Yozo Miyake. Electrodiagnosis of Retinal Diseases

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2 Yozo Miyake Electrodiagnosis of Retinal Diseases

3 Yozo Miyake Electrodiagnosis of Retinal Diseases With 258 Figures, Including 93 in Color

4 Yozo Miyake Professor Emeritus, Nagoya University Head of the National Institute of Sensory Organs National Hospital Organization Tokyo Medical Center Higashigaoka, Meguro-ku, Tokyo , Japan Library of Congress Control Number: ISBN Springer-Verlag Tokyo Berlin Heidelberg New York ISBN Springer-Verlag Tokyo Berlin Heidelberg New York Printed on acid-free paper This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in other ways, and storage in data banks. The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Springer is a part of Springer Science+Business Media springeronline.com Springer-Verlag Tokyo 2006 Printed in Japan Typesetting: SNP Best-set Typesetter Ltd., Hong Kong Printing and binding: Nikkei Printing, Japan

5 Preface Soon it will be time for me to retire from my position as professor of ophthalmology in the Department of Ophthalmology, Nagoya University School of Medicine. I have therefore decided to summarize my experience of more than 30 years of studies on the clinical electrophysiology of vision. These studies were performed in our department through the hard work and good ideas of many co-workers, and the chapters of this book cover the rationale and results of our studies. Because excellent textbooks on clinical electroretinography already exist, my wish is not to write another textbook; instead, this book is in the form of essays that include my beliefs and philosophy on the clinical electrophysiology of vision. As such, this book does not include every clinical disease but only those that we have identified or studied in detail. In addition to full-field electroretinography (ERG), we developed the techniques and instrumentation to record focal macular ERG more than two decades ago. Using these techniques, we were able to determine several new physiological properties of the normal macula, many new pathophysiological mechanisms of known diseases, and some new clinical entities with unique functional properties. Fortunately, the recent advances of macular surgery and imaging are such that the macular configuration can easily be determined. During the process of surgery, we have obtained considerable information on the correlation of macular function and macular morphology using focal macular ERGs and optical coherence tomography (OCT). The development of multifocal ERGs followed our focal macular ERGs, and this technique has allowed the objective examination of macular function throughout the world. There has been no similar occasion in the past where the advancement of technology has allowed us to discover such correlations and, more importantly, to determine the mechanisms for many retinal diseases. As one who has dedicated his life to this area, I hope that this book will inspire young researchers and clinicians to enjoy the pleasure and fulfillment that can come from studying the retina. Most importantly, there are many more challenges that have to be taken on and conquered. Yozo Miyake Nagoya March 2005

6 Acknowledgments There are many people who have helped make this book a reality; however, some merit special attention. Dr. Hiroko Terasaki has contributed very much with her skills in the new surgical procedures and in psychophysical measurements in normal subjects and patients with retinal diseases who underwent retinal surgery. Dr. Mineo Kondo has always been with me to analyze the clinical data and to perform the animal experiments during the past 10 years. Dr. Masayuki Horiguchi worked with me for a long time before he moved to Fujita Health University as chairman and professor of the Department of Ophthalmology. He had many unique ideas and contributed greatly to our studies. Dr. Yoshihiro Hotta opened a new field of molecular genetics in our department and Dr. Makoto Nakamura has provided important molecular genetic data of our patients. It would not have been possible to complete this book without the invaluable contribution of these investigators. Special thanks go to Dr.Tatsuo Hirose of Boston,who was a great inspiration to me and who also pointed out the importance of focal macular ERGs when I was a young investigator. I learned basic retinal electrophysiology from Dr. Genyo Mitarai in Nagoya, and he has been an important teacher in my life. Finally, I would like to express my sincere gratitude to Dr. Duco Hamasaki of Miami, my close friend, for his kind revision and many valuable suggestions regarding the English content of this book. During the past 10 years, he has made an enormous contribution to Japanese ophthalmology by revising many manuscripts written by Japanese investigators that eventually were published in English journals. On behalf of the Japanese Society of Ophthalmology, I would like to thank him again. Yozo Miyake

7 Contents Preface V Acknowledgments VII 1 Principles and Methods Full-Field Electroretinograms Focal Macular ERGs Multifocal ERGs Electrooculography Optical Coherence Tomography 42 2 Hereditary Retinal and Allied Diseases Retinitis Pigmentosa Crystalline Retinopathy (Bietti) Batten Disease Kearns-Sayre Syndrome Choroideremia Gyrate Atrophy Enhanced S-Cone Syndrome X-Linked Retinoschisis Nettleship-Falls X-Linked Ocular Albinism Complete and Incomplete Types of CSNB Fundus Albipunctatus Oguchi s Disease Cone Dystrophy Rod Monochromacy 136

8 X Contents 2.15 Blue Cone Monochromacy Congenital Tritanopia Differential Diagnosis of Dominantly Inherited Juvenile Optic Atrophy Rod Cone Dysfunction Syndrome with an Unusual Form of ERG Association of Negative ERG with Diseases of Unknown Etiology Occult Macular Dystrophy Stargardt s Disease (Fundus flavimaculatus) Best s Disease Acquired Retinal Diseases Diabetic Retinopathy Retinal Circulatory Disturbances Retinal and Choroidal Detachment Inflammatory Diseases of Retina and Choroid Acquired Macular Diseases Central Serous Chorioretinopathy Aphakic or Pseudophakic Cystoid Macular Edema Idiopathic Epimacular Membranes Foveal Thickness and Focal Macular ERG Idiopathic Macular Hole Macular Pseudohole Age-Related Macular Degeneration 223 Subject Index 233

9 Principles and Methods1 The purpose of this chapter is to present the principles and techniques used to perform clinical electroretinography electroretinograms (ERGs) and electrooculograms (EOGs) and to show how they are incorporated into the examination of patients. Some special properties and the origin of ERG responses are shown for normal subjects to demonstrate the appearance and properties of normal ERGs. These observations should provide a foundation for the better understanding of abnormal ERGs in the analysis of clinical cases.

10 2 1 Principles and Methods 1.1 Full-Field Electroretinograms The development and advancement of clinical electroretinography (ERG) were the consequence of a better understanding of the cellular origins of the major components of the ERG initially demonstrated by Granit in 1934 [1]; the progressive improvement of the recording devices, as shown by introduction of the contact lens electrode by several investigators such as Riggs [2], Karpe [3], and Burian and Allen [4]; and the development of computers for improving the signal-to-noise ratio by averaging techniques. Many Japanese investigators have contributed significantly to full-field clinical ERG. Among the representative studies are the method for distinguishing cone from rod responses pioneered by Motokawa and Mita [5], the study of human oscillatory potentials (OPs) by Yonemura et al. [6], and the study of photopic ERG by Nagata [7]. In 1968 when I became an ophthalmologist, I thought that the major works on clinical ERG had already been done. However, looking back on the past 37 years, it is now realized that many advances in clinical ERG have taken place since then that have contributed greatly not only to the electrophysiology of the eye but to the understanding of many ophthalmological diseases. The human ERG recorded at the cornea and elicited by a full-field stimulus is a mass response generated by cells across the entire retina. To obtain reproducible amplitudes and implicit times in the responses, the stimulus and background light should be homogeneous and cover the entire retina, so all of the receptors are stimulated or adapted in a relatively homogeneous manner [8, 9]. The full-field, or Ganzfeld, stimulator represents such a stimulus. It is composed of a large-diameter (40 cm) hemispheric dome (Fig. 1.1), with a xenon stroboscopic light bulb placed at the top of the dome.this configuration allows presentation of diffuse and homogeneous stimuli and background illumination to the entire retina. This stimulus system has been recommended by the International Society of Clinical Electrophysiology for Vision (ISCEV) Standards Committee for use when obtaining clinical ERG recordings [10], and the ISCEV protocol is now being used internationally. The establishment of standardized recording conditions for full-field ERGs was an important accomplishment for the ISCEV because it allowed us to make reasonable comparisons of the ERGs recorded in any country throughout the world that record ERGs using ISCEV standards. Fig Ganzfeld (full-field) dome for full-field electroretinography (ERG) recordings

11 1.1 Full-Field Electroretinograms Intensity Response Function and ERG Components The full-field ERGs elicited by increasing stimulus intensities recorded from a normal subject after 1h of dark adaptation are shown in Fig The ERGs elicited by relatively weak stimulus intensities are shown at the left in Fig. 1.2, and the ERGs elicited by stronger stimulus intensities are shown at the right. The calibrations for the amplitude and time are different for the weak and strong ERGs. The maximum stimulus luminance (0 log unit) was 44.2 cd/m 2 s -1. At the left, the scotopic threshold response (STR) [11], a cornea-negative wave, is first recorded at -8.2 log units, approximately 0.6 unit higher than the psychophysical threshold. The maximum amplitude of the STR is 24 mv before it is masked by the developing b-wave. The implicit time of the STR near threshold is approximately 162 ms, and the implicit time decreases as the stimulus intensity increases. The STR originates from retinal neurons that are postsynaptic to the photoreceptors [11]. With some types of congenital stationary night blindness, the STR has unique properties [12] (see Section ) The b-wave is first seen at an intensity of -5.8 log units; the amplitude increases and the implicit time shortens as the stimulus intensity increases. The amplitude of the b-wave essentially saturates at -3.4log units; and at intensities higher than -0.8log unit, the oscillatory potentials (OPs) become clearly visible on the ascending limb of the b-wave. The a-wave is first seen at -1.7log units and increases progressively as the stimulus intensity increases. Many studies have shown that the a-wave of the full-field ERGs recorded in the dark is the leading edge of the photoreceptor potential [13]. The b-wave originates indirectly from bipolar and Mueller cells in the middle layers of the retina [14]. The OPs are seen as a series of three or four rhythmic wavelets having almost equal amplitude with an interpeak interval of about 6.5ms in humans [15]. The best experimental evidence indicates that the OPs reflect the activity of feedback synaptic circuits within the retina and represent an inhibitory or modulating effect of amacrine cells on the b-wave [16, 17]. Fig ERG intensity response series recorded from a normal subject exposed to a flash of relatively low intensity (left) and relatively high intensity (right). Note that the calibration differs for the ERGs in the two columns. Arrows indicate the stimulus onset. STR, scotopic threshold response; bs, scotopic b-wave. (From Miyake et al. [12], with permission)

12 4 1 Principles and Methods Standardized ERGs with Isolation of Rod and Cone Components Although the rods outnumber the cones 13 to 1 in the normal human retina, the cone system accounts for 20% 25% of the ERG response amplitude. For purposes of diagnosis, it often becomes necessary for the examiner to evaluate rod and cone activity separately. The full-field ERGs recorded in our clinic from a normal subject are shown in Fig After 30 min of dark adaptation, a rod (scotopic) ERG is recorded with a dim flash of light at approximately -3.9log units (Fig. 1.2). A mixed cone rod ERG (bright) is elicited by a single flash of white light at maximum intensity (log 0 units). A cone ERG and 30-Hz flicker ERG are recorded with a stimulus intensity of -0.8log unit, under a background illumination of 40 cd/m 2, which is sufficient to suppress all rod activity. The photopic recordings were made after 10min of light adaptation to 40cd/m 2.As shown later, the maximum photopic ERG can be obtained when recorded after light adaptation because the amplitude of the photopic ERG increases significantly after light adaptation [18] (see Section ). Our recording conditions are in accordance with the standards proposed by ISCEV [10] except that we use a higher intensity for the mixed rod cone ERGs. We have done this because the higher stimulus intensities show the OPs much clearer, and the negative configuration of the ERG can be detected more convincingly [19]. Fig Standard full-field ERGs with isolation of the rod and cone components

13 1.1 Full-Field Electroretinograms ERGs Elicited by Light-Emitting Diodes Light-emitting diodes (LEDs) are valuable as light sources to elicit full-field ERGs [20, 21]. The LEDs are small and inexpensive, and they require low currents to drive them. They can be controlled by simple electronic circuits to give either a continuous light output or extremely brief flashes over a large range of intensities. In addition, LEDs are available that emit different wavelengths and have different optical properties. A new contact lens electrode with built-in high-intensity white LEDs was recently constructed [22]. We use this system on special patients to test specific properties of the ERGs [22] Structure of LED Contact Lens Electrode The relative spectral emission of the white LEDs used in the contact lens electrode is shown in Fig These LEDs have a relatively broad, asymmetrical spectral bandwidth with two peaks, at approximately 430 and 540 nm, respectively (Fig. 1.4A). The output appears visibly white (Fig. 1.4B), and three of these white LEDs are incorporated into a standard contact lens electrode (Fig. 4.1C). The LEDs serve as the source of the stimulus and for background illumination. The stimulus light and background illumination pass through a diffuser lens and become a broad, homogeneous light that stimulates the entire retina, similar to a Ganzfeld stimulus. The intensity, frequency, and duration of the stimulus LEDs and the background LED are controlled by electrical currents obtained from a waveform generator that drive the LEDs. Fig Structure of the white light-emitting diode (LED) contact lens electrode. A Relative spectral emission of the LED. B Output that appears visible white. C Structure of the contact lens electrode with three built-in white LEDs. PMMA, polymethylmethacrylate. (From Kondo et al. [22], with permission)

14 6 1 Principles and Methods Standardized ERGs Electroretinograms can be recorded with LED contact lens electrodes that comply with ISCEV standards. ERGs recorded from a normal adult are shown in Fig. 1.5, left. All of these ERGs are similar to those elicited by conventional xenon discharge lamps in a Ganzfeld dome. This technique is useful for recording standardized ERGs from pediatric patients under general anesthesia, as shown in Fig The equipment needed to obtain recordings that correspond to the ISCEV standard ERGs is compact and easily portable. The ERGs recorded from a 3-monthold baby under general anesthesia using this system are shown in Fig. 1.5, right. Fig Full-field ERGs recorded with white LED contact lens electrode from a normal adult subject (left) and a normal 3-month-old baby (right) Fig Standard full-field ERG recording from a baby using this system. Top: LED contact lenses are placed in both eyes under general anesthesia. Bottom: Background illumination from the contact lens is used during the recording of the photopic ERGs under the dark

15 1.1 Full-Field Electroretinograms Monitoring ERGs During Vitreoretinal Surgery As vitreoretinal surgical techniques continue to advance, close monitoring of retinal function during these procedures has become important. Although ERGs directly reflect retinal function, monitoring during surgery has proven difficult. Each recording must be made quickly under aseptic conditions, and the instruments and electrodes must be such that they do not interfere with the retinal surgeon. Furthermore, ERGs need to be cone-mediated because the eye undergoing surgery is intensively light-adapted. The LED-contact lens electrode has been found to be highly suitable for this purpose [23]. The LED-contact lens is easily sterilized and is used as both a stimulus source and a recording electrode for 30-Hz flicker ERGs during vitreoretinal surgery (Fig. 1.7). Each recording requires approximately 7 s. The changes in the ERGs during surgery in a patient with a shallow retinal detachment in the macular region, associated with a macular pucker, are shown in Fig The operation was performed with the patient under local anesthesia. The ERGs recorded after local anesthesia (Fig. 1.8, start), and after the introduction of the infusion needle into the vitreous cavity (Fig. 1.8, infusion) were not significantly different in regard to amplitude and peak time. However, after vitrectomy, which required 10 min, the peak time was delayed and the amplitude decreased. Additional studies have demonstrated that lowering the intravitreal temperature by applying an infusion solution kept at room temperature can alter the ERG during vitrectomy [24]. Filling the whole vitreous cavity with air after a preretinal membrane was peeled off resulted in a markedly reduced amplitude and delayed peak time. Seven days after surgery, when the air was resolved from the vitreous cavity, the ERG recovered to the preoperative amplitude and peak time. The extreme reduction of ERG amplitude following fluid air exchange or fluid silicone oil exchange in the vitreous cavity results from reduced electrical conductivity in the vitreous cavity [23, 25]. Fig LED electrode is sterilized and placed on the cornea undergoing surgery Fig Hz flicker ERGs recorded during vitrectomy in a patient with macular pucker. Start indicates the time the local anesthesia was completed and Infusion the time the infusion needle was introduced into the vitreous. (From Miyake et al. [23], with permission)

16 8 1 Principles and Methods On and Off Responses in Photopic ERGs It is well known that there are significant potential changes when a light stimulus is turned off [26]. These potential changes are called the off response, or d-wave, of the ERG. For conventional recordings, a stroboscopic flash is used to elicit the ERGs, and the off response is embedded in the on response. Because there are retinal diseases in which the on and off responses are affected differentially, it became extremely important for us to record the on and off responses separately using long-duration stimuli [27, 28]. Figure 1.9 shows a simplified schema of the rod and cone visual pathways in the mammalian retina (Fig. 1.9, left) and the long-flash photopic ERGs (Fig. 1.9, right), which were obtained by Sieving [28]. The photoreceptors transmit visual information to the bipolar cells with the rods containing only depolarizing bipolar cells (DBCs) through sign-inverting (-) synapses (on synapse). The cones contact both DBCs and hyperpolarizing bipolar cells (HBCs) through sign-inverting (-) synapses (on synapse) and sign-preserving (+) synapses (off synapse), respectively. The cone on and off bipolar cells contact, respectively, the on and off ganglion cells directly. The rod bipolar cells do not make synapses to the ganglion cells but contact on and off bipolar cells via A11 amacrine cells. The two types of synapse from the photoreceptors to the bipolar cells are selectively sensitive to different glutamate analogs [29, 30]. The sign-inverting synapse (on synapse) can be blocked by 2-amino-4-phosphonobutyric acid (APB). The sign-preserving synapse (off Fig Simplified schema showing retinal wiring of the rod and cone pathway (left) and monkey photopic ERG changes after treatment with APB (top right) and KYN (bottom right). APB, 2-amino-4-phosphonobutyric acid; PDA, cis-2,3-piperidine dicarboxylic acid; KYN, kynurenic acid; DBC, depolarizing bipolar cells; HBC, hyperpolarizing bipolar cell. (From Sieving [28])

17 1.1 Full-Field Electroretinograms 9 synapse) can be blocked by either cis-2,3- piperidine dicarboxylic acid (PDA) or kynurenic acid (KYN). Sieving demonstrated the contribution of these glutamate analogs to the DBCs and HBCs to the monkey long-flash photopic ERG [28]. As shown in Fig. 1.9 (on the right), the control ERG exhibits on responses (a-waves and b-waves) and off responses (dwave), with a negative plateau between the b- waves and d-waves. By blocking DBC activity, the photopic b-wave was suppressed and the a- wave and d-wave were enhanced. After blocking the HBCs with KYN, the a-wave and d-wave became smaller and the plateau was elevated above the baseline (Fig. 1.9, arrowheads). Based on these results, it has been proposed that the push-pull activity of the HBCs and DBCs is summated in the photopic ERGs recorded at the cornea. In summary, we have provided evidence that the a-wave of the photopic ERGs evoked by long- and short-duration flashes arises not only from the neural activity of the photoreceptors but also from hyperpolarizing bipolar cells. In addition, the b-wave and d-waves of the photopic ERGs elicited by long-duration flashes are produced by an interaction of the hyperpolarizing and depolarizing bipolar cells; and the cornea-positive peak of the short-flash ERG results from a summation of the b-wave at light onset and the d-wave at light offset [28, 31]. As already mentioned, the long-flash photopic ERG can provide important information in terms of the on and off visual pathways in retinal diseases; clinically, however, the recording procedure is not a simple one to apply. Using the LED, one can record the long-flash photopic ERG easily. The stimulus duration can be regulated by a small LED control device. The photopic ERGs elicited by stimulus durations of 3 250ms with a stimulus intensity of 250cd/m 2 and steady background illumination of 40 cd/m 2 are shown in Fig [22]. When the stimulus duration is relatively long (100 ms or longer), the d-wave (off wave) is clearly seen after the stimulus is turned off. One can see that with short-stimulus durations the on and off response components interact to produce a single positive deflection, called the b-wave. Interestingly, the d-wave plays a major role in shaping the main positive peak of the shortflash ERG. This is an important finding when we analyze the photopic short-flash ERG in patients with diseases where the b-wave is absent and the d-wave preserved, such as with complete type congenital stationary night blindness [27] (see Section ). Fig Photopic ERGs recorded with various stimulus durations from a normal subject. (From Kondo et al. [23])

18 10 1 Principles and Methods Short-Wavelength Cone ERGs Recording short-wavelength cone (S-cone) ERGs is valuable clinically because it allows us to evaluate the short wavelength S-cone system. S-cone ERGs have been recorded by stimulation with strong blue stimuli on a bright yellow background, which suppresses the middle- and long-wavelength (LM) cone systems [32 34]. The procedure is not as simple and easy as it may seem; but with the LED contact lens electrode system, an inexpensive, commercially available electrode and an ordinary slide projector are required, as shown in Fig [35]. LEDs emitting blue light (lmax, 450nm) were used in the LED built-in contact lens electrode (NLPB 500; Nichia, Tokushima, Japan). The yellow background light was provided by a yellow filter (Kodak Wratten No. 12) placed in a slide projector and projected onto the contact lens electrode. The diffuser in the contact lens produces a full-field homogeneous yellow background illumination. S-cone and LM-cone ERGs elicited by long-duration stimuli of LED are compared in Fig The amplitude is much smaller in the S-cone ERG, and the implicit time of the b-wave is longer than that of the LM-cone ERG. The components that reflect the off visual system (a-waves and d- waves) are essentially absent because, unlike the LM-cone system, the S-cone is connected mainly to the on visual system [36]. The intensity response series of S-cone ERGs recorded from a normal subject is shown in Fig The maximum response was recorded as above 3.1 log photopic trolands. Fig LED built-in contact lens electrode with blue emitting LEDs. (From Horiguchi et al. [35], with permission) Fig Comparison of LM cone (top) and S-cone (bottom) ERGs with long-duration stimuli in a normal subject. The a-wave and d-wave are essentially absent in the S-cone ERGs Fig Intensity response series for S-cone ERGs recorded from a normal subject. Maximum response was recorded above 3.1 log photopic trolands (phot td). (From Horiguchi et al. [35], with permission)

19 1.1 Full-Field Electroretinograms Unique Properties of Cone-Mediated (Photopic) ERGs There are some unique properties of the retina that are seen only in cone-mediated (photopic) ERGs. The mechanisms that account for such properties are not fully understood. However, such phenomena and our previous studies can be used to analyze the mechanisms involved in their generation Amplitude Increase During Light Adaptation After sufficient dark adaptation, the amplitude of the ERGs recorded during the course of light adaptation gradually increases to the point that the amplitude of the fully light-adapted photopic ERGs are sometimes as much as 200% of that recorded at the beginning of the lightadaptation process. This phenomenon has been reported in humans and other animals [37 41], but the mechanism for this increase is not fully understood. Several explanations have been proposed, such as a change of standing potential of the eye [38], an interaction between cones and rods [40 42], and redepolarization of the cone photoreceptors [43]. This phenomenon [44] is shown in Fig The relative amplitudes of the 30-Hz flicker ERG in 30 normal subjects as a function of time during light adaptation shows that the amplitude gradually increased during the first 5 15 min of light adaptation, and the mean of the maximum amplitude is 1.68 ± 0.60 times larger than the amplitude of the response at 1min. We found that the eye must be completely darkadapted for this phenomenon to be observed Fig Changes in 30-Hz flicker ERGs during light adaptation in a normal subject (left) and the mean (±SD) relative amplitude in 30 normal subjects during light adaptation (right). (From Miyake et al. [44], with permission)

20 12 1 Principles and Methods [41]. The 30-Hz flicker ERGs during light adaptation after 30 min of dark adaptation [DA(+)] and without dark adaptation [DA(-)] in a normal subject are shown in Fig Increased amplitude is observed only when the dark adaptation prior to the recordings is sufficiently long. The contribution of rods to this increase was clearly demonstrated in an isolated carp retina [42] (Fig. 1.16). After the carp retina was isolated from the retinal pigment epithelium (RPE) and placed in the dark for 60 min, photopic ERGs were recorded during the course of light adaptation (Fig. 1.16, left). The isolated retina was then placed in the dark again for 60 min, after which photopic ERGs were recorded again for 5 min under light-adapted conditions. In the first recording, the amplitude increased dramatically during the 5 min of light adaptation; in the second recording, the amplitude was large initially and did not increase (Fig. 1.16, right). These results demonstrated that RPE is not needed for eliciting this increase. More importantly, rhodopsin is necessary for this phenomenon because once rhodopsin is bleached in an isolated retina it cannot regenerate during dark adaptation. On the other hand, cone photopigments can regenerate even in isolated retinas. Thus, in the first recording the isolated retina had both rhodopsin and cone photopigments, resulting in the increased amplitude. In the second recordings the retina had only cone pigments, and rods cannot be activated, so the amplitude did not increase. Because we found that rods contribute to the increased amplitude of photopic ERGs during light adaptation, the rods may inhibit the cones while recording the photopic ERGs. If the Fig Changes in the relative amplitude of 30-Hz flicker ERGs during light adaptation after 30 min of dark adaptation [DA (+)] (top) and without previous dark adaptation [DA (-)] (bottom) in a normal subject. (From Miyake et al. [41])

21 1.1 Full-Field Electroretinograms 13 increased amplitude of the photopic ERG results from rod cone interactions, the horizontal cells probably play a role; and we would expect the absence of horizontal cell function to result in disappearance of this phenomenon. However, even in the isolated photoreceptor potential (P111) of carp retina [42] and an eye with a central retinal arterial occlusion in humans, where the horizontal cells are not functional [44], this increase was observed to some degree.it is possible that alterations in the temporal response characteristics of the horizontal cells operate slowly via interplexiform feedback by means of dopamine and horizontal cells coupling; and in this case, the slow increase in the flicker response would parallel the changes in the temporal adaptation of the retina. It has also been reported that in the psychophysical experiments paralleling the electrophysiological ones the subjective sensitivity did not increase; rather, it slightly decreased during the same time of the ERG increase, thereby demonstrating a difference between subjective-sensitivity and suprathreshold ERGs [38]. We assume, therefore, that although this phenomenon may ultimately have something to do with rod cone interaction, and this kind of interaction may be different from the electrophysiological or psychophysical phenomena suggested by others [38, 39, 41, 44, 45]. One of the reasons we believe that it is worthwhile to investigate this phenomenon fully is that an exaggerated increase in 30-Hz flicker ERGs was observed only in the incomplete (not the complete) type of congenital stationary night blindness [44] (see Section ). Fig Changes in photopic ERGs during light adaptation in isolated carp retina after 60 min of dark adaptation (left) and after 60 min of dark adaptation followed by recording of photopic ERGs under light adaptation (right). (From Horiguchi et al. [42])

22 14 1 Principles and Methods Photopic Hill Phenomenon The amplitude of the b-wave of the human photopic ERG elicited by short-flash increases with increasing stimulus intensities at lower intensities reaches a plateau and then decreases at higher stimulus intensities. Because a plot of the b-wave amplitude as a function of the stimulus intensity has an inverted U shape, this phenomenon has been termed the photopic hill phenomenon [45]. The photopic, short-flash ERGs elicited by increasing stimulus intensities in a normal subject are shown in Fig At the lower stimulus intensities, the amplitude of the b-wave increases with increasing stimulus intensities until it reaches a maximum at a stimulus intensity of 3.0logcd/m 2. Further increases in the stimulus intensity result in a progressive decrease in the amplitude of the b- wave. This unusual property of the human photopic b-wave was first described by Peachey et al. [45] and has been confirmed by others [46, 47]. To confirm this phenomenon and compare it to the components of the photopic ERG, we studied photopic ERGs elicited by a short flash (5 ms) and a long flash (250 ms) of 2.7 logcd/m 2 under a constant background of 40 cd/m 2 (Fig. 1.17) [47]. In the short-flash recordings, the a- wave, b-wave, and i-wave were evaluated. The amplitudes of the short-flash b-wave and i-wave showed the photopic hill, decreasing at higher stimulus intensities; the a-wave amplitude did not show the photopic hill phenomenon and continued to increase with increasing stimulus intensity up to the maximum stimulus intensity. The implicit times of the b-wave remained unchanged but then increased at higher stimulus intensities, whereas those of the a-wave decreased with increasing stimulus intensity up to the maximum stimulus intensity. In the long-flash recordings, the b-wave did not decrease but plateaued. The d-wave (off response) decreased at higher stimulus levels, as did the short-flash elicited b-wave. The implicit times of the b-wave remained unchanged until 1.9 log cd/m 2 and then increased, confirming the results of earlier studies [45, 46]. The implicit time for the d- wave increased with increasing stimulus intensities at the higher stimulus levels, as did the b-wave implicit times elicited by short-flash stimuli. At the higher stimulus intensities the amplitude of the d-wave decreased, and another slow positive component (Fig. 1.17, asterisk) appeared and increased gradually in amplitude and timing; it dominated the off response. The long-flash a-wave showed a pattern similar to that of the short-flash ERG a-wave; that is, the amplitude continued to increase and the implicit time decreased for the entire range of stimuli. Because the b-wave and the d (off)-wave interact to produce a single positive response with short flashes (see Fig. 1.10), the decrease in the b-wave amplitude at high stimulus intensities is caused by the decrease in the d-wave at the higher stimulus intensities. These observations can explain the major mechanism of the photopic hill in photopic ERGs elicited by short-flash stimuli. Our further study of this phenomenon using pharmacological agents in primate ERGs showed that the photopic hill results mainly from the reduction of the on component amplitude at higher intensities and the delay in the positive peak of the off component at higher intensities [48].

23 1.1 Full-Field Electroretinograms 15 Fig Left: Photopic short-flash ERGs elicited from a normal subject by various stimulus intensities. Stimulus duration is 5 ms and the constant background illumination is 40 cd/m 2. Right: Photopic long-flash ERGs elicited by various stimulus intensities in the same normal subject. Vertical dashed line indicates 30 ms. At the higher stimulus intensities, the amplitude of the d-wave decreases, and another slow positive component (asterisk) dominates the off response. (From Kondo et al. [47], with permission)

24 16 1 Principles and Methods Rod Cone Interactions in Full-Field ERGs Little was known about whether the interaction could be evaluated by standard full-field ERGs. We have found that rod cone interactions can be detected in the standard full-field ERG by carefully selecting suitable recording conditions.a rod cone interaction can be seen in the full-field ERGs recorded with deep red stimuli (Kodak Wratten No. 29) in a normal subject (Fig. 1.18). The upper two recordings are the responses elicited by a stimulus intensity of cd/m 2 s -1 (Fig. 1.18, stimulus A, left) and 0.1 cd/m 2 s -1 (Fig. 1.18, stimulus B, right) after 30 min of dark adaptation. As can be seen in both responses, when the full-field ERG is elicited by a deep red stimulus in the dark, the earlier photopic component (Fig. 1.18, photopic b-wave, or BP) and the later scotopic component (Fig. 1.18, scotopic b-wave, or BS) are recorded separately to give a double peak response. The BP was first reported by Motokawa and Mita in 1947, and the initial peak was called the X-wave [5]. ERGs were then recorded under six different white background illuminations (B.G.) ranging in intensity from to cd/m 2 (B.G. 0 indicates no background illumination). The changes in the cone (BP) and rod (BS) components were evaluated immediately after the onset of the B.G. illumination. Our results from 13 normal subjects indicated that the amplitude of BS decreased in accordance with the intensity of the background illumination for both stimuli. The amplitudes of BP for stimulus A increased slightly but not significantly, but those with stimulus B increased significantly at all background intensities (Fig. 1.19). In both stimuli, the amplitude of a-wave did not change significantly. These results indicate that rod cone interaction can be evaluated by standard full-field ERG technique with a proper combination of the stimulus light and background illumination.

25 1.1 Full-Field Electroretinograms 17 Fig Rod cone interactions in full-field ERGs. Full-field ERGs recorded with a relatively weak red stimulus (A) and relatively intense red stimulus (B) in the dark after 30 min of dark adaptation (top) and under white background illumination (B.G.) with changing intensities. B.G. 0 and 6 indicate no background and maximum background illumination, respectively. BP, photopic b-wave; BS, scotopic b-wave Fig Changes in the relative amplitude (% of maximum amplitude) of the scotopic b-wave (BS, top) and photopic a-wave and b-wave (BP, bottom) in 13 normal subjects recorded after stimulus A or stimulus B. Amplitude of BS gradually decreases as the intensity of the background illumination increases. The amplitude of BP significantly increases in B only when the background illumination is on

26 18 1 Principles and Methods References 1. Granit R (1933) The components of the retinal action potential in mammals and their relation to the discharge in the optic nerve. J Physiol 77: Riggs LA (1941) Continuous and reproducible records of the electrical activity of the human retina. Proc Soc Exp Biol Med 48: Karpe G (1945) The basis of clinical electroretinography. Acta Ophthalmol Suppl 24: Burian HM,Allen L (1954) A speculum contact lens electrode for electroretinography. Electroencephalogr Clin Neurophysiol 6: Motokawa K, Mita T (1942) Uber eine einfachere Untersuchungsmethode und Eigenschaften der Aktionsstrome der Netzhaut des Menschen. Tohoku J Exp Med 42: Yonemura D, Tsuzuki K, Aoki T (1962) Clinical importance of the oscillatory potential in the human ERG. Acta Ophthalmol Suppl 70: Nagata M (1962) Studies on photopic ERG of human eye. Acta Soc Ophthalmol Jpn 66: Berson EL, Gouras P, Hoff M (1969) Temporal aspects of the electroretinogram. Arch Ophthalmol 81: Gouras P (1970) Electroretinography: some basic principles. Invest Ophthalmol 9: Marmor MF, Zrenner E (1998) Standard for clinical electroretinography (1999 update). Doc Ophthalmol 97: Sieving PA, Frishman LJ, Steinberg RH (1986) Scotopic threshold response of proximal retina in cat. J Neurophysiol 56: Miyake Y, Horiguchi M, Terasaki H, Kondo M (1994) Scotopic threshold response in complete and incomplete types of congenital stationary night blindness. Invest Ophthalmol Vis Sci 35: Brown KT (1968) The electroretinogram: its components and their origin. Vision Res 8: Newman EA, Odette LL (1984) Model of electroretinogram b-wave generation: a test of the K + hypothesis. J Neurophysiol 51: Cobb WA, Morton HB (1954) A new component of the human electroretinogram. J Physiol 123: Wachtmeister L, Dowling JE (1978) The oscillatory potentials of the mudpuppy retina. Invest Ophthalmol Vis Sci 17: Yonemura D, Kawasaki K (1979) New approaches to ophthalmic electrodiagnosis by retinal oscillatory potential, drug-induced responses from retinal pigment epithelium and cone potential. Doc Ophthalmol 48: Miyake Y, Horiguchi M, Ota I, Takabayashi A (1988) Adaptational change in cone-mediated electroretinogram in human and carp. Neurosci Res Suppl 8: Miyake Y (1993) Clinical ERG recordings and data analysis: ISCEV protocol and controversial points. Folia Ophthalmol Jpn 44: Krakau CE, Nordenfelt L, Ohman R (1977) Routine ERG recording with LED light stimulus. Ophthalmologica 175: Kooijman AC, Damhof A (1980) ERG lens with built-in Ganzfeld light source of stimulation and adaptation. Invest Ophthalmol Vis Sci 19: Kondo M, Piao CH, Tanikawa A, Horiguchi M, Miyake Y (2001) A contact lens electrode built-in high intensity white light-emitting diodes. Doc Ophthalmol 102: Miyake Y, Yagasaki K, Horiguchi M (1991) Electroretinographic monitoring of retinal function during eye surgery. Arch Ophthalmol 109: Horiguchi M, Miyake Y (1991) Effect of temperature on electroretinographic readings during closed vitrectomy in human. Arch Ophthalmol 109: Miyake Y, Horiguchi M (1998) Electroretinographic alterations during vitrectomy in human eyes. Graefe Arch Clin Exp Ophthalmol 236: Cooper S, Creed RS, Granit R (1933) A note on the retinal action potential of the human eye. J Physiol 79: Miyake Y, Yagasaki K, Horiguchi M, Kawase Y (1987) On- and off-responses in photopic electroretinogram in complete and incomplete types of congenital stationary night blindness. Jpn J Ophthalmol 31: Sieving PA (1993) Photopic on- and off-pathway abnormalities in retinal dystrophies. Trans Am Ophthalmol Soc 91: Slaughter MM, Miller RF (1981) 2-amino-4-phosphonobutyric acid: a new pharmacological tool for retina research. Science 211: Slaughter MM, Miller RF (1983) Bipolar cells in the mudpuppy retina use an excitatory amino acid neurotransmitter. Nature 303: Nagata M (1962) Studies on photopic ERG of human eye. Acta Soc Ophthalmol Jpn 66: Padomos P, van Norren D, Jaspers Faijer JW (1978) Blue cone function in a family with an inherited tritan defect, tested with electroretinography and psychophysics. Invest Ophthalmol Vis Sci 17: Yokoyama M (1979) Blue sensation in eye diseases. Jpn J Clin Ophthalmol 33: Miyake Y, Yagasaki K, Ichikawa H (1985) Differential diagnosis of congenital tritanopia and dominantly inherited juvenile optic atrophy. Arch Ophthalmol 103: Horiguchi M, Miyake Y, Kondo M, Suzuki S, Tanikawa A, Koo HM (1995) Blue light-emitting diode built-in contact lens electrode can record

27 1.1 Full-Field Electroretinograms 19 human S-cone electroretinogram. Invest Ophthalmol Vis Sci 36: Kolb H, Lipets LE (1991) The anatomical basis for color vision in the vertebrate retina. In: Gouras P (ed) The perception of colour. London, Macmillan, pp Burian HM (1954) Electric responses of the human visual system. Arch Ophthalmol 51: Armington JC, Biersdorf WR (1958) Long-term light adaptation of the human electroretinogram. J Comp Physiol Psychol 51: Kawabata H (1960) Course of the potential change in the human electroretinogram during light adaptation. J Opt Soc Am 50: Hood DC (1972) Adaptational changes in the cone system of the isolated frog retina. Vis Res 12: Miyake Y, Horiguchi M, Yagasaki K (1986) Increment of the amplitude human photopic ERG during light adaptation. Acta Soc Ophthalmol Jpn 90: , Horiguchi M, Miyake Y, Takabayashi A (1988) Increment of cone ERG during light adaptation: carp retina (in vivo and in vitro). Acta Soc Ophthalmol Jpn 92: Gouras P, MacKay CJ (1989) Growth in amplitude of the human cone electroretinogram with light adaptation. Invest Ophthalmol Vis Sci 30: Miyake Y, Horiguchi M, Ota I, Shiroyama N (1987) Characteristic ERG flicker anomaly in incomplete congenital stationary night blindness. Invest Ophthalmol Vis Sci 28: Peachey NS, Alexander KR, Fishman GA, Derlacki DJ (1989) Properties of the human cone system electroretinogram during light adaptation. Appl Optics 28: Wali N, Leguire LE (1992) The photopic hill: a new phenomenon of the light adapted electroretinogram. Doc Ophthalmol 80: Kondo M, Piao CH, Tanikawa A, Horiguchi M, Terasaki H, Miyake Y (2000) Amplitude decrease of photopic ERG b-wave at higher stimulus intensities in humans. Doc Ophthalmol 44: Ueno S, Kondo M, Niwa Y, Terasaki H, Miyake Y (2004) Luminance dependence of neural components that underlies the primate photopic electroretinogram. Invest Ophthalmol Vis Sci 45:

28 20 1 Principles and Methods 1.2 Focal Macular ERGs The design and development of the instrument required for recording focal macular ERGs from normal subjects and patients with macular diseases have been major accomplishments in my life. I first took part in the study of focal macular ERGs in 1976 with Tatsuo Hirose in Boston [1] and have continued to refine the various aspects of this technique up to the present. The principle of recording a focal macular ERG includes presenting a small stimulus to the macula and recording the response from the stimulated area. Many investigators have tried to obtain reliable responses from the human macula, but the results have not been satisfactory routine clinical examinations [2 6]. To eliminate contaminating stray light responses, background illumination must be used to depress the sensitivity of the area surrounding the stimulus [7, 8]. By combining the focal stimulus with background illumination, focal responses can be recorded. It is also essential to monitor the location of the stimulus on the fundus during the recordings, particularly in eyes with a central scotoma, to be certain that only the fovea is stimulated [1, 9]. In 1981, we succeeded in building an instrument for recording focal macular ERGs [10, 11], and more than 3500 patients with various macular diseases have been examined to date [12]. The results have been informative, and valuable data have been obtained on the normal and abnormal physiology of the macular area of the retina.

29 1.2 Focal Macular ERGs The System Observation and Stimulation Systems To develop an instrument to record focal macular ERGs with the capability of monitoring the location of the stimulus on the fundus, we modified an infrared television fundus camera (Canon CR-45NM). An overall view and diagram of the system are shown in Figs and 1.21, respectively. The light for viewing the fundus (2, in Fig. 1.21) passes through an infrared filter (4) before entering the eye (11). The fundus image is reflected into the television camera (22) and is viewed on a television screen with an overall field of view of 45 (24). The light for this viewing system is obtained from a tungsten light bulb (27), and the light beam passes through a fixation plate (26) with 16 of arc fixation target. By moving the fixation plate (26), the fixation point can be moved over 25 of the central fundus. Another target, attached to the side of the fundus camera, is used for fixation by the fellow eye when a large central scotoma is present in the eye being examined. A 200-watt halogen lamp (33, in Fig. 1.21) is used as the source for the light stimulus. A rotating chopper blade (35) driven by pulses from an electronic stimulator (31) controls the frequency and duration of the light stimuli. The rise and decay time of the stimulus chopped by the shutter is 4.2 ms. The stimulus light is carried to the fundus camera by a fiberoptic cable (36). The light is made homogeneous by a diffuser (37), and the spot size is varied by adjusting the aperture (38) on a movable plate (39). By moving this plate (39), the stimulus spot can be moved over 25 of the central fundus, and its position can be monitored on the television screen. The intensity and color of the light stimulus can be changed by inserting neutral density and colored filters into the filter holder (40). Photographs of the stimulus spot on the fundus can be taken with a 35-mm camera (28) or a Polaroid camera (30). The light source for the background illumination is another tungsten lamp (50, in Fig. 1.21). The light passes through a diffuser (48) to give homogeneous background illumination. The intensity of the background illumination is controlled by neutral density filters (49), and the light is transmitted into the eye at a visual angle of 45. Additional background illumination is used for the peripheral retina outside the central 45. A plastic hemisphere, 10 cm in diameter, is attached to the top of the fundus camera (46). Miniature lamps (47) are installed on the inner wall of the hemisphere and are covered by a diffuser. The intensity of the peripheral background illumination is equalized subjectively to that obtained from the fundus camera. Thus, homogeneous background illumination of nearly the entire visual field is obtained.

30 22 1 Principles and Methods Fig Overall view of the observation and stimulation systems for focal macular ERG and visually evoked response (VER) recordings. The examiner records the ERGs while monitoring the stimulus on the fundus by the infrared television fundus camera (A). A plastic hemisphere with miniature lamps is attached to the top of the camera to obtain background illumination for the peripheral retina (B). A Burian-Allen bipolar contact lens is used to record the ERGs (C). (From Miyake et al. [10]) Fig Optical components of the observation and stimulation systems. 1, reflector; 2, observation lamp; 3, condenser lens; 4, infrared filter; 5, flash tube; 6, condenser lens; 7, mirror; 8, annulus; 9, relay lens; 10, relay lens; 11, patient s eye; 12, objective lens; 13, beam splitter; 14, mirror with an aperture; 15, focusing lens; 16, imaging lens; 17, beam splitter; 18, movable lens; 19, field lens; 20, beam splitter; 21, imaging lens; 22, infrared television camera; 23, cable; 24, television monitor; 25, relay lens; 26, fixation plate; 27, lamp; 28, 35- mm film camera; 29, relay lens; 30, Polaroid camera; 31, controller; 32, reflector; 33, exciting light source; 34, motor; 35, chopper; 36, optic fiber; 37, diffuser; 38, aperture plate; 39, movable plate; 40, filter; 41, mirror; 42, mirror; 43, mirror; 44, projection lens; 45, reflector; 46, diffuser; 47, lamp; 48, diffuser; 49, filter; 50, lamp. (From Miyake et al. [10], with permission)

31 1.2 Focal Macular ERGs Recording System A Burian Allen bipolar contact lens electrode (Fig. 1.20C) is used to record the ERGs. This lens allows the examiner to observe the fundus through the fundus camera clearly,and it allows a sharp image of the stimulus to be formed on the retina. When the ERG and visual evoked response (VER) are recorded simultaneously, the two responses are fed to two amplifiers, and the output of the amplifiers is fed to a signal processor for signal summation. Usually, 256 or 512 responses are summed with a stimulus frequency of 4.5Hz. Using an artifact rejection system, baseline fluctuations larger than 40mV are rejected from the summation. The luminances of the stimulus light and background illumination are and 2.84 cd/m 2, respectively.

32 24 1 Principles and Methods Proof of Focal Responses To prove that the responses recorded by our system are really focal, a 5 diameter stimulus spot was moved in 7.5 steps from the optic disk through the fovea to 15 temporal to the fovea. The ERGs and VERs recorded simultaneously at each position from a normal subject are shown in Fig [13]. The mean amplitudes of the responses from four normal subjects are shown at the bottom of Fig The amplitudes of the ERG and VER were largest when the stimulus spot was on the fovea, and they became smaller as the spot was moved away from the fovea. Most importantly, a response was not present when the stimulus spot was on the optic disk, indicating that the responses were not contaminated by stray light responses. Fundus photographs from three patients with unilateral differently sized macular colobomas are shown in Fig [13]. The sizes of the macular coloboma were approximately 8 10, 11 12, and in diameter in Fig Left: A 5 diameter stimulus spot was moved in 7.5 steps from the optic disk through the fovea to 15 temporal to the fovea. A small spot on the fovea is a fixating target, which is useful for keeping the examining eye stable during each recording. Right, top: ERGs and VERs recorded simultaneously at each position from a normal subject. Right, bottom: Relative amplitudes of ERGs and VERs from four normal subjects. The ERG and VER amplitudes are maximum in the fovea and are absent at the optic disk. Filled circles, ERG; open circles, VER. (From Miyake [13])

33 1.2 Focal Macular ERGs 25 cases 1, 2, and 3, respectively. The full-field photopic ERGs and full-field 30-Hz flicker ERGs of the affected and normal fellow eyes are shown in Fig The amplitudes of full-field photopic ERGs of the affected eye are within the normal range but are smaller than those of the normal fellow eye in cases 2 and 3. However, the 30-Hz flicker ERGs from the two eyes did not differ significantly in any of the patients. These results indicate that the full-field conemediated ERGs are of limited value but may be better than the 30-Hz flicker ERGs for evaluating macular function. Additional information can be obtained by studying focal macular ERGs. The simultaneously recorded focal macular ERGs and VERs elicited from the affected and normal fellow eyes in these three cases are shown in Fig Fig Fundus photographs showing different sizes of macular colobomas. The sizes of the colobomas are approximately 8 10 (case 1), (case 2), and (case 3). (From Miyake et al. [13], with permission) Fig Full-field photopic ERGs (left) and full-field 30-Hz flicker ERGs (right) from the affected eye and the normal fellow eye in the three patients with macular colobomas shown in Fig The full-field photopic ERGs are smaller in the eye with the coloboma in cases 2 and 3, although the 30-Hz flicker ERGs from the two eyes did not differ significantly in any of the patients. (From Miyake [13], with permission)

34 26 1 Principles and Methods [13]. The size of the stimulus spot was adjusted so it was approximately the same as that of the colobomas, and the stimulus spot was placed exactly on the coloboma by monitoring the fundus. The ERGs and VERs were unrecordable in all cases, indicating that the stimuli for these recordings were stimulating the retina only underneath the spot, and the responses were indeed focal. Fig Focal macular ERGs and VERs recorded simultaneously from the eyes with macular colobomas and normal fellow eyes in the three patients shown in Figs and The diameters of the stimulus spots were 6 (case 1), 10 (case 2), and 15 (case 3). The ERGs and VERs are unrecordable in all cases, indicating that the stimuli were stimulating the retina only underneath the spot, and the responses were indeed focal. (From Miyake [13], with permission)

35 1.2 Focal Macular ERGs Macular Oscillatory Potentials As described in the previous section on fullfield ERGs, oscillatory potentials (OPs) are wavelets superimposed on the ascending slope of the b-wave of the conventional ERG and are generated independently of the a-waves and b- waves. The site of generation of the OPs is not yet fully known, but experimental evidence indicates that OPs reflect the activity of inhibitory feedback synaptic circuits in the retina. Although many studies have investigated their physiological properties and clinical value, the OPs in humans were evaluated as components of the total ERGs elicited by ganzfeld stimuli until we succeeded in recording the OPs from the human macula using the focal macular ERG recording system in 1988 [13, 14]. The focal macular ERGs seen in Fig were elicited by five different-diameter stimulus spots in 2.5 steps projected on the macula in a normal subject. The a-waves and b-waves of the ERGs were recorded with a time constant (TC) of 0.03s and a 100-Hz high-cut filter, and the OPs were recorded with a TC of 0.003s and Fig Focal macular ERGs recorded simultaneously with two time constants (right) from a normal subject.the stimuli were differently sized spots centered on the macula (left). A time constant (T.C.) of 0.03 s with a 100-Hz high-cut filter was used to record a-waves and b-waves; and a T.C. of s with a 300-Hz high-cut filter was used to recorded oscillatory potentials (Ops). (From Miyake [13])

36 28 1 Principles and Methods a 300-Hz high-cut filter. The OPs consisted of three or four wavelets (O1 O4) and were clearly observed in the responses to all stimulus spot sizes. To investigate the distribution of OPs in the human macular area, we used ring or annular stimuli, as shown in Fig We adjusted the stimulus conditions so the amplitudes of the a- waves and b-waves were essentially the same for the circular stimuli and annular stimuli (Fig. 1.28). Under these conditions, the OPs were significantly larger with the annular stimuli than with the circular stimuli, suggesting that the distribution of OPs is different from those of the a-waves and b-waves in the human macular region [13, 14]. The changes in the amplitude of response to the spot sizes and annuli indicated that the distribution of the neural elements generating the OPs is relatively sparse in the fovea. However, they become relatively more dense than those generating the a- waves and b-waves in the parafovea and even more dense in the perifovea. Another unique property of the macular OPs is the nasotemporal asymmetry [15]. Semicircular stimuli were used to compare the ERGs elicited by stimulating the temporal and nasal macula, as shown in Fig Focal ERGs elicited by stimulating the temporal and nasal retina with semicircular stimuli and circular stimuli (15 in diameter) are shown in Fig The amplitudes and implicit times of the a- waves and b-waves in the nasal retina are almost identical to those from the temporal retina, whereas the amplitudes of the OPs are much larger in the temporal retina than in the nasal retina. The amplitude of the focal ERGs recorded with the circular stimulus was approximately the same as the sum of the amplitudes of the temporal and nasal ERGs. These new properties of the macular OPs, as distinct from the a-waves and b-waves, have been confirmed by others recently with multifocal ERGs [16, 17]. The asymmetrical amplitudes of the OPs in the nasal and temporal retina may have resulted from the various Fig Circular (top) and annular (bottom) stimuli on the macula

37 1.2 Focal Macular ERGs 29 retinal elements contributing to the OPs. The OPs reflect neuronal activity in the inner nuclear layer of the retina and are probably mediated by the amacrine cells or the interplexiform cells. It is interesting that there is some correlation between the distribution of dopamine-containing amacrine cells in macaque retina and that of OPs in the human macular region [18]. The significant temporal and nasal asymmetry only in OPs was surprising (Figs. 1.29, 1.30). Some reports have suggested that this asymmetry may be related to a nasotemporal difference in the number of cones and ganglion cells or to asymmetry of the optical density of photopigments in the foveal cones. However, we have not found any reports that provide evidence for asymmetry of the OPs. Fig Comparison of focal macular ERGs elicited by a circular and an annular stimulus on the macula in four normal subjects. It was adjusted so there was little difference in the amplitudes of the a-waves and b-waves between the two recording conditions, but the OPs are much larger with the annular stimuli. (From Miyake et al. [14])

38 30 1 Principles and Methods Fig Semicircular stimuli with the edge of the semicircle passing through the vertical axis Fig Comparison of focal ERGs using semicircular stimuli on the nasal and temporal macular areas and a circular stimulus (15 ). The OPs in the temporal macula are significantly larger than those in the nasal macula, and only the OPs show this significant asymmetry. (From Miyake et al.[15], with permission)

39 1.2 Focal Macular ERGs Components of Focal Macular ERG in Humans Focal macular ERGs recorded from a normal human subject demonstrating the various components are shown in Fig The a-waves and b-waves, OPs, on and off components, and flicker responses are shown. Because these components originate from the neural activity of different retinal neurons in different retinal layers, a layer-by-layer analysis of macular function can be performed objectively by analyzing the components. Fig Components of the focal macular ERG recorded from a normal subject. ON and OFF responses recorded with 1-Hz stimulus frequency (top); a-wave, b-wave, and OPs recorded with 5-Hz stimulus frequency (middle); and 30-Hz flicker responses (bottom) are shown

40 32 1 Principles and Methods References 1. Hirose T, Miyake Y, Hara A (1977) Simultaneous recording of focal macular electroretinogram and visual evoked response: focal stimulation under direct observation. Arch Ophthalmol 95: Arden GB, Bankes JLK (1966) Foveal electroretinogram as a clinical test. Br J Ophthalmol 50: Van Lith GHM, Henkes HE (1970) The relationship between ERG and VER. Ophthalmol Res 1: Jacobson JH, Kawasaki K, Hirose T (1969) The human electroretinogram and occipital potential in response to focal illumination of the retina. Invest Ophthalmol 8: Nagata M, Honda Y (1970) Studies on local electric response of the human retina. 1. An instrument for stimulating local retinal areas in various photopic conditions. Acta Soc Ophthalmol Jpn 74: Nagata Y, Honda Y (1970) Studies on local electric response of the human retina. III. The areaintensity relation in focal stimulation on the macula. Acta Soc Ophthalmol Jpn 74: Fry CA, Bartley SH (1935) The relationship of stray light in the eye to the retinal action potential. Am J Physiol 111: Boynton RM (1951) Stray light and the human electroretinogram. J Opt Soc Am 43: Sandberg MA, Effron MH, Berson EL (1978) Foveal cone electroretinograms in dominant retinitis pigmentosa with reduced penetrance. Invest Ophthalmol Vis Sci 17: Miyake Y, Yanagida K, Kondo K, Ota I (1981) Subjective scotometry and recording local electroretinogram and visual evoked response. Jpn J Ophthalmol 25: Miyake Y, Awaya S (1984) Stimulus deprivation amblyopia: simultaneous recording of local macular electroretinogram and visual evoked response. Arch Ophthalmol 102: Miyake Y (2002) What can we know from focal macular ERG? Jpn J Clin Ophthalmol 56: Miyake Y (1988) Studies of local macular ERG. Acta Soc Ophthalmol Jpn 92: Miyake Y, Shiroyama N, Ota I, Horiguchi M (1988) Oscillatory potentials in electroretinograms of the human macular region. Invest Ophthalmol Vis Sci 29: Miyake Y, Shiroyama N, Horiguchi M, Ota I (1989) Asymmetry of focal ERG in human macular region. Invest Ophthalmol Vis Sci 30: Wu S, Sutter EE (1995) A topographic study of oscillatory potentials in man. Vis Neurosci 132: Bearse MA, Shimada Y, Sutter EE (2000) Distribution of oscillatory components in the central retina. Doc Ophthalmol 100: Mariani AP, Kolb H, Nelson R (1984) Dopaminecontaining amacrine cells of rhesus monkey retina parallel rods in spatial distribution. Brain Res 322: 1 8

41 1.3 Multifocal ERGs Multifocal ERGs The techniques for recording multifocal ERGs were developed by Sutter and Tan in 1992 [1]. With this method, focal ERGs can be recorded simultaneously from multiple retinal locations during a single recording session using crosscorrelation techniques. Unlike conventional focal macular ERGs, there are still questions about how this method works and what it measures because the technique is relatively new. Two techniques that have been used to understand multifocal ERGs were to (1) analyze the waveforms and components of the multifocal ERGs using pharmacological agents [2, 3] and (2) compare conventional focal macular ERGs and multifocal ERGs from patients with known macular diseases [4].

42 34 1 Principles and Methods Principle The stimulus matrix, the multifocal responses, and a topographic plot of the amplitudes of the standard multifocal ERGs are shown in Fig The retina was stimulated with an array of hexagonal stimuli generated on a computer monitor. The stimulus matrix consists of 103 hexagonal elements driven at a 75-Hz frame rate. The sizes of the hexagons were scaled with eccentricity to elicit approximately equalamplitude responses at all locations. Each hexagon has a 50% chance of being light each time the frame changes. The pattern appears to flicker randomly, but each element follows a fixed, predetermined m-sequence so the overall luminance of the screen over time is relatively stable. By correlating the continuous ERG signal with the on and off phases of each stimulus element, the focal ERG signal associated with a specific hexagonal element is recorded. An array of the 103 focal responses of the multifocal ERG and a topographic map of the amplitudes of the ERGs at each locus are shown for a normal subject. Fig Stimulus matrix (top), multifocal ERG responses (middle), and a topographic plot of the amplitudes (bottom) of standard multifocal ERG recordings from a normal subject.the array in the middle shows a response from the area around the optic disk

43 1.3 Multifocal ERGs 35 The multifocal ERG responses shown in Fig are the first-order kernels, and how the first- and second-order kernels are derived (as reported by Sutter et al [5]. and Hood [6]) is shown in Fig The first-order kernel is obtained by adding all the records following presentation of a white hexagon and then subtracting all the records following a black hexagon (Fig. 1.33A). The second-order kernel is a measure of how the multifocal ERG response is influenced by the adaptation to successive flashes. The first slice of the secondorder kernel is calculated by comparing the two responses shown in Fig. 1.33B (arrows). The upper large arrow points to the response to a flash preceded by a flash; the lower large arrow points to the response to a flash preceded by a dark hexagon. If these two responses are not identical, the first slice of the second-order kernel appears; it is calculated by subtracting one response from the other. The first slice of the second-order kernel represents the effect of an immediately preceding flash; the second slice of the second-order is a measure of the effect of the flash two frames earlier. Fig Derivation of the first- and second-order kernels of multifocal ERGs. White and black hexagons indicate whether the hexagons are on or off during that frame change. Hexagons with diagonal lines indicate a frame that could have been on or off. (From Sutter et al. [5] and Hood [6])

44 36 1 Principles and Methods Origin of Components of Multifocal ERGs Whereas the origin of each component of the full-field photopic ERGs elicited by short- and long-duration stimuli is fairly well known, the origin of the components of the multifocal ERG elicited by binary m-sequence (pseudorandom) stimuli has not been fully determined. A comparison of the waveforms of the first-order kernel of the multifocal ERG to the full-field photopic ERG elicited by short flashes, suggesting that they originate from the same retinal neurons [6]. It is generally accepted that little of the multifocal ERG response is generated by the cone receptors per se; rather, it is dominated by the responses of the on and off bipolar cells [4, 6]. Pharmacological studies on rabbits [2] and monkeys [3] showed that the second-order kernel receives a strong contribution from cells in the inner retinal layers [6].

45 1.3 Multifocal ERGs Recording On and Off Responses by Multifocal ERGs The photopic ERGs elicited by long-duration stimuli provide important information on bipolar cell function because this allows an independent evaluation of the on and off responses in the cone visual pathway [7] (see Fig. 1.9). However, standard multifocal ERG procedures do not provide information that can be used to evaluate these cells.by modifying the multifocal stimulating conditions, we have successfully recorded the on and off responses of the multifocal ERGs from the human retina and have explored how each component (a-, b-, and d-waves) changes at different retinal eccentricities [8, 9]. To do this, as shown in Fig. 1.34, each hexagonal element was modulated between stimulus A (eight consecutive dark frames followed by eight consecutive light frames) and stimulus B (16 consecutive dark frames) according to a binary m-sequence. Under these stimulus conditions, multifocal on and off responses were recorded. Each focal response was calculated as the difference between the mean response to stimulus A and the mean response to stimulus B. To minimize rod activity and the effect of scattered light, some background illumination was used for both the dark frames and the periphery of the television monitor. An example of the 61 multifocal on and off responses recorded from the left eye of a normal subject is shown in Fig Each component of the focal photopic on responses (awaves and b-waves) and off responses (d-wave) is identifiable. Representative focal responses averaged from five stimuli with increasing eccentricities are shown in Fig The scales are varied to obtain approximately equal size responses at the five loci. The a-wave and d- wave become relatively larger with increasing eccentricity when compared with the b-wave. These changes were statistically significant for five normal subjects. This differential distribution of the on and off components of the photopic ERG must be considered when a disease is evaluated using this technique.

46 38 1 Principles and Methods Fig Top: Stimulus array of 61 hexagonal elements. Bottom: stimulus pattern for recording multifocal on and off responses. Each hexagon was modulated between stimulus A (8 consecutive white frames followed by 8 consecutive dark frames) and stimulus B (16 consecutive dark frames) according to a binary m-sequence. Each focal ERG was calculated as the difference between the mean response to stimuli A and B. (From Kondo et al. [8, 9], with permission) Fig Multifocal photopic on and off responses in a normal subject. Arrow points to the response from the area of the optic disk. (From Kondo and Miyake [9], with permission) Fig Changes in the waveform with retinal eccentricity. Averaged ERG waveforms from five eccentric annuli are shown for two normal subjects (A.O. and M.K.). The waveforms were normalized to produce approximately equal b-wave amplitudes. (From Kondo and Miyake [9], with permission)

47 1.3 Multifocal ERGs Adaptational State As described above, the amplitude of the photopic ERG increases during the course of light adaptation when recorded after sufficient dark adaptation (see Section ). This phenomenon is important from two points of view when recording multifocal ERGs: first, recordings should be made only after the changes in the light-adapted responses have stabilized to obtain valid responses during clinical tests; and second, topographical variations in the neuronal makeup of the retina may alter the degree of amplitude increase during the course of light adaptation [8, 9]. An example of the increased amplitude of the multifocal ERGs in a normal subject after 0, 4, and 16 min of light adaptation following 30 min of dark adaptation is shown in Fig [9]. There is an obvious increase in the amplitude for the peripheral ERGs, whereas the increase is not apparent in the central region. This difference was shown to be significant in five normal subjects. These findings indicate that the rod cone interactions, the mechanism for this phenomenon, are different in the central and peripheral retina. This difference in the topographical distribution of the rod cone interaction is most likely caused by the higher concentration of rods in the peripheral retina [8, 9]. Fig Relative amplitude of the positive components of multifocal ERG at various retinal eccentricities with time.the increase in amplitude is smallest in the central retina and becomes larger toward the periphery. (From Kondo and Miyake [9], with permission)

48 40 1 Principles and Methods References 1. Sutter EE, Tan D (1992) The field topography of ERG components in man. 1. The photopic luminance response. Vis Res 32: Horiguchi M, Suzuki S, Kondo M, Tanikawa A, Miyake Y (1998) Effect of glutamate analogues and inhibitory neurotransmitters on the electroretinograms elicited by random sequence stimuli in rabbits. Invest Ophthalmol Vis Sci 39: Hood DC, Frishman LJ, Sazik S, Viswanathan S, Robson JG,Ahmed J (1999) Evidence for a ganglion cell contribution to the primate electroretinogram (ERG): effects of TTX on the multifocal ERG in macaque. Vis Neurosci 16: Kondo M, Miyake Y, Horiguchi M, Suzuki S, Tanikawa A (1995) Clinical evaluation of multifocal electroretinogram. Invest Ophthalmol Vis Sci 36: Sutter EE, Shimada Y, Li Y, Bearse MA (1999) Mapping inner retinal function through enhancement of adaptive components in the m-erg. In: Vision science and its applications. OSA Technical Digest Series. Optical Society of America, Washington, DC, pp Hood DC (2000) Assessing retinal function with the multifocal technique. Prog Retinal Eye Res 19: Sieving PA, Murayama K, Naarendorp F (1994) Push-pull model of the primate photopic electroretinogram: a role for hyperpolarizing neurons in shaping the b-wave. Vis Neurosci 11: Kondo M, Miyake Y, Horiguchi M, Suzuki S, Tanikawa A (1998) Recording multifocal electroretinogram on and off responses in humans. Invest Ophthalmol Vis Sci 39: Kondo M, Miyake Y (2000) Assessment of local cone on- and off-pathway function using multifocal ERG technique. Doc Ophthalmol 100:

49 1.4 Electrooculography Electrooculography In 1948 Du Bois Reymond reported that in the normal eye there is a flow of electrical current that is oriented so the cornea is relatively more positive than the posterior pole of the eye. This potential difference is referred to as the standing potential or resting potential of the eye. The electrooculogram (EOG) is an indirect measure of the amplitude of the standing potential, which changes during dark and light adaptation. To obtain an EOG, electrodes are placed at the inner and outer canthi of the eyes, and the patient is asked to look back and forth between a pair of fixation lights.when the cornea moves closer to one of the electrodes, it becomes more positive and the other electrode becomes more negative. The opposite happens when the eyes move to the other side. The changes in the amplitude of the EOG in the dark-adapted and light-adapted state of a normal subject are shown in Fig The smaller amplitudes are recorded when the eyes make the saccadic eye movements in the dark; this is called the dark trough. The peak amplitude is recorded against a steady light background, which is called the light peak. The light peak/dark trough (L/D) ratio is an index (Arden index) used to assess retinal function [1]. A ratio of 1.80 is the lower limit of normal in our clinic. The origin of the retinal standing potential is thought to be in the retinal pigment epithelium (RPE). However, the light rise is generated by light stimulation of the photoreceptor RPE complex; and it is detected only if certain structures in the middle retinal layer are normal. Reference 1. Arden GB, Baradda A, Kelsey JH (1962) New clinical test of retinal function based upon the standing potential of the eye. Br J Ophthalmol 46: Fig Electrooculography of a normal subject

50 42 1 Principles and Methods 1.5 Optical Coherence Tomography Optical coherence tomography (OCT) is a relatively new diagnostic imaging technique that can be used to obtain cross-sectional or tomographic images of biological tissues with micron resolution. By comparing the focal macular ERGs or multifocal ERGs with the OCT images, a layer-by-layer correlation can be obtained on the physiology and morphology of the macular area for various macular diseases [1]. The most recent model of the OCT (OCT3) can obtain images in which the retinal layers are clearly identifiable (Fig. 1.39). Fig Optical coherence tomography images of the macula in a normal subject showing the layered structure of the retina. RNFL, retinal nerve fiber layer; GCL, ganglion cell layer; RPE, retinal pigment epithelium, PR/IS, photoreceptor inner segment; PR/OS, photoreceptor outer segment/ INL, inner nuclear layer; ONL, outer nuclear layer; OPL, outer plexiform layer; IPL, inner plexiform layer; ELM, external limiting membrane Reference 1. Puliafito CA, Hee MR, Lin CP (1995) Imaging of macular diseases with optical coherence tomography. Ophthalmology 102:

51 2 Hereditary Retinal and Allied Diseases The diagnostic value of electroretinograms (ERGs) in the assessment and pathophysiological changes seen on the ERGs in the presence of hereditary retinal and allied diseases are presented in this section. The focus is on clinical findings in patients, but the chapter also touches briefly on the present status of research, if any, for each disease.

52 44 2 Hereditary Retinal and Allied Diseases 2.1 Retinitis Pigmentosa Retinitis pigmentosa (RP) is an inherited rod cone dystrophy in which the onset of symptoms, rate of progression, severity, and mode of inheritance are quite different for different patients. RP can be classified into two broad groups: typical and atypical.

53 2.1 Retinitis Pigmentosa Typical Retinitis Pigmentosa Typical RP is characterized by an abnormal course of dark adaptation, photophobia, night blindness, and loss of peripheral visual field. These alterations can be found separately or in some combination. During the early stage, the patients may have minimal, if any, ophthalmoscopic alterations. At more advanced stages, the characteristic fundus features of RP develop, including attenuated retinal vessels, intraretinal bone spicule pigmentation in the midperipheral fundus, and waxy pallor of the optic disks (Fig. 2.1). Several gene mutations have been detected in RP patients, but the genotypephenotype correlation is not completely distinct in most patients. Electroretinograms are essentially unrecordable in most patients, but patients at an early stage may have reduced ERGs to single flashes of light, and the cone ERGs are often better preserved than the rod ERGs (Fig. 2.2) [1 3]. The mixed rod cone ERGs elicited by a single bright flash are subnormal or undetectable. When the ERGs are reduced, the amplitudes of both a-waves and b-waves are reduced, indicating that the photoreceptors are extensively involved from the early stage. The rod ERGs are absent in most patients, but when present the implicit time of the b-wave is delayed. The cone ERGs and 30-Hz flicker ERGs are occasionally recordable at a relatively early stage of the disease but are significantly smaller than the comparable ERGs recorded from normal subjects. The implicit times of the cone and flicker ERGs are also prolonged. Unlike the full-field ERGs, the focal macular ERGs in RP patients are often recordable and can even be within the normal range in some patients [4]. The fundus (Fig. 2.3), full-field ERGs, and focal macular ERGs (Fig. 2.4) as well as a topographic map of the amplitudes of the multifocal ERGs (Fig. 2.5) recorded from a representative patient with typical RP are shown. Fig Fundus of a patient with typical retinitis pigmentosa (RP)

54 46 2 Hereditary Retinal and Allied Diseases The visual acuity of this patient was 1.2, and the visual fields were normal only in the central 15 in both eyes. The rod and cone components of the full-field ERGs were unrecordable, but the focal macular ERGs elicited by 5, 10, and 15 stimuli were within normal limits. The amplitudes of the multifocal ERGs were within normal limits in the macular area, but the topographic map of the multifocal ERGs showed an extremely reduced periphery, indicating marked reduction of the peripheral responses [5]. Among the RP patients with normal visual acuity, some have better preservation of the macular oscillatory potentials (OPs) than the a- waves and b-waves of the focal macular ERGs. Such examples are shown in Fig The reason macular OPs are selectively preserved is still unknown, although Banin et al. [6] reported an increase in the amplitude OPs of the full-field ERGs in transgenic pigs with a rhodopsin mutation. Some enhancement of inner retinal function may occur at certain stages of RP. Fig Full-field electroretinograms (ERGs) recorded from a normal control (top) and two RP patients at an early stage (case 1, middle) and a late stage (case 2, bottom) Fig Fundus of an RP patient (44-year-old man) with good visual acuity

55 Fig Full-field ERGs (left) and focal macular ERGs recorded with three different spots and two different time constants (T.C., right) from an RP patient shown in Fig Despite the undetectable full-field ERGs, all components, including the oscillating potentials (OPs), of the focal macular ERGs are within normal limits 2.1 Retinitis Pigmentosa 47

56 48 2 Hereditary Retinal and Allied Diseases Fig Topographic map of a multifocal ERG in a normal control (top) and an RP patient (bottom) showing a normal peak in the macular area but an extremely reduced peripheral sector Fig Focal macular ERGs elicited by a 10 spot with two different time constants (TC) from a normal subject (top) and from four RP patients with normal visual acuity. The amplitudes of the a-waves and b-waves are reduced, but those of the OPs are well preserved

57 2.1 Retinitis Pigmentosa Atypical Retinitis Pigmentosa Unilateral Retinitis Pigmentosa Patients are diagnosed with unilateral RP [7] when only one eye shows the characteristic changes of RP, and the other eye has normal psychophysical and electrophysiological findings. The ophthalmoscopic and fluorescein angiographic findings are also normal in the fellow eye. A follow-up period of at least 5 years is necessary to rule out delayed development in the second eye. In addition, inflammation, trauma, and other causes in the affected eye must be ruled out because these conditions can lead to ophthalmoscopic findings that resemble RP. To put it in concrete terms, diffuse unilateral subacute neuroretinitis (see Section 3.4.3), acute zonal occult outer retinopathy (AZOOR) (see Section 3.4.2), multifocal choroiditis, and panuveitis can present with unilateral fundus changes that may resemble typical RP [8]. The etiology of unilateral RP is unknown, and the patients with these characteristics rarely have other affected members in the family. Inflammation, trauma, and combined choroidal and retinal vascular occlusions are responsible for most cases. Unilateral RP was seen in a 30-year-old woman who first visited our clinic when she was 14 years old. Visual acuity was 1.0 in both eyes, and her visual fields were significantly different in the two eyes: The visual field of the left eye was normal, but that of the right eye was extremely constricted with preservation of only the central The fundus of the left eye was essentially normal, but the alterations in the fundus of the right eye were similar to those seen in patients with typical RP with bone spicule pigmentation, attenuation of retinal vessels, and diffuse atrophic changes of the RPE (Fig. 2.7). The full-field ERGs were normal in her left eye, and the rod and cone components in the right eye were nearly undetectable (Fig. 2.8). The focal macular ERGs, elicited by 5, 10, and 15 stimuli from both eyes, are compared in Fig The amplitudes and implicit times of the focal macular ERGs of the affected right eye were comparable to that in the normal left eye. Only the response to the 15 stimulus was slightly smaller than that for the right eye. These results indicate that our focal stimuli were indeed focal because normal ERGs (comparable to that recorded from the normal left eye) can be elicited from the small functioning retina (5 and 10 ) in the right eye. The topographical map of the multifocal ERGs showed a central peak, but the peripheral zone was markedly reduced in the right eye (Fig. 2.8). These ERG results indicate that although retinal function is normal in the left eye, only a small central retina is functioning normally in the right eye. The pathology of the right eye agrees well with the findings of typical RP. Because the ocular findings of the left eye did not show any significant change during the 16-year follow-up period, the diagnosis is most likely unilateral RP.

58 50 2 Hereditary Retinal and Allied Diseases OD OS Fig Fundus of a patient with unilateral RP. The right eye is affected Fig Full-field ERGs (left), focal macular ERGs (mferg) with three stimulus spots (right), and topography of multifocal ERGs from a patient with unilateral RP (bottom) shown in Fig Despite undetectable rod and cone responses in full-field ERGs of the right eye, the focal macular ERGs and central peak of multifocal ERG are nearly the same as those of the normal fellow eye

59 2.1 Retinitis Pigmentosa Paravenous Retinochoroidal Atrophy Paravenous retinochoroidal atrophy is a nonprogressive, regional chorioretinal atrophy of unknown etiology. Although most cases are not familial, some do occur in siblings and in successive generations [9, 10]. Fundus photographs of a patient with paravenous retinochoroidal atrophy are shown in Fig This 36-year-old woman was referred about 25 years ago because of the abnormal appearance of her fundus, which was detected during clinical screening. Her fundus showed clumps of pigment in the perivascular areas, predominantly paravenous. The pigment clumps were associated with zones of peripapillary chorioretinal atrophy. Between the affected zones, the appearance of the retina and choroid were normal. Fluorescein angiography showed a defect of the retinal pigment epithelium (RPE) in the atrophic zones, suggesting degeneration of the RPE. The condition was bilateral, although the right eye was affected more extensively than the left eye. The optic nerve head and the caliber of the retinal vessels were normal. Many of the patients with paravenous retinochoroidal atrophy are asymptomatic and have normal visual function. The visual acuity in this patient was 1.2 in both eyes. The amplitudes of the full-field ERGs (Fig. 2.10) were smaller than normal, particularly in the right eye for both the rod and cone components. Although the amplitudes were smaller than normal, the implicit times were within normal limits, suggesting that the retina is not diffusely involved as it would be in RP [11]. Defects in the visual field were detected only in the areas corresponding to chorioretinal atrophy, and the amplitudes of the multifocal ERGs (mfergs) were reduced only in the area corresponding to choroidal atrophy. This patient has been followed for 25 years, and the ocular findings have not shown any progression. Fig Fundi of both eyes of a patient with paravenous chorioretinal atrophy. The right fundus is more extensively affected than the left fundus

60 52 2 Hereditary Retinal and Allied Diseases Fig Full-field ERGs (top) and topographic maps of multifocal ERGs (mferg) from both eyes (bottom) in the patient whose fundi are shown in Fig. 2.9

61 2.1 Retinitis Pigmentosa Grouped Pigmentation of Retina Grouped pigmentation of the retina, also called bear-track pigmentation, is a nonhereditary, nonprogressive congenital condition [12]. The fundus and fluorescein angiograms show round and irregularly shaped lesions representing RPE hypertrophy scattered throughout the retina (Fig. 2.11). The results of ERG (Fig. 2.12), electrooculography (EOG), and other visual functions tests are within normal limits. The multifocal ERGs are not reduced in the area of the spotty pigmentation, indicating that the retinal function is not impaired in the pigmented areas (Fig. 2.13). Fig Photograph of the fundus (left) and fluorescein angiogram (right) from a patient with grouped pigmentation of the retina

62 54 2 Hereditary Retinal and Allied Diseases Fig Topographic map of multifocal ERGs in the patient with grouped pigmentation of the retina shown in Fig Fig Full-field ERGs from a normal subject and from the patient with grouped pigmentation of the retina shown in Fig References 1. Armington JC, Gouras P, Tepas DI, Gunkel RD (1961) Detection of the electroretinogram in retinitis pigmentosa. Exp Eye Res 1: Berson EL (1987) Electroretinographic findings in retinitis pigmentosa. Jpn J Ophthalmol 31: Heckenlively JR,Yoser SL, Friedman LH, Oversier JJ (1988) Clinical findings and common symptoms in retinitis pigmentosa. Am J Ophthalmol 105: Miyake Y (1988) Studies of local macular ERG. Acta Soc Ophthalmol Jpn 92: Kondo M, Miyake Y, Horiguchi M, Suzuki S, Tanikawa A (1995) Clinical evaluation of multifocal electroretinogram. Invest Ophthalmol Vis Sci 36: Banin E, Cideciyan AV, Aleman TS, Petters RM, Wong F, Milam AH, et al (1999) Retinal rod photoreceptor-specific gene mutation perturbs cone pathway development. Neuron 23: Carr RE Siegel IM (1973) Unilateral retinitis pigmentosa. Arch Ophthalmol 90: Gass JDM (1997) Unilateral retinitis pigmentosa. In: Stereoscopic atlas of macular diseases, diagnosis and treatment (4th edn). Mosby, St. Louis, pp Noble KG (1989) Hereditary pigmented paravenous chorioretinal atrophy. Am J Ophthalmol 108: Small KW, Anderson WB Jr (1991) Pigmented paravenous retinochoroidal atrophy; discordant expression in monozygotic twins. Arch Ophthalmol 109: Hirose T, Miyake Y (1979) Pigmentary paravenous chorioretinal degeneration: fundus appearance and retinal functions. Ann Ophthalmol 11: Buettner H (1975) Congenital hypertrophy of the retinal pigment epithelium in Maine. Am J Ophthalmol 79:

63 2.2 Crystalline Retinopathy (Bietti) Crystalline Retinopathy (Bietti) Crystalline retinopathy is a condition first described by Bietti in 1937 [1]. Patients with crystalline retinopathy are initially seen when they are middle-aged because of reduced visual function. The alterations are often associated with night blindness and are slowly progressive. The fundus has numerous yellowish white glistening deposits resembling crystalline granules scattered throughout the posterior pole in all retinal layers bilaterally [1]. Typically, the optic disks and retinal vessels are normal. There may be marginal crystalline deposits in the cornea, and when present the deposits are sparkling yellow or white, round, polygonal, or needle-like crystals located in the anterior stroma in the perilimbal region [1, 2]. It has been reported that the crystalline deposits in the cornea can be detected more clearly by specular microscopy than by conventional slitlamp examination [3]. Indeed, we have had cases in which the crystalline deposits were not detected by slit-lamp examination but were clearly seen by specular microscopy [4]. Photographs of the fundus and the cornea as seen by specular microscopy in two patients with crystalline retinopathy are shown in Fig Fluorescein angiography revealed diffuse atrophy of the RPE, and atrophy of the choriocapillaris is occasionally present in the areas corresponding to the depigmented areas. The ophthalmoscopically observed crystalline deposits do not result in abnormal fluorescein findings. The progression of the disease process is similar in patients with and without crystalline deposits in the cornea. Changes in the fluorescein angiograms and visual field in a patient with Bietti s crystalline retinopathy during a 5- to 6-year follow-up are shown in Fig Extensive areas of nonperfusion of the choriocapillaries were present paracentrally that progressively enlarged and became confluent. The nonperfused areas extended to the periphery of the fundus during the 5- to 6-year follow-up. Visual field defects were detected in the areas corresponding to the nonperfused areas. Full-field ERGs may be normal, reduced, or undetectable depending on the stage. The ERGs become progressively more depressed during the follow-up period as shown in Fig The amplitudes of the rod and cone components of the ERGs are reduced in parallel, indicating that both rods and cones are affected simultaneously and almost equally. The mode of inheritance is autosomal recessive, and it was recently found that this disease is caused by mutations in the CYP4V2 gene [5]. All of the patients whose ERGs were shown in this section had a mutation in this gene [6].

64 56 2 Hereditary Retinal and Allied Diseases Fig Crystalline deposits in the cornea (arrows) detected by specular microscopy (left) and in the posterior pole of the fundus (right) in two patients with Bietti crystalline retinopathy. (From Takikawa et al. [4]) eyesight eyesight Fig Changes in fluorescein angiography (left) and the visual field (right) in a patient with crystalline retinopathy during a 5-year follow-up. (From Takikawa et al. [4])

65 2.2 Crystalline Retinopathy (Bietti) 57 Fig Changes in full-field ERGs of the patient whose fundus is shown in Fig (From Takikawa et al. [4]) References 1. Bietti GB (1937) Uber familiares Vorkommen von Retinitis punctata albescens (verbunden mit Dystrophia marginalis cristallinea corneae ), Glitzern des Glaskorpers und anderen degenerativen Augenveranderungen. Klin Monatsbl Augenheilkd 99: Bagolini B, Ioli-Spada G (1968) Bietti s tapetoretinal degeneration with marginal corneal dystrophy. Am J Ophthalmol 65: Wakita M, Hayakawa M, Kato K, Kanai J (1990) Cases with crystalline retinopathy. Research Committee on Chorioretinal Degeneration, The Ministry of Health and Welfare of Japan, Tokyo, pp Takikawa C, Miyake Y, Yagasaki K (1992) Reevaluation of crystalline retinopathy based on corneal findings. Folia Ophthalmol Jpn 43: Li A, Jiao X, Munier FL, Schorderet DF,Yao W, Iwata F, et al (2004) Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2. Am J Hum Genet 74: Lin J, Nishiguchi KM, Nakamura N, Dryja TP, Berson EL, Miyake Y (2005) Recessive mutations in the CYP4V2 gene in East Asian and Middle Eastern patients with Bietti crystalline corneoretinal dystrophy. J Med Genet 42:e38

66 58 2 Hereditary Retinal and Allied Diseases 2.3 Batten Disease The late infantile and juvenile forms of neuronal ceroid-lipofuscinosis are known as Batten disease [1]. The mode of inheritance of this disease is autosomal recessive. Although many cases of Batten disease have been reported worldwide, only a few patients have been reported to be Japanese [2], suggesting that the incidence of the disease is lower among the Japanese population. Patients with Batten disease have a lysosomal storage disease that results in the accumulation of insoluble fluorescent lipoproteins, believed to be ceroid and lipofuscin pigments [3]. These pigments are normally associated with aging. Most of the patients with Batten disease who have been described in the literature were at an advanced stage, so the clinical findings in the early stages are still unknown. We have monitored the visual functions and ocular findings in two siblings with Batten disease for more than 2 years. One of them visited our clinic initially at an early stage of the disease [4]. This 5-year-old boy was examined at the time his elder brother was examined. He had no complaints and no history of systemic or ocular disorders at that time. His visual acuity was 1.0 in both eyes. The fundus had a slightly abnormal reflex in the macula but was otherwise normal. The a-wave of the full-field ERGs was normal, but the b-wave was smaller than the a-wave, resulting in a negative-type ERG (Fig. 2.17). During the 2- to 3-year follow-up, his visual acuity decreased to 0.1 in 10 months, and the full-field ERGs became nearly undetectable by 24 months, with progressive reduction of the b-wave/a-wave (b/a) ratio (Fig. 2.17). The fundus developed bull s-eye maculopathy at 18 months followed by diffuse degeneration of the RPE (Fig. 2.18, left) and attenuation of the retinal vessels associated with optic atrophy in 28 months. As for his older brother, electron microscopy of lymphocytes in the peripheral blood showed a fingerprint pattern (Fig. 2.18, right), and juvenile neuronal ceroid-lipofuscinosis was diagnosed. Thus, we were able to follow the course of the disease process in this boy from an early stage to an advanced stage. His older brother, a 7-year-old boy, was first examined by us because of visual disturbances. His visual acuity was 0.07 (OD) and 0.04 (OS), and his fundus showed bull s-eye maculopathy and diffuse RPE degeneration with slight optic atrophy. The retinal vessels were attenuated. Electron microscopy of lymphocytes of peripheral blood showed a fingerprint pattern. The full-field mixed rod cone ERGs elicited by bright stimuli were undetectable. His visual acuity decreased rapidly to hand motion vision 5 6 months later.in addition,the patient had epileptic seizures, and his disorder was diagnosed as juvenile neuronal ceroid-lipofuscinosis. This patient exhibited the ocular findings of a relatively advanced stage of Batten disease. From a diagnostic point of view, the important finding was the negative ERGs even when the other ocular findings were essentially normal [2, 4]. During progression of the disease, the amplitudes of the a-wave and the b-wave decreased, and the b/a ratio became smaller, indicating enhancement of the negativity in the ERG. Although histological studies of the early stage of Batten disease have not been reported, histopathological examination

67 2.3 Batten Disease 59 Fig Mixed rod cone ERGs and relative amplitude of the b-wave/a-wave ratio (b/a ratio) during the course of Batten disease. Both a-waves and b-waves decreased rapidly and were unrecordable 2 years after the initial visit. It should be noted that the a-wave was always larger than the b-wave (negative type). Filled circles, right eye (OD); open circles, left eye (OS). (From Horiguchi and Miyake [4], with permission) Fig Left: Fundus photograph (top) and fluorescein angiogram (bottom) from a patient with Batten disease, showing bull s-eye maculopathy and diffuse RPE degeneration. Right: Finger-point pattern in an electron micrograph of a lymphocyte from a patient with Batten disease.(from Horiguchi and Miyake [4], with permission)

68 60 2 Hereditary Retinal and Allied Diseases of the retina of an animal model of this disorder showed that the primary lesion is in the inner retinal layers [1, 5]. The ERG findings of the patient supports these animal results because such negative ERGs are usually observed in patients with inner retinal layer dysfunction, such as retinal circulatory disturbances, congenital retinoschisis, and congenital stationary night blindness. The negative ERGs seen at the early stage of Batten disease may be useful when assigning an early diagnosis. Furthermore, rapid deterioration of the ERG and visual acuity are unusual in other hereditary retinal disorders and thus may be one of the characteristics of this disorder. References 1. Copenhaver RM, Goodman C (1960) The electroretinogram in infantile, late infantile and juvenile amaurotic family idiocy. Arch Ophthalmol 63: Shimada H, Tashiro T, Matsui M, Owada M, Kitagawa T (1983) Correlation of funduscopic and histological features in a case with Batten disease. Jpn J Clin Ophthalmol 37: Beckerman BL, Rapin I (1975) Ceroid lipofuscinosis. Am J Ophthalmol 80: Horiguchi M, Miyake Y (1992) Batten disease: deteriorating course of ocular findings. Jpn J Ophthalmol 36: Goebel NH, Zeman W, Damaske E (1974) The fine structure of the retina in neuronal ceroidlipofuscinosis. Am J Ophthalmol 77:25 39

69 2.4 Kearns-Sayre Syndrome Kearns-Sayre Syndrome The association of pigmentary retinopathy with mitochondrial myopathy has been well recognized [1]. The Kearns-Sayre syndrome, strongly associated with deletions in mitochondrial DNA [2], is one of the distinct syndromes of mitochondrial myopathy [3]. It is characterized by a triad of signs onset before 15 years of age, progressive external ophthalmoplegia, pigmentary retinopathy as well as by one or more of the following problems: heart block, cerebellar ataxia, high cerebrospinal fluid protein [4]. The stage of the disease can be determined by analyzing the appearance of the fundus and the visual functions of patients with pigmentary retinopathy [5] (Figs. 2.19, 2.20, 2.21): stage 0, fundus appearance, visual functions, and ERGs are within normal limits; stage 1, salt and pepper retinopathy is present over the entire retina, as in cases 1 and 2 (Fig. 2.19) but the visual functions and ERGs are still normal; stage 2, visual functions and ERGs are abnormal (case 3), with the fundus appearing similar to stage 1; stage 3, chorioretinal atrophy progresses around the optic disk and some areas of the retina (Fig. 2.21), and the ERGs are not detectable (case 3); and stage 4, more extensive chorioretinal atrophy, and the fundus appears similar to that seen with choroidal sclerosis.

70 62 2 Hereditary Retinal and Allied Diseases Fig Fundus photograph (left) and fluorescein angiogram (right) at stage 1 (case 1) showing salt and pepper retinopathy. (From Ota et al. [5]) Fig Full-field ERGs in a normal subject and three patients with Kearns Sayre syndrome at different stages. In cases 1 and 3, the ERGs recorded at two times are shown. Case 3 shows significant deterioration of all ERG components during the 6-year follow-up. (From Ota et al. [5])

71 2.4 Kearns-Sayre Syndrome 63 Fig Fluorescein angiograms showing the progression of chorioretinal atrophy around the optic disk during a 6-year follow-up of case 3. Top: initial visit. Bottom: six years later. (From Ota et al. [5]) References 1. Kearns TP (1965) External ophthalmoplegia, pigmentary degeneration of the retina, and cardiomyopathy: a newly recognized syndrome. Trans Am Ophthalmol Soc 63: Moraes CT, DiMauro S, Zeviani M (1989) Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med 320: Mullie MA, Harding AE, Petty RK (1985) The retinal manifestations of mitochondrial myopathy: a study of 22 cases. Arch Ophthalmol 103: Zeviani M, Bonilla E, De Vivo DC, DiMaruro S (1989) Mitochondrial diseases. Neurol Clin 7: Ota I, Miyake Y, Awaya S (1989) Studies of ocular fundus and visual functions in Kearns-Sayre syndrome: with special reference to the new stage classification. Acta Soc Ophthalmol Jpn 93:

72 64 2 Hereditary Retinal and Allied Diseases 2.5 Choroideremia Choroideremia is an X-linked recessive chorioretinal dystrophy [1]. The course of visual function deterioration is similar to that of RP. Affected men usually report the onset of night blindness at years of age and later become aware of the loss of peripheral visual fields. The central vision is affected only during middle age or later. It has been reported that aberrant splicing of the choroideremia gene (CHM) is the most likely cause of choroideremia [2]. Despite such functional similarities to RP, the appearance of the fundus is different. Unlike RP, the fundus of choroideremia patients exhibits atrophy of the choroid, normal retinal vessels, and an absence of optic atrophy (Fig. 2.22) [1]. In late-stage, fluorescein angiography demonstrates marked loss of the RPE and the choroidal vessels, including the choriocapillaris in the central macular area. However, many choroidal vessels are revealed that had been difficult to see ophthalmoscopically. The carrier state is important for diagnosing this disease [1, 3]. The fundi of female carriers almost always have characteristic mottling and depigmentation of the RPE, which is most marked in the mid-periphery (Fig. 2.23). The ERG is often unrecordable from the early stage of the disease (Fig. 2.24) [1, 3]. Despite such marked changes in the fundus of female carriers, the visual functions, including the ERGs, are essentially normal in most carriers (Fig. 2.24). These findings in carriers are important for making a correct diagnosis of hemizygotes [1, 3]. Fig Fundus photograph (top) and fluorescein angiogram (bottom) of a 31-year-old man with choroideremia

73 2.5 Choroideremia 65 Fig Fundus photograph (left) and fluorescein angiogram (right) of a 45-year-old female carrier of choroideremia Fig Full-field ERGs of a normal subject (left), a patient with choroideremia (middle), and a carrier of choroideremia (right) References 1. Heckenlively JR, Bird AC (1988) Choroideremia. In: Heckenlively JR (ed) retinitis pigmentosa. Lippincott, Philadelphia, pp Van der Hurk JAJM, Schwartz M, van Bokhaven H, van de Pol TJR (1997) Molecular basis of choroideremia (CHM): mutations involving the Rab escort protein-1 (REP-1) gene. Hum Mutat 9: Rubin ML, Fishman RS, McKay RA (1966) Choroideremia; study of a family and literature review. Arch Ophthalmol 76:

74 66 2 Hereditary Retinal and Allied Diseases 2.6 Gyrate Atrophy Gyrate atrophy of the choroid is a rare, recessively inherited chorioretinal atrophy that results from an inborn error of metabolism. Gyrate atrophy is caused by generalized deficiency of the mitochondrial matrix enzyme, ornithine aminotransferase [1] and is manifested early in life as sharply demarcated garland-shaped zones of chorioretinal atrophy in the mid-periphery of the fundus (Fig. 2.25) [2]. The macula is usually involved later in life. Pallor of the optic disk, vitreous opacities, and narrowing of the retinal vessels may develop at a relatively advanced stage of the disease. Most patients have a high degree of myopia and night blindness, and loss of the peripheral visual field accompanies the fundus changes. The ERG is usually markedly reduced or absent during early childhood even when the fundus changes are minimal (Fig. 2.26). An expression defect of the ornithine aminotransferase gene was identified in gyrate atrophy [3]. There are two clinical subtypes of gyrate atrophy based on the in vivo response to vitamin B 6 : patients who are B 6 -responsive and those who are not responsive. The patients who are vitamin B 6 -responsive generally have a milder disease than those who are vitamin B 6 unresponsive [4]. Fig Fundus photograph (left) and fluorescein angiogram (right) of a 39-year-old man with gyrate atrophy. (From Ota et al. [2])

75 2.6 Gyrate Atrophy 67 Fig Full-field ERGs of the patient whose fundus is shown in Fig References 1. Takki KK (1974) Gyrate atrophy of the choroid and retina associated with hyperornithinaemia. Br J Ophthalmol 58: Ota I, Miyake Y, Ichikawa H (1985) A family with gyrate atrophy. Jpn Rev Clin Ophthalmol 79: Inana G, Hotta Y, Zintz C, Takki K, Weleber RG, Kennaway NG, et al (1988) Expression defect of ornithine aminotransferase gene in gyrate atrophy. Invest Ophthalmol Vis Sci 29: Wilson DJ, Weleber RG, Green WR (1991) Ocular clinicopathologic study of gyrate atrophy. Am J Ophthalmol 111:24 33

76 68 2 Hereditary Retinal and Allied Diseases 2.7 Enhanced S-Cone Syndrome Enhanced S-cone syndrome (ESCS) is a newly identified hereditary retinal disorder with several unique functional properties [1, 2]. Initially, this disorder was classified as a type of congenital stationary night blindness, but it was later found that most of the cones in these eyes were the short-wavelength-sensitive cones (S-cones) [3, 4]. The syndrome is caused by mutations in the PNR (photoreceptor-specific nuclear receptor) gene [5]. The PNR gene is a retinal orphan nuclear receptor that determines the phenotype of the cones during embryogenesis; it is required for the differentiating middle- and long-wavelength-sensitive cones (ML-cones) from S-cones. Mutation of the PNR gene arrests cone differentiation at a stage where most cones are still S-cones. The clinical findings associated with ECSC include congenital night blindness, progressively decreasing visual acuity, supernormal S-cone ERGs, and characteristic fundus alterations. The inheritance is autosomal recessive [1 5]. At present, we have studied three patients with ESCS who had PNR gene mutations [6, 7]. The fundus shows cystic changes in the macula with or without annular pigmentary retinopathy just outside the vascular arcades (Fig. 2.27). Fig Fundus photograph, fluorescein angiograms, and optical coherence tomography (OCT) from two patients with enhanced S-cone syndrome (ESCS).The cystic changes in the macula can be seen in the photograph (A) and the OCT image (C) from a 20-year-old man.the fluorescein angiogram shows the macula to be normal, with some pigmentary change just outside the vascular arcade (B) (case 2). Note the association of submacular proliferation (D) with choroidal neovascularization (E), as well as the OCT image (F) in a 10-year-old boy with ESCS (case 1). (From Nakamura et al. [7])

77 2.7 Enhanced S-Cone Syndrome 69 One of our younger patients (a 10-year-old boy) had neovascular maculopathy in one eye [7]. Fluorescein angiography is essentially normal in the macular area of these patients without leakage of fluorescein dye. These findings indicate that the cystoid changes in the macula are not similar to that in eyes with macular edema, and the pathology is more comparable to that of retinoschisis. Optical coherence tomography (OCT) images of an eye with ESCS show the cystic changes in the macula that are present in most patients. The macular changes are subtle in some patients, but OCT can detect the small cysts. Full-field ERGs reveal the diagnostic findings in this disorder (Fig. 2.28). The rod ERGs are undetectable. The amplitudes of the a-wave and b-wave of the bright flash, mixed rod cone ERGs may be normal or supernormal, with a significant delay in the implicit times; the OPs are essentially absent. The cone ERGs are larger than that of normal controls with delayed implicit times. It is interesting that the amplitude and shape of the cone ERGs recorded under light-adapted conditions are almost identical to the ERGs recorded under dark-adapted conditions (bright flash ERGs). This finding is one of the keys to the diagnosis of ESCS. It indicates that the main component of the ERG is cone-driven. Despite such large cone ERGs, the 30 Hz flicker ERG is extremely small with delayed implicit times, suggesting Fig Full-field ERGs from a normal control and three patients with ESCS. All patients with ESCS have unrecordable rod ERGs but large bright flash (mixed rod cone) ERGs with delayed a-waves and b-waves and no OPs. The cone ERGs are large, but the 30-Hz flicker ERGs are markedly reduced. The cone ERGs were recorded under background illumination to suppress the rod activity, and the same intensity was used for the bright flash ERGs. In the normal control, the cone ERG was markedly decreased in amplitude with the background illumination, and the implicit time of the b-wave was shortened. However, in all patients with ESCS, the amplitude and implicit time of the cone ERG was essentially the same as the bright flash ERG in the dark. (From Miyake [6])

78 70 2 Hereditary Retinal and Allied Diseases that the large cone ERGs reflect the function of the S-cone. The unusual enhancement of the S-cone ERGs in these patients can be clearly demonstrated by comparing the cone ERGs recorded with stimuli that selectively stimulate S-cones and selectively stimulate the ML-cones. When the intensities of the red (ML-cones) and blue (S-cones) wavelength stimuli are balanced to produce equal-amplitude cone ERG b-waves from normal eyes, the blue stimuli elicit much larger b-waves than the red stimuli in ESCS patients (Fig. 2.29). These ERG results indicate that the supernormal ERGs elicited by bright white stimuli are S-cone driven in ESCS patients. As was shown in Section , the S-cone ERG has a depolarizing waveform with a large b-wave (on response), and the a-wave and d- wave (off response) are essentially absent. This is because S-cones connect only to on bipolar cells in primates. However, it is interesting that the S-cone ERGs in patients with ESCS have large a-waves and d-waves (Fig. 2.30), indicating that the S-cones in eyes with ESCS may have connections not only to on bipolar cells but also to off bipolar cells [8]. Fig ERGs elicited by photopically balanced red and blue stimuli in a normal subject and three patients with ESCS. ERGs elicited by red stimuli show extremely small responses, whereas those elicited by blue stimuli show large responses. (From Miyake [6]) Fig Photopic long-flash ERGs from a normal subject and a patient with ESCS. Unlike the waveform of blue cone ERGs, a large a-wave and d-wave are recorded from a patient with ESCS. (From Miyake [6])

79 2.7 Enhanced S-Cone Syndrome 71 References 1. Marmor MF, Jacobson SG, Foerster MH, Kellner U, Weleber RG (1990) Diagnostic clinical findings of a new syndrome with night blindness, maculopathy and enhanced S cone sensitivity. Am J Ophthalmol 110: Hood DC, Cideciyan AV, Roman AJ, Jacobson SG (1995) Enhanced S-cone syndrome: evidence for an abnormally large number of S cones. Vis Res 35: Fishman GA, Peachey NS (1989) Rod-cone dystrophy associated with a rod system electroretinogram obtained under photopic conditions. Ophthalmology 96: Marmor MF (1989) Large rod-like photopic signals in a possible new form of congenital stationary night blindness. Doc Ophthalmol 71: Haider NB, Jacobson SG, Cideciyan AV, Swiderski R, Streb LM, Searby C, et al. (2000) Mutation of a nuclear receptor gene, NR 2 E 3, causes enhanced S cone syndrome, a disorder of retinal cell fate. Nat Genet 24: Miyake Y (2003) Hereditary retinal diseases with selective abnormalities in blue cone function. Folia Ophthalmol Jpn 54: Nakamura M, Hotta Y, Piao CH, Kondo M, Terasaki H, Miyake Y (2002) Enhanced S-cone syndrome with subfoveal neovascularization. Am J Ophthalmol 133: Kolb H, Lipets LE (1991) The anatomical basis for color vision in the vertebrate retina. In: Gouras P (ed) The perception of colour. Macmillan, London, pp

80 72 2 Hereditary Retinal and Allied Diseases 2.8 X-Linked Retinoschisis X-Linked retinoschisis (XLRS) is a slowly progressive disease. It is not rare, and it is occasionally misdiagnosed as several other disorders, including amblyopia, nonspecific macular degeneration, retinal pigmentary dystrophy, and rhegmatogenous retinal detachment [1]. ERGs provide decisive information for the diagnosis [2 4].

81 2.8 X-Linked Retinoschisis Fundus Findings The characteristic features of the fundus of patients with XLRS (Fig. 2.31) are schisis in the foveal area (foveoschisis) with either a wheellike configuration with radiating spoke-like striations (Fig. 2.31A) or clearly visible microcysts (Fig. 2.31B); an absence of vascular leakage in the macula as seen by fluorescein angiography (Fig. 2.31C); cystic spaces in the macula revealed by OCT (Fig. 2.31D); and peripheral retinoschisis in about 50% of the eyes, often with inner retinal breaks (Fig. 2.31E). Breaks in the outer retina may be associated with retinoschisis (Fig. 2.31F) and can be sealed by photocoagulation (Fig. 2.31G). A golden tapetal reflex is frequently observed in the peripheral retina (Fig. 2.31H), and some patients have flecks in the posterior pole (Fig. 2.31I). During the course of the disease process, the appearance of the fundus in patients with XLRS Fig Characteristic findings of X-linked retinoschisis (XLRS). A, B Foveoschisis. C Normal fluorescein angiogram. D Cystic spaces in an OCT image. E Peripheral retinoschisis with an inner retinal hole. F Outer retinal hole underneath retinoschisis. G Outer retinal hole after photocoagulation. H Golden tapetal reflex. I Flecks in the posterior pole. (From Miyake [4])

82 74 2 Hereditary Retinal and Allied Diseases varies considerably, as shown in Fig The cystic appearance of the macula may change to nonspecific macular degeneration (Fig. 2.32A), and fluorescein angiography may show hyperfluorescence due to window defects in the RPE (Fig. 2.32B). Extensive pigmentary changes of the retina (Fig. 2.32C) may be present, sometimes associated with sheathing of the vessels and abnormal appearance of the optic disks (Fig. 2.32D). Fluorescein angiography shows extensive RPE degeneration (Fig. 2.32E), and closure of retinal vessels may be seen resulting in avascular zones (Fig. 2.32F,G) with new vessel formation (Fig. 2.32H,I). Some patients have a retinal detachment associated with outer retinal breaks and vitreous hemorrhage. All of these changes make the correct diagnosis difficult. The schisis occurs in the plane of the nerve fiber and ganglion cell layers of the retina. It has long been suggested that degenerating Mueller cells or inner retinal cells may be the primary cause of the pathological changes [5]. Fig Atypical findings of XLRS. A Nonspecific macular degeneration. B Window defect of retinal pigment epithelium (RPE) in a fluorescein angiogram. C Extensive pigments in the fundus. D Retinal degeneration associated with an abnormal optic disk and sheathing of the vessels. E Extensive window defect of the RPE seen on a fluorescein angiogram. F Avascular zone in the peripheral retina. G Nonperfused area with leaking vessels in the margin. H New vessel formation. I Fluorescein leakage from new vessels. (From Miyake [4])

83 2.8 X-Linked Retinoschisis Visual Acuity and Refractive Errors The visual acuity of patients with XLRS at various ages is shown in Fig Most patients, including young ones, show moderately poor visual acuity that gradually decreases with increasing age. Hypermetropia has been shown to be a frequent accompaniment of this disorder. In fact, many patients with XLRS are first diagnosed with hypermetropic amblyopia or with heterotropia during infancy, and only during follow-up examinations are they found to have XLRS. A plot of the axial length as a function of the refractive error is shown in Fig for patients with XLRS, demonstrating that the hypermetropia is axial hypermetropia, not refractive hypermetropia [6]. Fig Visual acuity (ordinate) as a function of age (abscissa) in patients with XLRS Fig Axial length (ordinate) as a function of the refractive error (abscissa) in patients with XLRS.The refractive error is significantly more hypermetropic and the axial length is significantly shorter than normal, indicating that the hypermetropia in patients with XLRS is axial hypermetropia. (From Kato et al. [6], with permission)

84 76 2 Hereditary Retinal and Allied Diseases Electrophysiology Full-field ERGs and EOGs Full-field ERGs are of significant diagnostic value [1 4]. The ERGs elicited by relatively bright flash stimuli under dark-adapted conditions have a negative configuration in most patients with XLRS (Fig. 2.35). Abnormalities in the full-field ERGs are present even when the retinoschisis is confined to the fovea ophthalmoscopically. This indicates a diffuse functional abnormality in the entire retina. During the early stage the amplitude of the a-wave is normal, but that of the b-wave is smaller than the a-wave. The OPs are smaller than normal or may be absent. At an intermediate stage the a-wave may also be reduced, but the b-wave is even more reduced, keeping the negative configuration. ERGs may become undetectable at the most advanced stage. This is a rare observation, and we have observed only two such eyes among our 57 patients with XLRS [7]. However, once the ERGs become undetectable, the diagnosis may be difficult. The alterations of the fundus may be similar to those in patients with RP (Fig. 2.32C), and a differential diagnosis from RP is crucial. The correct diagnosis can be made by a family survey, the ocular findings of the other eye, and molecular genetic analysis. The full-field rod and cone ERGs recorded from a representative patient with XLRS are shown in Fig The rod and cone ERGs are both reduced with delayed b-wave implicit times. The EOG is normal [2, 3]. These ERG and EOG findings suggest that the abnormal ERGs in patients with XLRS result from dysfunction of the on and off bipolar cells in the rod and cone pathways. Fig Mixed rod cone (bright flash) ERGs from a normal subject and three patients with XLRS at different stages

85 2.8 X-Linked Retinoschisis 77 Because the negative ERGs and subnormal rod, cone ERGs resemble the ERGs of patients with the incomplete type of congenital stationary night blindness (incomplete CSNB) [8], differential diagnostic tests to distinguish XLRS and incomplete CSNB are important, particularly when the macular changes in patients with XLRS are subtle (see Section ). One of the differential diagnostic tests is the S (blue)-cone ERG. The S-cone ERG is essentially absent in patients with XLRS (Fig. 2.37), as in complete CSNB, whereas it is clearly present in incomplete CSNB [9] (see Section ). Fig Full-field rod and cone ERGs from a 17-year-old male patient with XLRS Fig Blue (B)-cone and red-green (R-G)-cone ERGs from a normal subject and two patients with XLRS. Only the B-cone ERG is absent. (From Yagasaki and Miyake [9])

86 78 2 Hereditary Retinal and Allied Diseases Focal Macular ERGs To characterize focal macular ERGs from patients with XLRS, we have divided the patients into two groups [10]. Group 1 includes those who have foveoschisis with little or no change in their foveal fluorescein angiograms, and group 2 includes those with advanced macular changes with nonspecific macular degeneration. The focal macular ERGs elicited by 5, 10, and 15 spots from representative patients from both groups are compared with those from a normal subject in Fig In group 1 (case 1), the a-wave amplitudes are within the normal limits, but the amplitudes of the b-waves and OPs are significantly smaller than those for normal control subjects. The mean b-wave/ a-wave (b/a) ratios are significantly smaller than in normal eyes, and the ratio decreases with decreasing spot size. The implicit times of the a-waves, b-waves, and OPs are significantly delayed. In group 2 (case 2), the focal macular ERG is nearly absent. These results of focal macular ERGs suggest that the pathology in the macula during the early stage of XLRS may be mainly in the bipolar cell layer. The on bipolar cells may be more severely affected than the off bipolar cells because the a-wave is relatively better preserved than the b-wave. During the late stage, when fluorescein angiography shows window defects of the RPE, the macular cones may also be affected, resulting in undetectable ERGs. Fig Focal macular ERGs elicited by 5, 10, and 15 diameter stimuli from a normal subject and from patients in groups 1 and 2. A time constant (T.C.) of 0.03 s with a 100-Hz high-cut filter was used to record a-waves and b-waves (at the left in each case), and a T.C. of s was used to record OPs. The mean visual acuity for group 1 was 0.6, and for group 2 it was 0.1. (From Miyake et al. [10])

87 2.8 X-Linked Retinoschisis Multifocal ERGs The amplitudes of the first-order kernel of the multifocal ERGs in group 1 patients with XLRS are markedly reduced in the central retina, corresponding to the area of the foveal schisis (Fig. 2.39) [11]. The amplitude of the focal responses outside the foveal area varies widely, but most patients show some degree of reduced amplitude, although the implicit times are significantly delayed. These findings suggest that the pathology of XLRS affects the implicit times more than the amplitude. As mentioned, a schisis is present in the periphery in about 50% of patients with XLRS. It is interesting to study how the peripheral retinoschisis affects the ERG responses in these areas. Two patients with peripheral retinoschisis were examined [11]. Drawings of their fundus and their visual field maps are shown in Fig The gray areas of the multifocal ERGs in Fig indicate the retinal areas corresponding to peripheral retinoschisis. The multifocal ERG amplitudes in the areas of peripheral retinoschisis are within the normal range and are not different from those from the adjacent retinal areas without retinoschisis. These results suggest that the outer and middle retinal layers are still functioning relatively well despite the balloon-like retinoschisis. This is reasonable because the splitting of the retina is in the nerve fiber layer, and the nerve fiber layer does not contribute to the multifocal ERGs. In the patients in group 2, the amplitudes of the local cone responses are smaller than the 95% confidence limits at nearly all loci in the 30 field. The amplitude of the second-order kernel is substantially smaller and essentially absent at nearly all locations. This is true even in retinal areas where the amplitudes of the first-order kernels are normal. The summated first-order kernel and the second-order kernel waveforms in normal subjects and XLRS patients are compared in Fig The amplitude of the summated secondorder kernel is more reduced than that of normal controls, and the second-order kernel is more reduced than the first-order kernels, presumably owing to widespread dysfunction of the proximal retina.

88 80 2 Hereditary Retinal and Allied Diseases Fig Averaged waveforms of the multifocal ERGs for three eccentric rings (1&2, 3&4, 5&6). Results for 13 normal subjects and 7 XLRS patients of group 1 are superimposed. The dotted vertical line is drawn at 30 ms. (From Piao et al. [11], with permission) Fig Fundus and Goldmann kinetic visual fields of two patients with peripheral retinoschisis and large inner retinal holes. (From Piao et al. [11], with permission)

89 2.8 X-Linked Retinoschisis 81 Fig The 103 focal first-order kernels of multifocal ERGs recorded from a normal control (top left), an XLRS patient without peripheral retinoschisis (P1), and the two XLRS patients with peripheral retinoschisis shown in Fig (P2, P3). Gray circles indicate the retinal areas corresponding to the peripheral retinoschisis. The responses in the area of the foveoschisis are relatively smaller than in other areas, but the responses in the areas of peripheral schisis are not smaller than those in the adjacent retinal areas without retinoschisis. (From Piao et al. [11], with permission) Fig Summed first-order kernels (A) and second-order kernels (B) for 103 local responses from 15 normal subjects and 7 patients. All of these responses are superimposed in the upper traces; averaged waveforms are presented in each lower trace. (From Piao et al. [11], with permission)

90 82 2 Hereditary Retinal and Allied Diseases Golden Tapetal-like Fundus Reflex The ophthalmoscopic appearance of the fundi of patients with XLRS is either a homogeneous or streaked tapetal-like reflex in the midperipheral retina. The appearance has been described as flaking gold, gold-dusted, goldenyellow, grayish white, or yellowish white (Fig. 2.31H). The mechanism underlying this reflex remains to be determined. This reflex in the eyes of patients with XLRS closely resembles the color of the fundus of eyes with Oguchi s disease. The abnormal reflex in Oguchi s disease disappears after extensive dark adaptation (Mizuo phenomenon, see Section 2.12) [12]. De Jong et al. reported that this change in the appearance of the fundus with dark adaptation can also be seen in eyes with XLRS [13]. They hypothesized that excess extracellular K + in the retina causes the golden reflex. We have had two patients with XLRS who had the tapetal-like reflex and developed vitreous hemorrhage. Vitrectomy was performed by peeling the posterior hyaloid membrane. The tapetal-like reflex, which had been present before the massive vitreous hemorrhage, disappeared after the posterior hyaloid was peeled from the retinal surface [14] (Fig. 2.43). If the hypothesis of de Jong et al. is correct, our findings suggest that the flow of K + toward the vitreous cavity may be accelerated by peeling the posterior hyaloid, leading to a decrease in K + concentration in the inner retina and disappearance of the golden reflex. However, despite the disappearance of the golden reflex following peeling of the posterior hyaloid, the postoperative ERG did not change significantly (Fig. 2.44). Fig tapetal-like golden reflex in the inferior retina of a 42-year-old man wth XLRS before peeling the posterior hyaloid (A) and the disappearance of the tapetallike reflex afterward (B). (From Miyake and Terasaki [14], with permission) Fig ERGs recorded with bright white light before (A) and after (B) surgery in the patient with XLRS shown in Fig A normal control is shown at the bottom (C). Arrowheads indicate the stimulus onset. (From Miyake and Terasaki [14], with permission)

91 2.8 X-Linked Retinoschisis Molecular Genetics Recent molecular genetic studies have provided new insights into the mechanism involved in the retinal dysfunction of XLRS [15]. The gene causing XLRS encodes a retina-specific polypeptide, RS1, also called retinoschisim. RS1 is expressed on the cell surface of rod and cone photoreceptors and on bipolar cells but not on Mueller cells or ganglion cells. This protein is thought to play an important role in cellular adhesion and the cell cell interaction that maintains the integrity of retinal neurons. RS1- deficient mice showed overall disorganization of the retinal cell layers, splitting of the inner nuclear layer, and reduction of the ERG b-wave amplitude.

92 84 2 Hereditary Retinal and Allied Diseases Unusual Forms of XLRS Case with Normal Full-field ERGs In 1999 Sieving and coworkers reported on a 13-year-old boy with XLRS who had a preserved b-wave [16]. He was a member of a family affected by XLRS, with an Arg213Try mutation in the XLRS1 gene. His affected 54- year-old grandfather had negative-type ERGs. A similar patient from our clinic is shown in Fig [17]. This 26-year-old man was first examined at age 7 years because of reduced visual acuity of 0.7 in both eyes. Ophthalmoscopically, he had foveal cysts in both eyes but no other signs of retinoschisis; a golden tapetal reflex was not detected. During the 19-year follow-up, full-field ERGs were recorded six times, and the b-wave of the mixed rod cone (single bright flash) ERGs were always normal, as was the a-wave. However, the focal macular ERGs had a negative configuration (Fig. 2.46). Despite the normal full-field ERGs, he was diagnosed as having XLRS because a novel missense mutation, Pro193Ser (c.577c to T), in the XLRS gene was found in his blood DNA [17]. The findings in these patients indicate that we cannot exclude a diagnosis of XLRS in patients with foveal cysts even when the fullfield ERGs are normal. Although most patients with XLRS have widespread and diffuse dysfunction of the bipolar cell layer, including the fovea, as well as reduced b-waves in their fullfield ERGs, the pathology may be localized only in the fovea, as it was in this patient. Fig Fundus of a patient with XLRS. There was a mutation, Pro193Ser, in the XLRS gene. Foveal schisis was present, but other parts of the retina appeared normal Fig Full-field bright flash, mixed rod cone ERGs (left) and focal macular ERGs elicited by a 15 spot (right) from a normal subject and the patient with XLRS whose fundus is shown in Fig. 2.44

93 2.8 X-Linked Retinoschisis Peripheral Schisis Without Foveoschisis As mentioned above, foveoschisis or nonspecific macular degeneration is always present in patients with XLRS. We have studied one patient who had a peripheral schisis with normal maculas. This 15-year-old boy had visual acuity of 1.0 in both eyes also visual field defects in both eyes. His maternal brother was reported to have poor visual acuity but was not available for examination. A peripheral schisis with inner retinal breaks in the inferior retina was present in both fundi, but ophthalmoscopy and fluorescein angiography showed that the maculas were normal (Fig. 2.47). The full-field ERGs were the negative type, but the focal macular ERGs were normal (Fig. 2.48). Gene analysis has not been performed. The ERGs of these patients suggest that, unlike most patients with XLRS, the functional abnormality is not widespread or homogeneous. It is limited to the area of the schisis that can be seen ophthalmoscopically. A B Fig Fundus of a patient with XLRS. A Peripheral retinoschisis with inner retinal holes is present. B The ophthalmoscopic appearance of the macula is normal Fig Full-field bright flash (mixed rod cone) ERGs (left) and focal macular ERGs elicited by a 15 spot (right) from the patient whose fundus is shown in Fig. 2.47

94 86 2 Hereditary Retinal and Allied Diseases XLRS Associated with Multiple White Flecks in the Retina White flecks in the retina may be associated with XLRS, as shown in Fig. 2.31I [18]. The visual functions, including ERG findings, are similar to those of typical XRLS patients. These flecks resemble to some degree those seen in patients with fundus albipunctatus with a mutation of the RDH5 gene, which is highly expressed in the RPE and causes fundus albipunctatus. However, all of these patients with multiple white flecks have mutations only in the XLRS1 gene, and they do not have RDH gene mutations [19]. These results indicate that the association of multiple flecks in the retina is a phenotypic variation of XLRS. References 1. Deutman AF (1971) Sex-linked juvenile retinoschisis. In: Deutman AF (ed) Hereditary dystrophies of the posterior pole of the eye. Charles C Thomas, Springfield, IL, pp Miyake Y, Miyake S,Yamagida K, Kanda T (1981) X- chromosomal congenital retinoschisis: its fundus polymorphism and visual function. Acta Soc Ophthalmol Jpn 85: Hirose T, Wolf E, Hara A (1976) Electrophysiological and psychophysical studies in congenital retinoschisis of X-linked recessive inheritance. Doc Ophthalmol 13: Miyake Y (2003) Macular dystrophy (survey). Acta Soc Ophthalmol Jpn 107: Manschot WA (1972) Pathology of hereditary juvenile retinoschisis. Arch Ophthalmol 88: Kato K, Miyake Y, Kachi S, Suzuki T, Terasaki H, Kawase Y, et al (2001) Axial length and refractive error in X-linked retinoschisis. Am J Ophthalmol 131: Nakamura N, Miyake Y, Niwa M (1991) Diagnostic problems in a case of retinal detachment with juvenile retinoschisis. Jpn Rev Clin Ophthalmol 85: Miyake Y, Yagasaki K, Horiguchi M, Kawase Y, Kanda T (1986) Congenital stationary night blindness with negative electroretinogram: a new classification. Arch Ophthalmol 104: Yagasaki K, Miyake Y (1983) Blue cone ERG in X- linked congenital retinoschisis. Folia Ophthalmol Jpn 34: Miyake Y, Shiroyama N, Ota I, Horiguchi M (1993) Focal macular electroretinogram in X-linked congenital retinoschisis. Invest Ophthalmol Vis Sci 34: Piao CH, Kondo M, Nakamura M, Terasaki H, Miyake Y (2003) Multifocal electroretinograms in X-linked retinoschisis. Invest Ophthalmol Vis Sci 44: Mizuo G (1913) A new discovery in the dark adaptation in Oguchi s disease. Acta Soc Ophthalmol Jpn 17: De Jong PTVM, Zrenner E, van Meel GJ, Keunenn EE, van Norren D (1991) Mizuo phenomenon in X- linked juvenile retinoschisis: pathogenesis of the Mizuo phenomenon. Arch Ophthalmol 109: Miyake Y, Terasaki H (1999) Golden tapetal-like fundus reflex and posterior hyaloid in a patient with X-linked juvenile retinoschisis. Retina 19: The Retinoschisis Consortium (1998) Functional implication of the spectrum of mutations found in 234 cases with X-linked juvenile retinoschisis (XLRS). Hum Mol Genet 7: Sieving PA, Bingham EL, Kemp J, Richards J, Hiriyanna K (1999) Juvenile X-linked retinoschisis from XLRS1 Arg213Trp mutation with preservation of the electroretinogram scotopic b-wave. Am J Ophthalmol 128: Nakamura M, Ito S, Terasaki H, Miyake Y (2001) Japanese X-linked juvenile retinoschisis: conflict of phenotype and genotype with novel mutations in the XLRS1 gene. Arch Ophthalmol 119: van Schooneveld MJ, Miyake Y (1994) Fundus albipunctatus-like lesions in juvenile retinoschisis. Br J Ophthalmol 78: Hotta Y, Nakamura M, Okamoto Y, Nomura R, Terasaki H, Miyake Y (2001) Different mutation of the XLRS1 gene causes juvenile retinoschisis with retinal white flecks. Br J Ophthalmol 85:

95 2.9 Nettleship-Falls X-Linked Ocular Albinism Nettleship-Falls X-Linked Ocular Albinism Nettleship-Falls ocular albinism is an X-linked recessively inherited retinal disease characterized by reduced visual acuity,translucent irides, congenital nystagmus, photophobia, hypopigmentation of the fundi, and foveal dysplasia (Fig. 2.49) [1, 2]. Full-field ERGs and EOGs are normal (Fig. 2.50), and focal macular ERGs are moderately reduced because of the foveal dysplasia (Fig. 2.51). Histopathological examination of the retina has revealed evidence of foveomacular dysplasia [3], including absence of a foveal pit, which can also be detected by OCT (Fig. 2.52). The ganglion cell layer is present throughout the macula and resembles that seen in the parafoveal area of normal subjects. In a variant of X-linked ocular albinism in Black and Japanese men, the transillumination defect of the iris and the characteristic fundus hypopigmentation may not be present as shown in Fig Visual acuity may be better than that in typical X-linked ocular albinism. In such cases, the diagnosis may require skin biopsy. However, it should be noted that asymptomatic female carriers of these mutations always show streaky and mottled RPE ophthalmoscopically, which is of diagnostic value (Fig. 2.53) [2]. The full-field ERGs and the focal macular ERG and OCT are normal in the female carriers. Fig Iris hypopigmentation (left) and fundus photograph (right) from a 35-year-old male patient with Nettleship-Falls ocular albinism. The visual acuity was 0.4

96 88 2 Hereditary Retinal and Allied Diseases Fig Full-field ERGs from a normal control and the patient whose fundus is shown in Fig Fig Focal macular ERGs elicited by 5 and 10 spots from a normal control and the patient shown in Fig Fig OCT of a patient with Nettleship-Falls ocular albinism. A ganglion cell layer is present throughout the macula and resembles that seen in the perifoveal area of normal individuals

97 2.9 Nettleship-Falls X-Linked Ocular Albinism 89 Fig Fundi of four female carriers of Nettleship-Falls ocular albinism, showing streaky and mottled retinal pigment epithelium References 1. Nettleship E (1909) On some hereditary diseases of the eye. Trans Ophthalmol Soc UK 29:LVII CXCVIII 2. Falls HF (1951) Sex-linked ocular albinism displaying typical fundus changes in the female heterozygote. Am J Ophthalmol 34(Pt 2): Garner A, Jay BS (1980) Macromelanosomes in X- linked ocular albinism. Histopathology 4:

98 90 2 Hereditary Retinal and Allied Diseases 2.10 Complete and Incomplete Types of CSNB This section is one of the most important because of the time and energy we have spent studying the various types of congenital stationary night blindness (CSNB). Patients with the Schubert-Bornschein type of CSNB [1] have normal fundi; and the mixed rod cone ERGs, elicited by a single bright flash in the dark, has a negative configuration (negative-type ERG; amplitude of the a-wave > amplitude of the b-wave). Our phenotypic and molecular genetic analyses have proved that the Schubert-Bornschein type of CSNB is made up of two clinical entities: the complete type of CSNB (CSNB1) and the incomplete type of CSNB (CSNB2) [2]. The distinction between the complete and incomplete types of CSNB was based on rod function and was evaluated by routine darkadaptometry and rod-mediated ERGs. Patients with complete CSNB lack rod function, whereas those with incomplete CSNB have residual rod function.although these two types of CSNB have common findings, such as normal fundi and negative ERGs with normal electrooculograms (EOGs), there are several important differences (described later). This new classification of the CSNBs with normal fundi led us to identify a new clinical entity, the incomplete type of CSNB [1]. Before then, patients with incomplete CSNB had been diagnosed as having a phenotypic subtype of the complete type of CSNB. The hereditary mode of transmission of complete CSNB is either X-linked recessive or autosomal recessive, whereas that for incomplete CSNB is X-linked recessive only. In extensive studies, we have not been able to find any differences in the ocular findings in patients with X-linked versus those with autosomal recessive hereditary complete CSNB. Our classification has been verified by molecular genetic analyses [3]. It has been reported that X-linked complete CSNB has a mutation of the leucine-rich repeat proteoglycan (NYX) gene [4, 5], whereas X-linked incomplete CSNB has a mutation in the calcium channel (CACNA1F) gene [6, 7]. In addition, dysfunction of either the on bipolar cells alone (complete CSNB) or of both the on and off bipolar cells (incomplete CSNB) has been demonstrated [7 9]. This difference has allowed us to investigate the function of the on and off bipolar cells individually in clinical patients.

99 2.10 Complete and Incomplete Types of CSNB Fundus Appearance The fundus photographs of patients with complete and incomplete CSNB, which was verified by molecular genetics [10, 11], are shown in Figs and The fundus in both types of CSNB is essentially normal. However, because complete CSNB is often associated with high myopia, most patients with this disorder display the characteristics of a myopic fundus and may show slight temporal pallor of the optic disk and/or a tilted disk. Incomplete CSNB has been suggested to be the same clinical entity as the Forsius-Erickson type of ocular albinism (Åaland Island eye disease) [12] because of the similarities of the ERGs. However, none of our patients had hypopigmentation of the fundus. Fig Fundi of patients with complete congenital stationary night blindness (CSNB) with leucine-rich repeat proteoglycan (NYX) gene mutation [NYX(+)] and without NYX gene mutation [NYX(-)]. The hereditary mode of transmission in complete CSNB with an NYX gene mutation is X-linked recessive, and that of complete CSNB without an NYX gene mutation is most likely autosomal recessive Fig Fundi of patients with incomplete CSNB with a mutation of the calcium channel (CACNA1F) gene. None of the patients showed the hypopigmentation of the fundus that is always seen with Forsius-Eriksson syndrome. (From Miyake [10])

100 92 2 Hereditary Retinal and Allied Diseases Visual Acuity and Refractive Errors Distribution of the corrected visual acuity of patients with both types of CSNB is shown in Fig The visual acuities ranged from 0.1 to 1.0 (mean ). The visual acuities of the patients with complete CSNB do not differ significantly from those with incomplete CSNB [10]. The distribution of the refractive errors in the two groups is shown in Fig Many patients with complete CSNB have moderate to high myopic refractive errors, whereas those with incomplete CSNB have mild myopic to hyperopic refractive errors. The difference in the mean refractive errors is significant [10]. Fig Distribution of visual acuity of complete and incomplete CSNB. (From Miyake [10]) Fig Distribution of refractive errors of complete and incomplete CSNB. (From Miyake [10])

101 2.10 Complete and Incomplete Types of CSNB Subjective Dark-Adaptation Curves Representative dark-adaptation curves from a normal subject and from patients with complete and incomplete CSNB are shown in Fig With complete CSNB, the cone threshold is elevated above that of normal individuals, and the rod threshold is the same as the cone threshold (i.e., no rod threshold). With incomplete CSNB, a rod threshold is present, although the final threshold is elevated by approximately log units above normal [2, 10]. Fig Comparison of darkadaptation curves for a normal control, a patient with complete CSNB, and a patient with incomplete CSNB. The dark-adaptation curve was measured at 15 of the superior retina with an 11 target with a Goldmann- Weekers adaptometer. (From Miyake [10])

102 94 2 Hereditary Retinal and Allied Diseases Initial Complaints of Patients The chief complaints at the initial visit of our 49 complete CSNB and 41 incomplete CSNB patients are listed in Table 2.1. Most of our patients had an initial complaint of blurred vision. Because of the normal fundus appearance, the correct diagnosis was not easy unless electroretinography was performed. It should be noted that only 1 of the 41 patients with incomplete CSNB complained of night blindness. The absence of a complaint of night blindness is important because if it was not reported it we might overlook CSNB in the differential diagnosis. We may not obtain ERGs from patients complaining of decreased vision without night blindness. Table 2.1. Chief complaints at initial visit of CSNB patients Complaint Complete type Incomplete type Low visual acuity Night blindness 15 1 Strabismus 13 5 Nystagmus 10 8 Familial survey 2 5 Others 4 1

103 2.10 Complete and Incomplete Types of CSNB Full-field ERGs Standard Full-field ERGs Representative examples of the standard fullfield ERGs recorded from patients with both types of CSNB are compared to those with normal eyes in Fig The rod ERG is absent in complete CSNB; it is present but reduced in incomplete CSNB. The mixed rod cone ERGs elicited by a single bright flash has a negative configuration with normal a-wave amplitude and reduced b-wave amplitude in both types of CSNB. The OPs are absent in the complete type but present in the incomplete type [2, 10]. The normal a-wave amplitude with reduced or absent rod ERGs suggests that both types of CSNB have a defect not in the rod photoreceptors but in the second-order neurons or their synapses in the rod visual pathway. The defect is almost complete in complete CSNB, whereas it is incomplete in incomplete CSNB. The cone and 30-Hz flicker ERGs appear nearly normal in complete CSNB except that the a- wave of the cone ERG has a plateau-like bottom (Fig. 2.59). In contrast, the cone and 30-Hz flicker ERG are extremely reduced in incomplete CSNB, which is highly characteristic and extremely important for the differential diagnosis. Fig Full-field ERGs recorded from a normal subject (left), a patient with complete CSNB (middle), and a patient with incomplete CSNB (right). The a- wave of a cone ERG in a complete CSNB patient shows a plateau-like flat bottom

104 96 2 Hereditary Retinal and Allied Diseases Hz Flicker ERG During Light Adaptation It was noted in Section that the amplitude of the cone-mediated ERGs in normal subjects increases by times during the course of light adaptation after sufficient dark adaptation. As shown in Fig. 2.60, this increase was seen in both types of CSNB, but the increase was exaggerated in incomplete CSNB [13]. Although the amplitudes of the 30-Hz flicker ERGs recorded after 30min of dark adaptation are small in incomplete CSNB, as mentioned, it is markedly increased (by times) after 10 min of light adaptation. This exaggerated increase is never seen in patients with complete CSNB, but they have a normal increase in the amplitude. The mechanism of this phenomenon is still unknown, but we believe that rod cone interactions may play an important role in creating this phenomenon (see Section ). Fig Changes in 30-Hz flicker ERGs during the course of light adaptation. ERGs were recorded after 30 min of dark adaptation from a normal control, a patient with complete CSNB, and a patient with incomplete CSNB. An exaggerated increase in the amplitude of the ERG is observed during light adaptation only in the eye with incomplete CSNB. (From Miyake et al. [13])

105 2.10 Complete and Incomplete Types of CSNB Scotopic Threshold Response The ERGs elicited by various intensities of dim stimuli (Fig. 2.61, top) and bright stimuli (Fig. 2.61, bottom) from a normal subject,two patients with complete CSNB, and two patients with incomplete CSNB are shown in Fig [14].As was shown in Section for a normal subject, the cornea-negative scotopic threshold response (STR) is recorded at an intensity of -8.2 log units, and the implicit time decreases as the stimulus intensity is increased. At -5.8 log units, the b-wave becomes clearly visible for the first time, and the amplitude increases with increasing stimulus intensities (Fig. 2.61, bottom), until it saturates at -1.4 log units. The a-wave begins to appear at -1.7 log units and the OPs at -0.8 log units. Fig ERGs elicited by various stimuli from a normal control, two patients with complete CSNB, and two patients with incomplete CSNB.The ERGs elicited by lower-intensity flashes are shown in the upper set (A) and those by higher intensities in the lower set (B). The time scale and calibration of amplitude of the upper and lower ERGs are different. (From Miyake et al. [14], with permission)

106 98 2 Hereditary Retinal and Allied Diseases With complete CSNB, neither the STR nor the b-wave was recorded when the stimulus intensity was low (Fig. 2.61, top). At an intermediate stimulus intensity of -4.4 log units (Fig. 2.61, bottom), both the a-waves and b- waves appear, with the a-wave having a normal amplitude. The a-waves and b-waves increase with increasing stimulus intensities, but the b- wave saturates quickly, resulting in an ERG with the amplitude of the a-wave larger than that of the b-wave, a negative-type ERG. OPs are undetectable in eyes with complete CSNB. With incomplete CSNB, the STR is first seen at a slightly higher threshold than in normal subjects, at -7.6 log units. However, the implicit time is approximately 80 ms longer than normal. A small b-wave appears at -5.8log units, as in normal subjects, with a comparable implicit time. At higher intensities, the b-wave amplitude saturates at -3.4 log units and is smaller than in the normal subject. The a-wave, on the other hand, continues to increase progressively, resulting in a negative ERG. The OPs are clearly visible. The interaction of the STR with the rod (scotopic) b-wave (bs) is interesting. Despite the subjective elevation of the rod threshold in patients with incomplete CSNB, the stimulus threshold for the b-wave may not be elevated, and the b-wave near threshold intensity may be of normal amplitude and implicit time. The STRs recorded from four normal subjects and four patients with incomplete CSNB at -6.8log units are compared with the near-threshold b-wave recorded at -5.4log units in Fig The negative peak of the STR and the positive peak of the b-wave have nearly the same implicit times in normal subjects, indicating that the b-wave is a summation of the positive P11 component and the negative STR. It is conceivable that when the STR is small or when its peak is greatly delayed, as in incomplete CSNB, the b-wave consists only of the positive P11 component. Thus, the b-wave amplitude may appear normal at this stimulus intensity because it does not include the negative STR component. Fig Scotopic threshold response (STR) recorded from normal subjects and patients with incomplete CSNB at -6.8 log units, compared with the near-threshold b- wave recorded at -5.4 log units. The negative peak of the STR and the positive peak of the b-wave have nearly the same implicit time in normal subjects; in those with incomplete CSNB, the implicit time of the negative STR is significantly delayed whereas the implicit time of the b-wave is normal. (From Miyake et al. [14], with permission)

107 2.10 Complete and Incomplete Types of CSNB On and Off Responses in Photopic ERGs The fundamental differences between rod and cone connections to the bipolar cells [9] were shown previously in Fig. 1.9 in Section The photoreceptors transmit visual information to the bipolar cells, which are the secondorder neurons. Rods contact only depolarizing (on) bipolar cells (DBCs), creating on visual pathways only. On the other hand, cones have more extensive postsynaptic connections. They synapse onto various cone bipolar cells, some of which are depolarizing cells and, like the rod DBCs, form the cone on pathway with a sign-inverting (-) synapse. Cones also make synapses with hyperpolarizing bipolar cells (HBCs) through sign-preserving (+) synapses in the cone off pathway. These two types of synapse are each selectively sensitive to different glutamate analogs. The sign-inverting (-) synapse can be blocked by 2-amino-4-phosphonobutyric acid (APB), and the sign-preserving (+) synapses are blocked by either +cis-2,3-piperidine dicarboxylic acid (PDA) or kynurenic acid (KYN). These drugs can preferentially block either the on or off pathways in the retina [15, 16]. Using photopic ERGs elicited by longduration square-wave stimuli,we found that the cone on response generated by depolarizing on bipolar cells is selectively and severely depressed in patients with complete CSNB [8]; moreover, the waveform is similar to that of monkeys after APB is injected into the vitreous to block the synapse between photoreceptors and on bipolar cells (Fig. 2.63). The off response, on the other hand, which is generated by hyperpolarizing bipolar cells, is intact in Fig Comparison of photopic long-duration ERGs recorded from a monkey and a human. Left: Normal control ERG for the monkey eye and after being treated by 2-amino- 4- phosphonobutyric acid (APB). Right: ERGs recorded from a normal human control, from a patient with complete CSNB, and from a patient with incomplete CSNB. (From Miyake et al. [8], with permission) Fig Photopic ERGs elicited by square wave stimuli of various durations from a normal control and a patient with complete CSNB. Thick lines underneath the responses represent the stimulus duration. (From Miyake [10])

108 100 2 Hereditary Retinal and Allied Diseases patients with complete CSNB, leading us to hypothesize that the on function of both the rod and cone visual pathways is completely blocked in eyes with complete CSNB. The complete defect of the on pathway results in the complete night blindness detected in patients with complete CSNB because rods connect only to the on bipolar cells. It is interesting to consider why the standard brief flash cone ERG consists of a normalappearing response despite the defects of the on component evaluated by the long-flash photopic ERG. The mechanism involved in generating this phenomenon is shown in Fig With long-duration stimuli, the a-waves, b- waves, and d-waves are clearly separated.as the stimulus duration is shortened, the d-wave approaches the b-wave; and when the stimulus duration is short (brief flash stimuli), the positive component of the photopic ERG consists mainly of the d-wave. Therefore even when the b-wave, a component of the on response, is absent (as in complete CSNB), the d-wave replaces the b-wave, and a positive wave is recorded with brief-flash stimuli [10]. With incomplete CSNB, on the other hand, the story is more complex, with both subnormal on and off responses. We hypothesized that the on and off systems are incompletely disturbed at the level of the bipolar cells in patients with incomplete CSNB [10]. This hypothesis was confirmed by the standard full-field ERGs recorded from the monkey s eye after being treated by neurotransmitter blocking agents [10]. The technique of full-field ERGs recording from monkeys under the same conditions as human patients is shown in Fig The ERGs recorded after the on synapses were completely blocked by APB are identical to those recorded from complete CSNB patients (Fig. 2.66A). After the monkey eye was treated with low levels of APB and PDA to block both the on and off synapses incompletely, the shape of the full-field ERG is similar to that for incomplete CSNB (Fig. 2.66B) Fig Full-field ERGs being recorded from a monkey under the same conditions used for humans Fig Comparison of full-field ERGs recorded from a human subject and a monkey. A ERGs from a normal human subject, a patient with complete CSNB, and a monkey after treatment with high levels of APB. B ERGs from a normal human subject, a patient with incomplete CSNB, and a monkey after treatment with low levels of APB and PDA

109 2.10 Complete and Incomplete Types of CSNB S-Cone ERGs and Subjective Blue Sensitivity The S-cone ERGs are markedly different in the two types of CSNB because the S-cones connect only to the on bipolar cells, whereas ML-cones connect to both on and off bipolar cells [17]. Thus, the full-field S-cone ERG is undetectable in complete CSNB [18, 19], which is reasonable, but it is relatively well preserved in cases of incomplete CSNB [19] (Fig. 2.67). The wellpreserved S-cone ERG for incomplete CSNB is diagnostically important because the full-field ERGs of incomplete CSNB are similar to those of X-linked congenital retinoschisis. However, the S-cone ERGs from patients with X-linked congenital retinoschisis are selectively absent (see Fig in Section ). This functional difference is important for determining the pathogenesis of these two disorders. With complete CSNB, it is somewhat curious that despite the fact that S-cone ERGs are undetectable, subjective color vision is essentially normal [18]. The blue-on-yellow perimetric findings in five patients with complete CSNB and four patients with incomplete CSNB are shown in Fig The blue sensitivity is nearly normal in patients with incomplete CSNB [10] but is severely depressed in patients with complete CSNB. However, the blue sensitivity is well preserved in the central 10 to 15 in complete CSNB [20]. These findings solve the riddle of the discrepancy between the undetectable fullfield S-cone ERGs and normal color vision in patients with complete CSNB because psychophysically determined color vision is influenced mainly by the central visual field. In addition, these findings lead us to believe that the macula of complete CSNB patients may have a unique pathology that is different from that in other parts of the retina. This topic is discussed in the following section. Fig Full-field S-cone ERGs recorded from five normal subjects, five patients with complete CSNB, and three patients with incomplete CSNB. (From Miyake et al. [19]) Fig Blue-on-yellow perimetric fields from the five patients with complete CSNB and the four patients with incomplete CSNB whose ERGs are shown in Fig (From Terasaki et al. [20], with permission)

110 102 2 Hereditary Retinal and Allied Diseases Focal Macular ERGs and Multifocal ERGs As mentioned, the blue sensitivity is preserved only in the macula in patients with complete CSNB, suggesting that the on function is preserved only in the macula. This is supported by the results of full-field ERGs and focal macular ERGs elicited by long-duration stimuli. A comparison of full-field, long-duration photopic ERGs and focal macular ERGs recorded from a normal subject and from a patient with complete CSNB are shown in Fig [10]. The full-field ERG recorded from the patient with complete CSNB has a hyperpolarizing pattern (large a-waves and d-waves and almost undetectable b-waves), whereas the focal macular ERG has a large b-wave-like positive deflection with delayed implicit time. These findings suggest that some of the on function is preserved but only in the macula in complete CSNB, as was shown by preservation of the psychophysically determined blue sensitivity (see Fig. 2.68). Although the properties of this positive deflection in the macula have still not been determined, the pathophysiology of the macula may be different from that of other retinal areas in complete CSNB. Because the pathogenesis of complete CSNB is most likely due mainly to complete blockage of signal transmission between the photoreceptors and the on bipolar cells, it was interesting to study the focal retinal responses using multifocal ERG techniques [21]. The amplitudes of the first-order kernel of the multifocal ERGs in patients with complete CSNB are normal, but the implicit times are delayed over nearly the entire field (Fig. 2.70). There is no central depression. The second-order kernel, which is involved in adaptive mechanisms of the retina to repeated flashes and contains a large contribution from the neural cells in the proximal layers of the retina, is selectively reduced. The delay of the implicit times of the first-order kernel may be related to the severe reduction in the amplitude of the second-order kernel (Fig. 2.70). Fig Full-field long-flash photopic ERG and focal macular ERG recorded from a normal subject and a patient with complete CSNB. Despite the absence of a b-wave (on component) in the full-field ERG of the patient with complete CSNB, the focal macular ERG shows a large b-wave. OP, oscillatory potential. (From Miyake [10])

111 2.10 Complete and Incomplete Types of CSNB 103 Fig Left: Map of the amplitudes and implicit times of first-order kernels of multifocal ERGs for four patients with complete CSNB. White areas, values within the 5th to 95th percentile range of normal; black areas, amplitudes and implicit times outside the 5th to 95th percentile range of normal. Note that there are regional variations for both the amplitudes and implicit times of the multifocal ERG across the retina for normal subjects. The normal ranges of the amplitude and implicit time were calculated independently for all locations. Right: Summated second-order kernels for all 61 local responses for 20 myopic controls and four patients with complete CSNB. All responses were superimposed in the top trace and averaged in the bottom trace. (From Kondo et al. [21], with permission)

112 104 2 Hereditary Retinal and Allied Diseases Carrier State of X-Linked CSNB In 1983 we reported that the OPs of the fullfield, mixed rod cone ERG in patients with the X-linked Schubert-Bornschein type of CSNB were significantly reduced [22]. At that time, however, we thought that the Schubert-Bornschein type was one disease entity and had not classified CSNB into complete and incomplete forms. Therefore, our analysis was of complete and incomplete CSNB combined. After we classified CSNB into the two types [2], we reanalyzed the results and found that the full-field mixed rod cone ERGs of both complete and incomplete CSNB have a carrier state with reduced OPs [23]. Figure 2.71 shows the full-field rod cone ERGs recorded from female carriers of X- linked recessive complete and incomplete CSNB. A single flash ERG was recorded with a bright-white flash, 20 joules in intensity, after 30 min of dark adaptation. Two recordings were done simultaneously, using two different time constants (TC).A TC of 0.003s was used to evaluate OPs. In both types, only OPs are selectively reduced. Fig Single flash rod cone ERGs recorded with two different time constants in a normal subject (top) and in female carriers of complete (bottom left) and incomplete (bottom right). The a-wave and b- wave are normal, but the OPs show selective reduction of amplitude. The implicit time of OPs is within the normal range

113 2.10 Complete and Incomplete Types of CSNB Molecular Genetics Evidence of genetic heterogeneity in X-linked complete and incomplete CSNB was reported by Boycott et al. in 1998 [3]. Soon thereafter, the gene for X-linked incomplete CSNB was identified by Strom et al. [6] and Bech-Hansen et al. [7] as the pore-forming subunit of an L-type voltage-gated calcium channel (CACNA1F) that is found in the retina. Loss of the functional channel impairs the calcium influx into rods and cones that is needed for sustaining the tonic release of neurotransmitters from the presynaptic terminals. Among our Japanese patients with incomplete CSNB, all had the CACNA1F gene mutation, indicating that the phenotypic classification had provided a precise diagnosis of incomplete CSNB [10, 11]. A summary of the CACNA1F protein, showing all reported mutations including those of our studies, is presented in Fig The fundus photographs from all patients with incomplete CSNB who had been proven to have a mutation of the CACNA1F gene are shown in Fig. 2.53, and the full-field ERGs from all of these patients and the specific mutations are shown in Fig It is surprising that the shape of the ERGs was extremely uniform, and all patients had had a correct diagnosis of incomplete CSNB before undergoing a molecular genetic examination. This indicates how the full-field ERGs provide significant information for the correct diagnosis. In 2000 the NYX gene was cloned from the Xp11 region by Bech-Hansen et al. [4] and Pusch et al. [5] The NYX gene encodes the glycosylphosphatidyl (GTP)-anchored extracellular protein nyctalopin. Nyctalopin, a new, unique member of the small, leucine-rich proteoglycan family, may be the gene product that guides and promotes the formation and function of the on pathway in the retina. The full-field ERGs of patients with complete CSNB caused by a mutation in the NYX gene and ERGs from individuals who do not have this mutation are shown in Fig The fundus photographs of these patients were shown earlier, in Fig The inheritance pattern of the patients with the NYX gene mutation is X-linked recessive,and that of those without the NYX gene mutation is most likely autosomal recessive. The full-field ERGs are not significantly different in the two groups, and both groups show a uniform waveform.

114 106 2 Hereditary Retinal and Allied Diseases Fig Mutated sites in the CACNA1F gene reported in the literature, including our patients. Filled circles, our patients; circle with left diagonal lines, patients of Storm et al.; circles with right diagonal lines, patients of Bech-Hansen et al. (From Nakamura et al. [11], with permission) Fig Full-field ERGs recorded from a normal subject and 15 of our patients with incomplete CSNB and a CACNA1F gene mutation. The specific mutation is given in the right column. (From Nakamura et al. [11], with permission)

115 2.10 Complete and Incomplete Types of CSNB 107 Fig Full-field ERGs recorded from a normal subject (upper), 6 patients with complete CSNB and an NYX gene mutation (middle) and 5 patients with complete CSNB but without an NYX gene mutation (lower). The specific mutation is given in the right column of the NYX(+) patients (From Miyake [10])

116 108 2 Hereditary Retinal and Allied Diseases Possible Pathogenesis Pathophysiological studies on clinical patients and animal models as well as molecular genetic analyses suggest that patients with X-linked complete CSNB have an almost complete block of synaptic transmission from the photoreceptors to the on bipolar cells in both the rod and cone visual pathways. The off pathway, however, appears to be intact. Patients with autosomal recessive complete CSNB appear to have similar pathophysiology. In contrast, patients with incomplete CSNB have an incomplete defect of the synapses in the on and off bipolar cells in the rod and cone visual pathways (Fig. 2.75). Fig Possible pathogenesis of complete and incomplete CSNB. Patients with complete CSNB have complete blockage of the on synapses (solid cross lines), whereas those with incomplete CSNB have an incomplete defect of the on and off synapses in both rod and cone visual pathways (dashed cross lines)

117 2.10 Complete and Incomplete Types of CSNB Are Complete and Incomplete Cases of CSNB Really Nonprogressive? Long-term follow-up of the corrected visual acuity in patients with complete and incomplete CSNB [24] is shown in Fig For both types of CSNB, most patients do not show significant changes or even slight improvement in their visual acuity during the long follow-up period. This strongly indicates that both types of CSNB are nonprogressive, at least when assessed by visual acuity. The full-field ERGs also show little decrease in amplitude during long-term follow-up; an example is shown in Fig The single flash ERG (rod cone mixed) was recorded from a patient with incomplete CSNB in 1970 and repeated again under similar conditions in After 32 years, the ERG did not decrease in amplitude, but the b-wave amplitude had increased [10]. This patient was found to have the mutated CACNA1F gene, as in most patients with incomplete CSNB [11]. In addition to these findings, families with X-linked complete and incomplete CSNB sometimes have a grandfather and grandson who, despite the large difference in age, have essentially the same clinical findings. These observations suggest that these two disorders are essentially stationary. However, among the patients with a CACNA1F gene mutation, we have found that some had a progressive clinical course and severely deteriorated visual function [25, 26]. The full-field ERGs of a 31-year-old man showed typical findings of incomplete CSNB (Fig. 2.78A). This patient had a hemizygous Arg913 stop mutation in the CACNA1F gene [25] (Fig. 2.78B). The fundus, fluorescein angiograms, and visual fields are shown in Fig The patient had atrophic retinal lesions around the inferior vascular arcades in both eyes that resembled that of pigmented paravenous retinochoroidal atrophy or sectorial retinitis pigmentosa. Fluorescein angiography revealed window defects in the areas corresponding to the atrophy, and Goldmann kinetic perimetry detected relative scotomas in the same areas. Fundus photographs of another two brothers [26] are shown in Fig The younger, 56-year-old brother (Fig. 2.80A,B) had optic atrophy, attenuated retinal vessels, and slightly diffuse pigmentary atrophy in both eyes. The older, 64-year-old brother (Fig. 2.80C,D) had optic atrophy and severe chorioretinal degeneration in both eyes. Both patients had progressive decline of visual functions and had an in-frame mutation with deletion and insertion in exon 4 of the CACNA1F gene. In both patients, the mixed rod cone ERG had a negative configuration, which is characteristic of incomplete CSNB. However, OPs were absent, and the rod and cone ERGs, which are not usually seen in patients with incomplete CSNB, were unrecordable (Fig. 2.81, cases 1, 2). These findings of three patients in two pedigrees indicated that mutations of the CACNA1F gene often lead to ERG findings that correspond to those for incomplete CSNB, but the mutations also occasionally lead to ERG changes associated with other retinal dystrophies that have retinal and optic disk atrophy with progressively decreasing visual function.

118 110 2 Hereditary Retinal and Allied Diseases Fig Mixed rod cone ERGs recorded in 1970 and 2002 from a patient with incomplete CSNB. (From Miyake [10]) Fig Changes in visual acuity in patients with complete and incomplete CSNB during long-term follow-up periods. (From Miyake et al. [24]) Fig A Full-field ERGs recorded from a normal subject and a patient with a CACNA1F gene mutation. B Nucleotide sequence of CACNA1F using a sense primer in this patient. A hemizygous nonsense mutation of C to T in axon 24 (Arg913stop) is shown. The arrow indicates the position of the mutation. (From Nakamura et al. [25], with permission)

119 2.10 Complete and Incomplete Types of CSNB 111 Fig Fundus photographs (A, B), fluorescein angiograms (C, D), and Goldmann kinetic visual fields (E) of the patient with a CACNA1F gene mutation shown in Fig Right eye (A, C) and left eye (B, D) show an atrophic retinal region around the inferior vascular arcade with hyperfluorescence due to RPE alterations. Visual fields show a relative scotoma in the area corresponding to retinal atrophy (E). (From Nakamura et al. [25], with permission)

120 112 2 Hereditary Retinal and Allied Diseases Fig Fundi of two patients with CACNA1F mutations (cases 1 and 2). Case 1 shows optic atrophy, attenuated retinal vessels, and diffuse RPE atrophy in both eyes. Case 2 shows optic atrophy, attenuated retinal vessels in both eyes, and severe chorioretinal degeneration in the left eye. (From Nakamura et al. [26], with permission) Fig Full-field ERGs recorded from a normal subject, a patient with typical incomplete CSNB, and two patients with optic atrophy and CACNA1F gene mutations (cases 1 and 2). (From Nakamura et al. [26], with permission)

121 2.10 Complete and Incomplete Types of CSNB 113 References 1. Schubert G, Bornscein H (1952) Beitrag zur Analyse des menshlichen Electroretinograms. Ophthalmologica 123: Miyake Y, Yagasaki K, Horiguchi M, Kawase Y, Kanda T (1986) Congenital stationary night blindness with negative electroretinogram: a new classification. Arch Ophthalmol 104: Boycott KM, Pearce WG, Musarella MA, Weleber RG, Maybaum LA, Birch DG, et al. (1998) Evidence for genetic heterogeneity in X-linked congenital stationary night blindness. Am J Hum Genet 62: Bech-Hansen NT, Naylor MJ, Maybaum TA, Sparkes RL, Koop B, Birch DG, et al. (2000) Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness. Nat Genet 26: Pusch CM, Neitz C, Brandau O, Pesch K, Achatz H, Feil S, et al. (2000) The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein. Nat Genet 26: Strom TM, Nyakatura G, Apfelstedt-Sylla E, Hellebrand H, Lorenz B, Weber BH, et al. (1998) An L- type calcium-channel gene mutated in incomplete X-linked congenital stationary night blindness. Nat Genet 19: Bech-Hansen NT, Naylor MJ, Maybaum TA, Pearce WG, Koop B, Fishman GA, et al. (1998) Lossof-function mutations in a calcium-channel a 1 - subunit gene in Xp cause incomplete X-linked congenital stationary night blindness. Nat Genet 19: Miyake Y, Yagasaki K, Horiguchi M, Kawase Y (1987) On- and off-responses in photopic electroretinogram in complete and incomplete types of congenital stationary night blindness. Jpn J Ophthalmol 31: Sieving PA (1993) Photopic on- and off-pathway abnormalities in retinal dystrophies. Trans Am Ophthalmol Soc 91: Miyake Y (2002) Establishment of the concept of new clinical entities: complete and incomplete form of congenital stationary night blindness. Acta Soc Ophthalmol Jpn 106: Nakamura M, Ito S, Terasaki H, Miyake Y (2001) Novel CACNA1F mutations in Japanese patients with incomplete congenital stationary night blindness. Invest Ophthalmol Vis Sci 42: Weleber RG, Pillers DM, Powell BR, Hanna CE, Magenis RE, Buist NRM (1989) Åaland Island eye disease (Forsius-Eriksson syndrome) associated with contiguous deletion syndrome at Xp 21. Arch Ophthalmol 107: Miyake Y, Horiguchi M, Ota I, Shiroyama N (1987) Characteristic ERG flicker anomaly in incomplete congenital stationary night blindness. Invest Ophthalmol Vis Sci 28: Miyake Y, Horiguchi M, Terasaki H, Kondo M (1994) Scotopic threshold response in complete and incomplete types of congenital stationary night blindness. Invest Ophthalmol Vis Sci 35: Slaughter HM, Miller RF (1981) 2-Amino-4-phosphonobutyric acid: a new pharmacological tool for retina research. Science 211: Slaughter HM, Miller RF (1983) An excitatory amino acid antagonist blocks cone input to signconserving second-order retinal neurons. Science 219: Kolb H, Lipets LE (1991) The anatomical basis for color vision in the vertebrate retina. In: Gouras P (ed) The perception of colour. Macmillan, London, pp Kamiyama M, Yamamoto S, Nitta K, Hayasaka S (1996) S-cone electroretinogram b-wave in complete congenital stationary night blindness. Br J Ophthalmol 80: Miyake Y, Horiguchi M, Suzuki S, Kondo M, Tanikawa A (1997) Complete and incomplete type congenital stationary night blindness as a model of on-retina and off-retina. In: LaVail MM, Hollyfield JG, Anderson RE (eds) Degenerative retinal diseases. Plenum, New York, pp Terasaki H, Miyake Y, Nomura R, Horiguchi M, Suzuki S, Kondo M (1999) Blue-on-yellow perimetry in the complete type of congenital stationary night blindness. Invest Ophthalmol Vis Sci 40: Kondo M, Miyake Y, Kondo N, Tanikawa A, Suzuki S, Horiguchi M, et al. (2001) Multifocal ERG findings in complete type congenital stationary night blindness. Invest Ophthalmol Vis Sci 42: Miyake Y, Kawase Y (1984) Reduced amplitude of oscillatory potentials in female carriers of X-linked recessive congenital stationary night blindness. Am J Ophthalmol 98: Miyake Y (1991) Carrier state of congenital stationary night blindness. In: Heckenlively JR (ed) Principle and practice of clinical electrophysiology of vision. Mosby-Year Book, St. Louis, pp Miyake Y, Kawase K, Kanda T (1986) Study on congenital stationary night blindness. Jpn Rev Clin Ophthalmol 80: Nakamura M, Ito S, Terasaki H, Miyake Y (2002) Incomplete congenital stationary night blindness associated with symmetrical retinal atrophy. Am J Ophthalmol 134: Nakamura M, Ito S, Piao CH, Terasaki H, Miyake Y (2003) Retinal and optic disc atrophy associated with a CACNA1F mutation in a Japanese family. Arch Ophthalmol 121:

122 114 2 Hereditary Retinal and Allied Diseases 2.11 Fundus Albipunctatus Fundus albipunctatus is a type of congenital stationary night blindness with an autosomal recessive inheritance pattern [1]. The fundus of these patients has a characteristic appearance: a large number of discrete, small, round or elliptical, yellowish white lesions at the level of the RPE (Fig. 2.82). The most characteristic property of their visual function is a delay in dark adaptation, which can be detected by the psychophysically determined dark-adaptation curve [2] (Fig. 2.83) and by ERGs (Fig. 2.84) [2] and EOGs [3] (Fig. 2.85). It requires 2 3h to attain the final dark-adapted threshold, the maximum scotopic ERG responses, and the normal EOG light rise. The cone-mediated ERGs are essentially normal (Fig. 2.83), and the visual acuity and visual fields are within normal limits. In 1992 we found that fundus albipunctatus patients may also have widespread cone dysfunction [4]. Such patients often have bull s-eye maculopathy (Fig. 2.86) with progressively decreased of visual acuity and color vision. The Fig Fundus of a patient with typical fundus albipunctatus Fig Dark-adaptation curve obtained from a normal control, and from patients with fundus albipunctatus and Oguchi s disease

123 2.11 Fundus Albipunctatus 115 Fig Full-field ERGs recorded from a normal subject and from a patient with fundus albipunctatus after 30 min (middle) and 3 h (right) of dark adaptation (DA) Fig Fundus of a patient with fundus flavimaculatus associated with bull s-eye maculopathy. (From Miyake et al. [4]) Fig Light rise of the EOG in a patient with fundus albipunctatus after various periods of pre-dark adaptation. Note the marked increase in the light rise after an increase in the duration of dark adaptation up of 60 min. DA, dark adaptation; LA, light adaptation. (From Miyake et al. [3])

124 116 2 Hereditary Retinal and Allied Diseases full-field ERGs recorded from three patients are shown in Fig As with typical fundus albipunctatus, all patients had delayed recovery of the rod ERGs, and the maximum ERG responses were obtained only after prolonged dark adaptation. The maximum amplitude of the b-wave in some patients was smaller than normal (case 2), indicating that rod function even after prolonged dark adaptation does not completely return to normal levels. Unlike the typical fundus albipunctatus, all patients have a marked reduction of cone-mediated ERGs. The progressive decrease in visual function, widespread dysfunction of the cone system, and bull s-eye maculopathy suggest an association of fundus albipunctatus with cone dystrophy. An example of the changes in the fundus during a long follow-up period in a patient with fundus albipunctatus associated with cone dystrophy is also shown (case 3) in Fig This patient was first examined by us in 1981 at the age of 40 years, when he reported that he had had night blindness from a young age. His visual acuity was 1.2 in both eyes, and his fundus had the typical fundus albipunctatus pattern, with normal-appearing macula in both eyes (Fig. 2.88). His rod ERG was undetectable, and a negative-type mixed rod cone ERG was recorded after 30 min of dark adaptation (Fig. 2.87,case 3).The amplitude in the ERGs became normal when recorded after 3h of dark adaptation. However, unlike typical fundus albipunctatus, his cone-mediated ERGs were nearly absent, suggesting an association with cone dystrophy. At the initial examination, it was difficult to imagine that the disease in this patient was associated with cone dystrophy because his fundus appeared similar to that of typical fundus albipunctatus with a normalappearing macula, and his visual acuity was 1.2. What was intriguing was that his full-field cone-mediated ERGs were undetectable.this patient has been followed for more than 20 years, and bull s-eye maculopathy began to appear in 1992 (Fig. 2.88). He was found to have homozygous mutations in the RDH5 gene. In many of our patients with fundus albipunctatus, the cone-mediated ERGs are extremely abnormal or essentially absent when they are associated with cone dystrophy. When we first reported such patients, it was still unclear whether their disorder represented an advanced stage of fundus albipunctatus, a distinct disease entity, or a chance combination of two diseases. In 1999, the 11-cis retinol dehydrogenase gene, RDH5, was identified as the mutated gene in patients with typical fundus albipunctatus [5]. We have analyzed the genetic makeup of many patients with fundus albipunctatus and cone or macular dystrophy and found that all of them had homozygous or compound heterozygous mutations in the RDH5 gene [6]. Because some mutations were detected in both groups, and because there was a progressive decrease in visual functions in patients with cone dystrophy, it was concluded that mutations of the RDH5 gene can cause progressive cone dystrophy as well as congenital stationary night blindness. After analyzing our large series of patients, we concluded that approximately one-third of the patients with this disorder have associated cone dystrophy or macular dystrophy, and the disease process in such patients is progressive. This points to the important fact that fundus albipunctatus is not always stationary, and that about one-third of the patients have a progressive disease that is associated with diffuse cone dystrophy. We have thus changed the disease concept of fundus albipunctatus, which had been believed to be a subtype of CSNB.

125 2.11 Fundus Albipunctatus 117 Fig Full-field ERGs recorded from three representative patients with fundus albipunctatus associated with cone dystrophy. In each case, the upper tracings are the responses recorded after 30 min of dark adaptation, and the lower traces are the responses recorded after prolonged dark adaptation. All patients have a marked decrease of the cone-mediated ERGs. After a long period of dark adaptation, the rod ERGs increased to within the normal limits in cases 1 and 3 but were still smaller than the normal limits in case 2. (From Miyake et al. [4]) Fig Appearance of the fundus in a patient with fundus albipunctatus associated with cone dystrophy. The photographs were taken in 1981 (top) and 2002 (bottom)

126 118 2 Hereditary Retinal and Allied Diseases References 1. Carr RE, Margolis S, Siegel IM,Weale RE (1976) Fluorescein angiography and vitamin A and oxalate levels in fundus albipunctatus. Am J Ophthalmol 82: Carr RE, Ripps H, Siegel IM, Weale RE (1966) Rhodopsin and the elecrical activity of the retina in congenital nightblindness. Invest Ophthalmol Vis Sci 5: Miyake Y, Watanabe I, Asano T, Sakai T (1974) Further studies on EOG in retinitis punctata albescens (effects of change of dark adaptation on EOG). Folia Ophthalmol Jpn 25: Miyake Y, Shiroyama N, Sugita S, Horiguchi M, Yagasaki K (1992) Fundus albipunctatus associated with cone dystrophy. Br J Ophthalmol 76: Yamamoto H, Simon A, Eriksson U, Harris E, Berson EL, Dryja TP (1999) Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus. Nat Genet 22: Nakamura M, Hotta Y, Tanikawa A, Terasaki H, Miyake Y (2000) A high association with cone dystrophy in fundus albipunctatus caused by mutations of the RDH5 gene. Invest Ophthalmol Vis Sci 41:

127 2.12 Oguchi s Disease Oguchi s Disease Oguchi s disease, first reported by Oguchi in 1907 [1], is an unusual form of congenital stationary night blindness. It is characterized by a peculiar grayish white discoloration of the fundus (Fig. 2.89). In 1913 Mizuo found that this unusual fundus coloration disappeared after a long period of dark adaptation [2]. This change in fundus coloration is now called the Mizuo phenomenon (Fig. 2.89). Mutations in the arrestin gene [3] or the rhodopsin kinase gene [4] cause the recessive form of Oguchi s disease. Arrestin and rhodopsin kinase act in sequence on reactive rhodopsin to stop the phototransduction cascade. Most patients who have been reported with mutations in the arrestin gene are Japanese [5]. Visual acuity, visual field, and color vision are normal in patients with Oguchi s disease. Rod function is absent both subjectively and electroretinographically after 30 min of dark adaptation, but the subjective rod function may reappear after 2 3 h of dark adaptation [6] (Fig. 2.83). Full-field ERGs recorded after 30 min of dark adaptation from seven patients with Oguchi s disease [7] are shown in Fig The rod ERGs are absent, and the cone-mediated ERGs are essentially normal. The mixed rod cone ERG (Fig. 2.91) has a negative configuration with relatively well-preserved OPs. For comparison, the mixed rod cone ERG of a patient with complete CSNB is also shown. The a-wave amplitude in Oguichi patients is reduced compared to that of normal controls and patients with complete CSNB. After 3h of dark adaptation, the amplitudes of the a-wave and b-wave of the mixed rod cone ERGs are larger, but they are still not normal. Consistent findings in the mixed rod cone ERGs recorded after 30 min of dark adaptation in patients with Oguchi s disease are (1) negative ERGs with reduced a-waves; (2) nearly absent b-waves; (3) relatively well-preserved OPs; and (4) essentially normal cone-mediated ERGs (Fig. 2.91). The pathogenic defect in the cone visual pathway in Oguchi s disease is different from that of complete CSNB and incomplete CSNB. Unlike complete and incomplete CSNB, the amplitude and waveform of the photopic ERGs elicited by long-duration stimuli are normal, indicating that the on and off systems of the cone visual pathway are functioning normally (Fig. 2.92). The focal macular ERGs are also normal (Fig. 2.93). The EOG ratio in Oguchi s disease is lower than normal in most Japanese patients [7].

128 120 2 Hereditary Retinal and Allied Diseases Fig Fundus of a patient with Oguchi s disease while lightadapted (top) and after a long period of dark-adaptation (bottom), demonstrating the Mizuo phenomenon Fig Full-field ERGs recorded from a normal control and seven patients with Oguchi s disease. (From Miyake et al. [7], with permission)

129 2.12 Oguchi s Disease 121 Fig Full-field mixed rod cone ERGs recorded from a normal control, a patient with complete CSNB, and seven patients with Oguchi s disease. ERGs were recorded after 30 min (middle) and after 3 h (right) of dark adaptation. (From Miyake et al. [7], with permission) Fig Full-field photopic ERGs elicited by long-duration stimuli and recorded from a normal subject, a patient with Oguchi s disease, and a patient with complete CSNB. (From Miyake et al. [7])

130 122 2 Hereditary Retinal and Allied Diseases Fig Focal macular ERGs elicited by three differently sized spots from a patient with Oguchi s disease and recorded with two different time constants (T.C.). All components are within the normal range, indicating that the macula was functioning normally References 1. Oguchi C (1907) Uber eine Abart von Hemeralopie. Acta Soc Ophthalmol Jpn 11: Mizuo G (1913) On a new discovery in the dark adaptation of Oguchi s disease. Acta Soc Ophthalmol Jpn 17: Fuchs S, Nakazawa M, Maw M, Tamai M, Oguchi Y, Gal A (1995) A homozygous 1-base pair deletion in the arrestin gene is a frequent cause of Oguchi disease in Japanese. Nat Genet 10: Yamamoto S, Sippel KC, Berson EL, Dryja TP (1997) Defects in the rhodopsin kinase gene in patients with the Oguchi form of stationary night blindness. Nat Genet 15: Nakamura M, Yamamoto S, Okada M, Ito S, Tano Y, Miyake Y (2004) Novel mutations in the arrestin gene and associated clinical features in Japanese patients with Oguchi s disease. Ophthalmology 111: Carr RE, Gouras P (1965) Oguchi s disease. Arch Ophthalmol 73: Miyake Y, Horiguchi M, Suzuki S, Kondo M, Tanikawa A (1996) Electrophysiological findings in patients with Oguchi s disease. Jpn J Ophthalmol 40:

131 2.13 Cone Dystrophy Cone Dystrophy General Concepts Patients with cone dystrophy belong clinically and genetically to a heterogeneous group of patients with inherited retinal dystrophies. They are characterized by widespread degeneration of the cone photoreceptors, leading to impaired central vision, loss of color vision, and photophobia [1, 2]. The disease process is progressive. At the advanced stage, most patients with cone dystrophy also have abnormal scotopic vision (cone rod dystrophy) [2, 3]. Because impairment of the cones is widespread, the full-field photopic ERG is always severely depressed, which is key to diagnosing cone dystrophy (Fig. 2.94). Localized macular problems, as with some types of macular dystrophy, do not lead to a significant reduction of the photopic ERGs (see Section 1.2.2). The fundus in patients with cone dystrophy may be within normal limits or may have subtle changes in the early stage [1, 2, 4]. These changes may progress to bull s-eye maculopathy and diffuse atrophy of the RPE in the far-advanced stage (Fig. 2.95) [2]. It should be noted that the appearance of the fundus and fluorescein angiograms may be essentially normal even when full-field photopic ERGs are absent [1, 3, 4]. In such cases, patients may be misdiagnosed as having optic nerve disease, central nerve system disease, amblyopia, or occult macular dystrophy [5] (see Section 2.19) unless the full-field ERGs are carefully evaluated. We have reported that the findings from vitreous fluorophotometry are normal in most patients with cone dystrophy, indicating that the barrier function of the RPE is well preserved until the advanced stage [6]. This is in marked contrast to patients with retinitis pigmentosa (rod cone dystrophy), in whom vitreous fluorophotometry may reveal significant abnormalities even during the early stage. Long-term follow-up of the full-field ERGs in two patients with autosomal dominant (A) and recessive (B) cone dystrophy is shown in Fig [2]. In 1981 the rod ERG was normal, but the cone and 30-Hz flicker ERGs were extremely reduced (B). Thereafter, the rod ERG gradually decreased (cone rod dystrophy), and in 1998 it was essentially absent. The fundus in 1998 showed diffuse RPE degeneration with attenuation of the retinal vessels similar to findings in patients with retinitis pigmentosa (rod cone dystrophy).

132 124 2 Hereditary Retinal and Allied Diseases Fig Full-field ERGs recorded from seven patients with typical cone dystrophy. The rod and mixed rod cone bright flash ERGs are normal, but the cone-mediated ERGs (cone and 30-Hz flicker) are selectively reduced. The column at the left indicates the age and sex of patients (Y, years; M, male; F, female) Fig Fundi and fluorescein angiograms of patients with cone dystrophy. A Normal appearance. B Bull s-eye maculopathy. C Diffuse RPE degeneration

133 Fig Long-term follow-up of full-field ERGs recorded from patients with autosomal dominant (A) and autosomal recessive (B) cone dystrophy. (From Miyake [2]) 2.13 Cone Dystrophy 125

134 126 2 Hereditary Retinal and Allied Diseases Molecular Genetics To date, mutations in the peripherin/rds [7], CRX 8 [7], GUCY2D [9], and GUCA1A [10] genes have been reported to cause autosomal dominant cone dystrophy. Patients with cone dystrophy caused by GUCAIA mutations have relatively well preserved rod function until the late stage [10]. ABCR gene mutations have been reported to cause autosomal recessive cone dystrophy [11], and RPGR gene mutations cause X- linked recessive cone dystrophy [12]. GUCY2D is the gene coding for retinal guanylate cyclase-1 (PETGC-1), which consists of a membrane guanylate cyclase with PETGC-2. PETGC-1 is an important enzyme in the phototransduction cascade and catalyzes the conversion of guanosine triphosphate (GTP) to cyclic 3,5 -guanosine monophosphate (cgmp) [9]. Two Japanese families with RC38C and R838H mutations [13] are shown in Fig All of the affected members have high myopia and poor visual acuity ( ) with central or paracentral scotoma and severe color vision defects. The full-field rod ERGs are relatively well preserved with nearly undetectable cone and 30-Hz flicker ERGs (Fig. 2.98). The fundus has myopic changes, including chorioretinal atrophy around the optic disk, but minimal ophthalmoscopic abnormalities in the macula. Fluorescein angiography showed mild hyperfluorescent pigmentary changes or small, round hyperfluorescent areas in the macula (Fig. 2.99). Fig Pedigrees of two families with autosomal dominant cone dystrophy, showing the affected (solid symbols) and unaffected (open symbols) members. Family and patient numbers correspond to those in Figs and 2.99Arrows point to probands. Individuals whose DNA was tested are indicated by an. Squares, males; circles, females; slash through symbol, deceased. (From Ito et al. [13]) Fig Full-field ERGs recorded from a normal subject and three patients in the two families shown in Figs and 2.97.The family and case numbers in parentheses correspond to those shown in Fig (From Ito et al. [13])

135 Fig Fundus photographs (A, C, E) and fluorescein angiograms (B, D, F) of patients with mutations of the GUCY2D gene. Family and case numbers in parentheses correspond to those shown in Fig (From Ito et al. [13], with permission) 2.13 Cone Dystrophy 127

136 128 2 Hereditary Retinal and Allied Diseases Central or Peripheral Cone Dystrophy The concept of regional cone dystrophy has been suggested by some clinicians [14], and these eyes were thought to have central or peripheral cone dystrophy. With central or peripheral cone dystrophy, the central or peripheral cone system is predominantly impaired and the rod system is completely preserved, even in the area where the cone system is impaired. Occult macular dystrophy [5] is an example of a central cone dystrophy and is described later. We have reported that some patients with occult macular dystrophy show the pathophysiological properties of a central cone dystrophy, where only the macular cones are affected with preservation of the macular rods. These findings were detected by rod cone sensitivity profiles in the macula area (see Section 2.19). We have reported three patients from two pedigrees whose peripheral cone system was more affected than the central cone system and whose rod system was relatively normal [2, 15]. The fundi of these patients with peripheral cone dystrophy are essentially normal except for mild temporal pallor of the optic disk in some of the patients (Fig ). The corrected visual acuity in the three patients ranged from 1.2 to 0.2, and the color vision was abnormal in two of the three. The full-field cone ERGs were significantly reduced, but the rod responses were normal, as in patients with typical cone dystrophy (Fig ). However, the focal macular cone ERG were well preserved (Fig ), and the results of multifocal ERGs support the findings made by full-field and focal macular ERGs (Fig ). One of the patients (case 3) was examined 4 years after the initial examination using focal macular ERG because he had reported progressively increased blurring of his paracentral vision in the left eye. The responses clearly had become smaller during the 4 years (Fig ), suggesting that his retinopathy was progressive, even though his visual acuity was unchanged. Psychophysical rod cone perimetry demonstrated that only the peripheral cone system was impaired, and the peripheral rod sensitivity was completely normal (Fig ).

137 2.13 Cone Dystrophy 129 Fig Fundus photographs (top) and fluorescein angiograms (bottom) of three patients with peripheral cone dystrophy. Cases 1 and 2 show slight temporal pallor of the optic disk, but otherwise their fundi appear normal. (From Kondo et al. [15], with permission) Fig Full-field ERGs recorded from three patients with peripheral cone dystrophy. Cone-mediated ERGs are selectively impaired. (From Kondo et al. [15], with permission)

138 130 2 Hereditary Retinal and Allied Diseases Fig Focal macular ERGs recorded with 5, 10, and 15 spots from the three patients with peripheral cone dystrophy shown in Fig Focal macular ERGs were recorded in 1993 and 1997 in case 3 (bottom) and show a progressive decrease in the responses. (From Kondo et al. [15], with permission)

139 2.13 Cone Dystrophy 131 Fig Cone rod perimetry (two-color perimetry) in the same three patients with peripheral cone dystrophy. Cone sensitivity profiles (upper trace) were determined with 31 red (600 nm) spots across a 60 horizontal meridian under a white background. For rod sensitivity (lower traces), two-color perimetry with blue-green (500- nm) and red (650- nm) stimuli being used after 45 min of dark adaptation. Only the central cone was preserved. Rod sensitivity is normal over the entire retina. (From Kondo et al. [15], with permission) Fig Top:Trace arrays of multifocal ERGs recorded from a normal subject and two patients with peripheral cone dystrophy (cases 1 and 2; see Figs and 2.101). Bottom: Three-dimensional (3D) topographic maps of the multifocal ERGs shown in the trace arrays for the normal subject and the two patients with peripheral cone dystrophy. (From Kondo et al. [15])

140 132 2 Hereditary Retinal and Allied Diseases Unilateral Cone Dysfunction Syndrome We reported a 20-year-old Japanese woman who had an acute onset of unilateral cone dysfunction associated with bull s-eye maculopathy [16]. She complained of blurred central vision and abnormal color sensitivity of 3 days duration in her right eye. Her family history was negative, and her medical history revealed no previous or current systemic illnesses. At her initial visit, visual acuity was 0.03 (OD) and 1.5 (OS) with a central scotoma in the right eye. The fundus and fluorescein angiograms were normal at that time, but 3 months later bull s-eye maculopathy appeared in the right eye; her left fundus remained normal (Fig ). The full-field ERGs recorded from this patient are shown in Fig As shown in Fig A, her rod responses and mixed rod cone (bright white) responses were normal, and little difference was observed between the right and left eyes. However, the cone-mediated responses (cone and 30-Hz flicker) were severely reduced only in the right eye. The on and off components of the photopic ERGs (Fig B) elicited by long-duration stimuli were undetectable in the right eye. Kinetic visual field showed a relative central scotoma within 10 of fixation in the right eye, whereas the left eye was normal (Fig. 107A). The cone and rod perimetry (two-color perimetry) showed normal sensitivity in both rod and cone in the right eye, but only the cone sensitivity was severely depressed in the left eye (Fig. 107B). The pathogenesis of this disorder with severe impairment of the cone photoreceptors is unknown. However, a group of inherited Fig Fundus photographs (top) and fluorescein angiograms (bottom) of a patient with unilateral cone dysfunction in the affected right eye (left and middle); the normal left eye is shown as well (right).three days after onset, the fundus of the right eye was essentially normal; but 3 months after onset, bull s-eye maculopathy appeared. (From Nomura et al. [17], with permission)

141 2.13 Cone Dystrophy 133 retinal diseases should be ruled out. Furthermore, the possibility of exposure to toxins, such as chloroquine [17] or digoxin [18], which can cause cone dysfunction, could be ruled out because she had no history of taking such drugs. Because of her acute and severe clinical course, other factors such as inflammation should be considered. Fig Full-field ERGs (A) and photopic ERGs elicited by long stimuli (B) recorded from a patient with unilateral cone dysfunction. Cone-mediated responses are selectively depressed only in the right eye. (From Nomura et al. [17])

142 134 2 Hereditary Retinal and Allied Diseases Fig Kinetic perimetry (A) and cone and rod perimetry (B) in a patient with unilateral cone dysfunction. (From Nomura et al. [17])

143 2.13 Cone Dystrophy 135 References 1. Sloan LL, Brown DJ (1962) Progressive retinal degeneration with selective involvement of the cone mechanism. Am J Ophthalmol 54: Miyake Y (2000) Phenotypes of cone dysfunction syndrome. Folia Ophthalmol Jpn 51: Berson EL, Gouras P, Gunkel RD (1968) Progressive cone-rod degeneration. Arch Ophthalmol 80: Ohba N (1974) Progressive cone dystrophy: four cases of unusual form. Jpn J Ophthalmol 18: Miyake Y, Horiguchi M, Tomita N, Kondo M, Tanikawa A, Tekahashi H, et al. (1996) Occult macular dystrophy. Am J Ophthalmol 122: Miyake Y, Goto S, Ota I, Ichikawa H (1984) Vitreous fluorophotometry in patients with cone-rod dystrophy. Br J Ophthalmol 68: Nakazawa M, Kikawa E, Chida Y, Tamai M (1994) Asn244His mutation of the peripherine/rds gene causing autosomal dominant cone-rod degeneration. Hum Mol Genet 3: Freund CL, Gregory-Evans CY, Furukawa T, Papaioannou M, Looser J, Ploder L, et al. (1997) Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor. Cell 91: Perrault I, Rozet JM, Gerber S, Kelsell RE, Souied E, Cabot A, et al. (1998) A retgc-1 mutation in autosomal dominant cone-rod dystrophy. Am J Hum Genet 63: Payne AM, Downes SM, Bessant DA, Taylor R, Holder, GE, Warren MF, et al. (1998) A mutation in guanylate cyclase activator 1A (GUCA1A) in an autosomal dominant cone dystrophy pedigree mapping to a new locus on chromosome 6p21.1. Hum Mol Genet 7: Cremers FP, van de Pol DJ, van Driel M, den Hollander AI, van Haren FJ, Knoers NV, et al. (1998) Autosomal recessive retinitis pigmentosa and conerod dystrophy caused by slice site mutations in the Stargardt s disease gene ABCR. Hum Mol Genet 7: Demirci FY, Rigatti BW, Wen G, Radak AL, Mah TS, Baic CL, et al. (2002) X-linked cone-rod dystrophy (locus COD1): identification of mutations in RPGR exon ORF15. Am J Hum Genet 70: Ito S, Nakamura M, Ohnishi Y, Miyake Y (2004) Autosomal dominant cone-rod dystrophy with R838H and R838C mutations in the GUCY2D gene in Japanese patients. Jpn J Ophthalmol 48: Pinkers A, Deutman AF (1977) Peripheral cone disease. Ophthalmologica 54: Kondo M, Miyake Y, Kondo N, Ueno S, Takakuwa H, Terasaki H (2004) Peripheral cone dystrophy: a variant of cone dystrophy with predominant dysfunction in the peripheral cone system. Ophthalmology 111: Nomura R, Kondo M, Tanikawa A, Yamamoto N, Terasaki H, Miyake Y (2001) Unilateral cone dysfunction with bull s eye maculopathy. Ophthalmology 108: Krill AE, Deutman FA, Fishman M (1973) The cone degenerations (review). Doc Ophthalmol 35: Weleber RG, Shults WT (1981) Digoxin retinal toxicity: clinical and electrophysiological evaluation of a cone dysfunction syndrome. Arch Ophthalmol 99:

144 136 2 Hereditary Retinal and Allied Diseases 2.14 Rod Monochromacy Congenital rod monochromacy is an autosomal recessively inherited disorder characterized in the complete form by complete absence or severely depressed color vision, reduced visual acuity, nystagmus, and photophobia [1]. There is also an incomplete form of this disorder, where color vision and/or visual acuity are only mildly affected and nystagmus and photophobia may be absent [2]. In both forms, the fundus and fluorescein angiograms are normal, and the most characteristic feature in terms of the diagnosis is the selective reduction or absence of the photopic component of the full-field ERGs [2]. The ERG findings provide key diagnostic information, particularly in the incomplete form when visual acuity is relatively good [2]. The condition is stationary. Histological examination of eyes with complete monochromatism has shown 5% 10% reduction in the normal number of extrafoveal cones and abnormal structure of the foveal cones [3]. Molecular genetic studies have shown that mutations in the CNGB3 gene encoding the b-subunit of the cone photoreceptor cgmp-gated channel are responsible for achromatopsia [4]. A representative case of rod monochromacy [2] was seen in a 13-year-old girl (case 1) who is the sister of an 18-year-old young man (case 2). During a 10-year follow-up of the siblings, their visual functions did not deteriorate, and their fundi remained normal (Fig ). In case 1, the visual acuity was 0.1 OD and 0.4 OS, and color vision tests showed a mild acquired red-green deficiency. She had nystagmus but did not complain of photophobia. Her older brother (case 2) also had decreased visual acuity in the beginning, but his vision gradually improved to 1.0 with normal color vision in both eyes. Despite such differences in the visual functions in this sibling, his full-field ERGs were essentially identical to his sister s ERGs, showing selective absence of the photopic components (Fig ). The full-field ERGs indicated that both siblings had congenital stationary cone dysfunction. The question arose as to why case 2 had normal visual acuity and normal color vision despite the undetectable full-field cone ERGs. Rod cone (two-color) perimetry showed that the brother indeed had widespread dysfunction of the cones with normal rod function. However, the cone function was preserved in only a small portion in the foveola, which provided normal visual acuity and color vision.

145 2.14 Rod Monochromacy 137 Fig Fundus photographs and fluorescein angiograms for two siblings with rod monochromacy. (From Miyake [2]) Fig Full-field ERGs recorded from two siblings with rod monochromacy whose fundus photographs are shown in Fig (From Miyake [2]) References 1. Goodman G, Ripps H, Siegel IM (1963) Cone dysfunction syndrome. Arch Ophthalmol 70: Miyake Y (2000) Phenotypes of cone dysfunction syndrome. Folia Ophthalmol Jpn 51: Falls HF, Wolter JR, Alpern M (1965) Typical total monochromacy; a histological and psychophysical study. Arch Ophthalmol 74: Kohl S, Baumann B, Broghammer M, Jagle H, Sieving P, Kellner U, et al. (2000) Mutations in the CNGB3 gene encoding the b-subunit of the cone photoreceptor cgmp-gated channel are responsible for achromatopsia (ACHM3) linked to chromosome 8q21. Hum Mol Genet 9:

146 138 2 Hereditary Retinal and Allied Diseases 2.15 Blue Cone Monochromacy Blue cone monochromacy, a rare color vision disorder, was first described by Blackwell in 1957 [1]. It shares many characteristics with rod monochromacy. Blue cone monochromats differ from rod monochromats in their inheritance pattern; blue cone monochromats have an X-linked recessive pattern, whereas rod monochromats have an autosomal recessive inheritance. The molecular genetic study indicated that mutations exist in the red and green opsin in blue cone monochromats [2]. A pedigree of a Japanese family with blue cone monochromacy with three affected members and one female carrier is shown in Fig [3]. The fundus of one of these patients is shown in Fig , which is essentially normal, although in the late stage some atrophic changes may develop in the macula. The visual acuity is approximately , which is slightly better than that of the complete form of rod monochromacy. Unlike rod monochromats, the blue cone function is selectively preserved. The results of the Farnsworth dichotomous Panel D-15 test shows several crossing lines perpendicular to the tritan axis (Fig ). Examination with a Nagel anomaloscope yielded results similar to those seen with complete rod monochromatism, although most of the values are below those measured in a group of patients with complete rod monochromatism. The spectral sensitivity curve determined by increment thresholds of 1 steps showed a narrow curve with a peak around 440nm (Fig ). Fig Pedigree of family with blue cone monochromacy. Cross mark, examined; arrow, proband; black squares, affected members. (From Terasaki and Miyake [3], with permission) Fig Fundus of a 10-year-old boy with blue cone monochromacy (case 1). (From Terasaki and Miyake [3], with permission)

147 2.15 Blue Cone Monochromacy 139 The full-field ERGs recorded from members of this family were nearly normal for the rod ERGs, with absence of the photopic ERG in the three affected members (Fig ). Although the blue cone ERG is present in blue cone monochromats (Fig ), the amplitude of the blue cone ERG is too small to be detected in the full-field cone ERGs, and the implicit time is too long to follow 30-Hz flicker stimuli. The diagnosis of this disorder is based on the presence of severely affected color vision with preserved blue function, nearly unrecordable photopic ERGs,and a family pedigree compatible with an X-linked inheritance pattern. Fig Results of Farnsworth dichotomous Panel D-15 test from two patients with blue cone monochromacy. Several crossing lines were perpendicular to the tritan axis. (From Teraski and Miyake [3], with permission) Fig Spectral sensitivity curves determined by increment thresholds on a white background for case 1 (circles) and two agematched normal subjects (triangles). (From Terasaki and Miyake [3], with permission)

148 140 2 Hereditary Retinal and Allied Diseases Fig Full-field ERGs recorded from a family with blue cone monochromacy (carrier mother, two sons, and mother s brother), showing normal rod components and nearly absent cone components. (From Terasaki and Miyake [3], with permission) Fig Full-field ERGs elicited by photopically matched red and blue stimuli recorded from a normal subject, a rod monochromat, and two blue cone monochromats (cases 1 and 3). The patient with rod monochromacy shows absent red and blue responses, but the patients with blue cone monochromacy show small responses elicited by only the blue stimulus. The ERGs are characterized by an absent a-wave and a small b-wave with delayed implicit time. These are the properties of blue (S)-cone ERGs References 1. Blackwell HR, Blackwell OM (1957) Blue monocone monochromacy : a new color vision defect. J Opt Soc Am 47: Nathans J, Davenport CM, Maumenee IH, Lewis RA, Hijtmancik JF, Litt M, et al. (1989) Molecular genetics of human blue cone monochromacy. Science 245: Terasaki H, Miyake Y (1992) Japanese family with blue cone monochromatism. Jpn J Ophthalmol 36:

149 2.16 Congenital Tritanopia Congenital Tritanopia Differential Diagnosis of Dominantly Inherited Juvenile Optic Atrophy Congenital tritanopia is a rare disease with an autosomal dominant inheritance pattern [1]. It is characterized by tritanopic color vision defects, a normal fundus, and normal visual acuity (Fig ). Both rod and cone components of standard full-field ERGs are normal. Congenital tritanopia and dominantly inherited juvenile optic atrophy (DIJOA) have several clinical characteristics in common. In addition to having a dominant hereditary pattern, patients with DIJOA may also have tritanopic color vision defects [2]. However, these patients may have slightly to moderately reduced visual acuity, visual field defects, and temporal pallor of the optic disk (Fig ). The severity of these abnormalities varies even Fig Fundus photographs (top) and farnsworth dichotomous Panel D-15 test (bottom) from two patients with congenital tritanopia. The patients are 31-year-old woman (left) and her father, 67-year-old man (right)

150 142 2 Hereditary Retinal and Allied Diseases within the same family. Thus, in patients with minimal alterations, the changes in the visual acuity and visual field may be so subtle that a definitive diagnosis cannot be made unless other, more obviously affected family members are examined. It had been hypothesized that the two diseases may be the same clinical entity [3, 4]. However, as shown in Fig , the blue (S) cone ERG is unrecordable in patients with congenital tritanopia but is within the normal range in those with DIJOA [5]. These findings supported the argument that congenital tritanopia and DIJOA are not the same disease. The abnormal S-cone ERG in patients with congenital tritanopia indicates a retinal origin of the tritan defect, most likely in the blue cone itself. On the other hand, the normal blue cone ERG in patients with DIJOA indicates that the tritan defect is caused by disturbances of the visual pathway proximal to the layer of origin of the ERG, most likely in the optic nerve. This hypothesis has been proven to be conclusively correct by molecular genetic analyses. In 1992 we detected two point mutations in the gene encoding the blue-sensitive opsin, each leading to an amino acid substitution [6]. These findings showed that these mutations cause tritanopia (Fig ). On the other hand, Votruba et al. detected the genetic mutation (OPA1) locus to be within a 2 CM interval of chromosome 3q in patients with DIJOA [7]. Fig Fundus photographs (top) and Farnsworth dichotomous Panel D-15 test (bottom) for three patients with dominantly inherited juvenile optic atrophy. (From Tarasaki et al. [2])

151 2.16 Congenital Tritanopia 143 Fig Superimposed blue (S)-cone ERGs recorded from normal subjects, two patients with congenital tritanopia, and four cases of dominantly inherited juvenile optic atrophy (DIJOA). (From Miyake et al. [5]) Fig Model of the blue-sensitive opsin protein primary structure in relation to the lipid bilayer. Open circles, amino acids; filled circles, sites of G79R (left) and S241P (right). (From Weitz et al. [6]) References 1. Wright WD (1952) The characteristics of the tritanopia. J Opt Soc Am 42: Terasaki H, Miyake Y, Awaya S, Horio N (1995) Visual functions of dominantly inherited juvenile optic atrophy. Acta Soc Ophthalmol Jpn 99: Krill AE, Smith VC, Pokorny J (1970) Similarities between congenital tritan defects and dominant opticus-atrophy: coincidence or identity? J Opt Soc Am 60: Krill AE, Smith VG, Pokorny J (1971) Further studies supporting identity of congenital tritanopia and hereditary dominant optic atrophy. Invest Ophthalmol 15: Miyake Y, Yagasaki K, Ichikawa H (1985) Differential diagnosis of congenital tritanopia and dominantly inherited juvenile optic atrophy. Arch Ophthalmol 103: Weitz CJ, Miyake Y, Shinzato K, Montag E, Zrenner E, Went LN, Nathans J (1992) Human tritanopia associated with two amino acid substitutions in the blue-sensitive opsin. Am J Hum Genet 50: Votruba M, Moore AT, Bhattacharya SS, et al. (1997) Genetic refinement of dominant optic atrophy (OPA1) locus to within in a 2 CM interval of chromosome 3q. J Med Genet 34:

152 144 2 Hereditary Retinal and Allied Diseases 2.17 Rod Cone Dysfunction Syndrome with an Unusual Form of ERG Some unusual forms of retinal dysfunction have been reported that involve the cone and the rod photoreceptor systems in an extraordinary way. With the rod cone dysfunction syndrome, there is decreased sensitivity to light while at the same time its responsiveness to superthreshold light stimuli is enormously augmented [1 3]. This unusual combination is illustrated in three of our patients [4]. A 15-year-old girl (case 1), an 11-year-old girl (case 2), and a 32- year-old woman (case 3) had low visual acuity of with moderate to high myopia from birth. The family history was negative in the three patients. Night blindness was detected by dark-adaptation curves with elevation of the final rod thresholds by log units. The visual fields were almost normal except for slight constriction with small and dim targets. The color vision was markedly abnormal, with a scotopic pattern similar to that of rod monochromats. The fundus and fluorescein angiograms are essentially normal (Fig ), except for bull s-eye maculopathy in case 1 and slight optic atrophy in case 3. We have followed two of these patients for more than 10 years, and the clinical condition has not changed (i.e., it is stationary). The standard full-field ERGs recorded from these three patients are shown in Fig Compared with the results of age-matched normal young subjects, the amplitude of the scotopic (rod) ERG was markedly reduced, and the implicit time was delayed. The photopic (cone) and 30-Hz flicker ERGs were almost undetectable. The bright-flash mixed rod cone ERG was markedly altered; the a-wave had a step-like configuration, the OPs were reduced, and the b-wave amplitude was supernormal. The changes in the ERGs elicited by white flash stimuli of various intensities are shown in Fig Despite the undetectable b-wave recorded with dim stimuli, the b-wave became supernormal when recorded with stronger stimuli. The most remarkable aspect of this disorder is demonstrated in Fig The threshold, amplitude, and waveform of the flash ERGs are abnormal. The stimulus threshold is elevated by approximately 3.5 log units in all patients; but as the intensity of the stimulus is increased, the responses become larger in an extraordinary fashion. When the stimulus is high, the a-wave has been almost step-like in its waveform, and its amplitude is smaller than normal. On the other hand, the b-wave is supernormal with a normal implicit time. The ERG findings of this disorder are somewhat similar to those of the enhanced S-cone syndrome (i.e., markedly reduced or absent rod and 30-Hz flicker ERGs, supernormal b-wave, and step-like a-wave. However, the definitive differences are the markedly reduced or undetectable photopic (cone) and blue-cone ERGs. It is possible experimentally to produce changes similar to those observed in these patients by increasing the intracellular cyclic guanosine monophosphate (cgmp) in rods in several ways. These experimental conditions produce an increase in the amplitude, prolongation in the time course, and steepening of the intensity-response curve of the rod photoreceptor responses [5]. These experimental results may provide the key to solving the unique paradox of the

153 2.17 Rod-Cone Dysfunction Syndrome with an Unusual Form of ERG 145 elevated subjective dark-adapted thresholds associated with the supernormal responses in bright flash ERG in the dark-adapted condition. However, we have measured the cyclic nucleotide levels in the blood and urine of these patients, and our results did not show any significant abnormality, although the values were slightly higher than normal. Fig Fundus of a patient (case 3) with an unusual form of supernormal ERG Fig Full-field ERGs recorded from three patients with rod cone dysfunction showing an unusual ERG waveform. Despite the undetectable rod and cone ERGs, the mixed rod cone ERG with intense stimuli shows a supernormal b-wave with a step-like a-wave. (From Yagasaki et al. [4])

154 146 2 Hereditary Retinal and Allied Diseases Fig Intensity-response series for the ERGs recorded from a normal control and the three patients whose ERGs are shown in Fig (From Yagasaki et al. [4]) References 1. Abraham FA, Sandber MA (1977) An unusual type of juvenile foveal dystrophy: electrophysiologic study. Doc Ophthalmol Pro Series 11: Alexander KR, Fishman GA (1984) Supernormal scotopic ERG in cone dystrophy. Br J Ophthalmol 68: Gouras P, Eggers HM, MacKay CJ (1983) Cone dystrophy, nyctalopia, and supernormal rod responses: a new retinal degeneration. Arch Ophthalmol 101: Yagasaki K, Miyake Y, Litao RE, Ichikawa K (1986) Two cases of retinal degeneration with unusual form of electroretinogram. Doc Ophthalmol 63:73 82

155 2.18 Association of Negative ERG with Diseases of Unknown Etiology Association of Negative ERG with Diseases of Unknown Etiology The hereditary eye diseases associated with the negative-type ERG (a-wave larger than b-wave) with normal a-wave amplitude are congenital stationary night blindness, X-linked congenital retinoschisis, and Batten disease. Two additional conditions whose etiology is still uncertain are described in this section.

156 148 2 Hereditary Retinal and Allied Diseases Bull s-eye Maculopathy In 1989 we reported four male patients [1] who had bull s-eye maculopathy and an otherwise normal fundus except for a dark choroid seen on fluorescein angiography in one patient (Fig ). The bright flash, mixed rod cone ERG in the dark was made up of a normal a-wave but the b-wave that was reduced and smaller than the a-wave (Fig ). The full-field rod ERGs were moderately reduced, and the cone and 30- Hz flicker ERGs were relatively well preserved (Fig ). Other findings common to all four patients were moderately low visual acuity (normal visual acuity initially), mild to moderate color vision deficiency, normal peripheral visual fields, normal EOGs, near-emmetropia, and appearance predominantly in men. Recently, molecular genetic examinations were performed in all patients, and one patient (case 2) had a novel missense mutation, Ala101Pro (c.301g to C) in the XLRS1 gene, which was identified from his genomic DNA. He was thus diagnosed as having X-linked retinoschisis. Although bull s-eye maculopathy is rarely associated with X-linked retinoschisis, we should consider the possibility of this disorder when bull s-eye maculopathy is associated with negative ERGs. We could not find any mutation in the other patients. Case 1 showed a dark choroid, which is often seen with Stargardt disease, but no mutation of the gene associated with Stargardt disease was detected. Fig Full-field ERGs recorded from the four patients whose mixed rod cone ERGs are shown in Fig The ages of patients are 12 (case 1), 36 (case 2), 22 (case 3) and 40 years old (case 4). (From Miyake et al. [1], with permission)

157 2.18 Association of Negative ERG with Diseases of Unknown Etiology 149 Fig Mixed rod cone ERGs elicited by a bright flash recorded from a normal control and the four patients whose fluorescein angiograms are shown in Fig (From Miyake et al. [1], with permission) Fig Fluorescein angiograms of four patients with bull s-eye maculopathy and negative ERGs. Case 1 shows a dark choroid. Case 4 was diagnosed as having X-linked congenital retinoschisis by molecular genetic examinations. (From Miyake et al. [1], with permission)

158 150 2 Hereditary Retinal and Allied Diseases Familial Optic Atrophy with Negative ERG Earlier investigators reported that negative ERGs were rarely associated with optic nerve atrophy because patients with the inherited forms of optic atrophy had been reported to have normal ERG findings [2]. The optic atrophy was assumed to occur from transsynaptic degeneration of the bipolar cells. In 1992, in collaboration with Richard Weleber of Portland, Oregon, we found that the affected members of two families with presumably autosomal dominant optic atrophy also had negative-type ERGs (Fig ) [3]. They had poor central vision, and the decrease occurred during the second to third decade of life. Ophthalmological examinations showed that the affected members had visual acuities of , defective color vision, mild to moderate myopia, and pericentral or centrocecal scotomas. Optic atrophy was found in four of the five patients (Fig ). The age of the affected members ranged from 21 to 56 years (mean 42 years). The amplitude of the a-wave of the full-field ERGs (Fig ) and the scotopic rod cone ERGs were normal, but the amplitude of the b- wave was markedly reduced. The amplitudes of the rod responses were moderately reduced but with normal implicit times. The amplitudes of the b-wave of the photopic ERGs varied from normal to mildly reduced, and the implicit times were normal. The amplitudes of 30-Hz flicker ERGs were normal. The moderately low visual acuity of these patients may be caused by optic atrophy or some macular problem. The essentially normal focal macular ERGs suggest that the low visual acuity is caused by optic nerve dysfunction. Because negative ERGs are not seen with other familial optic atrophies, we concluded that this disease, with an association of optic atrophy and abnormal negative ERGs, represented a new genetic disorder. Fig Two pedigrees showing the family members with optic atrophy and negative ERGs. The black dot at the side of the symbols identifies individuals who were examined ophthalmoscopically. Males III-1 and III-2 of Family 2 were fraternal twins, one of whom died. Patients 4 and 6 of Family 2 also had McArdle s (Mc) disease, but this is an autosomal recessive trait unassociated with either optic atrophy or ERG abnormalities. (From Weleber and Miyake [2])

159 2.18 Association of Negative ERG with Diseases of Unknown Etiology 151 Fig Fundi of case 1 (top left), case 2 (top right), case 3 (center left), case 4 (center right), and case 5 (bottom). (From Weleber and Miyake [2])

160 152 2 Hereditary Retinal and Allied Diseases Fig Full-field ERGs recorded from a normal control and three patients (cases 1, 2, and 3) examined in Nagoya, Japan (A); and two patients (cases 4 and 5), a patient with complete CSNB, and a normal control examined in Portland, Oregon, USA (B). A Rod ERGs are subnormal, and mixed rod cone (bright white) ERGs have the shape of the negativetype ERG. The OPs are reduced. The cone and 30-Hz flicker ERGs are normal. B The blue light was scotopically balanced with the red light for production of equal-amplitude rod responses. Note that the rod b-waves responses to dim white light and dim blue light were subnormal for both patients and nearly undetectable for the patient with complete CSNB.The cone-mediated ERGs were normal. (From Weleber and Miyake [2]) References 1. Miyake Y, Shiroyama N, Horiguchi M, Saito A, Yagasaki K (1989) Bull s eye maculopathy and negative ERG. Retina 9: Yagasaki K, Miyake Y, Awaya S, Ichikawa H (1986) ERG (electroretinogram) in hereditary optic atrophy. Acta Soc Ophthalmol Jpn 90: Weleber RG, Miyake Y (1992) Familial optic atrophy with negative electroretinograms. Arch Ophthalmol 110:

161 2.19 Occult Macular Dystrophy Occult Macular Dystrophy Occult macular dystrophy is an unusual, inherited macular dystrophy characterized by progressively decreased visual acuity due to macular dysfunction, but the fundus and fluorescein angiograms are essentially normal. In 1989 we reported three patients in one family with hereditary macular dystrophy without a visible fundus abnormality [1]. Since then we have diagnosed 43 patients (26 men and 17 women) with this disease from 14 families and termed the disorder occult macular dystrophy [2] ( occult meaning hidden from sight ). The pedigrees of eight families with two or more affected members in each family are shown in Fig [3]. Many of the pedigrees suggest autosomal dominant heredity. The fundus photographs and fluorescein angiograms from three affected members of Family C [1] are shown in Fig ; the fundus and angiograms were normal. Full-field ERGs were normal in all these patients, but the focal macular ERGs were absent, indicating that the pathological basis for the depressed visual acuity lies in the macula. Recently, this localized dysfunction in the macula was confirmed by multifocal ERGs, which showed depressed responses in the central areas (Fig ). Our recent studies [4] of many patients indicated that the amplitudes of the multifocal ERGs are markedly reduced in the central 7 of the retina. Fig Occult macular dystrophy. Family pedigrees with two or more affected members in a single family are shown. Filled symbols, affected male or female; open symbols, normal male or female; arrow, propositus; cross mark, examined; oblique line, deceased. (From Miyake [3])

162 154 2 Hereditary Retinal and Allied Diseases Fig Fundus photographs (left) and fluorescein angiograms (right) of three patients with occult macular dystrophy in Family C of Fig Cases 1, 2, and 3 are a 29-year-old woman, a 19-year-old man, and a 55-year-old man, respectively. (From Miyake et al. [1]) Fig Full-field ERGs and focal macular ERG recorded from a normal subject and a patient with occult macular dystrophy (OMD). Full-field ERGs are normal but the focal macular ERG recorded with a 5 spot is absent in the OMD patient

163 2.19 Occult Macular Dystrophy 155 The differences in the amplitudes of the ERGs recorded from patients with occult macular dystrophy and from normal subjects become smaller toward the peripheral field. Most patients have a slight but significant delay in the implicit times across the whole testing field, and the differences in the implicit times between occult macular dystrophy and normal subjects do not change with retinal eccentricity. This suggests that the retinal dysfunction has a broader boundary than expected from the ERG amplitudes and psychophysical perimetric results (Fig ). Based on these findings, the pathology of this disorder was thought to be limited to the macula, although the macula appears normal ophthalmoscopically. Long-term follow-up examinations have been undertaken with some of our patients. A comparison of the fundus of a 29-year-old woman with occult macular dystrophy abserved in 1988 and then again in 2002 is shown in Fig The fundus remained normal during the 14 years of follow-up. The full-field ERGs also did not change significantly, whereas the focal macular ERGs deteriorated significantly during this period. The age of the affected members ranged from 9 to 71 years (mean 42 years). The distribution of visual acuity and age in this disease is shown in Fig It is interesting that some of the patients had normal visual acuity despite the fact that focal macular ERGs were definitely Fig Three-dimensional topography (left) and averaged waveforms (right) of multifocal ERGs for five eccentric rings in a normal subject and an OMD patient. Responses for 20 normal subjects and 8 patients with OMD are superimposed in the averaged waveforms. The vertical dotted line indicates an implicit time of 29.4 ms. (From Piao et al. [4], with permission)

164 156 2 Hereditary Retinal and Allied Diseases Fig Fundus photograph (top) and fluorescein angiography (bottom) of case 1 in Fig. 130 after 14 years of follow-up. The fundus and fluorescein angiography are still normal Fig Distribution of visual acuity (horizontal axis) versus age (vertical axis) in patients with occult macular dystrophy. Note that some patients show normal visual acuity

165 2.19 Occult Macular Dystrophy 157 reduced. These findings indicate that the focal macular ERG is key to diagnosing occult macular dystrophy. The cone and rod sensitivity profile showed that all patients had depressed cone sensitivity only in the macula, although many relatively young patients had normal rod sensitivity in the macula. All patients with good visual acuity also had decreased cone sensitivity in the macula, although the function of one point in the foveola may still be relatively well preserved (Fig ). It may be that the small center of the fovea in such patients functions well and thus accounts for the good visual acuity, but that the parafovea is dysfunctional, resulting in the poor response of focal macular ERGs. In many patients, the waveform of the focal macular ERG has a depolarizing pattern (the on type; Fig ), and the good preservation of rod function in the macula may be related to this property.a red-green defect in color vision is found in many patients, although some show a blue-yellow defect. Although the ophthalmoscopic appearance of the macula is normal,oct shows thinning of the macular area in many patients [5] (Fig ). Detailed analyses of the images indicate that the thinning is mainly of the outer nuclear layer. Because only the central cone system is impaired and the peripheral cone, peripheral rod, and central rod systems remain intact during the early stage of this disorder, the most suitable pathophysiological name for occult macular dystrophy may be central cone dystrophy, in contrast to peripheral cone dystrophy, [6] which was described in Section During the advanced stage, however, the macular rods may also become involved because patients with only macular cone involvement are significantly younger than those with both macular cone and rod involvement. Even at this stage, the macular appearance is still normal. Furthermore, it should be noted that even at an advanced stage the fullfield cone and rod ERGs are still within the normal range, indicating that this disorder does not produce widespread dysfunction even at the advanced stage. An essentially normal fundus has been reported with diffuse cone dystrophy [7] even though such eyes have shown significant deterioration of full-field cone ERGs (see Section ). The impression is that occult macular dystrophy may not be a rare disease and that many patients with this disorder may be misdiagnosed as having several other diseases, such as a psychological eye problem, optic nerve problem, central nerve problem, or amblyopia.

166 158 2 Hereditary Retinal and Allied Diseases Fig Rod cone (two color) perimetry (left) and cone perimetry (right) in two patients with occult macular dystrophy.the visual acuities of cases 1 and 2 are 0.2 and 1.0, respectively. In case 1, the macular cone sensitivity is depressed, but macular rod sensitivity is within the normal range. In case 2, the macular cone sensitivity is depressed, but only a small area of the fovea has good sensitivity.the dotted lines (left) and solid lines (right) indicate the normal range Fig Focal macular ERGs elicited by 10 or 15 stimuli recorded from patients with occult macular dystrophy. The waveform of the focal macular ERGs is a depolarizing pattern (the on type), showing a small a-wave, if any, and a relatively large b-wave

167 2.19 Occult Macular Dystrophy 159 Fig Optical convergence tomography (OCT) images from an age-matched normal control and a patient with occult macular dystrophy (OMD). (From Kondo et al. [5], with permission) References 1. Miyake Y, Ichikawa K, Shiose Y, Kawase Y (1989) Hereditary macular dystrophy without visible fundus abnormality. Am J Ophthalmol 108: Miyake Y, Horiguchi M, Tomita N, Kondo M, Tanikawa A, Takahashi H, et al. (1996) Occult macular dystrophy. Am J Ophthalmol 122: Miyake Y (2002) What can we know from focal macular ERG? Clin Ophthalmol Jpn 56: Piao CH, Kondo M, Tanikawa A, Terasaki H, Miyake Y (2000) Multifocal electroretinogram in occult macular dystrophy. Invest Ophthalmol Vis Sci 41: Kondo M, Ito Y, Ueno S, Piao CH, Terasaki H, Miyake Y (2003) Foveal thickness in occult macular dystrophy. Am J Ophthalmol 135: Kondo M, Miyake Y, Kondo N, Ueno S, Takakuwa H, Terasaki H (2004) Peripheral cone dystrophy: a variant of cone dystrophy with predominant dysfunction in the peripheral cone system. Ophthalmology 111: Ohba N (1974) Progressive cone dystrophy: four cases of unusual form. Jpn J Ophthalmol 18:50 69

168 160 2 Hereditary Retinal and Allied Diseases 2.20 Stargardt s Disease (Fundus flavimaculatus) Although it had been strongly stated that Stargardt s disease [1] and fundus flavimaculatus [2] are the same entity based on clinical findings [3], it was proven conclusively only by molecular genetic analysis [4]. Stargart s disease, a frequent cause of autosomal recessive macular dystrophy, is characterized by onset during juvenile to young adult years, decreased central vision, progressive bilateral atrophy of the RPE, and the presence of orange-yellow flecks in the macula and/or mid-periphery of the retina (Fig ). In most cases, the onset of visual symptoms occurs between the first to third decades of life. Fluorescein angiography has proved to be helpful in a number of ways with this disease. There is an absence or decrease in the normal background choroidal fluorescence, called a dark choroid or a silent choroid, in Stargardt s patients [5] (Fig ). Histopathological and histochemical studies have provided evidence that these patients have a diffuse lipo- Fig Fundus photograph and fluorescein angiogram from a patient with Stargardt s disease (fundus flavimaculatus). The dark choroid is shown in the fluorescein angiogram

169 2.20 Stargardt s Disease (Fundus flavimaculatus) 161 fuscin storage disease affecting the RPE, which is the cause of the dark or silent choroid [6]. Patients with Stargardt s disease can be subdivided into four groups based on the fundus and fluorescein angiographic findings: group 1, vermillion fundi and hidden choroidal fluorescence; group 2, atrophic maculopathy with or without flecks; group 3, atrophic maculopathy with late signs and symptoms of retinitis pigmentosa; and group 4, flecks not associated with macular atrophy [7]. Stargardt s disease has been thought to be a representative example of macular dystrophy (a localized retinal dystrophy), in contrast to retinitis pigmentosa and cone dystrophy (which are considered generalized retinal dystrophy) [8]. This is because the results of general retinal function tests, such as full-field ERGs and EOGs, are normal and only the focal macular ERG is abnormal or undetectable in Stargardt s disease. Indeed, early in the course of the disease, the ERG is usually normal (groups 1 and 2), and only in the more advanced stages do the photopic and scotopic ERGs become abnormal. Full-field ERGs and focal macular ERGs recorded from a 16-yearold male patient with Stargardt s disease in group 2 are shown in Fig The full-field ERG is normal, but the focal macular ERGs are undetectable. The causative gene for Stargardt s disease (fundus flavimaculatus) was identified as the retina-specific adenosine triphosphate (ATP)- binding cassette transporter, ABCR, a gene renamed the ABCA4 gene [4]. It was subsequently found that mutations of the ABCA4 gene also cause autosomal recessive retinitis pigmentosa [9]. Most patients with Stargardt s disease are compound heterozygotes, but patients with autosomal recessive retinitis pigmentosa are homozygous with null mutations in the ABCA4 gene. A severe type of Stargardt s disease (group 3) was found in a Japanese patient with homozygous mutations in the ABCA4 gene [10]. This severe type was progressive with diffuse retinal dysfunction, as in retinitis pigmentosa. It has been suggested that there is an association between the null mutations in the ABCA4 gene and panretinal degeneration [11]. Full-field ERGs recorded from a patient with Stargardt s disease and two patients with autosomal recessive retinitis pigmentosa are shown in Fig Both diseases were caused by null ABCA4 gene mutations, and the two patients with autosomal recessive retinitis pigmentosa were diagnosed with Stargardt s disease when they were younger. The disease was progressive, and the full-field ERGs became nearly undetectable,as shown in Fig The patient with Stargardt s disease also showed reduced scotopic and photopic responses during the second decade of life. Patients in group 4 are relatively rare. A 36-year-old woman was found to have multiple flecks in both fundi, and fluorescein angiography revealed multiple flecks of hyperfluorescence associated with a dark choroid, indicating group 4 Stargardt s disease (Fig ). She had no subjective complaint, and her visual acuity was 0.9 in both eyes. The full-field ERG, the focal macular ERG, and the multifocal ERGs were normal (Fig ). The multifocal ERGs recorded from the sites of the flecks were also normal, indicating that the flecks do not affect retinal function.

170 162 2 Hereditary Retinal and Allied Diseases Fig Full-field ERGs and focal macular ERGs recorded from a patient with Stargardt s disease Fig Full-field ERGs recorded from a normal subject, a patient with Stargardt s disease (case 1), and two patients with autosomal recessive retinitis pigmentosa (cases 2 and 3). Patients with Stargardt s disease and retinitis pigmentosa had null ABCA gene mutations. Case 1 was a 15-year-old boy who had reduced scotopic and photopic functions during his second decade of life. Case 2 was a 28-year-old man, and case 3 was a 41-year-old man, both of whom were diagnosed with Stargardt s disease when they were young. Their ERGs were severely deteriorated when they were tested recently. (From Fukui et al. [10])

171 2.20 Stargardt s Disease (Fundus flavimaculatus) 163 Fig Fundus photograph (top) and fluorescein angiogram (bottom) from a 36-year-old woman with group 4 Stargardt s disease. Multiple flecks in the posterior pole and dark choroid of fluorescein angiography are observed. The macula appears normal, and the visual acuity was 0.9 in both eyes Fig Focal macular ERGs recorded with three spots and multifocal ERGs recorded from the patient whose fundus and fluorescein angiogram are shown in Fig Regardless of the retinal area, all ERG responses are normal

172 164 2 Hereditary Retinal and Allied Diseases References 1. Stargardt K (1909) Über familiare, progressive Degeneration in der Maculagegend des Auges. Graefes Arch Ophthalmol 71: Franceschetti A (1965) A special form of tapetoretinal degeneration: fundus flavimaculatus. Trans Am Acad Ophthalmol Otolaryngol 69: Noble KG, Carr RE (1979) Stargardt disease and fundus flavimaculatus. Arch Ophthalmol 97: Allikmets R, Singh N, Sun H, Shroyer NF, Hutchinson A, Chidambaram A, et al. (1997) A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy. Nat Genet 15: Fish G, Grey R, Sehmi KS, Bird AC (1981) The dark choroid in posterior retinal dystrophies. Br J Ophthalmol 65: Steinmetz RL, Garner A, Maguire JI, Bird AC (1991) Histopathology of incipient fundus flavimaculatus. Ophthalmology 98: Gass JDM (1997) Stargardt s disease (fundus flavimaculatus). In: Stereoscopic atlas of macular diseases: diagnosis and treatment. Vol 1. Mosby, St. Louis, pp Miyake Y (1988) Study on local macular ERG. Acta Soc Ophthalmol Jpn 92: Martinez-Mir A, Paloma E, Allikmets R, Ayuso C, del Rio T, Dean M, et al. (1998) Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR. Nat Genet 18: Fukui T, Yamamoto S, Nakano K, Tsujikawa M, Morimura H, Nishida K, et al. (2002) ABCA4 gene mutations in Japanese patients with Stargardt disease and retinitis pigmentosa. Invest Ophthalmol Vis Sci 43: Maugeri A, Klevering BJ, Rohrschneider K, Blankenagel A, Brunner HG, Deutman AF, et al. (2000) Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy. Am J Hum Genet 67:

173 2.21 Best s Disease Best s Disease Best s disease (vitelliform macular dystrophy) is an autosomal dominant, pleomorphic, progressive disease of the RPE with an onset early in life [1]. The unique fundus appearance (Fig ) is used to classify the stages: previtelliform, vitelliform, pseudohypopyon, vitelliruptive, and atrophic [2]. The OCT images show a solid substance underneath the RPE in the macula (Fig ). The visual prognosis is relatively good, and most patients retain reading vision in at least one eye throughout life. The progression of the visual acuity reduction is slow and begins for the most part after the age of 40 years [3]. The full-field ERGs are normal at all stages [4], but as shown in Fig , the focal macular ERGs are slightly to moderately reduced, indicating that only the macula is affected. However, as shown in Fig , the EOG is markedly abnormal, with the light-to-dark ratio usually less than 1.50 [5]. The EOG ratios of the carriers of the disease are also usually subnormal [5]. In 1998 a mutation of the VMD2 gene was identified as causing Best s vitelliform macular dystrophy [6]. Adult-onset foveomacular vitelliform dystrophy [7] may show similar ophthalmoscopic findings in the macula. The lesion is symmetri- Fig Fundi of patients with Best s disease at various stages. A Vitelliform. B Pseudohypopyon. C Scrambled egg. D Atrophic. E OCT image

174 166 2 Hereditary Retinal and Allied Diseases cal, solitary, usually one-third to one disk diameter in size, round or oval, slightly elevated, yellowish, and subretinal. There is often a central pigmented spot in each eye (Fig ). The patients may be visually asymptomatic or have mild visual blurring and metamorphopsia in one or both eyes, usually with an onset between ages 30 and 50 years. The full-field ERGs and EOGs are essentially normal. The normal EOG is a key differential point between Best disease and adult-onset foveomacular vitelliform dystrophy. Fig Focal macular ERGs elicited by 5, 10, and 15 spots recorded from a normal control and patients at various stages of Best s disease. (From Kondo et al. [4])

175 2.21 Best s Disease 167 Fig Electrooculography of a normal control (filled circles) and a patient with Best s disease (open circles) Fig Fundus of a 48-year-old man with adult-onset foveomacular vitelliform dystrophy. Visual acuity was 0.5 in both eyes, and EOG was normal. No family history was detected References 1. Best F (1905) Uber eine hereditare Maculaaffection: Beitrag zur Vererbungslehre. Z Augenheilkd 13: Gass JDM (1977) Stereoscopic atlas of macular diseases; diagnosis and treatment, 2nd edn. Mosby, St. Louis, p Fishman GA, Baca W, Alexander KR (1993) Visual acuity in patients with Best vitelliform macular dystrophy. Ophthalmology 100: Kondo M, Kondo N, Tanikawa A, Horiguchi M, Miyake Y, Awaya S (1997) Clin Rev Ophthalmol Jpn 91: Deutman AF (1969) Electro-oculogram in families with vitelliform dystrophy of the fovea: detection of the carrier state. Arch Ophthalmol 81: Marquardt A (1998) Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best disease). Hum Mol Genet 7: Bloom LH, Swanson DE, Bird AC (1981) Adult vitelliform macular degeneration. Br J Ophthalmol 65:

176 3 Acquired Retinal Diseases

177 170 3 Acquired Retinal Diseases 3.1 Diabetic Retinopathy Diabetes mellitus is a heterogeneous disorder of carbohydrate metabolism with multiple etiological factors that ultimately lead to hyperglycemia. Diabetic retinopathy is a disease of the retinal blood vessels that develops in the complex metabolic milieu of systemic diabetes mellitus. Because of the multiple factors, the electrophysiological abnormalities are complex, and the changes are often difficult to interpret. In early studies, the oscillating potentials (OPs) of the electroretinograms (ERGs) were found to have reduced amplitude [1] and delayed timing during the early stage of the disease (Fig. 3.1). Reduced b-wave amplitudes were reported only in eyes with fairly advanced retinopathy. In this chapter, three relatively new studies on diabetic retinopathy are examined: ERGs after panretinal photocoagulation, ERG evaluation of vitrectomy candidates with diabetic retinopathy, and analysis of diabetic maculopathy using focal macular ERGs and OCT. Fig Oscillatory potentials (OPs) of full-field ERGs recorded from a normal subject (top) and two patients with relatively early-stage diabetic retinopathy (DMR; cases 1 and 2)

178 3.1 Diabetic Retinopathy Panretinal Photocoagulation and ERGs Panretinal photocoagulation (PRP) is often applied to diabetic eyes at the preproliferative or proliferative diabetic retinopathy stage (Fig. 3.2). Although the mechanism for improving retinal function after PRP has not been conclusively determined, its efficacy has been thoroughly documented in randomized clinical trials. The rationale initially proposed for the regression of new vessels following PRP was that the ischemic retina, which was postulated to be producing a vasoformative factor, was destroyed. Another explanation was that the retinal pigment epithelium (RPE) cells that were producing a vessel-inhibiting factor were destroyed. It has also been proposed that PRP may improve oxygenation of the ischemic inner retinal layers by destroying some of the metabolically highly active photoreceptor cells to allow the oxygen normally diffusing from the choriocapillaris to the photoreceptors to continue into the inner retina. In any case, the amplitudes of the full-field ERGs are reduced after PRP in eyes with diabetic retinopathy. The degree of reduction of the ERGs after PRP relative to that before PRP is shown in Fig In our study [2] the means of the a-waves and b-waves are reduced by 44% and 41%, respectively. The b-wave/a-wave (a/b) ratio is slightly increased after PRP, but the increase is not significant. The OPs are Fig Fluorescein angiogram after panretinal photocoagulation (PRP) in an eye with diabetic retinopathy

179 172 3 Acquired Retinal Diseases markedly reduced or not present before PRP in most patients. However, if they are present, they become undetectable after PRP. The macula is spared from photocoagulation during PRP (Fig. 3.2), but the question arises whether PRP affects macular physiology. Decreased consumption of oxygen in the extensively coagulated retina may lead to increased oxygen supply to the noncoagulated areas of the macula. On the other hand, some patients suffer from macular edema following PRP. Fullfield ERGs and focal macular ERGs before and after PRP are compared in Fig. 3.4, with special emphasis on the OPs [2, 3]. Following PRP, the OPs of the full-field ERGs are reduced in amplitude to nearly undetectable levels. However, the OPs of the focal macular ERGs, elicited by three differently sized stimuli, were not reduced. The amplitudes of the b-waves of the focal macular ERGs elicited by a 15 spot in a large series of patients before and after PRP are compared in Fig. 3.5 [3]. The amplitude of the b-wave after PRP is expressed as a percentage of that before PRP. To determine the variations in the focal macular ERGs in normal control subjects, the amplitude of the b-wave of the focal macular ERGs of normal subjects from two recordings at different times were compared. The variation in the focal macular ERGs in normal subjects was small. On the other hand, the interindividual variations in the amplitudes of the focal macular ERGs after PRP were large, with some showing a decrease and others an increase. The decrease and increase (average of amplitudes) were not statistically significant. These results suggest that PRP alters the macula of eyes with diabetic retinopathy in various ways, and it may either improve or worsen macular function. Fig Comparison of amplitudes of a-waves and b-waves recorded before and after panretinal photocoagulation (PRP) in eyes with diabetic retinopathy. (From Kondo and Miyake [2])

180 3.1 Diabetic Retinopathy 173 Fig Comparison of full-field electroretinograms (ERG) (top) and focal macular ERGs elicited by three differently sized stimulus spots (bottom) recorded before and after PRP in an eye with diabetic retinopathy. The OPs of the full-field ERGs are significantly reduced in amplitude, but the OPs of the focal macular ERGs are not changed following PRP. To evaluate the OPs, the time constant (T.C.) of s was used for recording Fig Right: Comparison of the relative b-wave amplitude of the focal macular ERG elicited by a 15 spot before and after PRP in patients with diabetic retinopathy. The amplitude after PRP is expressed as a percentage of that before PRP. Left: Variations of the relative b-wave amplitude in normal subjects from two recordings

181 174 3 Acquired Retinal Diseases Diabetic Vitreous Hemorrhage When massive vitreous hemorrhage prevents ophthalmoscopic examination of the fundus in patients with proliferative diabetic retinopathy, it makes it difficult to predict the surgical and visual outcome after vitrectomy. In these eyes, the amplitudes of the ERGs may be markedly reduced by various factors: pathological changes induced by the diabetic retinopathy; earlier PRP; vitreous hemorrhage. As mentioned, the PRP reduces the ERG amplitude, but the b/a ratios are unchanged (Fig. 3.3). Because most patients with vitreous hemorrhage have undergone PRP, it is difficult to arrive at a prognosis of the outcome after vitrectomy using only the a-wave and b-wave amplitudes. The b/a ratios provide more useful information about the prognosis after vitrectomy [4]. The preoperative full-field ERGs elicited by a single bright flash can be used to classify patients with diabetic retinopathy into three groups (Fig. 3.6): Group A includes those with a b/a ratio 1.0, and the OPs are clearly recordable. Group B includes those with a b/a ratio 1.0, but the OPs are absent. Group C comprises those with a b/a ratio < 1.0, with no recordable OPs. The distribution of the postoperative visual acuity for each group is shown in Fig The postoperative visual acuity for group C was significantly worse than that for group A or group B. The low b/a ratios may indicate a more severe ischemic retina, which in turn may account for the relatively good correlation with visual acuity. However, among the patients in group C, there were some whose postoperative visual acuity was good, indicating that a b/a ratio < 1.0 is not necessarily a contraindication for surgery. The light-filtering effect of a dense vitreous hemorrhage should also be considered when evaluating the preoperative ERG in diabetic patients. Severe vitreous hemorrhage reduces the intensity of the stimulus light reaching the retina, which can increase the b/a ratio (see Section 1.1.1). Therefore, a lower b/a ratio in a patient with an opaque vitreous indicates a greater decrease in the b/a ratio in clear media, suggesting more severe ischemia of the retina. Another interesting observation is that most patients who have distinct OPs preoperatively have good visual acuity (>0.5) after surgery. This observation is important when we discuss the visual prognosis with patients before surgery. Thick proliferative tissues are found at the disk (Fig. 3.8) intraoperatively in 36% of the patients in group A, 67% in group B, and 90% in group C. Hirose [5] suggested that the fibrous proliferation at the disk may restrict retinal circulation by compressing the central retinal artery. In conclusion, it should be emphasized that a considerable amount of useful information can be obtained from a simple preoperative ERG on diabetic patients with massive vitreous hemorrhage.

182 3.1 Diabetic Retinopathy 175 Fig Preoperative full-field ERGs recorded from a normal control and three diabetic patients with vitreous hemorrhage who were classified into three groups. (From Hiraiwa et al. [4], with permission) Fig Postoperative visual acuity in the three groups shown in Fig *P < HM, hand motion vision. (From Hiraiwa et al. [4], with permission) Fig Proliferative tissue on the optic disk in a patient with diabetic retinopathy

183 176 3 Acquired Retinal Diseases Focal Macular ERGs and Diabetic Maculopathy Diabetic maculopathy is one of the leading causes of blindness in diabetic retinopathy. The functional and morphological analysis of diabetic maculopathy is thus important for prognostic evaluation and treatment indications. The OCT images and the focal macular ERGs obtained from representative patients with diabetic maculopathy are shown in Fig Normal control (A), mild maculopathy (B), or focal macular edema (C) often show an FAG OCT Focal Macular ERG T.C sec T.C sec A B C D E F ON ON 1 mv 50msec Fig Fluorescein angiograms (FAG), optical convergence tomography (OCT), and focal macular ERGs (ERG) elicited by a 15 spot obtained from patients at different stages of diabetic maculopathy. A Normal control. B F Diabetic maculopathy associated with B microaneurysms, C focal macular edema, D diffuse cystoid macular edema, E ischemic maculopathy, and F retinal pigment epitheliopathy

184 3.1 Diabetic Retinopathy 177 abnormality of only the macular OPs, particularly a delay in the implicit times. The OCT images of these patients may show a macula slightly thicker than normal. Patients with diffuse macular edema may have more severe alteration of the OPs in regard to both amplitude and implicit time as well as a decrease in the b-waves. In patients with diffuse macular edema, the OCT always shows a thicker macula, sometimes associated with cystic spaces (D). Patients with ischemic maculopathy with an avascular zone in the macula (E) usually have undetectable OPs, reduced a-wave amplitude, and more reduced b-wave amplitude. OCT images show that the macula can be either thicker or thinner than normal. A patient with pigment epitheliopathy of the macula (F) can have undetectable OPs with markedly reduced a-waves and b-waves. The OCT may show a rather thin macula. We studied the focal macular ERGs recorded from 73 eyes at various stages of diabetic maculopathy and compared them to 62 agematched controls (Fig. 3.10). The amplitudes of the a-waves, b-waves, and OPs in eyes with diabetic maculopathy, and with ophthalmoscopically normal macula and macular microaneurysms, were not significantly different from normal, but they were reduced in eyes with focal and diffuse macular edema. However, the implicit times of the OPs were significant delayed even when the macula was ophthalmoscopically normal. Thus, as seen in full-field ERGs, the macular OPs are the most sensitive indicator of the functional changes during early diabetic maculopathy. Diabetic macular edema is the most common cause of decreased visual acuity in patients with diabetic maculopathy. At present, vitrectomy is an investigational technique used for treating diabetic macular edema, sometimes resulting in recovery of the anatomic configuration of the macula without photocoagulation [6]. The question then arises as to whether recovery of macular configuration is accompanied by recovery of the macular ERGs. We Fig Amplitudes and implicit times of the a-wave, b-wave, and OPs of patients at different stages of diabetic maculopathy and normal controls. NDR, no diabetic retinopathy; MA, microaneurysm; FME, focal macular edema; DME, diffuse macular edema; IMP, ischemic maculopathy; RPEP, retinal pigment epitheliopathy

185 178 3 Acquired Retinal Diseases found [7] that anatomical resolution of the macular edema as detected by OCT preceded functional recovery of the macular ERG 6 months after vitrectomy (Fig. 3.11). Many patients did not show significant recovery of the macular ERGs despite good recovery of macular configuration. However, 12 months after surgery, visual acuity was significantly improved and the b-wave amplitude of macular ERG had increased significantly (Fig. 3.12). Although there was a wide range of changes in the b-wave amplitude at 12 months, the increase in the b-wave correlated with the decrease in the foveal thickness (Fig. 3.12). A disparity in the time course and degree of recovery of the foveal thickness and macular function was found in eyes with diabetic macular edema after vitrectomy. It is conceivable that diabetic macular edema, an indication for vitrectomy, is often associated with additional macular pathology, such as ischemia, which cannot be improved by vitrectomy. Such pathology may influence the focal macular ERGs more than the changes induced by the macular edema. Fig OCT images and focal macular ERGs obtained before (left) and 6 months after (right) surgery from six patients with diabetic macular edema. (From Terasaki et al. [7], with permission)

186 3.1 Diabetic Retinopathy 179 Fig Change in visual acuity (A), foveal thickness measured by OCT (B), and amplitude of the a-waves and b-waves of the focal macular ERGs elicited by a 15 spot (C) obtained before and after surgery. *P < 0.05; ***P < (From Terasaki et al. [7], with permission) References 1. Yonemura D, Aoki T, Tsuzuki K (1962) Electroretinogram in diabetic retinopathy. Arch Ophthalmol 68: Kondo T, Miyake Y (1985) Effects of panretinal photocoagulation on posterior fundus in diabetic retinopathy: analysis of local macular electroretinogram and visual evoked response. Acta Soc Ophthalmol Jpn 89: Miyake Y (1988) Study on local ERG.Acta Soc Ophthalmol Jpn 92: Hiraiwa T, Horio N, Terasaki H, Suzuki T, Yamamoto E, Horiguchi M, et al (2003) Preoperative electroretinogram and postoperative visual outcome in patients with diabetic vitreous hemorrhage. Jpn J Ophthalmol 47: Hirose T (1977) Evaluation of retinal function in the presence of vitreous opacities. In: Vitreous surgery and advances in fundus diagnosis and treatment. Appleton-Century-Crofts, New York, pp Lewis H, Abrams GW, Blumenktanz MS, Campo RV (1992) Vitrectomy for diabetic traction and edema associated posterior hyaloidal traction. Ophthalmology 99: Terasaki H, Kojima T, Niwa H, Piao CH, Ueno S, Kondo M, et al (2003) Changes in focal macular electroretinograms and foveal thickness after vitrectomy for diabetic macular edema. Invest Ophthalmol Vis Sci 44:

187 180 3 Acquired Retinal Diseases 3.2 Retinal Circulatory Disturbances Central Retinal Vein Occlusion There are two important questions to consider about eyes with a central retinal vein occlusion (CRVO): Can the waveform of the ERG be used to classify the CRVO as ischemic and nonischemic types? Can ERGs be used to predict the development of neovascular glaucoma? It has been reported that the b/a ratios of the ERGs of the affected eyes of patients with a CRVO who developed neovascularization of the iris (NVI) were significantly lower than the ratios of the fellow eyes and lower than the ratios in the affected eyes of individuals who did not develop NVI [1, 2]. However, there are also cases where the ERG of a patient with an initially normal b/a ratio changes so the ratio becomes <1.0 or vice versa (Fig. 3.13). This suggests that the initial findings may change during the course of the disease. Even though such case variance is present, the b/a ratio is an important index for evaluating the prognosis of CRVO. Fig A 39-year-old woman had a central retinal vein occlusion (CRVO) in her right eye. Note the nonischemic pattern in the fluorescein angiogram (left, A) and ERG (right, A) at her initial visit. One month later, new hemorrhages appeared in the retina, the fluorescein angiogram shows a nonperfused area (left, B), and the waveform of the ERG has become negative (right, B). Two months later the ERG b-wave is further depressed (right, C)

188 3.2 Retinal Circulatory Disturbances Central Retinal Artery Occlusion In cases of complete central retinal artery occlusion (CRAO), the ERG consists of a normal or supernormal a-wave and a markedly reduced b-wave [2]. However, this is not the case in most patients [3]. Platelet-fibrin and cholesterol are the major types of emboli, and both are soft and consequently quickly become fragmented and cast into the distal radicles of the retinal circulation. As a result, by the time the patient is examined fluorescein angiography often fails to detect complete obstruction of the central retinal artery. The ERGs elicited by a single bright flash (mixed rod and cone ERG),the visual fields,and visual acuities of five patients with CRAO are shown in Fig Despite the extremely constricted visual fields and poor visual acuity, the ERGs in the affected eyes are well preserved. Although the b/a ratio in the affected eyes is lower than that of fellow eye, none of the ERGs from the affected eyes has a negative configuration. These results suggest that the function of the retinal layer related to the ERG can recover to some degree following recovery of the retinal Fig Mixed rod cone (bright flash) ERGs, visual fields, and visual acuity (right) obtained from the affected eye and normal fellow eye of five patients with central retinal artery occlusion (CRAO). Despite the severe decrease of the subjective visual functions, the ERGs are relatively well preserved

189 182 3 Acquired Retinal Diseases circulation, as demonstrated by fluorescein angiography. However, because the ganglion cells are more vulnerable to ischemia, they suffer irreversible damage soon after the occlusion. Thus, the marked deterioration of the subjective visual function in patients with CRAO may result largely from the damage to ganglion cells. The fundus appearance of ophthalmic arterial occlusion is similar to that of CRAO in the acute stage. However, when the ophthalmic artery is occluded, not only central retinal artery circulation but also choroidal circulation is disturbed, resulting in marked deterioration of the a-wave [3]. This finding is important for differentiating CRAO from ophthalmic arterial occlusion. Electrooculography (EOG) of CRAO shows a depressed light rise with a low base value. This finding indicates that the mid-retinal cells necessary for detecting the EOG light rise are compromised, producing an abnormal light peak/dark trough (L/D) ratio [3, 4]. References 1. Karpe G, Uchermann A (1955) The clinical electroretinogram. IV. The electroretinogram in circulatory disturbances of the retina. Acta Ophthalmol 33: Sabates R, Hirose T, McMeel JW (1983) Electroretinography in the prognosis and classification of central retinal vein occlusion. Arch Ophthalmol 101: Miyake Y (1974) Electro-oculographic change in retinal arterial occlusion and its analysis. Acta Soc Ophthalmol Jpn 78: Gouras P, Carr RE (1965) Light-induced DC responses of monkey retina before and after central retinal arterial interruption. Invest Ophthalmol 4:

190 3.3 Retinal and Choroidal Detachment Retinal and Choroidal Detachment Retinal detachment is separation of the sensory retina from the retinal pigment epithelium (RPE) (Fig. 3.15). The ERG cannot be recorded when the retinal detachment is complete. Therefore in cases of rhegmatogenous retinal detachments, the reduction of the ERG amplitude corresponds roughly to the extent of retinal detachment (Fig. 3.16). The EOG is usually quantified by the L/D ratio, which reflects not only the function of the RPE but also the photoreceptors and neurons in the middle retinal layer. The amplitude of the EOG, called the base value, can be measured noninvasively and represents the standing potential of the eye. Animal studies have shown that the standing potential of the eye originates principally from the RPE and represents the difference between the apical and basal membrane potentials of the RPE cells [1, 2]. However, the standing potential varies considerably with many, often minor, factors so the amplitude alone is of minor clinical value, except to note that it is extremely small. However, it has been proven that in normal subjects the amplitudes in the two eyes are not significantly different when tested simultaneously [3]. It is possible, therefore, to use a relative value (i.e., the percentage of the affected eye/fellow eye), as an assay for RPE disease provided the fellow eye is sound. It should be stressed that this is probably a more accurate and sensitive indicator of a deviation from normal. With rhegmatogenous retinal detachments, the L/D ratio is low but the base value remains normal [3] (Fig. 3.17). Choroidal detachment is separation of the choroid from the sclera, which results from accumulation of clear fluid or blood within and under the choroid (Fig. 3.15). The ERG may be normal or only slightly abnormal when only a choroidal detachment is present. It may be associated with rhegmatogenous retinal detachment, either preoperatively or postoperatively, and is sometimes seen in the uveal effusion syndrome. Choroidal detachments may also follow trauma or glaucoma surgery, often associated with hypotonic maculopathy. Fig Fundus showing retinal detachment (left) and choroidal detachment (right)

191 184 3 Acquired Retinal Diseases Because there are only a few reports on electrophysiological changes in eyes with a choroidal detachment, it is important to review the common EOG findings in patients with choroidal detachment [3]. When compared to the normal fellow eye, the EOG base value is not significantly reduced in eyes with rhegmatogenous retinal detachment. However, once choroidal detachment is associated with retinal detachment, the base value decreases significantly (Fig. 3.17). The base value amplitudes are shown in Fig as a function of the rhegmatogenous retinal detachment in 28 eyes without choroidal detachment (group 1) and 11 eyes with it (group 2). Most eyes without choroidal detachment have normal or increased base values, whereas all eyes with choroidal detachment have markedly reduced base values. There is no significant correlation of the base value amplitude with the intraocular pressure or the extent of the choroidal detachment (Fig. 3.18). Selective reduction of the EOG base value is also seen with hypotonic retinopathy caused by blunt trauma [4]. In such eyes, the extreme low intraocular pressure may lead to hypotonic maculopathy. The choroidal detachment is often present, although it may not always be detected ophthalmoscopically. The reason the base value does not decrease in eyes with a recent retinal detachment but does so in eyes with choroidal detachment is not known. However, these results indicate that contact between the retinal photoreceptors and RPE is less important than contact between the choroid and the RPE for generating the standing potential. Fig Mixed rod cone (bright flash) ERGs (left) and fundus drawings of three patients with rhegmatogenous retinal detachment (right)

192 3.3 Retinal and Choroidal Detachment 185 Fig A Electrooculogram (EOG) of a patient with unilateral rhegmatogenous retinal detachment and a normal fellow eye. B EOG of a patient with unilateral rhegmatogenous retinal detachment associated with choroidal detachment and a normal fellow eye. In each EOG, the black and white circles indicate the normal fellow eye and the affected eye, respectively Fig Base value and extent of retinal detachment without (group 1) and with (group 2) choroidal detachment. The base value amplitude is expressed as a percentage of the amplitude in the normal fellow eye. The number expressing the extent of retinal detachment represents the detached quadrant (4 indicating total retinal detachment). Dotted zone indicates the range (± SD) of control baseline values obtained by recording base values for the left versus the right eyes of 30 normal subjects. (From Miyake et al. [3], with permission) References 1. Yonemura D, Kawasaki K (1979) New approaches to ophthalmic electrodiagnosis by retinal oscillatory potential, drug-induced responses from retinal pigment epithelium and cone potential. Doc Ophthalmol 48: Miyake Y (1974) Electro-oculographic changes in retinal arterial occlusion and its analysis. Acta Soc Ophthalmol Jpn 78: Miyake Y, Akiyama K, Sugita S, Horiguchi M (1993) Electrophysiologic detection of choroidal detachment in eyes with rhegmatogenous retinal detachment. Retina 13: Nuno Y, Tanikawa A, Kachi S, Terasaki H, Miyake Y (2001) Recovery of visual function following surgery for persistent hypotony maculopathy secondary to traumatic cyclodialysis. Clin Ophthalmol Jpn 55:

193 186 3 Acquired Retinal Diseases 3.4 Inflammatory Diseases of Retina and Choroid Endophthalmitis Once postoperative endophthalmitis develops, its early recognition and prompt treatment are important for preserving visual function. In animal studies, the ERG b-wave in eyes with endophthalmitis induced by Enterococcus faecalis or Pseudomonas aeruginosa decreases within 2 3 days after inoculation of the microorganisms into rabbit eyes [1, 2]. Clinically, the mixed rod cone ERG is useful for the diagnosis and prognostic evaluation of eyes that develop endophthalmitis after intraocular lens implantation [3]. Eyes with early (within 1 week) endophthalmitis associated with a b/a ratio of <1.0 have a worse postoperative prognosis than eyes with late-onset endophthalmitis and/or a b/a ratio of >1.0. These observations are quite important when deciding on the appropriate time to perform vitrectomy. For example, a patient with endophthalmitis that was detected within 1 week after intraocular lens implantation and an ERG b/a ratio of <1.0 should undergo vitrectomy without delay. On the other hand, when endophthalmitis develops relatively long after surgery and the ERG b/a ratio is >1.0, the timing of the vitrectomy or other treatment is not as critical. Representative examples are shown in Fig Fig Left: Preoperative mixed rod cone (bright flash) ERGs recorded from two patients with endophthalmitis after intraocular lens implantation. The negative configuration of the ERG (case 1) suggests poorer visual prognosis after vitrectomy than for the patient with normal-shaped ERGs (case 2). Right: Postoperative fundus. Case 1 showed extensive retinal vascular occlusions (arrows), with poor postoperative visual function as expected. Case 2 showed an essentially normal fundus with good postoperative visual function. (From Horio et al. [3])

194 3.4 Inflammatory Diseases of Retina and Choroid MEWDS, AZOOR, Acute Idiopathic Blind Spot Enlargement Syndrome Multiple evanescent white dot syndrome (MEWDS) [4], acute zonal outer retinopathy (AZOOR) [5], and acute idiopathic blind spot enlargement syndrome [6] have several similar ophthalmological and demographic findings: unilateral, blurred vision, multiple paracentral scotomas usually including a temporal scotoma, photopsia, and blind spot enlargement; and it affects young women. These symptoms usually develop soon after a flu-like illness. Among these disorders, only MEWDS has ophthalmoscopic abnormalities, which include clusters of tiny white or light-orange dots in the foveola and multiple small, often poorly defined gray-white patches at the level of the RPE and outer retina (Fig. 3.20). The visual function and fundus abnormalities may return to normal in 7 10 weeks. It is likely that most patients reported as having the acute idiopathic blind spot enlargement syndrome and AZOOR probably had MEWDS, and the white lesions were either overlooked or had faded by the time of the examination. The common functional abnormality of these disorders is acute occult visual field loss resulting from receptor cell damage. Because the ophthalmoscopic fundus abnormalities are minimal except in MEWDS, the patients may easily be misdiagnosed as having pathological alterations of the central nervous system. The ERGs are useful for the diagnosis; the full-field ERGs have different degrees of abnormalities depending on the extent of the visual field loss. In unilateral cases, the ERG of the Fig Fundus of a patient with multiple evanescent white dot syndrome (MEWDS)

195 188 3 Acquired Retinal Diseases affected eye is always reduced compared to that of the normal fellow eye (Fig. 3.21). Above all, the most convincing diagnostic finding for these disorders is the approximate correspondence of the subjective visual field defect to the low-amplitude zone in the multifocal ERGs (Fig. 3.22). The multifocal ERG findings indicate the retinal nature of the visual field loss. Fig Comparison of full-field ERGs for the eye with MEWDS and the normal fellow eye shown in Fig All ERG components are slightly smaller in the affected eye than in the normal fellow eye Fig Static visual fields (A) and topographic map of the amplitudes of the multifocal ERG responses (B) recorded from the patient with MEWDS shown in Fig. 3.20

196 3.4 Inflammatory Diseases of Retina and Choroid 189 Moreover and importantly, multifocal ERGs may be used to detect subclinical retinal dysfunction in these disorders. The clinical course of acute idiopathic blind spot enlargement is exemplified by the case of a 35-year-old woman. This patient, in previous good health, noted a small purple flickering spot in the upper right field of her right eye. Her visual acuity was 1.0 in both eyes. Fundus examination and fluorescein angiography were normal, except for slight peripapillary hyperfluorescence (Fig. 3.23). Based on the blind spot enlargement of the static perimetry in her right eye, acute idiopathic blind spot enlargement was diagnosed. As shown in Fig. 3.24, abnormalities of the multifocal ERGs may remain in such patients even after the subjective static visual fields have recovered normal sensitivities at almost all locations [7]. Fig Fundus photograph and fluorescein angiography of the right eye with acute idiopathic blind spot enlargement syndrome. (From Kondo et al. [4], with permission)

197 190 3 Acquired Retinal Diseases Fig Results of static visual fields (A) and multifocal ERGs obtained from a patient with acute idiopathic blind spot enlargement syndrome shown in Fig These measurements were made 2 weeks (A D) and 4 months (E H) after the onset. The left-most panel is the gray scale of the static visual field thresholds. The second panel from the left shows the deviation plot of the static visual field. The third and fourth panels are the 61 response arrays and topographic map of the multifocal ERG responses. Note that the amplitudes of the ERG responses are reduced in a broad area in the temporal field where the visual fields have normal sensitivities at almost all locations. (From Kondo et al. [4], with permission)

198 3.4 Inflammatory Diseases of Retina and Choroid Diffuse Unilateral Subacute Neuroretinitis Diffuse unilateral subacute neuroretinitis (DUSN) [8] is caused by an unidentified species of nematodes that may wander in the subretinal space for 4 years or longer and cause progressive ocular damage. DUSN is characterized by early visual loss, vitritis, papillitis, retinal vasculitis, and recurrent crops of evanescent, grayish white outer retinal lesions that may develop in one eye of an otherwise healthy individual. At a late stage, there is severely reduced vision, optic atrophy, retinal vessel narrowing, and diffuse RPE degeneration. The appearance of the fundus can resemble that in several other diseases at different stages, such as optic neuritis, sarcoidosis, MEWDS, unilateral optic atrophy, unilateral retinitis pigmentosa, among others. Ancylostoma caninum, a hookworm of dogs, is a common cause of DUSN. One of the reasons this syndrome is included here is because diagnosing DUSN is not always easy and the ERG findings can be helpful especially at the early stage. Full-field ERGs from the affected eye are usually reduced at all stages of the disease and are often moderately or severely reduced, with the b-wave affected more than the a-wave during the later stages of the disease [8 10]. The pathogenesis of DUSN appears to result from a local toxic reaction of the outer retina to the by-products of the worm, which are left in its wake, as well as a more diffuse toxic reaction affecting both the inner and outer retinal tissues. This latter reaction is manifested initially by rapid loss of visual function and alterations of the ERGs, suggesting inner retinal abnormalities. At a more advanced stage, the loss of ganglion cells (optic atrophy) and narrowing of the retinal vessels indicate damage to the inner retina. There are at least two endemic areas for the nematode in the United States. It is also found in the Caribbean islands and Latin America, and individual cases have been reported from other countries including Japan. The patient to be described [9, 10] was a 30-year-old man who had noticed reduced visual acuity 3 years earlier while living in Sao Paulo, Brazil. He was referred to our clinic for a diagnosis and possible treatment. His visual acuity was 1.5 (OD) and 0.07 (OS), and he had a central scotoma in the left eye with a defect in the nasal field. The rod and cone components of the fullfield ERGs were moderately reduced, and the mixed rod cone ERG had a negative configuration (Fig. 3.25). His multifocal ERG amplitudes in the nasal retina including the macula were reduced, which roughly corresponded with the defect of visual field (Fig. 3.26).As shown in Fig. 3.27, the nematode was not detected initially in our case even with a detailed examination of the fundus (Fig. 3.27A). The blood vessels in the posterior pole of the fundus were attenuated, and mild optic atrophy was present (Fig. 3.27A). Fluorescein angiography showed diffuse RPE mottling (Fig. 3.27B). Twelve days later, a nematode was detected ophthalmoscopically and was photographed by scanning laser ophthalmoscopy (Fig. 3.27C). The nematode was killed by laser photocoagulation (Fig. 3.27D), and examination 2 years later showed no further progression of the visual loss or depression of the ERGs.

199 192 3 Acquired Retinal Diseases Fig Full-field ERGs recorded from a patient with diffuse unilateral subacute neuroretinitis (DUSN) comparing the affected eye and the normal fellow eye. Note that the mixed rod cone (bright) ERG shows a negative configuration. (From Tanikawa et al. [3]) Fig Visual fields of the affected left eye and multifocal ERGs for both eyes in a patient with DUSN. (From Ito et al. [2])

200 3.4 Inflammatory Diseases of Retina and Choroid 193 Fig A Fundus photograph. B Composite fluorescein angiogram. C Fundus photograph obtained using a scanning laser ophthalmoscope (SLO). D Fundus photograph after killing the nematode by laser photocoagulation. At the initial examination, the nematode was not detected in the fundus (A), but thereafter it was photographed clearly by SLO (C, arrow)

201 194 3 Acquired Retinal Diseases Rubella Retinitis Rubella retinitis is the most common ocular manifestation of congenital rubella, with the appearance of the fundus taking several forms [11]. Salt-and-pepper mottling of the RPE may be localized only in the posterior pole, or it may extend farther into the peripheral retina (Fig. 3.28). Both eyes are affected in 80% of the patients. These alterations of the RPE may occur alone or may be associated with other ocular abnormalities (e.g., cataracts and microphthalmos) and systemic abnormalities, including deafness and congenital heart disease. Pathologically, the salt-and-pepper changes in the fundus are caused by altered pigmentation and some atrophy of the RPE [12]. Because the retina and choroid are unaffected, full-field ERGs, focal macular ERGs, EOG, visual acuity, and color vision are normal (Fig. 3.29). It should be noted that the results of electrophysiological tests are all normal despite the ophthalmoscopic appearance of a severely affected retina. Rubella retinopathy may mimic inherited dystrophies of the RPE, the carrier state of X- linked ocular albinism (see Section 2.9, Fig. 2.53), X-linked choroideremia and its carrier state (see Section 2.5, Fig. 2.23), and some toxic diseases of the RPE. Fig Fundus photograph (top) and fluorescein angiogram (bottom) obtained from a 20-year-old man with rubella retinitis. The visual acuity was 1.5 for both eyes

202 3.4 Inflammatory Diseases of Retina and Choroid 195 Fig Full-field ERGs and focal macular ERGs recorded from a normal control and the patient shown in Fig Despite the marked change in the retinal pigment epithelium, the ERGs are normal

203 196 3 Acquired Retinal Diseases Luetic Chorioretinitis Congenital or acquired syphilis can present as pigmentary retinopathy that resembles, in some aspects, advanced retinitis pigmentosa [13]. However, the retinal pigmentary changes are more varied and patchy, and the pigment deposits are in clumps with large patches of black pigment associated with the chorioretinal scars (Fig. 3.30). Interstitial keratitis is often associated with congenital syphilis (Fig. 3.30). The prognosis for vision with congenital luetic choroiditis is better than that with retinitis pigmentosa. Full-field ERGs are usually subnormal, unlike the undetectable ERGs from retinitis pigmentosa (Fig. 3.31). Fig Fundus photograph (left) and interstitial keratitis (right) of congenital luetic chorioretinopathy in a 44-year-old woman with visual acuity of 0.4 Fig Full-field ERGs from a normal subject and the patient with congenital luetic chorioretinopathy shown in Fig The appearance of the fundus is similar to that of retinitis pigmentosa, although relatively good responses were recorded

204 3.4 Inflammatory Diseases of Retina and Choroid 197 References 1. Hatano H, Sasaki T, Tanaka N (1988) Pseudomonas endophthalmitis in rabbits: intravitreal inoculation of two Pseudomonas strains. Acta Soc Ophthalmol Jpn 92: Stevens SX, Jensen HG, Jett BD, Cilmore MS (1992) A hemolysin-encoding plasmid contributes to bacterial virulence in experimental Enterococcus faecalis endophthalmitis. Invest Ophthalmol Vis Sci 33: Horio N, Terasaki H, Yamamoto E, Miyake Y (2001) Electroretinogram in the diagnosis of endophthalmitis after intraocular lens implantation. Am J Ophthalmol 132: Aaberg TM (1988) Multiple evanescent white dot syndrome. Arch Ophthalmol 106: Gass JDM (1993) Acute zonal occult outer retinopathy. J Clin Neuroophthalmol 13: Fletcher WA, Imes RK, Goodman D, Hoyt WF (1988) Acute idiopathic blind spot enlargement; a big blind spot syndrome without optic disc edema. Arch Ophthalmol 106: Kondo N, Kondo M, Miyake Y (2001) Acute idiopathic blind spot enlargement syndrome: prolonged retinal dysfunction revealed by multifocal electroretinogram technique. Am J Ophthalmol 132: Gass JDM, Gilbert WR, Guerry RK, Scelfo R (1978) Diffuse unilateral subacute neuroretinitis. Ophthalmology 85: Ito Y, Miyake Y, Terasaki H, Awaya S (1997) Ocular findings of diffuse unilateral subacute neuroretinitis. Jpn Rev Clin Ophthalmol 91: Tanikawa A, Ito Y, Terasaki H, Miyake Y (1997) Electrophysiological findings of diffuse unilateral subacute neuroretinitis. Jpn Rev Clin Ophthalmol 91: Alfano JE (1966) Ocular aspects of the maternal rubella syndrome. Trans Am Acad Ophthalmol Otolaryngol 70: Boniuk M, Zimmerman LE (1967) Ocular pathology in the rubella syndrome. Arch Ophthalmol 77: Duke-Elder S, Dobree JH (1967) System of ophthalmology, diseases of the retina. Mosby, St. Louis, pp 100, 172, 221, 252, 530

205 4 Acquired Macular Diseases Recent advances in vitreoretinal surgery are such that patients with many acquired macular diseases can now undergo surgery and regain normal macular configuration. Despite the normal configuration after surgery, however, some patients still do not obtain good visual function. It is particularly important and interesting to investigate how the pathophysiology of the macula changes following the recovery of macular configuration. Our focal macular electroretinography (ERG) system allows us to assess macular function objectively, layer by layer, via examining the a-wave, b-wave, oscillating potentials (OPs), and off (d)-wave [1, 2]. With the advent of optical coherence tomography (OCT) [3], an objective layer-by-layer assessment of the macular morphology can be obtained with a high degree of precision. We are now at a time when the relations between the psychophysical visual function, objective macular function (focal macular ERGs), and macular morphology (OCT) can be compared before and during recovery from macular surgery. This chapter is devoted to a review and summary of our results on focal macular ERGs, correlating them with the OCT findings and other examinations that assess the pathophysiology of the macula before and after treatment for various macular diseases. References 1. Miyake Y (1988) Studies on local macular ERG. Acta Soc Ophthalmol Jpn 92: Miyake Y, Shiroyama N, Ota I, Horiguchi M (1988) Oscillatory potentials in electroretinograms of the human macular region. Invest Ophthalmol Vis Sci 29: Puliafito CA, Hee MR, Lin CP (1995) Imaging of macular diseases with optical coherence tomography. Ophthalmology 102:

206 200 4 Acquired Macular Diseases 4.1 Central Serous Chorioretinopathy Idiopathic central serous chorioretinopathy typically affects young and middle-aged adults. Ophthalmoscopically, the sensory retina appears to be elevated because of the accumulation of serous fluid between the photoreceptors and the retinal pigment epithelium (RPE) cells (Fig. 4.1). Typically, the patient experiences metamorphopsia, relative scotoma, and micropsia. Visual acuity is often only slightly reduced and may be improved to near normal by a weak hyperopic correction. The focal macular ERGs of five representative patients with central serous chorioretinopathy [1] are shown in Fig. 4.2A. The a-wave and b-wave amplitudes of all of the affected eyes are reduced,and the implicit times are delayed. Our study of a large series of patients with relatively recent-onset unilateral central serous chorioretinopathy and bestcorrected visual acuity ranging from 0.4 to 1.5 (mean 1.0) showed that the amplitudes of the a-waves, b-waves, and OPs in the affected eyes were significantly smaller and the implicit times significantly longer than those in the normal fellow eyes [1]. The relative amplitudes of the b-wave (affected eye/normal fellow eye) are significantly smaller than the relative amplitudes of the a- wave, and the relative amplitudes of the OPs are significantly smaller than those of the a-waves and b-waves. Because the OPs and b-waves are significantly more depressed than the a-waves in the presence of macular detachment, central serous chorioretinopathy may involve functional Fig Fundus photograph (left) and optical convergence tomography (OCT) (right) obtained from a patient with central serous chorioretinopathy

207 4.1 Central Serous Chorioretinopathy 201 disturbances in the inner retinal layer as well as the photoreceptors [1]. In many of our cases, focal macular ERGs were recorded again 2 5 months after the macular detachment had resolved spontaneously or by photocoagulation. The results of five representative patients at the convalescent stage are shown in Fig. 4.2B. Our analysis of a large series of patients at the convalescent stage with the macula attached showed that the amplitudes and implicit times of the a-waves and b-waves in the affected eyes were not significant different from that in the normal fellow eyes. However, the OPs were still significantly smaller in the affected eyes, indicating that only recovery of the OPs was significantly delayed [1]. With central serous chorioretinopathy, it is conceivable that the macular photoreceptors are damaged because of the sensory retinal detachment. Therefore, this disease may be considered a model of macular photoreceptor damage. Indeed, it has been shown that all the components of focal macular ERGs have reduced amplitude and delayed implicit time, indicating photoreceptor damage. However, it is interesting that the data indicate that the inner retinal layers were also damaged, and their recovery was delayed after the subretinal fluid was resorbed. Fig A Focal macular electroretinograms (ERGs) elicited by a 10 spot recorded from five representative patients with central serous chorioretinopathy. B Focal macular ERGs elicited by a 10 spot recorded from the five patients shown in A at the convalescent stage. Results of the affected eyes are compared with those of the normal fellow eyes. T.C., time constant. (From Miyake [1], with permission)

208 202 4 Acquired Macular Diseases The mechanism by which central serous chorioretinopathy affects the inner retina is unknown. However, as shown in Fig. 4.3, OCT reveals thickening of the sensory retina in the macula area when subretinal fluid is present; interestingly, this thickening of the macula remains even after the subretinal fluid is absorbed during the convalescent stage and the macular OPs are selectively abnormal [2]. The thickened macula may indicate that macular edema, which is known to depress inner retinal function, is still present during the convalescent stage and is the cause of the decreased OPs. Therefore, functional changes in eyes with central serous chorioretinopathy probably result from both the sensory detachment and edema of the macula. Fig Comparison of the OCT images and focal macular ERGs from patients with central serous chorioretinopathy when subretinal fluid is present (upper) and when it is resolved (lower). The findings of the normal fellow eye are shown in the right column. When the subretinal fluid is present (active stage), the sensory retina is thicker than that of the normal fellow eye. Even after the subretinal fluid is resolved (convalescent stage), the sensory retina is still thicker than that of the normal fellow eye, which causes selective reduction of the macular oscillatory potentials (OPs). (From Miyake et al. [2]) References 1. Miyake Y, Shiroyama N, Ota I, Horiguchi MC (1988) Local electroretinographic responses in idiopathic central serous chorioretinopathy. Am J Ophthalmol 106: Miyake Y (2002) What can we know from focal macular ERG? Jpn Clin Ophthalmol 56:

209 4.2 Aphakic or Pseudophakic Cystoid Macular Edema Aphakic or Pseudophakic Cystoid Macular Edema Cystoid macular edema (CME), a common complication of cataract surgery, manifests as leakage of plasma from the perifoveal capillaries, formation of macular cystoid spaces, and marked visual impairment [1, 2]. The disease may or may not resolve spontaneously, and vitrectomy leads to successful resolution of the edema in some patients with CME. Fluorescein angiograms and OCT images of a patient with typical CME before and after vitrectomy are shown in Fig The fluorescein angiogram (Fig. 4.4A) shows extensive fluorescein leakage from the macular capillaries, and OCT reveals multiple cystic spaces in the macula before surgery. After vitrectomy, fluorescein leakage is not present (Fig. 4.4B), and the macular configuration evaluated by OCT returns to normal. Although CME may be associated with several retinal diseases, aphakic and pseudophakic CMEs are good models for studying the principle of the pathophysiology of CME. This is because, unlike the CME in diabetic retinopathy or central retinal vein occlusion, there are few background abnormalities such as ischemia or damaged RPE. Thus, the pathophysiology may be relatively simple to analyze. The interpretations may then be extended to analysis of more complex CME, such as that seen with diabetic retinopathy. Fig Fluorescein angiograms and OCT images obtained before (A) and after (B) vitrectomy from a 72-year-old man with pseudophakic cystoid macular edema (CME)

210 204 4 Acquired Macular Diseases Focal Macular ERGs The focal macular ERGs in the affected eyes of patients with aphakic or pseudophakic CME without systemic disease may be classified into three types (Fig. 4.5) [3]. In type 1, the amplitudes of the OPs are reduced compared to that of the normal fellow eye, but the amplitudes of the a-waves and b-waves are nearly normal. In type 2, the amplitude of the OPs and b-waves are reduced, but the a-wave is normal; and in type 3 the amplitude of the OPs, a-waves, and b-waves are reduced. The distribution of the best-corrected visual acuity for each type of CME is shown in Fig The difference in visual acuity between types 1 and 3 is statistically significant. Fluorescein angiograms and focal macular ERGs in eyes with CME and after the resolution of CME are illustrated for three representative cases in Figs. 4.7 to 4.9. Case 1 (Fig. 4.7) was a 51-year-old man who had had cataract surgery on his right eye with implantation of a posterior chamber lens. His preoperative visual acuity of 0.1 improved to 0.9 postoperatively but then gradually decreased to 0.6 five months later. Fluorescein angiography disclosed CME in the right eye. The OPs of the focal macular ERGs were selectively reduced (type 1) compared with that of the normal fellow eye. Six months later the CME resolved spontaneously, and fluorescein angiography disclosed a Fig Focal macular ERGs recorded from representative patients with types 1, 2, and 3 pseudophakic CME.The stimulus spot was 10 in diameter. (From Miyake et al. [3], with permission) Fig Distribution of best-corrected visual acuity in patients with types 1, 2, and 3 aphakic or pseudophakic CME. The difference between types 1 and 3 is statistically significant (P = ). (From Miyake et al. [3], with permission)

211 4.2 Aphakic or Pseudophakic Cystoid Macular Edema 205 normal pattern with no leakage; the visual acuity improved to 1.2. The focal macular ERGs returned to normal levels, with the amplitudes of the OPs comparable to those recorded from the fellow eye. Case 2 (Fig. 4.8) was a 70-year-old woman who visited our hospital 14 months after cataract surgery with implantation of a posterior chamber lens in her right eye. Her visual acuity was 0.2, and CME was detected with fluorescein angiography. The focal macular ERG had a type 2 pattern, with normal a-waves and reduced b-waves and OPs. Because vitreous was incarcerated by the iris, pars plana vitrectomy was performed to separate the vitreous from the iris. Five months after vitrectomy her visual acuity had improved to 0.7, and the CME was no longer present (seen by fluorescein angiography). The focal macular ERG recovered to the type 1 pattern in which only the OPs were reduced. Thus, the focal macular ERGs changed from type 2 to type 1 after resolution of the CME by vitrectomy. Case 3 (Fig. 4.9) was a 60-year-old man who was examined after bilateral intracapsular cataract extraction 16 and 20 months earlier. Fluorescein angiography disclosed CME in the right eye. The focal macular ERGs had a type 3 pattern with reduced a-wave, b-wave, and OP amplitudes. Careful examination showed that vitreous was incarcerated in the corneoscleral wound, and the pupil was distorted. Pars plana vitrectomy was performed to detach the vitreous from the wound to restore the shape of the pupil. Four months after vitrectomy, his visual acuity was 0.3, and fluorescein angiography disclosed less severe CME. The focal macular ERGs recorded 4 months after vitrectomy had a type 2 pattern; that is, the a-wave amplitude recovered almost to the level seen in the fellow eye, but the b-wave and OP amplitude remained smaller than that in the normal eye. With aphakic or pseudophakic CME, the amplitudes of the OPs are reduced and the implicit times are delayed regardless of the Fig Case 1. Focal macular ERGs (left) and fluorescein angiograms (right) when CME is present (top) and resolved (bottom). After spontaneous resolution of the CME, the focal macular ERG recovered from type 1 (top) reverts to normal (bottom). (From Miyake et al. [3], with permission)

212 206 4 Acquired Macular Diseases visual acuity. These findings suggest that OPs are the most sensitive indicator of CME. The progressive increase in the severity of CME is manifested by a decrease in the b-wave followed by a reduction of the a-wave. Therefore, analysis of each component of the focal macular ERG can be used to quantify the severity of CME [3]. Fig Case 2. Focal macular ERGs (left) and fluorescein angiograms (right) before vitrectomy (top) and 5 months after vitrectomy (bottom). After resolution of the CME by vitrectomy, the focal macular ERG recovered from type 2 to type 1. (From Miyake et al. [3], with permission) Fig Case 3. Focal macular ERGs (left) and fluorescein angiogram (right) recorded before vitrectomy (top) and 4 months after vitrectomy (bottom). After resolution of the CME, the focal macular ERG changed from type 3 to type 2. (From Miyake et al. [3], with permission)

213 4.2 Aphakic or Pseudophakic Cystoid Macular Edema Full-field ERGs It is conceivable that the full-field ERGs may be within the normal limits in cases of simple aphakic or pseudophakic CME without an associated systemic disease such as diabetes. This is true because the abnormal fundus and fluorescein angiographic findings are limited to the macula or within the posterior pole. The full-field ERGs should be normal because the peripheral retina contributes more significantly than the macula to the full-field ERGs.However, our study of full-field ERGs showed that, although there were no significant differences in the amplitudes and implicit times of the a- waves and b-waves between the affected eyes and the fellow eyes without CME, the amplitudes of OPs were significantly reduced in the affected eyes [4] (Figs. 4.10, 4.11). The degree of reduction of the OPs was strongly correlated with visual acuity (Fig. 4.12), and the mean implicit time of the first OP was significantly delayed in the affected eyes. The abnormal OPs of the full-field ERGs indicated that the abnormality was not limited to the macula but had spread over the entire retina. What do these findings mean? Chemical mediators are biosynthesized at the site of the primary lesion in various diseases, and it has been postulated that they diffuse into the vitreous and cause macular edema postoperatively [5]. Why do the chemical mediators act only on the macula and not on other parts of the retina or eye? The results of full-field ERG suggest that, even without a visible vasculopathy, as in diabetic retinopathy, the inflammatory chemical mediators do affect the retinal vessels over a large area of the retina in the presence of aphakic or pseudoaphakic CME. This suggests that CME is only one manifestation of a more diffuse intraocular pathological alteration. Fig Mixed rod cone (bright flash) ERGs recorded from eight representative eyes with pseudophakic CME and normal fellow eyes. The OPs, recorded with a short time constant (0.003 s), are shown below the regular ERGs and are markedly smaller in the affected eyes. (From Terasaki et al. [4], with permission)

214 208 4 Acquired Macular Diseases Fig Left: Summated amplitude of the OPs of the full-field mixed rod cone ERGs recorded from the affected eyes (ordinate) and the normal fellow eye (abscissa). Right: Implicit time of OP1 recorded from the affected eyes (ordinate) and fellow eyes (abscissa). Normal values for the total amplitudes of OPs and implicit time of OP1 are indicated by shaded backgrounds. (From Terasaki et al. [4], with permission) Fig Relation between the best-corrected visual acuity (log MAR units) and the ratio of the full-field total OP amplitudes of the affected eyes to normal fellow eyes. A significant correlation was found between visual acuity and total OP amplitude. (From Terasaki et al. [4], with permission) References 1. Irvine SR (1953) A new defined vitreous syndrome following cataract surgery: interpreted according to recent concepts of the structure of the vitreous. Am J Ophthalmol 36: Gass JDM, Norton EWD (1966) Cystoid macular edema and papilledema following catarct extraction; a fluorescein funduscopic and angiographic study. Arch Ophthalmol 76: Miyake Y, Miyake K, Shiroyama N (1993) Classification of aphakic cystoid macular edema with focal macular electroretinograms. Am J Ophthalmol 116: Terasaki H, Miyake K, Miyake Y (2003) Reduced oscillatory potentials of the full-field electroretinogram of eyes with aphakic or pseudophakic cystoid macular edema. Am J Ophthalmol 135: Miyake K (1995) Cystoid macular edema as part of diffuse intraocular symptoms. Folia Ophthalmol Jpn 46:

215 4.3 Idiopathic Epimacular Membranes Idiopathic Epimacular Membranes Epimacular membranes (Fig. 4.13) can be caused by trauma, inflammation, retinal vascular disease, and retinal detachment surgery. We have studied the focal macular ERGs of patients with unilateral idiopathic epimacular membrane (IEM) to determine how the altered retinal function correlates with visual acuity and OCT images [1, 2]. We found that the changes in the focal macular ERG while the macula was altered and after recovery of the macula closely resemble those seen in the presence of aphakic (pseudophakic) CME (see Section 4.2). Focal macular ERGs demonstrating the damaged and recovered stages are shown in Fig A 56-year-old woman noted decreased vision in her right eye with visual acuity of 1.0; the visual acuity in her left eye was 2.0. She had an IEM in the right eye, and the a-waves and b- waves of her focal macular ERGs for the right eye were not significantly different from those in the normal fellow eye at the initial visit. However, OPs of the right eye were smaller (Fig. 4.14A). Six months later, the best-corrected visual acuity in her right eye had decreased to 0.1, and the a-waves, b-waves, and OPs of the focal macular ERGs were markedly reduced. There was also a decrease in the b-wave/a-wave (b/a) ratio (Fig. 4.14B). Vitrectomy was then per- Fig Fundus photograph (top) and OCT (bottom) of a patient with idiopathic epimacular membrane (IEM)

216 210 4 Acquired Macular Diseases formed to remove the ERM in her right eye, and 10 months after surgery her best-corrected visual acuity improved to 0.8. At this time, the a-wave amplitude had recovered nearly to the level in the fellow eye, but the b-wave and the OPs remained smaller than in the fellow eye, resulting in a lower b/a ratio (Fig. 4.14C). Fifteen months after surgery, the b-wave and OPs improved, and the b/a ratio was almost identical to that in the fellow eye (Fig. 4.14D). In our analysis of 37 eyes with an IEM [2], the relative amplitudes (affected eye/normal fellow eye) of the a-waves, b-waves, and OPs were 75%, 69%, and 45%, respectively. The lower b/a wave ratio in the affected eyes resulted from a significantly greater reduction of the b-wave amplitude than the a-wave amplitude. The reduced amplitude of OPs was significantly greater than that of the other two components, and the implicit times were significantly prolonged for all components. These findings are similar to those for eyes with aphakic or pseudophakic CME. There was a significant correlation between the preoperative relative b-wave amplitude and visual acuity and between the preoperative relative a-wave amplitude and postoperative visual acuity (Fig. 4.15). The OCT examinations showed that the mean thickness of the preoperative foveal and parafoveal retina in the affected eyes was significantly thicker than the mean of the normal fellow eyes. After surgery, the thickness decreased significantly, although it was still thicker than in the normal fellow eyes [2]. The changes in the waveform of the focal macular ERG and the OCT findings before and after vitrectomy in two patients with an IEM are shown in Fig After surgery, the foveal thickness was decreased in both patients. In case 1, all components of the preoperative focal macular ERGs had reduced amplitudes, but the a-wave amplitude was relatively better preserved (decreased b/a ratio). The b-waves and a-waves had recovered to normal levels 3 months after surgery, in conjunction with an Fig Focal macular ERGs elicited by a 10 spot before (A, B) and after (C, D) vitrectomy in a patient with unilateral IEM. A On the patient s initial visit, only the OPs were attenuated. B Six months later, the a-wave and b-wave amplitude and the b/a ratio were also reduced. C Ten months after successful removal of the IEM, the a-wave amplitude recovered. OPs were still absent. D Fifteen months after vitrectomy, the ERGs recovered almost to normal. (From Tanikawa et al. [1], with permission)

217 4.3 Idiopathic Epimacular Membranes 211 Fig A There was a significant correlation between the relative b-wave amplitude (affected eye/fellow eye) of focal macular ERGs and the best-corrected visual acuity in patients with IEM (r = 0.5, P = 0.007). B There was a significant correlation between the preoperative a-wave amplitude and postoperative visual acuity (r = 0.543, P = ). (From Niwa et al. [2], with permission) Fig Changes in the waveform of the focal macular ERGs elicited by a 15 stimulus and the OCT images before and after surgery in two patients with IEM. After surgery, the foveal thickness had decreased in both patients. Top: In case 1 (eye with preserved a- wave amplitude), the b-wave amplitude first recovered at 3 months after surgery, and the change was associated with an increased b/a ratio. The focal macular ERG examined 12 months after surgery demonstrated recovery of the OPs. Bottom: In case 2 (eye with reduced a-wave amplitude), the a-wave amplitude first recovered at 5 months after surgery, and recovery was associated with a decreased b/a ratio. The focal macular ERG examined 22 months after surgery showed increased b-wave and OP amplitudes. The macular configuration in OCT was still abnormal. (From Niwa et al. [2], with permission)

218 212 4 Acquired Macular Diseases increase in the b/a ratio. The focal macular ERGs examined 12 months after surgery demonstrated recovery of the OPs. In case 2, the a-wave amplitude was first detected to have recovered at 5 months after surgery, and recovery was associated with a decrease in the b/a ratio. The b-wave and OP amplitudes of the focal macular ERGs were increased at 22 months after surgery. There were significant correlations between the preoperative a-wave amplitude and postoperative visual acuity (Fig. 4.15B) and between the postoperative OPs amplitude and postoperative parafoveal thickness (Fig. 4.17). Fig There was a significant correlation between postoperative OP amplitude and postoperative parafoveal thickness (r =-0.460, P = 0.011). OP amplitudes are shown as a percentage of those in the normal fellow eye. (From Niwa et al. [2], with permission) References 1. Tanikawa A, Horiguchi M, Kondo M, Suzuki S, Terasaki H, Miyake Y (1999) Abnormal focal macular electroretinograms in eyes with idiopathic epimacular membrane. Am J Ophthalmol 127: Niwa T, Terasaki H, Konde M, Piao CH, Suzuki T, Miyake Y (2003) Function and morphology of macula before and after removal of idiopathic epiretinal membrane. Invest Ophthalmol Vis Sci 44:

219 4.4 Foveal Thickness and Focal Macular ERG Foveal Thickness and Focal Macular ERG The results of focal macular ERGs and OCTs from patients with central serious chorioretinopathy, aphakic or pseudophakic CME, and IEM have some findings in common that contribute to our understanding of the relation between macular morphology and macular ERG. The macula OPs at the early stage of aphakic or pseudophakic CME and IEM are selectively reduced, and this reduction was observed during the convalescent stage of central serous chorioretinopathy even after the submacular fluid had been resorbed. The common change in these patients was the increase in the OCT-determined thickness of the macula, which was due to macular edema. These observations indicate that the macular OPs are the most sensitive indicator among the focal macular ERG components when the macula is edematous with minimal systemic pathology. It was also determined that macular OPs have the slowest recovery following treatment of macular edema. This relation was confirmed by the significant correlation between the macular thickness measured by OCT and the amplitude of macular OPs in many patients with IEM after vitrectomy (Fig. 4.17). When macular edema is long-standing or severe,the b-wave and then the a-wave may also become depressed. These findings indicate that the pathological process first affects the OPs, followed by the b-wave, and finally the a-wave as the macula thickness increases. The recovery process follows the reverse course; the a-wave recovers first, followed by the b-wave, and finally the OPs. This rule is important when analyzing complicated cases of macula edema associated with significant background pathology, such as diabetic macular edema (see Section 3.2.3).

220 214 4 Acquired Macular Diseases 4.5 Idiopathic Macular Hole Pathophysiology and Macular ERGs Eyes with an idiopathic full-thickness macular hole usually have reduced visual acuity and an absolute central scotoma caused by the macular hole. Relative scotomas are usually detected in areas surrounding the hole that can be identified by OCT (Fig. 4.18). The loss of retinal function is attributed to the defect in the central retina, the surrounding cuff of subretinal fluid, thickening of the retina, and tractional elevation of the retina surrounding the macular hole. Multifocal ERGs may demonstrate the volcano-like depression of the central retina (Fig. 4.18). Fig Fundus photograph (top left), OCT (bottom left) and topographic maps of multifocal ERGs (top right) obtained from a patient with an idiopathic macular hole. The macular hole is surrounded by the cuff. Multifocal ERG topography shows the volcano-like depression at the central peak

221 4.5 Idiopathic Macular Hole 215 It is extremely important to monitor the location of the stimulus when recording the focal macular ERGs in patients with an idiopathic macular hole to determine the relation between the stimulus spot and the macular hole. This relation can be studied precisely with our system because focal macular ERGs are recorded under the fundus monitor. As shown in Fig. 4.19, when the spot is smaller than or equal to the macular hole, a response cannot be recorded (Fig. 4.19A). When the spot is slightly larger than the macular hole, the stimulus light stimulates the parafoveal cuff and a reduced response with delayed implicit time is recorded (Fig. 4.19B). When the spot is much larger than the macular hole, a large response is elicited from the normal perifoveal retina. Although the amplitude is still smaller than that of the normal fellow eye, the implicit time is not delayed because the implicit time of the b-wave reflects the function of the surrounding normal retina. Another interesting phenomenon is seen in the focal macular ERGs elicited by a large spot in patients with an idiopathic macular hole. When the stimulus used to stimulate the affected eye and the normal fellow eye are balanced to elicit nearly equal-amplitude a-waves and b-waves, the OPs of the affected eyes are always larger than those of the fellow eyes (Fig. 4.20). This is caused by the unique distribution of OPs around the macular region, as described earlier [1]. Namely, the distribution of OPs is larger in parafovea than fovea and eyes with macular hole are stimulated more in parafovea than fovea (see Section 1.2.3, Fig. 1.28).

222 216 4 Acquired Macular Diseases Fig Relation between the size of the macular hole, the size of the stimulus spot, and focal macular ERG responses. Fundus photographs (top), stimulus spot on the fundus (middle), and focal macular ERGs recorded from the affected eye and the normal fellow eye (bottom). A When the stimulus spot is smaller than or equal to the macular hole, the macular ERG is absent. B When the stimulus spot is slightly larger than the macular hole, the b-wave amplitude is smaller and the implicit time is longer than that in the normal fellow eye. This indicates that the response is elicited from the cuff surrounding the macular hole. C When the stimulus spot is much larger than the macular hole, the amplitude of the b-wave is slightly smaller and the implicit time is normal. This ERG response is evoked from the normal retina outside the cuff Fig Focal macular ERGs recorded from four patients with an idiopathic macular hole. The size of the stimulus spots is balanced to elicit approximately equal-amplitude a-waves and b-waves from the affected eye and the normal fellow eye. Two time constants (T.C.) are used simultaneously to evaluate a- waves and b-waves (0.03 s) and OPs (0.003 s)

223 4.5 Idiopathic Macular Hole Surgical Treatment and Focal Macular ERGs Recent advances of vitreoretinal surgery have made it possible to close the macular hole and recover the normal configuration of the macula, which can be confirmed by OCT (Fig. 4.21). The surgical technique to close the macular hole consists of standard three-port pars plana vitrectomy and separation of the posterior hyaloid from the retina after removing the cortical vitreous. Residual vitreous cortex is removed when it is present around the macular hole. After vitrectomy, fluid-gas exchange is performed [2]. The changes in the focal macular ERGs before and after macular hole surgery [3] are shown in Fig A 65-year-old man had noted decreased vision in his left eye for 6 months. Examination disclosed a stage 3 fullthickness macular hole, and his visual acuity was 0.08 (OD) and 1.0 (OS). Focal macular ERGs were recorded with 2, 3, and 4 stimulus spots from both eyes before surgery. The different stimulus spot sizes are photographically superimposed on the fovea to compare the sizes of the stimulus spot and the macular hole. In the affected eye, responses were not recorded when the stimulus size was equal to or smaller than the size of the macular hole (2 and 3 ). When the stimulus spot was larger than the macular hole (4 ), a response suggestive of a focal macular ERG was recorded (A). The patient underwent surgery, and the macular hole was closed. Six months later his visual acuity improved to 0.4, and focal macular ERGs were successfully recorded even with the smallest 2 spot. These results confirmed that the area of retinal deficit, the macular hole, was closed by the surgery, and function had returned (B). The focal macular ERGs elicited by 4 and 5 stimulus spots before and after surgery in four Fig OCT images obtained from a 56-year-old woman with an idiopathic macular hole before (PRE OP) and after (POST OP) vitrectomy. The macular hole is closed. The preoperative visual acuity of 0.3 improved to 0.8 postoperatively

224 218 4 Acquired Macular Diseases patients with a full-thickness macular hole are shown in Fig The amplitudes of the b- wave of the focal macular ERGs were increased in all eyes, and the implicit times were decreased after the surgery. In our study of a large series of patients [3], the preoperative b-wave implicit time measured with a 5 spot significantly correlated with the postoperative corrected visual acuity (Fig. 4.24). In addition, the postoperative b-wave amplitude and implicit time of the focal macular ERGs elicited by a 5 spot significantly correlated A with the postoperative visual acuity. These results strongly suggest that parafoveal function in the area surrounding the macular hole is closely related to the visual prognosis after surgery in patients with an idiopathic macular hole. To increase the closure rate of macular holes, removing the internal limiting membrane (ILM) in addition to routine vitrectomy has recently been advocated [4]. The exact role of the ILM in retinal physiology has not been determined, although the ILM is the basal B Fig A Preoperative fundus photograph and photographs with 2, 3, and 4 stimulus spots superimposed on the fovea as seen on the television monitor (left). Preoperative focal macular ERGs of the eye with the macular hole are compared to those from the fellow eye (right). B Postoperative fundus photograph compares the three spots used to the size of the macular hole (left). Postoperative focal macular ERGs comparing the responses of fellow eye. (From Terasaki et al. [3], with permission) Fig Focal macular ERGs elicited by a 4 spot (top) and a 5 spot in four patients with a fullthickness macular hole before (Pre-op) and after (Post-op) surgery. All eyes show increased amplitude and decreased implicit time of the b-wave. (From Terasaki et al. [3], with permission)

225 4.5 Idiopathic Macular Hole 219 lamina of Mueller cells and is connected to the end-feet of the Mueller cells [5]; and Mueller cells are involved in generation of the ERG b- wave [6]. In addition, the anionic sites on the ILM may act as a charge barrier between the retina and the vitreous cavity [7]. The changes in the focal macular ERG after conventional vitrectomy without ILM removal (ILM-on) and with ILM removal (ILM-off) are compared [8] in Fig Six weeks after vitrectomy without ILM peeling, the amplitudes of the b-waves and OPs of the focal macular ERGs were larger, and an additional increase was observed 6 months after surgery. On the other hand, the patient with ILM-off showed a marked decrease in the amplitudes of the b- waves and OPs 6 weeks after surgery, which then recovered to the preoperative level at 6 months. Analysis of a large series of patients showed that visual acuity increased significantly after surgery in both groups, and no significant difference was found between the two groups. However, recovery of the b-wave in focal macular ERGs in the ILM-off group was significantly delayed until 6 months after surgery compared with that of the ILM-on group, suggesting slower recovery of retinal physiology in the macular region in the ILMoff group. Fig There is a significant correlation between the preoperative b-wave implicit time elicited by a 5 spot and the postoperative best-corrected visual acuity (r = 0.62; P = 0.001). (From Terasaki et al. [3], with permission)

226 220 4 Acquired Macular Diseases Fig Left: Representative focal macular ERGs recorded before and 6 weeks and 6 months after surgery for an idiopathic macular hole without internal limiting membrane (ILM) removal (ILM-on) and the fellow eye. Right: Changes in the focal macular ERG in an eye with the ILM removed (ILM-off) and the fellow eye. The b-wave and OPs were markedly reduced 6 weeks after surgery but had recovered at 6 months to the same level as that before surgery. (From Terasaki et al. [6], with permission) References 1. Miyake Y, Shiroyama N, Ota I, Horiguchi M (1988) Oscillatory potentials in electroretinograms of the human macular region. Invest Ophthalmol Vis Sci 29: Johnson RN, Gass JD (1988) Idiopathic macular holes: observations, stages of formation, and implications for surgical intervention. Ophthalmology 95: Terasaki H, Miyake Y, Tanikawa A, Kondo M, Ito Y, Horiguchi M (1998) Focal macular electroretinograms before and after successful macular hole surgery. Am J Ophthalmol 125: Park DW, Sipperley JO, Sneed SR, Dugel PU, Jacobson J (1999) Macular hole surgery with internallimiting membrane peeling and intra-vitreous air. Ophthalmology 106: Nishihara H (1989) Studies on the ultrastructure of the inner limiting membrane of the retina. I. Surface replication study on the inner limiting membrane of the retina. Acta Soc Ophthalmol Jpn 93: Terasaki H, Miyake Y, Piao CH, Hori K, Niwa T, Kondo M (2001) Focal macular ERGs in eyes after removal of macular ILM during macular hole surgery. Invest Ophthalmol Vis Sci 42:

227 4.6 Macular Pseudohole Macular Pseudohole A macular pseudohole resembles a fullthickness macular hole in terms of its shape, but the pathophysiology is quite different. The pseudohole is created by spontaneous contraction of an epiretinal membrane surrounding the fovea. The pseudohole is not a retinal hole but a round defect of the epimacular membrane over the fovea. The natural course of a macular pseudohole is generally good, with preservation of near-normal visual acuity [1]. In some cases, however, further contraction of the epiretinal membrane distorts the fovea, resulting in decreased visual acuity. A fundus photograph and an OCT image of an eye with a macular pseudohole are shown in Fig When the focal macular ERG elicited by a 15 spot was analyzed [2], we found a significant correlation between the reduction of the a-waves and b-waves and the parafoveal thickness (Fig. 4.27). There was a significant reduction in the mean amplitudes of the a- waves, b-waves, and OPs in the affected eyes compared with fellow eyes. The relative amplitudes of the a-wave, b-wave, and OPs were 84.0%, 74.8%, and 62.4%, respectively. Thus, the decrease in the amplitude was greatest for the OPs followed by the b-waves and then the a- waves. The implicit times of a-waves, b-waves, and OPs were delayed significantly. These results were similar to those obtained from eyes with an idiopathic epimacular membrane without a macular pseudohole (see Section 4.3). A significant correlation was found between the relative amplitude (affected eye/normal fellow eye) of the b-wave elicited by the 5 stimulus and the visual acuity (Fig. 4.28). This correlation probably resulted from using the 5 spot, which is small and reflects the function of the small central area where the epiretinal membrane is absent. Fig Fundus photograph (top) and OCT image (bottom) in a 56-year-old woman with a macular pseudohole. Visual acuity was 1.0

228 222 4 Acquired Macular Diseases Fig There was a significant correlation between the relative amplitudes (affected eye/fellow eye) of the a-wave (top) and the b-wave (bottom) elicited by a 15 spot and the thickness of the parafoveal retina in patients with a macular pseudohole. (a-wave: r = 0.674, P = ; b-wave: r = 0.804; P < ) (From Suzuki et al. [2], with permission) Fig There was a significant correlation between the relative amplitudes of the b-wave elicited by a 5 spot and best-corrected visual acuity (VA). (r = 0.918, P = ) (From Suzuki et al. [2], with permission) References 1. Creven CM, Slusher MM, Czyz CN (1998) The natural history of macular pseudoholes. Am J Ophthalmol 125: Suzuki T, Terasaki H, Niwa T, Mori M, Kondo M, Miyake Y (2003) Optical coherence tomography and focal macular electroretinogram in eyes with epiretinal membrane and macular pseudohole. Am J Ophthalmol 136:62 67

229 4.7 Age-Related Macular Degeneration Age-Related Macular Degeneration Age-related macular degeneration (AMD) is a chronic degenerative disease that affects primarily the choriocapillaris, Bruch s membrane, and the RPE. It is the most common cause of legal blindness in the United States and Europe, and the incidence of AMD in Japan has been increasing during the past 20 years. AMD is classified into two types: dry and exudative. The exudative form, also called disciform macular degeneration, is characterized by the development of choroidal neovascularization, which causes serous and hemorrhagic detachment of the retina, resulting in poor central vision. The ophthalmoscopic appearance of AMD is shown in Fig Some AMD is treatable with laser photocoagulation, photodynamic therapy, or Fig Fundus photograph (A), OCT image (B), fluorescein angiogram (C, D each left), and indocyanine green angiogram (C, D each right) of early-phase (C) and late-phase (D) in age-related macular degeneration (AMD) obtained from a 62-year-old man. Present are submacular hemorrhages, a choroidal neovascular membrane, and sensory detachment of the macula. The visual acuity was 0.2

230 224 4 Acquired Macular Diseases vitreoretinal surgery. Because the condition tends to be self-limiting, retinal function in the periphery is relatively well preserved and complete loss of vision is rare. With both types of AMD, full-field ERGs are usually nearly normal, and the focal macular ERGs and multifocal ERGs demonstrate only abnormal macular function (Fig. 4.30). Fig Full-field ERGs (A), focal macular ERGs (B), and topographic map of the amplitudes of a multifocal ERG (C) recorded from a patient with AMD

231 4.7 Age-Related Macular Degeneration How Does Subretinal Hemorrhage Damage the Retina? A thick subretinal hemorrhage situated under the fovea occasionally has a natural course that leads to severely decreased visual function even in those without choroidal neovascularization. Animal experiments have shown that the photoreceptors can be damaged by the toxic effects of the iron released by red blood cells as well as by mechanical blockage by the hemorrhage, which hinders metabolic exchange between the photoreceptors and the RPE cells [1]. Subretinal macular hemorrhages can be successfully removed by vitrectomy using tissue plasminogen activator [2], leading to an improvement in the postoperative visual acuity of patients whose vision was good before the hemorrhage [3] (Fig. 4.31). Changes in the focal macular ERGs elicited by a 10 spot in five patients who had a submacular hemorrhage removed by vitrectomy using tissue plasminogen activator are shown in Fig The submacular hemorrhage was caused by rupture of a macroaneurysm in three of the eyes, AMD in one of the eyes, and an unknown reason in the fifth eye. The duration of the subretinal hemorrhage ranged from 3 to 14 days. All of the patients had extremely poor visual acuity (from hand motion to 0.05) before surgery, and the visual acuity improved to after surgery. Three points can be made based on these results. First, focal macular ERGs were undetectable in all of these patients before surgery regardless of the duration of the submacular hemorrhage. This is definitely different from the results from patients with idiopathic central serous chorioretinopathy, where serous fluid, not blood, accumulates between the photoreceptors and the RPE. Patients with central serous chorioretinopathy usually have much better visual acuity with good-amplitude focal macular ERGs (see Section 4.1). This difference indicates that blood can alter the function of the photoreceptors much more so than can serous fluid. Second, the decline of photoreceptor function is partially reversible when blood is removed from the subretinal space even after 14 days, as shown by the recovery of the focal macular ERG in case 5. However, it is more likely that the earlier the blood is removed the better is the recovery. The third point is that there is little if any toxic effect of recombinant tissue plasminogen activator injected at clinically useful doses.

232 226 4 Acquired Macular Diseases Fig Top: Preoperative fundus photograph with a 10 spot superimposed on the fovea. The image was obtained while recording the macular ERG in a patient with submacular hemorrhage. Bottom: Postoperative photograph. The retinal blood is almost completely removed. (From Terasaki et al. [3], with permission) Fig Focal macular ERGs recorded from five patients with subretinal macular hemorrhage. The stimulus spot was 10 in diameter. The fellow eye of case 5 shows no response because of macular degeneration of unknown cause. After surgical drainage of the subretinal hemorrhage using human plasminogen activator, there is partial recovery of the ERG in all patients. (From Terasaki et al. [3], with permission)

233 4.7 Age-Related Macular Degeneration Removal of Choroidal Neovascular Lesions Surgical removal of choroidal neovascular (CNV) lesions is undertaken to preserve or regain central neurosensory retinal function as an alternative treatment to conventional laser photocoagulation in eyes with AMD (Fig. 4.33). The focal macular ERGs elicited by a 15 spot before and after removing CNV lesions in three patients are shown [4] in Fig The amplitudes of the a-waves, b-waves, and OPs were markedly reduced or unrecordable with prolonged implicit times before surgery. These findings indicated severe impairment of macular cone function, which agrees with a histological report that there is marked photoreceptor loss in eyes with AMD. Most patients had a significant recovery at 3 months after surgery, with the b-wave amplitude selectively increased without an increase in the a-wave amplitude. These findings suggest further recovery of inner retinal function, particularly the on bipolar cells. The postoperative increase in b-wave amplitude in eyes with preoperative recordable b- waves significantly correlated with the decrease in the mean parafoveal thickness measured by OCT [4] (Fig. 4.35). This suggests that inner retinal function is impaired by retinal edema, and the decreased thickness of the macula contributes to the recovery of the inner layer function of the macula. Fig OCT images obtained from a 56-year-old man with AMD before and after choroidal neovascular (CNV) lesion removal

234 228 4 Acquired Macular Diseases Fig Focal macular ERGs recorded from a normal control and three patients with AMD before and after CNV removal. The visual acuity is also shown. (From Terrasaki et al. [4]) Fig Percentage increase in the amplitude of the b-wave and the percentage decrease in the mean parafoveal thickness measured at four points on four sides of the fovea in vertical and horizontal scans. The results are significantly correlated (r = 0.688, P = ). (From Terasaki et al. [4], with permission)

235 4.7 Age-Related Macular Degeneration Macular Translocation Surgery Although surgical removal of a subfoveal CNV can be performed in some patients with AMD, the main disadvantage of the procedure is reduced visual function that results from damage to the RPE underneath the macula. Foveal or macular translocation surgery is an operative procedure in which the fovea is moved from diseased RPE onto healthy RPE [5]. This surgery has the potential to improve or preserve central visual function in eyes after removing a subfoveal CNV. One common technique of macular translocation surgery involves a 360 circumferential retinotomy followed by a subretinal infusion of fluid to create total retinal detachment from the RPE. The completely detached retina is then rotated to move the macula from the original position on the RPE to healthy RPE, resulting in a new retina and RPE complex. This complicated surgery has been well performed by Terasaki, my colleague, in many patients, and the results have been evaluated [6 8]. The fundus photographs and OCT images of a patient with AMD before and after macular translocation surgery are shown in Fig From the point of view of retinal physiology, this technique poses several interesting and important issues that should be considered. First, what is the visual function of the entire retina after it is translocated to the new RPE? To answer this question, full-field ERGs recorded from three representative patients with AMD before and after macular translocation with 360 retinotomy were compared [6] (Fig. 4.37). In summary of many patients, the amplitudes of the rod and cone components of the full-field ERGs were reduced by 25% 40%, with slight prolongation of the implicit times after the surgery. Interpreting these results has not been easy because, in addition to translocating the entire retina to the new RPE, we had to take into consideration surgical trauma to the retina caused by transient total retinal detachment, the 360 circumferential retinotomy, and the massive photocoagulation after reattaching the retina. However, the degree of reduction of the full-field ERGs after surgery was surprisingly small, suggesting that the sensory retina can function well at the new RPE site. Second, how does the shifted macula function on the new RPE? The answer is obtained from the changes in visual acuity and the focal macular ERG before and after surgery [7]. In our large series of patients, visual acuity improved significantly after surgery; moreover, the amplitudes of the focal macular ERGs increased and the implicit times decreased significantly after surgery (Fig. 4.38). These results indicate that the newly located macula does maintain and organize the neural components well, resulting in improved visual acuity.

236 230 4 Acquired Macular Diseases Fig Fundus photographs (top) and OCT images (bottom) obtained from a 77-year-old woman with AMD before and after macular translocation with 360 retinotomy. The macula was shifted to the inferior part of the retina,where the RPE underneath the macula was healthy. Her visual acuity improved from 0.06 to 0.60 following surgery. (From Terasaki et al. [8], with permission) Fig Full-field ERGs recorded from three representative patients with AMD before and after macular translocation with 360 retinotomy. (From Terasaki et al. [6]) Fig Focal macular ERGs recorded from three representative patients with AMD before as well as early (6 12 months) and late (18 30 months) after macular translocation with 360 retinotomy. (From Terasaki et al. [7])