Clinical and Genetic Characteristics of East Asian Patients with Occult Macular Dystrophy (Miyake Disease): East Asia Occult Macular Dystrophy Studies Report Number 1.

PURPOSE: To describe the clinical and genetic characteristics of the cohort enrolled in the East Asian studies of occult macular dystrophy (OMD). DESIGN: International, multicenter, retrospective cohort studies. PARTICIPANTS: A total of 36 participants from 21 families with a clinical diagnosis of OMD and harboring pathogenic RP1L1 variants (i.e., Miyake disease) were enrolled from 3 centers in Japan, China, and South Korea. METHODS: A detailed history was obtained, and comprehensive ophthalmological examinations including spectral-domain OCT were performed. All detected sequence variants in the RP1L1 gene were reviewed, and in silico analysis was performed, including allele frequency analyses and pathogenicity predictions. MAIN OUTCOME MEASURES: Onset of disease, visual acuity (VA) converted to the logarithm of the minimum angle of resolution (logMAR), OCT findings, and effect of detected variants. RESULTS: Eleven families from Japan, 6 from South Korea, and 4 from China were recruited. There were 12 female and 24 male participants. The median age of onset was 25.5 years (range, 2-73), and the median age at the latest examination was 46.0 years (range, 11-86). The median VA (logMAR) was 0.65 (range, -0.08-1.22) in the right eye and 0.65 (-0.08-1.10) in the left eye. A significant correlation between onset of disease and VA was revealed. The Classical morphologic phenotype showing both blurred ellipsoid zone and absence of interdigitation zone of the photoreceptors was demonstrated in 30 patients (83.3%), and subtle photoreceptor architectural changes were demonstrated in 6 patients (16.6%). Eight pathogenic RP1L1 variants were identified, including 6 reported variants and 1 novel variant: p.R45W, p.T1194M/p.T1196I (complex), p.S1199C, p.G1200A, p.G1200D, p.V1201G, and p.S1198F, respectively. Two variants were recurrent: p.R45W (11 families, 52.4%) and p.S1199C (5 families, 23.8%). The pathogenic missense variants in 10 families (47.6%) were located within the previously reported unique motif, including 6 amino acids (1196-1201). CONCLUSIONS: There is a large spectrum of clinical findings in Miyake disease, including various onset of disease and VA, whereas the characteristic photoreceptor microstructures were shared in most cases. Two hot spots including amino acid numbers 45 and 1196-1201 in the RP1L1 gene were confirmed in the East Asian population.

Clinical characteristics of occult macular dystrophy in family with mutation of RP1l1 gene.

PURPOSE: To report the clinical characteristics of occult macular dystrophy (OMD) in members of one family with a mutation of the RP1L1 gene. METHODS: Fourteen members with a p.Arg45Trp mutation in the RP1L1 gene were examined. The visual acuity, visual fields, fundus photographs, fluorescein angiograms, full-field electroretinograms, multifocal electroretinograms, and optical coherence tomographic images were examined. The clinical symptoms and signs and course of the disease were documented. RESULTS: All the members with the RP1L1 mutation except one woman had ocular symptoms and signs of OMD. The fundus was normal in all the patients during the entire follow-up period except in one patient with diabetic retinopathy. Optical coherence tomography detected the early morphologic abnormalities both in the photoreceptor inner/outer segment line and cone outer segment tip line. However, the multifocal electroretinograms were more reliable in detecting minimal macular dysfunction at an early stage of OMD. CONCLUSION: The abnormalities in the multifocal electroretinograms and optical coherence tomography observed in the OMD patients of different durations strongly support the contribution of RP1L1 mutation to the presence of this disease.

Detailed analyses of microstructure of photoreceptor layer at different severities of occult macular dystrophy by ultrahigh-resolution SD-OCT.

Purpose: To analyze the microstructures of the photoreceptor layer in detail in eyes with occult macular dystrophy (OMD, Miyake's disease) by ultrahigh-resolution spectral-domain optical coherence tomography (UHR-SD-OCT). Observations: Twenty-eight normal subjects and 5 patients with OMD of different severities were studied. Cross-sectional images through the fovea were recorded with a UHR-SD-OCT system with a depth resolution of <2.0 µm. In patients with OMD, the UHR-SD-OCT images revealed abnormal photoreceptor microstructures which were not detected in the conventional SD-OCT images. The UHR-SD-OCT images showed that the interdigitation zone (IZ) was not present and the outer segments were hyperreflective with hyperreflective dots (HRDs) aligned like string of pearls during the earlier stages. There was a disruption of the ellipsoid zone (EZ) which appeared as clusters of larger HRDs, and these HRDs became less apparent with increasing time. The outer segments became hyporeflective and rod IZ became apparent with longer duration of the disease process. Conclusions and Importance: The UHR-SD-OCT images show detailed characteristics of the photoreceptor microstructures of different severities during the progression of OMD. These detailed observations will help in understanding the mechanisms involved in the retinal pathology and should provide important information for their treatments.

Microstructural changes of photoreceptor layers detected by ultrahigh-resolution SD-OCT in patients with autosomal recessive bestrophinopathy.

Purpose: To determine the changes in the microstructures of the photoreceptors in patients with autosomal recessive bestrophinopathy (ARB) by ultrahigh-resolution spectral-domain optical coherence tomography (UHR-SD-OCT). Methods: Five eyes of 4 patients with ARB were studied. Cross-sectional images of the fovea were recorded by the UHR-SD-OCT system with a depth resolution of <2.0 µm. Results: The UHR-SD-OCT images revealed changes in the outer retinal structures that were dependent on the severity of the photoreceptor atrophy. There was an increase in the reflectivity and appearance of small hyperreflective dots (HRDs) in the outer segments, followed by an irregularity and decrease in the length of the outer segments, then a disruption of the ellipsoid zone (EZ) band, and appearance of large HRDs corresponding to the segmented ellipsoids. Finally, there was a disappearance of the large HRDs followed by a localized thinning of the outer nuclear layer and appearance of hyperreflective foci above the region of the disrupted EZ. Conclusions: UHR-SD-OCT can record images that show detailed changes of the microstructures of the photoreceptors at different stages of ARB. These observations should help in determining the mechanisms involved in retinal pathology and should provide important information on the effectiveness of treatments.

Distribution of retinal responses evoked by transscleral electrical stimulation detected by intrinsic signal imaging in macaque monkeys.

PURPOSE: The distribution of the electrical current over the retina when electrical pulses are delivered transsclerally has not been clearly determined objectively and quantitatively in humans. The purpose of this study was to determine the pattern of electrically evoked neural activity in the monkey retina by using intrinsic signal imaging. METHODS: The intrinsic signals of monkey retinas were recorded as changes in the reflectance of infrared light from the retina after transscleral electrical stimulation by DTL electrodes. The effects of changing the stimulus parameters (e.g., intensity, duration, and frequency) of the electrical current, were investigated. RESULTS: Electrical stimulation evoked a uniform change in the reflectivity across the posterior pole of the retina; that is, the intrinsic signals changed uniformly. A peak of the intrinsic signal was not observed at the fovea. The threshold of the intrinsic signal was not significantly different for the macula, perimacula, and optic disc, and the threshold did not differ under dark- and light-adapted conditions. The strength of the signals increased with longer stimulus durations, and the maximum signals were obtained when the stimulus frequency was between 15 and 20 Hz. CONCLUSIONS: Intrinsic signals of the monkey retina evoked by transscleral electrical stimulation are elicited uniformly across the posterior pole of the fundus and most likely arise from activation of the inner or middle layers of the retina. These functional measurements could serve as a diagnostic tool for mapping the inner retinal activity, by which the site of a lesion can be noninvasively imaged.

Intrinsic signal imaging in macaque retina reveals different types of flash-induced light reflectance changes of different origins.

PURPOSE: Intrinsic signal imaging is a newly developed technique that can map the neural activity of tissues noninvasively. It has been used to map the functional organization of the retina by recording flash-induced light reflectance changes in the cone and rod photoreceptors. The purpose of this study was to investigate the properties of the intrinsic signals in the monkey's retina. To accomplish this, the intrinsic signals and the electroretinograms (ERGs) evoked by the same stimuli were measured under different recording conditions. METHODS: The fundus of macaque monkeys was observed with infrared light and recorded with a charge-coupled device (CCD) camera. The intrinsic signals were measured as retinal light reflectance changes induced by diffuse or focal flash stimuli. ERGs were recorded under the same stimulating conditions. The reflectance changes induced by different flash intensities, flash intervals, and background luminance were compared. RESULTS: The intrinsic signals were categorized into different groups based on the location in the fundus. Fast signals (peak: approximately 100 ms) were recorded from the posterior retina including the fovea, and slow signals (peak: 5.0-6.0 seconds) were recorded from the optic disc and nonfoveal posterior retina. The threshold of the slow signal changes was comparable to that of the ERG b-wave, and the thresholds of the fast signals were higher than that of the ERG a- and b-waves. CONCLUSIONS: The retinal intrinsic signals are composed of several components with different response properties and different sources. This recording technique may be useful for mapping the retinal function in eyes with various disorders.

Parafoveal Photoreceptor Abnormalities in Asymptomatic Patients With RP1L1 Mutations in Families With Occult Macular Dystrophy.

Purpose: To report the clinical characteristics of asymptomatic cases with RP1L1 gene mutations in four families with occult macular dystrophy (OMD). Methods: Four asymptomatic cases from four families were selected from a cohort of 40 subjects (16 families) with RP1L1 pathogenic variants. Clinical data of the four asymptomatic cases and three symptomatic patients in the same families were reviewed. The three asymptomatic cases did not have any visual symptoms in either eye, and one was unilaterally affected. Ophthalmologic examinations, including spectral-domain optical coherence tomography (OCT) were performed, and the morphologic characteristics of the photoreceptor layer of the asymptomatic cases were compared to those of the symptomatic patients within the same family. Results: The OCT images demonstrated photoreceptor abnormalities in the parafoveal regions in all of the four asymptomatic cases (i.e., absence of the interdigitation zone and blurring of the ellipsoid zone). However, these microstructures were preserved at the foveal center. The longitudinal reflectivity profiles clearly identified this distinct pattern in the asymptomatic cases. In contrast, no distinct abnormalities were detected by other examinations including perimetry, fundus autofluorescence images, and multifocal electroretinograms (ERGs). Conclusions: The sparing of the central foveal photoreceptor layer accounts for the well-preserved visual acuity in the asymptomatic patients. The sparing may represent either the initial phase of typical OMD or a subtype of macular lesion associated with OMD. It is necessary to examine asymptomatic subjects in families with OMD because some of them may progress to the typical phenotype of OMD.

Mapping cone- and rod-induced retinal responsiveness in macaque retina by optical imaging.

PURPOSE: To map the distribution of cone- or rod-induced retinal responsiveness by optical imaging from macaque retina. METHODS: The light reflectance changes in the posterior retina after a flash stimulus in anesthetized rhesus monkeys were measured by a modified fundus camera system equipped with a charge-coupled device (CCD) camera. The response topography of the optical signals was obtained in either light- or dark-adapted conditions. RESULTS: With infrared observation light, the whole posterior pole became darkened after the stimulus. The response topography in light-adapted conditions demonstrated a steep peak of darkening at the fovea, together with the gradual decrease of signal intensity away from the fovea toward the periphery. In dark-adapted conditions, the optical signal showed additional peaks along the circular region surrounding the macula at the eccentricity of the optic disc, together with the central peak at the fovea. A statistically significant positive correlation was obtained between the light reflectance changes in infrared observation light and the focal responses in multifocal electroretinogram (mfERG) at the corresponding retinal locations. CONCLUSIONS: The response topography in the retina, obtained by optical imaging, was consistent with psychophysical cone or rod sensitivity in humans and anatomic cone or rod distribution in humans and macaques. The cone- or rod-induced retinal responsiveness within the posterior pole region was noninvasively recorded within a short recording time.

Stimulus-induced changes of reflectivity detected by optical coherence tomography in macaque retina.

PURPOSE: To investigate the properties and origin of retinal intrinsic signals by functional optical coherence tomography (fOCT) in macaque retinas. METHODS: We modified a spectral domain OCT system to be able to give short-duration flashes or continuous light stimulation to the retina of three adult macaque monkeys (Macaca mulatta) under general anesthesia. Changes in the intensities of the OCT signals following the stimulus were determined. RESULTS: Stimulus-evoked decreases or increases in the OCT signals were observed in the photoreceptor inner segment ellipsoids and outer segments, respectively. Experiments with focal and colored stimuli confirmed that these fOCT signals originated from the photoreceptors. No diffuse changes in the OCT signals were detected in the inner retinal layers; however, there were slow changes in small discrete areas where the retinal vessels were located. The polarity of the fOCT signals in the inner retinal layer was dependent on each activated region, and one of the possible sources of the reflectance changes was the light-scattering changes of the retinal vessels. CONCLUSIONS: The fOCT signals in the macaque retina consist of at least three components: light-scattering changes from the photoreceptor inner segment ellipsoids, light-scattering changes from the outer segments, and slow light-scattering changes from the blood vessels in the inner retina. This technique has the potential of mapping local neuronal activity three-dimensionally and may help in the diagnosis of retinal disorders of different retinal origins.

Valsalva retinopathy developing during Japanese cheerleading training ("ouendan").

PURPOSE: Valsalva hemorrhagic retinopathy is characterized by retinal hemorrhages that develop after a Valsalva maneuver that consists of a forcible exhalation against a closed glottis, thereby creating a sudden increase in the intrathoracic or intraabdominal pressure. We present a patient who developed retinal and vitreous hemorrhages with multiple retinal nonperfused areas after extreme physical training with shouting on a mountainous area. This exercise was part of his training as a member of a Japanese traditional cheerleading team. METHOD: Case presentation. RESULTS: A 19-year-old man developed an acute decrease in the vision to 0.3 in his left eye after running on hilly roads at approximately 800 m while shouting fight songs for several hours. Ophthalmoscopy showed a fresh vitreous hemorrhage that covered the entire macula and was connected to the optic disk in the left eye. The vitreous hemorrhage spontaneously resolved and an intraretinal hemorrhage and nonperfused area emerged. His visual acuity returned to 1.2. CONCLUSION: Prolonged, strenuous physical exertion with shouting during training exercises can lead to Valsalva hemorrhagic retinopathy. Several other factors, such as hot weather, altitude, and dehydration, may have played an additive role in increasing the venous pressure and hypoxia in the retinal vessels, which then caused the retinopathy.

Functional topography of rod and cone photoreceptors in macaque retina determined by retinal densitometry.

PURPOSE: The purpose of this study is to determine the topography of bleaching in rods, middle/long-wavelength (M/L) and short-wavelength (S) cones in the macaque retina by using a modified retinal densitometry technique. METHODS: A modified commercial digital fundus camera system was used to measure continuously the intensity of the light reflectance during bleaching with band pass lights in the ocular fundus of three adult Rhesus monkeys (Macaca mulatta) under general anesthesia. The topography of bleaching in rods, M/L-, and S-cones was obtained separately by considering the characteristic time course of the reflectance changes, depending on the wavelengths of light and retinal locations. RESULTS: The distribution of M/L-cones response had a steep peak at the foveal center and was elongated horizontally. The distribution of rod responses was minimum at the foveal center and maximum along a circular region at the eccentricity of the optic disc. The distribution of S-cone responses was highest at the fovea and was excavated centrally. There was a circular region with the maximal responses at 0.38 to 1.0 degrees from the foveal center. CONCLUSIONS: With the current imaging technique, not only the steep peak of the M/L-cone responses at the fovea, but the ring-shaped distribution of rod responses in the periphery and the central reduction of S-cone response could be determined with good resolution.

Fundus autofluorescence in autosomal dominant occult macular dystrophy.

OBJECTIVE: To characterize fundus autofluorescence (FAF) images of eyes with autosomal dominant occult macular dystrophy (OMD). METHODS: All patients received a comprehensive ophthalmologic examination for diagnosis of OMD. We evaluated the FAF images in 13 eyes of 7 patients with autosomal dominant OMD by confocal scanning laser ophthalmoscopy with excitation at 488 nm and emission more than 500 nm. RESULTS: The FAF images showed unspecific weak foveal hyperfluorescence in 4 eyes of 2 patients; one showed a thin hyperfluorescence in the temporal fovea bilaterally and the other showed weak hyperfluorescence in the fovea bilaterally. The optical coherence tomographic images showed abnormalities of the photoreceptor inner segment-outer segment line and cone outer segment tip line in all patients. However, 5 patients had normal FAF images regardless of morphological abnormalities of the photoreceptor. CONCLUSIONS: Fundus autofluorescence is a useful method to acquire additional information of photoreceptor/retinal pigment epithelium function in eyes with OMD. Fundus autofluorescence will be also helpful for the differential diagnosis of eyes with OMD vs eyes with other dystrophies that have a distinctive FAF pattern.

Outer retinal microstructure in a case of acute idiopathic blind spot enlargement syndrome.

PURPOSE: To present a patient with acute idiopathic blind spot enlargement syndrome who had abnormal changes in the outer retinal microstructure limited to areas with reduced responses on multifocal electroretinograms as well as to the area involving a scotoma. METHODS AND RESULTS: We report the case of a 44-year-old man who developed an arcuate scotoma which was associated with a physiological blind spot in the left eye. The ophthalmoscopic, fluorescein angiographic, and full-field electroretinogram findings were normal. The amplitudes of the multifocal electroretinograms were reduced in the area of the scotoma. Optical coherence tomography showed that both the external limiting membrane and the inner and outer segment (IS/OS) line were intact, but that the middle cone outer segment tip line between the IS/OS line and the retinal pigment epithelium was absent in the nasal macular area of the left eye. CONCLUSIONS: These findings indicate that the integrity of not only the external limiting membrane and IS/OS line but also the cone outer segment tip line is important for the function of the retina.

Pattern-reversal visual-evoked potential in patients with occult macular dystrophy.

PURPOSE: Occult macular dystrophy (OMD) is a hereditary retinal disease characterized by a normal fundus, normal full-field electroretinograms (ERGs), progressive decrease of visual acuity, and abnormal focal macular ERGs. The purpose of this study was to report pattern-reversal visual-evoked potential (pVEPs) findings in OMD patients. PATIENTS AND METHOD: The pVEPs recorded from four patients with OMD (aged 42-61 years; 2 men and 2 women) were reviewed. The visual acuities ranged from 20/200 to 20/30. The amplitudes of the N-75 and P-100 (P2 amplitude) and the latency of the N-75 components (N1 latency) were analyzed. RESULTS: The mean (±SD) P2 amplitude was 2.7 ± 1.9 µV for the 5', 4.8 ± 2.9 µV for the 10', 3.2 ± 2.1 µV for the 20', and 4.4 ± 3.5 µV for the 40' checkerboard stimuli. The N1 latency was 122.2 ± 6.4 ms for the 5', 105.0 ± 11.5 ms for the 10', 97.7 ± 10.0 ms for the 20', and 91.0 ± 13.7 ms for the 40' checkerboard stimuli. The mean P2 amplitude was reduced and the N1 latency was delayed in comparison with the laboratory standard for the Keio University Hospital. CONCLUSIONS: The delayed latency and reduced amplitude suggest a major contribution of the central cone pathway to the pVEPs.

Novel snapshot imaging of photoreceptor bleaching in macaque and human retinas.

PURPOSE: Various methods have been used to obtain a topographic map of bleached photopigments in human retinas in the past. The purpose of this study was to determine whether the bleaching topography of the photoreceptors could be obtained by snapshot imaging reflectometry. METHODS: Four to five fundus photographs of one rhesus monkey and three healthy human subjects were taken by white flashes at intervals of 4 s, with a commercial fundus camera with minimal modifications. The flash-induced reflectance increases (bleaching) were calculated by dividing the reflectance of the first image into the subsequent images, pixel by pixel. RESULTS: The topography of the bleached macula corresponded well with the anatomical distribution of the cones. The ratio of reflectance changes in the center to that in the surrounding tissue was high for red and low for green and blue images. These results indicate that the reflectivity changes were not artifacts but were derived from changes in the photopigment density in the cones and rods. CONCLUSIONS: The topography of bleached photoreceptors obtained with a commercial fundus camera from one monkey and three healthy human subjects showed that this technique has potential as a new clinical method for examining photoreceptor function in both normal and diseased retinas.

Origins of retinal intrinsic signals: a series of experiments on retinas of macaque monkeys.

Diffuse flash stimuli applied to the ocular fundus evoke light reflectance decreases of the fundus illuminated with infrared observation light. This phenomenon, which is independent of the photopigment bleaching observed as an increase in the reflectance of visible light, is called intrinsic signals. Intrinsic signals, in general, are stimulus-evoked light reflectance changes of neural tissues due to metabolic changes, and they have been extensively investigated in the cerebral cortex. This noninvasive objective technique of functional imaging has good potential as a tool for the early detection of retinal dysfunction. Once the signal properties were studied in detail, however, it became apparent that the intrinsic signals observed in the retina have uniquely interesting properties of their own due to the characteristic layered structure of the retina. Experiments on anesthetized macaque monkeys are reviewed, and the possible origins of the intrinsic signals of the retina are discussed.

Evaluating neural activity of retinal ganglion cells by flash-evoked intrinsic signal imaging in macaque retina.

PURPOSE: Intrinsic signal imaging (ISI) detects light-induced microstructural or metabolic changes in retinal tissues. Thus, activities of the rod and cone systems could be mapped topographically. However, no direct evidence indicates the cellular origin of the signals. The purpose of this study was to determine whether and how retinal ganglion cells (RGCs) contribute to ISI. METHODS: In anesthetized macaque monkeys, the properties of intrinsic signals were investigated by simultaneous measurement of the retina and the primary visual cortex (V1) with different wavelengths of observation light, measurement of the flash-induced blood flow changes by laser Doppler flowmetry, and intravitreal injection of tetrodotoxin (TTX). RESULTS: Slow components of ISI correspond well to the flash-induced blood flow increase. Intrinsic signals of the posterior retina are partially decreased, and the signal of the optic disc is completely abolished by intravitreal injection of TTX at a concentration that should reduce the neural activities of RGCs. The intrinsic signal at the fovea did not change significantly after TTX injection. CONCLUSIONS: Photoreceptors in the outer retina and RGCs in the inner retina are major contributors to the intrinsic signals, and the activity of the RGCs can be mapped by using fast and slow components of the signal in the posterior retina. The functional organization of the RGC layer has not been objectively mapped; results presented here indicate that the ISI has the potential to do this.

Transcorneal electrical stimulation of retina to treat longstanding retinal artery occlusion.

PURPOSE: To report the outcome of transcorneal electrical stimulation (TES) of the visual system on long-standing retinal artery occlusion (RAO). DESIGN: Open labeled, case series. PATIENTS AND METHODS: Two patients with central RAO (15 and 33 months respectively) and one with branch RAO (26 months) underwent TES therapy. Subjective and objective ophthalmological evaluations were performed before and after the TES. The ages of the patients were 38, 49, and 63 years. The TES (20 Hz biphasic pulses, 30 minutes, up to 1100 uA) was delivered by a bipolar contact lens electrode once a month for 3 months. Perimetric and/or electrophysiological examinations were performed as outcome measures. RESULTS: The visual acuity improved by more than 0.2 logMAR units in two cases, and the visual fields were improved in all three cases. The multifocal ERGs which had been reduced in the loci corresponding to the ischemic retinal area were improved after the treatment in two cases. Neither ocular nor systemic adverse effects were observed except for transient superficial keratitis. CONCLUSIONS: TES of the retina can improve retinal function in eyes with long-standing RAOs.