Retinal stray light originating from intraocular lenses and its effect on visual performance van der Mooren, Marie Huibert

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1 University of Groningen Retinal stray light originating from intraocular lenses and its effect on visual performance van der Mooren, Marie Huibert IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2016 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): van der Mooren, M. H. (2016). Retinal stray light originating from intraocular lenses and its effect on visual performance [Groningen]: Rijksuniversiteit Groningen Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 Printed by: Scholma Print & Media Cover: images edited by Robert Rosén Lay-out: Bram Koopman ISBN: (printed version) ISBN: (electronic version) Copyright 2016, M. van der Mooren, Groningen, The Netherlands. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording or any information storage or retrieval system, without the written permission of the copyright owners.

3 Retinal stray light originating from intraocular lenses and its effect on visual performance Proefschrift ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op woensdag 21 september 2016 om uur door Marie Huibert van der Mooren geboren op 17 oktober 1960 te Eethen

4 Promotores Prof. dr. N. M. Jansonius Prof. dr. J.J.M. Hooymans Copromotor Dr. S.A. Koopmans Beoordelingscommissie Prof. dr. G.P.M. Luyten Prof. dr.ir. G.J.Verkerke Prof. dr. M-J. Tassignon

5 Preface This thesis may be of importance for all those interested in quality of vision. Whenever I had to explain the sources causing retinal stray light and its effects on vision to my friends, colleagues and family, their interest was immediate because it is closely related to safety and healthy ageing. Working in the field of vision science and ophthalmology became, was and is often an addiction. It is an honor spending my working time on the research, development and manufacturing of intraocular lenses in order to provide cataract patients with the best possible solutions. This thesis shows I was exceptionally fortunate that I had the opportunity to study and to discuss many different aspects, ranging from the physical background to the visual impact retinal stray light can have on patients. This thesis is dedicated to my wife Angela, my daughter Juliette and my son Filip. Marrie, Engelbert, July 2016

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7 Contents Chapter 1 General Introduction 9 Chapter 2 Explanted multifocal intraocular lenses 15 van der Mooren M, Steinert R, Tyson F, Langeslag M, Piers P. J Cataract Refract Surg 2015; 41: Chapter 3 Rostock Glare Perimeter: A distinctive method for Quantification of Glare 25 Meikies D, van der Mooren M, Terwee T, Guthoff RF, Stachs O. Optometry and Vision Science 2013;90: Chapter 4 Comparison of Dysphotopsia Effects in Phakic and Pseudophakic Eyes using Rostock Glare Perimeter 37 Meikies D, van der Mooren M, Guthoff RF, Stachs O. Klin Monatsbl Augenheilkd 2013;230: Chapter 5 Degradation of visual performance with increasing levels of retinal stray light 53 van der Mooren M, Rosén R, Franssen L, Lundstrӧm L, Piers P. Submitted to IOVS November 5 th 2015 Chapter 6 Combining in vitro test methods for measuring light scatter in intraocular lenses 71 van der Mooren M, van den Berg T, Coppens J, Piers P. Biomed Opt Express 2011; 2: Chapter 7 Impact of intraocular lens material and design on light scatter: In vitro study 81 Langeslag MJM, van der Mooren M, Beiko GHH, Piers PA. J Cataract Refract Surg 2014; 40: Chapter 8 Effect of glistenings in intraocular lenses 97 van der Mooren M, Fransen L, Piers P. Biomedical Opt Express 2013;8: Chapter 9 General Discussion 115 Summary 121 Samenvatting 125 Acknowledgement 128 Curriculum Vitae 129

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9 Chapter 1 General introduction

10 Chapter 1 Chapter 1 Many of you will recognize the experience of having vision difficulties in the presence of a bright light source in your field of view, for example in a room where you have difficulty recognizing a person in front of a bright window. The bright window causes a veil of light, which deteriorates the contrast of the person you would like to see clearly. Such conditions are not represented when a well-illuminated letter chart test is used in a dimly lit room when your ability to distinguish small details is measured in the office of a clinician. This thesis contains studies that reveal methods and results that help to understand the effects of such veils of light on quality of vision, specifically in relation to cataract surgery. This introduction section starts with a basic description of the eye s anatomy and cataract surgery and leads to the objectives and outline of this thesis. The human eye is a light sensory organ that captures visual information, crucial for many of the tasks a human performs. Figure 1 shows the basic anatomy of the eye. Body Ciliary muscle Sclera Source: including sclera and ciliary muscle Figure 1 Anatomy of the eye. The sclera is the rigid white outer layer covering the eyeball with at front of eye the transparent cornea acting as an optical element. Behind the cornea, the colored iris divides the eye chamber filled with aqueous humor into an anterior and a posterior part. The crystalline lens is the second optical element located just behind the iris. The vitreous body is a transparent jellylike tissue between the crystalline lens and the retina. The photoreceptors, cones and rods, are located as a layer in the retina. There are red, green, and blue light-sensitive cones; the rods are not color sensitive but are responsible for 10

11 General introduction The eye enables humans to navigate under very different light conditions. The retinal illuminance is controlled by the iris acting similarly to a diaphragm in a camera. If the luminance of the scenery is low, like for example in an overcast night, the rods take over from the cones to provide visual information. A dim star made visible by peripheral located rods may disappear when the image of the star moves to the rod-free fovea. Motion is best detected by the peripheral retina, while visual acuity is higher in the central retina, i.e., the fovea. In a well-focused eye, the cornea and the adjustable crystalline lens image an object onto the retina. Glasses, contact lenses or refractive surgery may be applied to correct for refractive errors. Accommodation is the ability to maintain a sharp image on the retina by changing the crystalline lens power. Lens power changes are the result of contraction of the ciliary muscle changing the crystalline lens curvatures. Reading is easy at a young age when the accommodative amplitude is large. With aging, the crystalline lens becomes stiff and is not able to accommodate anymore. As a consequence, nearby objects are not sharply imaged onto the retina anymore and people will need reading glasses. Ageing may also result in a cloudy crystalline lens causing scattering of light over the retina: stray light. An increase in stray light deteriorates the contrast of images at the retina and thus contrast sensitivity is reduced. When the cloudiness of the lens becomes noticeable to the person involved, the cloudy lens is called cataractous. Figure 2 illustrates the effect of a reduction in contrast caused by increased stray light caused in a mild cataract case. The pedestrian in front of an oncoming car is less visible for a person with mild cataract compared to a person with healthy eyes. Figure 2 Night driving scene for person with healthy eyes (left) and for person with a mild cataract (right) 11 Chapter 1 vision at low light levels. The highest density of cones is in the fovea, the most central part of the macula, also called the yellow spot. In the surrounding retinal periphery, there is a high density of rods and a lower density of cones. There are no photoreceptors present in the blind spot because this is where the optic nerve leaves the eye to connect with the brain. Objects are imaged on the retina, detected and processed by the rods and cones, and signals are then transferred through the optic nerve to the brain for interpretation.

12 Chapter 1 Chapter 1 When retinal stray light becomes too large and/or visual acuity becomes too low, resulting in patient complaints, a cataract extraction procedure may be performed. This is a surgical intervention where the crystalline lens is removed, leaving the lens capsule in place. An intraocular lens is then implanted in the empty lens capsular bag to restore vision. Figure 3 shows a typical intraocular lens consisting of an optic body and two haptics to fixate the lens in the remaining lens capsular bag. haptic optic Figure 3 Intraocular lens Cataract surgery is the most successful and most often performed surgery to date; it is executed more than 20 million times a year world wide. During the last two decades, cataract surgery technology has evolved enormously. Improvements include advancements in surgical techniques, intraocular lens design and intraocular lens power calculation. Lens power calculation is important to minimize the refractive error after surgery. Today, the majority of the intraocular lenses are monofocal. This means that patients need reading glasses for seeing near objects because the lenses do not accommodate. New developments in intraocular lens design aim to reduce spectacle dependency for intermediate and near vision while maintaining good uncorrected distance vision without any visual side effects. Recently introduced multifocal, trifocal and extended range of vision intraocular lenses perform better than their predecessors, but improvements are still needed. It remains a challenge in cataract diagnosis to determine if surgery needs to be performed on patients who have visual acuity which is considered to be adequate but who have significant visual complaints. Most commonly, such complaints are presumed to be caused by increased retinal stray light. While visual acuity is determined easily with the wellknown letter chart, the amount and the effect of stray light is not so easily determined. In a slit lamp exam, a clinician assesses the condition of the crystalline lens and this is, depending on the type of cataract, not a trivial task. Light from the slit lamp incident on the crystalline lens is scattered backward into the clinician s eye, and is scattered forward 12

13 General introduction onto patient s retina. An increased retinal stray light level and a reduced visual acuity are both manifestations of cataract but they are to a certain extent independent of each other: cataract patients may have a normal visual acuity and clearly abnormal stray light levels, and vice versa. To date, there is no established, widely used method to measure the amount of retinal stray light. Chapter 1 A remaining challenge after cataract surgery is the formation of after-cataract, i.e., cloudiness across the intraocular lens optic, again causing an increased retinal stray light level several years after the initial surgery. This cloudiness is caused by proliferation of remaining lens cells which grow on the lens capsule, thereby causing capsular opacification. Although after-cataract can easily be removed by laser treatment, there is a significant incidence causing a large economic burden on the health care system. In intraocular lenses, inhomogeneities in the optic body and lens surface irregularities may occur which are sources of retinal stray light. These may result in complaints such as blurry and hazy vision and potentially affect the safety and quality of life of the person involved. To conclude, there are challenges remaining in many parts of the total cataract surgicalprocedure. Investigations that aim to understand the sources of retinal stray light and its effects on visual performance may contribute to better vision in elderly patients and thus to healthy aging. 13

14 Chapter 1 Chapter 1 Outline of this thesis The objectives of this study were (1) to determine the impact of stray light on visual performance, (2) to evaluate a new technique that aims to quantify stray light, and (3) to determine the contribution of intraocular lenses to retinal stray light. In Chapter 2, two case studies are presented, discussing the blurry and hazy vision of two pseudo-phakic patients due to stray light originating from their intraocular lenses. Their visual complaints led to intraocular lens exchange; the stray light was caused by the presence of micro-vacuoles in the optic body of these intraocular lenses. Micro-vacuoles are often referred to as glistenings due to their appearance when visualized in, e.g., a slit lamp exam. The glistenings induce retinal stray light which results in the visibility of a halo around light sources. Such halo s are clearly visible at night and can be annoying when driving a car, illustrating the clinical relevance. In Chapter 3, the development of the Rostock Glare Perimeter is described. This device was developed in order to measure the size of the halo in the presence of a glare source. Chapter 4 presents a study conducted with the Rostock Glare Perimeter in phakic and pseudophakic patients. In Chapter 5, the effect of retinal stray light on the visual performance of healthy, phakic subjects was studied. Different levels of retinal stray light were induced by using photographic filters. Halo size, luminance threshold detection, and contrast sensitivity with and without the presence of a glare source were measured as function of stray light level. Chapter 6 describes two methods for in-vitro assessment of stray light of intraocular lenses. The two combined methods have the capability to record both forward and backward light scatter and to separate the stray light contribution of the intraocular lens from contributions originating from the cornea, the vitreous body, and/or the retina. Chapter 7 presents the stray light characteristics of the most commonly used intraocular lenses, stratified according to material and lens design, using the measurement methods described in Chapter 6. Hydrophobic and hydrophilic acrylic lens materials were tested together with refractive spherical, aspheric, and diffractive multifocal intraocular lens designs. Stray light induced by micro-vacuoles in four different acrylic intraocular lens types is addressed in Chapter 8. The stray light measurements were verified using optical theory. Chapter 9 contains a general discussion and concludes with an outlook on the future. 14

15 Chapter 2 Explanted multifocal intraocular lenses Reprinted from Journal of Cataract and Refractive Surgery, Vol. 41, van der Mooren M, Steinert R, Tyson F, Langeslag M, Piers P, Explanted multifocal intraocular lenses, Pages , Copyright 2015, with permission from ASCRS and ESCRS (Elsevier) AMO Groningen BV, Netherlands (van der Mooren, Langeslag, Piers) Gavin Herbert Eye Institute, University of California, Irvine, USA (Steinert) Cape Coral Eye Center, Cape Coral, Florida, USA (Tyson) Supported in part by a departmental development grant to University of California, Irvine, California, from Research to Prevent Blindness, New York, New York, USA. Presented in part at the XXIX Congress of the European Society of Cataract and Refractive Surgeons, Vienna, Austria, September 2011; the ASCRS Symposium on Cataract, IOL and Refractive Surgery, Chicago, Illinois USA, April 2012; and the XXX Congress of the European Society of Cataract and Refractive Surgeons, Milan, Italy, September 2012.

16 Chapter 2 Chapter 2 We report 2 cases in which single-piece multifocal acrylic intraocular lenses (IOLs) were explanted because of complications related to the presence of glistenings in the bulk of the IOL optic. In both cases, the patients complained about blurry or hazy vision. In vivo slitlamp examinations prior to IOL explantation confirmed the presence of severe glistenings in the IOL optic in 1 case and moderate glistenings in the second case. In the first case, the symptoms resolved and both corrected and uncorrected distance visual acuities improved by 4 lines following IOL exchange with a monofocal IOL. In the second case, the visual symptoms persisted with a hard contact lens. Symptoms resolved following an exchange with a monofocal IOL that was free of glistenings. These findings indicate that straylight caused by IOLs with glistenings may be clinically significant in cases in which multifocal IOLs are implanted and patients require optimized retinal sensitivity. The single-piece hydrophobic acrylic Acrysof intraocular lens (IOL) (Alcon Laboratories, Inc.) is the most widely used IOL. Several recent studies based on large numbers of patients implanted with Acrysof IOLs ( 100 patients) conclude that moderate to severe or dense glistenings occur in 60% to 87% of patients with these IOLs. 1 5 The formation and the severity of glistenings have been correlated with longer followup times Two studies that evaluated the progression beyond 1 year found glistening formation to be stable. 2,11 Whether glistenings affect visual performance, and if so how, is frequently a question. We report 2 cases in which the presence of glistenings in the optics of singlepiece multifocal Acrysof IOLs may have led to severe vision complaints requiring IOL explantation. CASE REPORTS Case 1 A 77-year-old man had bilateral cataract extraction in 2006 with implantation of multifocal IOLs (Acrysof Restor SN60AD3). Mild dry age-related macular degeneration (AMD) was subsequently diagnosed in both eyes. Prior to IOL explantation, the patient presented at Cape Coral Eye Center with severe complaints of glare at night, difficulty reading and driving, and blurry vision in both eyes. During slitlamp examination, peripheral posterior capsule opacification and dense glistenings were observed in both IOL optics (Figure 1). In the left eye, the uncorrected distance visual acuity (UDVA) was 20/100 and the corrected distance visual acuity (CDVA), 20/70. In January 2011, an IOL exchange with a 24.5 diopter (D) monofocal Tecnis Z9002 IOL (Abbott Medical Optics, Inc.) relieved the visual symptoms. The UDVA improved to 20/40 and the CDVA to 20/30. The IOLs in both eyes were explanted. The multifocal IOL in the left eye was explanted in 1 piece and stored in a saline solution at room temperature, enabling in vitro modulation transfer function (MTF), dioptric power, and straylight measurements on an optical bench; dark-field microscopy; 16

17 Explanted multifocal intraocular lenses and confocal microscopy. Image J software (National Eye Institute, Bethesda, Maryland, USA) was used to analyze the size and density of the glistenings in vivo and in vitro on confocal images. Because glistenings gradually decrease when the explanted IOL is kept at room temperature, glistenings were induced in the laboratory to the in vivo level by raising the IOL temperature to that of the eye. The IOL was then cooled to room temperature and measured at the moment the glistening sizes and density were similar to the sizes and density in vivo at slitlamp examination just before explantation. All in vitro measurements were taken before and after the IOL was exposed to temperature changes. Figure 2 shows the dark-field image before and after induction of glistenings. The MTF measurements were low but appeared not to be affected by glistenings, and the measured dioptric power was 24.0 D. The straylight level of the explanted IOL was high and close to the level of a 70-year-old healthy crystalline lens (Figure 3). Chapter 2 Figure 1. Case 1: A slitlamp image (left) and Image J results obtained from the center portion of the IOL (right). Figure 2. Case 1: Dark-field image before (left) and after (middle) the temperature procedure and in vitro Image J results obtained from a confocal image after the temperature procedure (right). The glistening level resulted in approximately 15% of light being scattered, and therefore this light was not imaged but rather appeared as veiling glare or haze on the retina. The 17

18 Chapter 2 IOL in the right eye was exchanged with the monofocal Tecnis Z9002, and the CDVA and UDVA improved as in the left eye. No other ocular conditions were identified in either eye, and despite the remaining mild AMD in both eyes, the level of glistenings is considered the major cause of the vision complaints. Chapter 2 Figure 3. The gray and black solid lines represent the straylight levels for a healthy 20-year-old lens and a healthy 70-year-old crystalline lens, respectively, as a function of retinal eccentricity. The colored lines represent the levels of the explanted IOLs before(base) and after the temperature procedure. Case 2 A 53-year-old man who previously had laser in situ keratomileusis (LASIK) had no visual complaints until a cataract developed. Cataract extraction was performed in 2009 with implantation of a 19.5 D multifocal Acrysof Restor SN60AD3 IOL in both eyes. Approximately 6 months postoperatively, the patient began complaining of halo and glare in the right eye but not in the left eye. Examination revealed significant glistenings in the IOL optic in the right eye but only mild glistenings in the optic in the left eye. The symptoms did not improve with conservative management including topical lubrication and a hard contact lens trial, and the patient presented at Gavin Herbert Eye Institute 2 years after the cataract surgeries. He complained of unacceptable severe glare, fluctuations in vision, and overall cloudy vision in the right eye. A slitlamp examination revealed moderate to dense glistenings in the IOL optic in the right eye and trace glistenings in the optic in the left eye. The UDVA in the right eye was 20/50, and the CDVA was 20/25; the CDVA improved to 20/20 with a hard contact lens. However, the patient stated that the glare and haze persisted in the presence of the hard contact lens and remained unacceptable. No other ocular comorbidities were diagnosed. In October 2011, an IOL exchange was performed in the right eye with implantation of a D monofocal Tecnis ZCB00 IOL. The visual symptoms ceased, the UDVA improved to 20/25, and the CDVA improved to 20/15. The multifocal IOL was explanted in 1 piece and stored in a 18

19 Explanted multifocal intraocular lenses saline solution at room temperature, and the same in vitro procedure was followed as in Case 1. The in vivo level of glistenings is illustrated in Figure 4. Chapter 2 Figure 4. Case 2: Two slitlamp images of 2 inspection angles. Figure 5 shows the dark-field images before and after induction of glistenings. The measured MTF was low but appeared not to be affected by glistenings. The straylight level of the explanted IOL was well above that of a healthy 20-year-old crystalline lens (Figure 3). The glistening level resulted in approximately 9% of light scattered onto the retina, using the same methodology as in Case 1. The patient was more satisfied with the quality of vision in the right eye, which had the IOL exchange, than in the left eye. Although the IOL optic in the left eye had trace levels of glistenings, the patient had no complaints of visual symptoms and was unwilling to lose his ability to read. Because both eyes had a similar ocular history leading to the IOL exchange in the right eye, the level of glistenings is considered to be the major factor in the vision complaints. Figure 5. Case 2: Dark-field image before (left) and after (middle) the temperature procedure and a confocal image after the temperature procedure (right). 19

20 Chapter 2 DISCUSSION Chapter 2 In the 2 cases presented, the light scatter and MTF were measured on a validated optical bench 12,13,A and the scattered light percentage was determined by the measured size and density of the glistening level shown in the ImageJ B pictures in Figures 2 and 5 and calculated using the method outlined by van der Mooren et al. 14 Contrast sensitivity and visual acuity are standard vision tests assessing foveal visual quality most commonly performed under photopic conditions. Several clinical studies have investigated the effect of glistenings in IOLs on visual acuity and contrast sensitivity. Four of 6 studies report that glistenings adversely affect contrast sensitivity, 1,6,15,16 and 2 studies are ambiguous. 2,11 Two studies show a drop in visual acuity with elevated levels of glistenings. 7,11 More studies show that high-contrast visual acuity is not affected by glistenings. 2 4,6,8,15 17 In our first case, the severity of straylight was so high that visual acuity was reduced. The observed mild AMD still existed following IOL exchange, and therefore the AMD does not appear to have been a contributing factor to the visual symptoms. There are many potential glare sources in this case, such as the corneal state (dry eyes, tear film, higher-order corneal aberrations, or other corneal irregularities), the IOL multifocality, and the glistenings. The patient's cornea was normal and therefore unlikely to contribute to the visual symptoms. The Acrysof SN60AD3 diffractive multifocal IOL produces 2 primary foci 18 ; when the patient is performing a distant task or a near task, 1 focus is out of focus, creating a halo that exhibits approximately 1% of intensity compared with the focal intensity. This halo is constrained in a retinal angle of 20 minutes of arc. In addition, veiling glare of less intensity is spread over the retina because of the higher order foci. Halos cause specific visual symptoms that are well described and different from the complaint symptoms noted in our 2 cases. Therefore, IOL multifocality does not seem to be the major contributing factor to the visual complaints, although it may be a confounding factor that reduced the retinal sensitivity. The glistenings produce 2 retinal glare peaks with maxima at 2 degrees and at 15 degrees, 14 each peak containing half of the 15% incident light scattered because of the glistenings. Because the scattered light due to the glistenings is localized and has the highest intensity of all potential sources, we think it is the major cause of the observed visual symptoms. The IOL exchange was performed with a replacement monofocal IOL because AMD had been diagnosed, reducing the retinal sensitivity. The UDVA and CDVA for monofocal and multifocal IOLs have generally been shown to be comparable. 19 This suggests that exchanging a monofocal IOL for a multifocal IOL played no role in the increase in visual acuity. The visual acuity improvement was larger in Case 1 than in Case 2 and may be explained by the severity level of the glistenings. 20

21 Explanted multifocal intraocular lenses In the second case, the same IOL model was implanted in both eyes but only the right eye experienced severe visual symptoms. The IOL optic in the left eye had only trace levels of glistenings, reflecting the well-known variation in the severity of glistenings across Acrysof IOLs. 14 The patient had had LASIK in both eyes and later developed cataracts. To exclude the cornea as a factor in the vision complaints, the corneal stability was checked with a hard contact lens and no improvement in the symptoms of haze and glare were observed by the patient. Corneal topography was within normal parameters for a myopic LASIK; moreover, the patient did not have similar complaints prior to cataract formation and multifocal IOL implantation. The other potential glare source in this case is the IOL multifocality itself. However, the patient tolerated the multifocality in the contralateral eye. Although the patient could have elected an IOL exchange for a new multifocal IOL, the multifocal design of a different brand of IOL without the risk for glistenings would not have resolved the uncertainty associated with multifocality versus glistenings as the source of the visual complaints. The principle control was the tolerance of the multifocal IOL without glistenings in the contralateral eye. Chapter 2 In conclusion, both cases support the hypothesis that glistenings in combination with multifocal optics may result in clinically significant visual symptoms due to straylight. 21

22 Chapter 2 REFERENCES Chapter 2 1. Minami H, Torii K, Hiroi K, Kazama S. [Glistening of the acrylic intraocular lenses]. [Japanese] Rinsho Ganka 1999; 53: Colin J, Orignac I. Glistenings on intraocular lenses in healthy eyes: effects and associations. J Refract Surg 2011; 27: Colin J, Orignac I, Touboul D. Glistenings in a large series of hydrophobic acrylic intraocular lenses. J Cataract Refract Surg 2009; 35: Mӧnestam E, Behndig A. Impact on visual function from light scattering and glistenings in intraocular lenses, a long-term study. Acta Ophthalmol 2011; 89: Available at: Accessed December 8, Peetermans E, Hennekes R, Hennekes R. Long-term results of Wagon Wheel packed acrylic intra-ocular lenses (AcrySof). Bull Soc Belge Ophtalmol 1999; 271: Waite A, Faulkner N, Olson RJ. Glistenings in the single-piece, hydrophobic, acrylic intraocular lenses. Am J Ophthalmol 2007; 144: Colin J, Praud D, Touboul D, Schweitzer C. Incidence of glistenings with the latest generation of yellow-tinted hydrophobic acrylic intraocular lenses. J Cataract Refract Surg 2012; 38: Moreno-Montãnes J, Alvarez A, Rodrıguez-Conde R, Fernandez-Hortelano A. Clinical factors related to the frequency and intensity of glistenings in AcrySof intraocular lenses. J Cataract Refract Surg 2003; 29: Tognetto D, Toto L, Sanguinetti G, Ravalico G. Glistenings in foldable intraocular lenses. J Cataract Refract Surg 2002; 28: Yoshida S, Matsushima H, Nagata M, Senoo T, Ota I, Miyake K. Decreased visual function due to high-level light scattering in a hydrophobic acrylic intraocular lens. Jpn J Ophthalmol 2011; 55: Christiansen G, Durcan FJ, Olson RJ, Christiansen K. Glistenings in the AcrySof intraocular lens: pilot Study. J Cataract Refract Surg 2001; 27: van der Mooren M, van den Berg T, Coppens J, Piers P. Combining in vitro testmethods formeasuring light scatter in intraocular lenses. Biomed Opt Express 2011; 2: Available at: Accessed December 8, Norrby S, Piers P,Campbell C, van der Mooren M. Model eyes for evaluation of intraocular lenses. Appl Opt 2007; 46: van der Mooren M, Franssen L, Piers P. Effects of glistenings in intraocular lenses. Biomed Opt Express 2013; 4: Available at: Accessed December 8, Dhaliwal DK, Mamalis N, Olson RJ, Crandall AS, Zimmerman P, Allredge OC, Durcan FJ, Omar O. Visual significance of glistenings seen in the AcrySof intraocular lens. J Cataract Refract Surg 1996; 22: Gunenc U, Oner FH, Tongal S, Ferliel M. Effects on visual function of glistenings and folding marks in AcrySof intraocular lenses. J Cataract Refract Surg 2001; 27:

23 Explanted multifocal intraocular lenses 17. Hayashi K, Hirata A, Yoshida M, Yoshimura K, Hayashi H. Longterm effect of surface light scattering and glistenings of intraocular lenses on visual function. Am J Ophthalmol 2012; 154: e2 18. Davison JA, Simpson MJ. History and development of the apodized diffractive intraocular lens. J Cataract Refract Surg 2006; 32: Calladine D, Evans JR, Shah S, Leyland M. Multifocal versus monofocal intraocular lenses after cataract extraction. Cochrane Database Syst Rev 2012; issue 9, art. no. CD Summary Available at: CD pub3/pdf/abstract. Accessed December 8, 2014 Chapter 2 OTHER CITED MATERIAL A. van der Mooren M, Weeber H, Piers P. Verification of the average cornea eye ACE model. IOVS 2006; 47:ARVO E-abstract 309. Abstract available at: Accessed December 8, 2014 B. Rasband W. ImageJ; Image Processing and Analysis in Java. Bethesda, Maryland, Research Services Branch, National In stitutes of Health, Bethesda. Available at: Accessed December 8,

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25 Chapter 3 Rostock Glare Perimeter: A distinctive method for Quantification of Glare Reprinted from Optometry and Vision Science, Vol. 90, Meikies D, van der Mooren M, Terwee T, Guthoff RF, Stachs O, Rostock Glare Perimeter: A distinctive method for Quantification of Glare, Pages Copyright 2013, with permission from American Academy of Optometry(Wolters Kluwer Heath, Lippincott Williams & Wilkins) AMO Groningen BV, Netherlands (van der Mooren, Langeslag, Piers) Gavin Herbert Eye Institute, University of California, Irvine, USA (Steinert) Cape Coral Eye Center, Cape Coral, Florida, USA (Tyson) This study was supported by a grant from the Dutch government IS and INT and German grant REMEDIS. Presented in part at the 2009 annual meeting of the Association for Research in Vision and Ophthalmology (ARVO), Fort Lauderdale, Florida.

26 Chapter 3 ABSTRACT Purpose. Disability glare induced by headlights of oncoming cars has been associated with reduced quality of vision. This study aimed at developing the Rostock Glare Perimeter to quantify dysphotopsia effects under simulated realistic conditions. Chapter 3 Methods. Sixty phakic subjects of different ages were dazzled by a bright light source centered at a projection screen 3.30m away from the subject s eye. Using a projected marker moving outward from the screen center with angular steps of 0.25 in 12 directions, the area where the subject cannot distinguish the white spot from the glare effects of the light source was determined. A corresponding mean radius in a field angle relative to the subject s eye was defined as a measure for disability glare. Monocular and binocular measurements were performed, and a separate repeatability and reproducibility study was executed to determine the precision of the Rostock Glare Perimeter. Results. A significant mean positive correlation of disability glare with age (r = 0.534, p < 0.001) was found. The disability glare ranged from 0.33 to 1.8, and a strong (r = 0.93, p < ) binocular summation effect was found. The repeatability and reproducibility limit of the Rostock Glare Perimeter method is 0.14 for 95% confidence interval. Conclusions. The Rostock Glare Perimeter method is sensitive to detect age-related disability glare differences and to find binocular summation for disability glare in a healthy population for small field angles with high angular resolution. These findings suggest that the Rostock Glare Perimeter method is a helpful device to quantify symptoms of glare. Key Words. disability glare, quality of vision, visual assessment, dysphotopsia, binocular summation 26

27 Rostock Glare Perimeter: A distinctive method for Quantification of Glare Various approaches were developed to objectively quantify the severity of disability glare, 1-3 for example, a halometer, 4 a glaremeter, 5 and a stray light meter. 6 Other devices measure reduced contrast sensitivity, for example, the Brightness Acuity Tester (Marco Ophthalmic, Inc., Jacksonville, FL), 7 or high- or low-contrast visual acuity, for example, the Berkeley Glare Test, 8 with and without a glare source at different angular distance in the visual field. The latest development is the C-Quant (OCULUS Optikgeräte GmbH, Wetzlar, Germany), an instrument for the measurement of retinal straylight based on a compensation comparison method using an 8-Hz flickering annulus as stimulus. 9 To evaluate the subjective perception, also scores such as subjective glare ratings 5 or questionnaires with photographs illustrating pertinent optical phenomena, for instance, the one developed by Aslam, 10 have been used. Glare is, beside reduced visual acuity, a significant condition for patients with cataract. Previous investigations showed increased glare sensitivity even in eyes with beginning opacity of the lens. 11 However, also, after uneventful cataract surgery, some of the patients suffer from dysphotopsia effects to the extent that they revert to the preoperative condition; in some cases, the symptoms may even be more severe. 12 According to their own testimony, subjects with multifocal lenses generally enjoy improved visual acuity, and they are less prone to need spectacles than subjects with monofocal lenses. 13 Visual acuity being comparable members of the former group enjoy better near vision and a greater depth of field. 14 Multifocal lenses, however, are generally known for reducing the contrast sensitivity in low-contrast conditions and for causing optical phenomena often described as halos Besides cataract surgery, also all refractive correction procedures are of interest for the evaluation of disability glare. Standardized measurement of such optical phenomena, simulating realistic conditions encountered by the patients in daily life, however, is not yet feasible and should be pursued as a long-term objective of this project. This article describes the Rostock Glare Perimeter for investigating disability glare, based on the everyday situation where a person in the dark-blinded by the headlights of an oncoming vehicle-is unable to see less brightly lit objects, such as pedestrians on the side of the road. Chapter 3 METHODS Description of the Rostock Glare Perimeter The subject sits at a distance of 3.30 m from a projection screen with a central cold light source with fiber optics of 2 mm diameter (LQ1100; LINOS, Göttingen, Germany). The illuminance is 0.65 lux at the level of the eye, and the subject gazes at this light source during the examination as illustrated in Figure 1. The light from the central light source was geared to the middle between the eyes, so that it reached each eye around an angle of 0.5. A software tool produced a black background projected onto the screen by a projector (Mitsubishi HC4900, Mitsubishi Electric Europe B.V., Ratingen, Germany) with a luminance of less than 0.01 cd/m 2 on an area of 1.12 m (height) x 1.50 m (width). 27

28 Chapter 3 Chapter 3 Furthermore, the software provided on the screen a white marker, stepwise moving outward from the center at a speed of 0.25 /s. The geometry of the marker was a square with an angular size of 0.09 and a luminance of 22 cd/m 2. In a random sequence, this spot moved sequentially in one of a total of 12 directions. As soon as the subject was able to differentiate the marker from the halo of the dazzling light source, he or she was instructed to announce this verbally. The respective distance to the central light source was recorded. In the next step, the direction was changed at random. In the end, 12 directions in equal distances were investigated, each with a total of three repetitions per monocular and binocular measurement. Because the measured blind area is assumed to be circular, it has a defined radius. This radius on the projection screen is translated into a certain field angle relative to the subject s eye. In the context of this study, this angle in degrees is used as a measure for disability glare. During the entire investigation, the pupil size was measured using the Plusoptix S04 PowerRef II (Plusoptix GmbH, Nuremberg, Germany). It was installed 1 m in front of the subject s eyes, below eye level, so that it did not cover the concerning parts of the screen. This device also allowed monitoring the subject s fixation of the central light source. Light levels were detected by the photometer Tek Lumicolor (Tektronix, Köln, Germany). Measurements were performed in a room with scotopic lighting conditions (< 0.01 cd/m 2 ). Refraction errors of the subjects tested with Snellen acuity were corrected with glasses in a trial frame. To obtain comparable test results, each subject was given a glass in front of each eye, even if it was emmetropic. A dark adaptation of at least 5 min was performed before every measurement. Figure1. Experimental setup of the Rostock Glare Perimeter: a subject is sitting 330 cm from a screen with a central cold light source (0.65 lux at eye level); a beamer projects a marker (size of 0.09, luminance of 22 cd/m 2 ) on the screen, stepwise moving outward with a speed of 0.25 /s. 28

29 Rostock Glare Perimeter: A distinctive method for Quantification of Glare Subjects Sixty phakic subjects of different age groups were investigated. There were 33 female and 27 male subjects selected and divided into six age groups of 10 subjects according to the demographic overview from Table 1. Inclusion criteria were best corrected distance visual acuity of at least 0.0 logmar and an ophthalmologic uneventful medical history. Cataract patients were excluded by slitlamp microscopy. TABLE 1. Characterization of subjects examined by Rostock Glare Perimeter Chapter 3 Study Design Evaluation study procedures were performed in accordance with the ethical standards of the Declaration of Helsinki, and informed consent was obtained from all participants before their inclusion in the study. The subjects were examined by monocular and binocular disability glare testing, so all together each subject was examined three times. The pupil diameter was recorded during all examinations. They were asked to assess their subjectively perceived disability glare by subjective glare rating 5 using a scale between 0 and 3. Grade 0 indicates no glare symptoms at all, grade 1 means minor symptoms, grade 2 indicates moderate symptoms, and grade 3 stands for severe symptoms. The repeatability and reproducibility study was performed with three trained inexperienced operators, and in total, four subjects were measured three times on the right eye. The subjects were familiar with vision tests, and each operator measured three subjects. Statistical Analysis The measured monocular and binocular disability glares were statistically described and were analyzed for normal distribution at 5% significance level. Only nonparametric tests such as the Mann-Whitney Utest and Spearman correlation analysis were used for this purpose, since a Gaussian distribution could not be presumed, which will be foreclosed later on using the Kolmogorov-Smirnov test. Disability glare was also analyzed for correlation with maximum pupil diameter, subjective glare rating, age, and gender. 29

30 Chapter 3 Chapter 3 Disability glare was exponentially fitted with age, and standard t test was applied for agecorrected gender comparison. Pearson coefficients were calculated to determine the level of correlation for the age fit. The presence of binocular summation was analyzed by equating the binocular disability glare with the quadratic summation of the monocular outcomes. Furthermore, Pearson coefficient was calculated to determine the level of correlation. The monocular disability glare values were subtracted from each other, and the difference distribution was analyzed for symmetry by calculating the average and skewness. The within-operator (repeatability) and inter-operator (reproducibility) limits were calculated for 95% confidence interval using analysis of variance. The repeatability and reproducibility limit was calculated by quadratic summation of the within-operator limit and the inter-operator limit. RESULTS For the right eye, the disability glare ranged from 0.39 to 1.78 with a median value of 0.69, and for the left eye, the disability glare ranged from 0.40 to 1.85 with a median value of The binocular disability glare ranged from 0.33 to 1.58 with a median value of 0.59.The Kolmogorov-Smirnov test revealed with high probability (p < 0.001) that the disability glare of all eyes measured by Rostock Glare Perimeter is showing a non- Gaussian distribution. In conjunction with this study, neither the maximum pupil diameter nor the subjective glare rating showed a significant correlation with disability glare, as depicted in Table 2. The monocular and binocular outcomes for three subjects with similar binocular disability glare and different subjective glare rating are displayed in Figure 2. Binocular disability glare (r = 0.62) and monocular disability glare (r = 0.48) showed median age dependence and is illustrated by the binocular result in Figure 3. The correlation between binocular disability glare and age had a power of 99% for p = Among male subjects, disability glare obtained by binocular measurement (0.76 ±0.33 ) was higher than among female ones (0.58 ± 0.19 ), but when corrected for age, there was no statistically significant difference. Binocular disability glare could be predicted with high probability (r = 0.93, p < ) from the quadratic summation of the monocular disability glare outcomes divided by 3 found by the least square method. The predicted versus the observed binocular disability glare is displayed in Figure 4. The monocular disability glare difference between the right eye and the left eye was found to be symmetric (skewness of 0.068) and centered (mean of 0.01 ). With a power of 90% (p = 0.05), the binocular disability glare (0.66 ± 0.27 ) was lower than monocular disability glare (0.81 ± 0.30 ). The result of the precision study for the within-operator limit is 0.13, and for the inter-operator limit, it is 0.05.The repeatability and reproducibility limit for the Rostock Glare Perimeter method is

31 Rostock Glare Perimeter: A distinctive method for Quantification of Glare TABLE 2 Additional parameters and their correlation with disability glare Chapter 3 Figure 2. Three examples of Rostock Glare Perimeter outcomes (monocular and binocular) in subjects with subjective glare ratings of 0, 1, and 2 : despite different subjective glare ratings, binocular disability glare is similar. In most cases, binocular disability glare is lower than monocular disability glare. The three circles in each graph illustrate the three repeated measurements per session. On the radial axis, the distance to the central light source is plotted in pixel on the user interface of the Blackscreen software. 31

32 Chapter 3 Chapter 3 Figure 3. Correlation between age and binocular disability glare (r = 0.62). Figure 4. Predicted versus observed binocular disability glare (r = 0.93): predicted binocular disability glare calculated by the quadratic summation of monocular disability glare divided by 3. 32

33 Rostock Glare Perimeter: A distinctive method for Quantification of Glare DISCUSSION The Rostock Glare Perimeter simulates a realistic glare situation that is daily encountered on dark roads with oncoming traffic. A bright light source imitates realistic light levels 20 (0.65 lux at eye level) during night driving and a projected light spot simulates a roadside pedestrian yielding low field angle outcomes. The experimental setup is spacious, so assessment of disability glare is possible under far monocular and binocular visions, which is close to reality. As shown in this investigation based on the phakic population, there is a mean positive correlation between age and disability glare, what can be the most probable reason for non-normal disability glare distribution. Roughly, it was found that the binocular field angle at age 75 years is with a factor of 2 larger than that for a young person. The age-related increase of the density and inhomogeneity of the natural lens alone intensifies the light scattering effect and thus also increases disability glare, which is a common finding. 21,22 As expected, our study did not detect any correlation between pupil size and disability glare. Pupil size affects the retinal illuminance caused by the stimulus and the glare source equally. The minimal correlation between the objectively measured disability glare and the self-evaluation by subjective glare rating might be attributed to interindividual differences in the processing and interpretation of stimuli and sensitivity tolerance. This brings about a certain risk of underestimating the degree of visual impairment by glare, for instance, in traffic situations. Because the individual subjects are not necessarily aware of disability glare, as evidenced by the nonexisting correlation with the subjective glare rating in this study and also found, for example, by Ehmer et al., 23 nighttime traffic brings about additional hazards that might be elucidated by the Rostock Glare Perimeter. Chapter 3 Binocular disability glare was predicted by the quadratic summation of the monocular disability glare values divided by 3. A pure optical summation would yield a factor of 2, and our outcome suggests the presence of a neural component for the further suppression of disability glare. The binocular summation factor for disability glare is of the same magnitude as found in other studies when investigating the binocular summation for visual acuity and contrast sensitivity. The precision of the Rostock Glare Perimeter was expressed in repeatability and reproducibility limit and was not directly compared with other methods because the setup is distinct for the type of stimulus to be detected. Besides, most methods use a glare source at various fixed field angles, and in the Rostock Glare Perimeter method, the field angle is an outcome. Some of the drawbacks of the Rostock Glare Perimeter may include increasing fatigue during investigation with time, plus the aspect that the motion of the marker also complicates its detection. This affects the fixation ability because the subject - more or less unconsciously - tends to scan the screen to find the marker. Furthermore, sometimes, reflecting light from the spectacles could influence the recognition of the marker. Some of these aspects were mitigated 33

34 Chapter 3 Chapter 3 through measuring each meridian three times. This is confirmed through the results of the monocular difference distribution, which is symmetric and centered. Assuming that the healthy phakic population has, on average, the same quality for disability glare in the right and left eyes, it is concluded that the subject fixation was, on average, in line with the center of the screen. Although the option of an out-to-in strategy for marker presentation may have simulated a night driving situation better, we have chosen the in-to-out strategy for marker presentation to shorten the measurement procedure and because marker alignment is easier and it also avoids after-image effects. Advantages of the Rostock Glare Perimeter are that the speed, luminance, and size of the marker and the illuminance of the glare source are adaptable. Note that the chosen settings (speed = 0.25 /s, L = 22 cd/m 2, size = 0.09 ) are optimal for contrast detection. 24 When the marker size of 0.09 is back calculated to a spatial frequency of 5.8 cycles per degree or a visual acuity of 0.7 logmar, it is evident that all subjects were limited by acuity detection and not by acuity resolution. Future investigations are planned on varying the illuminance of the cold light source, the marker size, and the marker luminance to study the impact on the field of view that the subjects would need. The application of a computer-recorded user response may help facilitate the execution of all these new experiments. The Rostock Glare Perimeter is a new method of quantifying glare problems under simulated realistic conditions. It is evidently sensitive enough to detect age-dependent differences and to find binocular summation for disability glare in subjects with healthy eyes for small field angles with high angular resolution. This makes it possible to use this approach for the assessment of the visual quality in refractive and cataract surgery, which may lead to improved refractive correction procedures and optical designs of intraocular lenses. 34

35 Rostock Glare Perimeter: A distinctive method for Quantification of Glare REFERENCES 1. Paulsson LE, Sjostrand J. Contrast sensitivity in the presence of a glare light. Theoretical concepts and preliminary clinical studies. Invest Ophthalmol Vis Sci 1980; 19:401Y6. 2. Vos JJ. On the cause of disability glare and its dependence on glare angle, age and ocular pigmentation. Clin Exp Optom 2003; 86:363Y Abrahamsson M, Sjostrand J. Impairment of contrast sensitivity function (CSF) as a measure of disability glare. Invest Ophthalmol Vis Sci 1986; 27:1131Y6. 4. Gutierrez R, Jimenez JR, Villa C, Valverde JA, Anera RG. Simple device for quantifying the influence of halos after lasik surgery. J Biomed Opt 2003;8:663Y7. 5. Lee HK, Choe CM, Ma KT, Kim EK. Measurement of contrast sensitivity and glare under mesopic and photopic conditions following wavefront-guided and conventional LASIK surgery. J Refract Surg 2006; 22:647Y Butuner Z, Elliott DB, Gimbel HV, Slimmon S. Visual function one year after excimer laser photorefractive keratectomy. J Refract Corneal Surg 1994; 10:625Y Holladay JT, Prager TC, Trujillo J, Ruiz RS. Brightness acuity test and outdoor visual acuity in cataract patients. J Cataract Refract Surg 1987; 13:67Y9. 8. Bailey IL, Bullimore MA. A new test for the evaluation of disability glare. Optom Vis Sci 1991; 68:911Y7. 9. Franssen L, Coppens JE, van den Berg TJ. Compensation comparison method for assessment of retinal straylight. Invest Ophthalmol Vis Sci 2006; 47:768Y Aslam TM, Dhillon B, Tallentire VR, Patton N, Aspinal P. Development of a forced choice photographic questionnaire for photic phenomena and its testingvrepeatability, reliability and validity. Ophthalmologica 2004; 218:402Y Eisenmann D, Jacobi FK, Dick B, Jacobi KW, Pabst W. [Glare sensitivity of phakic and pseudophakic eyes]. Klin Monbl Augenheilkd 1996; 208:87Y Schwiegerling J. Recent developments in pseudophakic dysphotopsia. Curr Opin Ophthalmol 2006; 17:27Y Javitt JC, Wang F, Trentacost DJ, Rowe M, Tarantino N. Outcomes of cataract extraction with multifocal intraocular lens implantation: functional status and quality of life. Ophthalmology 1997; 104: 589Y Arens B, Freudenthaler N, Quentin CD. Binocular function after bilateral implantation of monofocal and refractive multifocal intraocular lenses. J Cataract Refract Surg 1999; 25:399Y Steinert RF, Aker BL, Trentacost DJ, Smith PJ, Tarantino N. A prospective comparative study of the AMO ARRAY zonal-progressive multifocal silicone intraocular lens and a monofocal intraocular lens. Ophthalmology 1999; 106:1243Y Holladay JT, Van Dijk H, Lang A, Portney V, Willis TR, Sun R, Oksman HC. Optical performance of multifocal intraocular lenses. J Cataract Refract Surg 1990; 16:413Y Gimbel HV, Sanders DR, Raanan MG. Visual and refractive results of multifocal intraocular lenses. Ophthalmology 1991; 98:881Y Rossetti L, Carraro F, Rovati M, Orzalesi N. Performance of diffractive multifocal intraocular lenses in extracapsular cataract surgery. J Cataract Refract Surg 1994; 20:124Y8. Chapter 3 35

36 Chapter 3 Chapter Leyland M, Pringle E. Multifocal versus monofocal intraocular lenses after cataract extraction. Cochrane Database Syst Rev 2006;18: CD van den Berg JT, van Rijn LJ, Kaper-Bongers R, Vonhoff DJ, Völker-Dieben HJ, Grabner G, Nischler C, Wilhelm H, Gamer D, Schuster A, Franssen L, de Wit GC, Coppens JE. Disability glare in the aging eye. Assessment and impact on driving. J Optom 2009; 2:112Y Allen MJ, Vos JJ. Ocular scattered light and visual performance as a function of age. Am J Optom Arch Am Acad Optom 1967; 44:717Y IJspeert JK, de Waard PW, van den Berg TJ, de Jong PT. The intraocular straylight function in 129 healthy volunteers: dependence on angle, age and pigmentation. Vision Res 1990; 30:699Y Ehmer A, Rabsilber TM, Mannsfeld A, Sanchez MJ, Holzer MP, Auffarth GU. [Influence of different multifocal intraocular lens concepts on retinal stray light parameters]. Ophthalmologe 2011; 108:952Y Kelly DH. Motion and vision: II. Stabilized spatiotemporal threshold surface. J Opt Soc Am 1979; 69:1340Y9. 36

37 Chapter 4 Comparison of Dysphotopsia Effects in Phakic and Pseudophakic Eyes using Rostock Glare Perimeter Reprinted from Klin Monatsbl Augenheilkd, Vol. 230, Meikies D, van der Mooren M, Guthoff RF,Stachs O, Comparison of Dysphotopsia Effects in Phakic and Pseudophakic Eyes using Rostock Glare Perimeter Pages Copyright 2013, with permission from Georg Thieme Verlag KG Department of Ophthalmology, University of Rostock, Germany (Meikies, Guthoff, Stachs) AMO Groningen BV, Netherlands (van der Mooren)

38 Chapter 4 Abstract Background: Pseudophakic dysphotopsia as unwanted side effect after cataract surgery are becoming increasingly important. The so-called glare perimetry allows a realistic quantification of these phenomena. The article presents the method on the example of healthy subjects and pseudophakic patients. Patients and Methods: Using glare perimetry phakic and pseudophakic subjects were examined for differences in disability glare. For this, data from 60 phakic persons of different ages (45 ± 17.1 years) were used. As pseudophakic subjects 31 carriers of monofocal lenses (70 ± 6.7 years) and 25 carriers of multifocal lenses (71 ± 8.5 years) were tested. Chapter 4 Results: Disability glare was significantly smaller in the phakic group (1.00 ± ) than in the pseudophakic group (1.56 ± ). Among the pseudophakic eyes those with a multifocal lens (1.69 ± ) were significantly more sensitive to glare than those with a monofocal lens (1.43 ± ). Conclusion: Glare perimetry allows an objective quantification of effects of dysphotopsia under realistic conditions. Pseudophakic eyes show a higher sensitivity to glare than eyes with the natural clear lens. Here, eyes with multifocal lenses prove to be particularly sensitive to glare. Key words: disability glare, glare perimeter, pseudophakic dysphotopsia, intraocular lenses 38

39 Comparison of Dysphotopsia Effects in Phakic and Pseudophakic Eyes using RGP Vergleich von Dysphotopsieeffekten bei phaken und pseudophaken Augen mit dem neuen Rostock Glare Perimeter Zusammenfassung Hintergrund: Pseudophake Dysphotopsien als unerwünschte Begleiterscheinungen nach Kataraktchirurgie gewinnen zunehmend an Bedeutung. Die sogenannte Glare Perimetrie ermöglicht eine realitätsnahe Quantifizierung dieser Phänomene. Der Beitrag stellt die Methode am Beispiel von augengesunden Probanden und pseudophaken Patienten vor. Patienten und Methoden: Mithilfe der Glare Perimetrie wurden phake und pseudophake Probanden auf Unterschiede in der Blendempfindlichkeit untersucht. Dafür wurden Daten von 60 phaken Personen unterschiedlichen Alters (45 ± 17,1 Jahre) genutzt. Als pseudophake Probanden wurden 31 Monofokallinsen-Träger (70 ± 6,7 Jahre) und 25 Multifokallinsen-Träger (71 ± 8,5 Jahre) getestet. Ergebnisse: Die Blendempfindlichkeit war in der phaken Gruppe (1,00 ± 0,336 ) signifikant kleiner als in der pseudophaken Gruppe (1,56 ± 0,622 ). Unter den pseudophaken Augen waren Augen mit einer Multifokallinse (1,69 ± 0,367 ) signifikant blendempfindlicher als solche mit einer Monofokallinse (1,43 ± 0,492 ). Chapter 4 Schlussfolgerung: Die Glare Perimetrie erlaubt eine objektive Quantifizierung von Dysphotopsieeffekten unter realitätsnahen Bedingungen. Pseudophake Augen zeigen eine höhere Blendempfindlichkeit als Augen mit der natürlichen klaren Linse. Dabei erweisen sich Augen mit Multifokallinsen als besonders empfindlich gegenüber Blendung. Schlüsselwörter: Blendempfindlichkeit, Glare Perimeter, Pseudophake Dysphotopsien, Intraokularlinsen 39

40 Chapter 4 Chapter 4 Einleitung Patienten nach Katarakt-OP, die bei den traditionellen Messungen der Sehschärfe gut abschneiden, berichten teilweise über schlechtes Sehen oder Lichtsensationen in alltäglichen Situationen [1]. Zusätzliche Lichtphänomene auf der Netzhaut werden Photopsien genannt. Sie überlagern das reale Netzhautbild. Wenn sie subjektiv stören oder die Sehleistung herabsetzen, wird von Dysphotopsien gesprochen. Positive Dysphotopsien sind helle Artefakte auf der Netzhaut, die in Form von Lichtbögen, Streifen, Ringen und Halos auftreten können. Diese unerwünschten Phänomene wurden unter anderem bei Patienten nach Kataraktchirurgie mit Intraokularlinsen (= IOLs ) aus verschiedenen Materialien gefunden [2]. Sie wurden häufig mit Kanteneffekten der IOLs in Verbindung gebracht, während negative Dysphotopsien noch weitgehend unergründet bleiben und eher mit den anatomischen Strukturen des Patienten assoziiert zu sein scheinen. Sie entstehen, wenn der Lichteinfall auf bestimmte Teile der Netzhaut verhindert wird, äußern sich als Schatten oder dunkle Punkte und können mit der Zeit verschwinden [3]. Eine Möglichkeit der Quantifizierung solcher Phänomene stellt das Rostocker Glare Perimeter dar [4]. Dieses orientiert sich an realistischen Bedingungen,wie sie im Verkehr bei Dunkelheit unter direkter Blendung durch eine starke Lichtquelle, wie z.b. Scheinwerfer eines entgegenkommenden Autos, herrschen. Damit konnte unter anderem festgestellt werden, dass eine mittlere positive Korrelation von Blendempfindlichkeit und Alter besteht und die Blendempfindlichkeit unter binokularer Summation abnimmt. Die Mehrheit der Patienten nach Kataraktchirurgie weist diese Probleme nicht auf beziehungsweise nur in bestimmten Situationen ohne subjektive Beeinträchtigung; aber ein kleiner Teil leidet an Problemen dieser Natur, die dem präoperativen Zustand vergleichbar beziehungsweise sogar größer sind [5]. Multifokallinsen-Träger berichten im Allgemeinen über ein besseres Sehvermögen, weniger Einschränkungen des Sehens und weniger Brillengebrauch als Monofokallinsen- Träger [6]. Bei vergleichbarer Sehschärfe lassen sich bei Ersteren ein besseres Sehen in der Nähe und eine größere Tiefenschärfe feststellen [7]. Multifokallinsen sind allerdings allgemein dafür bekannt, die Kontrastsensitivität in Niedrig-Kontrast-Bedingungen zu reduzieren und optische Phänomene hervorzurufen, die oft als Halos beschrieben werden [8 11]. Der theoretische Nachteil der Multifokal- IOLs ist, dass das einfallende Licht aufmehrere Fokusse verteilt wird, sodass das einzelne Netzhautbild jeweils eine geringere Lichtintensität erhält [12], und reduzierter Kontrast und Dysphotopsien begünstigt werden [13]. Im Rahmen dieser Studie sollte anhand von Probanden mit Mono- und Multifokal- IOLs auch untersucht werden, ob zwischen diesen Gruppen Unterschiede in der Blendempfindlichkeit bestehen, die mit dem Glare Perimeter messbar sind. Dysphotopsien nach Katarakt-OP werden zwar eher selten beklagt, können aber imeinzelfall so störend sein, dass die verursachende IOL zum Beispiel gegen eine IOL mit abgerundeten Kanten ausgetauscht werden muss, wodurch die Blendungsphänomene meist verschwinden [14 40

41 Comparison of Dysphotopsia Effects in Phakic and Pseudophakic Eyes using RGP 16]. So waren Dysphotopsien auch der hauptsächliche Grund für den rückläufigen Gebrauch von ovoiden IOLs [17]. Pseudophake Dysphotopsienwerden meist beim nächtlichen Autofahren erlebt [18] und stellen in diesem Bereich eine erhebliche Störung, wenn nicht sogar Gefahr dar. Es wurde beispielsweise gezeigt, dass einige Patienten nach Katarakt-OP eine so starke Blendempfindlichkeit besaßen, dass bei ihnen normalerweise für die Nacht keine Fahrtauglichkeit mehr vorlag [19, 20]. Dass dies keine seltenen Einzelfälle sein dürften, wird aus einer telefonischen Umfrage von Tester et al. deutlich, in deren Rahmen 40% der IOL-Träger, die nicht im Dunkeln fahren, angaben, dass der Grund Blendungsprobleme seien [2]. Alarmierend sind nicht zuletzt die Ergebnisse von Lachenmayr et al. [21], die in umfassenden Nachuntersuchungen von verunfallten Verkehrsteilnehmern nachweisen konnten, dass Unfälle bei Dunkelheit signifikant häufiger bei Personen mit reduzierter Dämmerungssehschärfe und erhöhter Blendempfindlichkeit vorkamen als bei Personen mit unauffälligem mesopischen Sehvermögen. Ein wichtiger Faktor in der Diskussion über Dysphotopsien ist Streulicht. Dies ist die bekannte Ursache von Disability Glare [22]. Streulicht wirft einen Lichtschleier auf die Netzhaut, wodurch der Kontrast des realen Bildes reduziert wird. Entlang der optischen Achse kann es in der Kornea, in der kristallinen Linse, im Glaskörper und auch durch Reflektion vom Fundus entstehen. Eine erhöhte Blendempfindlichkeit (gemessen anhand von Glare Scores ) kann mit dem Alter und bei Patienten mit Kornealödem, Hornhautnarben, Keratokonus und Linsenkapseltrübung auftreten [23]. Weiterhin kann periphere Lichtfokussierung über die limbusnahe Hornhaut Blendung verursachen, sowohl bei phaken Personen als auch bei Patienten mit IOLs [24 26]. Bei Multifokal-IOLs kann der zusätzliche Fokus (im Gegensatz zu Monofokallinsen) zu einer Überlappung des retinalen Bildes durch ein zweites mit größerem Durchmesser führen. Ähnliches gilt für multifokale Kontaktlinsen [27]. Neben dem Design können auch das Material und die Optik der IOL einen Einfluss auf dysphotoptische Phänomene haben [28 31], zum Beispiel der Refraktionsindex [18] und das Kantendesign. Eine andere Ursache für Blendungsphänomene kann eine zu weite Pupille sein. Hierbei können auch Lichtstrahlen auf die Netzhaut fallen, die an der Optik vorbei in das Auge gelangen und zu einem Halo führen [32]. Positioning Holes wurden in Einzelfällen mit ungewollten Seheindrücken in Verbindung gebracht und daraufhin eliminiert [33,34]. Chapter 4 Patienten und Methoden Glare Perimeter Um die Einschränkung durch Blendung realistisch abschätzen zu können, simuliert die Glare Perimetrie die alltägliche Situation, die entsteht, wenn eine Person im Straßenverkehr bei Dunkelheit von einem entgegenkommenden Fahrzeug geblendet und dadurch am Erkennen von weniger beleuchteten Objekten behindert wird. Dafür wurde eine sehr helle Lichtquelle auf einem schwarzen Hintergrund zentriert. Um das Licht 41

42 Chapter 4 herum gibt es einen Blendungshof, in dem ein anderes Objekt geringerer Helligkeit nicht wahrgenommenwerden kann. Mit zunehmender Blendempfindlichkeit wird die Fläche dieses Hofs größer. Mit Hilfe des Glare Perimeters wird eine Begrenzung dieser sogenannten blinden Fläche für die jeweilige Versuchsperson festgelegt. Die resultierenden Werte repräsentieren die Blendempfindlichkeit des Probanden und ermöglichen so quantifizierbare Aussagen über Einschränkungen, wie sie auch durch Dysphotopsieeffekte bedingt sein können. In der Skizze (Abb. 1) ist der Versuchsaufbau schematisch dargestellt. Chapter 4 Abb. 1 Schematischer Versuchsaufbau des Glare Perimeters. Die Messung findet in einem Raum mit skotopischen Beleuchtungsbedingungen statt. Ein Stativ mit Kinn- und Stirn-Stütze fixiert die Position der Augen. Eine Kaltlichtquelle mit Fiberoptik in Verbindung mit einem Lichtleiter (LINOS, Deutschland) liefert die zentrale Blendungsquelle mit einer Lichtintensität von 0,65 lux am Probandenauge (gemessen mit J17, Lumacolor Photometer,Tektronix). Die Dunkeladaptionszeit beträgt 5min. Ein Beamer (HC4900, Mitsubishi, Japan) projiziert über eine Distanz von 4,50m die Benutzeroberfläche der Software Blackscreen vs auf die Leinwand. Dazu gehört ein schwarzer Hintergrund mit annähernd 0,01 cd/m² Leuchtdichte und ein weißer Punkt mit 5mm Durchmesser und 22 cd/m² Leuchtdichte als Marker, der zunächst direkt auf der Lichtquelle abgebildet wird und sich dann schrittweise in die Peripherie bewegt. Der Proband wird aufgefordert, für die Dauer der Untersuchung direkt in das zentrale Licht zu schauen. Der weiße Marker wird in 1-sekündigen Abständen automatisch schrittweise in eine zufällig bestimmte Richtung aus der Mitte heraus bewegt, dargestellt durch die gepunktete Linie nach oben links in Abb. 2. Sobald die Versuchsperson den Marker vom Blendhof der Lichtquelle unterscheiden kann, muss sie dies verbal melden. Der Marker wird dann umgehend vom Untersucher manuell gestoppt und das Computerprogramm speichert den aktuellen Abstand zur zentralen Lichtquelle ab. Anschließend wird zufällig die Richtung geändert, sodass letztendlich 12 Richtungen im Abstand von 30 untersucht 42

43 Comparison of Dysphotopsia Effects in Phakic and Pseudophakic Eyes using RGP werden und zwar jeweils mit insgesamt 3 Wiederholungen pro Messung. Die Endpunkte aller 12 untersuchten Winkel (siehe Abb. 2)markieren jeweils den Rand der blinden Fläche. Wenn diese als Kreisfläche angenommen wird, besitzt sie einen definierten Radius. Dieser Radius auf der Leinwand wird in einem bestimmten Sehwinkel im Probandenauge abgebildet. Dieser Winkel in Grad wird als Dimension der Blendempfindlichkeit verwendet. Chapter 4 Abb. 2 Ausmessung des Blendhofs (Erläuterungen siehe Text). Probandenauswahl Ziel dieser Studiewar die Untersuchung von augengesunden Probanden und Patienten mit verschiedenen Intraokularlinsen auf eventuelle Unterschiede. Dafür wurde die Glare Perimetrie an insgesamt 218 Augen von 3 verschiedenen Probandengruppen angewendet. Dabei handelte es sich um 1. phake Testpersonen 2. Patienten nach Katarakt-OP mit Monofokal-Intraokularlinsen 3. Patienten nach Katarakt-OP mit Multifokal- Intraokularlinsen. Die Probanden in Gruppe (2) und (3) mit Intraokularlinsen werden im folgenden Text auch zusammenfassend als Pseudophake bezeichnet. Als Kontrollgruppe stellvertretend für die nicht kataraktoperierte Population wurden die Ergebnisse der 60 phaken Personen in 6 verschiedenen Altersgruppen (siehe Tab. 1) verwendet, welche in der ersten Studie zum Glare Perimeter [4] untersucht worden waren. Der Altersdurchschnitt lag in diesem Kollektiv bei 45 ± 17,1 Jahren. 33 der Probanden waren weiblich, 27 männlich. Alle phaken Augen wiesen einen bestkorrigierten Visus von mindestens 1,0 auf. Weiterhin wurden auch 31 Monofokallinsen-Träger mit einem durchschnittlichen Alter von 70 ± 6,7 Jahren untersucht. Darunter befanden sich 20 weibliche und 11 männliche Probanden. Nur die operierten Augen wurden getestet (ngesamt = 48). Der Visus reichte in dieser Gruppe von 0,5 bis 1,25. Der postoperative Zeitraum nach IOL-Implantation betrug 9 ± 20,9 Monate. Es wurden auch die Messergebnisse jeweils beider Augen von 25 Multifokallinsen-Trägern mit einem 43

44 Chapter 4 Chapter 4 Altersdurchschnitt von 71 ± 8,5 Jahren erhoben. Darunter befanden sich 14 Frauen und 11 Männer (ngesamt = 50). Für dieses Kollektiv wurden Visuswerte von 0,4 bis 1,0 erhoben. Die Messungenwurden 16 ± 16,8 Monate nach Implantation durchgeführt. Die Multifokallinsen-Gruppe setzte sich aus 16 Probanden mit jeweils einer Silikon-IOL in dem einen und einer Akryl-IOL im 2. Auge zusammen und 9 Probanden mit IOLs von asymmetrischer Lichtverteilung. Im Folgenden wird für multifokale Intraokularlinse auch die Abkürzung MIOL verwendet. Der Mittelwert des bestkorrigierten Fernvisus [logmar] betrug 0,07 (± 0,039) für die phake Gruppe, 0,01 (± 0,074) für die monofokale und 0,12 (± 0,092) für die multifokale Gruppe. Eventuelle Refraktionsfehler wurden für die Messungen korrigiert. Umeinemöglichst hohe Vergleichbarkeit der Probandengruppen (phak, pseudophak monofokal, pseudophak monofokal) zu garantieren, ist eine Subdifferenzierung der Patientengruppen not- wendig. Diese erfolgte nach bestkorrigiertem Visus. Somit wurde eine gesonderte Analyse aller gemessenen Augen und der Subgruppen mit einem bestkorrigierten Visus 0,9 (b) bzw. 1,0 vorgenommen. Nach Erhebung der persönlichen Daten (Name, Geburtsdatum und Geschlecht) wurde mit Hilfe von Sehprobentafeln der Visus (im Dezimalsystem) bestkorrigiert bestimmt, bei den phaken Probanden mittels Spaltlampenmikroskopie eine Katarakt ausgeschlossen und bei den pseudophaken Probanden der Linsentyp und der Zeitpunkt der Implantation (Monat/Jahr) erfragt. Statistische Auswertung Tab. 1 Einteilung der phaken Gruppe nach dem Alter der Probanden Altersgruppe der Phaken N bis 24 Jahre Jahre Jahre Jahre Jahre Jahre 10 Die statistischen Berechnungen wurden mit SPSS 15.0 durchgeführt. Um die Vergleichbarkeit zu gewährleisten, wurden alle phaken und nur solche pseudophaken Augen berücksichtigt, die einen bestkorrigierten Visus von mindestens 0,9 aufwiesen (175 von 218). Da ein Visus von 1,0 bei nur 14 Augen mit Monofokallinsen und nur 2 Augen mit Multifokallinsen vorlag, wurden für die meisten statistischen Berechnungen alle pseudophaken Augen mit einem Visus von 0,9 einbezogen (n monofokal = 27, n multifokal = 14). Für vergleichende Untersuchungen zwischen phaken und pseudophaken Augen wurden nur die Daten von Augen mit gleichem Visus (1,0) verwendet. Als Grundlage für die Ermittlung statistischer Kenngrößen wurde die Blendempfindlichkeit [Grad] verwendet. Das Signifikanzniveau wurde auf 5% festgelegt. 44

45 Comparison of Dysphotopsia Effects in Phakic and Pseudophakic Eyes using RGP Ergebnisse Messungen an einzelnen Probanden Die ersten Probemessungen erfolgten an 3 weiblichen Versuchspersonen mit einem Visus von 1,0 und ohne Augenerkrankungen, abgesehen von der vorausgegangenen senilen Katarakt der pseudophaken Probanden (Tab. 2). Zu Beginn wurde die mit dem Glare Perimeter gemessene Blendempfindlichkeit als Flächeninhalt der blinden Fläche auf der Leinwand angegeben, was eine erste, anschauliche Auswertung ermöglichte ( Abb. 3). Es wird deutlich, dass die Blendempfindlichkeit am kleinsten bei der phaken Testperson und am größten bei der Probandin mit der Multifokallinse ist. Die Multifokallinsen- Trägerin wurde jeweils rechts und links monokular und binokular untersucht. Daraus ergaben sich die in Abb. 4 dargestellten Werte der Blendempfindlichkeit. Diese ersten Ergebnisse waren vielversprechend und sollten daher in einem großen Kollektiv auf allgemeine Gültigkeit geprüft werden. Dafür wurden insgesamt 218 Augen von 116 Probanden mit der Glare Perimetrie untersucht. 67 (57,8%) der Versuchspersonen waren weiblich, 49 (42,2%) männlich. Tab. 2 Charakterisierung der ersten einzehnen Probanden Proband Alter Linse 1 39 beidseits natürliche kristalline Linse 2 85 im rechten Auge Monofokallinse (Acriflex 414 (jetzt: Lentis L-200);Wavelight AG,Erlangen; Silikon;+21,0Dpt.)43Monate postoperativ 3 70 Multifocallinse(Acrysof ReSTOR Natural 10L (SN60D3);Alcon;Akryl;20,5Dpt.) rechtes Auge circa 3 Monate, linkes Auge circa 2 Monate postoperativ Chapter 4 Abb. 3 Erste Ergebnisse der Blendempfindlichkeitsmessung an einzelnen Probanden (jeweils das rechte Auge wurde gemessen): Links ist schematisch der Flächeninhalt der blinden Fläche dargestellt. Rechts sind die korrespondierenden Begrenzungen der blinden Fläche aus allen 3 Untersuchungsdurchgängen gegenübergestellt. 45

46 Chapter 4 Abb. 4 Monokulare und binokulare Blendempfindlichkeit der Multifokallinsen-Trägerin (= blinde Fläche ) von rechtem (blau) und linkem (rot) Auge: Sie war bei den einzelnen Augen unterschiedlich groß und jeweils größer als die in der binokularen (grün) Messung. Chapter 4 Häufigkeitsverteilung der gemessenen Blendempfindlichkeit In Abb. 5 ist die Häufigkeitsverteilung der Blendempfindlichkeit für alle untersuchten Augen (a), alle Augen mit einem bestkorrigierten Visus von 0,9 (b) und alle Augen mit einem bestkorrigierten Visus von 1,0 (c) zusammengefasst. In den Boxplots in Abb. 6 wurden die 3 Probandengruppen bezüglich der gemessenen Blendempfindlichkeit gegenübergestellt. In Abb. 6a sind alle Probanden berücksichtigt, in Abb. 6b alle Probanden mit einem bestkorrigierten Visus 0,9 und in Abb. 6c vergleichbare Probanden mit einem bestkorrigierten Visus von 1,0 und einem Alter von 65 bis 74 Jahren. Abb. 5 Summierte absolute Häufigkeiten der Blendempfindlichkeit: alle untersuchten Augen (a), alle Augen mit einem bestkorrigierten Visus 0,9 (b), alle Augen mit einem bestkorrigierten Visus 1,0 (c). 46

47 Comparison of Dysphotopsia Effects in Phakic and Pseudophakic Eyes using RGP Abb. 6 Blendempfindlichkeit unterschieden nach Probandengruppen: alle Augen (a), alle gemessenen Augen mit einem bestkorrigierten Visus 0,9 (b), alle Augenmit bestkorrigiertem Visus = 1,0 und Alter des Probanden zwischen 65 und 74 Jahren (c). Vergleich der Probandengruppen Die Blendempfindlichkeit aller untersuchten Augen war am geringsten in der phaken Gruppe mit 0,81 (± 0,303) und am höchsten in der multifokalen Gruppe mit 1,78 (± 0,357). Die Blendempfindlichkeit der monofokalen Gruppe lag mit 1,46 (± 0,489) dazwischen (Abb. 6a). Weiterhin konnte nachgewiesen werden, dass phake Personen mit einem Visus von 1,0 mit p < 0,001 statistisch hoch signifikant weniger blendempfindlich sind (1,00 ± 0,336 ) als die Träger einer IOL (1,56 ± 0,622 ). Da, wie bereits gezeigt wurde, ein Einfluss des Alters auf die Blendempfindlichkeit besteht, wurden gesondert diemessergebnisse von Probanden mit einem vergleichbaren Alter, im konkreten Fall von 65 bis 74 Jahren, betrachtet (Abb. 6c). Auch in diesem Fall besteht statistisch signifikant eine niedrigere mittlere Blendempfindlichkeit der Phaken (1,16 ± 0,340 ) gegenüber den IOL-Trägern (1,74 ± 0,74) mit p = 0,028. Bei vergleichbarer Sehschärfe (bestkorrigierter Visus 0,9) war die Blendempfindlichkeit der multifokalen Gruppe statistisch signifikant (p = 0,020) höher als die der Monofokalen (1,69 ± 0,367 vs. 1,43 ± 0,492, siehe Abb. 6b). Dabei war das durchschnittliche Alter vergleichbar: 67,3 ± 7,69 Jahre in der multifokalen und 68,8 ± 7,32 Jahre in der monofokalen Gruppe. Chapter 4 47

48 Chapter 4 Diskussion Chapter 4 Als markantes Ergebnis ging aus dieser Studie hervor, dass Pseudophake eine höhere Blendempfindlichkeit aufwiesen als gesunde Phake. Hingegen lagen die Streulichtwerte der Pseudophaken in den Messungen von De Vries et al. größtenteils unter denen von Phaken (ohne Katarakt oder Blendbeschwerden) gleichen Alters. Zu berücksichtigen ist hier jedoch die größere Exzentrizität auf der Netzhaut (~ 7 Grad beim C-Quant versus ~ 1 2 Grad bei der Glare Perimetrie) [35]. Als Begründung der super-normalen Werte der Pseudophakenwurde zu bedenken gegeben, dass IOLs im Gegensatz zur älteren kristallinen Linse keine Lamellen haben, klar und dünner sind [22]. Signifikant niedriger seien die Werte aber nur bei Probanden mit einem Alter von mindestens 70 Jahren, was damit begründet wird, dass ab diesem Alter in der Normalpopulation ein gravierender Anstieg des Streulichtlevels von statten geht, was eine größere Verbesserung durch IOL- Implantation zulässt. Aus dieser Reduktion der Streulichtwerte leiteten de Vries et al. eine Reduktion von Blendung und Halos ab [35]. Aus diesen Unterschieden lässt sich schlussfolgern, dass Streulicht nicht gleichbedeutend mit Blendempfindlichkeit, gemessen mit dem Glare Perimeter, ist, und dass pseudophake Dysphotopsien vielleicht stärker von anderen Faktoren,wie zum Beispiel retinaler und zentraler Reizverarbeitung, beeinflusst werden als durch das Streulicht an sich. Weiterhin konnte herausgestellt werden, dass innerhalb der Gruppe der Intraokularlinsen-Träger die Monofokallinsen den Multifokallinsen bezüglich der Blendempfindlichkeit überlegen waren. Dieses Ergebnis geht konform mit einer Studie von Hessemer et al. aus dem Jahr 1994, wo bei den damals untersuchten diffraktiven multifokalen IOLs das mesopische Sehen ohne und unter Blendung schlechter ausfiel als bei monofokalen IOLs [36]. Auch bei Testung der Tritan Colour Contrast Sensitivity unter Blendung zeigten refraktive Multifokal-IOLs schlechtere Werte als Monofokal-IOLs [13]. Mit der Compensation Comparison Method wurden bezüglich des Streulichtlevels ebenfalls niedrigere Werte bei den Monofokal-IOLs gemessen als bei den Multifokal-IOLs [35]. Keine statistisch signifikanten Unterschiede zwischen Mono und Multifokal-IOLs hingegen wurden in einer Untersuchung der Kontrastempfindlichkeit unter Blendung mit Halogenlicht gefunden, wie es in Scheinwerfern im Straßenverkehr Verwendung findet [37]. Bewertung von IOLs In der bisherigen Literatur wurden diverse Untersuchungstechniken zur Beurteilung von IOLs angewendet, darunter eine ganze Reihe physikalischer Tests, aber auch subjektive Einschätzungen in Form von Patientenbefragungen. Neben diesen vorhandenen Kriterien zur Bewertung von IOLs kann auch das Glare Perimeter seinen Beitrag leisten. Unerwünschte optische Effekte kämen laut Häring et al. bei refraktiven MIOLs signifikant häufiger vor als bei Monofokal-IOLs. In dieser Studie konnte mit dem Glare Perimeter bei diffraktiven MIOLs eine höhere Blendempfindlichkeit festgestellt werden als bei 48

49 Comparison of Dysphotopsia Effects in Phakic and Pseudophakic Eyes using RGP verschiedenen Monofokal-IOLs, was die Ergebnisse von Häring unterstützen könnte. Im Gegensatz dazu stellten Eisenmann et al. [38] keine statistisch signifikanten Unterschiede zwischen monofokalen und refraktiven Array Multifokal-IOLs fest. Aufgrund der zahlreichen, zum Teil sehr theoretischen, angewendeten Testmethoden ist ein direkter Vergleich der bisherigen Forschungsergebnisse kaum möglich. Eine Methode zur einheitlichen Messung und somit zur Feststellung signifikanter Unterschiede ist nötig, um effektive Verbesserungen der IOL-Verträglichkeit zu ermöglichen. Hier könnte das Glare Perimeter Verwendung finden. Kataraktchirurgie Blendempfindlichkeit stellt eine häufige Beschwerde bei Patienten mit Katarakt dar. Nun stellt sich die Frage, ob allein dieser Leidensdruck bei beginnender, noch nicht visusrelevanter Katarakt bereits eine OP rechtfertigt. Dazu können die Ergebnisse einer Studie von Tester et al. herangezogen werden [2]. Sie befragten telefonisch 302 Patienten nach Katarakt-OP und 50 Kontrollpatienten mit Presbyopie über Blendung, Lichtempfindlichkeit und ungewollte Seheindrücke. IOL-Träger mit Linsen aus anderem Material als PMMA berichteten zu 12 bis 26% über Blendung, was auch 22% der Kontrollpatienten taten. Daraus schlussfolgerten sie, dass die zuvor genannten IOLs eine ähnliche Prävalenz von Blendungseffekten haben wie eine beginnende Katarakt. Das bloße Auftreten von Blendempfindlichkeit sollte tendenziell eher nicht zur Entscheidung für die OP führen, wenn das Auftreten ähnlicher Beschwerden postoperativ fast genauso wahrscheinlich ist. Allerdings wird bei dieser Überlegung nur dem Aspekt der Häufigkeit von Blendphänomenen Rechnung getragen. Mithilfe des Glare Perimeters wäre nun auch eine Quantifizierung der Blendbeschwerden möglich und somit ein Vergleich zwischen Katarakt- und pseudophaken Patienten. Damit ließe sich unter Umständen aufzeigen, dass die Beeinträchtigung der Patienten durch Blendempfindlichkeit bei beginnender, noch nicht visusrelevanter Katarakt stärker ist als beim Tragen von Intraokularlinsen. Dies könnte einen früheren operativen Eingriff bei noch tolerablem Visus und geringem klinischen Erscheinungsbild rechtfertigen. Chapter 4 Beurteilung der Nachtfahrtauglichkeit Neben optischen Voraussetzungen beeinflussen auch motorischkoordinative und konditionelle Aspekte die Fahrtauglichkeit, wie sie auch bei Untersuchungen mit dem Glare Perimeter eine Rolle spielen. Da Blendempfindlichkeit den einzelnen Probanden teilweise selbst nicht auffällt, lauern im nächtlichen Straßenverkehr zusätzlich Gefahren, die mit dem Glare Perimeter aufgedeckt werden könnten. In einer Studie von Eisenmann et al. [38] zeigten Patienten mit Katarakt eine signifikant schlechtere Kontrastempfindlichkeit unter Blendung, größere Halos und einen ausgeprägteren Visusabfall bei Gegenlicht als pseudophake Patienten mit monofokaler oder multizonal 49

50 Chapter 4 progressiver IOL. Er fordert dementsprechend eine besonders kritische Untersuchung auf Nachtfahrtauglichkeit von Patienten mit beginnender Katarakt bei eventuell noch für den Führerschein ausreichender Sehschärfe. Hier läge ein weiteres mögliches Anwendungsgebiet für das Glare Perimeter. Die Ergebnisse dieser Studie bezüglich der Blendempfindlichkeit tragen auch ein weiteres Stück dazu bei, die Nachtfahrtauglichkeit von Patienten mit Multifokal-IOLs kritisch zu betrachten, die bereits seit ihrer Markteinführung im Jahr 1993 diskutiert wird [39]. Schlussfolgerung Chapter 4 Trotz guter bis sehr guter Ergebnisse bei den traditionellen Messungen der Sehqualität stellen Dysphotopsien ein großes postoperatives Problem in der Kataraktchirurgie dar, besonders bei Patienten mit Multifokallinsen. Dass der untersuchende Augenarzt womöglich keine Ursache am Auge beziehungsweise der IOL finden kann, mag den Patienten nur noch zusätzlich irritieren. Ebenso können subjektiv schwere Beeinträchtigungen durch erhöhte Blendempfindlichkeit bei Patienten mit beginnender Katarakt schon vorliegen, bevor eine Visusreduktion eingetreten ist, die eine Operation rechtfertigen würde. Mit dem Glare Perimeter konnten sowohl zwischen phaken und pseudophaken Probanden als auch zwischen verschiedenen Linsendesigns Unterschiede gefunden werden. Weiterführende Untersuchungen mit einer höheren Probandenzahl in den einzelnen Gruppen sind notwendig, um die Signifikanz der gefundenen Unterschiede zu erhöhen. Um eine Vergleichbarkeit der unterschiedlichen Probandengruppen zu garantieren müssen diese alters- und visusgematcht sein. Die gegenwärtigen Untersuchungen zeigen Unterschiede in den Blendungseffekten bei IOLs verschiedenen Designs (monofokal, multifokal), wobei unterschiedliche Designvarianten multifokaler IOL noch genauer untersucht werden müssen. Diagnostische Bedeutung kann das Glare Perimeter haben, wenn mithilfe der dadurch nachgewiesenen kritischen Blendempfindlichkeit zum Beispiel früher eine OP gerechtfertigt ist. Schließlich kann schon bei beginnender Katarakt das Sehvermögen unter Blendung so eingeschränkt sein, dass eine Nachtfahrtauglichkeit nicht mehr gegeben ist [38]. Interessenkonflikt Nein 50

51 Comparison of Dysphotopsia Effects in Phakic and Pseudophakic Eyes using RGP Literatur 1 Nadler D. Glare and Contrast Sensitivity in Cataracts and Pseudophakia. In: Nadler M, Miller D, Nadler D, Eds. Glare and Contrast Sensitivity for Clinicians. New York: Springer; 1990: Tester R, Pace NL, Samore M et al. Dysphotopsia in phakic and pseudophakic patients: incidence and relation to intraocular lens type(2). J Cataract Refract Surg 2000; 26: Mahar PS. Negative dysphotopsia after uncomplicated phacoemulsification. Pak J Ophthalmol 2013; 29: Meikies D, van der Mooren M, Terwee T et al. Rostock Glare Perimeter: a distinctive method for quantification of glare. Optom Vis Sci 2013, 90: Schwiegerling J. Recent developments in pseudophakic dysphotopsia. Curr Opin Ophthalmol 2006; 17: Javitt JC, Wang F, Trentacost DJ et al. Outcomes of cataract extraction with multifocal intraocular lens implantation: functional status and quality of life. Ophthalmology 1997; 104: Arens B, Freudenthaler N, Quentin CD. Binocular function after bilateral implantation of monofocal and refractive multifocal intraocular lenses. J Cataract Refract Surg 1999; 25: Steinert RF, Aker BL, Trentacost DJ et al. A prospective comparative study of the AMO ARRAY zonal-progressive multifocal silicone intraocular lens and a monofocal intraocular lens. Ophthalmology 1999; 106: Holladay JT, Van Dijk H, Lang A et al. Optical performance of multifocal intraocular lenses. J Cataract Refract Surg 1990; 16: Gimbel HV, Sanders DR, Raanan MG. Visual and refractive results of multifocal intraocular lenses. Ophthalmology 1991; 98: , discussion Rossetti L, Carraro F, Rovati M et al. Performance of diffractive multifocal intraocular lenses in extracapsular cataract surgery. J Cataract Refract Surg 1994; 20: Maxwell A, Nordan LT. Multifocal intraocular lenses. In: Thorofare NJ, Ed. Current concepts of multifocal intraocular lenses. New York:McGraw-Hill Professional; Pieh S, Hanselmayer G, Lackner B et al. Tritan colour contrast sensitivity function in refractive multifocal intraocular lenses. Br J Ophthalmol 2001; 85: Farbowitz MA, Zabriskie NA, Crandall AS et al. Visual complaints associated with the AcrySof acrylic intraocular lens(1). J Cataract Refract Surg 2000; 26: Ellis MF. Sharp-edged intraocular lens design as a cause of permanent glare. J Cataract Refract Surg 2001; 27: Davison JA. Clinical performance of Alcon SA30AL and SA60 AT singlepiece acrylic intraocular lenses. J Cataract Refract Surg 2002; 28: Leaming DV. Practice styles and preferences of ASCRS members 1993 survey. J Cataract Refract Surg 1994; 20: Davison JA. Positive and negative dysphotopsia in patients with acrylic intraocular lenses. J Cataract Refract Surg 2000; 26: Chapter 4 51

52 Chapter 4 Chapter 4 19 Aust W. [Scattered light in implanted artificial lenses in a model trial].klin Monatsbl Augenheilkd 1986; 188: van der Heijde GL,Weber J, Boukes R. Effects of straylight on visual acuity in pseudophakia. Doc Ophthalmol 1985; 59: Lachenmayr B, Buser, A, Keller O. Sehstörungen als Unfallursache. In: Berichte der Bundesanstalt für Strassenwesen. Bremerhaven: Wirtschaftsverlag NW; Van Den Berg TJ, Van Rijn LJ, Michael R et al. Straylight effects with aging and lens extraction. Am J Ophthalmol 2007; 144: JK IJ, dewaard PW, van den Berg TJ et al. The intraocular straylight function in 129 healthy volunteers; dependence on angle, age and pigmentation. Vision Res 1990; 30: CoroneoMT, Pham T, Kwok LS. Off-axis edge glare in pseudophakic dysphotopsia. J Cataract Refract Surg 2003; 29: Kwok LS, Daszynski DC, Kuznetsov VA et al. Peripheral light focusing as a potential mechanism for phakic dysphotopsia and lens phototoxicity. Ophthalmic Physiol Opt 2004; 24: Maloof AJ, Ho A, Coroneo MT. Influence of corneal shape on limbal light focusing. Invest Ophthalmol Vis Sci 1994; 35: Pieh S, Lackner B, Hanselmayer G et al. Halo size under distance and near conditions in refractive multifocal intraocular lenses. Br J Ophthalmol 2001; 85: Arnold PN. Photic phenomena after phacoemulsification and posterior chamber lens implantation of various optic sizes. J Cataract Refract Surg 1994; 20: Masket S, Geraghty E, Crandall AS et al. Undesired light images associated with ovoid intraocular lenses. J Cataract Refract Surg 1993; 19: Wallin TR, Hinckley M, Nilson C et al. A clinical comparison of singlepiece and three-piece truncated hydrophobic acrylic intraocular lenses. Am J Ophthalmol 2003; 136: Bournas P, Drazinos S, Kanellas D et al. Dysphotopsia after cataract surgery: comparison of four different intraocular lenses. Ophthalmologica 2007; 221: Mellerio J, Palmer DA. Entopic halos. J Physiol 1969; 201: 62P 63P 33 Landry RA. Unwanted optical effects caused by intraocular lens positioning holes. J Cataract Refract Surg 1987; 13: Apple DJ, Lichtenstein SB, Heerlein K et al. Visual aberrations caused by optic components of posterior chamber intraocular lenses. J Cataract Refract Surg 1987; 13: de Vries NE, Franssen L, Webers CA et al. Intraocular straylight after implantation of the multifocal AcrySof ReSTOR SA60D3 diffractive intraocular lens. J Cataract Refract Surg 2008; 34: Hessemer V, Frohloff H, Eisenmann D et al. [Mesoptic vision in multiband monofocal pseudophakia and in phakic control eyes]. Ophthalmologe 1994; 91: Schmitz S, Dick HB, Krummenauer F et al. Contrast sensitivity and glare disability by halogen light after monofocal and multifocal lens implantation. Br J Ophthalmol 2000; 84: Eisenmann D, Jacobi FK, Dick B et al. [Glare sensitivity of phakic and pseudophakic eyes]. Klin Monatsbl Augenheilkd 1996; 208: Hessemer V, Eisenmann D, Jacobi KW. [Multifocal intraocular lenses an assessment of current status]. Klin Monatsbl Augenheilkd 1993;203:

53 Chapter 5 Degradation of visual performance with increasing levels of retinal stray light van der Mooren M, Rosen R, Franssen L, Lundstrom L, Piers P. Submitted to Investigative Ophthalmology & Visual Science November 5 th 2015 AMO Groningen BV, Netherlands (van der Mooren, Rosén, Franssen, Piers) KTH Royal Institute of Technology, Biomedical & X-ray Physics, Stockholm, Sweden (Lundström) This research was supported by the Swedish Research Council ( ), and EUREKA grant INT

54 Chapter 5 ABSTRACT PURPOSE: To quantify the effect of induced stray light on halo size, luminance threshold and contrast sensitivity. METHODS: Retinal stray light was induced in five healthy subjects using different photographic filters. The stray light induced ranged from levels observed in intraocular lenses (IOLs) with glistenings to cataract level, and was measured both psychophysically with commercially available instruments and on an optical bench. The visual impact was measured for halo size, luminance detection threshold, and contrast sensitivity with and without a glare source. RESULTS: The amount of retinal stray light induced by the different filters was similar when measured, using the psychophysical method and the optical bench method. Stray light levels mirroring a typical glistenings case causes the halo size to increase by 21 %, the luminance detection threshold to increase by 156 %, and contrast sensitivity to decrease by 10% to 21 % dependent on spatial frequency and presence of a glare source. The visual impact percentages for a typical cataract case are respectively 76%, 2130% and 30% to 49%. In the presence of a glare source, contrast sensitivity losses were larger and shifted to lower spatial frequencies. Chapter 5 CONCLUSIONS: Low levels of retinal stray light can cause significant increases in halo sizes, elevations in luminance detection thresholds and reductions in contrast sensitivity whether or not a glare source is present. The visual effect for a severe glistening case can be comparable to a mild cortical cataract case. 54

55 Degradation of visual performance with increasing levels of retinal stray light Introduction Some of the most significant visual disturbances affecting cataract patients are caused by retinal stray light. Nevertheless, the visual impact of relatively low levels of stray light can be hard to quantify, as it does not cause a drop in visual acuity. The diagnoses of these visual problems are most commonly made using slit lamp exams of potential sources of stray light. Direct psychophysical measurements of stray light levels are available as commercial instruments. However, the visual impact of measured stray light with these instruments is still not well understood. The level of retinal stray light determines the level of disability glare and can be a reason for persistent visual complaints [1]. Scatterers in the crystalline lens or micro vacuoles present in the optic body of an intraocular lens (IOL) are sources that can cause retinal stray light. The resulting disability glare may constitute visual complaints like hazy or blurry vision leading to cataract extraction or IOL explantation [2, 3]. The stray light behavior of the eye as a function of age, pigmentation, and angle have been studied extensively [4-6], and the influence of age can be used to illustrate the effect of stray light in the presence of a cataract [6]. Furthermore, the stray light behavior of micro vacuoles or glistenings has been described in the past for four different types of IOLs [7]. However, retinal stray light is currently not routinely measured in clinical practice as a way to diagnose cataract or glistenings; the opacification of the crystalline lens or the micro vacuoles in the optic body are routinely only assessed in a slit lamp exam. This exam subjectively illustrates the effect of backward scattered light from the opacities in the crystalline lens or the micro vacuoles in the IOL optic, while it is the forward light scattering distributed over the retina that determines the visual impairment. Therefore, there is a need to relate visual complaints of patients and the corresponding slit lamp exam to understand visual performance measures and clarify the visual impairment caused by retinal stray light. Chapter 5 In clinical practice, vision is assessed most commonly with visual acuity (VA) and occasionally with contrast sensitivity tests. Cataract patients may have uncompromised VA but may still complain of poor vision [8] limiting the clinician s ability to accurately diagnose the complaints. Visual acuity and retinal stray light are known to be independent quantities and measures [9] because they assess different aspects of vision. VA is a measure of the foveal image quality of high contrast details and therefore does not change with increasing stray light until excessive levels are reached, whereas retinal stray light determines the level of disability glare. Disability glare can be defined as the contrast reduction of a visual scene due to the retinal veiling luminance induced by a glare source in the field of view. Several studies found decreased contrast sensitivity for all, or part of, the spatial frequencies reported in the presence of cataract [8, 10-14]. The level of decrease in contrast may depend on the cataract morphology investigated: cortical, nuclear or posterior subcapsular [10-13]. Similarly, five studies have shown decreased 55

56 Chapter 5 contrast sensitivity for the higher spatial frequencies when glistenings are present in the body of the IOL optic [15-19] and two studies were non-conclusive [20, 21]. Despite these studies, general understanding of the implication of these relatively low levels of retinal stray light on visual function is limited and uncertain even in cases when retinal stray light is measured and quantified [2, 21-23]. Therefore, in this study, an improved contrast sensitivity test with and without the presence of a glare source and a luminance detection threshold test are used to create quantifiable visual performance measures of the impact of retinal stray light. Halo size is chosen as another visual performance measure because its clinical significance is intuitively understandable. In daily life, even low amounts of scatter may cause significant visual problems if glare sources are present. In this investigation, we systematically induced low degrees of scatter, typical of the levels found for glistenings and moderate degrees of cataracts, and measured the visual effects with and without the presence of glare sources. The objective of this study was to determine the visual consequences of scatter by relating varying levels of stray light to several measures of the quality of vision. Methods Chapter 5 This section describes all methods and materials used to induce and to measure stray light, as well as the methods used to determine the relationship between stray light and visual performance. Subjects In this investigation, measurements were performed on five right eyes of five healthy subjects between the ages of 28 and 53 years at the Royal Institute of technology, Stockholm. Four subjects were emmetropic and one habitually wore contact lenses (-2.50 D). The study conformed to the tenets of the declaration of Helsinki and was approved by the regional ethics committee in Stockholm, Sweden (2013/ /1). Written informed consent was obtained prior to the start of the study. Stray light and photographic filters The scatter parameter s as function of angle ө is defined as s(ө ) = PSF(ө )* ө 2, where PSF is the point spread function [5]. The PSF describes the light intensity distribution over the retina and declines steeply with angle ө. To record and distinguish visual effects in the periphery, the PSF is multiplied by angle squared resulting in the scatter parameter describing relative light power distribution over the retina. Within the central one degree, the PSF is dominated by defocus or wavefront aberrations of the eye that are determined by the shape and relative position of the ocular optics. The scatter parameter is an important and visually relevant measure of performance for angles larger than one degree, where the PSF is dominated by ocular scatter sources like cataract or glistenings. 56

57 Degradation of visual performance with increasing levels of retinal stray light This part of the PSF can also be described by photometric quantities as the ratio between veiling luminance on the retina and illuminance of the glare source at the pupil plane. In this experiment photographic filters are used to induce stray light of varying levels on the retina of the eyes of the subjects. These filters were chosen to reflect the levels of scatter by varying ocular conditions. In order to cover the range of values that would represent stray light caused by glistenings the scatter parameter should range from s=3 deg 2 /sr to s=10 deg 2 /sr [7] and for cataracts the scatter parameter should range from s=10 deg 2 /sr to s=30 deg 2 /sr [9,24]. Three photographic Black Pro-Mist (BPM) filters BPM¼, BPM1 and BPM3 (The Tiffen Company, NY, USA) were chosen from a range of filters based on the values of scatter that were induced by these filters. The stray light of the filters were characterized using an optical bench based technique that has been described in detail previously [25]. This optical bench method measures the stray light parameter, s, as a function of angle ө. Retinal stray light at an average angle of 7 degrees was measured using the compensation comparison method implemented in the C-quant (Oculus, Germany) [1]. In addition to the standard setup, a C-quant was modified by extending the distance of the eye piece so that the stray light could be measured for an average angle of 2.5 degrees. The C-quant provides in vivo measures of the logarithm of the stray light parameter log(s). Halo Size The halo size was measured using the Rostock Glare Perimeter [26]. In the Rostock Glare Perimeter, a small square marker is detected as it moves outwardly from a central glare source. The subject fixates on the glare source, and indicates when the marker becomes visible, which will reproduce the psychophysical halo radius using the method of adjustment. The square marker has a side length of 0.1 degrees, a luminance of 25 cd/m 2 and the subject sits 3 m away. The glare source has an illuminance of 0.4 lux at the eye, and the procedure is repeated three times in 12 different meridians. The perceived retinal halo is constructed by connecting all measurement outcomes from each meridian and averaging the halo radius R to determine log(r) for each subject and each stray light level. Chapter 5 Luminance threshold The luminance detection threshold was determined using a modified Rostock Glare Perimeter with a novel procedure developed for this study. In this procedure, a two alternative forced choice method was used to determine the detection threshold at a fixed angular distance to the glare source. The task of the subject was to indicate the location of the 0.1 degree square stimulus, which appeared for 0.5 seconds above or below the glare source. The luminance threshold of the marker was determined by an 57

58 Chapter 5 adaptive Bayesian algorithm and 50 trials were used to find the luminance level at which the subjects would indicate the correct location of the marker with 75 % probability. The procedure took less than two minutes. The subject was located 2.5 meters from the central glare source which had an illuminance of 0.75 lux at the eye. The procedure was repeated three times for each subject and condition, and the logarithm of the luminance, log (L) at the threshold was used as the outcome measure. Contrast Sensitivity The complete Contrast Sensitivity Function (CSF) was measured in 100 trials with the quick CSF method [27] using a calibrated CRT screen displaying Gabor gratings with a mean luminance of 48 cd/m 2. The CSF was also measured with a glare source placed in the horizontal nasal field at 2.5 degrees and 7 degrees respectively with an illuminance of 12 lux at the eye. A range of contrast sensitivity levels was determined starting from a spatial frequency of 1 cycle per degree (cpd) with a sampling rate of log (cpd), and the area under the contrast sensitivity curve log (AULCSF) was determined for each subject and stray light level. The procedure took less than four minutes for one condition. Procedure Chapter 5 All five subjects were measured over a period of several days, in randomized order with and without the three photographic filters placed in a trial frame using all of the methods described. Analysis For each subject, the induced stray light of the filters was calculated by subtracting the measured stray light level without any filter from the stray light level with each filter. The average measured degree of induced stray light for all subjects was compared to the optical bench measurement result for each filter of the linear stray light parameters for 2.5 degrees and 7 degrees. The stray light levels were then correlated with each visual outcome for the angles of 2.5 degrees and 7 degrees. Because the same subject was measured with different filters, the within subject data points are interdependent. Therefore, the relationship between all stray light outcomes and visual performance outcomes were fit using the partial least squared (PLS) method Modde 5, (Umetrics AB, Umea, Sweden) to isolate the effect of stray light from any subject dependent effect. The confidence level is set to 95%. Results were compared to a typical baseline stray light value, which is 1.1 log(s) for a 70 year old healthy or a typical pseudo-phakic subject [9]. To determine the stray light effect caused by glistening and cataract on the baseline stray light level, the induced stray light level of an average glistening case of s=5 deg 2 /sr [3,7] and a moderate cataract case of s=20 deg 2 /sr [24] were then added to the baseline stray light level. These induced stray 58

59 Degradation of visual performance with increasing levels of retinal stray light light values in log(s) were used to calculate the effects of a typical glistening case and a moderate cataract case on all measured visual performance outcomes. A night driving scene as perceived by a typical pseudo-phakic case was used to simulate the visual impact for a typical glistening case, a severe glistening case (s=9 deg 2 /sr) [7] and a mild cortical cataract case (s=11 deg 2 /sr) [24]. The headlights were assumed to be glare sources giving an illuminance of 0.6 lux with an average background luminance of 1 cd/m 2. The images themselves have a size of 20. To the image, we have added the veiling luminance produced by glistenings or cataract. For the cataract case log(s) is assumed to be constant over the field because the size of the scatterers is comparable to the wavelength of light while for the glistenings case the stray light profile as measured by van der Mooren et. al. [7] has been used, with peaks at 2.5 and 15. The glistening stray light profile is angle dependent because the micro vacuoles have sizes larger than the wavelength of light, ranging from 2 to 40 micrometer [7]. Results Stray light The stray light characteristics measured on the optical bench were comparable to the average induced stray light levels as measured with the extended and standard C-quant in the five subjects (figure 1). This implies that the induced retinal stray light is purely an optical effect caused by the inhomogeneity of the filter. As expected, the stray light level of the filters at 2.5 degrees is higher than that measured at 7 degrees. Furthermore, it can be seen that the photographic filters induce stray light levels ranging from 3 to 30 deg 2 /sr and that therefore the filters are able to simulate the stray light effects caused by glistenings in IOLs and by cataract cases. Chapter 5 Figure 1 Average induced retinal stray light measured in five subjects with (left) the extended C- Quant and (right) the standard C-Quant compared to optical bench measurement results for each filter. Error bars indicate standard deviations. 59

60 Chapter 5 To illustrate the effects caused by a typical glistening case and a moderate cataract case, the induced stray light in these cases were added to the baseline stray light level and plotted against the baseline level (Figure 2). It is clear that the induced effect on stray light is larger for subjects having lower baseline stray light values. For a typical pseudo-phakic subject or a 70 year old healthy subject the baseline retinal stray light level is 1.1 log(s), and will increase by 0.15 log(s) for a typical glistening case and by 0.4 log(s) for a moderate cataract case (figure 2). Chapter 5 Figure 2 Retinal stray light effects of typical glistening case and moderate cataract case as a function of baseline stray level. The simulated images (figure 3) show the potential impact for a typical and severe glistening case and a mild cortical cataract case. The larger the induced stray light level, the less visible is the crossing pedestrian because of the increasing halo of the oncoming car. The severe glistening case resembles the mild cortical cataract case. 60

61 Degradation of visual performance with increasing levels of retinal stray light Figure 3 Night driving scene perceived by (top left) a typical pseudo-phakic case and (top right) typical pseudo-phakic glistening case, and (bottom right) severe pseudo-phakic glistening case and (bottom right) mild cortical cataract case. Partial Least Squares (PLS) Fitting The PLS fit showed that for all visual test outcomes there were no fundamental interaction between the observed stray light levels and the subjects tested. This also explains why the linear regression yielded similar correlation results as obtained with the PLS method. The reported slopes were calculated using the standard linear regression method. Chapter 5 Halo Size The measured halo size was highly correlated with the level of stray light at both 2.5 degrees and 7 degrees (R2=0.75 and R2=0.79 respectively) (figure 4). The halo size increased with a slope of 0.55 log units for one log(s) unit increase in stray light at 2.5 degrees. For one log(s) unit increase in stray light at 7 degrees the halo radius increased with 0.61 log units. This means that the halo size measurement is half as sensitive as the stray light measurement regardless of the angle for which the stray light is determined. Recalculated, this means that for a 0.15 log(s) stray light increase at 2.5 degrees (typical glistening case), the halo radius increased by 21% and for 0.40 log(s) stray light increase at 7 degrees (cataract case) the halo radius increased by 76%. 61

62 Chapter 5 Figure 4 Halo size as function of stray light level (left) at 2.5 degrees, and (right) at 7 degrees for five subjects. Luminance threshold Chapter 5 The measured luminance threshold as a function of stray light level at 2.5 degrees and 7 degrees had a high correlation (R2=0.73 and R2=0.71 respectively) (figure 5). The luminance threshold increased with a slope of 2.72 log units for one log(s) unit increase in stray light at 2.5 degrees. For one log(s) unit increase in stray light at 7 degrees the luminance threshold increased with a slope of 3.73 log units. The luminance threshold measurement is therefore almost four times as sensitive as the stray light measurements at 7 degrees. For a 0.15 log(s) stray light increase at 2.5 degrees (typical glistening case), the luminance threshold increased by 156 % and for a 0.4 log(s) stray light increase at 7 degrees (cataract case) the luminance threshold increased with 2130 %. This illustrates the detrimental effect of cataract by showing that there is a more than 20 fold loss in luminance threshold for a moderate cataract case. Figure 5 Luminance thresholds as function of stray light level (left) at 2.5 degrees, and (right) at 7 degrees for five subjects. 62

63 Degradation of visual performance with increasing levels of retinal stray light Contrast Sensitivity For all measured conditions, the area under the contrast sensitivity function log (AULCSF) was highly correlated with induced stray light for each subject but the baseline level varied between individuals. This trend is displayed by the average slope of log (AULCSF) of all five individuals as function of stray light level. For one log(s) unit increase in stray light at 2.5 degrees, log(aulcsf) without a glare source and with a glare source located at 2.5 degrees decreased by 0.48 to 0.87 log units respectively with high correlation (R2=0.70 and R2=0.83 respectively)(figure 6). Figure 6 Area of contrast sensitivity (AULCSF) as function of stray light level at 2.5 degrees for (left) without glare source and (right) with glare source at 2.5 degrees for five subjects. For one log(s) unit increase in stray light at 7 degrees, log(aulcsf) without and with a glare source located at 7 degrees decreased by 0.59 and 0.67 log units respectively with a high degree of correlation (R2=0.78 and R2=0.64 respectively)(figure 7). The retinal stray light effect on contrast sensitivity (CS) was largest for a glare source located at 2.5 degrees. Chapter 5 Figure 7 Area of contrast sensitivity (AULCSF) as function of stray light level at 7 degrees for (left) without glare source and (right) with glare source at 7 degrees for five subjects. 63

64 Chapter 5 The effects of a typical glistening case and a cataract case on the contrast sensitivity as a function of spatial frequency follow the same trends, however the degree of severity differs (figure 8). The effect of increased stray light on CS without a glare source is largest for spatial frequencies between 7.5 cpd and 25 cpd. When stray light is elevated by the level associated with a typical glistenings case the CS for this spatial frequency range decreases between 14% and 20%, and when stray light is elevated by the level associated with a moderate cataract case the CS for this spatial frequency range decreases between 30% and 42%. The effect of stray light on CS with a glare source present is largest for spatial frequencies between 1.5 cpd and 10 cpd. When stray light is elevated by the level associated with a typical glistening case the CS for this spatial frequency range decreases between 10% and 21%, and when stray light is elevated by the level associated with a moderate cataract case the CS for this spatial frequency range decreases between 34% and 49%. CS was reduced by a maximum of 20% at 15 cpd for a typical glistening case and 42% at 18 cpd for a cataract case. These percentages are 21% at 3.5 cpd and 49% at 3 cpd respectively when contrast was measured in the presence of a glare source. The presence of a glare source further decreases the CS when stray light levels are elevated. Additionally, the presence of the glare source shifts the CS decrease to the lower spatial frequency range. Chapter 5 Figure 8 Baseline contrast sensitivity (solid blue line), contrast sensitivity for stray light elevated to a typical glistening level (dotted gray line), and contrast sensitivity for stray light elevated to a cataract case (dashed red line). The left graph shows contrast sensitivities without glare source and the right with a glare source present at 2.5 degrees. 64

65 Degradation of visual performance with increasing levels of retinal stray light Discussion The aim of this study was to develop a better understanding of the functional effects of increased retinal stray light caused by various visual disruptions (cataracts, glistenings) on visual performance. We found a significant and consistent impact of stray light on all three visual tests for all subjects. Retinal stray light, induced with photographic filters and measured subjectively by compensation comparison with the C-Quant, corresponds remarkably well with stray light as measured on the optical bench. This suggests that perception of retinal light scatter is not limited by the retinal structures and image processing in the subsequent visual pathways but is for the most part defined by the optical light scatter distribution over the retina. These findings support the fact that the tail of the PSF can be described in photometric terms as the ratio between the retinal veiling luminance and the illuminance of the glare source at the pupil plane. Comparable measurement results have been found in earlier studies for glare sources located at an average angle of 7 degrees for filters BPM1, BPM2 and BPM3 [24], and these findings are corroborated by the current study for an angle of 2.5 degrees and for lower light scatter levels as represented by the filter BPM¼. The induced retinal stray light values studied, range from levels comparable to a moderate degree of cataract [9, 24] down to levels comparable to that found for IOLs with glistenings [7] as well as for two explanted IOLs having stray light values of 4 and 6 deg 2 /sr for angles at 2.5 degrees [3]. These stray light levels are lower than the severe glistenings case that had 9 deg 2 /sr and showed comparable effects to the mild cortical cataract condition in the image simulations of the night driving scenes. This suggests that stray light caused by glistenings can have comparable levels as caused by cataract. Chapter 5 The stray light effects induced by glistenings are predominantly distributed around two retinal peaks located at an angle of 2.5 and 15 degrees [7]. This means that the standard C-quant is not the most suitable instrument to detect the effects of glistenings, as it operates with a glare source located at an average angle of 7 degrees. The extended C- quant used in this study, that performs stray light measurements at an average angle of 2.5 degrees is therefore a better instrument for measuring these effects. Another method used to measure the stray light from glistenings is the Scheimpflug technique [22, 23] which quantifies backward light scatter. However, the perception by the patient depends on the forward (retinal) light scatter. Forward stray light levels can be as much as 300 times larger than that of the measured backward scatter due to the fact that glistenings induce Mie scatter [7]. This may help to explain the reason why two IOLs were explanted with reports of surface glistening and glistening in the IOL optic as most probable cause [2] in spite of the fact that backward scatter appeared to be acceptable. The total light transmittance [28,29] of IOLs with glistenings and surface light scatter have been measured to be identical to that of clear control IOLs, implying that incident light is 65

66 Chapter 5 forward scattered. The effects of retinal stray light should be measured in a forward direction and the scattered light distribution over the retina should be known in order to help understand and explain the origin of such visual complaints. For cataract cases the forward scatter between 1 and 30 degrees is uniformly distributed over the retina [24], and the ratio between forward scatter and backward scatter in cataract has been shown to be on average a factor of approximately 2.3 [30], which is much less than that shown for glistenings due to the smaller size (0.7µm) of the responsible scatterers in cataract [31]. Chapter 5 The results of this study show that increased retinal stray light causes decreased visual performance for all of the tests performed, even for stray light levels shown to be typical of those induced by glistenings in IOLs. The relevance of the chosen visual performance tests are supported by the chosen settings for the level of illuminance at the eye and the level of the stimulus luminance. Increased halo size has been reported to be correlated to forward light scatter [32]. Halo size measurement provides a psychophysical test of an otherwise highly subjective factor [33]. The luminance threshold test is a detection task intended to capture the impact of stray light in low light environments, where both glare source and stimuli are of a low strength. Degraded performance for this type of visual task may represent a risk factor under low light conditions such as night driving. The luminance threshold test was found to be the most sensitive visual performance test executed, and shows the dramatic effect stray light may have under these conditions. The measure illustrates for example that a 20 fold increase in luminance may be necessary under low light conditions in order to detect a pedestrian crossing the street in the presence of an oncoming car. The distance to respond to this hazard decreases by factor 20, indica ng a potential reduction in the ability to react to targets while driving a car at night. In light of this fact, the complaints of some cataract patients who have adequate visual acuity may be better understood. In diagnosis of cataract, a luminance threshold test may help support an inconclusive slit exam of the crystalline lens. This may also be a diagnostic tool in cases where micro-vacuoles in intraocular lenses are suspected to be sources of the visual complaints. The outcomes of the luminance threshold test warrant further investigation into the development of a visual field perimetry protocol for this purpose by appropriately adapting size, angle and luminance of the stimulus, as well as the background luminance. Finally, the contrast sensitivity test measures visual capability in an environment with higher luminance, where resolution tasks are required. Contrast sensitivity with and without glare are also relevant factors in driving [34]. Contrast sensitivity losses of 14% to 20%, as induced by low amounts of retinal stray light, have been predicted [7]. This demonstrates the clinical relevance of small elevated levels of retinal stray light. The retinal stray light effect on contrast sensitivity was largest with a glare source present at 66

67 Degradation of visual performance with increasing levels of retinal stray light 2.5 degrees, causing a veiling luminance deteriorating the contrast of the image on the retina. The effect for a glare source located at 7 degrees is less due to the limited size of the halo radius. Individual variation in the relationship found between contrast sensitivity and stray light, as was measured in this study, is expected among the subjects, as age and neural factors also contribute to the contrast sensitivity function. Decreased CS has been reported in a number of intraocular lens studies with and without glistenings [15-19], and was of the same order of magnitude as measured in our study with the BPM¼ filter. The quick CSF method employed in this study allows for a more sensitive measurement of the contrast sensitivity than the 40% between consecutive levels used in standard contrast vision tests. This may explain why contrast loss has not always been concluded in intraocular lens studies on glistenings. CS loss with a higher magnitude was found for some types of cataracts [8,10-14]. In detail, these studies showed that the CS loss was largest for the cataract type posterior subcapsular opacity and less for nuclear and cortical opacities. These higher amounts of contrast losses measured in the past are of the same order of magnitude as measured in our study with BPM3 filter. Although our study induces stray light extra ocular, measuring visual effects with filters is a fair approximation to measurements with scatters in the eye. In conclusion, retinal stray light correlates strongly with the outcomes of the methods used to measure visual function. Levels of retinal stray light as induced by glistenings and cataract have a measurable and significant impact on visual function. Chapter 5 67

68 Chapter 5 References Chapter 5 1. Fransen L, Coppens J, van den Berg T. Compensation comparison method for assessment of retinal straylight. Invest Ophtalmol Vis Sci 2006;47: Dai Y, Huang Y, Liu T, et al Laboratory analyses of two explanted hydrophobic acrylic intraocular lenses. Indian J Ophthalmol 2014;62: van der Mooren M, Steinert R, Tyson F, et al. Explanted multifocal intraocular lenses. (accepted for publication in JCRS april2015) 4. IJspeert JK, de Waard PW, van den Berg TJ, et al.. The intraocular straylight function in 129 healthy volunteers; dependence on angle, age and pigmentation. Vision Res 1990;30: van den Berg TJTP. Analysis of intraocular straylight, especially in relation to age. Optom Vis Sci 1995;72: de WaardPW, IJspeert JK, van den Berg TJ, et al.intraocular light scattering in age-related cataracts. Invest Ophthalmol Vis Sci 1992;33: van der Mooren M, Fransen L, Piers P. Effects of glistenings in intraocular lenses. Biomedical Opt Express 2013; 8: Koch DD. Glare and contrast sensitivity testing in cataract patients. J Cat Refract Surg 1989;15: van den Berg TJTP, van Rijn LJ, Michael R, et al.straylight effects with aging and lens extraction.am J Ophthalmol 2007;144: Williamson TH, Strong NP, Sparrow J, et al. Contrast sensitivity and glare in cataract using the Pelli-Robson chart. Br J Ophthalmol 1992; 76: Adamsons I, Rubin GS, Vitale S, et al. The effect of early cataracts on glare and contrast sensitivity. A pilot study. Arch Ophthalmol 1992;110: Chua BE, Mitchell P, Cumming RG. Effects of cataract type and location on visual function: The Blue Mountains Eye Study. Eye 2004;18: Shandiz JH, Derakhshan A, Daneshyar A, et al. Effect of Cataract Type and Severity on Visual Acuity and Contrast Sensitivity J Ophthalmic Vis Res 2011; 6 : Elliott DB, Situ P. Visual acuity versus letter contrast sensitivity in early cataract. Vision Research 1998;38: Dhaliwal DK, Mamalis N, Olson RJ, et al. Visual Significance of glistenings seen in the AcrySof intraocular lens. J Cataract Refract Surg 1996;22: Gunenc U, Oner FH, Tongal S, et al. Effects on visual function of glistenings and folding marks in AcrySof intraocular lenses. J Cataract Refract Surg 2001;27: Waite A, Faulkner N, Olson RJ. Glistenings in the single-piece, hydrophobic, acrylic intraocular lenses. Am J Ophthalmol 2007;144: Xi L, Liu Y, Zhao F, et al. Analysis of glistenings in hydrophobic acrylic intraocular lenses on visual performance. Int J Ophthalmol 2014;7: Minami H, Toru K, Hiroi K, et al. Glistening of Acrylic Intraocular Lenses. Rinsho Ganka (Jpn J Clin Ophthalmol) 1999;53: Christiansen G, Durcan FJ, Olson RJ, et al. Glistenings in the AcrySof intraocular lens: pilot study. J Cataract Refract Surg 2001; 27:

69 Degradation of visual performance with increasing levels of retinal stray light 21. Colin J, Orignac I. Glistenings on intraocular lenses in healthy eyes: effects and associations. J Refract Surg 2011;27: Mönestam E, Behndig A. Impact on visual function from light scattering and glistenings in intraocular lenses, a long-term study. Acta Ophthalmol 2011;89: Nagata M, Matsushima H, Mukai K, et al. Clinical evaluation of the transparency of hydrophobic acrylic intraocular lens optics. J Cataract Refract Surg 2010;36: de Wit GC, Franssen L, Coppens JE, et al. Simulating the straylight effects of cataracts.j Cataract Refract Surg 2006;32: van der Mooren M,van den Berg T, Coppens J, et al.combining in vitro test methods for measuring light scatter in intraocular lenses.biomedical Opt Express 2011;2: Meikies D, van der Mooren M, Terwee T, et al.rostock Glare Perimeter: A distinctive method for Quantification of Glare. Optometry and Vision Science 2013;90: Lesmes LA, Lu ZL,Baek J, et al.bayesian adaptive estimation of the contrast sensitivity function: the quick CSF method. J Vision 2010;10: Werner L, Morris C, Liu E, et al. Light transmittance of 1-piece hydrophobic acrylic intraocular lenses with surface light scattering removed from cadaver eyes. J Cataract Refract Surg 2014;40: Morris C, Werner L, Barra D, et al. Light scattering and light transmittance of cadaver eyeexplanted intraocular lenses of different materials. J Cataract Refract Surg 2014;40: Bettelheim FA, Ali S. Light scattering of normal human lens III. Relationship between forward and backward scatter of whole excised lenses. Exp Eye Res 1985;41: Van den Berg TJTP, Spekreijse H. Light scattering model for donor lenses as a function of depth. Vision Research 1999;39: Puell MC, Perez-Carrasco MJ, Palomo-Alvarez C, et al. Relationship between halo size and forward light scatter. Br J Ophthalmol 2014;98: Meikies D, van der Mooren M, Guthoff RF, et al. Comparison of Dysphotopsia Effects in Phakic and Pseudophakic Eyes using Rostock Glare Perimete. Klin Monatsbl Augenheilkd 2013; 230: Owsley C. Vision and driving in the elderly. Optometry and Vision Science 1994;71: Chapter 5 69

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71 Chapter 6 Combining in vitro test methods for measuring light scatter in intraocular lenses Reprinted from Biomedical Optics Express, Vol. 2, van der Mooren M, van den Berg T, Coppens J, Piers P Pages Copyright 2011, with permission from Optical Society of America AMO Groningen BV, Netherlands (van der Mooren, Piers) Netherlands Institute for Neuroscience, Amsterdam, Netherlands (van den Berg, Coppens). This research is supported by Dutch grant ISO 62031

72 Chapter 6 Abstract Intraocular lenses (IOLs) are designed for implantation for vision correction following cataract removal. The IOL typically replaces a cataractous natural lens that exhibits very high levels of light scattering. The amount of scattering is significantly reduced with an IOL, though it is rarely quantified and both the surface and the bulk of the intraocular lens may contribute to light scatter at some level, and in some cases potentially affecting patients post-operative quality of vision. The purpose of this paper is to describe two complementary in-vitro quantitative methods for measuring light scatter caused by IOLs. The first method directly measures light scatter from the lens in one plane for angles larger than two degrees. The second method measures light scatter in an eye model including the focal point out to three degrees in the image plane. The measured amount of light scatter from an IOL is typically lower than that found in healthy donor crystalline lenses of various ages that are used as a basis for comparison. OCIS codes: ( ) Stray light; ( ) Scattering measurements; ( ) Ophthalmic optics and devices. Chapter 6 72

73 Combining in vitro test methods for measuring light scatter in intraocular lenses 1. Introduction Knowledge of the total intensity distribution over a large angular range on the retina may predict aspects of quality of vision. The normal point spread function (PSF) of the human eye has a range spanning approximately ten orders of light intensity distributed over 180 degrees [1]. Whereas the human eye is capable of perceiving this dynamic range in light intensity and retinal eccentricity, currently neither single in-vivo nor single in-vitro instruments have been able to measure a comparable PSF in its entirety. This paper describes two complementary in vitro methods to measure the angular light distribution caused by IOL light scatter. Light scatter can be described as the deflection of light rays in random directions by irregularities in the propagation medium. Inelastic light scatter phenomena such as Raman and Brillouin light scatter are not considered here. Both, surface and bulk of the IOL may contribute to intraocular light scatter. Bulk in-homogeneities such as lens material density and/or composition fluctuations, voids, inclusions and the presence of micro vacuoles inside the lens body will deflect light rays to the retinal periphery causing them not to be refracted to the fovea. This effect could also occur when machine lines, forceps imprints, or other surface defects are present. Another source of light ray deflection is the lens design itself. Lens geometries such as diffractive patterns may cause light rays intended for foveal image formation to propagate to the retinal periphery causing glare. In the beginning of last century Cobb [2] introduced a method to determine retinal stray light. Stray light is defined by dividing equivalent luminance by the illuminance of the glare source falling into the eye. The equivalent luminance is defined as the luminance that has the same visual effect as the glare source [1]. In vivo, a wide angular range of stray light can be determined psychophysically by assessing this equivalent luminance. Stiles [3] and Holladay [4] found that for phakic eyes this ratio approximates 10/θ 2 for angles θ of 1 to 30 degrees. With this definition stray light corresponds to the skirts of the PSF properly normalized. A stray light parameter, s, has been introduced that is defined according to Eq. (1) [5], where a and p are age and pigmentation respectively. Chapter 6 s(θ,a,p) = PSF(θ,a,p)xθ 2 [degrees 2 / sr]. (1) For healthy eyes of various ages and color (pigment), s is relatively constant over a large range of the angular domain. Norm values for s are presented in Vos et al [1]. The crystalline lens of young eyes contributes approximately one third to the stray light of the total eye and this is formulated in Eq. (2). The norm function for a 70yr old crystalline lens is calculated following Eq. (3). s lens (θ,20,1) =⅓ PSF (θ,20,1)xθ 2. (2) s lens (θ,70,1) = ( PSF( θ,70,1)) -⅔( PSF( θ,20,1))xθ 2. (3) 73

74 Chapter 6 The chosen value of p = 1 corresponds to average Caucasian eyes. In this paper these calculated s values are used as references for comparison with stray light levels found in IOLs. 2. Method 1 A method for measuring light scatter in human donor crystalline lenses has been described in depth by van den Berg [6]. The same setup with minor modifications can be used to determine the same for IOLs (Fig. 1). A wavelength controlled light beam is incident on an IOL placed in a 10mm wide fluid filled optical quality glass cell. The beam shape is defined by the field stop. Fig. 1. Schematic of in vitro setup method 1. Chapter 6 The PSF is determined by measuring the light power P (θ) at stray light angle θ divided by the product of receptance solid angle Ω and total power P 0 transmitted by the IOL as formulated in Eq. (4). PSF(θ) = P(θ) / (Ωx P 0 ) (4) For an aperture diameter of 3mm in front of the camera lens and a distance of 140mm from camera aperture to IOL, Ω = sr and the angular width is 1.2 degrees. The IOL is centered by using a laser pointer in the center of the camera wheel. The cooled scientific grade 16-bit CCD camera and the glass cell are placed in a dark room separate from the light source with filters. The camera shutter times increased from 100ms to 10s with increasing measurement angles in order to be able to detect the decreasing amount of light power. The light power P 0 at zero degrees is measured by inserting a density filter and enlarging the camera aperture to 22 mm resulting in Ω = 0.02 sr. It is possible to determine forward as well as backward scatter for an angular range of 135 degrees for pencil illumination as well as slit illumination. The finite width of the aperture and intensity of the transmitted light beam is the limiting factor for the smallest angle to be measured and is approximately two degrees but is dependent on the IOL tested and light 74

75 Combining in vitro test methods for measuring light scatter in intraocular lenses wavelength. The background stray light level of the fluid filled cell without IOL had to be below the level of 0.1 degrees 2 /sr, otherwise the glass cell was rejected or cleaned and refilled with fresh immersion fluid. Fig. 2. Typical examples of acrylic IOLs scatter in purified water at 30degrees forward direction. (a) IOL with a center thickness of 0.7mm. (b) IOL with a center thickness of 0.5mm containing micro vacuoles. The light scatter results (Fig. 2) were made with an 80μm slit illumination at 30 degrees in broadband green light and purified water as immersion fluid. In such recording bulk scatter can be seen separated from surface scatter. An interface was present between IOL and purified water resulting in a stray light level of approximately 5 degrees 2 /sr. The picture on the right shows an example where in-homogeneities in lens material resulted in additional bulk light scatter. A saline solution reduces interface scattering significantly (below 1 degrees 2 /sr) and is recommended as immersion fluid in testing IOLs in order to better mimic the in vivo condition. Chapter 6 75

76 Chapter 6 Fig. 3. Typical straylight level for a monofocal IOL measured in saline using method 1. The stray light level (Fig. 3) for a monofocal IOL is compared to a 20 year and 70 year old healthy crystalline donor lens according to Eqs. (2) and 3. The stray light level is lower than that of a healthy human crystalline lens, irrespective its age. 3. Method 2 Chapter 6 In method 1, because the location of the IOL is very close to the nodal point of the eye, a cornea was deemed unnecessary. In this set-up the scatter induced angular intensity distribution remains similar for an IOL in a liquid cell with or without a cornea in front. Subsequently, vergence and refraction will not affect the measured intensity distribution. In method 2, the measurements take place for angles close to on-axis or paraxial angles. An artificial cornea in front of the cell is introduced to emulate the refraction contribution to the image intensity distribution of the PSF. The setup (Fig. 4) is identical to the eye model prescribed in the ISO guidelines for IOL quality testing [7]. Fig. 4. Schematic setup for method 2. The artificial cornea, an equi-biconvex BK7 lens, provides the same power as the ISO cornea, and it reproduces the average corneal spherical aberration with Zernicke coefficient c(4,0) = 0.27μm for 6mm cornea aperture and the average longitudinal chromatic aberration of 0.4mm between hydrogen F and C lines [8]. The configuration of method 2 has good infinite object testing capability [9] and is used for image quality 76

77 Combining in vitro test methods for measuring light scatter in intraocular lenses assessment of IOLs by determining the modulation transfer function MTF from the measured line spread function LSF. The stray light aspect can be approached from the tails of the LSF. The basic setup has a limited angular range of ± 0.8 degrees and is extended by stepwise lateral displacement of the CCD camera by a total of approximately 0.5mm with for each step a new shutter time ranging from 0.1ms to 4s. An 8 bits or cooled scientific grade 12 bits CCD camera is used. The light intensities to be measured for method 2 are higher than for method 1 and therefore a less stringent dark condition is necessary. The glass cell and the light path to the CCD camera are shielded from the very dim environment light. The recorded intensity distributions are stitched together. The distance dp from pixel location to peak intensity is used to calculate the angle θ at the pixel location with ATAN (dp/m*nd) where ND = 21mm is the nodal distance for a medium powered IOL. M is the calibrated magnification (9.1X, NA0.45) of the used APO microscope objective lens. The angular intensity is resolved to degrees for a CCD pixel size of 6.45μm. Figure 5 shows an example where an LSF of a monofocal lens was stitched together in five steps leading to an intensity range of six decades and an angular range of ± 2.5 degrees. Since the LSF is the integral of the PSF along the imaged slit the reliable angle from which the stray light could be determined is governed by the object angle of the slit target length and collimator focal length. This is demonstrated and indicated in Fig. 5 by the 0.43 degrees of angular width at the location of the shoulder points corresponding to the ratio of 3mm slit length and 400mm collimator length. In this case, accurate stray light results could only be obtained for radial angles much larger than degrees. When a pinhole target is placed in the focal point of the collimating lens a larger part of the central PSF can be recorded. The maximum angle measured could extend to three degrees dependent on test target, wavelength and IOL tested. For angles larger than 0.1 degrees the background s value of cornea and fluid filled cell without IOL had to be 0.5 log unit below the level of a healthy 20yr old crystalline lens according to Eq. (2). Chapter 6 Fig. 5. Five LSF recordings were stitched together with sufficient overlap. For each recording, the legend shows the CCD displacement from the optical axis. The central recording is also used to determine the MTF. In this recording a 8 bits CCD is used 77

78 Chapter 6 For rotationally symmetric systems it is adequate to record the radial PSF. The PSF is again determined according Eq. (4). The solid angle is determined by the imaging optics and the magnifying objective lens projecting the image onto the CCD. Each pixel subtends the square of the pixel size ps and Ω is calculated as ps 2 /(M*ND) 2. For a pinhole target the transmitted power is the volume under the stitched PSF curve. For the case of a slit target the transmitted power is the area under the stitched LSF curve multiplied by the length of the imaged slit in number of pixels. 4. Discussion Two quantitative in-vitro methods are described and demonstrated to be complementary in the angular domain. The combined methods have the capability to record ten decades of light intensity variation from focal image to forward scatter position of 30 degrees, with the possibility of extending to 135 degrees. There is a blind angular range of approximately 25 degrees centered around 90 degrees. Edge glare effects could be considered as a separate source of light scatter [10]. For angles larger than 0.5 degrees, a monofocal IOL essentially free of bulk in-homogeneities has lower stray light levels than that of a healthy human crystalline lens, irrespective of its age (Fig. 6). Positive effects of cataract surgery on stray light levels are discussed in literature. In vivo straylight measurements with a glare source at seven degrees were done before and after surgery [11,12]. Chapter 6 Fig. 6. Method 1 and method 2 combined for a monofocal lens that is essentially free from bulk inhomogenieties. The angular axis is a log scale to illustrate both methods. In vitro light scatter measurements in intraocular lenses are useful because they reveal stray light levels separately from other in vivo contributing stray light factors such as that from the cornea, vitreous or retina. Stray light may not necessarily impact visual acuity but it could seriously hinder good quality vision. Forward light scatter will be incident on the retina and therefore reduces patients quality of vision. Forward scatter and backward 78

79 Combining in vitro test methods for measuring light scatter in intraocular lenses scatter can bedetermined in vitro in one setup and both scatter directions can be compared. If there is a difference in forward and backward scatter levels, this may then serve as an explanation for differences found in clinical observations which are dominated by backward scatter versus patients perceptions which depend on forward scatter. The main purpose of this paper is to describe an overview of laboratory methods for objectively measuring scatter from IOLs. Measurement results are given to illustrate the method, and not to evaluate different IOLs in detail. Methods defined in this paper may be used in the future to examine the clinical phenomena of scatter in several monofocal and diffractive multifocal IOLs and to determine whether scatter introduced by these lens designs may contribute significantly to disability glare. Chapter 6 79

80 Chapter 6 References and links Chapter 6 1. J. J. Vos, Disability glare, CIE Report 135/1 (CIE, 1999). 2. P. W. Cobb, The influence of illumination of the eye on visual acuity. I. Introductory and historical, Am. J.Physiol. 29, (1911). 3. W. S. Stiles, The effect of glare on the brightness difference threshold, Proc. R. Soc. Lond., B 104(731), (1929). 4. L. L. Holladay, The fundamentals of glare and visibility, J. Opt. Soc. Am. 12(4), (1926). 5. T. J. T. P. van den Berg, Analysis of intraocular straylight, especially in relation to age, Optom. Vis. Sci. 72(2),52 59 (1995). 6. T. J. T. P. van den Berg, Depth-dependent forward light scattering by donor lenses, Invest. Ophthalmol. Vis.Sci. 37(6), (1996). 7. ISO , Opthalmic implants Intraocular lenses Part 2: optical properties and test methods (1999). 8. M. van der Mooren, H. Weeber, and P. Piers, Verification of the average cornea eye ACE model, Invest.Ophthalmol. Vis. Sci. 47, E-abstract 309 (2006). 9. S. Norrby, P. Piers, C. Campbell, and M. van der Mooren, Model eyes for evaluation of intraocular lenses, Appl. Opt. 46(26), (2007). 10. J. T. Holladay, A. Lang, and V. Portney, Analysis of edge glare phenomena in intraocular lens edge designs, J.Cataract Refract. Surg. 25(6), (1999). 11. T. J. T. P. van den Berg, L. J. van Rijn, R. Michael, C. Heine, T. Coeckelbergh, C. Nischler, H. Wilhelm, G.Grabner, M. Emesz, R. I. Barraquer, J. E. Coppens, and L. Franssen, Straylight effects with aging and lens extraction, Am. J. Ophthalmol. 144(3), (2007). 12. K. W. van Gaalen, S. A. Koopmans, J. M. M. Hooymans, N. M. Jansonius, and A. C. Kooijman, Straylight measurements in pseudophakic eyes with natural and dilated pupils: one-year follow-up, J. Cataract Refract.Surg. 36(6), (2010). 80

81 Chapter 7 Impact of intraocular lens material and design on light scatter: In vitro study Reprinted from Journal of Cataract and Refractive Surgery, Vol. 40, Langeslag MJM, van der Mooren M, Beiko GHH, Piers PA Explanted multifocal intraocular lenses, Pages , Copyright 2014, with permission from ASCRS and ESCRS (Elsevier) AMO Groningen BV, Netherlands (Langeslag, van der Mooren, Piers) St. Catharines, Canada (Beiko)

82 Chapter 7 PURPOSE: To determine the typical in vitro straylight levels for intraocular lenses (IOLs) of different materials and designs. SETTING: Abbott Medical Optics, Inc., Groningen, the Netherlands. DESIGN: Experimental study. METHODS: Two optical bench setups were used to determine baseline straylight levels of IOLs placed in a saline-filled cuvette: one for forward scatter positions between 0.6 and 3.0 degrees and one for positions up to 22.0 degrees. Line-spread functions were measured using the small angle setup, and scattered light intensity was measured using the wide-angle setup. From these measurements, the angular dependent straylight parameter was calculated. Ten IOLs of different materials (hydrophobic and hydrophilic) and designs (monofocal or diffractive multifocal and spheric or aspheric) were studied, and their measured straylight levels were compared with the levels in a 20-year-old and a 70-year-old healthy noncataractous human crystalline lens. RESULTS: Irrespective of the material or design, monofocal IOLs had straylight levels below or close to those of a 20-year-old human crystalline lens. Diffractive multifocal IOLs had straylight levels higher than those of monofocal IOLs but less than those of a 70-year-old human crystalline lens. With increasing angle, hydrophobic IOLs showed a gradual decrease in straylight level. After an initial decrease, hydrophilic IOLs showed an increase in straylight level for larger angles. Chapter 7 CONCLUSIONS: The baseline straylight levels of IOLs were design and material dependent (hydrophobic < hydrophilic; monofocal < diffractive multifocal). Most monofocal IOLs had straylight levels below the levels in a 20-year-old human crystalline lens. 82

83 Impact of intraocular lens material and design on light scatter: In vitro study Imperfections in ocular media cause light entering the eye to be scattered. Natural imperfections can be irregularities that occur at the interface of ocular media (eg, cornea to aqueous) or particles, such as proteins, that are present in the medium. This causes part of the light, initially directed toward the focus point on the retina, to disperse onto the surrounding retina. Consequently, less light will reach the focal point on the retina. The scattered light, or straylight, thus diminishes the contrast of the optical image formed. 1,2 The natural crystalline lens also contributes to the scattering of light. In young crystalline lenses, the amount of scatter is minimal, but as the natural lens ages, the amount of straylight originating from the crystalline lens increases because of the natural aging process of the lens. 3 6 The increased straylight causes visual symptoms such as disability glare during night driving and hindrance from low sun during daytime. 2 Cloudy lenses or cataracts are the extreme of the aging process; light passing through a cataractous lens is more scattered, resulting in a significant loss of contrast. 7 Even though straylight may cause as much functional vision loss as visual acuity and the impact of light scattering from cataracts is well understood, current clinical assessment for cataract surgery is primarily based on visual acuity measurements and slitlamp examination of the density of the crystalline lens. Retinal straylight from light scattering due to cataracts may, however, case as much functional vision loss as poor visual acuity. 5,8 11 Additionally, retinal straylight and visual acuity behave independently. 1,5 7,9,12 Therefore, several clinical investigators have advocated the use of an increase in straylight as an indication for cataract surgery. 2,5,8 11 Previous in vivo measurements using the C-Quant straylight meter (Oculus Optikgeräte GmbH) show that pseudophakic eyes have straylight levels comparable to or below that of healthy eyes. 5 This finding demonstrates that the cataract is the largest source of intraocular light scatter and that its extraction and replacement with an intraocular lens (IOL) lowers the amount of straylight and the related visual effects. Commercially available IOLs differ in their material, design, and manufacturing method, all of which are potential sources of light scatter 5,13 ; however, the extent to which they introduce straylight and how that relates to typical straylight levels in healthy young and old eyes have not been well defined. Increased knowledge of the straylight introduced by different types of IOLs would contribute to a broader and better understanding of the visual consequences of IOL designs and materials. This knowledge would also help in managing patient expectations, which is especially important given the increased attention to light scatter and its role in functional vision loss. In this study, in vitro measurements were performed to determine the baseline straylight levels for IOLs differing in design, material, and/or manufacturing method. The obtained results were compared between individual types of IOLs as well as with the straylight levels published for 20-year-old and 70-year-old healthy crystalline lenses. 13 Chapter 7 83

84 Chapter 7 MATERIALS AND METHODS The straylight levels of 10 types of IOLs were studied. Only sterile IOLs were used. The IOLs were made from 4 acrylic materials labeled as hydrophobic and 2 acrylic materials labeled as hydrophilic. They had 4 optical designs: spheric or aspheric and monofocal or diffractive multifocal. Table 1 summarizes the details of the IOLs and the nomenclature used to address them in this article (acrylic A to F). 14,15,A The IOLs' straylight was measured in 2 laboratory-based setups, together covering an angular domain from the optical axis up to 22 degrees. A short overview of both setups is given below. A more detailed description of the measurements and their background has been given by van der Mooren et al. 13 Straylight The straylight parameter s(q) introduced by van der Berg 4 allows quantification of the amount of straylight, both in vivo and in vitro. By definition, the straylight parameter is the equivalent luminance divided by the illuminance of the glare source falling into the eye x angle square. 16 The straylight corresponds to the skirts of the point-spread function (PSF) as presented in equation s(θ) = PSF(θ)xθ 2 [degrees 2 / sr]. (1) Chapter 7 Setup 1: Small Angle (up to 3.0 Degrees) Figure 1. Small-angle measurement setup. The first setup, to measure scatter for small angles, is shown in Figure After being hydrated in saline for at least 24 hours, the IOLs were placed in a saline-filled cuvette and 84

85 Impact of intraocular lens material and design on light scatter: In vitro study placed on an optical bench in an eye model that reproduces the spherical (c [4.0] = 0.27 mm) and chromatic (0.4 mm between hydrogen F and C lines) aberration of an average pseudophakic eye 17,B using white light and a 4.0 mm aperture. A 3.0 mm slit, corresponding to 0.5 degree, was used to collect information on the outer skirts of the PSF. 13 The light intensity distribution of each IOL was obtained using a stepwise lateral displacement of the charge coupled device (CCD) camera, which captured the linespread function. Using 5 steps, an intensity range of 6 orders of magnitude over an angle of ±3 degrees with respect to the optical axis was obtained (Figure 2). For each position, a different shutter time was applied to cover the maximum light intensity range for that particular position. The PSF was obtained by integrating the line-spread function along the image slit. The angular position was calculated from the pixel position, the magnification, and the nodal point. From the PSF and the angular positions, the angular dependent straylight parameters, s(θ), for forward scatter positions between 0.6 and 3.0 degrees were calculated using equation 1. 13,16 Figure 2. Five line-spread function measurements represented by 5 colors were stitched together to obtain the line-spread function over the entire angular range. The lateral displacement of the CCD with respect to the central optical axis is denoted in the legend for each line-spread function recording. Chapter 7 85

86 Chapter 7 Setup 2: Wide Angle (up to 22.0 Degrees) Figure 3. Wide-angle measurement setup. The wide-angle setup is shown in Figure After the IOLs were hydrated in saline for at least 24 hours, the straylight was measured by placing the IOLs in a saline-filled cuvette. A light source was defined and directed using several lenses and filters. The intensity of the light transmitted by the IOL was measured using a CCD camera at different angles relative to the incident beam. The CCD camera and the cuvette were shielded by a black curtain. Similar to the small-angle setup, the camera's shutter times were increased with increasing measurement angle to detect the decreasing light intensity. 13 All analyses were performed using a 4.0 mm aperture. The PSF was calculated from the measured light intensities, light power P(θ), using equation 2, in which Ω represents the solid angle and P 0 is the total light transmitted by the IOL. 13 Chapter 7 PSF(θ) = P(θ) / (Ωx P 0 ) (4) Subsequently, the straylight parameter s(θ) was calculated from the PSF and the forward scatter angle using equation Data Analysis The straylight levels for the IOL designs and materials were compared with each other and with the published levels for healthy noncataractous 20- and 70-year-old human crystalline lenses. 13 By definition, the setup measures the tail of the line-spread function; however, the straylight parameter s(θ) is calculated from the PSF. Because in the smallangle method the linespread function approximates the PSF for angles greater than 0.5 degree, results are presented for 0.6 degree outward. For angles smaller than 0.6 degree, no valid PSF values could be measured because of the use of a 0.5 degree slit target. For 86

87 Impact of intraocular lens material and design on light scatter: In vitro study both measurement setups, the measurements were considered to be symmetrical around the optical axis. Therefore, the results from the negative and positive angles were averaged. The results from the small-angle and wide-angle measurements were combined for each IOL. One IOL was measured for each model listed in Table 1. For 4 IOL models, straylight from at least 2 different IOLs was measured. For each of the IOL models, the maximum standard deviation was 5% of the mean straylight values for the complete angular range. Based on this outcome, it was considered reasonable to use the measurements on 1 IOL for each model as a representable baseline. Table 1. Characteristics of the IOLs in the study. Description Labeled Material Refractive index* Water content IOL Model IOL Design Manufacturer Acrylic A Hydrophobic 1.47 (at 35 C) ~2% 14,15 AAB00 Monofocal/spherical Abbott Medical ZCB00 Monofocal/aspheric Optics, Inc. ZMB00 Multifocal/aspheric Acrylic B Hydrophobic 1.55 ~1% 14,15 SN60AT Monofocal/spherical Alcon, Inc. SN60WF Monofocal/aspheric SN60D3 Multifocal/spherical Acrylic C Hydrophobic (at 35 C) ~5% 14 MX60 Monofocal/aspheric Bausch & Lomb, Inc. Acrylic D Hydrophobic (at 23 C) ~1% 15 FY-60AD Monofocal/aspheric Hoya Corp. Acrylic E Hydrophilic (hydrated, at 20 C) 26% A ADAPT-AO Monofocal/aspheric Bausch & Lomb, Inc. Acrylic F Hydrophilic %* Softec-HD Monofocal/bi-aspheric Lenstec, Inc. *Source: Directions for use RESULTS Material Comparison The straylight levels for the 4 monofocal aspheric IOLs made from materials labeled as hydrophobic acrylic were well below those of the straylight levels of a 20-year-old human crystalline lens. For small forward scatter angles in the range of 0.6 to 3.0 degrees, straylight levels of the IOLs were similar to each other and decreased with increasing angle (Figure 4). For larger angles, the curve representing the straylight levels for acrylics A and B tended to flatten out; however,the curves for acrylics C and D showed a small increase in straylight levels as the forward scatter angle increased from 4 to 20 degrees. In Figure 5, the straylight levels for IOLs made from materials labeled as hydrophilic acrylic are presented. For small forward light scatter angles (up to 3.0 degrees), straylight levels were well below the levels of a 20-year-old human crystalline lens. For angles larger than 3.0 degrees, the straylight levels increased, reaching that of a 20-year-old human crystalline lens at forward scatter angles of approximately 20.0 degrees. Chapter 7 87

88 Chapter 7 Figure 4. Material comparison between monofocal aspheric IOLs made from 4 different hydrophobic acrylic materials (acrylica to D). Chapter 7 Figure 5. Material comparison between monofocal aspheric IOLs made from 2 different hydrophilic materials (acrylics E and F). 88

89 Impact of intraocular lens material and design on light scatter: In vitro study Design Comparison To determine whether design-related differences influenced straylight, 1 spheric and 1 aspheric monofocal IOL made from hydrophobic acrylics A and B were compared (Figure 6). All the spheric and aspheric monofocal IOLs showed decreasing straylight levels for the small forward scatter angles, with the overall levels remaining well below those of a 20- year-old human crystalline lens. In general, the aspheric monofocal IOLs had slightly lower straylight levels than the spheric monofocal IOLs. Figure 7 compares the straylight levels for monofocal and diffractive multifocal IOLs made from hydrophobic acrylics. Both diffractive multifocal IOLs had a 4.0 diopter addition power. Straylight levels for diffractive multifocal IOLs were higher than those for monofocal IOLs but remained below those of a 70-year-old human crystalline lens. Additionally, for scatter angles greater than 2.0 degrees (aspheric design) or 7.5 degrees (spheric design), straylight levels of diffractive multifocal IOLs decreased to levels below those of a 20-year-old human crystalline lens and flattened out with larger angles. Chapter 7 Figure 6. Design comparison of 1 spheric and 1 aspheric monofocal IOL made from acrylics A and B. 89

90 Chapter 7 Chapter 7 Figure 7. Design comparison of IOLs made from (a) acrylic A having a monofocal aspheric and a diffractive multifocal aspheric design (top) and (b) acrylic B having a monofocal spheric and a diffractive multifocal spheric design (bottom). 90

91 Impact of intraocular lens material and design on light scatter: In vitro study DISCUSSION Intraocular lenses were measured in an ideal in vitro situation. The absolute and relative straylight levels measured should therefore be considered as a baseline situation. In vivo, the amount of straylight will be defined not only by the type of IOL, but also by the presence of other light-scattering interfaces such as the capsular bag, striae, and the presence of posterior and/or anterior capsule opacification. These biological aspects as well as material inhomogeneity may vary from person to person and may change over time. Monofocal IOLs had straylight levels below or close to the levels of a 20-year-old human crystalline lens, irrespective of the material or design (spheric or aspheric). Diffractive multifocal IOLs had relatively higher straylight levels, but the levels did not exceed those of a 70-year-old human crystalline lens, and with increasing angle, the levels dropped to less than those of a 20-year-old human crystalline lens. These larger forward scatter angles correspond to the region that is considered to be outside the region affected by the halo that results from a diffractive multifocal design. 18 The differences in straylight levels between monofocal and diffractive multifocal IOL designs can be assigned to the straylight originating from the higher-order foci of the diffractive surface. Removing a cataractous lens and replacing it with an IOL is expected to lower the lens' contribution to straylight in the eye. This is consistent with the observations by van den Berg et al., 5 who compared in vivo straylight levels before and after cataract surgery. Analysis of straylight levels at different forward scatter angles revealed that most of the hydrophobic acrylic IOLs showed a decrease in straylight levels with increasing forward scatter angles until they reached a plateau for the large angles (Figure 4). In contrast, for hydrophilic IOLs, the initial decrease in straylight levels for smaller angles was followed by a similar gradual increase for larger angles (Figure 5). A veil is apparent on the hydrophobic IOLs at large scatter angles; for example Figure 8 shows the photographs taken during the measurements for a hydrophobic and a hydrophilic acrylic IOL from the same manufacturer at a small (1.5 degrees) and a large (22.0 degrees) forward scatter angle. A veil is clearly seen on the hydrophilic IOL at 22.0 degrees forward scatter angle. Water content may also vary among the hydrophobic acrylic IOLs (Table 1). A review of Figures 4 and 5 shows a trend toward increasing straylight parameter values at scatter angles of 3.0 degrees onward for acrylic material C that is similar to that for hydrophilic IOLs. The absolute increase in the straylight parameter value for hydrophobic material C is not as large as that for the hydrophilic IOLs. Material C has the highest water content of all hydrophobic materials tested (Table 1) but not as high as the hydrophilic materials; this may point toward a relationship between the IOL materials' water content and the straylight parameter behavior for large forward scatter angles. Future work may focus on investigating possible mechanisms explaining this observation. In addition to IOL material and design, surface and bulk irregularities arising from the manufacturing process may influence the amount of straylight measured. In this study, IOLs from different Chapter 7 91

92 Chapter 7 manufacturers were used and therefore the manufacturing process may have influenced the straylight levels observed. The eye model used for the small-angle measurements was designed to reproduce the average corneal spherical aberration. Straylight levels of spheric and aspheric IOLs measured in this study were low and their relative differences may not be attributed to spherical aberration because this factor is expected to play a role for angles that are much smaller than 0.6 degrees. The higher straylight values obtained from the small-angle setup measurements in the overlapping angular range for all IOLs except the multifocal spheric lens B (Figure 7) may be explained by a difference in the base straylight level of the measurement setups used in this study. Straylight measurements require the accurate determination of light intensities over a large range of values. In the low intensity regions, accurate straylight measurements become increasingly challenging. This may lead to variation in absolute straylight parameter values when the same IOL is measured under different conditions (eg, on another day) or when the same IOL model from a different manufacturing batch is measured. This is especially true for monofocal IOLs as they showed straylight levels close to the straylight levels of the setup without an IOL. Intraocular lenses were only measured when the straylight value for the setup alone was at least 0.5 log unit below the level of a healthy noncataractous 20-year-old human crystalline lens, as described by the in-depth explanation of this method by van der Mooren et al. 13 Chapter 7 Additionally, a repeatability study has been performed on a monofocal and a multifocal IOL with 3 repetitions on each IOL. The maximumstandard deviation was 13% of the mean straylight values for the complete angular range. The results presented in this study can help predict the consequences of a change in IOL design, material, or manufacturing process on the postoperative straylight level in pseudophakic eyes. The baseline levels that we measured can be used to inform patients of the expected straylight level and possible improvement in visual effects. Future work may include in vivo measurements of aged IOLs and/or the comparison of the in vitro straylight levels presented in this paper with the straylight levels from in vivo measurements in pseudophakic eyes. In conclusion, this study found that most monofocal IOLs have straylight levels below the levels published for a healthy noncataractous 20-year-old human crystalline lens. Light scattering is influenced by IOL material and design; hydrophobic IOLs tend to have lower straylight levels than hydrophilic IOLs for scatter angles larger than 3.0 degrees and IOLs with a monofocal IOL design have lower straylight levels than IOLs having a diffractive multifocal design. 92

93 Impact of intraocular lens material and design on light scatter: In vitro study Figure 8. Acrylic C (left) and acrylic E (right) monofocal IOLs taken in the wide-angle setup at a forward scatter angle of 1.5 degrees (top) and 22.0 degrees (bottom) (white light, in saline). A veil is clearly visible on the hydrophilic IOL at large angles (bottom right). WHAT WAS KNOWN Intraocular light scatter due to cataracts is a known source of functional vision loss. Extraction of the cataractous lens and replacement with an IOL lowers the amount of straylight. WHAT THIS PAPER ADDS In vitro straylight measurements of different IOLs show that baseline straylight levels depend on their design and material (monofocal <diffractive multifocal; hydrophobic < hydrophilic). Irrespective of the material, all monofocal IOLs show in vitro baseline straylight levels below the levels reported for a 20-year-old healthy human crystalline lens. Chapter 7 93

94 Chapter 7 REFERENCES Chapter 7 1. Zuckerman JL, Miller D, Dyes W, Keller M. Degradation of vision through a simulated cataract. Invest Ophthalmol 1973; 12: Available at: September 1, vandenbergtjtp,franssenl,coppens JE.Ocularmedia clarity and straylight. In: Dartt DA, ed, Encyclopedia of the Eye. Oxford,UK, Academic Press, 2010; 3, Available at: pdf. Accessed September 1, IJspeert JK, de Waard PWT, van den Berg TJTP, de Jong PTVM. The intraocular straylight function in 129 healthy volunteers; dependence on angle, age and pigmentation. Vision Res 1990; 30: van den Berg TJTP. Analysis of intraocular straylight, especially in relation to age. Optom Vis Sci 1995; 72: van den Berg TJTP, van Rijn LJ, Michael R, Heine C, Coeckelbergh T, Nischler C, Wilhelm H, Grabner G, Emesz M, Barraquer RI, Coppens JE, Franssen L. Straylight effects with aging and lens extraction. Am J Ophthalmol 2007;144: de Waard PWT, IJspeert JK, van den Berg TJTP, de Jong PTVM. Intraocular light scattering in age-related cataracts. Invest Ophthalmol Vis Sci 1992; 33: Available at: Accessed September 1, van den Berg TJTP. Importance of pathological intraocular light scatter for visual disability. Doc Ophthalmol 1986; 61: van der Meulen IJE, Gjertsen J, Kruijt B, Witmer JP, Rulo A,Schlingemann RO, van den Berg TJTP. Straylight measurements as an indication for cataract surgery. J Cataract Refract Surg 2012; 38: Elliott DB, Hurst MA, Weatherill J. Comparing clinical tests of visual loss in cataract patients using a quantification of forward light scatter. Eye 1991; 5: Available at: Accessed September 1, Paulsson L-E, Sj ostrand J.Contrast sensitivity in the presence of a glare light; theoretical concepts and preliminary clinical studies. Invest Ophthalmol Vis Sci 1980; 19: Available at: Accessed September 1, Elliott DB, Bullimore MA. Assessing the reliability, discriminative ability, and validity of disability glare tests. Invest Ophthalmol Vis Sci 1993; 34: Available at: Accessed September 1, Hess R, Woo G. Vision through cataracts. Invest Ophthalmol Vis Sci 1978; 17: Available at: Accessed September 1, van der Mooren M, van den Berg T, Coppens J, Piers P.Combining in vitro test methods for measuring light scatter in intraocular lenses. Biomed Opt Express 2011; 2: Available at: PMC /pdf/505.pdf. Accessed September 1, Bozukova D, Pagnoulle C, Jérôme C. Biomechanical and optical properties of 2 new hydrophobic platforms for intraocular lenses. J Cataract Refract Surg 2013; 39:

95 Impact of intraocular lens material and design on light scatter: In vitro study 15. Werner L. Glistenings and surface light scattering in intraocular lenses. J Cataract Refract Surg 2010; 36: Vos JJ, van den Berg TJTP. Report on disability glare. CIE Collection Vision and Colour; Physical Measurement of Light and Radiation. CIE 1999; 135:1 9. Available at: Accessed September 1, Norrby S, Piers P, Campbell C, van der Mooren M. Model eyes for evaluation of intraocular lenses. Appl Opt 2007; 46: Pieh S, Lackner B, Hanselmayer G, Z ohrer R, Sticker M,Weghaupt H, Fercher A, Skorpik C. Halo size under distance and near conditions in refractive multifocal intraocular lenses. Br J Ophthalmol 2001; 85: Available at: nlm.nih.gov/pmc/articles/pmc /pdf/v085p00816.pdf. Accessed September 1, 2014 OTHER CITED MATERIAL A. Behndig A, Bellucci R, Pynson J, Brooks L. The Akreos IOLs; clinically proven to provide quality of vision.uspublication,april Available at: /m/bl/united%20states/files/downloads/ecp/surgical/the-akreos-iols.pdf. Accessed September 1, 2014 B. van dermoorenm,weeberh, Piers P.Verification of the average cornea eye ACE model. IOVS 2006; 47:ARVO E-abstract 309. Available at: Accessed September 1, 2014 Chapter 7 95

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97 Chapter 8 Effect of glistenings in intraocular lenses Reprinted from Biomedical Optics Express, Vol. 8, van der Mooren M, Fransen L, Piers P Pages Copyright 2013, with permission from Optical Society of America. AMO Groningen BV, Netherlands (van der Mooren, Franssen, Piers) The authors acknowledge Tom van den Berg, Michelle Langeslag and Joris Coppens for their contributions to this paper. We acknowledge financial support from EUREKA grant INT

98 Chapter 8 Abstract Glistenings consist of multiple microvacuoles in intraocular lenses (IOLs) that cause retinal stray light and may affect quality of vision. For four IOL types, the microvacuole particle size distribution and particle volume density was measured using confocal light microscopy and dark field microscopy, and the corresponding extinction coefficient γ was determined. The light scatter contribution induced by microvacuoles was measured as function of both angle and extinction, and was verified by calculations using Mie theory. Two IOL types possessed significant glistenings having stray light levels higher than that of a healthy 20 year old crystalline lens corresponding to γ 0.08 mm 1 OCIS codes: ( ) Optical effects on vision; ( ) Stray light; ( ) Ophthalmic optics and devices Chapter 8 98

99 Effect of glisterings in intraocular lenses 1 Introduction The phenomenon of inclusions or microvacuoles in intraocular lenses (IOLs) has been discussed extensively in ophthalmic literature for more than twenty five years. They are often referred to as glistenings due to their appearance when visualized e.g. in a slit-lamp exam. In our study, we consider a microvacuole to be a void located in the IOL bulk filled with the fluid surrounding the IOL. Glistenings are considered to be the visual effect caused by multiple microvacuoles. This study describes how light propagates through a lens containing such microvacuoles and discusses the effects on quality of vision based on the light intensity distribution as a function of retinal eccentricity. Several papers report clinical studies investigating the impact of glistenings in intraocular lenses on contrast sensitivity (CS) and visual acuity (VA). In total, 6 studies examined the effect of glistenings on CS. Four of these studies reported that glistenings had a significant negative effect on the high spatial frequency CS [1 4] and two studies were non-conclusive [5,6]. While some studies do show a decrease in VA with increased severity of glistenings [6,7] the general consensus in the literature tends to be that visual acuity is unaffected by glistenings [1 3,5,8 13]. These studies found no common conclusion concerning the effect of glistenings on measured visual quality. This may be due to the fact that quality of vision is not measurable in one comprehensive test and the aforementioned standard vision testing methodologies require only a very small part of the retina to respond to stimuli. In vitro studies report a positively correlated relationship between the total integrated light scatter and the severity of glistenings [14,15]. Also, several in vivo studies found increased levels of intraocular stray light [8,13,16]. In vitro studies allow us to isolate the scatter contribution of the IOL from that of the ocular media. They enable the study of light scatter patterns from the patients perspective, i.e. in the forward direction, and also from the clinicians perspective, i.e. in the backward direction [17]. Absorption removes and scattering redirects energy from the propagating light beam forming the retinal image. The attenuation in light intensity of the original beam is called extinction and this phenomenon is described by Beer s law. The transmitted light intensity decreases exponentially with the path length traveled by the propagating beam in a medium, in our case the IOL. Microvacuoles are almost completely transparent in visible light. For the visible wavelength range, absorption plays no role in light attenuation caused by the microvacuoles, and the effects measured are solely caused by scattering. In addition to light scatter measurements, it is also possible to perform light microscopy on the same IOL. In this paper, our aim is to relate microvacuole density and size distribution to light scatter as a function of visual angle based on Mie theory. Mie formulae are applied in various scientific fields from chemistry, medicine and astronomy to meteorology. The lunar corona shown in Fig. 1 illustrates the optical effects of the clouds in front of the bright moon acting both as a grating and as a prism [18]. Chapter 8 99

100 Chapter 8 Fig. 1. Lunar corona. The water droplets in a cloud separate the incident moon light into two optical fields. One field consists of the light diffracted by the surfaces of the water droplets creating a white halo and the other field traverses the water droplets creating colored fringes. The strength and size of the halo is determined by the density and size distribution of the water droplets. The lunar corona is an anomalous scattering pattern because it is composed of two optical fields. The water droplets in the cloud act similarly to the microvacuoles in the intraocular lenses. In this paper, methods used in atmospheric optics are applied for our specific investigation by adapting all parameters applicable such as refractive indices and particle distribution. This study presents measurements of light scatter and extinction determination based on confocal light microscopy and dark field microscopy for IOLs containing microvacuoles. The angular distribution of the scatter function will provide information that can be used to optimize a clinical setup to test the influence of microvacuoles on visual performance. Our findings also explain various literature reports on contrast sensitivity and visual acuity related to glistenings in clinical studies. 2. Materials and methods Chapter 8 The following sixteen hydrophobic acrylic IOLs were included in this study: five Acrysof IOLs (Alcon Laboratories Inc, Forth Worth, Texas, USA), three isymm IOLs (HOYA Surgical Optics Inc, Singapore), three envista IOLs (Bausch & Lomb, Rochester, New York, USA) and five Tecnis IOLs (Abbott Medical Optics Inc, Santa Ana, California, USA). All lenses were removed from their packages and directly immersed in saline solution in fluid cells. Microvacuoles were induced by taking the IOL from its room temperature environment and placing it into an oven at ocular temperature of 35 C for a period of more than 8 hours. The lenses were removed from the oven for measurement at room temperature. The densities of induced microvacuoles vary with the time following their removal from the oven. For this reason, restrictions were made with respect to the time points of 100

101 Effect of glisterings in intraocular lenses measurements. The light scatter measurements and lens imaging with confocal microscopy and dark field microscopy were performed within a two-hour period. Confocal microscopy has a limited depth of focus, as such multiple images were made throughout the thickness of the lens and the images were then stacked. It also has a small field of view resulting in the need for three or more lateral displacements across the lens in order to image the complete central optic body. Dark field microscopy is a setup where the intraocular lens is retro-illuminated with an annulus of light and has a large field of view. If there are no inclusions or other sources for light scatter, the image will be black. The Image J program was used to determine size and density of the microvacuoles from the stacked confocal microscopy images for dense populations or from dark field microscopy photographs for tiny populations of microvacuoles. The size distribution and density together with the indices of refraction for microvacuole and IOL material contribute to the extinction coefficient γ [mm 1 ], shortened to extinction in this paper. For each IOL γ was determined using Eq. (1) [19], where N(a) is the microvacuole size distribution per unit volume and a is the microvacuole radius and Q is the scatter extinction efficiency factor defined in Eq. (2) [19]. The phase lag ρ experienced by the central ray that passes through the full diameter of the microvacuole is 2ka m-1, where m is the ratio of the refractive indices of microvacuole and IOL material n. Wave number k is equal to 2πn/λ where λ is the wavelength of light used. γ = 0 π 2 a Q( a) N( a) da (1) Q(ρ)=2-(4/ρ)sin ρ+(4/ρ 2 )(1-cos ρ) (2) Factor Q oscillates around the value of 2 illustrating the efficiency for light scatter in large particles. The oscillation damps with increasing phase lag Light scatter measurements Using two lab-based methods, the scattered light intensity distribution was measured as a function of angle. These in vitro light scatter methods capturing the high dynamic angular and intensity range have previously been described by van der Mooren et al [20]. The output of these two methods is expressed in a scatter parameter s [deg 2 /sr] defined as point spread function PSF(θ) multiplied by the square of visual angle θ. In the first method used to make small angle measurements, an artificial cornea was included in order to measure physiologically realistic stray light contributions close to the focal point. The second method that measures at angles larger than three degrees is able to measure the forward and backward scatter. The measured outcomes were compared with the light scatter levels for 20 yr and 70 yr old healthy crystalline lenses. Chapter 8 101

102 Chapter 8 To isolate the light scatter induced by the microvacuoles, light scatter measurements with and without microvacuole induction were subtracted from each other. These results were compared to calculations using implemented Mie theory in the MIEPlot software program [21]. The measured particle distributions were introduced in the program together with the refractive indices for the IOL materials, and n = 1.33 for the microvacuoles. The MIEplot software program outputs the angular intensity distribution I(θ) over 360 degrees with a chosen angular resolution of 0.1 degrees, and is normalized to 1 by integration over the forward hemisphere. The fraction of the incident light intensity which was scattered is defined in Eq. (3) where t is the thickness of the lens. f(γ) = 1 - exp(-γt) (3) The scatter function was then calculated by multiplying this fraction by the normalized intensity distribution and the angle squared as shown in Eq. (4). s(θ,γ) = f(γ)i (θ) θ 2 (4) Furthermore, the calculated intensity distribution I(θ) outcome was verified with Mie theory using Eq. (5). The formula consists of the sum of a refracted part [19] with μ = m-1 and x = ka and the Fraunhofer diffraction pattern described by the standard Bessel function J 1. I(θ) =4μ 2 x 2 /(4μ 2 + θ 2 ) 2 + x 4 ((1+cosθ)/2) 2 (J 1 (xsin θ)/xsin θ) 2 (5) 2.2. Simulated visual effect Chapter 8 A slit-lamp exam performed by a surgeon, gives information that is related to the backward scatter position, whereas the patient perceives forward scatter. For particles smaller than the wavelength of light, the scatter is uniformly distributed and the surgeon can therefore adequately assess the level of intraocular scatter. When the particle size is larger than the wavelength of visible light, forward scatter is much stronger than backward scatter. A slitlamp image at 45 degrees was taken to illustrate this effect. The ratio between the forward and backward scattered intensities for this angle was calculated by using the MIEplot program. Light transmittance through an IOL is of importance for maintaining contrast throughput. The portion of the incoming light that is scattered over the retina reduces image contrast. In this study, the light transmission through an IOL was calculated as a function of extinction. Fresnel reflections, blue and UV filters and other features affecting light transmission were excluded and only the effect of the presence of microvacuoles was assessed. For all lenses that followed the procedure for microvacuole induction, the fraction of light intensity left for image formation was 102

103 Effect of glisterings in intraocular lenses calculated as exp(-γt) and expressed as the percentage of light transmission for t = 0.5mm. Contrast was defined in terms of background luminance L b and target luminance L t as (L t - L b ) / L b. For a uniform background, the luminance contrast agrees well with perceived contrast. The luminance L v [cd/m2], which is added as retinal veiling glare to an image, is predicted by se/ θ 2, where E is the illuminance [lux] at the eye from a glare source at an angle θ. This concept of equivalent veiling luminance was introduced by Stiles and Holladay [22] for steady-state conditions. They found for a broad field of view (1 to 30 degrees) a constant value of s = 10 for phakic subjects. In our study, for pseudophakia, s was approximated with s(θ,γ) for the microvacuole effect and a constant value of 10 was added based on the average stray light level of various IOLs obtained by 220 stray light measurements with an extended glare source [23]. The effect of glare is demonstrated by the luminance contrast described in Eq. (6). C = (L t L b ) / (L b L v ) (6) The perceived contrast varies across the image not only because of the angular scatter function but also because it is dependent on the condition and task the subject is performing. As illustrative examples, we calculated the impact on contrast vision as a function of extinction for three tasks with the different lighting conditions defined in Table 1. Table 1 Description of three daily tasks under different conditions condition L t [cd/m 2 ] E[lux] θ[deg] L b [cd/m 2 ] 1. Night driving with oncoming car Computer screen next to window Contrast sensitivity test with glare L t is the luminance of the object to discern and L b is the background luminance with a glare source with illuminance E at angular distance θ. The first set of lighting conditions describes a night driving situation where the background road luminance was set to 0.5 cd/m 2. An oncoming car at a distance of 100 meters at an angle of 3 degrees has a headlight illuminance of 0.34 lux at the eye of the driver. The condition for veiling glare was considered constant for some period of time because when the oncoming car comes closer the ratio E/ θ 2 is constant. The illuminance increases quadratic with distance and the ratio is kept constant due to the increase in angle. The driver had to discern a crossing pedestrian with a luminance of 1 cd/m 2. The second set of lighting conditions describes an office where an employee works behind a computer screen with luminance variation from 200 cd/m 2 to 20 cd/m 2 next to a window illuminating 150 lux of daylight at the employee s eye. The third set of lighting conditions describes that of a dark clinical measurement lane where a subject performs a contrast sensitivity test (L t = 85 cd/m 2, L b = 2 cd/m 2 ) with a glare source. Chapter 8 103

104 Chapter 8 3. Results An overview of the lenses tested is given in Fig. 2 together with their measured microvacuole characteristics. Fig. 2. Microvacuole characteristics. The error bars indicate the standard deviation. The numbers of microvacuoles per cubic millimeter for the envista IOLs and the Tecnis IOLs are so small that the bars are hardly visible. The lenses were tested on one of the two available stray light methods due to time constraints of the methodology. The top row of Fig. 3 displays dark field images that correspond to the confocal microscopy images shown in the bottom row for all four types of IOLs. Chapter 8 Fig. 3. Top row shows dark field images and bottom row confocal images. The range of the extinction coefficients is displayed in between rows. The images from left to right with γ = 0.11mm 1, γ = 0.00 mm 1, γ = 0.18 mm 1 and γ = 0.02 mm 1. Bar indicates 50 μm. 104

105 Effect of glisterings in intraocular lenses The microvacuoles are non-spherical and an effective diameter is used to characterize the size while the non-uniformity of sizes is characterized by the standard deviation. For the Acrysof lenses the number of microvacuoles ranged from 46 to 3862 per cubic mm. The number of microvacuoles for the isymm IOLs ranged from 2545 to 6495 per cubic mm, for the envista IOLs 3 to 6 microvacuoles per cubic mm were found and the number for the Tecnis lenses ranged from 12 to 36 microvacuoles per cubic mm. The microvacuoles in the envista IOLs had an effective diameter of approximately 33 μm and in the Tecnis IOLs 25 μm while the sizes in the isymm IOLs and Acrysof IOLs were significantly smaller, 5.2 μm and 6.2 μm, respectively. For all cases, the standard deviation is approximately 30% of the average microvacuole diameter. The phase lag ρ was larger than 5 for all cases, and the scatter efficiency factor Q was equal to 2 for all lenses. This means that for all lenses the refracted scatter is incoherent, and that twice the intensity incident on a microvacuole was scattered. The extinction was calculated according to Eq. (1) for all IOLs and ranged from 0.02 to 0.24 mm 1 for Acrysof lenses. For the envista IOLs γ ranged from 0.00 to 0.01 mm 1, for the isymm IOLs γ ranged from 0.18 to 0.25 mm 1, and for the Tecnis lenses γ ranged from 0.01 to 0.04 mm Light scatter measurements Figure 4 displays all light scatter measurement results after microvacuole induction and are labeled with the corresponding measured extinctions that can be found in the legend. The scatter measurements at three degrees showed a higher than expected outcome because of the large angular width (1.2 degrees) of the camera aperture [20] relative to the measurement angle. In that study [20] the measurement result performed on one lens without any glistenings on both setups agreed well. In Fig. 4 the measurement results of both methods are displayed for different lenses with different levels of glistenings, and the results of both methods agree well with theory as shown in Fig. 5 and will be described later. For the lenses which have low extinctions the results between the two methods deviate due to very low signal levels, but are well below the level of a 20 yr old crystalline lens. In general, it is found that when γ is smaller than 0.08 mm 1, the light scatter is less than that of a 20 yr old crystalline lens, and when γ is larger than approximately 0.25 mm 1, the light scatter is more than that of a 70 yr old crystalline lens. For extinctions between 0.08 mm 1 and 0.25 mm 1, the light scatter level is between that of a 20 yr old and 70 yr old crystalline lens. Two scatter functions s(θ, γ = 0.11) and s(θ, γ = 0.24) calculated using MIEplot for microvacuoles with an average diameter of 6 μm and a standard deviation of 2 μm are displayed in Fig. 5. The stray light function shows two peaks, one at two degrees and a broader peak at 15 degrees. These calculations compare well to the optical scatter levels induced, obtained from the subtraction of measurements results after and before microvacuole induction. Chapter 8 105

106 Chapter 8 Fig. 4. Scatter level as a function of visual angle compared to a 20 yr and a 70 yr old healthy crystalline lens. The numbers in the legend denote extinction and symbols in the graph denote the IOL type ( Acrysof, envista, and isymm, Tecnis). The low angle measurements are represented with symbols; the actual measurements have much higher resolution. Chapter 8 Fig. 5. Induced light scatter of two small-angle (solid black line γ = 0.11 mm 1 and solid redline γ = 0.18 mm 1 ) and two large-angle measurements (symbols: γ = 0.12 mm 1 and γ = 0.24 mm 1 ) compared to two outcomes using MIEPlot program for γ = 0.11 and 0.24 mm 1 (dashed). The lower scatter angle measurements show lower peaks and narrower widths than the calculations. It is important to take note of the fact that the results are displayed on a loglog scale and the difference in width is within 1 degree, and the peak difference is approximately 1 deg 2 /sr. The measured red curve had an extinction of 0.18 mm 1, and the 106

107 Effect of glisterings in intraocular lenses peak is as expected in between the calculated values of 0.11 mm 1 and 0.24 mm 1. The decomposed scatter intensity outcomes of the MIEplot program compare well with MIEtheory formulated in Eq. (5). The peak at two degrees is caused by diffraction and the peak at 15 degrees by refraction of light traversing the microvacuoles Simulated visual effect In Fig. 6, an Acrysof IOL is shown viewed with slit illumination at 45 degrees in the forward and backward direction, and both images were scaled to the same intensity level. The calculated intensity ratio between forward and backward scatter for this angle is 390. For all lenses with microvacuoles, light intensity transmission is calculated using Beer s law shown in Fig. 7. The envista IOL transmitted 100%, the four Tecnis IOLs at least 98%, the two isymm IOLs transmitted approximately 90%, and the Acrysof IOLs show a variable performance level between 89% and 99%. This can be seen as the percentage of light remaining for image formation. Fig. 6. Backward (left) and Forward (right) scatter for Acrysof lens at 45 degrees [17]. Chapter 8 Fig. 7. Light transmission (%) left for image formation. 107

108 Chapter 8 The results of the luminance contrast calculations are shown in Fig. 8 for each set of lighting conditions presented in Table 1. In each case, the contrast decreases with increasing level of extinction. For an extinction of 0.15 mm 1, the contrast dropped 19%, 17% and 15% respectively for case 1, 2 and 3 compared to an IOL with no microvacuoles. For case 3, the background luminance is very small compared to the target luminance and the contrast is determined by L t /L v. In this case, the contrast reduction can be determined directly from the light intensity transmission graph (Fig. 7). When γ = 0.15 mm 1, the intensity transmittance for image formation is 92.5%. Correspondingly, the light scattered is 7.5%, which is half of the percentage of the contrast reduction. Fig. 8. Luminance contrast as a function of extinction for three common daily tasks. Labels refer to the lighting conditions defined in Table 1. Chapter 8 108

109 Effect of glisterings in intraocular lenses 4. Discussion Several recent studies, based on large numbers of patients implanted with Acrysof IOLs ( 100 patients or more) conclude that moderate to severe/dense glistenings occur in 60-87% of patients implanted with these lenses [4,5,9,13,24]. The glistenings formation, as well as the severity of glistenings, has been correlated with longer follow-up times [3,7,10,24 26]. Very few studies that evaluate the progression beyond one year find glistening formation to be stable [5,6]. Temperature fluctuations in the eye are mentioned as one of the factors for this progression. In vitro we also observed an increase in glistening formation when cyclical temperature changes were induced. The extinction values for two Acrysof IOLs progressed from 0.08 mm 1 and 0.12 mm 1 to 0.29 mm 1 when the procedure for microvacuole induction was repeated two times. Following cyclical temperature changes induced stray light values above that of the healthy 70 year old crystalline lens. The Tecnis IOLs made of the acrylic Sensar material were not associated with glistenings except for only one in vitro study that found minimal non-significant glistenings [27]. The envista IOLs claim to be glistenings-free. The qualifications, nonsignificant glistenings and glistenings-free are arbitrary and our study enables us to define and grade glistenings in a functional and quantitative way. We define a lens with significant glistenings to be a lens that has microvacuoles such that it causes stray light levels to be raised above those of a healthy 20 year old crystalline lens. This level of stray light is further specified as γ 0.08 mm 1, which corresponds to 4% light scatter of the incident light beam. According to this definition, all three isymm IOLs and four of the five Acrysof IOLs were associated with significant glistenings (Fig. 7) and correspondingly with a light transmittance that is less than 96%. Although, no studies have been published in English language literature, for the isymm IOLs, our in vitro method of microvacuole formation shows similar trends to what is found in published in vivo studies. We acknowledge that our investigational technique is not necessarily an exact simulation of how all investigated IOLs will respond in vivo. Microvacuole induction in IOLs is a dynamic process and the applied time constraints for measurements were necessary to investigate the relationship between the determined extinctions and measured light scatter levels. A controlled waiting period was used directly after the lens had been removed from the oven (eye temperature) to allow for the condensation formation to disappear. During induction, it was observed that the microvacuoles originate from the center of the lens and spread out towards the periphery of the lens optic. When the lens is in a constant temperature environment for more than a day, all microvacuoles disappear. The material close to the edges and lens surfaces is free from the microvacuoles that are denser close to the visual axis (Fig. 9). Chapter 8 109

110 Chapter 8 Fig. 9. Dark field images Acrysof lens 10X (left) and 40X (right). Chapter 8 Microvacuoles are thought to be caused by a combination of material and manufacturing process related factors. Reports from Japan discuss surface light scatter and nanoglistenings present at the surface of the Acrysof IOL [28 33]. This surface phenomenon is not incorporated in the analysis performed in the present study. We focused on the glistenings in the bulk of the IOL and their impact on vision. Additional stray light and dark field microscopy measurements were performed on five Acrysof lenses intended for the Japanese market. For these lenses it was claimed that glistenings were reduced following improvements in the manufacturing process. These IOLs had stray light values of approximately 7 deg 2 /sr at two degrees, results that are typical for extinction values between 0.11 mm 1 and 0.18 mm 1 such as are shown in Fig. 3. Dark field microscopy images for two magnifications are shown in Fig. 9 for one lens. The determination of the extinction of an IOL with microvacuoles elucidates the basic principles of the scatter process. The calculated scatter efficiency factor of two in all cases measured in this study supports the idea of the existence of two optical fields. From the measurements performed, it can be concluded that the extinction of an IOL or light attenuation from an incident beam can be compared with the age-related increase in light scatter found in the natural crystalline lens. The induced light scatter measured in the presence of the microvacuoles show two peaks determined by diffraction and refraction that are verified by Mie theory and resemble the effect of a lunar corona, i.e. a white halo and a colored band. The surgeon may underestimate the significance of the phenomenon of glistenings in an IOL slit-lamp exam because the forward scatter perceived by the patient is more than 300 fold stronger than the observed backward scatter. Glare conditions are very commonly present while executing daily tasks. Common traffic scenes involve more field of view than the standard clinical vision tests. An important aspect in quality of vision is the ability to navigate in traffic whether as a pedestrian or as a vehicle driver or cyclist. Ultimately, knowing how the incident light of a scene is focused and scattered by the cornea and lens onto the retina provides information necessary to estimate the effect of 110

111 Effect of glisterings in intraocular lenses any perturbation on vision. Currently, no single clinical or pre-clinical assessment provides this information in one measurement because the light intensity used for an arbitrary daily task varies approximately nine orders of magnitude over the total retina. In this study, we made use of two in vitro stray light methods to obtain this information. We have shown that for three common lighting conditions, glistenings reduce contrast. When a highcontrast task is performed, the reduction caused by glistenings may not be a noticeable hindrance, while for a low-contrast task the contrast loss will have a much larger impact. To quantify the visual effect of glistenings, we can simulate from the induced light transmission loss the contrast reduction for tasks where the background luminance is low compared to target luminance. Most clinical studies report that glistenings have no effect on visual acuity. This can be explained by the induced scatter function obtained as a function of visual angle as shown in Fig. 5. A visual acuity of 20/20 corresponds to less than 0.02 degrees of visual angle. For the small angles used in VA measurements, scatter plays a less significant role than for larger angles. This changes when target luminance and target contrast are low causing reduced retinal image contrast due to the lower light transmission for image formation. This conclusion is supported by studies that show a decrease in contrast sensitivity especially for higher spatial frequencies. For the higher spatial frequencies, the contrast sensitivity is lowest. Standard contrast vision tests have steps between consecutive levels of 40%. Not all studies find an effect for all spatial frequencies because in order to consistently illustrate the effect of stray light for these viewing conditions, extinction levels of at least 0.20 mm 1 are necessary. To consistently measure the clinical effect of glistenings on vision, contrast steps smaller than 40% should be used. Additionally, lowcontrast examinations with low luminance, or contrast tests where the glare source is positioned at angles close to that of the scatter function maxima, could also illustrate the effect of glistenings. In summary, the size, distribution, and density, together with the indices of refraction for microvacuoles and IOL materials contribute to the extinction coefficient γ. We have shown that glistenings can be quantified in this one parameter, the extinction coefficient, and that their impact on contrast vision can be simulated using the veiling luminance. The isymm IOLs and the majority of the Acrysof IOLs showed significant levels of glistenings. It can be concluded that IOL manufacturers should consider evaluating IOL stray light as a standard procedure in the release of new IOL models. In addition, it can be concluded that in order to ensure that glistenings do not cause a significant increase in stray light, the extinction coefficient should remain below 0.08 mm 1, that which results in a stray light level equivalent to a 20 yr old healthy crystalline lens. Chapter 8 111

112 Chapter 8 References en links Chapter 8 1. D. K. Dhaliwal, N. Mamalis, R. J. Olson, A. S. Crandall, P. Zimmerman, O. C. Alldredge, F. J. Durcan, and O. Omar, Visual significance of glistenings seen in the AcrySof intraocular lens, J. Cataract Refract. Surg. 22(4), (1996). 2. U. Gunenc, F. H. Oner, S. Tongal, and M. Ferliel, Effects on visual function of glistenings and folding marks in AcrySof intraocular lenses, J. Cataract Refract. Surg. 27(10), (2001). 3. A. Waite, N. Faulkner, and R. J. Olson, Glistenings in the single-piece, hydrophobic, acrylic intraocular lenses, Am. J. Ophthalmol. 144(1), (2007). 4. H. Minami, K. Toru, K. Hiroi, and S. Kazama, Glistening of Acrylic Intraocular Lenses, Rinsho Ganka 53(5), (1999) (Jpn. J. Clin. Ophthalmol.). 5. J. Colin and I. Orignac, Glistenings on intraocular lenses in healthy eyes: effects and associations, J. Refract. Surg. 27(12), (2011). 6. G. Christiansen, F. J. Durcan, R. J. Olson, and K. Christiansen, Glistenings in the AcrySof intraocular lens: pilot study, J. Cataract Refract. Surg. 27(5), (2001). 7. J. Colin, D. Praud, D. Touboul, and C. Schweitzer, Incidence of glistenings with the latest generation of yellowtinted hydrophobic acrylic intraocular lenses, J. Cataract Refract. Surg. 38(7), (2012). 8. K. Hayashi, A. Hirata, M. Yoshida, K. Yoshimura, and H. Hayashi, Long-term effect of surface light scattering and glistenings of intraocular lenses on visual function, Am. J. Ophthalmol. 154(2), , e2 (2012). 9. J. Colin, I. Orignac, and D. Touboul, Glistenings in a large series of hydrophobic acrylic intraocular lenses, J. Cataract Refract. Surg. 35(12), (2009). 10. J. Moreno-Montañés, A. Alvarez, R. Rodríguez-Conde, and A. Fernández-Hortelano, Clinical factors related to the frequency and intensity of glistenings in AcrySof intraocular lenses, J. Cataract Refract. Surg. 29(10), (2003). 11. E. Wilkins and R. J. Olson, Glistenings with long-term follow-up of the Surgidev B20/20 polymethylmethacrylate intraocular lens, Am. J. Ophthalmol. 132(5), (2001). 12. L. Werner, Glistenings and surface light scattering in intraocular lenses, J. Cataract Refract. Surg. 36(8), (2010). 13. E. Mönestam and A. Behndig, Impact on visual function from light scattering and glistenings in intraocular lenses, a long-term study, Acta Ophthalmol. (Copenh.) 89(8), (2011). 14. D. H. Kim, R. H. James, R. J. Landry, D. Calogero, J. Anderson, and I. K. Ilev, Quantification of glistenings in intraocular lenses using a ballistic-photon removing integrating-sphere method, Appl. Opt. 50(35), (2011). 15. T. Oshika, Y. Shiokawa, S. Amano, and K. Mitomo, Influence of glistenings on the optical quality of acrylic foldable intraocular lens, Br. J. Ophthalmol. 85(9), (2001). 16. M. Nagata, H. Matsushima, K. Mukai, W. Terauchi, T. Senoo, H. Wada, and S. Yoshida, Clinical evaluation of the transparency of hydrophobic acrylic intraocular lens optics, J. Cataract Refract. Surg. 36(12), (2010). 17. M. van der Mooren, J. Coppens, M. Bandhauer, and T. van den Berg, Light scatter characteristics of acrylic intraocular lenses, Invest. Ophthalmol. Vis. Sci. 48, E-abstract 3126 (2007). 18. L. Cowley, P. Laven, and M. Vollmer, Rings around the sun and moon: coronae and diffraction, Phys. Educ. 40(1), (2005). 19. H.C. van de Hulst, Light Scattering by Small Particles (Dover Publications Inc., 1981), pp. 129, 176,

113 Effect of glisterings in intraocular lenses 20. M. van der Mooren, T. van den Berg, J. Coppens, and P. Piers, Combining in vitro test methods for measuring light scatter in intraocular lenses, Biomed. Opt. Express 2(3), (2011). 21. P. Laven, MiePlot: A computer program for scattering of light from a sphere using Mie theory & the Debye series, accessed January L. L. Holladay, The fundamentals of glare and visibility, J. Opt. Soc. Am. 12(4), (1926). 23. T. J. Van Den Berg, L. J. Van Rijn, R. Michael, C. Heine, T. Coeckelbergh, C. Nischler, H. Wilhelm, G. Grabner, M. Emesz, R. I. Barraquer, J. E. Coppens, and L. Franssen, Straylight effects with aging and lens extraction, Am. J. Ophthalmol. 144(3), , 363.e1 (2007). 24. E. Peetermans and R. Hennekes, Long-term results of wagon wheel packed acrylic intraocular lenses (AcrySof), Bull. Soc. Belge Ophtalmol. 271, (1999). 25. D. Tognetto, L. Toto, G. Sanguinetti, and G. Ravalico, Glistenings in foldable intraocular lenses, J. Cataract Refract. Surg. 28(7), (2002). 26. S. Yoshida, H. Matsushima, M. Nagata, T. Senoo, I. Ota, and K. Miyake, Decreased visual function due to highlevel light scattering in a hydrophobic acrylic intraocular lens, Jpn. J. Ophthalmol. 55(1), (2011). 27. N. Z. Gregori, T. S. Spencer, N. Mamalis, and R. J. Olson, In vitro comparison of glistening formation among hydrophobic acrylic intraocular lenses, J. Cataract Refract. Surg. 28(7), (2002). 28. H. Nishihara, S. Yaguchi, T. Onishi, M. Chida, and M. Ayaki, Surface scattering in implanted hydrophobic intraocular lenses, J. Cataract Refract. Surg. 29(7), (2003). 29. H. Nishihara, M. Ayaki, T. Watanabe, T. Ohnishi, T. Kageyama, and S. Yaguchi, Comparison of surface light scattering of acrylic intraocular lenses made by lathe-cutting and castmolding methods long-term observation and experimental study, Nippon Ganka Gakkai Zasshi 108(3), (2004) (article in Japanese). 30. S. Yaguchi, H. Nishihara, W. Kambhiranond, D. Stanley, and D. J. Apple, Light scatter on the surface of AcrySof intraocular lenses: part I. Analysis of lenses retrieved from pseudophakic postmortem human eyes, Ophthalmic Surg. Lasers Imaging 39(3), (2008). 31. K. Miyata, S. Otani, R. Nejima, T. Miyai, T. Samejima, M. Honbo, K. Minami, and S. Amano, Comparison of postoperative surface light scattering of different intraocular lenses, Br. J. Ophthalmol. 93(5), (2009). 32. H. Matsushima, K. Mukai, M. Nagata, N. Gotoh, E. Matsui, and T. Senoo, Analysis of surface whitening of extracted hydrophobic acrylic intraocular lenses, J. Cataract Refract. Surg. 35(11), (2009). 33. K. Miyata, M. Honbo, S. Otani, R. Nejima, and K. Minami, Effect on visual acuity of increased surface light scattering in intraocular lenses, J. Cataract Refract. Surg. 38(2), (2012). Chapter 8 113

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115 Chapter 9 GENERAL DISCUSSION

116 Chapter 9 The objectives of this study were (1) to determine the impact of stray light on visual performance, (2) to evaluate a new technique that aims to quantify stray light, and (3) to determine the contributions of intraocular lenses to retinal stray light. Stray light levels induced by intraocular lenses are design and material dependent [1, chapter 7] and may increase in the presence of micro-vacuoles in the optic body of an intraocular lens [2, chapter 8]. Retinal stray light caused by micro-vacuoles in intraocular lenses may affect vision as illustrated by the intraocular lens explant case studies [3, 4, chapter 2]. This was also illustrated by the degraded visual performance of five healthy subjects when comparable low amounts of retinal stray light were induced [5, chapter 5]. It can be concluded that some intraocular lenses induce retinal stray light levels that may cause serious visual symptoms. Chapter 9 The visual impact of relatively low levels of stray light is hard to quantify in clinical practice, as it does not cause a significant decrease in visual acuity. Stray light is usually assessed using slit lamp exams, looking for potential sources of stray light, that is, cloudy optical media. Direct psychophysical measurement of stray light levels is possible by using the C-quant apparatus [6]. This instrument has the limitation that the glare source is at a fixed location of seven degrees on average. If stray light is uniformly distributed over the retina such as in cataract, then the location of the glare source is not important. For nonuniformly distributed stray light such as in the presence of glistenings, the distance between stimulus and the location of the glare source should match the retinal stray light profile in order to determine the visual impact. Other measures, such as the halo size induced by a light source may help clarify the impact of retinal stray light. Earlier, the halo size was reported to be correlated with the amount of forward light scatter [7]. The Rostock Glare Perimeter was developed [8, chapter 3] to quantify the halo size under simulated, but realistic, conditions. We found that the halo size increased with age [8, chapter 3] and that pseudo-phakic subjects had a larger halo size than healthy phakic subjects [9, chapter 4]. The method also showed that the halo size was reduced when binocular test conditions were used [8, chapter 3] and that patients with a monofocal IOL had a smaller halo size than patients with a multifocal IOL [9, chapter 4]. All these findings suggest that the Rostock Glare Perimeter method is a helpful device to quantify symptoms of retinal stray light. However, before regular clinical use of the Rostock Glare Perimeter is feasible, the psychophysical measurement procedure needs to be changed from a method of adjustment to a forced choice method. Also, it would be interesting to investigate if there are differences in retinal stray light effects using the Rostock Glare Perimeter among the various newly introduced multifocal lenses. Even if they are similar in distance power, optical design principle and material, they may differ largely in terms of induced stray light because of chosen reading power and specific implemented diffractive or refractive technology. 116

117 General Discussion In addition, when using the Rostock Glare Perimeter one can change the background luminance glare source strength and target size to simulate different conditions. For instance, a luminance detection threshold test was developed making use of the same device [5, chapter 5]. The luminance threshold test is a detection task intended to capture the impact of stray light in low light environments, with low light levels both for glare source and stimuli. Degraded performance on this type of task could be a risk factor for, e.g., safe night driving. Relationships were found for increases in retinal stray light with visual performance measures: halo size, luminance detection threshold, and contrast sensitivity [5, chapter 5]. The luminance threshold test was the most sensitive visual performance test: it showed a 20 fold increase for a moderate cataract case. Hence, a luminance threshold test might be helpful in the case of an inconclusive slit lamp exam of the crystalline lens, to decide if cataract surgery should be offered to the patient or not. It may also be a diagnostic tool in cases where micro-vacuoles in intraocular lenses are suspected to be a source of visual complaints. Another visual test that can be used to study the impact of retinal stray light on visual performance is contrast sensitivity testing. The quick contrast sensitivity test [10] was able to detect differences in contrast sensitivity more easily than traditional contrast sensitivity tests because of a higher resolution in contrast levels and spatial frequency levels as well as shorter test duration. In chapter 6 two complementary in-vitro quantitative methods [11, chapter 6] were developed that allowed us to show that stray light levels in intraocular lenses are designand material dependent [1, 2, chapters 7 and 8]. Stray light induced by intraocular lenses may exceed stray light levels of a healthy 20 year old human crystalline lens and may even reach levels of a 70 year old human crystalline lens. Because of these adverse effects, the retinal stray light potential of intraocular lenses should be a product specification for lens manufacturers and the limit may be determined based on future studies addressing tolerance to retinal stray light. A first proposed limit for induced stray light is to be below the level of a healthy 20 year old crystalline lens [2, chapter 8]. In-vitro light scatter measurements in intraocular lenses are also useful because they allow for the assessment of stray light levels separately from sources of stray light that inevitably occur in-vivo such as that from the cornea, the vitreous body, and the retina. Furthermore, forward scatter and backward scatter of light can be determined in-vitro in one setup and both scatter directions can be compared. If there is a difference in forward and backward scatter levels, this may then serve as an explanation for differences found in clinical observations like in slit lamp exams which are dominated by backward scatter versus patients perceptions which depend on forward scatter. In one study, pseudo-phakic subjects were found to have an average stray light level comparable to that of a healthy 70 yr old eye [12] while based on the stray light levels of IOLs, a stray light level comparable to that of a young eye was expected. It would be worthwhile to study the origin of this unexpected result. Potential sources of the high Chapter 9 117

118 Chapter 9 stray light levels could be the lens capsule and after-cataract (PCO) [13, 14, 15]. A study comparing the in-vitro and in-vivo stray light levels for one intraocular lens type may help to explain these results using the developed in-vivo and in-vitro technology described this study. To better understand the visual complaints of the two patients described in chapter 2 for which the intraocular lenses were exchanged, the developed knowledge was used to relate the effect of the measured stray light levels in the explanted lenses to the visual performance measures. The elevated stray light levels measured in-vitro corresponded to significant increases in halo size and luminance detection thresholds, and a significant decrease in contrast sensitivity [16]. Although these outcomes are retrospective in nature, it may help clinicians to understand visual complaints resulting from low amounts of retinal stray light. Peripheral vision and motion detection capacities are used for navigation purposes and studies of the effect of stray light on the peripheral retina may show an effect on the execution of these tasks. This is even more relevant for patients with advanced age related macular degeneration because they rely on their peripheral vision. Continued improvement in technologies and knowledge of the effects of retinal stray light holds promise for the future. This leads to more advanced assessment of the quality of vision before and after refractive and cataract surgery, which may lead to improved diagnostic procedures, refractive correction procedures and optical designs of intraocular lenses. Chapter 9 In my opinion, improvements in diagnostic procedures should be addressed first in order to make advancements in the total field of refractive and cataract surgery. The availability of a single instrument that is able to measure the light intensity distribution over the entire functional retina resulting from a point source in object space, will enable an objective assessment of many important aspects of vision. The central part of this light intensity distribution (the point spread function) describes the eye s wavefront aberrations that determine visual acuity and contrast sensitivity, and its skirt describes the level of retinal stray light [chapter 6]. The intermediate part of the intensity profile is another interesting topic to investigate, i.e., the potential interaction between the wavefront aberrations and retinal stray light [17]. The availability of such a single diagnostic test may be an additional screening tool in addition to the traditional letter chart in cataract and refractive procedures, and visual complaints. In a wider context, such a comprehensive test may substantially contribute to healthy aging, and reduce the burden on the health care system when it can determine whether it is advisable to extend driver s licenses in the aging population or play a role in screening in professions where vision is relevant for safety. 118

119 General Discussion References 1. Langeslag MJM, van der Mooren M, Beiko GHH, Piers PA. Impact of intraocular lens material and design on light scatter: In vitro study J Cataract Refract Surg 2014;40: van der Mooren M, Franssen L, Piers P. Effects of glistenings in intraocular lenses. Biomed Opt Express 2013; 4: van der Mooren M, Steinert R, Tyson F, et al. Explanted multifocal intraocular lenses. J Cataract Refract Surg 2015; 41: Dai Y, Huang Y, Liu T, et al Laboratory analyses of two explanted hydrophobic acrylic intraocular lenses. Indian J Ophthalmol 2014; 62: van der Mooren M, Rosén R, Franssen L, Lundström L Piers P Degradation of visual performance with increasing levels of retinal stray light To be submitted to BJO or AJO. (partly presented ESCRS 2014) 6. Franssen L, Coppens JE, van den Berg TJ. Compensation comparison method for assessment of retinal straylight. Invest Ophthalmol Vis Sci 2006; 47:768Y Puell MC, Perez-Carrasco MJ, Palomo-Alvarez C, et al. Relationship between halo size and forward light scatter. Br J Ophthalmol 2014; 98: Meikies D, van der Mooren M, Terwee T, Guthoff RF, Stachs O. Rostock Glare Perimeter: A distinctive method for Quantification of Glare. Optometry and Vision Science 2013; 90: Meikies D, van der Mooren M, Guthoff RF, Stachs O. Comparison of Dysphotopsia Effects in Phakic and Pseudophakic Eyes using Rostock Glare Perimeter. Klin Monatsbl Augenheilkd 2013;230: Lesmes LA, Lu ZL,Baek J, et al.bayesian adaptive estimation of the contrast sensitivity function: the quick CSF method. J Vision 2010;10: van der Mooren M, van den Berg T, Coppens J, Piers P. Combining in vitro test methods for measuring light scatter in intraocular lenses. Biomed Opt Express 2011; 2: van den Berg TJTP, van Rijn LJ, Michael R, Heine C, Coeckelbergh T, Nischler C, Wilhelm H, Grabner G, Emesz M, Barraquer RI, Coppens JE, Franssen L. Straylight effects with aging and lens extraction. Am J Ophthalmol 2007;144: van Bree MC, van der Meulen IJE, Franssen L, Coppens JE, Reus NJ, Zijlmans BLM, van den Berg TJTP Imaging of Forward Light-Scatter by Opacified Posterior Capsules Isolated from Pseudophakic Donor Eyes Investigative Ophthalmology & Visual Science, July 2011, Vol. 52, No van Bree MC, van der Meulen IJE, Franssen L, Coppens JE, Zijlmans BLM, van den Berg TJTP In-vitro recording of forward light-scatter by human lens capsules and different types of posterior capsule opacification Experimental Eye Research 2012; 96, Rozema JJ, Coeckelbergh T, Caals M, Bila M, Tassignon MJ. Retinal straylight before and after implantation of the Bag in the Lens IOL. Invest Ophthalmol Vis Sci Jan 14;54(1): Van der Mooren, M., Steinert, R. F., Tyson, F., Rosen, R., Lundstrom, L., & Piers, P. A. (2015). Understanding visual complaints of two intraocular lens explant cases. Investigative Ophthalmology & Visual Science, 56(7), Chapter 9 119

120 Chapter Pérez, GM, Manzanera, S, Artal, P. Impact of scattering and spherical aberration in contrast sensitivity. Journal of Vision2009, 9(3):19, Chapter 9 120

121 Summary

122 Summary Intraocular lenses are designed for vision correction following cataract removal. The intraocular lens typically replaces a cataractous natural lens that exhibits very high levels of light scattering. The amount of scattering is significantly reduced with an intraocular lens, though it is rarely quantified. Both the surface and the bulk of the intraocular lens may contribute to light scatter at some level, and in some cases affect patients postoperative quality of vision. The clinical importance of retinal stray light induced by intraocular lenses is illustrated by two cases where single-piece multifocal acrylic intraocular lenses were explanted because of complications related to the presence of glistenings in the bulk of the intraocular lens optic. Both cases support the hypothesis that glistenings may result in clinically significant visual symptoms due to stray light. The halo around a light source is a clinical manifestation of retinal stray light. The Rostock Glare Perimeter was developed in order to measure the size of the halo in the presence of a glare source. An expected significant mean positive correlation of halo radius with age was found. Smaller halo sizes in phakic subjects were found compared to pseudo-phakic subjects indicating that current intraocular lenses do not outperform a clear crystalline lens for the conditions tested. Among the pseudo-phakic subjects, the monofocal lens group had a smaller halo size than the multifocal lens group. The halo size measured in the binocular condition was significantly reduced when compared to the monocular condition. To quantify and to improve our understanding of the visual consequences of stray light, the influence of induced retinal stray light was measured via halo size, low luminance detection threshold in the presence of a glare source and contrast sensitivity with and without a glare source. Various retinal stray light levels were simulated in five healthy subjects using different photographic filters. The level of stray light induced was measured both psychophysically with a commercially available instrument and in an optical bench, and the two outcomes were found to be similar. Low levels of induced retinal stray light that can be measured with the commercially available instrument but which do not affect visual acuity can cause significant increases in halo size, result in elevated luminance detection thresholds and cause reduced contrast sensitivity with and without a glare source present. Two complementary in-vitro quantitative methods for measuring light scatter of isolated intraocular lenses were developed. The combined methods are capable of recording ten decades of light intensity variation from the focal image position out to all forward and backward scatter positions. The measured amount of light scatter could be compared to stray light levels of healthy crystalline lenses of various ages. Intraocular lenses from hydrophobic and hydrophilic acrylic materials with spherical, aspheric, and diffractive surface were tested. Irrespective of the material or design, monofocal intraocular lenses had stray light levels below or close to those of a 20-year-old human crystalline lens. 122

123 Summary Diffractive multifocal intraocular lenses had stray light levels higher than those of monofocal intraocular lenses but less than those of a 70-year-old human crystalline lens. After an initial decrease for small angles, hydrophilic intraocular lenses showed an apparent increase in stray light level for larger angles. Two of the four acrylic intraocular lens types tested, showed significant levels of glistenings causing stray light levels higher than that of a healthy 20 year old human crystalline lens. Based on these findings, it can be concluded that the stray light levels of intraocular lenses are design and material dependent and may cause moderate to severe visual symptoms. 123

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125 Samenvatting

126 Samenvatting Intraoculaire lenzen zijn ontwikkeld voor herstel van het gezichtsvermogen na een staaroperatie. De intraoculaire lens vervangt de troebele natuurlijke ooglens die lichtverstrooiing op het netvlies veroorzaakt. Verondersteld wordt dat de hoeveelheid lichtverstrooiing significant verminderd na plaatsing van een intraoculaire lens, hoewel het niveau van lichtverstrooiing zelden daadwerkelijk gemeten wordt. Zowel het oppervlak als het materiaal van de intraoculaire lens draagt bij aan de totale lichtverstrooiing en in sommige gevallen heeft dat invloed op de kwaliteit van het gezichtsvermogen van een patiënt na de staaroperatie. Het klinisch belang van strooilicht veroorzaakt door een intraoculaire lens wordt aangetoond door twee casestudies waarin multifocale intraoculaire lenzen van acryl materiaal uit het oog zijn verwijderd vanwege complicaties gerelateerd aan de aanwezigheid van glistenings in het materiaal van de intraoculaire lens. Beide casestudies ondersteunen de hypothese dat glistenings kunnen resulteren in klinisch significante visuele symptomen, veroorzaakt door strooilicht. De lichtkrans (halo) rond een lichtbron is een klinische manifestatie van strooilicht. De Rostock Glare Perimeter werd ontwikkeld om de afmeting van de halo in aanwezigheid van een lichtbron te bepalen. Zoals verwacht werd een significante gemiddelde positieve correlatie van de halo met leeftijd vastgesteld. Proefpersonen zonder intraoculaire lenzen, d.w.z. met een natuurlijke lens, hadden een kleinere halo dan proefpersonen met intraoculaire lenzen, wat aangeeft dat de huidige intraoculaire lenzen de heldere natuurlijke lens niet overtreffen, in deze testcondities. Onder de proefpersonen met intraoculaire lenzen had de monofocale groep kleinere halo s dan de multifocale groep. De met twee ogen gemeten halo was significant kleiner in vergelijking tot de met één oog gemeten halo. Om de visuele impact van strooilicht te kwantificeren en beter te begrijpen, is de invloed van geinduceerd strooilicht gemeten door middel van de afmeting van de halo, de drempelwaarde van een helderheidsdetectietest in aanwezigheid van een lichtbron en de contrastgevoeligheid met en zonder een lichtbron. Het extra strooilicht werd toegediend aan vijf gezonde proefpersonen met behulp van verschillende fotografische filters. Het extra veroorzaakte strooilichtniveau is zowel subjectief met een commercieel beschikbaar instrument als op een optische bank gemeten en de resultaten van beide methoden bleken vergelijkbaar te zijn. Lage extra strooilichtniveaus die met een commercieel beschikbaar instrument gemeten kunnen worden, maar geen impact hebben op de gezichtsscherpte, kunnen 1) een significante toename veroorzaken van de halogrootte, 2) de drempelwaarde van helderheidsdetectie verhogen en 3) contrastgevoeligheid met of zonder de aanwezigheid van een lichtbron verminderen. 126

127 Samenvatting Twee complementaire in-vitro kwalitatieve methoden zijn ontwikkeld voor het meten van lichtverstrooiing door geïsoleerde intraoculaire lenzen. De twee methoden hebben samen het vermogen om tien decaden aan lichtintensiteitsvariaties te bepalen vanaf het brandpunt tot en met alle voorwaartse en achterwaartse verstrooiingsposities. De gemeten niveaus van lichtverstrooiing kunnen vergeleken worden met de strooilichtniveaus van een gezonde natuurlijke lens van verschillende leeftijden. Lenzen van hydrofobe en hydrofiele acryl materialen met een sferisch, een a-sferisch en een diffractief oppervlak werden getest. Monofocale intraoculaire lenzen gaven strooilichtwaarden lager of waarden vergelijkbaar met die van een 20-jarige natuurlijke menselijke ooglens, onafhankelijk van het materiaal of het design. Diffractieve multifocale intraoculaire lenzen gaven strooilichtwaarden hoger dan monofocale intraoculaire lenzen, maar lager dan de waarden van een 70-jarige natuurlijke menselijke ooglens. Na een initiële toename voor kleine hoeken, lieten hydrofiele intraoculaire lenzen een duidelijke toename van strooilichtwaarden zien voor grotere hoeken. Twee van de vier geteste acryl intraoculaire lenstypes lieten glistenings zien die strooilichtniveaus veroorzaakten hoger dan die van een gezonde 20-jarige natuurlijke ooglens. Op basis van deze uitkomsten kan geconcludeerd worden dat strooilichtniveaus van intraoculaire lenzen afhankelijk zijn van design en materiaal en ernstige visuele symptomen kunnen veroorzaken. 127

128 Acknowledgement First of all I acknowledge my parents who always motivated me to study while they never had the opportunity to study after primary school. I would like to express my gratitude to my thesis supervisors Nomdo Jansonius, Anneke Hooymans and Steven Koopmans, for their gentle guidance and their dedication in helping me introducing and discussing the results and place them into perspective. Thanks to all co-authors and collaborators, it was a pleasure. Thanks to all of my colleagues world-wide who helped and inspired me from the start of my career in process and product development of intraocular lenses more than 20 years ago. This thesis has his origin the moment Patricia Piers motivated me to keep developing my career. I thank her for her support and guidance and together with Gerard Hoekstra, for offering me the possibility to follow this PhD program. Marrie, Engelbert, July

129 Curriculum Vitae

130 Curriculum Vitae Marrie van der Mooren was born 17 October 1960, and graduated in 1987 from the Technical University Twente in Applied Physics, became quartermaster in the military service and thereafter a high school science teacher. In 1989 he moved his career to research engineer at the University of Nijmegen in the field of single crystal growth and non linear optics. In 1994 he joined AMO Groningen BV (Abbott Vision) as product development engineer, where he became involved in the Baerveldt Glaucoma shunt and was technical leader and designer for several intraocular lenses including the first Tecnis and Tecnis Multifocal intraocular lens. He developed mechanical and optical test methods according to ISO guidelines. In 2005 he moved to the research department and as scientist responsible for initiating and leading research programs related to clear multifocal vision, intraocular retinal stray light and peripheral vision. He currently holds the position of Research Team Leader. 130