocular pressure (IOP) and/or peripheral anterior synechiae (PAS), which are the defining features of angle closure in an eye with an anatomically

■

■

■

■

■

narrow angle (this stage is termed primary angle closure). The natural history finally culminates in glaucomatous optic neuropathy (termed primary angle closure glaucoma when it occurs in conjunction with angle closure as previously defined). This classification indicates the presence or absence of abnormalities requiring treatment, and specifies visually significant end organ damage (glaucomatous optic neuropathy). In addition to describing the stage of disease, it is important to identify the mechanism causing angle closure. This requires an additional system to be used in parallel. In addition to glaucomatous optic neuropathy, there are several forms of ocular tissue damage that may result in visual dysfunction as a consequence of angle closure, such as cataract, endothelial cell loss and anterior ischaemic optic neuropathy. These should be separately identified clinical management targeted at these specific processes. The most widely used classification of mechanism is the four-point system, which identifies obstructions to aqueous outflow at progressively more posterior levels: (a) pupil block; (b) ciliary body-induced; (c) lens-induced; (d) retrolenticular causes. The art of gonioscopy is indispensable to the diagnosis and management of all forms of glaucoma. The development of new anterior chamber imaging techniques in the clinical assessment of angle, such as ultrasound biomicropscopy and anterior segment OCT, are a useful supplement to clinical examination and gonioscopy, which will further improve understanding of the mechanisms responsible for angle closure.

42

5 The Classification of Primary Angle-Closure Glaucoma

5.1 Background

5

Glaucoma has recently emerged as the second most common cause of blindness worldwide, and the leading cause of irreversible blindness [1]. Quigley has calculated that open-angle glaucoma (OAG) accounts for 75% of all glaucomatous optic neuropathy, with approximately 60 million people affected by 2010, and some 16 million suffering primary angle-closure glaucoma (PACG). This latter figure is likely to rise to 21 million by 2020 [2]. The disease is especially prevalent in Asian people, and affects women and the elderly most often [3–6]. In addition, it is now believed that PACG is more rapidly progressive and visually destructive than primary OAG [7, 8]. Therefore, early identification and appropriate management are important for preventing loss of vision and for optimising the delivery of effective preventive/curative procedures such as laser iridotomy [9–11]. However, early diagnosis depends on an appropriate nosological framework which is relevant to the condition and based on scientific evidence. The division of adult glaucoma cases into primary and secondary forms is used to indicate the presence of a separate, distinct pathological process responsible for raised intraocular pressure in secondary glaucoma. Secondary glaucoma is typically a unilateral disease, characterised by high intraocular pressure, and—if effective treatment is not commenced—a rapidly progressive glaucomatous optic neuropathy, often leading to blindness. Most commonly, secondary glaucoma occurs as a consequence of anterior segment neovascularisation, uveitis, trauma (in-cluding surgery, especially aphakia), the use of steroid medication, and other less common causes. Secondary glaucoma is usually classified as OAG or ACG. ACG is a group of disorders that share a common pathological pathway where contact between the iris and the trabecular meshwork occurs. “Primary” angle-closure glaucoma is in fact a secondary glaucoma, where the optic neuropathy occurs as a consequence of raised intraocular pressure (IOP) resulting from an identifiable process: iridotrabecular contact (ITC). The “primary” process in PACG is ITC, occurring as a consequence of one or more abnormalities in the relative or absolute size or position of anterior segment structures, or by abnormal forces in the posterior segment that alter the anatomy of the anterior segment. Different approaches to classification of angle-closure have been based on combinations of the following: ■ ■

The presence or absence of additional pathology— denoting primary or secondary angle closure The location of the mechanism causing angle closure

■

■

■

The constellation of clinical features that accompany the presentation of angle closure, including the presence or absence of symptoms and the level of IOP, either at presentation or in response to certain “provocative” tests—acute, intermittent (subacute), and chronic angle closure The presence or absence of peripheral anterior synechiae (PAS)—appositional angle closure vs. synechial angle closure The presence or absence of glaucomatous optic neuropathy

The predominant approach to classification has been that based on symptoms of raised IOP. However, research in Asia suggests that angle closure is predominantly an asymptomatic disease in the majority of sufferers (66–75% of cases) [3, 4, 12–14]. In the last decade, an increase in research activity focussing on angle closure glaucoma has highlighted the need to standardise the definition and classification of the disease. This chapter describes the current approaches to classification of angle closure, and describes the outcome of the Third AIGS (Association of International Glaucoma Societies) Consensus Meeting on angle-closure glaucoma [15].

5.2 The Purposes of Disease Classification Classification systems provide a framework for describing the presence and severity of disease, why it occurs, and how different treatments will benefit patients. In most fields of medicine, as understanding of the disease increases, they have typically evolved from descriptions of a combination of symptoms, through an understanding of the anatomical location of abnormalities, to the aetiology and pathogenesis. For clinical purposes, it is highly desirable for a classification scheme to help to describe how and why a patient suffers from a specific disease process and how to manage the condition most effectively. Indeed, an appropriate system of classification is crucial for achieving the highest standards of clinical care. Ultimately, every patient is unique, and should be treated as such. However, it is only possible to make progress in understanding disease processes, and how best to control them, by looking for common patterns through formal study—through research. Outcomes from clinical trials cannot be compared unless the broad concepts of disease classification are uniform. The study of the prevalence and incidence of disease will only yield meaningful results if the classifications used reflect characteristics of importance. It has been suggested that there is a “dichotomy of purpose” between the clinical and research settings. Indeed, in a clinical setting, a myriad of clinical signs may be identified and be relevant to the

5.4 Definition of an “Occludable” or Narrow Angle

care of the patient. The identification and assimilation of these signs into a management plan is a complex process requiring many years of training and experience to master. The codification of such complex decision-making processes is beyond the scope of this chapter. However, since modern medical science adopts a progressively more evidence-based approach, the principles of management are based on systematic research. Major advantages of a standard classification scheme are the promotion of a common language used by all involved, the clarification of thought processes around disease mechanisms and disease (or pre-disease state) prognosis, and the ability to make valid comparisons between datasets.

5.3 The Evolution of Classification Schemes for Angle-Closure Glaucoma Angle-closure glaucoma was probably the first form of glaucoma to be recognised as a separate diagnostic entity from cataract. Von Graefe described surgical peripheral iridectomy as a method of treating glaucoma. Initial classifications of glaucoma evolved to identify congestive, post-congestive and absolute stages of disease, with several types of disease identified, including a symptomatic course (which includes an acute episode causing pain and inflammation) as well as an asymptomatic form (either of which could lead to total blindness). The advent of gonioscopy resulted in a quantum leap in the sophistication of diagnostic methodology and the potential for understanding the pathological mechanisms responsible for angle closure. It allowed the relationship between the iris and the trabecular meshwork to be observed directly for the first time. More recently, the advent of anterior segment imaging has allowed a clearer understanding of the mechanisms that cause the narrowing of the angle, as well as an understanding of the limitations of some clinical observations such as gonioscopy. The most familiar and enduring classification of angle closure identified three subcategories based on the presence or absence of symptoms. ■

■

■

Acute: Abrupt onset of symptomatic elevation of IOP resulting from total closure of the angle that is not self-limiting Sub-acute or intermittent: Abrupt onset of symptomatic elevation of IOP resulting from total closure of the angle that is self-limiting and recurrent Chronic: Elevated IOP resulting from angle closure that is asymptomatic

Some have also described a fourth subcategory, latent angle closure, which is evidence that angle closure is either

43

likely or may have occurred intermittently. Evidence includes a positive provocative test or the finding of primary peripheral anterior synechiae (PAS) in an eye that has an open but narrow angle. However, this term is no longer widely used, perhaps because PAS with or without elevated IOP is considered chronic angle closure. The advantages of this scheme are that it is familiar to doctors and easy to understand for patients who have a symptomatic episode of angle closure. However, the implicit assumption within this system is that most angle closure is symptomatic. The scheme has evolved ad hoc from early clinical observations, and reflects a level of understanding of natural history and pathology that is less complete than the one we have today. It has no evidence base and no proven validity in predicting prognosis. The major flaws are an absence of emphasis on the presence or risk of significant loss of visual function, and the fact that it does nothing to guide the ophthalmologist in devising a logical management plan. The term glaucoma has traditionally been attached to all grades of disease regardless of the presence or absence of optic neuropathy, as a perpetuation of the idea that glaucoma is defined by an elevation of intraocular pressure. However, this idea has become outmoded in the diagnosis and management of primary OAG. The same rigorous, scientific approach to classifying angle closure is now becoming more widespread.

5.4

Definition of an “Occludable” or Narrow Angle

The threshold at which angle closure is considered a possible diagnosis is not clearly defined. The concept of defining the threshold by describing the characteristics of an “occludable” angle is both logical and pragmatic. The terms “anatomically narrow angle” and “occludable angle” are generally seen as synonymous, and are used to indicate the anatomical predisposition to angle closure. However, debate surrounds the use of each, particularly as neither specifies that iridotrabecular contact (ITC, which is currently seen as the defining characteristic of pathological angle closure) is present. The epidemiological research standard used to define “occludable” angles in studies in Alaska, South Africa, Mongolia, Singapore and Bangladesh was that the posterior (usually pigmented) trabecular meshwork was hidden from view by the peripheral iris for three-quarters of its circumference or more [3, 4, 14, 16, 17]. This definition was first used by Arkell et al. for their study in Alaska, and used later in other studies for the sake of consistency to allow comparison between studies. Analysis of data from

44

5

5 The Classification of Primary Angle-Closure Glaucoma

Mongolia and Singapore has shown that around half of all participants in population studies who have “primary” PAS (i.e. no other identifiable cause) are excluded by this definition. Later, Thomas used a more liberal definition of 180° of trabecular meshwork hidden from view in his cross-sectional and longitudinal studies in Vellore, southern India [18, 19]. This slightly more liberal threshold is still likely to exclude some people who have primary PAS or appositional angle closure. This belief is supported by the fact that Becker and Shaffer originally suggested that an iridotrabecular angle of 20° was the threshold at which angle closure should be considered a possibility [20]. This was based on nothing other than careful observation in clinical practice, but has been supported by findings from the analysis of data from population surveys in high-risk populations. The reason why signs of angle closure, such as PAS and/or post-appositional deposits of iris stromal pigment, are seen in narrow but open angles is demonstrated by a video recording of an ultrasound biomicroscopy (UBM) examination of a patient who had suffered symptomatic angle closure in the opposite eye [21]. The recording shows iridocorneal contact in the dark, which rapidly changes to an open angle of approximately 20° when the room lights are switched on. The magnitude and rapidity of this variation is striking, and underlines the importance of levels of illumination in identifying cases of angle closure. It is probably a limitation of the technique that gonioscopy (still the reference standard examination for the diagnosis of angle closure) relies on visible light, which, even in the most careful examination when light is kept away from the pupil, may affect the configuration of the angle, causing artefactual widening. One recent study comparing anterior segment optical coherence tomography (AS-OCT) with gonioscopy found that AS-OCT detected more closed angles than did gonioscopy [22]. This was interpreted as a superior diagnostic performance of AS-OCT, probably because the examinations were performed in dark-room conditions, whereas gonioscopy, even in the hands of experts, requires some light from the slit lamp.

5.5

Primary Open-Angle Glaucoma is a Diagnosis of Exclusion

Nonetheless, an evidence-based assessment of the current definition of “risk” (i.e. an occludable angle) shows that the current diagnostic threshold (i.e. 180–270° of TM obscured) is probably far too stringent. As suggested above, gonioscopy using visible light probably underdetects cases where iridotrabecular contact is occurring. There is a strong case in favour of shifting the burden

of proof from the current de facto stance that requires we prove a patient has angle closure to proving that a patient does not have angle closure. As angle closure can potentially be “cured” with early detection and a single laser procedure (laser iridotomy), it may be that ophthalmologists are missing an opportunity to provide effective therapy to many with gonioscopically narrow angles that cause appositional closure, and consequently raised intraocular pressure.

5.6 Classification of Angle Closure in Epidemiological Research (ISGEO Scheme) A classification for use in prevalence surveys and other epidemiological research has been published [23]. It identifies three conceptual stages in the natural history of angle closure, from iridotrabecular contact (ITC) to anterior segment signs of disease (raised lop and/or PAS), and finally culminating in glaucomatous optic neuropathy. (a) Primary angle-closure suspect (PACS): ITC in three or more quadrants, but normal IOP, disc and field, without evidence of PAS. (b) Primary angle-closure (PAC): ITC in three or more quadrants with either raised IOP and/or primary PAS. Disc and field are normal. (c) Primary angle-closure glaucoma (PACG): ITC in three or more quadrants plus evidence of glaucomatous damage to optic disc and visual field (with similar approaches to those used for POAG). The diagnosis of glaucomatous optic neuropathy has been codified in the ISGEO scheme using three levels of evidence. Category 1 stipulates structural and functional abnormalities consistent with glaucoma. Category 2 stipulates that, in the case of advanced loss of vision where field-testing cannot be performed using automated perimetry, glaucoma can be diagnosed on the basis of advanced structural damage to the optic disc. Category 3 applies to cases where the disc cannot be seen. Glaucoma is diagnosed on the basis of visual acuity < 3/60 and either IOP > 24 mm Hg or signs of previous filtering surgery. It has been proposed that this category be expanded to include those with iris ischaemic sequelae (iris whirling, poorly reactive pupils and iridoschisis) and either an afferent pupil defect or no light perception. It is recognised that the current ISGEO scheme makes no allowance for variation in disc size, and that this is an important (previously recognised) omission. This scheme has been employed widely in the research classification of cases. The incidence of each category is

5.10 Classification System for Angle-Closure Glaucomas

known. In addition, it is useful to record physical signs of anterior segment ischaemia (distortion of radial iris fibres), or necrosis (subcapsular opacities in the lens— glaukomflecken). The inclusion of two sub-categories of PAC was discussed for the ISGEO scheme (i.e. ischaemic and nonischaemic), but there is no current consensus on this point. The major deficiency with this approach is that it does not identify the mechanism responsible for angle closure, and requires an additional scheme to be used in parallel for this purpose. However, it does indicate the presence or absence of abnormalities requiring treatment, and it specifies visually significant end organ damage (glaucomatous optic neuropathy). There are several other causes of ocular tissue damage and visual dysfunction that are associated with angle closure, and should be separately identified in the clinical management and research assessments of people with this condition. Additional description of these factors adds an additional level of clinical sophistication if desired. These include: Angle-Closure and Ocular Tissue Damage (a) Corneal endothelial loss (b) Trabecular meshwork damage (c) Lens damage (glaukomflecken and nuclear sclerosis) (d) Iris damage (dilated, unresponsive pupil, and iridoschisis, ectropion uveae). (e) A flat pale optic disc similar in appearance to that of anterior ischaemic optic neuropathy (f) Glaucomatous optic neuropathy

5.7 Trabecular Meshwork Damage in Angle Closure Damage to and obstruction of the trabecular meshwork is the mechanism by which rises in IOP occur in angle closure. There are different mechanisms by which trabecular obstruction or dysfunction may occur. ■

■

Appositional closure causing a pre-trabecular outflow obstruction. This is the primary mechanism in symptomatic “acute” PAC. This is also the predominant mechanism in asymptomatic presentations, at least in the early stages of disease. Appositional closure causing a trabecular-level outflow obstruction. It is biologically plausible that longterm, low-grade contact and friction between TM and iris causes degradation of TM structure and function. A single histological study reported marked TM degeneration away from areas of PAS in asymptomatic angle closure [24]. Epidemiological data supports this finding, as higher IOP occurs in open but narrower angles [25].

■

45

Synechial closure. This is the most plausible and wellrecognised route to deteriorating outflow facility. The extent of synechial closure is associated with the degree of elevation of intraocular pressure. However, it is recognised that appositional angle closure may lead to glaucomatous optic neuropathy without PAS being present [18].

It seems most likely that all three of these processes (apposition, TM failure and PAS) are co-existent in the same eye.

5.8

An Anatomical Basis for the Primary Angle Closure Mechanism

Angle closure is characterized by the presence of iridotrabecular contact (ITC), which may lead to trabecular dysfunction, peripheral anterior synechiae (PAS), elevated intraocular pressure (IOP), glaucomatous optic neuropathy, glaucomatous functional loss and possibly blindness. In angle closure, obstruction of the trabecular meshwork may be caused by forces acting at one or more of four separate anatomical sites, each progressively more posterior to the other: the iris (most commonly pupillary block), the ciliary body (most commonly plateau iris), the lens (“phacomorphic glaucoma”), and forces posterior to the lens (often referred to as “malignant” glaucoma). This classification, popularised by Ritch and colleagues [26], helps describe the various mechanisms responsible for angle closure. This in turn helps plan a logical programme of treatment. Each case will typically have one predominant location of blockage, but may have a component of obstruction at each of the levels preceding it. In some patients multiple mechanisms play a role. The appropriate treatment becomes more complex for each more posterior level of blockage, as each level may also require treatment for lower levels of blockage.

5.9 5.9.1

Classification System for Angle-Closure Glaucomas Level I: Iris and Pupil

Pupillary block is the most common mechanism responsible for primary angle closure [9, 26, 27]. It is a physiological phenomenon whereby a pressure gradient exists between the posterior and anterior chambers. The greater the pressure gradient, the greater the convexity of the iris profile. This in turn increases the possibility of iridotrabecular contact. Pupillary block accounts for approximately 75% of cases of angle closure. In the remaining 25% of cases, there is typically an element of pupil block [9, 27].

46

5

5 The Classification of Primary Angle-Closure Glaucoma

In East Asia, mixed mechanism angle closure is believed by some to be especially prevalent [28]. Laser iridotomy eliminates the pressure differential between anterior and posterior chambers and relieves the iris convexity. The iris assumes a planar configuration and the iridocorneal angle widens in most cases. Barkan reported that the peripheral iris appears bulky, with marked circumferential folds crowding the angle [29]. Such eyes are susceptible to closure of the angle when the pupil dilates physiologically or pharmacologically. These cases would not respond to laser iridotomy, and would be considered “non-pupil-block” cases of angle closure. More recently, studies using ultrasound biomicroscopy (UBM) have helped identify particular anatomical characteristics associated with the failure of an iridotomy to successfully open a closed angle. These were (1) a very shallow axial anterior chamber, (2) a thicker iris, (3) a more anteriorly inserted iris, and (4) a smaller trabecular–ciliary process distance (often used as an indicator of plateau iris).

5.9.2

quantitative analyses [34, 35, 36]. In addition, AS-OCT, and to a lesser extent UBM, can be performed under dark room conditions. Both level I and II blocks are usually classified as “primary” disease (providing no other pathological processes are identified), whereas levels III and IV are typically classified as secondary, being the result of other pathological processes, distinct from the crowding of anterior segment anatomy that characterises primary disease. All of these factors may be sufficient to cause pathological angle closure. However, in some cases, an external trigger is required. These may be either physiological or pharmacological in nature, and may include near-work activities such as reading or sewing, or exposure to dark, for example a visit to the cinema [26]. In addition, several pharmacological agents are know to increase the risk of angle closure, as a result of either sympathomimetic or parasympatholytic actions, or from idiosyncratic reactions to medications resulting in suprachoroidal effusions [37, 38]. More recently, some serotonergic agents have been reported to precipitate angle closure in some people [39].

Level II: Ciliary Body

Plateau iris configuration is the term given to the gonioscopic appearance in which the peripheral third of the iris rises steeply from its insertion before making an abrupt angulation towards the visual axis. The iris profile is otherwise flat. This configuration may predispose to closure of the angle. This configuration of the peripheral iris was first described by Tornquist [30]. The “syndrome” was reported by Wand [31]. In eyes with plateau iris, the anterior chamber appears to have normal axial anterior chamber depth. The chamber angle may be narrow, however, as a consequence of the more anteriorly positioned peripheral iris. Using ultrasound biomicroscopy (UBM), the structures posterior to the iris that are hidden from clinical observation can be examined and their anatomical relationships assessed [32, 33]. This technology has enhanced the development of an anatomical classification of angle closure, and in particular has demonstrated that some cases of plateau iris have anteriorly positioned ciliary processes. This in turn causes the peripheral iris to be positioned more anteriorly, and results in the angulation of the peripheral iris. In these cases, the iridociliary sulcus is seen to be closed. Another, newer, imaging technology, anterior segment optical coherence tomography (ASOCT), allows the anterior chamber angle to be imaged without contact [34]. This is an advantage over (UBM), although UBM offers vastly superior resolution for structures posterior to the iris pigment epithelium [34, 35]. A particular advantage of both of these techniques over clinical examination is the ability to subject the images to

5.9.3

Level III: Lens-Induced Angle Closure

Most cases of level I and II block are the result of lens size or position, and most cases of primary angle closure have some element of lens opacity in the form of nuclear sclerosis, or cortical opacity. However, these are not classified as lens-induced, which is the term reserved for cases characterised by a sudden change in lens thickness or position, as occurs in lens subluxation or intumescence (i.e. “phacomorphic” glaucoma) [26]. Cases typically present with symptoms of sudden increases in intraocular pressure, causing pain and blurred vision.

5.9.4

Level IV: Ciliolenticular Block/Aqueous Misdirection/“Malignant Glaucoma”

These cases of angle closure are caused by forces posterior to the lens that push the lens–iris diaphragm forward. It is thought that a pressure differential is created between the vitreous and aqueous compartments, with aqueous being misdirected behind an intact anterior hyaloid face [26, 40, 41]. In other cases, the lens may be displaced anteriorly by other mechanisms, such as iatrogenic gas fills, large vitreous haemorrhages, or uveitis, causing inflammation of ciliary body [26]. One of the more common clinical scenarios is the finding of high intraocular pressure and a very shallow anterior chamber following trabeculectomy surgery.

References

These cases often require several interventions aimed at relieving the block at levels I, II and III. Ultimately, the management may involve complete decompartmentalisation of the eye, requiring surgical iridectomy, lens extraction, posterior capsulotomy, and in some cases pars plana vitrectomy [26, 42]. Two key clinical points to emphasise are that level I and II tend to be bilateral with anatomical features that are symmetrical, and are managed initially by constricting the pupil (usually with pilocarpine). Level III and IV blocks tend to be asymmetrical (with a shallow anterior chamber in the affected eye, and a relatively deeper AC in the other), and are managed with mydriatics (e.g. atropine).

Summary for the Clinician ■ ■

■

■

■

5.10

Gonioscopy

Gonioscopy remains the “reference standard” for diagnosing angle closure, and remains an essential component of the complete ocular examination. There are three widely used clinical grading systems, each with its own strengths and weaknesses. The Scheie system describes the structures seen and is simple and intuitive for nonspecialists [43]. An important weakness of this approach is that the number of structures seen can vary considerably depending on the direction of gaze and the orientation of the gonioscope. The Shaffer system is more widely preferred by glaucoma specialists [44]. It describes the geometric width of the iridocorneal angle. The Spaeth system allows the most detailed recording of angle characteristics: the geometric width of the iridotrabecular angle, the iris profile, as well as the true and apparent levels of insertion. It is helpful to avoid describing findings using derivative numbering systems (0–4, or 0–IV), but instead to describe exactly what was seen; for example, an iridotrabecular angle of 10° is a more precise description than “grade 1”. The best lens to use remains controversial. Many specialists feel that the use of a four-mirror lens is mandatory. Many others disagree—dynamic gonioscopy can be performed with a Goldmann oneor two-mirror gonioscope, and many closed angles can be “manipulated” open using a Goldmann lens. However a small proportion of appositionally closed angles cannot. In these cases, the use of a four-mirror lens is mandatory. For this reason, the minimum standard is to use a four-mirror lens. However, the ideal is to have both a four-mirror lens and a magnifying Goldmann lens available. The latter offers the opportunity for a more stable, clear view, and will probably give the occasional or inexperienced user more confidence in identifying important landmarks.

47

Most angle-closure cases are asymptomatic Expert opinion is that anyone with 6 or more clock hours of irido-trabecular contact should undergo prophylactic laser iridotomy Classification should identify both the stage of natural history and the mechanism causing closure. Three conceptual stages of the disease are identified as i. anatomically narrow angles, ii. Primary angle-closure (narrow angles with raised IOP and /or peripheral anterior synechiae), iii. Narrow angles with glaucomatous optic neuropathy Four broad classes of mechanisms causing angleclosure are: i. pupil block, ii. Variations in shape, and position of the peripheral iris, iii. Lens associated, iv. Retro-lenticular (ciliary block, or malignant glaucoma)

References 1. Resnikoff S, Pascolini D, Etya’ale D, Kocur I, Pararajasegaram P, Pokharel GP et al. (2004) Global data on visual impairment in the year 2002. Bull World Health Organ 82:844–851 2. Quigley HA, Broman AT (2006) The number of persons with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90:262–267 3. Foster PJ, Baasanhu J, Alsbirk PH, Munkhbayar D, Uranchimeg D, Johnson GJ (1996) Glaucoma in Mongolia—A population-based survey in Hövsgöl Province, Northern Mongolia. Arch Ophthalmol 114:1235–1241 4. Foster PJ, Oen FT, Machin DS, Ng TP, Devereux JG, Johnson GJ et al. (2000) The prevalence of glaucoma in Chinese residents of Singapore. A cross-sectional population survey in Tanjong Pagar district. Arch Ophthalmol 118: 1105–1111 5. He MG, Foster PJ, Ge J, Huang WY, Zheng YF, Friedman DS et al. (2006) Prevalence and clinical characteristics of glaucoma in adult Chinese: a population-based study in Liwan District, Guangzhou. Invest Ophthalmol Vis Sci 47:2782–2788 6. Seah SKL, Foster PJ, Chew PT, Jap A, Oen F, Fam HB et al. (1997) Incidence of acute primary angle-closure glaucoma in Singapore. An island-wide survey. Arch Ophthalmol 115:1436–1440 7. Foster PJ, Johnson GJ (2001) Glaucoma in China: how big is the problem? Br J Ophthalmol 85:1277–1282 8. Bourne RRA, Sukudom P, Foster PJ, Tantisevi V, Jitapunkul S, Lee PS et al. (2003) Prevalence of glaucoma in Thailand: a population based survey in Rom Klao District, Bangkok. Br J Ophthalmol 87:1069–1074 9. Nolan WP, Foster PJ, Devereux JG, Uranchimeg D, Johnson GJ, Baasanhu J. (2000) YAG laser iridotomy treatment for primary angle-closure in east Asian eyes. Br J Ophthalmol 84:1255–1259

48

5

5 The Classification of Primary Angle-Closure Glaucoma

10. Aung T, Ang LP, Chan SP, Chew PTK (2001) Acute primary angle-closure: long-term intraocular pressure outcome in Asian eyes. Am J Ophthalmol 131:7–12 11. Ang LP, Aung T, Chew PT (2003) Acute primary angle closure in an Asian population: long-term outcome of the fellow eye after prophylactic laser peripheral iridotomy. Ophthalmology 107:2092–2096 12. Congdon N, Wang F, Tielsch JM (1992) Issues in the epidemiology and population-based screening of primary angle-closure glaucoma. Surv Ophthalmol 36:411–423 13. Congdon N, Quigley HA, Hung PT, Wang TH, Ho TC (1996) Screening techniques for angle-closure glaucoma in rural Taiwan. Acta Ophthalmol Scand 74:113–119 14. Salmon JF, Mermoud A, Ivey A, Swanevelder SA, Hoffman M. (1993) The prevalence of primary angle -closure glaucoma and open angle glaucoma in Mamre, Western Cape, South Africa. Arch Ophthalmol 111:1263–1269 15. Weinreb RN, Friedman DS (eds) (2006) Angle closure and angle closure glaucoma. Kugler, The Hague 16. Arkell SM, Lightman DA, Sommer A, Taylor HR, Korshin OM, Tielsch JM (1987) The prevalence of glaucoma among eskimos of Northwest Alaska. Arch Ophthalmol 105:482–485 17. Rahman MM, Rahman N, Foster PJ, Haque Z, Zaman AU, Dineen B et al. (2004) The prevalence of glaucoma in Bangladesh: a population based survey in Dhaka division. Br J Ophthalmol 88:1493–1497 18. Thomas R, Parikh R, Muliyil J, Kumar R (2003) Five-year risk of progression of primary angle closure to primary angle closure glaucoma: a population-based study. Acta Ophthalmol Scand 81:480–485 19. Thomas R, George R, Parikh R, Muliyil J, Jacob A (2003) Five year risk of progression of primary angle closure suspects to primary angle closure: a population based study. Br J Ophthalmol 87:450–454 20. Becker B, Shaffer RN (1965) Diagnosis and therapy of the glaucomas. CV Mosby, St. Louis, MO, pp. 177–194 21. Gazzard G, Foster PJ, Friedman DS, Khaw PT, Seah SK (2004) Light to dark physiological variation in irido-trabecular angle width. Br J Ophthalmol 88:1357–1482 (video supplement) 22. Nolan WP, See J, Chew PT, Friedman DS, Smith SD, Radhakrishnan S et al. (2007) Detection of primary angle closure using anterior segment optical coherence tomography in Asian eyes. Ophthalmology 114:33–39 23. Foster PJ, Buhrmann RR, Quigley HA, Johnson GJ (2002) The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol 86:238–242 24. Sihota R, Lakshimaiah NC, Walia KB, Sharma S, Pailoor J, Agarawal HC (2001) The trabecular meshwork in acute and chronic angle closure glaucoma. Ind J Ophthalmol 49:255–259 25. Foster PJ, Machin D, Wong TY, Ng TP, Kirwan JF, Johnson GJ et al. (2003) Determinants of intraocular pressure and its association with glaucomatous optic neuropathy in Chinese Singaporeans: the Tanjong Pagar Study. Invest Ophthalmol Vis Sci 44:3885–3891 26. Ritch R, Lowe (1996) In: Ritch R, Shields MB, Krupin T (eds) The glaucomas. 2nd edn. CV Mosby, St. Louis, MO, pp. 801–840

27. Gazzard G, Friedman DS, Devereux JG, Chew PT, Seah SK (2003) A prospective ultrasound biomicroscopy evaluation of changes in anterior segment morphology after laser iridotomy in Asian eyes. Ophthalmology 110:630–638 28. Wang N, Wu H, Fan Z (2002) Primary angle closure glaucoma in Chinese and Western populations. Chin Med J 115:1706–1715 29. Barkan O (1938) Glaucoma: classification, causes, and surgical control. Am J Ophthalmol 21:1099 30. Tornquist R (1958) Angle-closure glaucoma in an eye with a plateau type of iris. Acta Ophthalmol 316:413 31. Wand M, Grant WM, Simmons RJ (1977) Plateau iris syndrome. Trans Am Acad Ophthalmol Otolaryngol 83:122–130 32. Mandell MA, Pavlin CJ, Weisbrod DJ, Simpson ER (2003) Anterior chamber depth in plateau iris and pupillary block as measured by ultrasound biomicroscopy. Am J Ophthalmol 136:900–903 33. Li PS, Lai JS, Lam DS (2004) Anterior chamber depth in plateau iris and pupillary block as measured by ultrasound biomicroscopy. Am J Ophthalmol 137:1169–1170 34. Radhakrishnan S, Goldsmith J, Huang D, Westphal V, Dueker DK, Rollins AM et al. (2005) Comparison of optical coherence tomography and ultrasound biomicroscopy for detection of narrow anterior chamber angles. Arch Ophthalmol 123(8):1053–1059 35. Leung CK, Chan WM, Ko CY, Chui SI, Woo J, Tsang MK, Tse RK (2005) Visualization of anterior chamber angle dynamics using optical coherence tomography. Ophthalmology 112(6):980–984 36. Chalita MR, Li Y, Smith S, Patil C, Westphal V, Rollins AM, Izatt JA, Huang D (2005) High-speed optical coherence tomography of laser iridotomy. Am J Ophthalmol 140(6):1133–1136 37. Lowe RF (1961) Angle-closure glaucoma: acute and subacute attacks: clinical types. Trans Ophthalmol Soc Aust 21:65 38. Sakai H, Morine-Shinjyo S, Shinzato M, Nakamura Y, Sakai M, Sawaguchi S (2005) Uveal effusion in primary angle-closure glaucoma. Ophthalmology. 112(3):413–419 39. Costagliola C, Parmeggiani F, Sebastiani A (2004) SSRIs and intraocular pressure modifications: evidence, therapeutic implications and possible mechanisms. CNS Drugs 18(8):475–484 40. Shaffer RN (1954) The role of vitreous detachment in aphakic and malignant glaucoma. Trans Am Acad Ophthalmol Otolaryngol 58:217 41. Quigley HA (1980) Malignant glaucoma and fluid flow rate. Am J Ophthalmol 89:879 42. Sharma A, Sii F, Shah P, Kirkby GR (2006) Vitrectomy– phacoemulsification–vitrectomy for the management of aqueous misdirection syndromes in phakic eyes. Ophthalmology 113(11):1968–1973 43. Scheie HG (1957) Width and pigmentation of the angle of the anterior chamber. A system of grading by gonioscopy. Arch Ophthalmol 58:510–512 44. Speath GL (1971) The normal development of the human anterior chamber angle: a new system of describing grading. Trans Ophthalmol Soc UK 91:709–739

Chapter 6

6

Uveitic Glaucoma Agnieszka G. Nagpal, Nisha R. Acharya

Core Messages ■

■

■

The prevalence of ocular hypertension in patients with uveitis ranges from 7.6 to 23%. The duration and severity of uveitis are related to the development of ocular hypertension (OHT) and secondary glaucoma. Secondary glaucoma can occur through a variety of causes, including alterations to the composition of the aqueous humor and mechanical obstruction to outflow. Corticosteroids can also induce OHT and secondary glaucoma. Uveitic entities most commonly associated with OHT and secondary glaucoma include Fuchs’

6.1

Introduction

Glaucoma is a broad term that characterizes a large group of disorders that have optic neuropathy with visual field changes in common [1]. Elevated intraocular pressure is the most common risk factor for glaucomatous optic atrophy, and is a frequent complication of uveitis [1]. In this chapter, we will review current theories on the relationship between glaucoma and uveitis, and then discuss the uveitic entities most commonly associated with elevated intraocular pressure and secondary glaucoma. Finally, we will comment on the management of secondary glaucoma associated with uveitis.

6.2 The Epidemiology of Uveitis-Related Ocular Hypertension (OHT) and Secondary Glaucoma The literature regarding the epidemiology of secondary glaucoma from uveitis frequently defines secondary glaucoma as an intraocular pressure (IOP) of greater than 21 mmHg, or IOP requiring medical treatment, without specifically commenting on damage to the optic nerve and progressive visual field loss. In this context, the term “uveitis-related ocular hypertension” is more appropriately used [2]. The distinction between secondary glaucoma and OHT will be noted whenever possible. The prevalence of OHT in adults with uveitis ranges from 7.6 to 23% [3–9]. There are less data in the literature

■

heterochromic iridocyclitis, Posner–Schlossman syndrome, herpetic uveitis, juvenile inflammatory arthritis, and sarcoidosis. Medical treatment is often effective in controlling secondary glaucoma. Cessation of corticosteroids may require the addition of immunomodulating treatment to control inflammation. In glaucoma refractory to medical treatment, surgical options in combination with antimetabolites may be considered.

regarding the true prevalence of secondary glaucoma taking into consideration optic nerve and visual field loss. Panek et al. looked retrospectively at 100 patients (161 eyes) with uveitis and found OHT (defined as intraocular pressure > 21 mmHg on more than one examination, or if the patient was receiving antiglaucoma therapy at the time of initial exam and had a well-documented increase in IOP concurrent with inflammation) in 23 patients (31 eyes) [8]. Twenty-two percent of these patients had glaucomatous field loss [8]. Takahashi et al. looked at 1,099 patients with uveitis between 1974 and 2000 and found OHT (defined as IOP > 21 at two consecutive visits needing treatment with medication) in 19.7% of patients [5]. 38.9% of these patients had an abnormal visual field related to high IOP [5]. Secondary glaucoma based on optic nerve changes and elevated IOP was detected in 10.9% of eyes in a cohort of patients with Behçet’s disease by Elgin et al. [5] Herbert et al. looked at the prevalence of OHT (defined as IOP > 21 mmHg on two separate occasions) in 257 patients (402 eyes) with uveitis seen over a threemonth period [7]. They found the prevalence of OHT to be 41.8%, with 29.8% requiring treatment (for those requiring treatment, the IOP was >30 with or without optic nerve/visual field changes, or IOP > 21 with optic nerve/visual field changes) [7]. 9.6% of the eyes in the study developed secondary glaucoma, two-thirds of which required medical treatment and one-third of which required surgical treatment [7]. Risk factors

50

6

6 Uveitic Glaucoma

associated with increased IOP were active inflammation, steroid usage, increasing age, and number of years since diagnosis. Duration of uveitis has been shown to play a role in the development of OHT and secondary glaucoma. In the review of Panek et al., OHT was observed in 26% of eyes with chronic uveitis and 12% with acute disease [8]. Neri et al. reviewed the records of 391 patients with uveitis, and found the incidence of glaucoma (defined as IOP > 21 or glaucomatous optic nerve damage requiring medical and/ or surgical antiglaucoma treatment) after acute uveitis to be 7.6% at both three and twelve months [6]. In patients with chronic uveitis, the incidence of glaucoma at one and five years was 6.5 and 11.1% respectively, increasing to 22.3% after ten years [6]. Herbert et al. looked at the prevalence of OHT (defined as IOP > 21 mmHg on two separate occasions) in 257 patients with uveitis seen over a three-month period. OHT was found in 26% of eyes with acute uveitis and 46.1% of eyes with chronic uveitis, with 15.1 and 33.8% requiring treatment. In addition to chronicity, other risk factors associated with increased IOP were active inflammation, steroid usage, increasing age, and number of years since diagnosis. Severity of disease, as quantified through the presence of posterior synechiae, has also been associated with increased prevalence of secondary glaucoma [6, 10]. Anterior uveitis is most commonly associated with OHT and secondary glaucoma [3, 5].

Summary for the Clinician ■

■

OHT is more commonly associated with uveitis than secondary glaucoma with optic nerve and visual field changes The duration and severity of uveitis are associated with an increased frequency of OHT and secondary glaucoma

6.3 6.3.1

Pathogenesis of Uveitic Glaucoma Aqueous Dynamics in Uveitic Glaucoma

Maintenance of normal intraocular pressure is a delicate balance between aqueous humor production and outflow. In iridocyclitis, the inflamed ciliary body usually produces less aqueous humor. If outflow remains the same, the intraocular pressure will be decreased. Outflow may also be increased, exacerbating hypotony from ciliary body inflammation [11]. However, with an open angle, if there is an obstruction to outflow, intraocular pressure may be elevated.

Inflammatory cells, protein and fibrin from a disrupted blood–aqueous barrier can accumulate in the trabecular meshwork, resulting in the obstruction of aqueous outflow [12]. This can be a transient occurrence, but over time, may lead to irreversible damage [2]. Precipitates on the trabecular meshwork can obstruct outflow [13]. Swelling or dysfunction of the endothelium or trabecular lamellae can also result in decreased outflow [14]. Chronic mechanisms of outflow obstruction include scarring and obliteration of the trabecular meshwork or Schlemm’s canal, loss or dysfunction of trabecular endothelial cells, or the overgrowth of an endothelial–cuticular or fibrovascular membrane in the open angle, which may contract, resulting in closure of the angle [1, 2]. It has been suggested that a low perfusion rate may damage the trabecular meshwork. Johnson has shown that a perfusion rate of less than 1 microliter per minute may affect the functioning of the trabecular meshwork [15]. Thus, inflammation of the ciliary body and subsequent decreased aqueous production may lead to decreased perfusion and damage to the trabecular meshwork [16]. Biochemical changes in the aqueous humor of eyes with uveitis can cause IOP elevation by mediating aqueous production and obstructing aqueous outflow [2]. In experimental autoimmune uveitis, inflammatory cells can infiltrate and destroy the trabecular meshwork [17, 18]. They can also be directly cytotoxic to the surrounding tissue and liberate substances such as oxygen free radicals and proteolytic enzymes [17]. Cytokines may increase the IOP in uveitic eyes by increasing the inflammation, by stimulating neovascularization, and by having a direct effect on aqueous humor dynamics [19]. Cytokines may also have a direct effect on the TM cell population, either through a direct cytotoxic effect, or by stimulating cell migration away from the TM [20].

6.3.2

Mechanical Causes of Uveitic Glaucoma

Acute angle closure can occur through several mechanisms. Iridocyclitis, annular choroidal detachment, and posterior scleritis can cause inflammation and edema, leading to forward rotation of the ciliary body and acute angle closure [2]. Pars planitis and uveal effusion can cause choroidal and ciliary body detachment with subsequent angle closure [2]. Massive exudative retinal detachment can displace the lens–iris diaphragm anteriorly, resulting in angle closure [1]. In patients with anterior uveitis, adhesions can develop between the posterior surface of the iris and the anterior

6.4 Common Uveitic Entities Associated with OHT and Secondary Glaucoma

lens capsule, the vitreous face in aphakic patients, a sulcus or posterior chamber intraocular lens, or the residual capsule in pseudophakic patients [2]. These posterior synechiae can cause pupillary block by impeding the flow of aqueous between the posterior and anterior chamber [2]. This leads to iris bombé and closure of the anterior chamber angle [2]. Posterior synechiae occur more commonly in granulomatous than nongranulomatous disease [2]. In chronic inflammation, neovascularization, iris bombé, or peripheral anterior synechiae (PAS) may develop and result in closure of the angle [2]. It is believed that exudates and transudates from incompetent blood vessels in the setting of narrow angles may lead to PAS formation. These are usually broad bands attaching to the anterior trabeculum and even the cornea, and are more common in granulomatous conditions [2]. Although in some cases the anterior portion of the trabeculum may be visible on gonioscopy, the trabeculum may still be functionally closed [2]. In eyes that have less than 360° of PAS, the remainder of the angle may be compromised by the presence of pigment [2].

25]. Other studies have shown that dexamethasone can decrease the synthesis of collagen and the activity of tissue plasminogen activator [26, 27]. In cultured human trabecular meshwork cells, glucocorticoids increased the expression of the extracellular matrix protein fibronectin, which is seen in patients with COAG, and caused the formation of a crosslinked actin network in the trabecular meshwork cytoskeleton [28, 29]. It has also been hypothesized that corticosteroids may suppress the phagocytic activity of the trabecular endothelium, thus allowing the accumulation of debris which blocks outflow [1, 2]. Inhibition of the synthesis of PGE2 and PGF2a, which increase outflow facility, may also increase IOP [30]. Genetic influences may play a role in steroid-induced intraocular pressure elevation. For example, glucocorticoids induce the expression of myocilin mRNA, which is a protein involved in TM outflow resistance [16].

Summary for the Clinician ■

6.3.3

Steroid-Induced Glaucoma

Treatment of uveitis with corticosteroids can result in increased ocular pressure, and if not managed appropriately, in optic nerve damage. This condition is known as steroid-induced glaucoma, and occurs more frequently in people who have chronic open-angle glaucoma (COAG) or a family history of this disease [1]. Other risk factors include high myopia, type II diabetes mellitus, and connective tissue diseases [2]. As in COAG, the angle is usually open and there are no symptoms [1]. Increased intraocular pressure can occur within weeks (approximately two weeks) with more potent steroids, and within months with weaker steroids [1]. However, acute pressure rises can also occur [21]. Topical corticosteroid therapy is more often associated with a rise in intraocular pressure than systemic administration [1]. Periocular and intravitreal steroids can also cause elevations in IOP that may be more difficult to deal with given their longer-acting effects. Inhalational and nasal steroids have also been reported to cause increases in IOP [1]. It is thought that the rise in intraocular pressure from corticosteroid use is due to a decrease in outflow [1, 2]. Animal studies have shown that trabecular and anterior uveal tissues have a high concentration of glucocorticoid receptors and are most likely the tissues affected by glucocorticoids to decrease outflow [22, 23]. Corticosteroids may cause polymerized glycosaminoglycans to accumulate and block the trabecular meshwork [24,

51

■

■

A wide range of factors are associated with the development of OHT and secondary glaucoma from uveitis Clinical evaluation can help in determining whether mechanical obstruction is the cause of elevated intraocular pressure IOP must be carefully monitored when using any form of corticosteroids in uveitic patients, since IOP rises can be dramatic

6.4 Common Uveitic Entities Associated with OHT and Secondary Glaucoma While any uveitic entity can cause an increase in intraocular pressure if the inflammation is not adequately controlled through the mechanisms previously discussed, there are certain entities that are more strongly associated with OHT and secondary glaucoma (Table 6.1). These will be discussed below.

6.4.1

Glaucomatocyclitic Crisis: Posner–Schlossman Syndrome

Described in 1948 by Posner and Schlossman, this is a monocular disease affecting young to middle-aged adults that is characterized by recurrent attacks of mild anterior uveitis with marked elevations in intraocular pressure [31]. Typical symptoms include slight ocular

52

6 Uveitic Glaucoma

Table 6.1 Types of uveitis associated with OHT and secondary glaucoma [2]

6

Anterior uveitis

Intemediate uveitis

Posterior uveitis

Panuveitis

Other

JIA

Pars planitis

Toxoplasmosis

Sarcoidosis

Episcleritis

Fuchs’ heterochromic iridocyclitis

HTLV-1

Acute retinal necrosis

Behçet’s syndrome

Scleritis

Posner–Schossman syndrome

Sympathetic ophthalmia

Masquerade syndromes (malignancy, retinal detachment)

Herpetic uveitis (HSV, VZV, CMV)

Vogt–Koyanagi– Harada syndrome

Seronegative spondyloarthropathies

Syphilis

Traumatic

Tuberculosis

Idiopathic

Onchocerciasis

Lens-induced glaucoma (phacolytic, phacoanaphylactic, pseudophakic inflammatory glaucoma) Other infectious diseases (mumps, rubella, Hansen’s disease)

discomfort, blurred vision and halos, lasting several hours to a few weeks, and recurring monthly or yearly [31]. On examination, mild inflammation is seen in the anterior chamber with a few small, discrete, round keratic precipitates that usually resolve spontaneously in several weeks. Keratic precipitates may also be seen on the trabecular meshwork, and corneal edema may be present due to the markedly elevated intraocular pressure, usually in the 40–50 mm Hg range. The IOP returns to normal in-between episodes of inflammation, but a chronic secondary glaucoma can develop which results in visual loss. The etiology of this disease is unknown, but associations include HLA-Bw54, herpetic viral infection, increased aqueous production due to elevated levels of prostaglandins, and chronic open-angle glaucoma [32– 34]. Most attacks can be controlled with corticosteroids and antiglaucoma medications.

6.4.2

Fuchs’ Heterochromic Iridocyclitis

Fuchs’ heterochromic iridocyclitis is a relatively mild, chronic form of iridocyclitis associated with elevated intraocular pressure. Its characteristic feature is iris

heterochromia, although this may be very mild or absent [35]. Usually only one eye is affected, although both eyes can be involved [35]. Typically, a low-grade anterior chamber reaction with small, stellate, keratic precipitates involving the entire corneal endothelium is seen [35]. The iris typically has extensive stromal atrophy with transillumination defects, and iris nodules may be present [35]. Posterior synechiae are generally absent [35]. Affected individuals develop posterior subcapsular cataracts [35]. The angle is typically open and free of synechiae, but fine, bridging vessels that cross the trabecular meshwork can cause bleeding during cataract surgery [35]. Vitreous opacities and chorioretinal scars may also be seen [35]. Although the etiology remains unknown, associations include infections with toxoplasma, toxocara, previous trauma, retinitis pigmentosa, elevated IgG levels, and autoantibodies directed against the cornea [35]. More recently, there has been convincing data linking rubella to Fuchs’ iridocyclitis [36–38]. Corticosteroids are generally ineffective in treating the inflammation, distinguishing this syndrome from glaucomatocyclitic crisis. In addition, intraocular pressure elevation is not as common as in Posner–Schlossman syndrome; the incidence varies from 15 to 59% [35].

6.4 Common Uveitic Entities Associated with OHT and Secondary Glaucoma

However, the IOP is generally out of proportion to the mild amount of inflammation, and patients can have large fluctuations in IOP. Close follow-up and monitoring is recommended to detect the progression of glaucoma, and aggressive medical and surgical treatment is warranted if found [35]. A high proportion of patients do not respond to medical therapy, necessitating surgical treatment [35].

6.4.3

53

Treatment includes oral antivirals (acyclovir, famciclovir, and valacyclovir for HSV and VZV; and valganciclovir for CMV), topical corticosteroids and cycloplegic agents. IOP typically responds to control of the underlying inflammatory process, but glaucoma medications are typically prescribed initially to lower IOP. Approximately 12% of patients with keratouveitic glaucoma will develop persistent IOP elevation requiring chronic therapy [40].

Herpetic Disease

The herpes family of viruses [herpes simplex (HSV), herpes zoster (HZV), and cytomegalovirus (CMV)] can cause a uveitis associated with elevated IOP [39–41]. Herpes simplex and zoster, however, are more commonly associated with a rise in IOP than CMV. Most commonly, the uveal inflammation is a keratouveitis secondary to corneal disease, and can present acutely, or run a chronic or recurrent course. A retrospective study by Falcon and Williams at the Moorfields Eye Hospital found OHT in 28% of 183 patients with HSV [40]. The majority had stromal keratitis or a metaherpetic ulcer [40]. Interestingly, none of the patients presented with increased IOP at the first manifestation of corneal disease [40]. Townsend and Kaufman looked at the pathogenesis of glaucoma secondary to HSV in rabbit eyes [42]. On histologic examination, a diffuse mononuclear cell infiltration was present in the iris root and trabecular meshwork with disruption of the lamellar arrangements [42]. All animals with persistent pressure elevations had anterior synechiae and 50% had retrocorneal membranes covering 180° of the angle circumference [42]. Endothelial cells showed swelling, vacuolization of the cytoplasm, loss of the normal compact arrangement, and large empty patches where necrotic cells had sloughed off without replacement [42]. These findings suggest that increased IOP in HSV keratouveitis is related to trabeculitis. The pathophysiology of herpes zoster is thought to be similar to that of HSV-associated iridocyclitis. Secondary elevation of IOP and glaucoma occur in approximately 30% of cases, ranging from 16 to 56% [2, 43]. On clinical exam, diffuse, stellate, keratic precipitates covering the entire endothelium may be seen. Patchy or sectoral iris atrophy is characteristic of herpes infection. Retinitis and vasculitis may also occur. CMV can also cause IOP elevation associated with an anterior uveitis in immunocompetent persons. The clinical appearance can mimic HSV and VZV, with diffuse keratic precipitates, iris atrophy with transillumination defects, and focal edema from endotheliitis. IOP can be severely elevated, up to 70 mmHg [41, 44, 45].

6.4.4 Juvenile Inflammatory Arthritis (JIA) JIA is a systemic disorder occurring in children classified into three major types based on age of onset and degree of articular and systemic involvement during the first three months. These include systemic onset (Still’s disease), polyarticular onset, and pauciarticular onset [2]. The latter type accounts for the majority of patients with uveitis, and is further characterized by the presence of ANA antibodies [2]. The incidence of uveitis in JIA ranges from 2 to 21% [2]. In about 80% of cases, ocular involvement is bilateral, and the iridocyclitis is usually mild, insidious, chronic, and asymptomatic [2]. It is typically nongranulomatous, although granulomatous signs such as mutton fat keratic precipitates and Koeppe nodules have been observed [2]. Complications include band keratopathy, cataract, posterior synechiae, macular edema, papillitis, and secondary glaucoma [2]. The incidence of glaucoma varies from 14 to 42%, and is most often caused by closure of the angle by peripheral anterior synechiae, although open angle glaucoma with trabecular obstruction and steroid induced glaucoma may also occur [2, 46–48]. Medical treatment can control the glaucoma in about 50% of patients, with only 30% controlled over the long term [2]. Surgical options include goniotomy, trabeculodialysis, filtration surgery with antimetabolites, and drainage device implants.

6.4.5 Pars Planitis Pars planitis refers to idiopathic inflammation of the anterior vitreous and pars plana. It is a diagnosis of exclusion after ruling out other causes of intermediate uveitis, such as sarcoidosis, Lyme disease, tuberculosis, syphilis, and multiple sclerosis. On presentation, patients may be asymptomatic or have floaters or decreased vision. The disease is often bilateral but often asymmetric. Clinically, snowbanking, snowballs, peripheral retinal periphlebitis, anterior vitreous cells, and vitreous opacities may be seen [2]. Complications include glaucoma, cataract, CME, band keratopathy, papillitis, vitreous hemorrhage, and

54

6

6 Uveitic Glaucoma

tractional and rhegmatogenous retinal detachment [2]. The incidence of glaucoma varies from 7 to 8%, and is as high as 15% in children [2]. Mechanisms of increased IOP and glaucoma include peripheral anterior synechiae (PAS), posterior synechiae with iris bombé, neovascular glaucoma, open-angle glaucoma, and steroid-induced ocular hypertension [2].

6.4.6 Toxoplasmosis Ocular toxoplasmosis is caused by an obligate intracellular parasitic protozoan, Toxoplasma gondii. Transmission can occur in utero or postnatally. Cats are the definitive hosts of the parasite, and oocysts shed in cat feces can remain viable in the environment for long periods of time [49]. Postnatal infections are due to ingestion of tissue cysts in raw or undercooked meat, ingestion of oocysts on unwashed vegetables that are contaminated with soil containing cat feces, or from contaminated drinking water [49]. Toxoplasmosis is the most common cause of posterior uveitis, accounting for 7–15% of all cases of uveitis. Toxoplasma causes a focal necrotizing retinochoroiditis, often adjacent to a chorioretinal scar, as well as vitritis and perivasculitis [50]. Granulomatous anterior uveitis, neuroretinitis, punctate outer retinitis, and scleritis can also occur [50]. Complications include rhegmatogenous and exudative retinal detachment, retinal vessel occlusions, subretinal neovascularization, epiretinal membrane formation, macular edema, and glaucoma [50]. The prevalence of OHT in toxoplasmosis ranges from 3 to 38% [51]. A recent retrospective review of 61 patients with toxoplasmosis retinochoroiditis found elevated IOP in 38% of patients, with a trend suggesting that an increased anterior chamber response may be related. The IOP elevation was usually transient, normalizing as the episode of chorioretinitis resolved. In 3.3% of patients, IOP elevation required chronic medication or surgical treatment [51].

6.4.7

precipitates are characteristic, as are posterior synechiae and iris nodules [2]. Iris nodules may involve the pupillary border (Koeppe’s nodules), iris stroma (Busacca’s nodules), anterior chamber angle, and ciliary body [1, 2]. Posterior segment involvement includes periphlebitis with “candle wax drippings,” vitritis, choroidal granulomas, exudative retinal detachment, and optic nerve involvement [1, 2]. The incidence of glaucoma in sarcoid ranges from 10.9 to 25.5% [2]. Mechanisms of increased IOP and subsequent glaucoma include outflow obstruction by PAS, obstruction of the trabecular meshwork by inflammatory cells and nodules, neovascularization of the angle, and steroid-induced glaucoma [2]. Secondary glaucoma in uveitis associated with sarcoid is associated with poor visual outcomes; in one retrospective study of 60 patients with sarcoid-related uveitis, glaucoma was one of the risk factors associated with vision worse than 20/40 [53, 54].

6.4.8

Syphilis

Increased intraocular pressure and subsequent glaucoma can be seen in both the congenital and the acquired forms of syphilis. The most common ocular finding is interstitial keratitis (IK), which typically appears between the age of 5 and 16 [2]. Anterior uveitis is often present as well [2]. Closed-angle glaucoma occurs as a result of posterior synechiae with iris bombé, PAS, uveal cysts, and lens subluxation or complete dislocation [2]. Patients with IK early in infancy may develop a narrow angle which can predispose them to angle closure [2]. Open-angle glaucoma may also occur [2]. A recent retrospective review of 39 patients with uveitis secondary to syphilis found increased IOP in 18% coincident with the onset of inflammation [9]. Potential mechanisms to account for the increased IOP include clogging of the trabecular meshwork with inflammatory debris and/or a prostaglandin-mediated increase in vascular permeability causing increased aqueous humor production [9].

Sarcoidosis

Sarcoidosis is a multisystem inflammatory disorder of uncertain origin, characterized by noncaseating granulomas. It most commonly affects the lungs, eyes, and skin. It accounts for 3–7% of noninfectious uveitis cases, and ocular involvement is found in 20–30% of cases of systemic sarcoid [52, 53]. While sarcoidosis can affect any part of the eye, the most common ocular manifestation is anterior uveitis [2]. Mutton fat keratic

Summary for the Clinician ■ ■

Many uveitic entities are associated with OHT and secondary glaucoma Posner–Schlossman syndrome and Fuchs’ heterochromic iridocyclitis can be distinguished by their responsiveness to topical corticosteroids

6.5 Treatment of Uveitic Glaucoma

6.5 Treatment of Uveitic Glaucoma 6.5.1

Medical Treatment

Topical medications are the first line agents to be used in the management of elevated IOP associated with uveitis. These include beta blockers which decrease aqueous production. It is worth noting that metipranolol has been associated with granulomatous iridocyclitis and therefore should be avoided in patients with uveitis [16]. Adren ergic agonists, carbonic anhydrase inhibitors (topical, intravenous and oral), and hyperosmotic agents may also be used to control IOP. Miotics should be avoided in uveitic glaucoma, as they may potentiate the formation of posterior synechiae or pupillary membranes, cause discomfort by aggravating ciliary muscle spasm, and increase inflammation by enhancing breakdown of the blood–aqueous barrier [2]. Prostaglandin analogs may also be used to reduce elevated IOP. However, there have been reports associating them with uveitis and cystoid macular edema due to breakdown of the blood–aqueous barrier, so they are generally used with caution [55–61]. Latanoprost should also be used with caution in patients with a history of herpetic disease, as it has been linked to disease recurrence [16]. If an increase in IOP is thought to be secondary to corticosteroid use, corticosteroids may be tapered or switched to drugs with less tendency to elevate the IOP, such as loteprednol, fluorometholone, or rimexolone. In rare cases, the elevated IOP may persist despite discontinuing steroids [1]. This is more common in chronic users of corticosteroids [1]. In cases where corticosteroids were injected subconjunctivally or under Tenon’s capsule, it may be possible to surgically remove the steroid depot [2]. In patients with severe noninfectious uveitis with elevated IOP secondary to steroid use, systemic immunomodulating agents should be considered for control of inflammation. These include antimetabolites (methotrexate, mycophenolate mofetil, azathioprine), alkylating agents (cyclophosphamide and chlorambucil), and T cell inhibitors (cyclosporine and tacrolimus) [62]. Newer agents include the biologics, which target molecules in the inflammatory cascade and include tumor necrosis factor (TNF) alpha inhibitors (infliximab, adalimumab), IL-2 inhibitors (daclizumab), and co-stimulatory molecule inhibitors (abatacept). While relatively new, these agents have shown promise in controlling noninfectious uveitis refractory to corticosteroids and the traditional immunomodulating agents listed above.

55

6.5.2 Surgical Treatment In cases of pupillary block causing closed-angle glaucoma, a laser iridotomy can be used to re-establish a pathway for aqueous outflow. The combination of a Nd-YAG laser with an argon laser may be more effective in creating an opening in patients with dark irides [2]. Postoperative inflammation is common in all patients, but may be especially severe in those patients with active uveitis or a prior history of uveitis, and may result in closure of the iridotomy site. Aggressive treatment with topical corticosteroids is recommended to reduce this complication. A surgical iridectomy can be performed when laser iridotomy is unsuccessful or cannot be performed. Post-op inflammation in these cases is generally more severe and may require the use of systemic corticosteroids in the perioperative period [2]. Other surgical procedures for closed-angle, openangle, and mixed-mechanism glaucoma include goniotomy, trabeculodialysis, cyclophotocoagulation, trabeculectomy, and drainage device implantation. Goniotomy and trabeculodialysis have been used in young patients with uveitic glaucoma with moderate success, with IOP control in patients ranging from 56 to 72% [63–66]. Trabeculectomy with adjuvant antimetabolite therapy have been reported to improve the outcome of filtering surgery vs. trabecul-ectomy alone [2]. Mitomycin C (MMC) may be preferable to 5-fluorouracil in uveitic patients, as it has been shown to lower IOP more and for a longer duration than 5-fluorouracil in high risk glaucoma surgery [16, 67]. Aqueous drainage devices such as Ahmed and Molteno valves have been developed in order to avoid fibrosis of the draining fistula, especially when significant postoperative inflammation is likely [2]. They should be considered in aphakic patients (particularly those with JIA-associated uveitis) and patients with previous trabeculectomy failures [16]. MMC is currently being used with aqueous drainage devices to achieve lower IOP and prevent postoperative bleb encapsulation [16]. Aggressive preoperative topical and systemic corticosteroids can help to reduce and control inflammation in preparation for surgery [16]. Alternatively, an infraorbital depot of 40 mg of methylprednisolone can be given at the conclusion of surgery [16]. Postoperative inflammation or reactivation of uveitis can occur and can be managed with pre- and post-operative corticosteroids, as well as steroid-sparing immunomodulatory therapy if necessary.

56

6 Uveitic Glaucoma

Summary for the Clinician ■

6

■

■

Metipranolol and miotics should be avoided in patients with uveitis and glaucoma. Prostaglandin analogs should be used with care. Lower-strength topical corticosteroids may be substituted in cases of corticosteroid-induced OHT. Immunomodulating treatment may be considered when oral corticosteroids cannot be used. In cases of OHT and secondary glaucoma refractory to medical management, surgical options include trabeculectomy and aqueous drainage devices with antimetabolites.

6.6

Conclusion

Ocular hypertension and subsequent secondary glaucoma are potentially blinding complications of uveitis. Although the pathophysiology is incompletely understood, damage to the outflow channels and mechanical obstruction are contributing factors. Corticosteroid use also plays a significant role in contributing to OHT in uveitic patients. Common entities associated with OHT and secondary glaucoma include Fuchs’ heterochromic iridocyclitis, Posner–Scholssman syndrome, viral infection, sarcoidosis, and syphilis. Treatment options include both medical and surgical therapy. The advent of biologic agents may further reduce the incidence of uveitic glaucoma by controlling refractory inflammation and by reducing chronic corticosteroid use.

References 1. Allingham RR, Damji KF, Freedman S, Moroi SE, Shafranov G, Shields MD (2005) Shields’ textbook of glaucoma, 5th edn. Lippincott Williams & Wilkins, Philadephia, PA 2. Moorthy RS, Mermoud A, Baerveldt G, Minckler DS, Lee PP, Rao NA (1997) Glaucoma asociated with uveitis. Surv Ophthalmol 41(5):361–394 3. Merayo-Lloves J, Power WJ, Rodriguez A, Pedroza-Seres M, Foster CS (1999) Secondary glaucoma in patients with uveitis. Ophthalmologica 213(5):300–304 4. Elgin UBN, Batman A (2004) Incidence of secondary glaucoma in Behcet Disease. J Glaucoma 13(6):441–444 5. Takahashi T, Ohtani S, Miyata K, Miyata N, Shirato S, Mochizuki M (2002) A clinical evaluation of uveitisassociated secondary glaucoma. Jpn J Ophthalmol 46(5): 556–562

6. Neri P, Azuara-Blanco A, Forrester JV (2004) Incidence of glaucoma in patients with uveitis. Glaucoma 13(6):461–465 7. Herbert HM, Viswanathan A, Jackson H, Lightman SL (2004) Risk factors for elevated intraocular pressure in uveitis. J Glaucoma 13(2):96–99 8. Panek WC, Holland GN, Lee DA et al. (1990) Glaucoma in patients with uveitis. Br J Ophthalmol 74:223 9. Reddy S, Cubillan LD, Hovakimyan A, Cunningham ET (2007) Inflammatory ocular hypertension syndrome (IOHS) in patients with syphilitic uveitis. Br J Ophthalmol 91(12):1610–1612 10. Wolf MD, Lichter PR, Ragsdale CG (1987) Prognostic factors in the uveitis of juvenile rheumatoid arthritis. Ophthalmology 94:1242–1248 11. Toris CB, Pederson JE (1987) Aqueous humor dynamics in experimental iridocyclitis. Invest Ophthalmol Vis Sci 28:477 12. Epstein DL, Hashimoto JM, Grant WM (1078) Serum obstruction of aqueous outflow in enucleated eyes. Am J Ophthalmol 86:101–105 13. Roth M, Simmons RJ (1979) Glaucoma associated with precipitates on the trabecular meshwork. Ophthalmology 86(9):1613–1619 14. Mapstone R (1971) Vascular factors in the aetiology of secondary glaucoma. Trans Ophthalmol Soc UK 91: 741–748 15. Johnson DH (1996) Human trabecular meshwork cell survival is dependent on perfusion rate. Invest Ophthalmol Vis Sci 37(6):1204–1208 16. Kok HS, Barton K (2002) Uveitic glaucoma. Ophthalmol Clin North Am 15(3):375–387 17. Rao NA (1990) Role of oxygen free radicals in retinal damage associated with experimental uveitis. Trans Am Ophthalmol Soc 88:797–850 18. Rao NA, Wacker WB, Marak GE Jr(1979) Experimental allergic uveitis: clinicopathologic features associated with varying doses of S antigen. Arch Ophthalmol 97(10): 1954–1958 19. Wakefield D, Lloyd A (1992) The role of cytokines in the pathogenesis of inflammatory eye disease. Cytokine 4(1):1–5 20. Hogg P, Calthorpe M, Batterbury M, Grierson I (2000) Aqueous humor stimulates the migration of human trabecular meshwork cells in vitro. Invest Ophthalmol Vis Sci 41(5):1091–1098 21. Weinreb RN, Polansky JR, Kramer SG, Baxter JD (1985) Acute effects of dexamethasone on intraocular pressure in glaucoma. Invest Ophthalmol Vis Sci 26(2):170–175 22. Weinreb RN, Bloom E, Baxter JD, Alvarado J, Lan N, O’Donnell J, Polansky JR (1981) Detection of glucocorticoid receptors in cultured human trabecular cells. Invest Ophthalmol Vis Sci 21(3):403–407 23. McCarty GR, Schwartz B (1982) Increased concentration of glucocorticoid receptors in rabbit iris–ciliary body compared to rabbit liver. Invest Ophthalmol Vis Sci 23(4): 525–528

References 24. François J (1984) Corticosteroid glaucoma. Ophthalmologica 188(2):76–81 25. François J (1975) The importance of the mucopolysaccharides in intraocular pressure regulation. Invest Ophthalmol 14(3):173–176 26. Hernandez MR, Weinstein BI, Dunn MW, Gordon GG, Southren AL (1985) The effect of dexamethasone on the synthesis of collagen in normal human trabecular meshwork explants. Invest Ophthalmol Vis Sci 26(12):1784–1788 27. Snyder RW, Stamer WD, Kramer TR, Seftor RE (1993) Corticosteroid treatment and trabecular meshwork proteases in cell and organ culture supernatants. Exp Eye Res 57(4):461–468 28. Steely HT, Browder SL, Julian MB, Miggans ST, Wilson KL, Clark AF (1992) The effects of dexamethasone on fibronectin expression in cultured human trabecular meshwork cells. Invest Ophthalmol Vis Sci 33(7):2242–2250 29. Clark AF, Wilson K, McCartney MD, Miggans ST, Kunkle M, Howe W (1994) Glucocorticoid-induced formation of cross-linked actin networks in cultured human trabecular meshwork cells. Invest Ophthalmol Vis Sci 35(1): 281–294 30. Weinreb RN, Mitchell MD, Polansky JR (1983) Prostaglandin production by human trabecular cells: in vitro inhibition by dexamethasone. Invest Ophthalmol Vis Sci 24(12):1541–1545 31. Posner A, Scholssman A (1948) Syndrome of unilateral recurrent attacks of glaucoma with cyclitic symptoms. Arch Ophthalmol 39:517 32. Yamamoto S, Pavan-Langston D, Tada R, Yamamoto R, Kinoshita S, Nishida K, Shimomura Y, Tano Y (1995) Possible role of herpes simplex virus in the origin of Posner– Schlossman syndrome. Am J Ophthalmol 119(6):796–798 33. Kass MA, Becker B, Kolker AE (1973) Glaucomatocyclitis crisis and primary open-angle glaucoma. Am J Ophthalmol 75:668 34. Nagataki S, Mishima S (1976) Aqueous humor dynamics in glaucomato-cyclitis crisis. Invest Ophthalmol 15:365 35. Mohamed Q, Zamir E (2005) Update on Fuchs’ uveitis syndrome. Curr Opin Ophthalmol 16:356–363 36. Quentin CD, Reibe H (2004) Fuchs heterochromic cyclitis: rubella virus antibodies and genome in aqueous humor. Am J Ophthalmol 138:46–54 37. de Groot-Mijnes JD, de Visser L, Rothova A, Schuller M, van Loon AM, Weersink AJ (2006) Rubella virus is associated with Fuchs’ heterochromic iridocyclitis. Am J Ophthalmol 141:212–214 38. Birnbaum AD, Tessler HH, Schultz KL, Farber MD, Gao W, Lin P, Oh F, Goldstein DA (2007) Epidemiologic relationship between Fuchs’ heterochromic iridocyclitis and the United States rubella vaccination program. Am J Ophthalmol 144(3):424–428 39. Birnbaum AD, Tessler HH, Schultz KL, Farber MD, Gao W, Lin P, Oh F, Goldstein DA (2007) A case of hypertensive keratouveitis with endotheliitis associated with cytomegalovirus. Ocul Immunol Inflamm 15(5):399–401

57

40. Falcon MG, Williams HP (1978) Herpes simplex keratouveitis and glaucoma. Trans Ophthal Soc UK (98): 101–104 41. van Boxtel LA, van der Lelij A, van der Meer J, Los LI (2007) Cytomegalovirus as a cause of anterior uveitis in immunocompetent patients. Ophthalmology 114(7):1358–1362 42. Townsend WM, Kaufman HE (1971) Pathogenesis of glaucoma and endothelial changes in herpetic keratouveitis in rabbits. Am J Ophthalmol 71 (904–910) 43. Thean JH, Hall AJ, Stawell RJ (2001) Uveitis in Herpes zoster ophthalmicus. Clin Exp Ophthalmol 29(6):406– 410 44. de Schryver I, Rozenberg F, Cassoux N et al (2006) Diagnosis and treatment of cytomegalovirus iridocyclitis without retinal necrosis. Br J Ophthalmol 90(7):852–855 45. Markomichelakis NN, Canakis C, Zafirakis P, Marakis T, Mallias I, Theodossiadis G (2002) Cytomegalovirus as a cause of anterior uveitis with sectoral iris atrophy. Ophthalmology 109(5):879–882 46. Merayo-Lloves J, Power WJ, Rodriguez A, Pedroza-Seres M, Foster CS (2000) Secondary glaucoma in patients with juvenile rheumatoid arthritis-associated iridocyclitis. Acta Ophthalmol Scand 78(5):576–579 47. Paroli MPSS, Marino M, Pirraglia MP, Pivetti-Pezzi P (2003) Prognosis of juvenile rheumatoid arthritis-associated uveitis. Eur J Ophthalmol 13(7):616–621 48. Carvounis PEHD, Cha S, Burke JP (2006) Incidence and outcomes of uveitis in juvenile rheumatoid arthritis, a synthesis of the literature. Graefes Arch Clin Exp Ophthalmol 244(3):281–290 49. Holland GN (2003) Ocular toxoplasmosis: a global reassessment. Part I: epidemiology and course of disease. Am J Ophthalmol 136(6):973–988 50. Rothova A (2003) Ocular manifestations of toxopasmosis. Curr Opin Ophthalmol 14(6):344–348 51. Westfall AC, Lauer AK, Suhler EB, Rosenbaum JT (2005) Toxoplasmosis retinochoroiditis and elevated intraocular pressure: a retrospective study. J Glaucoma 14(1):3–10 52. Lobo A, Barton K, Minassian D, du Bois RM, Lightman S (2003) Visual loss in sarcoid-related uveitis. Clin Exp Ophthalmol 31(4):310–316 53. Jabs DA, Johns CJ (1986) Ocular involvement in chronic sarcoidosis. Am J Ophthalmol 102(3):297–301 54. Dana MR, Merayo-Lloves J, Schaumberg DA, Foster CS (1996) Prognosticators for visual outcome in sarcoid uveitis. Ophthalmology 103(11):1846–1853 55. Fechtner RDKA, Zimmerman TJ, Bullock J, Feldman R, Kulkarni P, Michael AJ, Realini T, Warwar R (1998) Anterior uveitis associated with latanoprost. Am J Ophthalmol 126(1):37–41 56. Smith SLPC, Sine CS, Hudgins AC, Stewart WC (1999) Latanoprost 0.005% and anterior segment uveitis. Acta Ophthalmol Scand 77(6):668–672 57. Packer MFI, Hoffman RS (2003) Bilateral nongranulomatous anterior uveitis associated with bimatoprost. J Cataract Refract Surg 29(11):2242–2243

58

6

6 Uveitic Glaucoma

58. Parentin F (2003) Granulomatous anterior uveitis associated with bimatoprost: a case report. Ocul Immunol Inflamm 11(1):67–71 59. Faulkner WJBS (2003) Acute anterior uveitis and corneal edema associated with travoprost. Arch Ophthalmol 121(7):1054–1055 60. Kumarasamy MDS (2004) Anterior uveitis is associated with travoprost. BMJ 329:205 61. Suominen SVJ (2006) Bilateral anterior uveitis associated with travoprost. Acta Ophthalmol Scand 84(2):275– 276 62. Jabs DA, Rosenbaum JT, Foster CS, Holland GN, Jaffe GJ, Louie JS, Nussenblatt RB, Stiehm ER, Tessler H, Van Gelder RN, Whitcup SM, Yocum D (2000) Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol 130(4):492–513

63. Freedman SFR-RR, Rojas MC, Enyedi LB (2002) Goniotomy for glaucoma secondary to chronic childhood uveitis. Am J Ophthalmol 133(5):617–621 64. Kanski JJ, McAllister JA (1985) Trabeculodialysis for inflammatory glaucoma in children and young adults. Ophthalmology 92:927–930 65. Ho CLWE, Walton DS (2004) Goniosurgery for glaucoma complicating chronic childhood uveitis. Arch Ophthalmol 122(6):838–844 66. Williams RDHH, Shaffer RN (1992) Trabeculodialysis for inflammatory glaucoma: a review of 25 cases. Ophthalmic Surg 23(1):36–37 67. Katz GJ, Higginbotham EJ, Lichter PR, Skuta GL, Musch DC, Bergstrom TJ, Johnson AT (1995) Mitomycin C versus 5-fluorouracil in high-risk glaucoma filtering surgery. Extended follow-up. Ophthalmology 102(9):1263–1269

Chapter 7

Nonpenetrating Glaucoma Surgery Efstratios Mendrinos, Tarek Shaarawy

7

Core Messages ■

■

■

Nonpenetrating glaucoma surgery (NPGS) refers to drainage procedures that restore aqueous humor filtration through a natural membrane, the trabeculo-Descemet’s membrane (TDM). It targets the presumed site of pathology, namely Schlemm’s canal and the juxtacanalicular meshwork. NPGS encompasses various surgical techniques, including ab-externo trabeculectomy, nonpenetrating deep sclerectomy and viscocanalostomy. The main advantage of NPGS is the prevention of early complications related to the penetration of

7.1

Introduction

In 1964 Krasnov published his first report on sinusotomy. This operation consisted of removing a lamellar band of sclera and opening Schlemm’s canal over 120° from ten to two o’ clock [1]. The inner wall of Schlemm’s canal was untouched and the conjunctiva was closed. Sinusotomy never became popular because it was a difficult operation; it needed a surgical microscope, and Schlemm’s canal had to be found, which was not easy. In the late 1960s and for the next three decades, trabeculectomy, as described by Sugar [2] in 1961 and Cairns [3] in 1968 became the gold standard technique for filtering surgery. However, even with the numerous modifications proposed to the original trabeculectomy, the lack of a reproducible postoperative intraocular pressure (IOP) reduction as well as early postoperative complications, such as overfiltration and hypotony, mainly related to penetration of the anterior chamber with sudden decompression of the eye, led several surgeons to reconsider Kraznov’s work. Several techniques of nonpenetrating filtering surgery based on sinusotomy have been described. Since the main aqueous outflow resistance is located at the juxtacanalicular trabeculum and the inner wall of Schlemm’s canal, these two anatomical structures were targeted. Nonpenetrating trabeculectomy was proposed by Zimmermann [4]

■

■

the anterior chamber. The main disadvantage is the long learning curve it demands. Its safety profile makes it the first choice in many cases. Primary and secondary angle-closure glaucomas are relative contraindications. Neovascular glaucoma is an absolute contraindication. NPGS is efficient at lowering the intraocular pressure. The use of space-occupying implants and Nd-YAG goniopuncture is associated with a higher success rate.

in 1984, and Arenas first published the term ab-externo trabeculectomy in 1991 [5]. Fyodorov stressed the removal of the corneal stroma behind the anterior trabeculum and Descemet’s membrane, and termed this “deep sclerectomy” [6]. This was also described by Kozlov [7] and later by Stegmann [8]. Currently, deep sclerectomy, along with ab-externo trabeculectomy and viscocanalostomy, are the mostly commonly used nonpenetrating procedures.

7.2 7.2.1

Deep Sclerectomy Superficial Scleral Flaps

The conjunctiva may be opened either at the fornix or at the limbus. A 5 × 5 mm superficial scleral flap is created that includes one-third of the scleral thickness (300 mm). To allow Descemet’s membrane to be reached later in the dissection, the superficial scleral flap must be cut 1–2 mm anteriorly into clear cornea (Fig. 7.1). The initial incision is made with a No. 11 stainless steel blade and the horizontal dissection with any crescent knife. In patients with a high risk of scleroconjunctival scar formation, a sponge soaked in mitomycine 0.02% may be placed for 45 s in the scleral bed and between the sclera and Tenon’s capsule, and then washed with balanced salt solution for 60 s.

60

7 Nonpenetrating Glaucoma Surgery

7

Fig. 7.1 Creation of a superficial scleral flap. A 5 × 5 mm superficial scleral flap is performed including one-third of the scleral thickness. In order to reach Descemet’s membrane later in the dissection, the superficial scleral flap has to be prolonged 1–2 mm anteriorly into the clear cornea

Fig. 7.2 Schematic representation of deep sclerectomy. Under the superficial scleral flap, a deep corneosclerotomy unroofing Schlemm’s canal is performed. Corneal tissue removal behind the anterior trabeculum and Descemet’s membrane is performed. When the anterior dissection is completed, the deep scleral flap is removed

one, leaving a step in the sclera on the three sides, allowing for a tighter closure of the superficial flap in the case of an intraoperative perforation of trabeculo-Descemet’s membrane (TDM). The deep scleral flap is then dissected horizontally using the blade. The remaining scleral layer should be as thin as possible (50–100 mm). Deep sclerectomy is preferably started first in the posterior part of the deep scleral flap. On reaching the anterior part of the dissection, Schlemm’s canal is unroofed; it is located anterior to the scleral spur, where the scleral fibers are regularly oriented, parallel to the limbus. In patients with congenital glaucoma, localization of the canal is more difficult because it is often situated more posteriorly. Schlemm’s canal is opened and the sclerocorneal dissection is prolonged anteriorly for 1–2 mm in order to remove the sclerocorneal tissue behind the anterior trabeculum and Descemet’s membrane. This step of the surgery is quite challenging because there is a high risk of perforating the anterior chamber. To avoid a perforation, the anterior trabeculum and Descemet’s membrane can be gently detached using a sponge, a spatula or a blunt metallic blade. The best way to perform this last dissection is to make two radial corneal cuts without touching the anterior trabeculum or Descemet’s membrane. This is performed with a 15° diamond knife or preferably with a No. 11 steel blade with the bevel side up. When the anterior dissection between the corneal stroma and Descemet’s membrane is completed, the deep scleral flap is removed by cutting it anteriorly using microscissors. At this stage of the procedure, there should be evident percolation of aqueous through the remaining trabeculum. To peel away the thin Schlemm’s canal endothelium and juxtacanalicular trabeculum, it is crucial to dry the exposed inner wall of Schlemm’s canal, which can then be grabbed with a fine forceps and peeled away easily by pulling on it (Fig. 7.3). This additional procedure corresponds to ab-externo trabeculectomy [4, 9]. To keep the intrascleral space created patent, an implant may be used. The superficial scleral flap is then repositioned and sutured with 10/0 sutures (Fig. 7.4).

7.3 ■

7.2.2

Deep Sclerectomy and Exposure of Trabeculo-Descemet’s Membrane

Deep sclerokeratectomy is performed by making a second deep 4 × 4 mm scleral flap (Fig. 7.2). The two lateral and the posterior deep scleral incisions are made using a No. 11 steel blade. The deep flap is smaller than the superficial

■ ■ ■ ■

Deep Sclerectomy Technique

A superotemporal intracorneal suture is used to expose the surgical quadrant. Fornix- or limbus-based conjuctival incision is performed. A 5 × 5 mm superficial scleral flap is dissected, extending 1–2 mm into clear cornea. A second 4 × 4 mm-deep scleral flap is created. Initiate the dissection flap by exposing the choroid and dissect slightly superficial to that.

7.4 The Use of Implants

■

■

61

the percolation of aqueous humor through the TDM membrane and remove the deep scleral flap. A space-maintainer implant is placed in the scleral bed when nonpenetrating deep sclerectomy is performed. When viscocanalostomy is performed, high-viscosity hyaluronic acid is injected into the ostia of Schlemm’s canal. The superficial scleral flap, Tenon’s capsule and the conjuctiva are then closed.

7.4 The Use of Implants

Fig. 7.3 Schematic representation of ab-externo trabeculectomy. The juxtacanalicular trabeculum and Schlemm’s canal endothelium are removed. The inner wall of Schlemm’s canal can be grabbed with a blunt forceps and peeled away easily by pulling on it

Fig. 7.4 Use of implants. An implant may be used to keep the intrascleral space created patent. A collagen implant is secured in the scleral bed with a single 10/0 nylon suture. The superficial scleral flap is then repositioned and sutured with 10/0 sutures

To avoid secondary collapse of the superficial flap, a space-maintainer implant is placed in the scleral bed. The first to be used was the Aquaflow collagen implant (Collagen Glaucoma Drainage Device, STAAR Surgical AG, Nidau, Switzerland) [10, 11], which is a highly purified porcine collagen dehydrated into a cylinder (4 mm × 1 mm × 1 mm). This device is placed radially in the center of the deep sclerectomy dissection, as far as possible anteriorly such that it is in contact with the remaining TDM membrane and secured in the scleral bed with a single 10/0 nylon suture (Fig. 7.4). It swells rapidly once exposed to the aqueous humor and is resorbed within 6–9 months after surgery [12]. Another device that has been proposed to maintain the scleral lake is the reticulated hyaluronic acid implant (SK-GEL, Corneal, Paris, France; an equilateral triangle 3.5 mm long and 500 mm thick or an isosceles triangle of size 4.5 mm × 3 mm with the same thickness) [13]. The advantages of this implant are that it occupies a large volume in the filtration area while allowing for sufficient circulation of the aqueous humor, and that it does not need to be sutured at the sclera. More recently, a nonabsorbable hydrophilic acrylic implant (T-flux implant, IOLTech Laboratories, La Rochelle, France) has been developed [14]. This is a T-shaped implant that creates an evacuating canal along the foot, and each arm of the T shape is inserted into one of the surgically created openings of Schlemm’s canal.

7.5 Viscocanalostomy ■ ■

■

Gently press on the floor of Schlemm’s canal to detach Descemet’s membrane from the corneal stroma. Extend the deep scleral flap anteriorly by making two radial corneal cuts with a No. 11 stainless steel blade with the bevel side up. Dry the exposed inner wall of Schlemm’s canal before peeling away the thin endothelium of Schlemm’s canal and the juxtacanalicular trabeculum. Watch for

Stegmann et al. [8] described a variant of NPGS and termed it viscocanalostomy to emphasize the importance of injecting high-viscosity sodium hyaluronate (Healon GV) into Schlemm’s canal as a means of improving aqueous drainage by this route. It has been postulated that physiologic aqueous humor drainage may then be restored without the formation of a filtration bleb because the superficial scleral flap is tightly sutured, meaning that

62

7

7 Nonpenetrating Glaucoma Surgery

aqueous humor regressing through the TDM can only reach the two surgically created ostia of Schlemm’s canal, travel circumferentially within it, and enter the collector channel ostia and ultimately the aqueous veins. They also proposed an increased outflow mechanism for the procedure’s success; aqueous humor that passes through the TDM window into the scleral bed can diffuse into the uveoscleral outflow system adjacent to it. The viscoelastic material is also placed in the scleral bed and may prevent fibrin crosslinking and early scarring. In vivo primate [15, 16] and human eye [15] studies reported that the injection of viscoelastic into Schlemm’s canal resulted in not only the dilatation of the canal and associated collector channels but also in focal disruptions of the inner wall endothelium of Schlemm’s canal and disorganization of the juxtacanalicular zone, resulting in direct communication of the juxtacanalicular zone’s extracellular spaces with the lumen of Schlemm’s canal. This may initially enhance conventional aqueous outflow [15], accounting for an approximately 30% increase in ouflow facility in nonhuman primates [16]. Disruption of the posterior wall of Schlemm’s canal may also provide direct communication between its lumen and the tissues of the ciliary body, thereby enhancing uveoscleral outflow [15].

7.6

Mechanisms of Filtration

There are two sites of interest when studying the mechanisms involved in the efficiency and safety of nonpenetrating surgeries: (1) the flow of aqueous humor through the TDM, and (2) the resorption of aqueous after its passage through the TDM.

7.6.1

Flow Through the TDM

The TDM offers resistance to aqueous humor outflow. This resistance appears to be low enough to ensure a low IOP and yet sufficiently high to maintain the anterior chamber depth and avoid postoperative complications in relation to hypotony. Vaudaux et al. studied the aqueous outflow through the TDM in an experimental model [17]. The mean rate of IOP decrease was 2.7 ± 0.6 mm Hg min−1. The ocular aqueous outflow resistance dropped from a mean of 5.34 ± 0.19 ml min−1 mm Hg−1 preoperatively to a mean of 0.41 ± 0.16 ml min−1 mm Hg−1 postoperatively. They also reported that the outflow facility increased from 0.19 ± 0.03 to 24.5 ± 12.6 ml min−1 mm Hg−1 after deep sclerectomy. The same study examined the surgical site histologically using ocular perfusion with ferritine, demonstrating that the main outflow through

the TDM occurred at the level of the anterior trabeculum [18]. There was, however, some degree of outflow through the posterior trabeculum and Descemet’s membrane.

7.6.2

Aqueous Humor Resorption

After the passage of aqueous humor through the TDM, four hypothetical mechanisms of aqueous resorption may occur: a subconjunctival filtering bleb; an intrascleral filtering bleb; a suprachoroidal filtration; and an episcleral vein outflow via Schlemm’s canal. 7.6.2.1 Subconjunctival Bleb

Just like after trabeculectomy, almost all patients that undergo nonpenetrating filtering surgeries have a diffuse, conjunctival bleb on the first postoperative day. As demonstrated by UBM studies, successful cases show a low and diffuse subconjunctival filtering bleb even years after surgery [19]. However, this bleb tends to be shallower and more diffuse than the one seen after trabeculectomy. It occurs more commonly with deep sclerectomy than with viscocanalostomy. Controversy exists regarding the issue of conjuctival blebs following viscocanalostomy. Negri-Aranguren [20] did not find filtering blebs except in one out of 23 eyes 7–9 months after viscocanalostomy, thus suggesting a mechanism of filtration other than the subconjuctival one. O’Brart et al. [21] reported evidence of subconjuctival blebs in all patients, with successful drainage and disappearance of the blebs in patients with drainage failure after viscocanalostomy, suggesting the significance of subconjuctival fibrosis. Drüsedau et al. [22] observed subconjuctival drainage in more than half of their patients at one year despite attempts to make the scleral flap watertight and to resuture leaks in the early postoperative period. In another study [23], conjuctival blebs were present in all eyes with successful IOP control, which may indicate that at least some of the drainage takes place after VCS by the subconjuctival route. 7.6.2.2 Intrascleral Bleb

During deep sclerectomy, a certain volume of sclera ranging between 5 and 8 mm3 is removed. Provided the superficial scleral flap does not collapse, this scleral volume may be transformed into an intrascleral filtering bleb. The use of implants is aimed at keeping this intrascleral space patent. In a study of deep sclerectomy with collagen implants by Kazakova et al. [24], an intrascleral bleb was observed in more than 90% of patients who

7.7 Nd:Yag Goniopuncture

received a collagen implant, and the mean volume of the intrascleral bleb was 1.8 mm3. In the intrascleral filtering bleb, the aqueous resorption mechanism may be different to the one that occurs in the subconjunctival space. The aqueous is probably resorbed by new aqueous drainage vessels, as has been demonstrated by Delarive et al. [25] This study showed that in the scleral space created after deep sclerectomy, regardless whether or not a collagen implant was used, new aqueous humor drainage vessels grew and resorbed the aqueous flow through the TDM.

Summary for the Clinician ■

■ ■

7.6.2.3 Suprachoroidal Space

Aqueous humor outflow into the suprachoroidal space may occur upon thinning the sclera by 90%; in fact, on UBM, it is possible to observe a hyporeflective suprachoroidal area, and this may represent the accumulation of fluid in the suprauveal space through the thin deep scleral wall [26]. However, this could also indicate a chronic localized ciliary body detachment with a subsequent reduction in aqueous production. Chiou et al. [12] found this UBM sign in 23 (51%) out of 45 cases of DSCI, and stated that its presence was associated with lower IOP that was statistically significant at two and three months postoperatively. Roters et al. [27] detected a suprachoroidal hyporeflective area in six (40%) out of 15 eyes one year after viscocanalostomy, but its presence was not associated with surgical success. Negri-Aranguren et al. [20] performed a similar study, but observed this area in only two of 23 eyes that underwent viscocanalostomy, and so they considered that this did not support a major role for the uveal pathway. It is not yet known how much aqueous is reabsorbed by this route, and further studies are needed to elucidate it. 7.6.2.4 Schlemm’s Canal

When performing deep sclerectomy dissection, Schlemm’s canal is opened and unroofed. On either side of the deep sclerectomy, the two surgically created ostia of Schlemm’s canal may drain the aqueous humor into the episcleral veins. This mechanism is probably more important after viscocanalostomy, during which the ostia and Schlemm’s canal are dilated with high-viscosity hyaluronic acid. This mechanism is supported by the observation that it produces a periodic appearance of the viscoelastic substance in the aqueous veins as blood is displaced [8]. It is probably also important with HEMA implants, because the two arms of the T-shaped implant are inserted into the two ostia of Schlemm’s canal, thereby preventing their collapse. Research is still needed to establish the importance of this mechanism.

63

■

■

■

The principal common concept in nonpenetrating glaucoma surgery is to create filtration through a naturally occurring membrane, the TDM, that acts as an outflow resistance site, allowing a progressive drop in IOP and avoiding postoperative ocular hypotony. The TDM consists of the trabeculum and the peripheral Descemet’s membrane. To expose the TDM, a deep sclerokeratectomy should be performed, thereby also providing a postoperative intrascleral space. The intrascleral space may act as an aqueous reservoir and filtration site, which may prevent the need for a large subconjunctival filtration bleb. The use of implants is aimed at keeping this space patent. The injection of viscoelastic material into Schlemm’s canal during viscocanalostomy results in dilatation of the canal and in the direct communication of the juxtacanalicular space with the lumen of Schlemm’s canal. Enhanced aqueous outflow through Schlemm’s canal may occur following viscocanalostomy. Aqueous humor outflow into the suprachoroidal space may also occur and partially account for filtration after nonpenetrating glaucoma surgery.

7.7

Nd:Yag Goniopuncture

When filtration through the TDM is considered to be insufficient because of elevated IOP, Nd:Yag goniopuncture can be performed. An insufficient surgical dissection can be the reason for elevated IOP in the first postoperative period or fibrosis of the TDM if it is required later than approximately nine months, which may lead to a flattened bleb. Using a gonioscopic contact lens, the aiming beam is focused into the semitransparent TDM. Using the free-running and Q-switched mode, with a power of 5–10 mJ, 2–15 shots are applied, resulting in the formation of microscopic holes through the TDM and allowing the direct passage of aqueous from the anterior chamber to the intrascleral space. In their studies on the results of deep sclerectomy, Shaarawy et al. performed goniopuncture in 42–46% of their patients who had undergone deep sclerectomy without implant, and in 46–51% of those who had undergone DSCI [28–30]. The immediate success rate was 91.6% [30]. In their study on the results of viscocanalostomy [31], 37% of their patients needed

64

7 Nonpenetrating Glaucoma Surgery

goniopuncture postoperatively to control raised IOP. The mean time between surgery and goniopuncture was 9.4 months, with an immediate reduction in mean IOP of 39.5%.

7 7.8 Technique ■ ■ ■ ■

Topical anesthesia with oxybuprocaine eyedrops 0.5% Using a gonioscopic contact lens, focus the aiming beam of the laser into the semitransparent TDM Settings: free-running and Q-switched mode, power 5–10 mJ 2–15 laser shots are applied

7.9

7.9.1

Indications for Nonpenetrating Glaucoma Surgery Primary Open Angle Glaucoma

NPGS targets the presumed site of pathology in primary open-angle glaucoma (POAG), namely the trabecular meshwork [32]. The site of aqueous outflow resistance is presumed to be the juxtacanalicular trabeculum, the inner wall of Schlemm’s canal, and the endothelial lining. Scraping, thinning out and peeling the posterior trabeculum improve filtration. In NPGS, deep sclerectomy and ab-externo trabeculectomy are both necessary to obtain an optimal decrease in outflow resistance. Nonpenetrating glaucoma surgery has the advantage of being less cataractogenic than trabeculectomy and ideally should be considered as a safer option in phakic patients with POAG. It is an efficient surgery in medically uncontrolled POAG [33].

7.9.2

Glaucoma in High Myopia

Conventional glaucoma surgery in patients with high myopia carries an especially high risk of complications because of the abnormal globe dimensions. NPGS appears to offer glaucoma patients with high myopia a safer outcome because of the gradual intraoperative IOP reduction. Hamel et al. studied NPGS in 21 highly myopic glaucoma patients with medically uncontrolled primary or secondary open-angle glaucoma [30]. Complete (IOP < 21 mm Hg) and qualified success rates were 38 and 81%, respectively, at four years following surgery. In their series, only two patients developed choroidal detachment.

7.9.3 Pseudoexfoliation and Pigmentary Glaucoma NPGS is a safe and valuable option in patients with PEXG and seems especially appropriate in these patients, given the increased permeability of the blood–aqueous barrier as well as the higher risk of complications with intraocular surgery, such as trabeculectomy in pseudoexfoliation syndrome eyes [34]. In a prospective study, Droslum [35] compared the results of deep sclerectomy with implant in pseudoexfoliative glaucoma (PEXG) with those in POAG and found higher complete success rates (IOP < 19 mm Hg without medical therapy) in the PEXG group after a mean follow-up of 18 months, with complete success seen in 60.7 and 37.9%, respectively. The difference was maintained after a longer mean follow-up of 3.5 years (50% in the PEXG group compared with 33% in the POAG group) [36]. NPGS is also a potential therapy for pigmentary glaucoma. It targets the site of pathology, namely the pigment-loaded trabecular meshwork, which can be reconditioned to establish filtration. To our knowledge there are no reported results in the literature for a large series of patients with pigmentary glaucoma. Existing data refer to a small number of patients with pigmentary glaucoma included in large series of patients with POAG.

7.9.4

Uveitic Glaucoma

Glaucoma secondary to uveitis presents a management challenge. When medical treatment fails to control IOP, surgery is indicated, although conventional techniques are at high risk of failure due to marked postoperative inflammation and scarring. Although the use of antimetabolites can improve the success rate of glaucoma surgery, it also increases the severity of well-known complications [37]. NPGS is indicated in these cases because it explores the site of resistance to aqueous outflow and is associated with less postoperative inflammation [38]. Deep sclerectomy and viscocanalostomy has been found to be a safe and effective surgical alternative in eyes with uncontrolled uveitic glaucoma [39, 40]. However, in cases in which multiple peripheral anterior synechiae have occurred, NPGS may not offer an efficient solution. Larger studies are needed to fully assess the role of NPGS in the management of uveitic glaucoma.

7.9.5

Congenital and Juvenile Glaucoma

The desire to reduce complications and fulfill the need for a good success rate that is comparable with those of current surgical standards has led to an evaluation of

7.10 Contraindications for Nonpenetrating Glaucoma Surgery

NPGS in congenital glaucoma. Tixier et al. [41] were the first to report on results of deep sclerectomy in 12 eyes with congenital glaucoma. No intra- or immediate postoperative complications were observed, and success was achieved in 75% of eyes (IOP < 16 mm Hg under general anesthesia at final examination). They concluded that deep sclerectomy is at least as effective as trabeculectomy in congenital glaucoma, with fewer complications due to the absence of anterior chamber penetration. Other authors have reported similar results with deep sclerectomy and viscocanalostomy on congenital and juvenile glaucoma [42–44]. When NPGS is insufficient because there is weak percolation through the TDM or it is technically demanding, it is always possible to combine it with other ab-externo procedures or to convert to penetrating glaucoma surgery, particularly in cases where the anatomy of the angle is severely distorted.

7.9.6

7.9.7

Hg) with or without medication in 77–92% of eyes at each follow-up vs. 30–50% of eyes in the second group. At one year after surgery, 89 and 37.5% of eyes were controlled in the first and second group, respectively, with no major complications. The authors, however, did not perform peeling of Schlemm’s canal endothelium during surgery. NPGS may be valuable as an initial procedure in aphakic patients who require surgery, at least in POAG.

Summary for the Clinician ■

■ ■

Glaucoma Associated with Sturge–Weber Syndrome

Sturge–Weber syndrome (SWS) is a rare congenital disease characterized by a facial angioma, an ipsilateral leptomeningeal hemangioma and ocular manifestations, including hemangiomas of the conjuctiva, episclera, uvea and retina. Glaucoma is the most common ophthalmic complication of SWS, occurring in 30–70% of patients [45]. Trabeculectomy has been reported to have good short-term results but carries the risk of massive choroidal effusion or expulsive hemorrhage, which is already increased in these patients [46, 47]. A few reports exist on the effect of NPGS on SWS [48, 49]. We consider NPGS a valuable therapeutic option that can be associated with medical and/or laser treatment, offering a safer and efficient alternative to trabeculectomy when it is technically possible. Further studies of NPGS for the treatment of glaucoma associated with SWS are warranted.

Glaucoma in Aphakia

The surgical management of uncontrolled IOP in aphakia remains one of the most difficult problems encountered in patients with glaucoma [50]. It is also a serious, sightthreatening complication in children who remain aphakic following congenital cataract surgery, with an incidence varying from 15 to 45% [51]. Zimmerman et al. [52] performed nonpenetrating trabeculectomy on 28 aphakic eyes, consisting of a first group of 18 eyes with chronic open-angle glaucoma and a second group of ten eyes with secondary and/or complicated glaucoma. Results were better in the first group with the IOP controlled (£ 24 mm

65

■

■

■

NPGS is an efficient surgery in medically uncontrolled POAG. It should be considered a safer option than trabeculectomy in phakic patients with POAG. NPGS appears to offer glaucoma patients with high myopia a safe filtering procedure. NPGS is a safe and valuable option in patients with pseudoexfoliative glaucoma, and seems especially appropriate in these patients given the increased permeability of the blood–aqueous barrier as well as the higher risk of complications with intraocular surgery. NPGS is also a potential therapy for pigmentary glaucoma. It targets the site of pathology, namely the pigment-loaded trabecular meshwork, which can be reconditioned to establish filtration. NPGS is indicated in uveitic glaucoma cases because it explores the site of resistance to aqueous outflow and is associated with less postoperative inflammation. NPGS may be indicated in some cases of congenital, juvenile glaucoma and aphakic glaucoma when the iridocorneal angle is not severely distorted. If not sufficient, it can be associated with other ab-externo procedures and/or with laser or medical treatment. Converting to penetrating surgery may be necessary in refractory cases.

7.10

7.10.1

Contraindications for Nonpenetrating Glaucoma Surgery Relative Contraindications

The relative contraindications for NPGS are inherent to the status of the trabeculum because this surgery relies on the integrity of this structure for its outcomes. 7.10.1.1 Narrow-Angle Glaucoma

There are no available studies in the literature on NPGS in narrow-angle glaucoma, but most authors consider this condition a relative contraindication [30]. Laser iridotomy

66

7

7 Nonpenetrating Glaucoma Surgery

or surgical iridectomy is mostly a temporary therapeutic option in narrow-angle glaucoma. Cataract extraction or removal of a clear crystalline lens deepens the anterior chamber and opens the angle of the eye. When narrowangle glaucoma has persisted for a certain length of time, glaucoma surgery is indicated in combination with lens extraction. For these combined procedures, NPGS may be attempted, even though the iris root is very close to the trabeculum and effective filtration may not occur immediately. 7.10.1.2 Status Post Laser Trabeculoplasty

In eyes previously treated by laser trabeculoplasty, the trabeculum may not be intact and could rupture during surgery. NPGS can be then converted to classical trabeculectomy. 7.10.1.3 Post-Traumatic Angle-Recession Glaucoma

In angle-recession glaucoma, the trabeculum loses its function because of scarification processes and NPGS may not be possible. An attempt at NPGS can be made, as the damage to the trabeculum is not always complete and its function may be restored by scraping and peeling its posterior surface.

or without antimetabolites. This is largely due to the fact that the eye is not fully penetrated as in trabeculectomy, and that the aqueous is percolated through the remaining TDM, thus preventing a sudden intra- and postoperative hypotony. Moreover, visual acuity is generally preserved after NPGS and returns to the preoperative level within the first postoperative week [54]. This is because postoperative cycloplegic medication is not used as well as due to low inflammation after surgery. Table 7.1 summarizes the advantages and disadvantages of NPGS. Complications of nonpenetrating glaucoma surgery can be intraoperative, early postoperative or late postoperative. These complications are listed in Table 7.2 and are discussed here.

7.11.1 Intraoperative Complications Probably the most common intraoperative complication of nonpenetrating surgery is perforation of the TDM. It is acceptable to have a perforation rate of about 30% in the first 10–20 cases. After the initial learning phase, the surgeon should expect a perforation in about 2–3% of cases. Karlen et al. [55] report a perforation in three out of the first ten surgeries (30%). With increased surgical experience, this complication was rare, occurring in three of the subsequent 96 deep sclerectomies (3.1%). Different types of perforations include transverse tears and TDM holes.

7.10.2 Absolute Contraindications NPGS is contraindicated in neovascular glaucoma, where new blood vessels invade the angle. NPGS will fail in these cases because the iridocorneal angle is invaded by blood vessels. The trabeculum loses its filtering function because of the presence of the neovascularization. This type of glaucoma is the most difficult to treat and until now only the implantation of drainage devices has yielded favorable results [53].

7.11.1.1 Transverse Tears

Occur at the junction of the anterior trabeculum and Descemet’s membrane, probably the weakest point of the TDM, and corresponds to Schwalbe’s line on gonioscopy. A perforation at this level will usually lead to the formation of a long tear, followed by immediate iris prolapse. 7.11.1.2 TDM Holes

Summary for the Clinician ■

■

Secondary angle closure etiologic entities are a relative contraindication. The decision, though, depends on the degree of angle closure. Neovascular glaucoma is an absolute contraindication.

7.11

Complications of Nonpenetrating Glaucoma Surgery

There is an agreement among published reports that nonpenetrating surgery offers a lower rate of complications when compared to conventional trabeculectomy, with

Holes may occur in the TDM during the anterior deep dissection. Holes may be small with no loss of depth of the anterior chamber or large and accompanied by a shallow or flat anterior chamber and/or iris prolapse. The two factors that determine the management of a TDM perforation are the size of it, the depth of the anterior chamber, as well as the presence of an iris prolapse [56]. Small holes with no iris prolapse or loss of anterior chamber depth can be ignored and the surgery continued normally. Small or large perforations with a shallow or flat anterior chamber and no iris prolapse should be dealt with in order to prevent subsequent iris prolapse or peripheral anterior synechia formation. Viscoelastic material should be injected, through a paracentesis, into

7.11 Complications of Nonpenetrating Glaucoma Surgery

67

Table 7.1 Advantages and disadvantages of nonpenetrating glaucoma surgery Advantages

Disadvantages

Low rate of postoperative complications

More difficult surgery

Shorter ambulatory care

Prolonged surgery time

Long learning curve Rapid visual acuity recovery

May need Nd-Yag goniopuncture

Limited postoperative inflammation

Increased cost (implant or viscoelastics)

Significantly less cataract formation More diffuse and shallow filtering blebs

Not applicable in neovascular glaucoma and relatively contraindicated in closed-angle glaucoma

Limited risk for endophthalmitis Safe surgery for end-stage glaucoma Easy postoperative follow-up Closed globe surgery

the anterior chamber under the TDM window to reform it and reposition the iris. The smallest possible amount of viscoelastic material of low molecular weight (Healon®) should be used to avoid a postoperative ocular pressure spike. In addition, an implant resting on the perforation site may be used to tamponade the hole. The superficial scleral flap should also be tightly sutured with 6–8 10/0 nylon sutures. Iris prolapse accompanying a long tear or large hole must lead to converting NPGS to trabeculectomy with a peripheral iridectomy; the superficial flap should again be tightly closed and viscoelastic material should be injected into the surgically created scleral space to increase the outflow resistance.

7.11.2

Early Postoperative Complications

7.11.2.1 Inflammation

The degree of inflammatory reaction following the surgical trauma is considerably less in nonpenetrating surgery compared to trabeculectomy. Chiou et al. [38], in a study of postoperative inflammation after deep sclerectomy with collagen implant and standard trabeculectomy, found significantly lower postoperative flare measurements in the first group, with the preoperative level reached within one week. In contrast, following trabeculectomy, the inflammation in the anterior chamber was much more intense and persisted for one month before getting down to the preoperative level. This may be due to the lack of iridectomy, irrigation, and penetration of the anterior chamber. Eyes at increased risk of postoperative inflammation, such as those with pseudoexfoliative glaucoma and particularly those with uveitic or traumatic glaucoma, may benefit from this procedure.

7.11.2.2 Hypotony and Associated Complications

The mean IOP after nonpenetrating filtering surgeries has been reported to be 5 mm Hg on the first postoperative day [8, 57]. Thus, about 50% of the patients present with an early ocular hypotony for some days. If short-lived and not associated with any secondary complication, ocular hypotony should not be regarded as a worrying complication. On the contrary, early hypotony without any perforation is an excellent indicator of good surgical dissection and a positive prognostic factor for long-term IOP reduction [28]. Moreover, the risk of longstanding hypotonia is minimal [8, 57], but when present can be complicated by hypotonic maculopathy [58]. Sanchez et al. [11] reported two cases of hypotonic maculopathy out of 168 eyes (1.2%) that underwent deep sclerectomy. Choroidal detachment is a rare complication. The available literature [8, 56, 59] reports an incidence rate of up to 5% after NPGS, whereas it can be observed in 20% of cases following trabeculectomy [60]. Prolonged hypotony in trabeculectomy eyes has been identified as the main risk factor for suprachoroidal hemorrhage [61], which has been rarely reported to occur after deep sclerectomy [62] or viscocanalostomy [63]. Therefore, hypotony after NPGS is common during the first postoperative week, but associated complications are significantly less than with conventional trabeculectomy. To date no case of completely flat anterior chamber has been reported after NPGS. This is due to the lack of an abrupt IOP decrease during nonperforating procedures [54]. A shallow anterior chamber can occasionally be observed. An overfiltrating bleb may be prominent and result in dellen formation near the corneal limbus.

68

7 Nonpenetrating Glaucoma Surgery

Table 7.2 List of complications that have been reported after nonpenetrating glaucoma surgery Intraoperative complications

7

■ Perforation of trabeculo-Descemet’s membrane (often

during the first surgical cases, rare thereafter) ■ Iris prolapse

Early postoperative complications ■ Anterior chamber inflammation (low levels) ■ Early hypotony ■ Late hypotony (rare) ■ Shallow anterior chamber ■ Hypotony maculopathy (very rare) ■ Choroidal detachment (rare) ■ Suprachoroidal hemorrhage (very rare) ■ Hyphema ■ Malignant glaucoma (very rare) ■ Descemet’s membrane detachment (hemorrhagic or not)

one out of 250–300 operated eyes [54]. The pathogenesis depends on the type of surgery. With viscocanalostomy, detachment is related to the viscoelastic injection into the artificial ostia of Schlemm’s canal, the canula probably being slightly misdirected [64]. After deep sclerectomy, this complication may be explained by the passage of aqueous humor from the scleral space to the subDescemet space at the anterior edge of Descemet’s window, secondary to an increased intrableb pressure as may occur after trauma, encysted bleb, and vigorous ocular massage. This is generally a self-resolving complication, but in severe cases descemetopexy can be tried with the injection of a viscoelastic or air into the anterior chamber to put the detached scroll back into place. 7.11.2.4 Hyphema

Hyphema is a complication with a low incidence after NPGS [56, 65]. It usually originates from a rupture of small iris vessels, ciliary processes, or from leakage of red blood cells through the TDM. No particular treatment is required.

(rare) ■ Intracorneal hematoma or inclusion of high-weight

sodium hyaluronate (very rare) ■ Implant exposure and migration (very rare) ■ Exudative retinal detachment (reported in association

with Sturge–Weber syndrome) ■ Wound and bleb leaks ■ Blebitis (rare) ■ Fungal keratitis (very rare) ■ Bacterial keratitis (our case)

Late postoperative complications ■ Late rupture of trabeculo-Descemet’s membrane ■ Peripheral anterior synechiae ■ Iris prolapse ■ Bleeding during gonioscopy (very rare) ■ Cataract progression ■ Low levels of corneal astigmatism and endothelial

cell loss ■ Bleb fibrosis ■ Encapsulated bleb ■ Scleral ectasia with or without bulging (very rare)

7.11.2.3 Descemet’s Membrane Detachment

Descemet’s membrane detachment is a rare complication after nonpenetrating filtering surgery, occurring in about

7.11.2.5 Wound and Bleb Leaks

Wound leaks or positive Seidel tests occur with the same frequency after trabeculectomy and NPGS, and are often due to inadequate conjunctival wound closure [56, 66]. In most cases, the leaking stops after one week and the discontinuation of steroid therapy. On rare occasions surgical intervention is necessary to repair the wound leak. In a two-year prospective study on the bleb characteristics of 125 eyes that underwent mitomycin C augmented glaucoma surgery, bleb leaks were more frequently observed in the trabeculectomy group than in the deep sclerectomy group (24.6% vs. 3.1%, respectively) [67]. 7.11.2.6 Infectious Complications

Blebitis is a well-known and potentially dangerous infection after trabeculectomy that can lead to endophthalmitis [68]. In NPGS, the TDM offers a barrier against the intraocular spread of bacteria. Out of a total of more than 2000 NPGS procedures, Roy and Mermoud [56] observed only one case of blebitis. No case of endophthalmitis has been reported to date. Infectious keratitis is a rare complication; there is a single case report of fungal keratitis occurring one week after viscocanalostomy in a 63 year-old patient [69]. 7.11.2.7 Postoperative Increase in IOP

Postoperative increase in IOP, secondary to the superficial scleral flap being too tightly closed, is regularly observed

7.11 Complications of Nonpenetrating Glaucoma Surgery

after trabeculectomy, and needs either laser suture lysis and/or ocular massage unless releasable sutures have been used. Because the main site of postoperative aqueous humor outflow resistance after nonpenetrating filtering surgery is located at the TDM level, this complication should not occur if the dissection of the membrane has been done properly. Early postoperative IOP spikes can be due to: 1. Insufficient surgical dissection—most common after nonpenetrating filtering surgeries by inexperienced surgeons. 2. Hemorrhage in the scleral bed, which usually spontaneously resorbs within a few days. 3. Excess viscoelastic remaining in the anterior chamber, which mainly occurs after combined surgeries or anterior chamber reformation following perforation of the TDM. This also resolves in a few days. 4. Malignant glaucoma. Shaarawy et al. also reported one out of 105 eyes that developed malignant glaucoma on the first postoperative day following DSCI, which was successfully treated with cycloplegics [57]. 5. Postoperative rupture of the TDM with iris prolapse [70], secondary to increased IOP from eye rubbing, Valsalva’s maneuver, etc. This should be managed with miotics and Nd:Yag laser to the prolapsed iris. If this doesn’t work, surgical iridectomy is indicated. 6. Peripheral anterior synechia formation at the site of the filtering window, often secondary to an intraoperative microperforation [70]. 7. Steroid induction within the first few postoperative weeks. Overall, IOP spikes are rare postoperative complications and should be treated according to each specific cause.

69

under control, no further treatment is needed. However, if the iris prolapse blocks the aqueous humor outflow and the IOP rises, medical, laser or surgical therapy should be considered. 7.11.3.2 Peripheral Anterior Synechiae and Iris Prolapse

The iris may adhere to the TDM window and form peripheral anterior synechiae (PAS) after the following situations: intraoperative microperforation of the TDM, or iris entrapment into a goniopuncture hole [70], which usually occurs rapidly after laser treatment, and rupture of the TDM (e.g., blunt trauma, eye rubbing, coughing) with subsequent iris prolapse. There may be an associated increase in IOP if there is insufficient aqueous humor flow through the membrane. A laser synechiolysis may be attempted to reposition the iris back; if this fails, a medical or secondary surgical treatment should be considered. 7.11.3.3 Cataract Progression

It was reported that cataract progression is not influenced by deep sclerectomy, contrary to trabeculectomy. The Advanced Glaucoma Intervention Trial estimated that the rate of cataract formation after the first trabeculectomy is 78% at five years. The risk of cataract is doubled if there is a significant postoperative inflammation or a flat anterior chamber [71]. Shaarawy et al. [28] followed 105 patients for a mean of 64 months and showed progression of existing age-related cataract in 25% of eyes, but no surgery-induced cataracts. 7.11.3.4 Bleb Fibrosis and Encapsulated Bleb

7.11.3 Late Postoperative Complications Unlike immediate postoperative complications, late postoperative complications occur with the same frequency in penetrating and nonpenetrating filtering surgeries. This may be explained by the fact that late complications are often related to excessive scarring of the operated tissues and that the surgical procedure as such does not influence this process. 7.11.3.1 Late Rupture of the TDM

The risk of membrane rupture decreases with time, because the post-membrane outflow resistance slowly builds up for several weeks after surgery. However, rupture can happen after severe ocular trauma. Often there is a concomitant iris prolapse with a distorted pupil and darkening of the subconjunctival area. If the IOP remains

Bleb fibrosis is due to conjunctival or episcleral fibrosis and is slightly more frequent after NPGS than after trabeculectomy [54]. In cases of increasing IOP, subconjunctival injections of an antimetabolite are required to stop the scarring process. An encapsulated bleb or Tenon’s cyst develops through a fibroblastic overgrowth that results in a tight-appearing opalescent bleb with a thick wall and vessels on the surface that entraps the aqueous humor in the subconjunctival space. These occur more often when antimetabolites are used, and their incidence after NPGS is comparable to that for trabeculectomy. If the IOP becomes uncontrolled, needling with or without antimetabolites and subconjunctival injections should be done. In cases of recurrence, excision of the cysts can be attempted. Shaarawy et al. [28] performed subconjuctival injections of 5-FU in 25 out of the 105 patients (23%) who underwent DSCI.

70

7 Nonpenetrating Glaucoma Surgery

7.11.3.5 Corneal Refractive and Endothelial Cell Changes

7

Surgically altered corneal curvature may affect postoperative refraction and visual acuity. NPGS induced less astigmatism in the early postoperative period and less corneal endothelial cell loss than trabeculectomy [72, 73]. The low levels of corneal astigmatism and endothelial cell loss induced by NPGS add to the potential advantages of the procedure that have been previously mentioned. 7.11.3.6 Scleral Ectasia

Scleral ectasia with bulging has been described in a 12-year old girl with chronic juvenile oligoarticular arthritis and glaucoma secondary to chronic uveitis three weeks after deep sclerectomy [74]. Since the scleral flap is weaker than in trabeculectomy and the deep scleral flap creates a zone of weakness, a thinner than usual sclera— as seen in patients with high myopia, associated rheumatoid or juvenile arthritis, or chronic uveitis—can lead to this condition. Due to anatomical vulnerability, the use of antimetabolites in these patients may increase the risk of this complication and requires careful consideration. Late scleral thinning has also been reported in two adults after NPGS with no underlying systemic disease [75].

7.12

Clinical Experience with Nonpenetrating Glaucoma Surgery

The last few years have witnessed a great number of publications and presentations on nonpenetrating glaucoma surgery, igniting interest in the glaucoma community. If the safety margin of glaucoma surgery could be increased significantly without sacrificing efficacy, surgical intervention for glaucoma might be considered earlier.

7.12.1 Viscocanalostomy The largest study of viscocanalostomy, reported by Stegmann et al. [8] in 1999, was a prospective study of 214 eyes of 157 African patients with OAG with an average follow-up of 35 months. The mean reduction of IOP was 64%. They reported a complete success rate (IOP ≤ 22 mm Hg without medication) in 82.7% of eyes. Qualified success (IOP ≤ 22 mm Hg with topical betaxolol hydrochloride) was achieved in 89% of eyes. Shaarawy et al. [31] presented their long-term results on viscocanalostomy in a prospective trial in which 57 eyes of 57 Caucasian patients were consecutively enrolled. The complete

success rate (IOP < 21 mm Hg without medication) was 60%, whereas the qualified success rate (IOP < 21 mm Hg with or without medication) was 90% at 60 months. Both studies concluded that viscocanalostomy provides reasonable long-term IOP control with few postoperative complications. Several other studies have reported viscocanalostomy results: Lüke et al. reported a complete success rate of 30% [76] and 40% [77] at one year in patients having viscocanalostomy, and Drüsedau et al. [22] found a complete success rate of 36% at one year and a qualified success rate of 79%; Sunaric-Mégevand et al. [78] reported a 68% complete success rate at one year, 60% at two years and 59% at three years, with qualified success rates of 88, 90 and 88%, respectively. In 2003, Carassa et al. [79] reported a 76% success rate in a two-year randomized controlled clinical trial. Wishart et al. [80] reported a complete success rate of 92.6% after a mean follow-up of three years. In 2004, Yalvac et al. [81] reported on a three-year prospective randomized trial where a complete success rate of 52.9% was achieved at six months in the viscocanalostomy group and 35.3% at three years. Qualified success was achieved in 90.7% of eyes at six months and 73.9% at three years. It is often difficult to compare intermediate and long-term follow-up studies because the success criteria are not uniform, but overall they indicate that viscocanalostomy has the potential to reduce IOP.

7.12.2

Deep Sclerectomy

Prospective studies of deep sclerectomy with collagen implant report complete success rates of 45–69% [29, 55, 66, 82, 83] with qualified success rates (IOP < 21 mm Hg with medication) that are much higher. In addition, the use of a collagen implant enhances the success rates and lowers the need for postoperative medications [11, 29, 83]. To enhance the filtration of deep sclerectomy, Kozlov et al. [10] described the use of a collagen implant placed within the scleral bed. They reported an 85% success rate, but no information regarding success criteria or follow- up is available. Shaarawy et al. [83] reported their long-term results from a randomized prospective trial of 104 eyes comparing deep sclerectomy with (DSCI) and without an implant (DS). The complete success rate (IOP ≤ 21 mm Hg without medication) was 34.6% at 48 months for the DS group and 63.4% for the DSCI group. Qualified success rate was 78.8% at 48 months and 94% for the DSCI group. The mean number of medications was reduced in the latter group, and no significant operative complications were observed in either group. They concluded that the use of the collagen implant offers a

7.12 Clinical Experience with Nonpenetrating Glaucoma Surgery

significant advantage in nonpenetrating glaucoma surgery by enhancing its success rate and lowering the need for postoperative medication. These results were confirmed by a subsequent study of 26 eyes reported by the same author, who randomly assigned a collagen implant to one eye of each patient, with the contralateral eye of the same patient having DS without implant [29]. The complete success rate (IOP < 21 mm Hg without medication) was 38% at 48 months for the DS-treated eyes, and 69% for the DSCI-treated eyes, with qualified success rates of 69% and 100%, respectively. For eyes treated with DSCI, IOP was 3.21 mm Hg lower than for those treated with DS alone.

7.12.3

Studies Comparing Trabeculectomy and Nonpenetrating Glaucoma Surgery

One of the most intriguing questions regarding nonpenetrating surgery is how well it fares compared to trabeculectomy—regarded for many decades as the gold standard against which all novel glaucoma procedures are tested. Randomized controlled trials comparing NPGS to trabeculectomy have a consensus on the superior safety profile of NPGS but are not in agreement when it comes to efficacy, where we find conflicting results about the IOP that can be achieved with NPGS compared to trabeculectomy. This is attributed to a number of factors, including the fundamental differences between NPGS and penetrating filtering techniques, the long learning curve of NPGS, and the need to use goniopuncture to achieve target IOPs. Yalvac et al. [81] and Carassa et al. [79] conducted comparative studies between viscocanalostomy and trabeculectomy with mean follow-ups of three and two years, respectively. They both concluded that trabeculectomy provides lower IOPs but is associated with higher complication rates. However, cumulative percentage probabilities of success were not statistically different between the two groups. We should also state that the authors either decided not to attempt goniopuncture in those viscocanalostomy eyes with postoperative IOP elevations, thus excluding a potential number of patients who could benefit from this adjunctive procedure, or considered it a surgical failure. El Sayyad et al. [84] compared prospectively the efficacy and safety of deep sclerectomy without implant and trabeculectomy in bilateral POAG. At 12 months of follow-up there was no statistical significance between the two groups regarding both the complete and qualified success rates. There was, however, a significantly lower

71

incidence of complications for the deep sclerectomy group as compared to the trabeculectomy group. Chiselita et al. [85] also compared DS without collagen implant to trabeculectomy in a randomized study and showed that the latter was more effective at lowering IOP at 18 months but gave a higher complication rate. It should be noted, though, that the authors did not perform goniopunctute during the follow-up, and their nonpenetrating technique differed in that only the external wall of Schlemm’s canal was removed without peeling its inner part and the adjacent trabecular meshwork. Considering goniopuncture to be a failure criterion can be compared, in our judgment, to considering suture lysis and capsulotomy as failure criteria of glaucoma and cataract surgeries, which is most uncommon. Mermoud et al. [66] prospectively compared two groups of DSCI (44 eyes) and trabeculectomy (44 eyes). The complete success rates (IOP < 21 mm Hg without medication) were 57% for the trabeculectomy group vs. 69% for the DSCI group. The number of postoperative medications was significantly lower in the DSCI group. The authors concluded that the success rates of both DSCI and trabeculectomy were comparable; however, a lower rate of complications was observed in the DSCI group.

Summary for the Clinician ■

■

■

■

Nonpenetrating glaucoma surgery is certainly safer than trabeculectomy and thus may have a worthwhile role earlier in the disease process. Its superior safety profile makes it the first choice in many cases. The major controversy that arises is over the success rates of NPGS compared to trabeculectomy. The learning curve of this surgery and the need to consider goniopuncture as an adjuvant to the procedure and not as a failure criterion cannot be overstated. The use of implants in nonpenetrating glaucoma surgery offers better IOP control for longer periods, thus enhancing success rates. Variable definitions of success, different followup times, and variable study designs make direct comparisons between reported results very challenging. A prospective randomized multicenter study is needed in order to be able to draw final conclusions about how nonpenetrating surgery fares compared to trabeculectomy, as well as to examine the different variations of techniques.

72

7 Nonpenetrating Glaucoma Surgery

References

7

1. Krasnov MM (1964) Sinusotomy in glaucoma. Vestn Oftalmol 77:37–41 2. Sugar HS (1961) Experimental trabeculectomy in glaucoma. Am J Ophthalmol 51:623 3. Cairns JE (1968) Trabeculectomy. Preliminary report of a new method. Am J Ophthalmol 66:673–679 4. Zimmerman TJ, Kooner KS, Ford VJ et al (1984) Trabeculectomy vs. nonpenetrating trabeculectomy: a retrospective study of two procedures in phakic patients with glaucoma. Ophthalmic Surg 15:734–740 5. Arenas E (1991) Trabectulectomy ab externo. Highlights Ophthalmol 19:59–66 6. Cherniavskii G, Mogilevskaya F, Suprun AV, Fedorova SM, Gurtovaya E (1971) Effectiveness of sinusotomy in open angle glaucoma. Vestn Oftalmol 5:20–23 7. Kozlov Bagrov SN, Anisimova SY, Osipov AV, Mogilevtsev VV (1990) Nonpenetrating deep sclerectomy with collagen. Eye Microsurgery 3:157–162 8. Stegmann R, Pienaar A, Miller D (1999) Viscocanalostomy for open-angle glaucoma in black African patients. J Cataract Refract Surg 25:316–322 9. Zimmerman TJ, Kooner KS, Ford VJ et al. (1984) Effectiveness of nonpenetrating trabeculectomy in aphakic patients with glaucoma. Ophthalmic Surg 15:44–50 10. Koslov VI, Bagrov SN, Anisimova M et al. (1990) Deep sclerectomy with collagen. Eye Microsurgery 3:44–46 11. Sanchez E, Schnyder CC, Sickenberg M, Chiou AG, Hediguer SE, Mermoud A (1996) Deep sclerectomy: results with and without collagen implant. Int Ophthalmol 20:157–162 12. Chiou AG, Mermoud A, Underdahl JP, Schnyder CC (1998) An ultrasound biomicroscopic study of eyes after deep sclerectomy with collagen implant. Ophthalmology 105:746–750 13. Sourdille P, Santiago PY, Ducournau Y (1999) Nonperforating surgery of the trabeculum with reticulated hyaluronic acid implant: why, how, what results?. J Fr Ophtalmol 22:794–797 14. Dahan E, Ravinet E, Ben-Simon GJ, Mermoud A (2003) Comparison of the efficacy and longevity of nonpenetrating glaucoma surgery with and without a new, nonabsorbable hydrophilic implant. Ophthalmic Surg Lasers Imaging 34:457–463 15. Smit BA, Johnstone MA (2002) Effects of viscoelastic injection into Schlemm’s canal in primate and human eyes: potential relevance to viscocanalostomy. Ophthalmology 109:786–792 16. Tamm ER, Carassa RG, Albert DM, et al. (2004) Viscocanalostomy in rhesus monkeys. Arch Ophthalmol 122:1826–1838 17. Vaudaux J, Uffer S, Mermoud A (1999) Aqueous dynamics after deep sclerectomy: in vitro study. Ophthalmic Pract 16:204–209 18. Rossier A, Uffer S, Mermoud A (2000) Aqueous dynamics in experimental ab externo trabeculectomy. Ophthalmic Res 32:165–171

19. Marchini G, Marraffa M, Brunelli C, Morbio R, Bonomi L (2001) Ultrasound biomicroscopy and intraocular-pressure-lowering mechanisms of deep sclerectomy with reticulated hyaluronic acid implant. J Cataract Refract Surg 27:507–517 20. Negri-Aranguren I, Croxatto O, Grigera DE (2002) Midterm ultrasound biomicroscopy findings in eyes with successful viscocanalostomy. J Cataract Refract Surg 28:752–757 21. O’Brart DP, Rowlands E, Islam N, Noury AM (2002) A randomised, prospective study comparing trabeculectomy augmented with antimetabolites with a viscocanalostomy technique for the management of open angle glaucoma uncontrolled by medical therapy. Br J Ophthalmol 86:748–754 22. Drusedau MU, von Wolff K, Bull H, von Barsewisch B (2000) Viscocanalostomy for primary open-angle glaucoma: the Gross Pankow experience. J Cataract Refract Surg 26:1367–1373 23. Yarangumeli A, Gureser S, Koz OG, Elhan AH, Kural G (2004) Viscocanalostomy versus trabeculectomy in patients with bilateral high-tension glaucoma. Int Ophthalmol 25:207–213 24. Kazakova D, Roters S, Schnyder CC et al. (2002) Ultrasound biomicroscopy images: long-term results after deep sclerectomy with collagen implant. Graefes Arch Clin Exp Ophthalmol 240:918–923 25. Delarive T, Rossier A, Rossier S, Ravinet E, Shaarawy T, Mermoud A (2003) Aqueous dynamic and histological findings after deep sclerectomy with collagen implant in an animal model. Br J Ophthalmol 87:1340–1344 26. Chiou AG, Mermoud A, Hediguer SE, Schnyder CC, Faggioni R (1996) Ultrasound biomicroscopy of eyes undergoing deep sclerectomy with collagen implant. Br J Ophthalmol 80:541–544 27. Roters S, Luke C, Jonescu-Cuypers CP et al. (2002) Ultrasound biomicroscopy and its value in predicting the long term outcome of viscocanalostomy. Br J Ophthalmol 86:997–1001 28. Shaarawy T, Flammer J, Smits G, Mermoud A (2004) Low first postoperative day intraocular pressure as a positive prognostic indicator in deep sclerectomy. Br J Ophthalmol 88:658–661 29. Shaarawy T, Mermoud A (2005) Deep sclerectomy in one eye vs deep sclerectomy with collagen implant in the contralateral eye of the same patient: long-term follow-up. Eye 19:298–302 30. Hamel M, Shaarawy T, Mermoud A (2001) Deep sclerectomy with collagen implant in patients with glaucoma and high myopia. J Cataract Refract Surg 27:1410–1417 31. Shaarawy T, Nguyen C, Schnyder C, Mermoud A (2003) Five year results of viscocanalostomy. Br J Ophthalmol 87:441–445 32. Johnson DH, Johnson M (2001) How does nonpenetrating glaucoma surgery work? Aqueous outflow resistance and glaucoma surgery. J Glaucoma 10:55–67

3.6 Tool and Visualization Tradeoffs 33. Cheng JW, Ma XY, Wei RL (2004) Efficacy of non-penetrating trabecular surgery for open angle glaucoma: a meta-analysis. Chin Med J (Engl) 117:1006–1010 34. Konstas AG, Tsironi S, Ritch R (2006) Current concepts in the pathogenesis and management of exfoliation syndrome and exfoliative glaucoma. Compr Ophthalmol Update 7:131–141 35. Drolsum L (2003) Conversion from trabeculectomy to deep sclerectomy. Prospective study of the first 44 cases. J Cataract Refract Surg 29:1378–1384 36. Drolsum L (2006) Longterm follow-up after deep sclerectomy in patients with pseudoexfoliative glaucoma. Acta Ophthalmol Scand 84:502–506 37. Mearza AA, Aslanides IM (2007) Uses and complications of mitomycin C in ophthalmology. Expert Opin Drug Saf 6:27–32 38. Chiou AG, Mermoud A, Jewelewicz DA (1998) Post-operative inflammation following deep sclerectomy with collagen implant versus standard trabeculectomy. Graefes Arch Clin Exp Ophthalmol 236:593–596 39. Miserocchi E, Carassa RG, Bettin P, Brancato R (2004) Viscocanalostomy in patients with glaucoma secondary to uveitis: preliminary report. J Cataract Refract Surg 30:566–570 40. Souissi K, El Afrit MA, Trojet S, Kraiem A (2006) Deep sclerectomy for the management of uveitic glaucoma]. J Fr Ophtalmol 29:265–268 41. Tixier J, Dureau P, Becquet F, Dufier JL (1999) Deep sclerectomy in congenital glaucoma. Preliminary results. J Fr Ophtalmol 22:545–548 42. Noureddin BN, El-Haibi CP, Cheikha A, Bashshur ZF (2006) Viscocanalostomy versus trabeculotomy ab externo in primary congenital glaucoma: 1-year follow-up of a prospective controlled pilot study. Br J Ophthalmol 90:1281–1285 43. Stangos AN, Whatham AR, Sunaric-Megevand G (2005) Primary viscocanalostomy for juvenile open-angle glaucoma. Am J Ophthalmol 140:490–496 44. Krzywicki S, Szala E (2002) Non-perforating deep sclerectomy ab externo with intrascleral implant in juvenile glaucoma]. Klin Oczna 104:222–225 45. Di Rocco C, Tamburrini G (2006) Sturge–Weber syndrome. Childs Nerv Syst 22:909–921 46. Bellows AR, Chylack LT Jr, Epstein DL, Hutchinson BT (1979) Choroidal effusion during glaucoma surgery in patients with prominent episcleral vessels. Arch Ophthalmol 97:493–497 47. Iwach AG, Hoskins HD Jr, Hetherington J Jr, Shaffer RN (1990) Analysis of surgical and medical management of glaucoma in Sturge–Weber syndrome. Ophthalmology 97:904–909 48. Rebolleda G, Munoz-Negrete FJ (2001) Nonpenetrating deep sclerectomy for Sturge–Weber syndrome. Ophthalmology 108:2152–2153 49. Audren F, Abitbol O, Dureau P, et al. (2006) Nonpenetrating deep sclerectomy for glaucoma associated with Sturge–Weber syndrome. Acta Ophthalmol Scand 84:656–660

73

50. Bellows AR, Johnstone MA (1983) Surgical management of chronic glaucoma in aphakia. Ophthalmology 90: 807–813 51. Kirwan C, O’Keefe M (2006) Paediatric aphakic glaucoma. Acta Ophthalmol Scand 84:734–739 52. Zimmerman TJ, Kooner KS, Ford VJ, et al. (1984) Effectiveness of nonpenetrating trabeculectomy in aphakic patients with glaucoma. Ophthalmic Surg 15:44–50 53. Schwartz KS, Lee RK, Gedde SJ (2006) Glaucoma drainage implants: a critical comparison of types. Curr Opin Ophthalmol 17:181–189 54. Ravinet E, Tritten JJ, Roy S, et al. (2002) Descemet membrane detachment after nonpenetrating filtering surgery. J Glaucoma 11:244–252 55. Karlen ME, Sanchez E, Schnyder CC, Sickenberg M, Mermoud A (1999) Deep sclerectomy with collagen implant: medium term results. Br J Ophthalmol 83:6–11 56. Roy S, Mermoud A (2006) Complications of deep nonpenetrating sclerectomy. J Fr Ophtalmol 29:1180–1197 57. Shaarawy T, Karlen M, Schnyder C, Achache F, Sanchez E, Mermoud A (2001) Five-year results of deep sclerectomy with collagen implant. J Cataract Refract Surg 27: 1770–1778 58. Gavrilova B, Roters S, Engels BF, Konen W, Krieglstein GK (2004) Late hypotony as a complication of viscocanalostomy: a case report. J Glaucoma 13:263–267 59. Guedes RA, Guedes VM (2005) Nonpenetrating deep sclerectomy in Brazil: a 3-year retrospective study. J Fr Ophtalmol 28:191–196 60. Brubaker RF, Pederson JE (1983) Ciliochoroidal detachment. Surv Ophthalmol 27:281–289 61. Tuli SS, WuDunn D, Ciulla TA, Cantor LB (2001) Delayed suprachoroidal hemorrhage after glaucoma filtration procedures. Ophthalmology 108:1808–1811 62. Neudorfer M, Sadetzki S, Anisimova S, Geyer O (2004) Nonpenetrating deep sclerectomy with the use of adjunctive mitomycin C. Ophthalmic Surg Lasers Imaging 35:6–12 63. Cheema RA, Choong YF, Algawi KD (2003) Delayed suprachoroidal hemorrhage following viscocanalostomy. Ophthalmic Surg Lasers Imaging 34:209–211 64. Kim CY, Seong GJ, Koh HJ, Kim EK, Hong YJ (2002) Descemet’s membrane detachment associated with inadvertent viscoelastic injection in viscocanalostomy. Yonsei Med J 43:279–281 65. Lachkar Y, Neverauskiene J, Jeanteur-Lunel MN et al. (2004) Nonpenetrating deep sclerectomy: a 6-year retrospective study. Eur J Ophthalmol 14:26–36 66. Mermoud A, Schnyder CC, Sickenberg M, Chiou AG, Hediguer SE, Faggioni R (1999) Comparison of deep sclerectomy with collagen implant and trabeculectomy in open-angle glaucoma. J Cataract Refract Surg 25:323–331 67. Anand N, Arora S, Clowes M (2006) Mitomycin C augmented glaucoma surgery: evolution of filtering bleb avascularity, transconjunctival oozing, and leaks. Br J Ophthalmol 90:175–180

74

7

7 Nonpenetrating Glaucoma Surgery

68. Ciulla TA, Beck AD, Topping TM, Baker AS (1997) Blebitis, early endophthalmitis, and late endophthalmitis after glaucoma-filtering surgery. Ophthalmology 104: 986–995 69. Tamcelik N, Ozdamar A, Kizilkaya M, Devranoglu K, Ustundag C, Demirkesen C (2002) Fungal keratitis after nonpenetrating glaucoma surgery. Cornea 21:532–534 70. Kim CY, Hong YJ, Seong GJ, Koh HJ, Kim SS (2002) Iris synechia after laser goniopuncture in a patient having deep sclerectomy with a collagen implant. J Cataract Refract Surg 28:900–902 71. Aigs I (2001) The Advanced Glaucoma Intervention Study: 8. Risk of cataract formation after trabeculectomy. Arch Ophthalmol 119:1771–1779 72. Egrilmez S, Ates H, Nalcaci S, Andac K, Yagci A (2004) Surgically induced corneal refractive change following glaucoma surgery: nonpenetrating trabecular surgeries versus trabeculectomy. J Cataract Refract Surg 30:1232–1239 73. Arnavielle S, Lafontaine PO, Bidot S, Creuzot-Garcher C, D’Athis P, Bron AM (2007) Corneal endothelial cell changes after trabeculectomy and deep sclerectomy. J Glaucoma 16:324–328 74. Milazzo S, Turut P, Malthieu D, Leviel MA (2000) Scleral ectasia as a complication of deep sclerectomy. J Cataract Refract Surg 26:785–787 75. Hyams M, Geyer O (2003) Iris prolapse at the surgical site: a late complication of nonpenetrating deep sclerectomy. Ophthalmic Surg Lasers Imaging 34:132–135 76. Luke C, Dietlein TS, Jacobi PC, Konen W, Krieglstein GK (2002) A prospective randomized trial of viscocanalostomy versus trabeculectomy in open-angle glaucoma: a 1year follow-up study. J Glaucoma 11:294–299 77. Luke C, Dietlein TS, Jacobi PC, Konen W, Krieglstein GK (2003) A prospective randomised trial of viscocanalostomy

78.

79.

80.

81.

82.

83.

84.

85.

with and without implantation of a reticulated hyaluronic acid implant (SKGEL) in open angle glaucoma. Br J Ophthalmol 87:599–603 Sunaric-Megevand G, Leuenberger PM (2001) Results of viscocanalostomy for primary open-angle glaucoma. Am J Ophthalmol 132:221–228 Carassa RG, Bettin P, Fiori M, Brancato R (2003) Viscocanalostomy versus trabeculectomy in white adults affected by open-angle glaucoma: a 2-year randomized, controlled trial. Ophthalmology 110:882–887 Wishart PK, Wishart MS, Porooshani H (2003) Viscocanalostomy and deep sclerectomy for the surgical treatment of glaucoma: a longterm follow-up. Acta Ophthalmol Scand 81:343–348 Yalvac IS, Sahin M, Eksioglu U, Midillioglu IK, Aslan BS, Duman S (2004) Primary viscocanalostomy versus trabeculectomy for primary open-angle glaucoma: three-year prospective randomized clinical trial. J Cataract Refract Surg 30:2050–2057 Shaarawy T, Mansouri K, Schnyder C, Ravinet E, Achache F, Mermoud A (2004) Long-term results of deep sclerectomy with collagen implant. J Cataract Refract Surg 30:1225–1231 Shaarawy T, Nguyen C, Schnyder C, Mermoud A (2004) Comparative study between deep sclerectomy with and without collagen implant: long term follow up. Br J Ophthalmol 88:95–98 El Sayyad F, Helal M, El-Kholify H, Khalil M, El-Maghraby A (2000) Nonpenetrating deep sclerectomy versus trabeculectomy in bilateral primary open-angle glaucoma. Ophthalmology 107:1671–1674 Chiselita D (2001) Non-penetrating deep sclerectomy versus trabeculectomy in primary open-angle glaucoma surgery. Eye 15:197–201

Chapter 8

New Glaucoma Surgical Devices Diamond Y. Tam, Iqbal Ike K. Ahmed

8

Core Messages ■

■

■

■

Trabeculectomy is a well-studied and established method of surgically lowering the intraocular pressure (IOP) by providing aqueous humor access to a subconjunctival filtering bleb, but it has a large complication profile and a high rate of hypotony, both early and late. Long tube shunts rely on posterior subconjunctival filtration for IOP lowering, but these also have significant risks, most significantly hypotony and suprachoroidal hemorrhage. The Ex-Press minishunt, placed under a scleral flap, may provide two-tiered control of aqueous egress during filtration surgery, potentially lowering the rate of hypotony in subconjunctival filtration surgery. Subconjunctival filtration is nonphysiologic and relies on the surgeon’s ability to control and modify wound healing and fibrosis. Many surgeons employ the use of antifibrotics (i.e., mitomycin C or 5-fluorouracil) to prevent bleb fibrosis to improve postoperative success, but this also increases the risk of potentially serious complications.

8.1

Introduction

The surgical treatment of glaucoma emerged in the late nineteenth century, with surgical iridectomy being the first procedure to be described [1]. This was followed by corneoscleral trephination in the 1920s [2], full-thickness fistulizing procedures in the 1950s [3], and then in 1968, trabeculectomy—arguably the most-performed glaucoma surgery still used today—was first described by Cairns [4]. Although techniques have improved, and the adjunctive use of antimetabolites has enhanced long-term success as measured by intraocular pressure (IOP) control, trabeculectomy remains a surgical procedure with a sizeable risk profile to glaucoma patients, over both

■

■

■

■

Canaloplasty is an ab externo nonpenetrating surgical technique which involves excision of a deep scleral flap, exposure of a trabeculoDescemet’s window (TDW) and 360° passage of a catheter and suture into Schlemm’s canal to enhance normal physiologic aqueous outflow via the conventional pathway. The trabecular micro-bypass iStent and the Trabectome electrocautery device are ab interno approaches to enhancing aqueous outflow via the conventional pathway, and involve procedures to bypass the juxtacanalicular meshwork to the distal outflow pathway. The gold microshunt is designed to augment aqueous egress through the uveoscleral outflow pathway via an ab externo approach to place a shunt connecting the anterior chamber to the suprachoroidal space. New glaucoma surgical devices seek to augment normal physiologic aqueous outflow pathways in order to provide effective IOP lowering with the avoidance of a bleb and its related risks, perhaps providing safer and earlier surgical options for patients.

the short and long term. Blebitis and endophthalmitis, overfiltration and hypotony, corneal endothelial cell loss, dellen, bleb overhang, bleb leaks, bleb fibrosis and encapsulation, and aqueous misdirection are among the many (mostly lifetime) risks in trabeculectomy surgery [5]. Although the first glaucoma drainage device in 1906 was a horse hair inserted through a corneal paracentesis [6], the first tube and plate glaucoma drainage devices first emerged in the late 1960s, when Molteno introduced the first glaucoma drainage implant [7, 8]. This was later followed by other designs, such as those by Krupin [9], Baerveldt [10], and Ahmed [11]. Used frequently in complex glaucoma patients, many of whom have failed medical, laser, and prior surgical treatments, these

76

8

8 New Glaucoma Surgical Devices

devices consist of a tube placed into the anterior chamber to allow for aqueous humor to flow posteriorly into an encapsulated filtration area typically 10–12 mm posterior to the limbus, into a reservoir sutured to the sclera. While this posterior filtration of aqueous humor allows the risks associated with anterior bleb formation to be avoided, tube shunt surgery resulted in a high risk of hypotony and overfiltration, sometimes leading to suprachoroidal hemorrhage. As a result, tube shunt devices commonly require flow restriction and regulation, both temporary and permanent. Despite these measures, overfiltration and hypotony, bleb encapsulation and fibrosis remain part of the complication profile of tube shunt surgery. Tube or plate exposure, tube lumen occlusion, corneal endothelial loss (even with proper tube positioning), tube migration, ptosis, and diplopia are also potential complications associated with glaucoma drainage devices. The long-term success of subconjunctival filtration surgery depends on episcleral and subconjunctival wound healing and our ability to modulate such processes, and is furthermore reliant on the surgeon’s ability to regulate aqueous outflow. These issues, along with the sizeable complication profile of these procedures, combined with the nonphysiologic nature of IOP lowering, have led to the development and advancement of glaucoma surgery to provide alternative means of shunting aqueous humor out of the anterior chamber. In 1893, incisional surgery of the anterior chamber angle was first described by De Vincentiis for the treatment of congenital glaucoma, and in the 1940s Barkan described the surgical technique of goniotomy, wherein a blade inserted through the limbus was used to incise “gelatinous persistent embryonic tissue” at the iris root to allow for aqueous humor to access Schlemm’s canal [12, 13]. This procedure proved to be successful in maintaining long-term IOP control in the pediatric population with congenital and infantile glaucoma, but similar success was not achieved in the adult population. However, surgery in Schlemm’s canal and goniosurgical procedures have continued to develop, such as laser ablation of the trabecular meshwork, laser trabeculopuncture, goniocurretage, the Glaukos trabecular micro-bypass iStent (Glaukos Corp., Laguna Hills, CA, USA) and the Trabectome microelectrocautery device (NeoMedix Corp., San Juan Capistrano, CA, USA). In addition to ab intero procedures, nonpenetrating surgery such as canaloplasty (iScience Interventional Inc., Menlo Park, CA, USA) have also emerged as external approaches to Schlemm’s canal. In addition to the conventional outflow pathway, aqueous humor also leaves the anterior chamber via the uveoscleral outflow pathway, consisting of the interstitium

of the ciliary body, suprachoroidal space, and ultimately egress through scleral vasculature. This has been reported to comprise anywhere from 20 to 54% of total aqueous humor egress in normal human eyes [14, 15]. Surgical approaches to augment suprachoroidal outflow have also been explored with cyclodialysis, suprachoroidal implants and seton devices, and most recently, an ab externo gold shunt placed in the suprachoroidal space. In this chapter, we will discuss novel devices which attempt to assist with flow regulation in the Ex-PRESS mini-glaucoma shunt (Optonol Ltd., Kansas, KS, USA), Schlemm’s canal surgical procedures, including nonpenetrating canaloplasty surgery, the Glaukos trabecular micro-bypass iStent, the Trabectome microelectrocautery device, and the suprachoroidal outflow gold shunt device (SOLX Inc., Waltham, MA). Current and new surgical approaches to glaucoma can be separated based on target space for flow, and surgical approach (external or internal); see Table 8.1. As many of these devices are currently in investigation and in clinical trials, published data is limited. In this chapter, we will present the best available data.

8.2

Basic Review of the Anatomy and Physiology of Aqueous Outflow and Drainage Devices

Intraocular pressure is regulated by the balance between production of aqueous humor by the ciliary body epithelium in the posterior chamber, its ability to freely travel anteriorly through the pupil, and ultimately egress into the venous circulation surrounding the eye. An elevated intraocular pressure (IOP) results from either excessive production of aqueous humor or increased resistance or compromise in outflow pathways. Two known pathways of aqueous humor egress are known: the conventional pathway and the uveoscleral pathway. The conventional pathway consists of the trabecular meshwork, Schlemm’s canal, and finally intrascleral and episcleral venous plexi. The uveoscleral pathway consists of the interstitium of the ciliary body, the suprachoroidal space, and egress through scleral vasculature. Table 8.1 The various surgical approaches to aqueous filtration and IOP lowering Episcleral flow

Schlemm’s canal flow

Suprachoroidal flow

• Ab externo

• Ab externo

• Ab externo

• Ab interno

• Ab interno

• Ab interno

8.2 Basic Review of the Anatomy and Physiology of Aqueous Outflow and Drainage Devices

It follows then that in order to bring about a reduction in IOP, two options exist: decreasing the production of aqueous humor via cyclodestructive procedures such as transscleral cyclocryotherapy, transscleral diode laser cycloablation, and more recently endocyclophotocoagulation; or augmenting aqueous outflow. Recent developments in glaucoma surgery have focused on devices that assist in improving aqueous outflow via three different pathways: subconjunctival filtration, Schlemm’s canal outflow, and suprachoroidal outflow.

8.2.1 8.2.1.1

Subconjunctival Filtration Anterior Filtration

Direct subconjunctival flow is not a normal physiologic pathway for aqueous humor. Anterior subconjunctival filtration is achieved by trabeculectomy, the procedure by which a fistula is created that connects the anterior chamber to the subconjunctival space, usually under a scleral flap. Both the conventional and uveoscleral pathways are thus bypassed and a subconjunctival reservoir, known as a bleb, is produced with aqueous in the subconjunctival space absorbed by episcleral and scleral vasculature into the surrounding orbital circulation, as well as transconjunctivally. Postoperative control of aqueous outflow in trabeculectomy relies somewhat on ostium size, but more so on scleral flap thickness and suture tension. Despite the aid of different suture techniques and postoperative laser suture lysis, achieving a low IOP while avoiding hypotony remains a major challenge. Subconjunctival wound healing and our ability to modulate this process is also critical in the long-term success of trabeculectomy. While the use of antimetabolites such as mitomycin C and 5-fluorouracil intra- and postoperatively has enhanced the success of filtering surgery, they also present unique complications, such as corneal endothelial toxicity, avascular encapsulated limbal blebs which are prone to leakage, especially with small subconjunctival application zones, and perhaps most importantly persistent long-term hypotony [16–19]. Despite all of the issues surrounding anterior filtration surgery, trabeculectomy has the advantanges of having a well-established history of potent IOP lowering, low cost, and technical familiarity to all glaucoma surgeons. 8.2.1.2

Posterior Filtration

Long tube shunt devices, such as the Molteno, Krupin, Baerveldt, Ahmed, and OptiMed drainage devices, have a tube to plate design, allowing aqueous humor to flow to

77

the postequatorial subconjunctival space and maintain a subconjunctival reservoir over the plate. Posterior filtration away from the limbus has the advantages of a less robust subconjunctival fibrosis reaction, a larger potential reservoir for aqueous fluid, and lower incidence of bleb dysesthesia. In a recent study of patients who had failed prior trabeculectomy, nonvalved tube shunts were found to have a lower incidence of postoperative complications, avoid persistent hypotony, and maintain IOP control over a one-year period when compared to a repeat trabeculectomy with adjunctive mitomycin C [20, 21]. Although traditionally reserved for cases of failed anterior filtration surgery, or where anterior filtration is unlikely to succeed, tube shunt surgery is being compared to trabeculectomy as a primary surgical procedure for glaucoma in current, ongoing studies. In addition, current studies comparing valved versus nonvalved tube shunt devices are ongoing.

8.2.2

Schlemm’s Canal Outflow

8.2.2.1

Proximal Outflow System

The conventional outflow pathway can be divided into a proximal outflow system, consisting of the uveoscleral, corneoscleral and juxtacanalicular trabecular meshwork, Schlemm’s canal and its collector channels, and a distal outflow system, consisting of aqueous veins, episcleral and intrascleral venous plexi. In the 1950s, Grant showed that 75% of aqueous outflow resistance was attributable to the trabecular meshwork [22, 23]. Subsequent work has provided strong evidence that the resistance point in the proximal outflow system is found in the juxtacanalicular trabecular meshwork (JTM) and the extracellular matrix [24]. Elevation of intraocular pressure in glaucoma is felt to be due to increased resistance at the JTM, and/or the collapse of Schlemm’s canal. Because of the many issues and potential complications surrounding subconjunctival penetrating glaucoma surgery, the aim to restore or enhance normal physiologic aqueous flow through Schlemm’s canal and nonpenetrating techniques has been explored since the late 1950s, and then as a procedure known as “sinusotomy” in the early 1960s [25–28]. These innovations were followed by guarded deep scleral flaps in the 1980s [29–31], viscodilation of the ostia of Schlemm’s canal in the 1990s [32], and then various implants in the late 1990s and early 2000s [33–35]. Most recently, a flexible microcathether has been developed (iScience Interventional Inc., Menlo Park, CA, USA) to facilitate cannulation of

78

8 New Glaucoma Surgical Devices

Outflow Facility as a Function of Suture Tension

8.2.2.2

Perfusion - 20 micron Prolene filament Alternating - No Tension: Tension

8

3

Tension

Flow (ul/ min)

2.5 2 1.5 1 0.5

No Tension

0 3500

4500

5500

6500 7500 Time (sec)

8500

9500

Fig. 8.1 A graph plotting aqueous outflow on the vertical axis versus time on the horizontal axis while a prolene suture in Schlemm’s canal is put on tension and released in an alternating fashion. Note that aqueous outflow increases when the suture is placed on tension

Schlemm’s canal for 360° and to allow viscodilation of the canal as well as circumferential suture passage. A recent study showed not only effective IOP lowering by this procedure, but also that greater distension in Schlemm’s canal produced a greater IOP decrease [36]. Data also released by iScience show that transtrabecular flow is enhanced with tension on the circumferential suture (Fig. 8.1). If the major resistance point in aqueous outflow is the trabecular meshwork, it follows that surgical approaches to bypass this point by allowing aqueous direct access to Schlemm’s canal would provide lowering of the IOP. As a result, ab interno surgery of Schlemm’s canal has also been explored as a surgical alternative to penetrating surgery. Goniotomy and laser trabeculopuncture have largely been unsuccessful due to scarring of the surgical area [37–41]. More recently, small silicone aqueous shunting devices have been developed to shunt aqueous directly from the anterior chamber into two cut ends of Schlemm’s canal [42, 43]. A titanium L-shaped trabecular micro-bypass stent (Glaukos Corp., Laguna Hills, CA, USA) has also been developed to bypass juxtacanalicular meshwork resistance [44]. Another device known as the Trabectome (NeoMedix Corp. San Juan Capistrano, CA, USA) is a microelectrocautery device designed to remove trabecular meshwork tissue and allow aqueous humor to access Schlemm’s canal directly. Initial clinical data has shown effectiveness in reducing IOP and a reduction in the number of glaucoma medications required for both of these devices [45].

Distal Outflow System

Beyond Schlemm’s canal, aqueous humor reaches the surrounding circulation via aqueous veins, episcleral and intrascleral venous plexi. Studies done as early as in the 1950s have demonstrated a relationship between episcleral venous pressure (EVP) and intraocular pressure [46]. The actual EVP may vary from individual to individual, and may range from 8 to 13 mmHg. This may be the floor at which further IOP lowering via Schlemm’s canal approaches may not be possible. In a recent study, patients were examined in an inverted posture and found to have elevated IOP correlating with elevated episcleral venous pressure [47]. It has also been established that patients with conditions such as Sturge–Weber syndrome, venous obstructive disease, arteriovenous malformations of the orbit, head, neck or mediastinum predisposing to elevated episcleral venous pressure are prone to developing elevated IOP and resultant glaucomatous optic atrophy [48, 49]. However, to date, no surgical attempts to reduce episcleral venous pressure have been reported. 8.2.2.3

Suprachoroidal Outflow

The uveoscleral outflow pathway consists of the interstitium of the ciliary body, the suprachoroidal space, and ultimately aqueous egress through scleral vasculature. It is known from medical therapy by prostaglandin analogs that enhancing uveoscleral outflow can produce potent IOP lowering. Surgical augmentation of uveoscleral outflow has been attempted first via creation of a cyclodialysis cleft, separating the ciliary body from the sclera via a transscleral approach [50–54]. While this procedure allows free communication of aqueous humor to the suprachorodial space, it has several limitations, including the risk of intraoperative and postoperative hemorrhage due to the vascular nature of uveal tissue, prolonged irreversible hypotony, late IOP spikes due to unexpected cleft closure, and scarring of the artificially created cleft. An ab interno approach has also been attempted and was equally as ineffective, with 75% of patients requiring further surgical intervention after the initial cyclodialysis creation at 60 days postoperatively [51]. Other studies involving the placement of high molecular weight hyaluronic acid, teflon tube implants, and other materials such as a hydroxyethyl methacrylate capillary strip and even a scleral strip into the cyclodialysis cleft to prevent closure and fibrosis of the cleft have also been described [55–58]. Such implants, however, are yet to demonstrate successful long-term

8.3 Subconjunctival Filtration Device: the Ex-PRESS Shunt

IOP control in glaucomatous human eyes. While suprachoroidal implantation of seton devices has also been reported, consistency and long-term success have not been described. Further, implantation of devices of this size in the suprachoroidal space raise concerns about prolonged risk of suprachoroidal hemorrhage, choroidal detachment and atrophy, and exudative retinal detachment [59, 60]. The gold suprachoroidal shunt (SOLX Inc., Waltham, MA, USA) represents the most recent development to attempt to augment uveoscleral outflow via an ab externo approach in glaucomatous eyes.

8.3

Subconjunctival Filtration Device: the Ex-PRESS Shunt

Although trabeculectomy has historically provided potent IOP lowering, Bindlish et al. reported that 42% of patients had late hypotony, defined as an IOP of less than six at six months [61]. Because of the challenges in achieving consistent flow in trabeculectomy, a new device has been developed to address this issue. The Ex-PRESS Mini Glaucoma Shunt (Optonol Ltd., Neve Ilan, Israel) is a stainless steel device designed to allow aqueous humor filtration into the subconjunctival space. Four different types exist (R-50, X-50, T-50, and X-200), differing in dimensions and lumen size (200 μm for the X-200 and 50 µm for the others), but all function by the same principle (Fig. 8.2). The shunt consists of a tip with one or several orifices into the anterior chamber for drainage of aqueous in through the 27-gauge shaft, which is designed

79

to approximate the thickness of human sclera. A spur present on the underside of the shaft prevents extrusion of the device, while an external plate prevents intrusion of the shunt into the anterior chamber and occlusion of the external ostium. While in original studies the shunt was placed directly under the conjunctiva into the anterior chamber, hypotony, conjunctival erosion and shunt migration necessitated the need for placement under a trabeculectomy-style scleral flap [63, 64, 65]. Biocompatibility has also been demonstrated in studies [67]. When implanted in ocular tissue, the device also appears to be safe when undergoing magnetic resonance imaging (MRI). To place the Ex-PRESS shunt, a conjunctival peritomy, limbal or fornix-based, is first created as in traditional trabeculectomy. Gentle cautery is applied to the sclera prior to creation of a scleral flap. While dissection of the flap should approximate that which the surgeon usually performs for trabeculectomy, the dimensions of the flap may need to be slightly larger and be initiated more posteriorly in order to ensure full coverage of the shunt plate by the scleral flap. Once the scleral spur has been visualized, the anterior chamber should be filled with viscoelastic or air in the area of anticipated shunt entry. Rather than an ostium created by a punch, trephine, or scissors, a 25- or 27-gauge needle or a 400 µm wide blade is used to enter the anterior chamber at the level of the scleral spur, parallel to the iris, and the ExPRESS shunt is injected into this needle tract (Figs. 8.3 and 8.4) [62]. Care should be taken to direct the needle or blade parallel to the iris plane, as a posteriorly directed tract can potentially lead to impingement of

Fig. 8.2 Three different models of the Ex-PRESS shunt, the R, X, and P, with the dimensions and specifications of each

80

8 New Glaucoma Surgical Devices

8

Fig. 8.3 A sapphire blade is being used to enter the anterior chamber at the level of the scleral spur under a trabeculectomy style scleral flap in order to place the Ex-PRESS shunt in the anterior chamber. The blade angle should be parallel to the iris plane

Fig. 8.5 A gonioscopic photograph of the Ex-PRESS shunt in appropriate position parallel to the iris plane without direct iris contact

Fig. 8.4 A surgical photograph of the P-50 model of the Ex-PRESS shunt placed in position through the previously created entry with the sapphire blade. Aqueous egress is seen from the shunt, as seen by the light reflection posterior to the shunt

Fig. 8.6 Like trabeculectomy, the scleral flap should be closed and flow carefully observed and titrated with suture tension. A 10-0 nylon suture is seen here with the sutures tied in a slipknot fashion for tension adjustment

the shunt on the iris and possible tip occlusion in the postoperative period (Fig. 8.5). No surgical peripheral iridotomy is necessary. Scleral flap suture tension is adjusted to generate a small amount of flow at a physiologic IOP, much as in trabeculectomy surgery (Fig. 8.6). The conjunctival closure is then performed as per the surgeon’s preferred closure technique. Again, not unlike trabeculectomy, postoperative adjunctive procedures that may potentially be necessary include laser suture lysis and bleb needling with or without antimetabolite assistance. While similar to traditional trabeculectomy in that the Ex-PRESS shunt relies on subconjunctival filtration and a postoperative bleb for IOP control, the shunt provides

a constant orifice size of 50 µm for filtration, requires a smaller wound entry into the anterior chamber, does not require a surgical iridectomy, and provides two-tier control of the egress of aqueous humor, from the size of the shunt lumen as well as flap suture tension. Although the advised exclusion criteria for use of the shunt include narrow- or closed-angle glaucoma, it is the anecdotal experience of the authors that outcomes when using the Ex-PRESS shunt have been similar in both open- and closed-angle glaucomas. While the shunt is designed to provide control in flow regulation during filtration surgery, hypotony and overfiltration remain a postoperative risk for the Ex-PRESS shunt. However, some studies have revealed that, when compared to trabeculectomy,

8.4 Schlemm’s Canal Devices

the Ex-PRESS shunt may result in a lower complication profile with less hypotony and hypotony-related complications in the early postoperative period [63]. While an innovative device in glaucoma surgery and an asset to surgeons in the quest for control and regulation of aqueous flow, the Ex-PRESS shunt still yet relies on nonphysiologic subconjunctival flow as its mechanism of IOP lowering. As a result, all of the issues that limit trabeculectomy and the complication profile associated with blebs accompany the Ex-PRESS shunt too. The advantages of this device as an adjunct to filtration surgery may be a lowered incidence of early postoperative hypotony and elimination of the need for a surgical iridectomy. Additionally, because of the technical familiarity of trabeculectomy, the learning curve for the incorporation of this device into filtering surgery is not a steep one, and it has shown to be effective when combined with phacoemulsification [66].

8.4

Schlemm’s Canal Devices: Canaloplasty/ iScience, Glaukos Trabecular Micro-Bypass Stent, and the Trabectome

8.4.1 Ab Externo Schlemm’s Canal Approaches: Nonpenetrating Schlemm’s Canaloplasty The goal of nonpenetrating glaucoma surgery is to access Schlemm’s canal from an ab externo approach in order to restore or enhance the normal aqueous conventional outflow pathway and avoid creation of a subconjunctival bleb. Stegmann first described viscocanalostomy, a procedure by which a few clock hours of Schlemm’s canal were intubated and inflated with viscoelastic [32]. Various implants emerged in the early 2000s to enhance the success of nonpenetrating surgery [33–35]. However, these procedures still relied on the formation of a bleb for successful IOP lowering. Canaloplasty, a procedure in which 360° intubation of Schlemm’s canal, along with suture-assisted distension of the canal, has the aim of restoring physiologic outflow via the conventional pathway without the formation of a fistula or bleb. Since surgery is typically, but not necessarily, carried out in the superior sclera, the eye must be in downgaze for the procedure to be possible. While usually done under topical anesthesia and, in the authors’ experience, patient cooperation usually sufficient, a corneal traction suture certainly may be required to assist in optimizing eye position. Attention should be given to the placement of a corneal traction suture, and this should be placed a few clock hours away from the intended surgical site. The surgical approach begins with a fornix-based conjunctival peritomy. Care must be taken during the

81

Fig. 8.7 A parabolic superficial scleral flap is created using a toothed forcep to fixate the globe and a crescent blade, in this case a diamond blade. The flap measures approximately 5mm in width at the limbus, and is approximately 5mm from the limbus to the posterior edge. The shape of the flap is parabolic to assist in watertight closure at the conclusion of the procedure

dissection to ensure that the posterior conjunctival lip is relaxed sufficiently to allow for a 4–5 mm scleral flap to be outlined. Posterior blunt dissection must also be carried out in order to ensure that conjunctival reapposition at the conclusion of the case will not be challenging. Gentle cautery is applied to the sclera, with care being taken to avoid major aqueous and ciliary veins. A parabolic flap is then created approximately 5 mm in width by 5 mm in anterior posterior length (Fig. 8.7). Although a scleral flap of any shape may be created, it is the authors’ preference to create a parabolic flap to facilitate watertight closure at the conclusion of surgery. An initial superficial scleral flap is then created to at least approximately one-third scleral thickness (typically approximately 300 µm) and carried forward into clear cornea. This is followed by the creation of a deep inner scleral flap approximately 1 mm in dimension that is smaller than the superficial flap. Only a very thin layer of scleral tissue (approximately 100 µm) should be left covering the choroid during dissection of the deep scleral flap. Adequate depth during this stage is critical in order to properly unroof Schlemm’s canal when the dissection is carried forward anterior to the scleral spur. Special care must be taken to not only maintain attention to anatomic landmarks, specifically the scleral spur, but also to stay at the same depth throughout the deep dissection (Figs. 8.8 and 8.9). In order to avoid perforation or penetration into the globe during deep scleral flap dissection, it is commonly a tendency during this portion of the procedure for dissection to become superficial. This results in difficulty identifying the true anatomic position of Schlemm’s canal or passing over rather than into the canal during dissection, both

82

8 New Glaucoma Surgical Devices

8

Fig. 8.8 The deep scleral flap dissection is carried out also using a toothed forcep and a crescent blade. Note that a thin layer of sclera remains in the base of the dissection, but choroid is readily visible, as evidenced by the blue/gray hue. The deep flap is created approximately 1 mm inside from the edge of the superficial flap

Fig. 8.10 The scleral spur is clearly visible, and immediately anterior to it, the Schlemm’s canal is carefully and gently exposed

Fig. 8.9 The deep scleral flap is carried forward, maintaining the same depth of dissection, and the white longitudinal scleral fibers of the scleral spur are visible on the right side of the bed of the deep dissection

Fig. 8.11 A light reflection reveals the outward bulge of Descemet’s membrane in what is commonly known as trabeculoDescemet’s window (TDW). Posterior to Descemet’s membrane is Schlemm’s canal, and the scleral spur clearly visible

resulting in a challenging scenario of having to backtrack and attempt to unroof Schlemm’s canal with only a very thin layer of remaining sclera and a resultant higher risk of penetrating into the anterior chamber. As the deep scleral flap is dissected forward and lifted anteriorly with toothed forceps, fibers of the outer wall of Schlemm’s canal should be visible anterior to the scleral spur (Fig. 8.10). Percolation of aqueous humor through the remaining tissue as well as regurgitation of blood from the cut ends of the canal may be encountered, both signaling proper tissue planes. At this point, a paracentesis should be created in the temporal clear cornea and aqueous encouraged to egress from the anterior chamber.

A low IOP is desired at this point prior to exposure of Descemet’s membrane, because a high IOP will result in outward bulging of the fragile membrane and a much higher chance of perforation during this delicate dissection. The deep flap dissection should continue anteriorly approximately 1–2 mm to expose Descemet’s membrane. Again, aqueous humor may be observed to slowly percolate through Descemet’s. This clear window that remains is commonly termed trabeculoDescemet’s window (TDW) (Fig. 8.11). Separation of the cornea from Descemet’s window should be performed with the use of surgical sponges such as Merocel (Merocel Corp., North Mystic, CT, USA) or Weck-cel (Medtronic,

8.4 Schlemm’s Canal Devices

Jacksonville, FL, USA), pushing down on Schwalbe’s line with great care, as excessive downward pressure or any sudden movement may easily result in perforation of the window. Once the trabeculodescemet window (TDW) is adequately exposed, if inadequare aqueous flow is evident, Mermoud forceps may be used to strip the inner wall of Schlemm’s canal, leaving bare trabecular meshwork, to enhance aqueous percolation. The deep flap is then excised anteriorly, being careful not to leave a large anterior lip covering the TDW. The cut ends of Schlemm’s canal are then intubated with a viscocanalostomy cannula, of 150 µm outer bore diameter, and a gentle injection of a small amount of high-viscosity sodium hyaluronate, such as Healon GV (Advanced Medical Optics, Inc., Santa Ana, CA, USA), is injected into each side. This is performed to facilitate introduction of the iScience device into Schlemm’s canal. The diameter of Schlemm’s canal is known to be approximately 300 µm in the normal human eye. Although evidence suggests that collapse of the canal in glaucoma may be a secondary effect to increased meshwork and inner wall resistance [68], once this has occurred, a vicious cycle may be initiated wherein the IOP elevates even further due to reduced circumferential aqueous outflow in Schlemm’s canal to the collector channels. In order to restore the patency of Schlemm’s canal, a 45 mm working length flexible polymer microcatheter of 200 µm shaft diameter and a rounded atraumatic 250 µm tip diameter has been developed (iScience Interventional Inc., Menlo Park, CA, USA) to provide 360° catheterization of Schlemm’s canal. The microcatheter consists of a central support wire to provide a backbone of support for guidance in advancing the cannula and for resistance to kinking. Additionally, the catheter consists of optical fibers to allow for the transmission of light from a laser-based micro-illumination system to the tip, culminating in a blinking red light, assisting the surgeon in the visualization and localization of the tip within Schlemm’s canal. Finally, a true lumen exists within the microcatheter to allow for materials such as viscoelastic to be injected into Schlemm’s canal (Fig. 8.12). The back end of the iScience device has two arms, one connected to the laser-based micro-illumination light source and the other connected to a screw mechanism syringe for delivery of viscoelastic. With the device secured to a Mayo stand and the surgical drape, the microcatheter is grasped using two nontoothed forceps, and the rounded atraumatic tip is carefully introduced into one of the cut ends of Schlemm’s canal. The microcatheter is slowly advanced using the forceps until the entire circumference of Schlemm’s canal has been intubated and the catheter has emerged from the other cut end of the canal (Fig. 8.13). Possible difficulties in passing

83

Fig. 8.12 The tip of the Schlemm’s canal microcatheter, with a small amount of viscoelastic emerging

the microcatheter throughout the circumference of Schlemm’s canal include encountering constrictions within the canal or collector channel ostia that may prevent passage of the device. Although resistance may be encountered during the passage of the microcatheter, it has been the authors’ experience that 360° passage of the catheter has been possible in the vast majority of cases. Techniques to assist passage if resistance is felt include focal depression, turning the eye away from the area, injection of viscoelastic, or withdrawal and passage of the microcatheter in the other direction. In addition, the passage of the microcatheter has been observed to sometimes proceed into the suprachoroidal space posterior to Schlemm’s canal. Early recognition is paramount, and the microcatheter should be retracted and passage reattempted with external scleral depression posterior to Schlemm’s canal, or the entire microcatheter should be removed and passage attempted in the opposite direction. Once successful passage of the catheter has occurred, a 10-0 prolene suture, with the needles cut off, is tied together with the loop tied to the two loose ends around the microcatheter near the tip (Fig. 8.14). The microcatheter is then withdrawn in the reverse direction of intubation while an assistant advances the viscoelastic forward using the injector attached to one of the distal arms of the device. Injection of viscoelastic—typically a high molecular weight compound like Healon GV (Advanced Medical Optics, Irvine, CA, USA)—expands the canal gently and is retained for several days. Care must be taken not to overinflate Schlemm’s canal, as vigorous injection of viscoelastic may cause Descemet’s membrane detachment. During passage or retraction of the microcatheter, it is common to see regurgitation of heme from Schlemm’s canal into the anterior chamber. Once the device has been removed, the 10-0 prolene is cut, leaving four

84

8 New Glaucoma Surgical Devices

8

Fig. 8.13 The Schlemm’s canal microcatheter being passed 360° through the canal. The arrow reveals the flashing laser-based micro-illumination light source that reveals the position of the catheter to the surgeon

Fig. 8.14 A 10-0 prolene suture is tied around the distal end of the microcatheter, to be retracted into Schlemm’s canal, placing the suture endocanalicularly

Fig. 8.15 Two ends of the 10-0 prolene suture emerge from each cut end of Schlemm’s canal. The surgeon must determine which ends correspond and then subsequently tie the sutures in a slipknot fashion in order to allow for the adjustment of suture tension

loose ends, essentially two circumferential sutures, with two ends emerging from either side of Schlemm’s canal. By pulling on each end, the surgeon must determine which ends correspond to the same suture. Each suture is

then tied in a slipknot fashion after some back and forth movement known as “flossing the canal.” Suture tension is adjusted by pulling the knot posteriorly until it can just barely reach the scleral spur (Figs. 8.15 and 8.16).

8.4 Schlemm’s Canal Devices

Fig. 8.16 One of the two sutures tied in Schlemm’s canal with tension, causing indentation of the TDW as seen by the light reflection

The same procedure is then carried out with the second suture. The suture is thought to produce a pilocarpinelike effect by placing the trabecular meshwork on stretch and enhancing circumferential flow through Schlemm’s canal and the collectors. The aim of canaloplasty is to restore physiologic outflow of aqueous humor through the conventional pathway without the formation of a bleb or the creation of a fistula. Thus, the superficial parabolic scleral flap is closed in a watertight fashion with five interrupted 10–0 nylon sutures (Fig. 8.17). High-viscosity sodium hyaluronate is then placed under the superficial scleral flap using the viscocanalostomy cannula to maintain the scleral lake, a reservoir for aqueous humor percolating through the

Fig. 8.17 Slit lamp photograph of the superior conjunctiva of a canaloplasty patient postoperatively, revealing the absence of a subconjunctival bleb, a watertight flap closure with interrupted nylon sutures

85

TDW to ultimately be absorbed into circulation through scleral, episcleral, choroidal vasculature or the cut ends of Schlemm’s canal. The conjunctiva is then closed in the preferred manner of the surgeon again in a watertight fashion. One recent study showed that at one-year follow- up, 94 patients undergoing canaloplasty had IOP that had lowered from 24.6 to 14.9 mmHg [36]. In addition, medication usage was reduced from 1.9 to 0.6 medications. Similar IOP lowering was also observed in patients undergoing combined canaloplasty and phacoemulsification with intraocular lens implantation [69]. The most common complications reported in the recent publications were hyphema and elevated IOP, with others such as Descemet’s detachment, hypotony, and choroidal effusion also constituting possible complications. Canaloplasty appears to lower IOP by re-establishing aqueous egress via the conventional outflow pathway through Schlemm’s canal and the collector channels, but also allows for flow through the trabeculodescemet window and into the scleral lake, the potential space under the superficial scleral flap. From the scleral lake, the aqueous may travel into the cut ends of Schlemm’s canal, into the surrounding vasculature, including the suprachoroidal space, or even subconjunctivally to form a bleb in some cases despite a tight scleral flap closure. As evidence that the scleral lake plays a significant role in success of canaloplasty, in the authors’ experience, some patients develop TDW fibrosis requiring postoperative YAG (yttrium–aluminum–garnet) laser TDW puncture to enhance IOP lowering and aqueous flow into this potential space (Figs. 8.18 and 8.19). Suture tension also plays an important role in canaloplasty. As mentioned

Fig. 8.18 Gonioscopic view of the TDW postoperatively, with two separate 10-0 prolene suture knots visible along with the suture present circumferentially in Schlemm’s canal

86

8 New Glaucoma Surgical Devices

8

Fig. 8.19 Gonioscopic photograph of the TDW of a patient who required postoperative YAG laser goniopuncture of the TDW to enhance aqueous outflow into the intrascleral lake for IOP control. The scrolled edges of Descemet’s membrane are visible immediately inferior to the suture in the view

previously, a recent study showed that the greater the distension of Schlemm’s canal, the greater the IOP reduction [36], and greater suture tension has been shown to enhance flow (see Fig. 8.1). Because of the centripetal force placed on Schlemm’s canal by the prolene suture, the trabecular meshwork is drawn, albeit a small distance, radially towards the center of the pupil (Fig. 8.20). This precludes this procedure from being performed in the patient who has a narrow angle or close proximity of the peripheral iris to angle structures, and caution is advised for patients with crowded anterior segments. Even in the patient who appears to have an open angle, peripheral anterior synechiae may develop, and in

Fig. 8.20 Anterior segment optical coherence tomography images of two different patients post-canaloplasty, showing indentation of Schlemm’s canal with the endocanalicular suture (arrow)

some cases iris incarceration has been observed into the scleral lake through microperforations of the TDW. Thus, patient selection is important and preoperative gonioscopy is of paramount importance to assess the angle structures as well as the iris profile. Canaloplasty also relies on an intact Schlemm’s canal. Thus, prior surgery such as previous trabeculectomy, scarring in Schlemm’s canal induced by medications, laser or prior surgery, or trauma at the corneoscleral limbus may preclude the use of this procedure in certain patients. It is the authors’ experience that previous argon laser trabeculoplasty may sometime create difficulty in passing the microcatheter through the canal, while prior selective laser trabeculoplasty does not appear to have the same issue. In summary, canaloplasty is a nonpenetrating ab externo procedure with the goal of reestablishing or augmenting aqueous outflow via the conventional pathway without dependence on a subconjunctival bleb. While clinical results at one year have demonstrated well-controlled IOP, low complication rates, reduced dependency on medication, and minimal postoperative management, the procedure remains one that is technically challenging, optimal tension of the Schlemm’s canal suture is not known, fibrosis of the TDW may require postoperative laser, long-term implications of a suture in Schlemm’s canal are unknown, closure or contraction of the intrascleral lake and its impact are not well understood, and the question remains of whether most patients have a maximal amount of physiologic outflow that can be obtained, thus determining the lowest IOP that can be attained by this procedure.

8.4.2 Trabecular Micro-Bypass Stent The juxtacanalicular tissue and inner wall of Schlemm’s canal are known to be the site of greatest outflow resistance [68, 70]. It is logical then that providing aqueous a pathway to bypass this resistance point and access Schlemm’s canal directly should provide IOP lowering, with the main resistance to aqueous outflow then being episcleral venous pressure. The trabecular micro-bypass stent (Glaukos Corp., Laguna Hills, CA, USA), named the iStent®, is designed to be part in the anterior chamber and part in Schlemm’s canal, providing direct communication between the two spaces. The major outflow resistance point is thus bypassed, allowing direct access of aqueous humor via the stent into Schlemm’s canal. The titanium metal stent is 1 mm in length, 0.1 mg in weight, and is an L-shaped structure with a “snorkel” on the short arm, which is designed to sit in the anterior chamber, and an open half-pipe lumen of 180 µm outside diameter on the long arm, with three retention barbs on

8.4 Schlemm’s Canal Devices

Fig. 8.21 Photographs of the Glaukos trabecular micro-bypass stent from above (top), below (middle), and the side (bottom), revealing the opening or “snorkel” which is designed to sit in the anterior chamber

the convex side of the stent to provide secure placement and prevent stent extrusion (Fig. 8.21). The tip of the long arm is pointed to aid in trabecular meshwork penetration during insertion of the stent. The convex side sits against the inner wall of Schlemm’s canal, while the open half-pipe faces the outer wall, allowing unimpeded access of aqueous entering the canal to the collector channels which enter the outer wall. The stent is placed via an ab interno approach, through a corneal paracentesis-type incision of approximately 1.5 mm in size. Alternatively, when performed in conjunction with cataract extraction, the cataract incision may also conveniently be utilized. Much like other goniosurgical procedures, a gonioprism is required for appropriate visualization of the angle. Although a Swan–Jacob lens is the authors’ preference, other direct visualization gonioscopic lenses may also be used. The patient’s head should be tilted away from the surgeon, and when operating temporally, the eye placed in adduction either by patient cooperation or by an assistant using a toothed forceps. It is important to note that the stent is available in both the right- and left-directed orientations. The stent is manufactured preloaded on a delivery system consisting of a lightweight handle with a button for the surgeon’s index finger in order to deploy the stent, and

87

a long slender shaft, housing the grasping prongs. The stent is located at the end of the shaft, grasped by a threepronged holding mechanism that secures the snorkel. The long arm of the stent is oriented at 90° to the shaft. The anterior chamber, and most importantly the area of the angle where the stent will be placed, should first be inflated with a high-viscosity viscoelastic such as Healon GV (Advanced Medical Optics Inc., Santa Ana, CA, USA) to create ample space for the visibility and accessibility of the trabecular meshwork. Due to the fragility of the trabecular meshwork tissue and the common event of heme reflux from Schlemm’s canal during stent placement, a successful initial attempt is the optimal outcome. Not dissimilar to the principles when using a phacoemulsification handpiece, the wound should act as a fulcrum during stent placement, as movements in the anterior chamber are brought about by hand movements in the opposite direction. Under direct gonioscopic visualization, the stent tip should approach the angle somewhat acutely and engage and pierce the trabecular meshwork. Using a temporal approach, placement in the nasal angle is usually easiest. Maintaining movements only in the plane of the meshwork, the stent is advanced until the long arm is seen to be fully in Schlemm’s canal. Gently and slowly returning the eye to primary position, the button on the handle is depressed to release the stent. Care must be taken during release of the stent, as the stent may be dislodged as well as retract out of Schlemm’s canal during this step. Following the release of the stent, a gentle tap is often required to the side of the snorkel to fully seat the stent properly in Schlemm’s canal (Figs. 8.22–8.27). Following proper stent placement, heme regurgitation from the snorkel or the trabecular meshwork entry point is commonly seen, necessitating

Fig. 8.22 An intraoperative gonioscopic photograph through a direct gonioprism, showing the trabecular micro-bypass stent approaching the angle on the injector

88

8 New Glaucoma Surgical Devices

8

Fig. 8.23 The stent has engaged and pierced the trabecular meshwork to be placed into Schlemm’s canal

Fig. 8.25 The stent has now been released from the preloaded injector. The stent is seen placed in the angle, while the prongs previously holding the stent can be seen after release

Fig. 8.24 The stent has been completely placed into Schlemm’s canal but has not yet been released from the injector

Fig. 8.26 The tip of the injector with the prongs retracted is used to gently tap the stent in order to properly and fully seat it in Schlemm’s canal

further viscoelastic injection to assist in visualization and confirmation of proper stent placement. Reported complications of placement include transient postoperative hyphema, stent malposition and blockage, and in few instances persistently elevated IOP, which eventually required trabeculectomy. In a theoretical mathematical model, a bypass of the trabecular meshwork with either unidirectional or bidirectional flow would increase facility of outflow by 13% and 26%, respectively, and the higher the initial IOP, the greater the reduction [71, 72]. In an in vitro setting of cultured human anterior segments, placement of a single stent resulted in the IOP lowering from an average of 21.4 to 12.4 mmHg [44]. The IOP effect of further stents placed in this in vitro setting was, however, not as clear. While the major point of resistance in the juxtacanalicular meshwork has been bypassed by the stent, the influence on the IOP then depends the ability of

aqueous to travel circumferentially for some distance, and the resistance to flow in Schlemm’s canal and the collector channels. While, in theory, the flow in Schlemm’s canal is circumferential, the collapse of the canal (as seen in glaucoma patients) may preclude flow to the entire canal and collector system with the insertion of a single stent. This again raises the issue as to whether multiple stents may bring about further IOP lowering in the in vivo patient. If circumferential flow is disrupted in the glaucoma patient, and if multiple stents may have a greater IOP effect than a single stent, there may be a benefit in placing stents near collector channels. These issues, however, remain to be studied. In a small study of six patients recently, mean preoperative IOP before insertion of a single stent was 20.2 mmHg, which decreased to between 14 and 15 mmHg at one-year followup, and this was accompanied by decreased use of medications [45]. Insertion of a single stent, combined with cataract

8.4 Schlemm’s Canal Devices

Fig. 8.27 Gonioscopic photograph postoperatively of a trabecular micro-bypass stent sitting in Schlemm’s canal with the snorkel positioned in the anterior chamber

extraction and intraocular lens implantation, revealed a mean reduction in IOP from 21.7 to 17.4 mmHg at 12month follow-up, with a range of reductions from 3.4 to 5.9 mmHg. The mean number of medications also showed a statistically significant decrease from 1.6 to 0.4 at 12-month follow-up [73]. In summary, the Glaukos trabecular micro-bypass stent is an ab interno device that seeks to re-establish or augment the conventional outflow pathway of aqueous humor by providing a direct communication between the anterior chamber and Schlemm’s canal. The procedure has the advantages of directly bypassing the major resistance point in the juxtacanalicular meshwork, utilizing small incisions or those already created for adjunctive cataract surgery, avoidance of a filtering bleb, decreased likelihood of hypotony due to episcleral venous pressure, minimal postoperative management, and finally the preservation of conjunctival tissues if there is a future need for filtering surgery. Like canaloplasty, this device should be used with caution in patients with narrow anterior chamber angles or peripheral iris to trabecular meshwork proximity, as the snorkel may become occluded with iris tissue in these circumstances. While some questions remain unanswered—such as the utility of targeted stent placement, the benefit of multiple stents, and if so, the optimum number of stents—the data have shown a sustained decrease in IOP and dependence on medications at one-year follow-up.

89

collector channels. While it has found success in the pediatric population [75], similar success has not been observed in adults [37, 74, 77]. While goniotomy and trabeculotomy in eyes where visibility is poor [76] have not found similar success in adults, they have led to the development of other procedures, such as laser trabecular ablation, laser goniopuncture and goniocurretage [41, 78, 79]. A new device, the Trabectome (NeoMedix Corp., San Juan Capistrano, CA, USA), has also been developed as a means of incising trabecular meshwork via electrocautery. The Trabectome consists of a disposable footpedalactivated handpiece and a console to adjust infusion, aspiration and electrosurgical energy. The handpiece consists of a 19-gauge infusion sleeve, a 25-gauge aspiration port, and a bipolar electrocautery unit 150 µm away from an insulated footplate. The footplate is 800 µm in length from the heel to the tip, has a maximum width of 230 µm, and maximum thickness of 110 µm (Fig. 8.28). The footplate is designed in a triangular shape with a pointed tip to aid penetration into the trabecular meshwork and is bent at 90° to the shaft of the handpiece. A cross-section of the footplate reveals an elliptical shape with an anterior posterior width of 5 µm at the tip to 50 µm at the bend, and a meridional diameter from 350 to 500 µm, designed to fit into Schlemm’s canal. As the handpiece is placed into the canal, the footplate is designed to direct trabecular tissue into the electrocautery unit, while its insulation and smooth design, combined with continuous irrigation, allow the outer wall of Schlemm’s canal and the collector channels to avoid injury and trauma. Surgical approach for the Trabectome is similar to that described for the Glaukos trabecular micro-bypass stent. The surgeon typically sits temporally and a 1.6 mm

8.4.3 Trabectome Goniotomy is the procedure by which an incision is made in the trabecular meshwork along several clock hours to permit aqueous humor direct access to the aqueous

Fig. 8.28 A schematic of the Trabectome handpiece tip, with dimensions shown on the right

90

8

8 New Glaucoma Surgical Devices

clear corneal incision is created to accommodate the electrocautery unit. Viscoelastic is used to stabilize the anterior chamber, and a gonioprism is required for direct intraoperative visualization of the trabecular meshwork during ablation. After inserting the instrument, engaging the trabecular meshwork and entering Schlemm’s canal with the footplate, the footpedal is depressed and ablation of the tissues is carried out in the direction of the tip of the footplate along Schlemm’s canal until direct visualization is no longer possible (Figs. 8.29–8.31). The instrument is then turned to face the opposite direction and ablation is carried out in a similar fashion again until direct visualization is no longer possible. The total arc length that is typically amenable to treatment is approximately 60°. With simultaneous irrigation and aspiration of tissue debris, the view remains clear and heme reflux is not typically seen. However, upon removal of the instrument and lowering of the IOP, heme reflux is invariably seen. A clear corneal suture and intracameral air at the conclusion of surgery seemed to correlate with smaller amounts of postoperative hyphema [82]. The largest published study to date in 101 patients showed a mean IOP preoperatively of 27.6 mmHg and a mean IOP of 16.3 mmHg after 30 months of followup in ten patients [80]. In a separate study by the same group, the mean number of medications decreased from 1.2 to 0.4 at six months’ follow-up [82]. However, a 16% failure rate was noted, as defined by an IOP of greater than or equal to 21 mmHg on topical medications or a patient requiring subsequent trabeculectomy. Reported complications of the procedure included most significantly partial peripheral anterior synechiae and goniosynechiae (14%), transient corneal injury (6%) consisting of epithelial defect (3%), Descemet’s hemorrhage (1%),

Fig. 8.29 Direct gonioprism view of the Trabectome handpiece approaching the trabecular meshwork. (Photo courtesy of Douglas J. Rhee, MD)

Fig. 8.30 The Trabectome actively ablating and passing through trabecular tissue. (Photo courtesy of Douglas J. Rhee, MD)

Fig. 8.31 Reflux of heme into the anterior chamber upon incision into the inner wall of Schlemm’s canal. (Photo courtesy of Douglas J. Rhee, MD)

Descemet’s scrolling/detachment (1%), persistent Descemet’s injury (1%), and hypotony (1%). For similar reasons to canaloplasty and the trabecular micro-bypass stent, this procedure must be chosen with caution in patients who have a narrow anterior chamber angle, as they may be more likely to form peripheral anterior synechiae postoperatively due inflammation and proximity of iris tissue to the angle. In summary, the Trabectome is a new ab interno electrocautery device designed to incise trabecular meshwork and the inner wall of Schlemm’s canal for approximately 60° of arc, allowing aqueous access to Schlemm’s canal and the collector channels, bypassing the juxtacanalicular meshwork resistance point. This procedure shares the advantages of the trabecular micro-bypass stent in that a small incision is utilized, there is avoidance of a filtering bleb, little postoperative management is required, and

8.5 Suprachoroidal Filtration Device: The SOLX Gold Microshunt

91

there is preservation of conjunctival tissues. Although similar to other gonio-incisional procedures in that its aim is to provide direct access of aqueous to Schlemm’s canal and the collector channels, previous procedures have been prone to damaging the outer wall of the canal and the collector channels, resulting in fibrosis and ultimately impedance of aqueous egress. In histopathological studies, the insulated footplate on the Trabectome appears to be much less traumatic to these structures that are critical to aqueous filtration [80]. While the published data to date shows IOP lowering and decreased dependence on medications, longer term follow-up is still required in a larger number of patients, collapse of the canal and/or formation of peripheral anterior goniosynechiae remains a significant concern, and more work is required to study the role of inflammatory mediators in the Schlemm’s canal and collector channels following electrocautery of the tissues. Finally, unanswered questions about the conventional outflow devices are whether there is a maximal amount of IOP lowering that can be attained, and whether this relates to other factors such as episcleral venous pressure.

8.5

Suprachoroidal Filtration Device: The SOLX Gold Microshunt

The suprachoroidal gold microshunt (SOLX® Inc., Occulogix, Waltham, MA, USA) is a 24-carat gold implant composed of two layers fused together vertically, resulting in a device measuring 5.2 mm long, 2.4 mm wide anteriorly, and 3.2 mm wide posteriorly (Fig. 8.32). Two models exist, the GMS (XGS-5) and GMS Plus (XGS10). The XGS-5 model is a 6.2 mg, 60 µm thick structure, concealing nine channels each of 25 µm width and 44 µm height through which aqueous humor drains from the anterior aspect of the shunt, which is situated in the anterior chamber, to exit the posterior aspect which is placed into the suprachoroidal space (Figs. 8.33 and 8.34). The XGS-10 model weighs 9.2 mg and has wider channels of height 68 µm instead. The intent of the shunt is to increase uveoscleral outflow from the anterior chamber into the suprachoroidal space, either through the channels or around the shunt itself. Because gold is a known inert and noncorrosive metal, its biocompatibility as an implant is good [83]. Gold as an intraocular foreign body in the anterior chamber has also been reported to have no adverse effects, even after many years [84]. Implantation of the microshunt begins with a 4 mm fornix-based conjunctival peritomy. A scleral incision of approximately 3.5 mm in length is then created 2 mm posterior from the limbus, or further posteriorly in highly myopic eyes (Fig. 8.35). The dissection is carried

Fig. 8.32 Magnified photograph of the SOLX gold suprachoroidal microshunt. The posterior aspect of the shunt is superior in this photograph, with the anterior aspect of the shunt pictured inferior

Fig. 8.33 A schematic diagram of the proper position of the gold microshunt, with the head in the anterior chamber while the tail rests in the suprachoroidal space

out to near full thickness depth, where the choroid is visible through a thin layer of sclera. A scleral pocket at 95% depth is then created by tunneling anteriorly towards the

92

8 New Glaucoma Surgical Devices

8

Fig. 8.34 The gold shunt is composed of two leaflets fused together. Here, an interior schematic view of the shunt is provided

Fig. 8.36 An intraoperative photograph of the dissection performed for placement of the gold microshunt. An anterior scleral shelf is seen with a 95% depth scleral tunnel. In the groove, a full-thickness cutdown to the suprachoroidal space is seen

Fig. 8.35 A cutdown is performed in the sclera to near-full thickness, with the blue hue of choroid visible in the base of the cutdown

Fig. 8.37 The gold shunt is placed into the anterior chamber by gently pushing the posterior edge forward without grasping the shunt

scleral spur. At this point, a vertical incision is then made into the choroidal space and suprachoroidal anesthesia and viscoelastic are administered with a blunt cannula (Fig. 8.36). Following the filling of the anterior chamber via a sideport incision with viscoelastic at the anticipated site of entry of the gold shunt or using an AC maintainer, an entry is made into the anterior chamber at the level of the scleral spur through the previously constructed scleral tunnel. The shunt is placed through the scleral incision, ensuring the head of the device is in the anterior chamber (Fig. 8.37). Positioning of the shunt is achieved posteriorly in the suprachoroidal space using a sharp 27-gauge needle against the shunt to gently encourage it into the suprachoroidal pocket expanded previously by viscoelastic

while grasping the wound with toothed forceps (Fig. 8.38). Alternatively, an instrument such as a Sinskey hook can be utilized on the lateral positioning holes. The posterior scleral lip of the wound should conceal all of the shunt openings on the posterior aspect. The anterior aspect of the wound can also be manipulated through the anterior chamber to aid in positioning of the shunt. Intraoperative gonioscopy can help to confirm the proper and intended positioning of the gold shunt in the anterior chamber. The anterior drainage openings should be clearly visible. The shunt should also be allowed to sit deep enough such that the posterior holes are all adequately in the suprachoroidal space. The overlying scleral wound is tightly sutured with 4–5 interrupted 10-0 nylon sutures to ensure watertight closure, as subconjunctival reservoir is not the intended

8.5 Suprachoroidal Filtration Device: The SOLX Gold Microshunt

Fig. 8.38 The tail of the gold shunt is placed into the suprachoroidal space and encouraged into place with the tip of a 27-gauge hypodermic needle

Fig. 8.39 A postoperative slit lamp photo of the gold suprachoroidal shunt. A prior failed subconjunctival bleb is seen adjacent to the gold shunt superiorly

mode of filtration in this surgical procedure (Figs. 8.39 and 8.40). Finally, a 10-0 vicryl horizontal mattress suture is placed to reappose conjunctiva. Proper positioning of the shunt consists of the anterior drainage openings located in the anterior chamber, visible by gonioscopy, the posterior holes wholly placed in the suprachoroidal space, and the shunt entry into the anterior chamber just above the level of the scleral spur (Fig. 8.41). The crescent-shaped anterior aspect of the shunt consists of a positioning hole, which can be used to adjust shunt positioning with an instrument such as a Sinskey hook. The posterior aspect of the shunt likewise possesses two lateral wings for shunt manipulation. Flow is directed through and around the shunt via the natural pressure gradient from the anterior chamber to the suprachoroidal space.

93

Fig. 8.40 Interrupted 10-0 nylon sutures are used to close the scleral incision in a watertight fashion

Fig. 8.41 A gonioscopic photograph postoperatively of the head of the gold shunt sitting in the anterior chamber emerging at the level of the scleral spur. Note that the anterior drainage openings are entirely in the anterior chamber

Early nonrandomized clinical data released by SOLX show a 33% reduction in IOP at one year with the XGS5 model, with a mean preoperative IOP of 27.4 ± 4.7 as compared with 18.1 ± 4.7 postoperatively in a group of 39 patients. The XGS-10 model showed similar reduction in IOP from 25.5 ± 6.0 to 18.0 ± 2.5 at the one-year timepoint in a group of 40 patients. The XGS-5 group decreased their number of topical medications from 1.97 ± 0.74 to 1.50 ± 0.94, while the XGS-10 group began preoperatively at 2.25 ± 0.84 and decreased to 0.85 ± 0.90 at one year. With success defined as an IOP of greater than 5 mmHg and less than 21 mmHg, ten out of the final 36 patients in the XGS-5 group at one year were classified as failures. In the XGS-10 group, using these same criteria, three out of the final 13 patients had inadequate IOP control.

94

8

8 New Glaucoma Surgical Devices

Postoperative imaging of the gold shunt by anterior segment optical coherence tomography shows the shunt in the surpachoroidal space and a reservoir of fluid surrounding it (Fig. 8.42). Complications of the gold shunt include cataract formation, choroidal detachment, shunt–cornea touch, shunt–iris touch, shunt exposure, shunt migration, peripheral anterior synechia formation to the shunt, anterior chamber inflammation, hyphema, hypotony, vitreous hemorrhage, infection, pain and blurred vision. The SOLX gold microshunt is an ab externo suprachoroidal drainage device that provides a conduit for aqueous humor to travel from the anterior chamber to the suprachoroidal space either through or around the device. This device is currently in Phase III trials for treatment of refractory glaucoma. Though the device is pending FDA approval, the size of the device and the relative lack of trauma required to implant the device into the suprachoroidal space may provide a viable alternative surgical approach to lowering of IOP.

8.6

Conclusion

The ideal surgical procedure for the treatment of glaucoma is one which is technically easy to perform, effectively and consistently reduces IOP, has a low risk of hypotony and its associated complications, does not require control of wound healing and postoperative management, and does not have the lifetime risks of infection, failure, and wound leak. Although early in their development, and pending longer-term results, device innovations such as those mentioned in this chapter have sought to achieve this goal. While trabeculectomy continues to be viewed by many as the gold standard of surgical IOP lowering, its

Fig. 8.42 Postoperative anterior segment optical coherence tomography (AS-OCT) images of the gold microshunt, revealing fluid surrounding the shunt (yellow arrows) as well as suprachoroidal fluid posterior to the tail of the shunt (red arrows)

risk profile is well known and complications, both intraoperative and postoperative, may be as visually disabling as the disease itself. Many of the most significant risks arise because of the formation of a nonphysiologic bleb, and as a result, many of the innovations discussed aim to avoid the formation of such a subconjunctival reservoir. It is also notable that while reported IOP may be low in trabeculectomy, results may be influenced by the many patients who have long-term hypotony. Tube shunt surgery likewise has significant risks, as outlined earlier, the most significant being that of hypotony. While early results with the new devices have been promising, the question remains as to whether the lowest attainable IOP in some of these procedures is limited by downstream resistance points. Indeed, in most studies, these devices typically appear to attain IOPs in the mid-teens (Fig. 8.43). While this may not be as low as is necessary in some glaucoma patients, it seems logical that perhaps earlier surgical intervention with these safer glaucoma devices to lower the IOP to the mid-teens may prevent the need for a lower target IOP, or in other words, the need for a subconjunctival filtration surgery and its inherent risks. Current glaucoma therapy includes, at one end of the spectrum, medications and laser trabeculoplasty, which have a mild-to-moderate IOP-lowering effect with low risk, and at the other end, subconjunctival filtration surgery with high IOP lowering effects, but which is accompanied by a high risk level as well. Newer glaucoma surgical procedures endeavor to reduce the risk profile while pushing the efficacy towards our current surgical gold standards. Without doubt, current new devices, most of which are in their first generation, will continue to develop with further results and understanding. As glaucoma surgery continues to evolve, the ideal surgical procedure is one that has a high efficacy

Fig. 8.43 A chart showing the expected possible IOP level attainable via differing routes of filtration surgery

8.6 Conclusion

95

Fig. 8.44 Treatment landscape of glaucoma, obtained by plotting IOP-lowering effectiveness versus risk. LTP, laser trabeculoplasty; ECP, endocyclophotocoagulation; GMS, gold microshunt; MMC, mitomycin C; GDD, glaucoma drainage devices or tube shunts

in terms of IOP level while having an accompanied low risk level. While some new devices have shown promise, no single procedure (including trabeculectomy) has brought the landscape of glaucoma therapy to this ideal state yet (Fig. 8.44). The most appropriate procedure to be performed on any patient should still depend on the clinical decision made by the surgeon in determining the amount of IOP lowering required and balancing that with the acceptable amount of risk in each individual situation.

■

Summary for the Clinician ■

■

■

Surgical IOP reduction can be achieved by subconjunctival filtration (trabeculectomy, tube shunt devices, Ex-PRESS shunt), Schlemm’s canal surgery (nonpenetrating canaloplasty, trabecular micro-bypass iStent, Trabectome), and suprachoroidal filtration (gold microshunt). Trabeculectomy and tube shunt devices have the advantages of established potent IOP lowering, but the disadvantages of a high risk and incidence of hypotony, reliance on a subconjunctival bleb, and its inherent short- and long-term risks. The Ex-PRESS shunt is designed to provide further flow control in trabeculectomy and has the advantages over traditional trabeculectomy of providing a constant orifice size, requiring a

■

smaller incision into the anterior chamber, and foregoing the need for an iridectomy. Disadvantages include the reliance on a subconjunctival bleb and its related complications. Canaloplasty relies on a nonpenetrating ab externo approach to Schlemm’s canal, augmenting the conventional outflow pathway to produce IOP lowering. Advantages include IOP lowering without a subconjunctival bleb, low complication rates, reduced dependency on medication, and minimal postoperative management. Disadvantages include technical difficulty and a steeper learning curve for new surgeons, possible need for postoperative laser augmentation, unknown optimal suture tension in Schlemm’s canal, unknown implications of the long-term presence of a suture in the canal, and perhaps a lower limit to which IOP can be lowered. The trabecular micro-bypass iStent is an ab interno Schlemm’s canal device that bypasses the known major point of resistance of the juxtacanalicular trabecular meshwork and inner wall of Schlemm’s canal. Advantages include the use of small incisions, or a cataract incision, the avoidance of a subconjunctival bleb, low risk profile, and conjunctival preservation in case future filtration surgery is required. Disadvantages include the technical issues with intraoperative

96

8 ■

■

■

8 New Glaucoma Surgical Devices

gonio-visualization, an unknown maximal amount of attainable IOP lowering, an unknown optimal number of stents, and the need for more long-term data with patients receiving single versus multiple stents. The Trabectome microelectrocautery device, like the Glaukos stent, bypasses the resistance point of the juxtacanalicular meshwork and inner wall of Schlemm’s canal. However, rather than a stent, the Trabectome ablates trabecular tissue for between 60–90° arc length in order to allow aqueous to access Schlemm’s canal and the collector channels directly. Advantages are similar to those for the trabecular bypass stent. Disadvantages include, again, technical issues with intraoperative gonio- visualization, the unknown maximal extent of IOP lowering attainable by this device, along with the unknown effect of possible inflammatory mediators released on the canal and collector channels after electrocautery of tissues, and the concern over the formation of peripheral anterior goniosynechiae. The gold microshunt is a suprachoroidal device that is designed to be placed via an ab externo approach to provide a conduit for aqueous humor to travel from the anterior chamber to the suprachoroidal space. Advantages of the gold microshunt include a relatively atraumatic insertion into the suprachoroidal space, the small size of the device, a low risk profile, as well as avoidance of a subconjunctival bleb. Disadvantages include the question of optimal lumen size, the potential for fibrovascular growth over the anterior drainage openings, and the potential for late closure of flow around the shunt due to fibrosis, similar to that in a cyclodialysis cleft. As devices continue to improve the safety of glaucoma surgery and to lower risk profiles, further studies must be done to show the long-term efficacy of IOP lowering with these new procedures. Early data show great promise for the future of glaucoma surgery.

References 1. Richey SO (1896) Management of glaucoma. Trans Am Ophthalmol Soc 7:723–730 2. Davenport RC (1926) The after results of corneo-scleral trephining for glaucoma. Br J Ophthalmol 10(9):478–484

3. Scheie HG (1958) Retraction of scleral wound edges; as a fistulizing procedure for glaucoma. Am J Ophthalmol 45(4, Pt 2):220–229 4. Cairns JE (1968) Trabeculectomy. Preliminary report of a new method. Am J Ophthalmol 66(4):673–679 5. Borisuth NS, Phillips B, Krupin T (1999) The risk profile of glaucoma filtration surgery. Curr Opin Ophthalmol 10(2):112–116 6. Rollett M, Moreau M (1907) Le drainage au crin de la chambre anterieure contre l’hypertonie et la douleur. Rev Gen Ophtalmol 26:289–292 7. Molteno ACB (1969) New implant for drainage in glaucoma: animal trial. Br J Ophthalmol 53:161–168 8. Molteno ACB (1969) New implant for drainage in glaucoma: clinical trial. Br J Ophthalmol 53:606–615 9. Krupin T, Podos SM, Becker B, Newkirk JB (1976) Valve implants in filtering surgery. Am J Ophthalmol 81(2): 232–235 10. Lloyd MA, Baerveldt G, Heuer DK, Minckler DS, Martone JF (1994) Initial clinical experience with the Baerveldt implant in complicated glaucomas. Ophthalmology 101(4):640–650 11. Coleman AL, Hill R, Wilson MR, Choplin N, KotasNeumann R, Tam M, Bacharach J, Panek WC (1995) Initial clinical experience with the Ahmed glaucoma valve implant. Am J Ophthalmol 120(1):23–31 12. Barkan O (1948) Goniotomy for the relief of congenital glaucoma. Br J Ophthalmol 32(9):701–728 13. Scheie HG (1949) Goniotomy in the treatment of congenital glaucoma. Trans Am Ophthalmol Soc 47:115–137 14. Bill A, Phillips CI (1971) Uveoscleral drainage of aqueous humor in human eyes. Exp Eye Res 12:275–281 15. Toris CB, Yablonski ME, Wang YL, et al. (1999) Aqueous humor dynamics in the aging human eye. Am J Ophthalmol 127:407–412 16. Palmer SS (1991) Mitomycin as adjunct chemotherapy with trabeculectomy. Ophthalmology 98(3):317–321 17. The Fluorouracil Filtering Surgery Study Group (1989) Fluorouracil filtering surgery study one-year follow-up. Am J Ophthalmol 108(6):625–635 18. Kupin TH, Juzych MS, Shin DH, Khatana AK, Olivier MM (1995) Adjunctive mitomycin C in primary trabeculectomy in phakic eyes. Am J Ophthalmol 119(1):30–39 19. Ticho U, Ophir A (1993) Late complications after glaucoma filtering surgery with adjunctive 5-fluorouracil. Am J Ophthalmol 115(4):506–510 20. Gedde SJ, Schiffman JC, Feuer WJ, Herndon LW, Brandt JD, Budenz DL (2007) Treatment outcomes in the tube versus trabeculectomy study after one year of follow-up. Am J Ophthalmol 143(1):9–22 21. Gedde SJ, Herndon LW, Brandt JD, Budenz DL, Feuer WJ, Schiffman JC (2007) Surgical complications in the tube

References

22.

23.

24.

25. 26. 27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

versus trabeculectomy study during the first year of follow-up. Am J Ophthalmol 143(1):23–31 Grant WM (1958) Further studies on facility of flow through the trabecular meshwork. AMA Arch Ophthal 60(4 Pt 1):523–533 Rosenquist R, Epstein D, Melamed S, Johnson M, Grant WM (1989) Outflow resistance of enucleated human eyes at two different perfusion pressures and different extents of trabeculotomy. Curr Eye Res 8(12):1233–1240 Ethier CR, Kamm RD, Palaszewski BA, Johnson MC, Richardson TM (1986) Calculations of flow resistance in the juxtacanalicular meshwork. Invest Ophthalmol Vis Sci 27(12):1741–1750 Epstein E (1959) Fibrosing response to aqueous; its relation to glaucoma. Br J Ophthalmol 43:641–647 Krasnov MM (1968) Externalization of Schlemm’s canal (sinusotomy) in glaucoma. Br J Ophthalmol 52:157–161 Ellingsen BA, Grant WM (1972) Trabeculotomy and sinusotomy in enucleated human eyes. Invest Ophthalmol 11:21–28 Johnstone MA, Grant WM (1973) Microsurgery of Schlemm’s canal and the human aqueous outflow system. Am J Ophthalmol 76:906–917 Koslov VI, Bagrov SN, Anisimova SY, et al. (1990) Nonpenetrating deep sclerectomy with collagen [in Russian]. Oftalmokhirurgiia 3:44–46 Fyodorov SN, Ioffe DI, Ronkina TI (1984) Deep sclerectomy: technique and mechanism of a new antiglaucomatous procedure. Glaucoma 6:281–283 Zimmerman TJ, Kooner KS, Ford VJ, Olander KW, Mandlekorn RM, Rawlings EF, Leader BJ, Koskan AJ (1984) Trabeculectomy vs. nonpenetrating trabeculectomy: a retrospective study of two procedures in phakic patients with glaucoma. Ophthalmic Surg 15:734–740 Stegmann R, Pienaar A, Miller D (1999) Viscocanalostomy for open angle glaucoma in black African patients. J Cataract Refract Surg 25:316–322 Sourdille P, Santiago P-Y, Villain F, Yamamichi M, Tahi H, Parel JM, Ducournau Y (1999) Reticulated hyaluronic acid implant in nonperforating trabecular surgery. J Cataract Refract Surg 25:332–339 Ambresin A, Shaarawy T, Mermoud A (2002) Deep sclerectomy with collagen implant in one eye compared with trabeculectomy in the other eye of the same patient. J Glaucoma 11:214–220 Sanchez E, Schnyder CC, Sickenberg M, Chiou AG, Hédiguer SE, Mermoud A (1996/97) Deep sclerectomy: results with and without collagen implant. Int Ophthalmol 20:157–162 Lewis RA, von Wolff K, Tetz M, Korber N, Kearney JR, Shingleton B, Samuelson TW (2007) Canaloplasty: circumferential viscodilation and tensioning of Schlemm’s

37.

38.

39. 40. 41.

42.

43. 44.

45.

46. 47.

48. 49. 50.

51.

52. 53. 54.

97

canal using a flexible microcatheter for the treatment of open-angle glaucoma in adults: interim clinical study analysis. J Cataract Refract Surg 33(7):1217–1226 Luntz MH, Livingston DG (1977) Trabeculotomy ab externo and trabeculectomy in congenital and adult-onset glaucoma. Am J Ophthalmol 83:174–179 Tanihara H, Negi A, Akimoto M, Terauchi H, Okudaira A, Kozaki J, Takeuchi A, Nagata M (1993) Surgical effects of trabeculectomy ab externo on adult eyes with primary open angle glaucoma and pseudoexfoliation syndrome. Arch Ophthalmol 111:1653–1661 Krasnov MM (1974) Q-switched laser goniopuncture. Arch Ophthalmol 92:37–41 Wickham MG, Worthen DM (1970) Argon laser trabeculotomy: long-term follow-up. Ophthalmology 86:495–503 Epstein DL, Melamed S, Puliatio CA, Steinert RF (1985) Neodymium: YAG laser trabeculopuncture in open-angle glaucoma. Ophthalmology 92:931–937 Spiegel D, Kobuch K (2002) Trabecular meshwork bypass tube shunt: initial case series. Br J Ophthalmol 86:1228– 1231 Yablonski ME (2005) Trabeculectomy with internal tube shunt: a novel glaucoma surgery. J Glaucoma 1:91–97 Bahler CK, Smedley GT, Zhou J, Johnson DH (2004) Trabecular bypass stents decrease intraocular pressure in cultured human anterior segments. Am J Ophthalmol 138(6):988–994 Spiegel D, Wetzel W, Haffner DS, Hill RA (2007) Initial clinical experience with the trabecular micro-bypass stent in patients with glaucoma. Adv Ther 24(1):161–170 Bain WE (1954) Variations in the episcleral venous pressure in relation to glaucoma. Br J Ophthalmol 38(3):129–135 Friberg TR, Sanborn G, Weinreb RN (1987) Intraocular and episcleral venous pressure increase during inverted posture. Am J Ophthalmol 103(4):523–526 Phelps CD (1978) The pathogenesis of glaucoma in Sturge– Weber syndrome. Ophthalmology 85(3):276–286 Bigger JF (1975) Glaucoma with elevated episcleral venous pressure. South Med J 68(11):1444–1448 Suguro K, Toris CB, Pederson JE (1985) Uveoscleral outflow following cyclodialysis in the monkey eye using a fluorescent tracer. Invest Ophthalmol Vis Sci 26:810–813 Jordan JF, Dietlein TS, Dinslage S, et al. (2007) Cyclodialysis ab interno as a surgical approach to intractable glaucoma. Graefe’s Arch Clin Exp Ophthalmol 245:1071–1076 Shields MB, Simmons RJ (1976) Combined cyclodialysis and cataract extraction. Ophthalmic Surg 7(2):62–73 Galin MA, Baras I (1975) Combined cyclodialysis cataract extraction: a review. Ann Ophthalmol 7(2):271–275 Gills JP, Paterson CA, Paterson ME (1967) Action of cyclodialysis utilizing an implant studied by manometry in a human eye. Exptl Eye Res 6:75–78

98

8

8 New Glaucoma Surgical Devices

55. Klemm M, Balazs A, Draeger J, Wiezorrek R (1995) Experimental use of space-retaining substances with extended duration: functional and morphological results. Graefes Arch Clin Exp Ophthalmol 233(9):592–297 56. Nesterov AP, Batmanov YE, Cherkasova IN, Egorov EA (1979) Surgical stimulation of the uveoscleral outflow: experimental studies on enucleated human eyes. Acta Ophthalmologica 57(3):409–417 57. Pinnas G, Boniuk M (1969) Cyclodialysis with teflon tube implants. Am J Ophthalmol 68(5):879–883 58. Krejci L (1972) Cyclodialysis with hydroxyethyl methacrylate capillary strip. Ophthalmologica 164:113–121 59. Ozdamar A, Aras C, Karacorlu M (2003) Suprachoroidal seton implantation in refractory glaucoma: a novel surgical technique. J Glaucoma 12:354–359 60. Jordan JF, Engels BF, Dinslage S, et al. (2006) A novel approach to suprachoroidal drainage for the surgical treatment of intractable glaucoma. J Glaucoma 15:200–205 61. Bindlish R, Condon GP, Schlosser JD, D’Antonio J, Lauer KB, Lehrer R (2002) Efficacy and safety of mitomycin-C in primary trabeculectomy: five-year follow-up Ophthalmology 109(7):1336–1341 62. Sarkisian SR (2007) Use of an injector for the Ex-PRESS™ mini glaucoma shunt. Ophthalmic Surg Lasers Imaging 38(5):434–436 63. Coupin A, Li Q, Riss I (2007) Ex-PRESS miniature glaucoma implant inserted under a scleral flap in open-angle glaucoma surgery: a retrospective study. Fr J Glaucoma 30(1):18–23 64. Maris PJG, Ishida K, Netland PA (2007) Comparison of trabeculectomy with Ex-PRESS miniature glaucoma device implanted under scleral flap. J Glaucoma 16:14–19 65. Dahan E, Carmichael TR (2005) Implantation of a miniature glaucoma device under a scleral flap. J Glaucoma 14(2):98–102 66. Traverso CE, De Feo F, Messas-Kaplan A, Denis P, Levartovsky S, Sellem E, Badalà F, Zagorski Z, Bron A, Gandolfi S, Belkin M (2005) Long term effect on IOP of a stainless steel glaucoma drainage implant (Ex-PRESS) in combined surgery with phacoemulsification. Br J Ophthalmol 89(4):425–429 67. Nyska A, Glovinsky Y, Belkin M, Epstein Y (2003) Biocompatibility of the Ex-PRESS miniature glaucoma drainage implant. J Glaucoma 12(3):275–280 68. Moses RA, Grodzki WJ Jr, Etheridge EL, Wilson CD (1981) Schlemm’s canal: the effect of intraocular pressure. Invest Ophthalmol Vis Sci 20(1):61–68 69. Shingleton B, Tetz M, Korber N (2008) Circumferential viscodilation and tensioning of Schlemm’s canal (canaloplasty) combined with temporal clear corneal phacoemulsification

70. 71. 72.

73.

74.

75.

76.

77.

78. 79.

80.

81.

82.

83. 84.

cataract surgery for the treatment of open angle glaucoma and visually significant cataract—one year results. J Cataract Refract Surg 34(3):433–440 Grant WM (1963) Experimental aqueous perfusion in enucleated human eyes. Arch Ophthalmol 69:783– 801 Zhou J, Smedley GT (2005) A trabecular bypass flow hypothesis. J Glaucoma 14(1):74–83 Zhou J, Smedley GT (2006) Trabecular bypass: effect of schlemm canal and collector channel dilation. J Glaucoma 15(5):446–455 Craven ER, Nichamin LD, Spiegel D (2008) Using the iStent to treat POAG in cataract patients: 12-month analysis. Paper presented at: ASCRS Symposium on Cataract, IOL, and Refractive Surgery, Chicago, IL, 4–9 April 2008 Herschler J, Davis EB (1980) Modified goniotomy for inflammatory glaucoma. Histologic evidence for the mechanism of pressure reduction. Arch Ophthalmol 98:684–687 Gramer E, Tausch M, Kraemer C (1996) Time of diagnosis, reoperations and long-term results of goniotomy in the treatment of primary congenital glaucoma: a clinical study. Int Ophthalmol 20:117–123 Mendicino ME, Lynch MG, Drack A, et al. (2000) Longterm surgical and visual outcomes in primary congenital glaucoma: 360 degrees trabeculotomy versus goniotomy. J AAPOS 4:205–210 Dickens CS, Hoskins HD Jr (1996) Epidemiology and pathophysiology of congenital glaucoma. In: Ritch R, Shields MB, Krupin T (eds) The glaucomas, vol 2, 2nd edn. CV Mosby, St. Louis, MO, p. 729–738 Hill RA, Baerveldt G, Ozler SA, et al. (1991) Laser trabecular ablation (LTA). Laser Surg Med 11:341–346 Jacobi PC, Dietlein TS, Krieglstein GK (1997) Technique of goniocurettage: a potential treatment for advanced chronic open angle glaucoma. Br J Ophthalmol 81:302–307 Minckler D, Baerveldt G, Ramirez MA, Mosaed S, Wilson R, Shaarawy T, Zack B, Laurie D, Francis B (2006) Clinical results with the trabectome, a novel surgical device for treatment of open-angle glaucoma. Trans Am Ophthalmol Soc 104:40–50 Francis BA, See RF, Rao NA, Minckler DS, Baerveldt G (2006) Ab Interno trabeculectomy: development of a novel device (Trabectome™) and surgery for open-angle glaucoma. J Glaucoma 15:68–73 Minckler DS, Baerveldt G, Alfaro MR, Francis BA (2005) Clinical results with the trabectome for treatment of openangle glaucoma. Ophthalmology 112:962–967 Eisler R (2004) Mammalian sensitivity to elemental gold (Au). Biol Tr Elem Res 100:1–17 Sen SC, Ghosh A (1983) Gold as an intraocular foreign body. Br J Ophthalmol 67:398–399

Chapter 9

Digital Glaucoma Patient Record and Teleconsultation Systems for Glaucoma Specialists: The European Glaucoma Society Glaucocard Project

9

Marc Schargus, Franz Grehn, The Glaucocard Workgroup

Core Messages ■ ■

■

Telemedicine and electronic documentation will play a major role in future healthcare systems Treatment of chronic diseases like glaucoma can benefit from electronic medical records with longterm follow-up data storage Data storage, data transfer and encryption have to follow international standards

9.1

Introduction

Many glaucoma studies have shown that due to demographic changes the prevalence of glaucoma and the cost of treating it will greatly increase over the next few decades [1, 2]. Considering that there were approximately 490 million people living in the European Union in 2006 and that glaucoma and ocular hypertension (OH) has an overall prevalence of about 3%, it can be estimated that there are currently about 9–25 million glaucoma and OH patients in Europe [3, 4]. Health economists advise that the use of modern information technologies in health care provides the opportunity for more transparency and increased quality of management. It has been calculated that this could lead to savings of about 12–15% in the cost of glaucoma care. As glaucoma is a chronic disease, a patient may see several ophthalmologists during his/her life and so important information can get lost over time. In addition, many examinations are repeated when patients with complex glaucoma cases are referred to a glaucoma center or when they change their ophthalmologist for other reasons. Only 10–16% of all glaucoma patients use some kind of “glaucoma passport.” This form of documentation is

■

■

International diagnostic and procedural classifications must be extended for the optimal documentation of glaucoma The EGS Glaucocard project is specially designed to suit long-term glaucoma data storage according to extended international classification standards

presently paper-based and not multilingual. Information about diagnosis, IOP and medication is stored, but only rarely other relevant data from follow-up examinations [5]. The amount of stored information is limited and documentation is time-consuming. Existing solutions only use printouts from various glaucoma examination devices and lack the capability to perform, e.g., automatic trend analysis of visual fields or other long-term analyses of examinations. Although some national glaucoma-related data sets are available, structured cross-national datasets for documenting and exchanging medical data and disease histories of glaucoma patients do not currently exist. Up to now, ophthalmologists and patients have not been able to transfer disease history, image or visual field examination data from one ophthalmologist to another in a simple, digitized manner. Project “Glaucocard” was set up by the European Glaucoma Society (EGS). The purpose of it is to develop an integrated and interconnected European glaucoma data record. One important step towards this goal is the development of a multilingual standardized cross-national “Glaucocard” data set which contains all of the information needed for initial and follow-up examinations of glaucoma patients [6]. Repeated data input for “Glaucocard” can be

100

9 Digital Glaucoma Patient Record and Teleconsultation Systems

avoided by using existing data from electronic medical record (EMR) systems, thus reducing workload.

9

9.2

History of Telemedicine in Ophthalmology

Telemedicine is an umbrella term for all electronically assisted options for delivering medical services and recorded medical information over long distances. Theoretically, telemedicine has been feasible since the invention of the telephone. The simplest example is the communication and exchange of data between two ophthalmologists by telephone. Telemedicine can be performed in real time, in a storeand-forward mode, or via hybrid techniques.

Store-and-Forward Mode Asynchronous teleophthalmology can be very simple, like sending patient data by e-mail. Sophisticated information can be transmitted, such as text and numerical data, as well as images, special examination printouts and raw data. Because the other ophthalmologist will review the data at a time convenient to him or her, the referrer will not receive the consultant’s reply immediately. One important advantage of this approach is that fast bandwidth and a permanent connection are not required, and immediate transfer of the data is not necessary. Thus, the cost and time needed to perform store-and-forward communication are low, which makes it highly convenient (Fig. 9.2).

Hybrid Mode Real-Time Mode Real-time telemedical communication allows people in different locations to see and speak with one another synchronously. The consultant can view images and interact with the presenter at a remote site. The most important advantage of real-time working is that the response is immediate and there is an opportunity for patient interaction. However, a higher bandwidth is required for real-time work than for store-and-forward, which makes it more expensive and so it is not available in many countries. Another disadvantage is the need for both participants in the system to be present at the same time, which is not easy to manage for general work schedules (Fig. 9.1).

Fig. 9.1 Real-time telemedicine

In hybrid mode telemedicine, a combination of real-time and store-and-forward modes is used. The clinical data are sent to the consultant for review prior to any videoconference. For example, optic nerve photographs, visual field examinations and video clips can all be sent in advance. The patient can then be examined in real time if required. Ophthalmology is a specialty that uses visual information intensively. Ophthalmologists are trained to interpret images. Store-and-forward teleophthalmology systems are well suited to the transmission of data and high-quality photographs to specialists for review. Therefore, ophthalmology (just like other specialties) has been involved in telemedicine projects for many decades.

9.3 The Concept of an Electronic Glaucoma Patient Health Record System

101

Fig. 9.2 Store-and-forward telemedicine

One of the initial applications of telemedicine in ophthalmology was a 1987 real-time-mode project to monitor retinal vessels during spaceflight. A system was developed at the Johnson Space Center in Houston, FL, USA, for real-time transmission of retinal images acquired by a portable video funduscope. It was tested on the space shuttle Columbia during mission STS-50 [7, 8]. New electronic links between specialists, hospitals, primary care physicians, and patients provide new opportunities in health services. Intrinsically driven to control health care costs, managed care organizations find telemedicine of great interest. One of the first pan-European telemedicine projects was called OPHTEL and connected seven private ophthalmologists, one university eye clinic, one diabetes center, and an Informatics Research Institute in five European countries for teleophthalmology consultation in 1988. OPHTEL tested store-and-forward e-mail systems and real-time videoconferencing for ophthalmology consultations [9–11]. Continuous progress in telecommunications technologies over the last two decades, including broadband data transfer via the Internet, has provided the means to transfer large amounts of data electronically. The costs of data transfer have decreased significantly since cheap flat rates and broadband connections have become available in developed countries. Most recent telemedicine projects are limited by being single, proprietary and only national in scope. These disadvantages have made it difficult to build up large inter-

national networks for ophthalmology subspecialties such as glaucoma. Specific glaucoma telemedicine projects are rare. Most projects focus on screening for glaucoma in large populations [12, 13]. In 2006 the European Glaucoma Society’s (EGS) “Glaucocard” project was launched. The purpose of this initiative is to develop an integrated and interconnected European electronic patient glaucoma record system primarily designed for the storage of glaucoma-related examination data, which can facilitate long-term evaluation of glaucoma.

9.3 The Concept of an Electronic Glaucoma Patient Health Record System 9.3.1

General Issues for Implementation

The conventional medical paper record is still standard in many hospitals and medical practices. The disadvantages of conventional paper records are obvious: ■ ■ ■ ■ ■ ■

They are only available at one site at a time They can get lost They cannot be sorted and filtered according to special criteria No standardization No automatic analysis Electronic media cannot be included

102

9

9 Digital Glaucoma Patient Record and Teleconsultation Systems

There are still some advantages to using paper records, such as easy transport, low cost and their ability to be maintained for decades without special electronic devices. However, computerization is extending into all areas of modern life, and ultimately electronic medical patient records will be used all over Europe. Anglo-American terminology uses various terms for an electronic patient record, such as an “electronic health record,” a “computerized patient record,” a “computerbased patient record,” an “electronic medical record,” a “computerized medical record,” an “electronic health care record” and a “continuous electronic care record.” As one can see, there are many different classifications for electronic data storage of patient-related medical data. In the following, the classification of Waegemann is described [14]. His classification is based on the natural development of information technology (IT) in medical facilities (Fig. 9.3). Level 1: Automated Record

Automated records include the patient’s administrative data, their visit times, and a link to their paper records.

Level 2: Computerized Medical Record (CMR)

The CMR is an electronic record that contains all medical documents, but only in a scanned format. This record can be used concomitantly with a paper record. Due to the lack of low standardization, this data storage cannot provide further analysis outside of the institution and cannot be used for standardized data evaluation and transfer.

Level 3: Electronic Medical Record (EMR)

An EMR includes a fully electronic record with structured documentation based on a specific terminology. It is usually used in just one institution or within only one software system. Level 4: Electronic Patient Record System (EPRS)

This type of electronic record contains all of the EMRs jointly created by different institutions (e.g., healthcare providers from different institutions and health care sectors).

Fig. 9.3 Levels of different classification for electronic data storage of patient-related medical data

9.3 The Concept of an Electronic Glaucoma Patient Health Record System

Level 5: Electronic Health Record (EHR)

An EHR is a longitudinal record that is maintained and updated from cradle to grave, storing data related to disease as well as health/wellness that have been provided by the patient and his/her medical care-givers. Our concept of introducing a glaucoma-related EPRS that can be used all over Europe requires a particular glaucoma EPRS that corresponds to Level 4 of Waegemann’s classification. The EPRS is a set of components that form the mechanism by which patient record systems are created, used, stored and retrieved. A patient record system is usually located within a health care provider setting. It includes people, data, rules and procedures, processing and storage devices, as well as communication and support facilities. Each user of the EPRS can generate new records that are added to the existing series of records. The content of an EPRS is another important issue. Information can refer to any kind of medical data, or it can only focus on a special disease, like glaucoma or diabetes mellitus. In chronic diseases, EMRs should be designed such that they cover the complete period from disease onset to death. In a next step, the purpose of the EMR must be defined. The primary usage of EMR for medical patient care, secondary applications like accounting and quality management, and tertiary usage for research and teaching or clinical epidemiology can all be defined. The Glaucocard project mainly aims to achieve clinical patient medical data storage with the option to use the data for secondary anonymous evaluations in clinical epidemiology and research. One of the most important steps is the development of structured medical and technical data sets and the framework of the project. Unfortunately, there are no accepted multilingual medical terminology sets for glaucoma care or glaucoma follow-up examinations. In the next section, we will provide an overview of the existing classifications of glaucoma and the development of glaucoma data sets. In addition, technical protocols for the operation of hardware and software for archiving and transmitting data must be created. Only a few glaucoma examination instruments are designed for external data exchange and implementation in an EPRS. The lack of a standard for exchanging data and the incompatibility between different systems has still not been solved. The Digital Imaging and Communications in Medicine (DICOM) standards developed by the American College of Radiology and the National Electronics Manufacturers Association for other specialties, like radiology, show that a worldwide standard

103

that makes the exchange of radiological image data easy between different institutes and even countries can be achieved. The work of the DICOM Workgroup WG 09 (Ophthalmology) is still in progress. The goal is to enable the standardized data transfer of all kinds of digital imaging and visual field examinations in ophthalmology. The incompatibility between different examination devices must be considered, and the exchange of data between different EPRSs on a national and international scale is also difficult. Many systems do not store data in a fully structured format. Therefore, data transferred to an EMR or EPRS can get lost, meaning that time-consuming double entries in the local and the teleophthalmology EMR systems are then needed. Also, translation support for entries can only be provided if data are entered in a structured format. Free text fields must be avoided, because the translation of free text is still erroneous and terms used locally cannot be implemented. Therefore, for the Glaucocard system, the EGS terminology and guidelines were mainly used as the basis for the data set [15]. The following considerations address the type of software and media used for data transfer. Telemedicine technology is evolving quickly. This year’s state of the art technical equipment may be out of date within a few years. As already mentioned, data transfer speeds have increased significantly within the last decade, and highspeed Internet connections are now used over nearly all of Europe. Data transfer costs are decreasing every year. The transmission capacity required for an actual ophthalmic examination and the image data for one patient is small compared to the data transferred every day by an enthusiastic Internet user. Therefore, a centralized data storage system is preferred when constructing an EPRS because it does not need external local storage media and can be upgraded centrally. Local workstations do not need to be updated with the latest hardware, because some of the data processing can be done in the central storage system. Medical practices and hospitals not connected to the Internet should not be excluded. Therefore, it is necessary to provide an external local storage device for them. One of the cheapest, smallest and most concise forms of storage media is the USB memory stick. Memory sticks with larger and larger capacities are available from year to year. A size of 1 GB can store the data from several years of glaucoma EMRs. One major concern is maintaining the confidentiality of individual records when they are managed electronically. In the European Union, several directives of the European Parliament and of the Council protect the processing and free movement of personal data, including for the purposes of health care. Therefore, a sophisticated

104

9

9 Digital Glaucoma Patient Record and Teleconsultation Systems

data security model must be developed for the data protection of stored and transferred glaucoma data. There are two types of encryption methods: asymmetric and symmetric data encryption. The encryption process used in each is the same: data passes through a mathematical formula called an algorithm, which converts it into encrypted data called ciphertext. These formulae require a variable from the user—called a key—which makes it difficult for anyone else to crack the encryption. With symmetric encryption, data is run through a program and a key is created that scrambles the data. Then the encrypted data is sent to the recipient and the decoding key is transmitted separately. Symmetric encryption is fast but not as safe as asymmetric encryption because someone could intercept the key and decode the information. Asymmetric encryption is more complex and more secure. Two related keys are required: a public key and a private key. One can make the public key available to anyone who might send in encrypted data. The key can only encode data; it cannot decode it. The private key stays safely with the person who receives the data. When somebody wants to send encrypted data, he encrypts it using the public key. When the recipient receives the ciphertext, he decrypts it with his private key. The additional safety of asymmetric encryption comes at a price: more computation is required, so the process takes longer. The compromise of using combined asynchronous/synchronous data encryption offers the most reliable solution. Another important part of designing and constructing an EPRS is the financial planning. To get a widely accepted solution it is necessary to use as much hard- and software from the existing computer hardware infrastructure as possible. As already mentioned, computer hard- and software evolves rapidly with a average lifetime of about 3–5 years. Internet-based webpages for the EPRS can be easily accessed by nearly every computer hardware system today, and thus offers a practically platform-independent solution. Existing local software solutions should be adapted to an EPRS system through customized import and export functions. Double data entry can be avoided by using existing data from the local EMR system, and so additional human time resources can be saved. Additional costs of EPRS, like data transfer, central storage and backup solutions, administrative costs, as well as technical and help support, must be financed either by health care providers or through private payments by the patient. The patient gets the prize of the secure, long-term storage of his/her chronic disease-related data. Disease management programs (DMPs) are becoming increasingly popular among health care providers.

Disease management is the concept of reducing healthcare costs and improving quality of life for individuals with chronic disease conditions like glaucoma by preventing or minimizing the effects of a disease or chronic condition through integrative care. Telemedicine can be the basis for these programs and can help to reduce costs and optimizing treatment. National DMP programs are under construction and EPRS can provide significant support for them. The cost savings will then hopefully be reinvested in the field of telemedicine so that further progress is made in this field.

9.3.2

Important Classifications for Electronic Glaucoma Medical Record Systems

Specific medical classifications—or medical coding—are important for the standardized and systematic storage of patient data as the basis for an EPRS. Descriptions of medical diagnoses and procedures must be transformed into universal medical code numbers according to international or national classifications. The structured, code-based storage of disease and examination data also enables easy translation to other languages, which would not be possible with free text fields using the many terms that have common and uncommon abbreviations. We performed a systematic review of research on existing clinical and IT-based medical and glaucoma code classifications and concepts from the last few years. These are listed and explained below.

9.3.2.1

Diagnostic Codes

Diagnostic codes are used to group and identify diseases, disorders, symptoms, and medical signs. The International Statistical Classification of Diseases and Related Health Problems (ICD) provides codes for classifying diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. It provides the worldwide basis for the coding of diseases and death. It was first introduced in 1901 as ICD 1 (International Classification of Causes of Death), and should be revised every ten years. The most significant changes were introduced in the ninth revision of the ICD in 1975, when the WHO expanded ICD 9 to 17 chapters. ICD 10 WHO [16], developed between 1983 and 1992, is not used as a uniform worldwide standard, because several countries still use the ICD 9 WHO, such as the USA. Countries like Germany (ICD 10 GM or “German Modification” [17, 18]), Australia (ICD 10 AM) and Canada (ICD 10 CA) already use the ICD 10 WHO with their own extensions. ICD 11

9.3 The Concept of an Electronic Glaucoma Patient Health Record System

WHO is under preparation and is expected to be introduced after 2013. The glaucoma-related ICD codes are still the same in all modifications, but the terminology and subclassifications used are not up-to-date. Currently, there are only ten different subclassifications for glaucoma. The Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) was revised in January 2002 (International Health Terminology Standards Development Organization (IHTSDO): SNOMED CT). It is a systematically organized computer-processable collection of medical terminology covering most areas of clinical information, such as diseases, findings, procedures, microorganisms and pharmaceuticals. It permits clinical data to be consistently indexed, stored, retrieved, and aggregated across specialties and sites of care. It also allows the contents of medical records to be organized, thus reducing the variability of the way in which the data is captured, encoded and used for the clinical care of patients and research. Logical Observation Identifiers Names and Codes (LOINC) is a database and universal standard for identifying laboratory observations. It was developed in 1994. LOINC was created in response to the demand for an electronic database for clinical care and management. Since its initiation, the database has expanded to include not just medical and laboratory code names, but also nursing diagnoses, nursing interventions, outcome classification, and a patient care data set. LOINC applies universal code names and identifiers to medical terminology. The purpose of it is to assist in the electronic exchange of clinical results (such as laboratory tests, clinical observations, outcome management and research). It contains only a few field codes for glaucoma data and can therefore be disregarded for the development of a glaucoma EPRS. 9.3.2.2

Procedure Codes

Procedure codes are numbers or alphanumeric codes that are used to identify specific health interventions taken by medical professionals. The version of the International Classification of Health Interventions (ICHI) termed the Condensed Classification of Health Interventions (CCHI) is a system of classifying procedure codes that is being developed by the WHO and further developed by the National Centre for Classification in Health (NCCH) of Australia [19]. It is the replacement for the former International Classification of Procedures in Medicine (ICPM), which was developed in 1978 but has been not revised since then [20]. It is currently only available as a beta release. As a

105

result, most nations developed their own incompatible standards for coding procedures and interventions. Several national classification procedure coding systems have been developed, like the OPS 301 2007 (Germany) [21], the Classification des Actes Medicaux Version 10 (CCAM) (France) [22], and the Nordic Medico-Statistical Committee (NOMESCO) Classification of Surgical Procedures [23]. The German OPS 301 2007 keeps very detailed information on glaucoma surgical procedures, is updated every year, and is therefore one of the preferred procedure classifications for a glaucoma EPRS. 9.3.2.3 Existing Glaucoma Clinical Pathways and Datasets

In 2005 the National Health Institute of Great Britain started a national program to develop templates for glaucoma care pathways and datasets [24]. The “NHS Do Once and Share (DOAS) Clinical Care Pathway and Dataset V1.0” focuses on clinical care for glaucoma patients and suspects. It covers a wide range of data fields for specific glaucoma documentation and is currently one of the most comprehensive data sets related to glaucoma. Unfortunately, it is only available in English (focusing on the NHS system), and is primarily designed for primary open-angle (POAG)/normal-tension glaucoma (NTG) and ocular hypertension (OHT) patients and suspects. The long list of data fields is time-consuming to fill out, and a technical realization has still not been published. The European Glaucoma Society (EGS) Guidelines, Second Edition, provide a comprehensive database for the development of a glaucoma data set and clinical pathway. Since the glaucoma classification is not adapted to any international standard it is proprietary; a conversion table will be defined, as done for the Glaucocard project [15]. 9.3.2.4 General Informatic Standards for Healthcare Systems

The following basic information technology standards are intended for the development of an EPRS that is not specifically focused on a glaucoma project. However, we will present them briefly here as they are worldwide standards in electronic medical documentation and are needed for the development of internationally accepted systems. HL7 is an international community of healthcare experts and information scientists that are collaborating to create standards for the exchange, management and integration of electronic healthcare information (see the Health Level 7 homepage at http://www.hl7.org). HL7 specifies a number of flexible standards, guidelines, and

106

9

9 Digital Glaucoma Patient Record and Teleconsultation Systems

methodologies by which different healthcare systems can communicate. It is currently available in Version 3 (HL7 V3). HL7 exchanges information with other standards development organizations and national and international sanctioning institutions (e.g., ANSI and ISO) in both the healthcare and the information infrastructure domains in order to promote the use of supportive and compatible standards. The HL7 Clinical Document Architecture (CDA) release 2 is an XML-based mark-up standard that is intended to specify the encoding, structure and semantics of clinical documents for exchange. The CDA tries to ensure that the content will be human-readable and is therefore required to contain narrative text, but it still contains structure and, most importantly, permits the use of codes to represent concepts. The Extensible Mark-up Language (XML) is a generalpurpose mark-up language (see the XML Core Working Group Public Page at http://www.w3.org/XML/Core). It is classified as an extensible language because it allows its users to define their own elements. Its primary purpose is to facilitate the sharing of structured data across different information systems, particularly via the Internet. It is used to both encode documents and serialize data. XML is recommended by the World Wide Web Consortium. It is a free open standard.

9.4 The EGS Glaucocard Project The Glaucocard project was launched in 2006 by the European Glaucoma Society. After several formal and informal preparations to set up an EPRS designed specifically for glaucoma patients, a European consensus conference was held in April 2007 in Olbia, Italy. The Glaucocard Consensus panel members defined a standardized glaucoma data set for a short and efficient glaucoma report on the abovementioned international standards of medical and ophthalmological documentation for Project Glaucocard. One important step in achieving this aim is the development of a multilingual standardized cross-national Glaucocard data set, a short data set for everyday use which contains all of the necessary information for initial and follow-up examinations of glaucoma patients. Previous concepts of teleconsultation projects like OPHTEL [9, 10] and DIABCARD [25–27], aiming at electronic communication between different ophthalmologists, were additionally analyzed and implemented. Different types of data storage and transfer methods using Smartcard, USB stick or Internet-based storage were evaluated in order to identify the most comprehensive way of exchanging data between ophthalmologists in

different European countries and to provide a basis for a future teleconsultation system for glaucoma specialists. Analysis of the different disease classifications revealed a wide variability in terms of the range, complexity and detail used in the field of glaucoma. As the aim of the Glaucocard project was to develop a multilingual data set for a glaucoma patient record, free text variables were avoided wherever possible. Until now, no automated system that allows the reliable translation of free text fields into different languages has been available. HL7 is the most commonly used data structure for data exchange between electronic medical record (EMR) systems. Therefore, administrative patient master data will be stored using the HL7 Patient Information segment (PID). CDA rel.2 was chosen for the base architecture of the clinical document due to the wide distribution of XML structure. By using an open XML standard it was possible to customize different EMR systems to the Glaucocard web interface for automatic data import and export. It was decided that a disease classification based on international classifications, specifically the ICD 10 WHO commonly used in Europe and the similar ICD 10 GM, would be used. Table 9.1 exemplifies the drawback of disease classification in ICD 10 for glaucoma. The ICD 10 codes for primary open-angle glaucoma inadequately summarize several subclassifications, e.g., normal-tension and pigmentary glaucoma. In an EMR system, the correct diagnosis can be defined through other field variables, but this is not possible from the raw data of the ICD 10 WHO/GM. To maintain the compatibility with the ICD 10 WHO, a two-digit extension had to be established in order to provide an accurate glaucoma classification, as seen in Table 9.2. The complete conversion table for ICD 10 WHO/GM and the EGS classification of glaucomas is shown in Table 9.3. These additional data can be added to another system by re-importing data from the Glaucocard data set, or they can be discarded, hence providing downgrade compatibility. It was agreed that the German OPS 301 2007 would be used for medical procedures. This provides the most

Table 9.1 Official ICD 10 WHO for H40.1 with subclassification H40.1

Primary open-angle glaucoma Glaucoma (primary)(residual stage): ■ Capsular with pseudoexfoliation of lens ■ Chronic simple ■ Low-tension ■ Pigmentary

9.4 The EGS Glaucocard Project

107

Table 9.2 Adopted EGS subclassification for the official ICD 10 WHO for H40.1 ICD 10 WHO code

Additional code

ICD 10 WHO official text

Official EGS terminology

H40.1

00

Primary open-angle glaucoma

Pseudoexfoliation glaucoma

H40.1

01

Primary open-angle glaucoma

Primary open-angle glaucoma/highpressure glaucoma (POAG/HPG)

H40.1

02

Primary open-angle glaucoma

Primary juvenile glaucoma

H40.1

03

Primary open-angle glaucoma

Pigmentary glaucoma

H40.1

04

Primary open-angle glaucoma

Primary open-angle glaucoma/normalpressure glaucoma (POAG/NPG)

Table 9.3 Most important clinical examination/history fields (fields in italics indicate additional raw data or PDF files from examination devices) General diseases General medication Ocular diseases Ocular surgery Ophthalmic medication/brand name/generic name Compliance in medication usage Intolerances Proven allergies Family history of glaucoma Proven glaucoma in family history by ophthalmologist Refraction Best corrected visual acuity IOD Central corneal thickness Anterior + posterior eye segment findings Gonioscopy (Spaeth/Shaffer) Morphology of optic disc Vertical CD ratio Size of disc Neuroretinal rim atrophy Actual disc hemorrhages Previous disc hemorrhages ISNT rule maintained Nerve fiber layer Disc notches Visual field assessments Optic disc photography GDx HRT FDT RTA OCT Free fields for additional examination devices

comprehensive development of the former ICPM, which has not been actualized since its introduction in 1978 by WHO. Free text data fields were also integrated into the preliminary dataset. No existing multilingual classifications for ocular clinical findings, allergies, intolerances or pharmacological databases exist which could be used for the Glaucocard dataset. Therefore, these fields remain free text fields. An overview of the main data fields relating to clinical findings and medical history is given in Table 9.3. The best corrected visual acuity can be recorded as logMAR, decimal acuity or Snellen acuity over a distance of 20 ft, respectively. Automated conversion into other visual acuity formats is provided in the Glaucocard software. Numeric data already stored locally in the EMR system, like central corneal thickness, visual acuity or refraction, can be transferred automatically if supported by the EMR system. Two different graduations can be chosen for gonioscopic findings according to the EGS Guidelines, either Spaeth’s or Shaffer’s angle grading systems. Details on the morphology of the optic disc can be documented via drop-down menus in less than one minute. This provides an accurate documentation of the optic disc in addition to the HRT or other images, including the vertical CD ratio, the size of the disc, maintenance of the ISNT rule, qualitative neuroretinal rim atrophy, nerve fiber layer loss, presence and localization of disc notches, and the number of actual or formerly documented disc hemorrhages. Until now, the activities of the DICOM Workgroup WG09 have not achieved a standardized data transfer for all kinds of digital imaging and visual field printouts similar to the systems used in radiology. Therefore, at this time, these data can be best stored to an electronic medical report through a commonly used open standard file format. The Portable Document Format (PDF) and Joint Photographic Experts Group (JPEG) formats offer a simple method for storing compressed

108

9

9 Digital Glaucoma Patient Record and Teleconsultation Systems

image data (like a printout) in a manageable data volume. Data export can be performed by pre-integrated export filters that are implemented in certain devices, or they can be performed by noncommercial export tools. Using these formats, data such as visual fields, optic disc photographs, GDx, HRT, OCT, FDT and RTA images can be automatically attached in the present Glaucocard version. In summary, the final dataset shows 130 field variables. Some fields require mandatory data input, but most of them can be filled out at one’s own discretion. The full EMR dataset and additional information can be viewed at http://www.glaucocard.org. EMR datasets are currently available in English and German; language sets in Spanish, Italian and Flemish are also planned. The condensed Glaucocard EMR Web Report, which can also be printed out, can be seen in Fig. 9.4. Data storage of the Glaucocard EMR can be performed by either transferring data centrally through the Internet to a web server, or by storing it on a smartcard or USB stick.

Fig. 9.4 Glaucocard electronic web report

The Internet-based communication concept of Glaucocard EPRS is shown in Fig. 9.5. Each adapted EMR system can easily send a Glaucocard EMR to the Glaucocard web server, where all Glaucocard EMRs are stored centrally. Data transfer is encrypted by combined asymmetric/symmetric encryption and the data is stored anonymously. Identification can only be achieved by invoking the individual Glaucocard number kept by the patient. Therefore, all data security issues are preserved. Importing data into adapted EMR systems is easy; even the raw data can be imported into local EMR systems if this feature is provided by the EMR software. Unadapted EMR systems can store an attached Glaucocard PDF report, depending on software architecture. Conventional paper-based practices and hospitals can access Glaucocard data via the HTML–web interface and fill out Glaucocard EMRs by hand or print reports for their paper-based charts. A special feature is the ability of the patient to read out his/her own Glaucocard EMR. For security reasons, the patient cannot change any data.

9.6 Conclusion

109

Fig. 9.5 Glaucocard system setup

By July 2007, we were able to demonstrate, using the pilot project of the Glaucocard System, that data transfer between two countries with three different EMR systems is feasible.

in order to optimize glaucoma treatment. This will result in increased quality of glaucoma care and save costs in health care by avoiding unnecessary re-examinations.

9.6 9.5

Future Prospects

It is planned that the Glaucocard system will start up in Central Europe by 2009. With the increasing digitization of hospitals, special disease management and follow-up programs will become more and more important for health care providers and ophthalmology practices. The Glaucocard system can be implemented in DMPs or general electronic health care programs. Since up to now there have only been national solutions for general electronic health care systems, a pan-European system for chronic diseases like glaucoma could provide one step towards the creation of European standards for glaucoma documentation. The digital data can also be used for referrals and to store or forward data for teleconsultations of glaucoma specialists

Conclusion

Teleophthalmology for glaucoma patients opens up many possibilities for improving patient care and increasing tertiary care in underdeveloped areas. For several years, teleophthalmology projects remained theoretical or experimental. The rapid development of information technology has made a cost-effective international EPRS feasible. EMR systems are not just time-consuming procedures for electronic data entry. Ophthalmologists can use the structured data stored in them for long-term follow-up examinations of patients and for teleconsultation systems in order to determine the best options for treatment. Patients also have access to their own glaucoma records, and multinational cooperation between ophthalmologists could lead to the international standardization of glaucoma terminology and guidelines.

110

9 Digital Glaucoma Patient Record and Teleconsultation Systems

The success of the pilot Glaucocard project opens the door to the integration of teleophthalmology into routine practice.

9

Summary for the Clinician ■

■

■

■

Electronic patient records should be based on standardized international classifications to allow transfer to other EMR systems. The application of EGS Guidelines to clinical documentation for glaucoma patients throughout Europe will help to create standardized, comparable patient records for long-term follow-up, and to optimize glaucoma care. Teleophthalmology can facilitate the consultation of glaucoma specialists for second opinions regarding glaucoma patients with complex medical histories. The EGS Glaucocard can be used for long-term data storage of glaucoma-related examination and history data. Using it should lead to increased quality of glaucoma care and should lower health care costs by avoiding unnecessary repeated examinations. Future developments may include a teleophthalmology system for second-opinion consultation.

2.

3. 4.

5.

6.

7.

8.

Acknowledgments The European Glaucoma Society Project “Glaucocard” is supported by the European Glaucoma Society (EGS), in part by an unrestricted grant from MSD/Chibret, ifa Systems AG, Fidus GmbH, and integration.AG. The Glaucocard Workgroup consists of: A. Anton, Universidad Autonoma de Barcelona, Spain; F. Dannheim, Seevetal, Germany; R. Hitchings, Moorfields Eye Hospital, London, UK; A.H. Hommer, Sanatorium Hera, Vienna, Austria; M. Hyppa, Karlsruhe, Germany; C.E. Traverso, Clinica Oculistica, DiNOG, Azienda Ospedale Universita San Martino, Genoa, Italy; R. Waedlich, ifa Systems AG, Frechen, Germany; S. Wente, ASW GmbH Fidus, Darmstadt, Germany; T. Zeyen, University Eye Hospital Leuven, Belgium.

References 1. Hitzl W, Hornykewycz K, Grabner G, Reitsamer HA (2007) On the relationship between age and prevalence

9.

10.

11.

12.

13.

and/or incidence of primary open-angle glaucoma in the “Salzburg-Moorfields Collaborative Glaucoma Study. Klinische Monatsblatter fur Augenheilkunde 224:115–119 Quigley HA, Broman AT (2006) The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90:262–267 Michelson G, Groh MJ (2001) Screening models for glaucoma. Curr Opin Ophthalmol 12:105–111 Traverso CE, Walt JG, Kelly SP, Hommer AH, Bron AM, Denis P, Nordmann JP, Renard JP, Bayer A, Grehn F, Pfeiffer N, Cedrone C, Gandolfi S, Orzalesi N, Nucci C, Rossetti L, Azuara-Blanco A, Bagnis A, Hitchings R, Salmon JF, Bricola G, Buchholz PM, Kotak SV, Katz LM, Siegartel LR, Doyle JJ (2005) Direct costs of glaucoma and severity of the disease: a multinational long term study of resource utilisation in Europe. Br J Ophthalmol 89:1245–1249 Dietlein TS, Jordan J, Dinslage S, Jacobi PC, Krieglstein GK (2005) Patient characteristics in a tertiary glaucoma center. Circumstances of treatment and attitudes of patients. Ophthalmologe 102:502–506 Schargus M, Grehn F, The Glaucocard Workgroup (2008) The European Glaucoma Society Glaucocard project: improved digital documentation of medical data for glaucoma patients based on standardized structured international datasets. Graefes Arch Clin Exp Ophthalmol. 2008 Sep 3. [Epub ahead of print] Caputo M (1994) The application of digital satellite comunications in conducting telemedicine. University of Texas, Houston, TX, pp. 1–94 Hunter N, Caputo M, Bilica R (1993) Portable dynamic fundus instrument: uses in telemedicine and research. In: Proceedings of the 7th Annual Workshop on Space Operations Applications and Research (SOAR), Houston, TX, 3–5 August 1993 Mertz M (1999) ByOPHTEL: a Bavarian project for rapid telemedical exchange of knowledge, files and skills between practitioners and hospitals in eye care. Stud health Technol Inform 64:164–172 Mertz M, Mann G, Zahlmann G, Obermaier M (1997) Scientific role of German ophthalmology in the European telecommunication project OPHTEL. Ophthalmologe 94:523–528 Zahlmann G, Walther HD, Liesenfeld B, Kaatz H, Kluthe S, Fabian E, Klaas D, Schnarr KD, Neubauer L, Obermaier M, Wegner A, Mertz M, Mann G (1998) Teleconsultation network for ophthalmology—experiences and results. Klinische Monatsblatter fur Augenheilkunde 212:111–115 Tuulonen A, Ohinmaa T, Alanko HI, Hyytinen P, Juutinen A, Toppinen E (1999) The application of teleophthalmology in examining patients with glaucoma: a pilot study. J Glaucoma 8:367–373 Schiffman JS, Li HK, Tang RA (1998) Telemedicine enters eye care: practical experience. J Ophthalmic Nursing Technol 17:102–106

References 14. Waegemann C (1999) Current status of EPR developments in the US towards an electronic health record Europe ‘99. Medical Record Institute, Newton, MA, pp. 116–118 15. European Glaucoma Society (2008) Terminology and guidelines for glaucoma, 3rd edition. Dogma S.r.l., Savona, Italy 16. WHO (2005) International classification of diseases and related health problems, 10th revision. WHO, Geneva, Switzerland 17. Biermann H (1995) ICD & ICPM in der Augenarztpraxis. Biermann, Zuelpich, Germany 18. DIMDI (2006) ICD-10-GM 2007, Systematisches Verzeichnis, 10. Revision—German Modification. Deutscher Ärzteverlag, Berlin 19. National Centre for Classification in Health (2007) Condensed Classification of Health Interventions (CCHI). NCCH, Sydney, Australia 20. WHO (1978) International Classification of Procedures in Medicine (ICPM). WHO, Geneva, Switzerland 21. Graubner B (2006) OPS 2007 2 Bände: Systematisches Verzeichnis mit Erweiterungskatalog, Operationen und

22.

23.

24.

25.

26. 27.

111

Prozedurenschlüssel—Internationale Klassifikation der Pro-zeduren in der Medizin. Deutscher Ärzteverlag, Berlin Agence Technique de l’Information sur l’Hospitalisation (2007) Kit de nomenclature Classification des Actes Medicaux (CCAM) V10. Agence Technique de l’Information sur l’Hospitalisation, Lyon, France Nordic Medico-Statistical Committee (NOMESCO) (2005) NOMESCO Classification of Surgical Procedures (NCSP), version 1.10. AN:sats—Tryk & Design a-s, Copenhagen Do Once and Share (DOAS) Glaucoma Project (2007) Glaucoma Clinical Care Pathway & Dataset v1.0, June 2006. DOAS Glaucoma Project, NHS, London Engelbrecht R, Hildebrand C (1997) DIABCARD: a smart card for patients with chronic diseases. Clin Perform Qual Health Care 5:67–70 Engelbrecht R, Hildebrand C (1999) Telemedicine and diabetes. Stud Health Technol Inform 64:142–154 Engelbrecht R, Hildebrand C, Brugues E, De Leiva A, Corcoy R (1996) DIABCARD—an application of a portable medical record for persons with diabetes. Med Inform 21(4):273–282

Index

Abatacept, 55 Adalimumab, 55 Adaptive optics (AO), 2, 6 African Americans, glaucoma blindness in, 13–14 Ahmed valve, 55, 77 Angle closure glaucoma anatomical basis for, 45 “anatomically narrow angle” and “occludable angle,” 43–44 background, 42 classification systems evolution of, 43 ISGEO scheme, 44–45 level I, 45–46 level II, 46 level III, 46 level IV, 46–47 primary, 44 trabecular meshwork in, 45 Annexin-5, 2, 8 Anterior ischaemic optic neuropathy, 45 Anterior segment ischaemia, 45 Anterior segment optical coherence tomography (AS-OCT), 44, 46 Anterior uveitis, 50 Apoptosing retinal cells, detection of (DARC), 2, 8–9 Appositional closure damages, 45 Aquaflow collagen implant, 61 Aqueous humor egress, pathways of, 76 Asian populations, prevalence of PACS among, 18 Baerveldt device, 77 Behçet’s disease, 49 Birefringence, 2 Bleb fibrosis, 69 Blebitis, 68 Bleb leaks, 68, 75 Brn3b, 7 Canaloplasty, 76, 81–86 Carbocyanine dyes, 7 Cataract extraction, 66 Cataract progression, 69 Chinese populations, prevalence of PACS among, 18 Chorioretinal scars, 52 Choroidal detachment, 50, 67 Ciliary body detachment, 50

Ciliary body inflammation, 50 Ciliolenticular block/aqueous misdirection/ “malignant glaucoma,” 46–47 Circadian rhythms significance to physiologic processes, 23 sources, 24–25 Cirrus (Carl Zeiss), 5–6 C-kit, 7 Coherence length, 3–4 Condensed Classification of Health Interventions (CCHI), 105 Confocal scanning laser ophthalmoscopy (cSLO), 2, 5–6 Congenital glaucoma, 76 Corneal birefringence, 2 Corneal endothelial loss, 45 Corticosteroids and glaucoma, 51–52 Cyclodialysis cleft, 78 Cytomegalovirus (CMV), 53 Daclizumab, 55 Deep sclerectomy, 64–65, 70–71 and exposure of Trabeculo-Descemet’s membrane, 60 procedure, 60–61 superficial scleral flaps, 59–60 use of implants, 61 Descemet’s membrane detachment, 68 Developmental neurobiology, 9 DIABCARD, 106 Diabetes and risk of glaucoma, 17 DiAsp (4-[4-didecylaminostyryl]-N-methyl-pyridinium iodide), 7 DiI (1,1´-dioctadecyl-3,3,3´,3´-tetramethylindocarbocyanine perchlorate), 7 DiO (3,3´-dioctadecyloxacarbocyanine perchlorate), 7 Dopamine, 23 EGS Glaucocard Project, 106–109 Encapsulated bleb, 69 Endocyclophotocoagulation, 77 Enhanced variable compensator (ECC-SLP), 2 Episcleral venous pressure (EVP), 23 Eskimos and glaucoma, 18 Ethnicity and glaucoma, 15–16 Ex-PRESS Mini Glaucoma Shunt, 79–81 Extensible Mark-up Language (XML), 106

114

Index

Family history and glaucoma, 15 Fibronectin, 51 Flossing, canal process, 84 Fluorometholone, 55 5-Fluorouracil, 77 Flying spot systems, 5 Fourier domain OCT (FD-OCT), 5 Fuchs’ heterochromic iridocyclitis, 52–53 Functional OCT (fOCT), 5 Ganglionectomy, 25 GDx-VCC technique, 35–37 Glaucoma, defined, 1 Glaucoma-related animal models, 8 Glaucomatous optic neuropathy, 42, 45 characteristic features of, 29 Glaukos trabecular micro-bypass iStent, 76 Goldmann applanation tonometry (GAT), 23 Goldmann lens, 47 Goniocurretage, 76 Gonioscopy, 18, 47 Goniotomy, 89 Granulomatous anterior uveitis, 54 Granulomatous iridocyclitis, 55 Green fluorescent protein (GFP) expression systems, 7 Hartman–Shack wavefront sensor, 6 Healon GV, 61, 67, 87 Health Level 7 website, 105–106 Heidelberg retinal tomography (HRT), 2, 30 pixel-based techniques, 35 stereometric parameters criticism of use of, 33 event analyses, 34 ONH sector rim area values, 34 Spearman rank correlation, 34 trend analyses, 34–35 vs. pixel-based techniques, 31–33 test-retest variability, 33, 36 topographical change analysis (TCA), 31 Hemorrhage, in scleral bed, 69 Herpes simplex (HSV), 53 Herpes zoster (HZV), 53 Herpetic disease, 53 Herpetic viral infection, 52 High-resolution reflectance imaging, 1 HLA-Bw54, 52 HL7 Clinical Document Architecture (CDA) release 2, 106 Horner syndrome, 23 24-Hour IOP, 23 and aqueous production, 24 effect of beta-blockers, 26 effect of prostaglandin analogs, 26 glaucoma and, 25–26

Goldmann equation of, 23 importance of, 23 medical management of, 26 normal vs glaucoma, 24 in OAG, 26 supine position, 24, 27 Hyaluronic acid, 78 implant, 61 Hybrid mode telemedicine, 100–101 Hydroxyethyl methacrylate capillary strip, 78 Hyphema, 68 Imaging techniques adaptive optics, 6 assess RNFL thickness, 2 associated with glaucomatous progression, 2 of cells in living systems, 2 confocal scanning laser ophthalmoscopy, 5–6 description of, 1–2 high-resolution reflectance imaging, 2–3 optical coherence tomography, 3–5 scanning laser polarimetry, 2 Infectious keratitis, 68 Infliximab, 55 Inner retinal layers, 1 Interferometry-based imaging system. See Optical coherence tomography (OCT) Interstitial keratitis (IK), 54 Intraocular pressure (IOP), 42, 90 and aqueous flow dynamics, 24 aqueous norepinephrine concentrations, 24 during canaloplasty, 82, 85 and classification of angle closure, 43 elevation of, 25 role of uveitis, 49–50 and glaucoma, 25–26 in HSV keratouveitis, 53 lowering methods, 9 normal, 23–24 in OAG group, 25–26 postoperative increase, 68–69 putative pathway for circadian control, 25 as risk factor for development of POAG, 14 role of cytokines, 50 and Schlemm’s canal, 86 surgical approaches to lowering, 76 Intrascleral filtering bleb, 62–63 In vivo imaging, of mouse eye, 6 Iridocyclitis, 50 Iridotrabecular contact (ITC), 43–45 Iris atrophy, 53 Iris bombé, 54 Iris damage, 45 Iris prolapse, 67 Irreversible blindness, 2

Index

Juvenile inflammatory arthritis (JIA), 53 Juxtacanalicular trabecular meshwork (JTM), 77 Juxtacanalicular trabeculum, 60, 64 Keratic precipitates, 52 Keratouveitis, 53 Krupin device, 77 Laser iridotomy, 42, 44, 46, 65 Laser trabeculoplasty, 66 Laser trabeculopuncture, 76 Latanoprost, 55 Lens damage, 45 Lens-induced angle closure, 46 Lens opacity and glaucoma, 37 Light-based non-invasive methods, 9 Logical Observation Identifiers Names and Codes (LOINC), 105 Loteprednol, 55 Low-coherence interferometry, 3 Lyme disease, 53 Magnetic resonance imaging, 35 Malignant glaucoma, 45, 69 Mermoud forceps, 83 Methylprednisolone, 55 Microcatheter, 83 Miotics, 55 Mitomycin C (MMC), 55, 77 Molteno valve, 55, 77 Mongolian, prevalence of PACS among, 18 Multiple sclerosis, 53 Myocilin mRNA, 51 Myopia glaucoma surgery in patients, 64 as risk factor for glaucoma, 16–17 Nd-YAG laser, 55 Neovascular glaucoma, 54 Neovascularization, 50–51, 54, 66 Neuroendocrine signaling molecules, 23 Neuroretinitis, 54 NHS Do Once and Share (DOAS) Clinical Care Pathway and Dataset V1.0, 105 Norepinephrine, 23 Ocular toxoplasmosis, 54 Open-angle glaucoma (OAG), incidence rate, 42 OPHTEL, 101, 106 Ophthalmological imaging techniques, future of, 9–10 Optical coherence tomography (OCT), 1, 37 Optic nerve head photography, 30 OptiMed drainage devices, 77

Paracentesis, 67 Pars planitis, 53–54 Peripapillary atrophy, 33 Peripheral anterior synechiae (PAS), 42–43, 69 Peripheral retinal periphlebitis, 53 Phacomorphic glaucoma, 45 Phosphatidylserine (PS), 8 Photoreceptor layers, 1 Pigmentary glaucoma, 64 Pixel-based techniques, 31–33, 35 Plateau iris configuration, 46 Polarisation, 2 Positron emission tomography, 35 Posner–Schlossman syndrome, 51–52 Posterior synechiae, 51–52, 54 Primary angle-closure glaucoma (PACG), 42, 44 prevalence, 18–19 risk factors, 18 Primary angle-closure (PAC), 44 Primary open-angle glaucoma (POAG), 44 age factor, 14–15 Barbados Eye Studies, 14 ethnicity, 15–16 family history, 15 intraocular pressure (IOP), 14 myopia, 16–17 other risk factors, 17 prevalence, 13–14 sex, 15 Prognosis, of glaucoma definite, 34 frequency of testing, 37 imaging techniques GDx-VCC, 35–37 Heidelberg retina tomograph (HRT), 31–35 optical coherence tomography (OCT), 37 optic nerve head photography, 30 lack of concordance, 38–39 principles, 29–30 retinal nerve fibre layer photographs, application of, 30 tentative, 34 Prostaglandin analogs, 55 Pseudoexfoliative glaucoma (PEXG), 64 Pupillary block and glaucoma, 45 Real-time telemedical communication, 100 Reflectivity changes, 2–3 Retinal Functional Imager (RFI), 3 Retinal ganglion cells (RGCs), 1 Retinal nerve fibre layer (RNFL), 1 Retinitis, 53 Retinitis pigmentosa, 52 Retrograde labelling, 7

115

116

Index

of RGCs, 2 RGC apoptosis, 8 RGC imaging techniques detection of apoptosing retinal cells (DARC), 8–9 green fluorescent protein (GFP) expression systems, 7 retrograde labelling, 7 RGC-specific fluorescent protein expression, 2 Rhodamine-labelled RGCs, 7 Rimexolone, 55 Risk factors, of glaucoma diabetes, 17 diastolic blood pressure, 17 ethnicity, 15–16 family history, 15 hypertension (HTN), 17 influence of blood pressure on optic nerve, 17 iridotrabecular contact (ITC), 44–45 myopia, 16–17 pulse pressure, 17 Sarcoid, glaucoma in, 54 Sarcoidosis, 53–54 Scanning laser polarimetry (SLP), 1–2 Scanning time, 4 Scheie grading system, 47 Schlemm’s canal, 59–62 diameter of, 83 flow through, 63 impact of collapse of, 88 Schlemm’s canal devices canaloplasty, 81–86 distal outflow, 78 proximal outflow, 77–78 suprachoroidal outflow, 78–79 trabectome, 89–91 trabecular micro-bypass stent, 86–89 Scleral ectasia, 70 Scleroconjunctival scar formation, 59 Secondary glaucoma, 42, 49 Semi-automated optic nerve head imaging devices, 30 Shaffer grading system, 47 Shunt devices, 77 Signal-to-noise ratio (SNR), 6 Sinusotomy, 59, 77 SOLX gold microshunt, 79, 91–94 Spaeth grading system, 47 Spectralis (Heidelberg Engineering), 5–6 Statistical image mapping (SIM), 35 Stereophotographic disc photographs, 30 Stereophotographic examination, 31 Steroid-sparing immunomodulatory therapy, 55 Store-and-forward telemedical communication, 100

Stratus (Carl Zeiss), 4 STRATUSOCT, 37 Sturge–Weber syndrome (SWS), 65 Subconjuctival fibrosis, 62 Subconjunctival bleb, 62 Subconjunctival filtration anterior, 77 long-term success of, 76 posterior, 77 Superficial scleral flaps, 59–60 Super luminescent diodes (SLDs), 4 Suprachiasmatic nucleus (SCN), 23 ablation of, 25 regulation of circadian rhythms, 24–25 Suprachoroidal space, 63 Surgical devices drainage implants, 75 Ex-PRESS Mini Glaucoma Shunt, 79–81 Schlemm’s canal system, 77–79 subconjunctival filtration, 77 Schlemm’s canal devices, 81–86 SOLX gold microshunt, 91–94 trabectome, 89–91 trabecular micro-bypass stent, 86–89 use of horse hair, 75 Surgical peripheral iridectomy, 43 Suture tension, 84 Swan–Jacob lens, 87 Synechial closure, 45 Syphilis, 53–54 Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT), 105 Telemedicine, in ophthalmology electronic glaucoma patient health record system classifications, 104–106 concept, 101–104 Digital Imaging and Communications in Medicine (DICOM) standards, 103 EGS Glaucocard Project, 106–109 terminology, 102–104 future prospects, 109 history, 100–101 Tenon’s capsule, 61 T-flux implant, 61 Thy1 promoter, 7 Time domain OCTs (TD-OCT), 4 Titanium metal stent, 86 Topographical change analysis (TCA), 31 3D Topographies, 6 Toxocara infection, 52 Toxoplasma gondii, 54 Toxoplasma infection, 52 Toxoplasmosis, 54

Index

Trabectome, 89–91 Trabecular meshwork in angle closure glaucoma, 45 damage, 45, 50 Trabeculectomy, nonpenetrating, 59 clinical experiences with deep sclerectomy, 70–71 trabeculectomy vs, 71 viscocanalostomy, 70 complications early postoperative, 67–69 intraoperative, 66–67 late postoperative, 69–70 contraindications for absolute, 66 relative, 65–66 deep sclerectomy, 59–61 filtration mechanism, 62–63 indications for in aphakia, 65 congenital and juvenile glaucoma, 64–65 glaucoma in high myopia, 64 pigmentary glaucoma, 64 primary open-angle glaucoma (POAG), 64 pseudoexfoliative glaucoma (PEXG), 64 Sturge–Weber syndrome (SWS), 65 uveitic glaucoma, 64 Nd:Yag goniopuncture, 63–64 procedure, 64 viscocanalostomy, 61–62 Trabeculo-Descemet’s membrane (TDM), 60 flow through, 62 holes, 66–67 late rupture of, 69 postoperative rupture of, 69 Trabeculo-Descemet’s window (TDW), 82–83 Transscleral cyclocryotherapy, 77 Transscleral diode laser cycloablation, 77 Trauma, 52

T-shaped implant, 61, 63 Tuberculosis, 53 TUNEL, 8 Ultrahigh resolution OCT (UHR-OCT), 4 Ultrahigh-speed spectral domain OCT (SD-OCT), 4 Ultrasound biomicroscopy (UBM), 44, 46 United States, prevalence of OAG, 14 Uveitic glaucoma aqueous dynamics in, 50 associated with OHT and secondary glaucoma Fuchs’ heterochromic iridocyclitis, 52–53 herpetic disease, 53 juvenile inflammatory arthritis (JIA), 53 pars planitis, 53–54 Posner–Schlossman syndrome, 51–52 sarcoidosis, 54 syphilis, 54 toxoplasmosis, 54 mechanical causes, 50–51 related ocular hypertension, 49–50 and steroid-induced glaucoma, 51 treatment, 55 Uveoscleral pathway, 76 Variable corneal compensator (VCC-SLP), 2 Vasculitis, 53 Viscocanalostomy, 61–62, 70 Viscoelastics, application of, 90 Visible-frequency light, 1 Vitreous opacities, 52 Wavelength-dependent reflectance, 1 Wilcoxon signed-rank statistical test, 34 Wound leaks, 68 XGS-5 model. See SOLX gold microshunt

117