Association of Retinal Artery and Other Inner Retinal Structures With Distribution of Tapetal-like Reflex in Oguchi’s Disease

Yu Kato,1–3 Kazushige Tsunoda,1,2 Kaoru Fujinami,1,2,4,5 Takeshi Iwata,6 Masamichi Saga,4 and Yoshihisa Oguchi4

1Department of , National Tokyo Medical Center, Tokyo, Japan 2Laboratory of Visual Physiology, National Institute of Sensory Organs, Tokyo, Japan 3Department of Ophthalmology, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan 4Keio University, School of Medicine, Department of Ophthalmology, Tokyo, Japan 5UCL Institute of Ophthalmology, London, United Kingdom 6Laboratory of Molecular and Cellular Biology, National Institute of Sensory Organs, Tokyo, Japan

Correspondence: Kazushige Tsuno- PURPOSE. To report novel ophthalmoscopic features of patients with Oguchi’s disease, and to da, Division of Vision Research, describe how they may be related to the unusual tapetal-like appearance. National Institute of Sensory Organs, 2-5-1 Higashigaoka, Meguro-ku, To- METHODS. Twenty-one eyes of 11 patients who were diagnosed with Oguchi’s disease were kyo 152-8902, Japan; investigated. Genetic screening of seven cases showed homozygous mutations in the SAG [email protected]. gene (c.926delA). The retinal appearance was retrospectively assessed in the fundus Submitted: December 5, 2014 photographs, and the optical coherence tomographic (OCT) and fundus autofluorescence Accepted: March 1, 2015 (AF) images. Citation: Kato Y, Tsunoda K, Fujinami RESULTS. In 11 eyes of 7 patients, clearly demarcated dark regions without tapetal-like reflex K, Iwata T, Saga M, Oguchi Y. Associ- were observed in the midperipheral retinal regions. In the dark regions, OCT showed lower ation of retinal artery and other inner reflectances in the photoreceptor layer but the AF images had normal reflectances. In nine retinal structures with distribution of eyes of six patients, the dark regions were partially demarcated by retinal arteries but not by tapetal-like reflex in Oguchi’s disease. veins. In nine eyes of five patients, the extent of the dark regions either increased or Invest Ophthalmol Vis Sci. decreased during the course of the disease process, and these changes were not due to the 2015;56:2162–2172. DOI:10.1167/ state of or a posterior vitreous detachment. In all eyes, the peripheral retinal iovs.14-16198 arteries but not veins had either high or low reflective regions along one side.

CONCLUSIONS. Although the alterations of the outer retinal layers are believed to be most responsible for the abnormal tapetal-like reflex in patients with Oguchi’s disease, these ophthalmoscopic features cannot be explained solely by the abnormality of the outer retina. Our findings suggest that the appearance of tapetal-like reflex is strongly affected by alterations of structures in the inner retinal layers. Keywords: Oguchi’s disease, tapetal-like reflex, Mizuo-Nakamura phenomenon, SAG gene, fundus photograph

guchi’s disease is an unusual form of congenital stationary the veins of a leaf, and the peripheral vessels had high O night blindness and is characterized by a golden or grayish- reflectivity along one side. white tapetal-like reflex of the fundus.1 This unusual reflex These characteristic ophthalmoscopic findings were report- disappears only after a long period of dark-adaptation.2 ed more than 100 years ago, and the origin of unusual fundus Mutations in the gene (s-antigen; SAG,OMIM reflex has been investigated by various methods: histopatho- 3 181031) or the rhodopsin gene (–coupled logical assessments,8,9 intraretinal injection of potassium 4 receptor kinase 1; GRK1, OMIM 180381) have been identified chloride,10 surgical removal of the vitreous,11 scanning laser as the causative genes. Most Japanese patients have mutations ophthalmoscopy,12 optical coherence tomography (OCT),13–16 in the SAG gene.3,5–7 and adaptive optics scanning light ophthalmoscopy.15 In spite Oguchi1 described the abnormal fundus appearance of the of all of these studies, the underlying mechanism of the tapetal- first patient (22-year-old man) in 1907. He reported that the retinal reflex in the periphery appeared finely marbled just as if like reflex has not been definitively determined. it was covered by hoarfrost. The degree of abnormality We have carefully examined the fundi of 11 patients with increased gradually toward the periphery. The choroidal vessels Oguchi’s disease, and found that there are ophthalmoscopic could not be observed except in the far periphery. The features that have not been reported. Our findings suggest that peripheral retinal vessels appeared much clearer than in the the inner retinal structures, including the vitreoretinal inter- normal retina but the tips of the vessels appeared darkened. face, retinal nerve fiber layer (RNFL), and retinal arteries, The vessels appeared elevated above the background just like contributed to the appearance of tapetal-like reflex. These

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findings provide important insights on the origin of the not seem to be associated with myopic changes (Table). unusual fundus reflex in eyes with Oguchi’s disease. Choroidal vessels could be clearly seen only in the dark regions (Fig. 2).

PATIENTS AND METHODS Optical Coherence Tomography and Fundus AF This was a retrospective case series performed at the National Imaging InstituteofSensoryOrgans,Tokyo,Japan,andinthe The OCT images showed that the reflectance of the Department of Ophthalmology, Keio University, Tokyo, Japan. photoreceptor layer was much higher in the region with An informed consent was received from all of the subjects for tapetal-like reflex than in the dark region, as previously the tests after an explanation of the procedures to be used. In described (Fig. 3). Regions with tapetal-like reflex had higher addition, permission was obtained to use their medical data for reflectivity of the photoreceptor inner segment ellipsoid (ISe) research. The procedures used adhered to the tenets of the line and of the layer of photoreceptor outer segment above Declaration of Helsinki, and approval to perform this study was the RPE. There were no apparent structural abnormalities in obtained from the Review Board/Ethics Committee of the either the inner or outer retinal layers or (Fig. 3A). In National Institute of Sensory Organs and Keio University. the AF images, there were no demarcated lesions correspond- Twenty-one eyes of 11 patients (4 men and 7 women, age ing to the dark regions in the fundus photograph (Fig. 3B, 12–79 years) who were diagnosed with Oguchi’s disease were asterisks). studied (Table). The left eye of patient 7 was excluded from the analysis because the fundus photographs were of poor quality. In all eyes, the fundus had a diffuse or localized golden tapetal- Expansion and Contraction of Dark Regions like reflex which is pathognomonic for Japanese cases of In nine eyes of five patients (patients 1, 2, 3, 4, 11), fundus Oguchi’s disease. The full-field scotopic ERGs were non- photographs had been serially taken over several years, and recordable after 30 minutes of dark-adaptation. The mixed we compared the changes in the tapetal-like reflex. In the rod-cone bright-flash responses had an electronegative shape right eye of patient 1, the dark region in the superior- with reduced a-wave and severely reduced or absent b-wave. temporal retina was replaced by the tapetal-like reflex from The photopic ERGs were normal. These ERG findings are the periphery that expanded toward the center (Fig. 4A). In typical of Oguchi’s disease. The visual acuity was normal in all the left eye of patient 2, the dark region in the nasal retina was of the patients except patient 10 who had untreated senile replaced by a tapetal-like reflex of the periphery that . expanded toward the center, and the dark region was not Genetic analyses were performed in seven patients, and all present at the age 22 years (Fig. 4B). In the right eye of patient had the same homozygous mutation in the SAG gene 3, the region with tapetal-like reflex in the inferior retina was (c.926delA), which is frequently found in Japanese patients 3,5–7 replaced by a dark region that expanded from the center with Oguchi’s disease. toward the periphery. Thus, the dark regions gradually Photographs of the posterior pole to the equator were expanded in this eye (Fig. 4C). In the right eye of patient 1, taken with fundus cameras (TRC-50X, TRC-50IA, and TRC- the regions with and without the tapetal-like reflex interlaced, 50DX type IA; Topcon, Tokyo, Japan), and the characteristic and the dark regions either expanded or contracted depend- features, such as distribution patterns of tapetal-like reflex and ing on the retinal locations during the follow-up period (Fig. appearance of the retinal vessels, were retrospectively assessed 4D). In total, only an expansion of the dark regions was independently by two experienced ophthalmologists (YK and observed in three eyes of two patients, and only a contraction KT). In cases in which the conclusions were different, of the dark regions was observed in three eyes of two discussions were held until both examiners agreed. patients. In three eyes of two patients, both expansion and Optical coherence tomography images were obtained in the contraction of the dark regions was observed depending on light-adapted condition by spectral-domain OCT (Cirrus HD- the retinal locations (Table). None of these patients noticed OCT, version 6.5; Carl Zeiss Meditec, Dublin, CA, USA) and by either an improvement or reduction of after the swept-source OCT (DRI OCT-1 Atlantis; Topcon) after distribution pattern changed. dilation. Fundus autofluorescence (AF) images were obtained To exclude the possibility that the changes in distribution of in the light-adapted condition with a confocal scanning laser the dark regions were due to the adaptation status, we ophthalmoscope (HRA 2; excitation light, 488 nm; barrier examined how the borders of dark regions changed during filter, 500 nm; field of view, 558; Heidelberg Engineering, light-adaptation in patient 1. After 3 hours of dark-adaptation, Heidelberg, German) following pupil dilation. the tapetal-like reflex was not detected in the entire retina, the Mizuo-Nakamura phenomenon, but the reflectivity of the retina did not become homogeneous (Fig. 5A). After light- RESULTS adaptation, the tapetal-like reflex reappeared, and the dark Dark Regions Demarcated by Retinal Arteries regions became clearly visible in the same location. The borders between the regions with and without tapetal-like Under room-light conditions of the outpatient clinic, a reflex are indicated by the white arrows in Figure 5B. Their tapetal-like reflex was observed in all of the cases, but its locations did not change during the course of the light- distribution was not homogeneous over the entire retina. In adaptation, which would indicate that the changes in 11 eyes of 7 patients, there were clearly demarcated dark distribution of the dark regions were not due to the adaptation regions without a tapetal-like reflex (Fig. 1, arrows; Table). state. These dark regions were located along or posterior to the equator in all 11 eyes. In nine eyes of six patients, the dark High and Low Reflective Regions Along Peripheral regions were partially demarcated by retinal arteries but not Arteries by veins (Fig. 2, arrows). In the dark regions, the retina appeared slightly depigmented compared with that of As described by Oguchi1 in 1907, the peripheral vessels had healthy Japanese individuals. The depigmentation was either high or low reflective regions running along the vessels observed in patients both with and without and did (Fig. 6). We also found that there were other characteristic

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Highly-Reflectivity Low-Reflectivity Regions Regions Clearly Demarcated Expansion or Reduction SAG Dark Regions Without Demarcation Along Follow-up of Dark Regions During Along Along Along Along Case Age Sex Mutation R/L SE Tapetal-like Reflex Retinal Arteries Period Follow-up Arteries Veins Arteries Veins

119M þ R 5.86 þþ5 y (14–19) Expansion/reduction þþ L 7.13 þþ Expansion/reduction þþ 222F þ R 3.25 þþ4 y (18–22) Reduction þþ L 2.75 þþ Reduction þþ 318F þ R þ1.25 þ8 y (10–18) Expansion þþ L 1.25 þþ Expansion þþ 414F þ R 4.38 4 y (10–14) þþ L 4.50 þ Reduction þþþ 5 12 M NE R 0.00 þþþþ L 0.00 þþ 614F þ R 0.00 þþ L þ0.50 þþ 719FNER6.00 þþ L 6.00 NE 822MNER4.25 þ L 2.85 þ 926F þ R 2.75 þþþþ L 2.25 þþ 10 73 M NE R þ2.88 þþ L þ2.75 þþ 11 79 F þ R þ2.50 þþ4 y (75–79) Expansion/reduction þþ L þ3.50 þþ Expansion þþ Numbers in parentheses indicate ages at initial and final examination. F, female; L, left; M, male; NE, not examined; R, right; SE, spherical equivalent; þ, observed in the fundus photograph; , not observed in the fundus photograph. IOVS j pi 2015 April j o.56 Vol. j o 4 No. j 2164 Tapetal-like Reflex in Oguchi’s Disease IOVS j April 2015 j Vol. 56 j No. 4 j 2165

FIGURE 1. Fundus photographs of eyes with Oguchi’s disease showing clearly demarcated dark regions. The dark regions without tapetal-like reflexes are located along or posterior to the equator (arrows) in patient 1 (A, B), patient 2 (C, D), patient 3 (E), and patient 11 (F).

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FIGURE 2. Dark regions demarcated by retinal arteries. The locations of the retinal arteries are shown by white dots in the right columns. The dark regions are partially demarcated by retinal arteries but not by veins (arrows), in the right eye of patient 1 (A), the left eye of patient 1 (B), the left eye of patient 2 (C), and the left eye of patient 3 (D).

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FIGURE 3. Optical coherence tomographic image (A) and fundus AF image (B) of a case with clearly demarcated dark regions. Horizontal scan image was obtained for 9.0 mm in the superior-temporal portion of the right eye in patient 1 across the regions with and without tapetal-like reflex ([A], right). The border between the dark region and the region with the tapetal-like reflex in the OCT image is indicated by an arrow. The reflectance of the photoreceptor layer is much higher in the region with tapetal-like reflex than in the dark region. There are no apparent structural abnormalities in either the inner retinal layers or outer retinal layers or the choroid. In the AF image, there are no demarcated lesions corresponding to the dark regions in the fundus photograph ([B], asterisks).

features in the reflectance of the retinal vessels. The highly peripheral artery (Fig. 6C, left). In the left eye (Fig. 6C, middle) reflective regions were observed only along one side of the and right eye (Fig. 6C, right) of patient 3, the dark regions were arteries but not along the veins (Fig. 6A, arrowheads). They observed along the peripheral arteries but were slightly had the same color as the tapetal-like reflex and appeared separated from the vessels (arrowheads in Fig. 6C, middle different from the strong vascular reflexes commonly and right). The same findings were observed in both eyes of observed in children. The highly reflective regions along the patient 4. arteries disappeared after 3 hours of dark-adaptation. The low reflective regions were observed either along one Dark Regions Along RNFL side or both sides of the arteries but not along the veins (Fig. 6B, arrowheads). Following 3 hours of dark-adaptation, the In the right eye of patient 4, there was a dark region without dark regions became undetectable due to the disappearance of tapetal-like reflex that ran parallel to the RNFL bundle (Fig. 7, the tapetal-like reflex in the surrounding regions. The highly left). Following prolonged dark-adaptation, the tapetal-like reflective regions along the retinal arteries were observed in all reflex decreased, and the border of the dark region completely of the 21 eyes of 11 patients, and those along the retinal veins disappeared(Fig.7,middle).Thisdarkregionwasnot were observed in only one eye of patient 4 (Table). The low observed in the fundus photographs 3 years and 6 months reflective regions along arteries were observed in 19 eyes of 10 later in this eye (Fig. 7, right). patients, and those along veins were not observed in any eyes (Table). Swept-Source OCT There were other unusual findings related to the retinal arteries. In the left eye of patient 4, both highly and lowly High-contrast vitreous images were obtained by swept-source reflective regions were observed at the same location of a OCT from the eyes of patient 1 (Fig. 8). The vitreous was

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FIGURE 4. Expansion and contraction of the dark regions during the follow-up period. The area of the dark region is reduced and the tapetal-like reflex expanded during the 4 year and 5 months follow-up in the superior portion of the right eye of patient 1 (A). The dark region is reduced and absent during the 4 year and 7 months follow-up in the left eye of patient 2 (B). The dark region expanded during the 2 years and 2 months follow- up in the right eye of patient 3 (C). The regions with and without tapetal-like reflex interlaced, and the dark region either expanded or contracted during the follow-up period depending on the retinal locations in the right eye of patient 1 (D). Photographs of individual patients were aligned so that their vertical retinal locations matched the others. The borders between the dark regions and the regions with tapetal-like reflex at the different ages of examination are indicated by white dots, black dots,orasterisks.

homogeneously distributed over the dark regions, and a DISCUSSION posterior vitreous detachment could not be observed. There were no apparent abnormalities in the vitreoretinal interface We examined the medical records of 11 cases of Oguchi’s observed along the border between the tapetal-like reflex and disease and found funduscopic findings that have not been dark regions (Fig. 8, arrows). reported. In the midperipheral region of the fundus, there

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FIGURE 5. Comparison of the borders of the dark regions during light-adaptation. Prolonged dark-adaptation for 180 minutes reduced the area of the tapetal-like reflex (Mizuo-Nakamura phenomenon) in the right eye of patient 1 ([A], left). After 20 minutes of light-adaptation, the tapetal-like reflex reappeared ([A], right). In the magnified image of the superior retina (B), the dark region became clearly visible at the same location and its border did not change during the course of light-adaptation (white arrows). DA, dark-adaptation; LA, light-adaptation. Arrows indicate the same retinal locations in the superior retina.

were clearly demarcated dark regions without tapetal-like defective Muller¨ cells and led to the tapetal-like reflex in both reflex where the retina, RPE, and choroid had normal layered X-linked and Oguchi’s disease. Considering the structures in the OCT images (Figs. 1, 3). The dark regions genetic origin of Oguchi’s disease in the outer retina, however, were partially demarcated by retinal arteries but not by the the above explanations do not seem reasonable. veins (Fig. 2). The distribution of the dark regions either Kuroda et al.11 presented a case of Oguchi’s disease in expanded or contracted during the course of the disease which the tapetal-like reflex disappeared following vitrectomy process, and these changes could not be simply explained by for the treatment of a rhegmatogenous . the state of adaptation or the presence of a posterior vitreous They concluded that surgical damage to both the inner limiting detachment (Figs. 4, 5). membrane and Muller¨ cells led to the release of Kþ into the The peripheral retinal vessels had either highly or lowly vitreous cavity. This then led to a decrease in the concentration reflective regions, and these were observed only along arteries of Kþ in the extracellular space and disappearance of the and not along veins (Fig. 6). There was a dark region without tapetal-like reflex.11 However, this phenomenon occurred tapetal-like reflex, whose location coincided with that of the under very pathological conditions after vitreous surgery and RNFL bundle (Fig. 7). could not explain the changes in the distribution patterns of The mechanism causing the tapetal-like reflex has not been the dark regions that occurred spontaneously. definitively determined. The results of histopathological The results of recent imaging studies have suggested that studies suggested the existence of an abnormal layer between alterations of the photoreceptor layer is associated with the the photoreceptor and the RPE and the presence of fuscin presence of the tapetal-like reflex. The alterations of the OCT bodies in the RPE.8 The presence of pigment granules in the images of the photoreceptor layer corresponded with the nerve fiber layer also has been reported in another study.9 The changes in the coloration of the fundus, which would suggest histopathological investigations, however, have not deter- that the regions around the photoreceptor outer segments are mined the origin of tapetal-like reflex. the sites of the abnormal coloration.13–15 This is supported by De Jong et al.10 suggested that an increase in the the causative mutation in the SAG gene, which encodes S- concentrations of extracellular Kþ produced the tapetal-like arrestin, a photoreceptor protein. reflex because it resembled spreading depression of electric Using a helium-neon laser (633 nm) scanning laser activity in the retina. They suggested that the increased ophthalmoscope (SLO), Usui et al.12 found diffuse, fine, white extracellular concentration of potassium was caused by particles in the deep layers of the retina that were not detected

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FIGURE 6. High and low reflective regions along the peripheral arteries. (A) Highly reflective regions are observed along the retinal arteries (arrowheads) but not along the veins. (B) Low reflective regions are observed along the retinal arteries (arrowheads) but not along the veins. (C) Both high- and low-reflectivity regions are observed at the same location of the retinal artery in the left eye of patient 4 ([C], left). The dark regions are observed along peripheral arteries, but located slightly apart from the vessels in the left eye ([C], middle) and right eye ([C], right) of patient 3. A, artery; V, vein.

in healthy subjects. The appearance of these particles abnormalities in the RPE in the areas with and without tapetal- coincided with the appearance of the tapetal-like reflex. They like reflex (Fig. 3B). suggested that the particles were located in the outer retina or There were, however several findings of the retinal RPE, and could be the cause of the abnormal fundus appearance that could not be explained solely by the appearance in Oguchi’s disease. abnormalities of the photoreceptor layer. The first was the The changes in the reflectance of the rod photoreceptor contribution of retinal arteries that demarcate the dark regions mosaics in the adaptive optics SLO also suggested that the without tapetal-like reflex (Fig. 2). The second was the highly photoreceptor layer contributed to the tapetal-like reflex.15 or lowly reflective regions along the retinal arteries (Fig. 6). In our cases, the regions without tapetal-like reflex Third was the region without tapetal-like reflex whose corresponded with the regions of decreased reflectivity in distribution coincided with that of the RNFL bundle (Fig. 7). the photoreceptor layer (i.e., layer between ISe and RPE in the These findings suggest that the inner retinal layers can affect OCT images) (Figs. 3A, 8A, 8B). As in previous studies, the the appearance of the tapetal-like reflex. photoreceptor layer is considered to be the most likely origin As described in the first report by Oguchi,1 the intensity of of the tapetal-like reflex in Oguchi’s disease. The results from the tapetal-like reflex varied depending on the direction of the the AF imaging indicated that there were no local metabolic observation light against the retina.17 A similar finding was

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FIGURE 7. A dark region running along the RNFL bundle can be seen in the nasal sector of the left eye of patient 4 (left). Prolonged dark-adaptation for 180 minutes reduced the tapetal-like reflex, and the border of dark region cannot be detected (middle). The dark region along the bundle of the RNFL disappeared during the 3 years and 6 months of follow-up (right). LA, light-adaptation; DA, dark-adaptation. Arrows indicate the same retinal locations in the nasal retina.

reported for patients with X-linked retinoschisis.10 This is like reflective materials after prolonged dark-adaptation. The probably because the layer where the tapetal-like reflex incident angle against the reflective materials, however, can be originates has the properties of a plane mirror, namely, the easily changed by the interfering retinal structures that have angle of reflection equals the angle of incidence. If the incident different refractive indices, such as a thickened vitreoretinal angle is almost perpendicular to the retinal surface, strong interface or vessel walls of retinal arteries or thickened RNFL. tapetal-like reflex can be observed, but if it is not, the intensity Changes in the distribution patterns of the tapetal-like reflex in of the reflex decreases.17 These reflective materials can be Figure 4 can be more easily explained by the modulation of either layered structures or particles or chemical materials outer retinal reflex due to the inner retinal structures than by embedded in the outer segment discs, which are well-aligned the local functional changes of the photoreceptors or RPEs per structures parallel to the retinal surface. The Mizuo-Nakamura se. The increased or decreased reflectivity of the tapetal-like phenomenon can be explained by the disappearance of mirror- reflex may be due to the refractive structures that change the

FIGURE 8. Optical coherence tomographic images across the regions with and without tapetal-like reflex. High-contrast vitreous images were obtained by a swept-source OCT. Horizontal line scan images in the superior portion of the right (A) and left (B) eyes in patient 1 are presented. The vitreous appears homogeneously distributed over the dark regions, and a posterior vitreous detachment cannot be observed. There were no abnormalities in the vitreoretinal interface along the border of the dark regions (arrows).

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incident angle of the observation light. For example, vitreous 4. Yamamoto S, Sippel KC, Berson EL, Dryja TP. Defects in the traction on the retina can change during the natural course of gene in the Oguchi form of stationary night the disease process, and this may change the reflection of the blindness. Nat Genet. 1997;15:175–178. vitreoretinal interface, leading to the changes in distribution of 5. Nakazawa M, Wada Y, Fuchs S, Gal A, Tamai M. Oguchi disease: the dark regions as observed in some of our cases (Fig. 2). phenotypic characteristics of patients with the frequent In addition, the direction and strength of the vitreoretinal 1147delA mutation in the arrestin gene. Retina. 1997;17:17– traction may change during aging even before the posterior 22. vitreous detachment is completed. This may explain the 6. Nakamura M, Yamamoto S, Okada M, Ito S, Tano Y, Miyake Y. spontaneous changes in the distribution patterns of the dark Novel mutations in the arrestin gene and associated clinical regions in younger patients. The observations by OCT, features in Japanese patients with Oguchi’s disease. Ophthal- however, could not detect either nonhomogeneous vitreous mology. 2004;111:1410–1414. distribution or posterior hyaloid detachment locally along the 7. Saga M, Mashima Y, Kudoh J, Oguchi Y, Shimizu N. Gene border of the dark regions (Fig. 8). The interfering materials analysis and evaluation of the single founder effect in Japanese that can decrease the tapetal-like reflex may be too small and patients with Oguchi disease. Jpn J Ophthalmol. 2004;48: thin to be detected by current imaging techniques. 350–352. The decreased or increased reflectivity along arteries could 8. Kuwabara Y, Ishihara K, Akiya S. Histopathological and be similarly explained (Fig. 6). Compared with the retinal electron microscopic studies on the retina of Oguchi’s disease. veins, the retinal arteries are composed of additional muscle Acta Soc Ophthalmol Jpn. 1963;67:1323–1351. layers and appear more hyperreflective.18 Light passing beside 9. Yamanaka M. Histologic study of Oguchi’s disease. Its the retinal arteries may be refracted and change the reflectance relationship to pigmentary degeneration of the retina. Am J from the outer retina, although part of dark regions along the Ophthalmol. 1969;68:19–26. artery look too large to be simply explained by this change (Fig. 10. de Jong PT, Zrenner E, van Meel GJ, Keunen JE, van Norren D. 6C). Mizuo phenomenon in X-linked retinoschisis. Pathogenesis of The alterations of the dark and tapetal-like reflex regions the Mizuo phenomenon. Arch Ophthalmol. 1991;109:1104– can be explained by changes in the refractive modulations in 1108. the inner retina. However, we could not find any metallic 11. Kuroda M, Hirami Y, Nishida A, et al. A case of Oguchi disease reflex in the dark regions even though we examined the retina with disappearance of golden tapetal-like fundus reflex after from different directions (data not shown). The border vitreous resection [in Japanese]. Nihon Ganka Gakkai between regions with and without tapetal-like reflex was Zasshi. 2011;115:916–923. always clear irrespective of the viewing angle. There must be 12. Usui T, Ichibe M, Ueki S, et al. Mizuo phenomenon observed another mechanism that changes the retinal reflectivity in by scanning laser ophthalmoscopy in a patient with Oguchi Oguchi’s disease. disease. Am J Ophthalmol. 2000;130:359–361. The tapetal-like reflex of the Mizuo-Nakamura phenomenon 13. Yamada K, Motomura Y, Matsumoto CS, Shinoda K, Nakatsuka has been reported in other diseases, such as X-linked cone-rod K. Optical coherence tomographic evaluation of the outer dystrophy,19 X-linked retinoschisis,10,20 and also in carriers of retinal architecture in Oguchi disease. Jpn J Ophthalmol. X-linked RP.21 The underlying mechanism for this reflex has 2009;53:449–451. not been clearly determined by our case series, and the 14. Takada M, Otani A, Ogino K, Yoshimura N. Spectral-domain discussion we have made regarding possible mechanisms is optical coherence tomography findings in the Mizuo-Naka- very speculative. However, our results have given us important mura phenomenon of Oguchi disease. Retina. 2011;31:626– insights on the origin of this unusual fundus reflex. 628. 15. Godara P, Cooper RF, Sergouniotis PI, et al. Assessing retinal Acknowledgments structure in complete congenital stationary night blindness and Oguchi disease. Am J Ophthalmol. 2012;154:987–1001. Supported by research grants from the Ministry of Health, Labor e1001. and Welfare, Japan, and a Grant-in-Aid for Scientific Research, 16. Sergouniotis PI, Davidson AE, Sehmi K, Webster AR, Robson Japan Society for the Promotion of Science, Japan. The author(s) AG, Moore AT. Mizuo-Nakamura phenomenon in Oguchi have no proprietary or commercial interest in any materials disease due to a homozygous nonsense mutation in the SAG discussed in this article. gene. Eye (Lond). 2011;25:1098–1101. The authors alone are responsible for the content and the writing 17. Sato T, Baba K. Appearance and disappearance of the fundus of the paper. disturbance in Oguchi’s disease. Am J Ophthalmol. 1961;51: Disclosure: Y. Kato, None; K. Tsunoda, None; K. Fujinami, 243–248. None; T. Iwata, None; M. Saga, None; Y. Oguchi, None 18. Hogan MJ, Feeney L. The ultrastructure of the retinal blood vessels. I. The large vessels. J Ultrastruct Res. 1963;39:10–28. References 19. Heckenlively JR, Weleber RG. X-linked recessive with tapetal-like sheen. A newly recognized entity 1. Oguchi C. Ueber eine Abart von Hemeralopie. Acta Soc with Mizuo-Nakamura phenomenon. Arch Ophthalmol. 1986; Ophthalmol Jpn. 1907;11:123–134. 104:1322–1328. 2. Mizuo G, Nakamura B. On new discovery in dark adaptation in 20. Robson AG, Mengher LS, Tan MH, Moore AT. An unusual Oguchi’s disease. Acta Soc Ophthalmol Jpn. 1914;18:73–126. fundus phenotype of inner retinal sheen in X-linked retinos- 3. Fuchs S, Nakazawa M, Maw M, Tamai M, Oguchi Y, Gal A. A chisis. Eye (Lond). 2009;23:1876–1878. homozygous 1-base pair deletion in the arrestin gene is a 21. Falls HF, Cotterman CW. Choroidoretinal degeneration: a sex- frequent cause of Oguchi disease in Japanese. Nat Genet. linked form in which heterozygous women exhibit a tapetal- 1995;10:360–362. like retinal reflex. Arch Ophthalmol. 1948;40:685–703.

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