Kohta Fujiwara

Association Between Aqueous Flare and Epiretinal Membrane in Retinitis Pigmentosa

PURPOSE Epiretinal membrane (ERM) is a frequent macular complication in patients with retinitis pigmentosa (RP). The etiology of ERM formation in RP is largely unknown. The purpose of this study was to investigate the association between aqueous flare, a surrogate index of intraocular inflammation, and ERM secondary to RP. METHODS We retrospectively studied a total of 206 eyes of 117 patients who were diagnosed with typical RP. Aqueous flare values were measured consecutively in 2012 and 2013 using a laser flare cell meter. Spectral-domain optical coherence tomography images and fundus photographs taken on the same day of the aqueous flare measurements were analyzed for ERM detection. RESULTS The mean values of aqueous flare, age, and frequency of male sex were significantly higher in the RP patients with ERM compared with the RP patients without ERM (P < 0.0001, P = 0.007, and P = 0.004, respectively). After adjustment for age and sex, the eyes in the highest quartile of aqueous flare had significantly higher odds of having ERM than those in the lowest quartile (odds ratio [OR], 2.68; 95% confidence interval [CI], 1.04-6.93), and the linear trend across flare levels was significant (P = 0.005). In addition, each 1-log-transformed increase in flare values was associated with an elevation of the likelihood of having ERM (OR, 2.59; 95% CI, 1.33-5.06). CONCLUSIONS Our analysis demonstrated that elevated aqueous flare is associated with ERM secondary to RP, suggesting that inflammation may be implicated in the pathogenesis of ERM formation in RP.

Risk factors for Posterior Subcapsular Cataract in Retinitis Pigmentosa

Purpose Posterior subcapsular cataract (PSC) is a frequent complication in patients with retinitis pigmentosa (RP). The risk factors for PSC formation in RP are largely unknown. The purpose of this study was to investigate the risk factors for PSC. Methods We retrospectively studied a total of 322 eyes of 173 patients who were diagnosed with typical RP. We considered the following possible risk factors for PSC: age, sex, hypertension, diabetes mellitus, high myopia, asthma, history of steroid intake, and aqueous flare. Aqueous flare values were measured consecutively in 2012 and 2013 using a laser flare cell meter. The lens including PSC was examined with a slit lamp after dilation with tropicamide 1% and phenylephrine 2.5%. Results The geometric mean values of aqueous flare and mean values of visual acuity were significantly higher for the RP patients with PSC compared to those without PSC (P = 0.0003, P = 0.0004, respectively). When the aqueous flare values were assessed continuously, each 1-log-transformed increase in flare levels was associated with an elevation of the likelihood of having PSC after multivariable adjustment (odds ratio: 1.71; 95% confidence interval: 1.05-2.77). There were no significant associations of the other possible risk factors with PSC. Conclusions Our analysis demonstrated that elevated aqueous flare is a significant risk factor for PSC formation. This result might provide insights into the association of inflammation and the pathogenesis of PSC formation in RP.

MUTYH promotes oxidative microglial activation and inherited retinal degeneration

Oxidative stress is implicated in various neurodegenerative disorders, including retinitis pigmentosa (RP), an inherited disease that causes blindness. The biological and cellular mechanisms by which oxidative stress mediates neuronal cell death are largely unknown. In a mouse model of RP (rd10 mice), we show that oxidative DNA damage activates microglia through MutY homolog-mediated (MUYTH-mediated) base excision repair (BER), thereby exacerbating retinal inflammation and degeneration. In the early stage of retinal degeneration, oxidative DNA damage accumulated in the microglia and caused single-strand breaks (SSBs) and poly(ADP-ribose) polymerase activation. In contrast, Mutyh deficiency in rd10 mice prevented SSB formation in microglia, which in turn suppressed microglial activation and photoreceptor cell death. Moreover, Mutyh-deficient primary microglial cells attenuated the polarization to the inflammatory and cytotoxic phenotype under oxidative stress. Thus, MUTYH-mediated BER in oxidative microglial activation may be a novel target to dampen the disease progression in RP and other neurodegenerative disorders that are associated with oxidative stress.

Optical coherence tomography angiography of the macular microvasculature changes in retinitis pigmentosa

To investigate the macular microvasculature changes by optical coherence tomography angiography (OCTA) and analyse the correlation between these changes and central visual function in patients with retinitis pigmentosa (RP).

Imaging of Retinal Vascular Layers: Adaptive Optics Scanning Laser Ophthalmoscopy Versus Optical Coherence Tomography Angiography

Purpose Retinal vascular networks are observed as a layered structure residing in a nerve fiber layer and an inner nuclear layer of the retina. This study aimed to evaluate reflectance confocal adaptive optics scanning laser ophthalmoscopy (AO-SLO) for imaging of the layered retinal vascular networks. Methods This study included 16 eyes of 16 healthy cases. On the fovea, 2.8- and 3.0 mm2-areas were imaged using a prototype AO-SLO and optical coherence tomography angiography (OCTA), respectively. AO-SLO images focused on the nerve fiber and photoreceptor layers were recorded in the area. Two different vessel images (capillary networks in the superficial layer and in all layers) were generated to examine if the deep capillary network could be distinguished. We compared AO-SLO with OCTA in imaging of the layered retinal vascular networks. Results Sufficient images of capillary networks for analysis could be generated when the motion contrast was enhanced with AO-SLO movies in seven cases (43.8%). The deep capillary network could be distinguished in the merged image. Vascular depiction performance in AO-SLO was significantly better than in OCTA at both 0.5- and 1.0-mm areas from the fovea (P < 0.05). Conclusions Retinal vascular imaging using AO-SLO might be a useful adjunct to OCTA as a supportive method to evaluate the retina in healthy patients and patients with disease. Translational Relevance In cases requiring accurate and detailed retinal vasculature observation, AO-SLO might be useful for evaluating retinal vascular lesions as a supportive imaging method of OCTA.

Insulin Resistance Is a Risk Factor for Increased Intraocular Pressure: The Hisayama Study

PURPOSE To investigate association of the homeostasis model assessment of insulin resistance (HOMA-IR), a surrogate index of insulin resistance, with IOP in a general Japanese population. METHODS In 2007, a total of 3119 Japanese community-dwellers, aged 40 years or older, underwent eye examinations, including IOP measurement with a noncontact tonometer. Of these, 2254 residents participated in this study. Fasting serum glucose and plasma insulin were measured to determine the HOMA-IR. The association of HOMA-IR with IOP was assessed using a linear regression model, adjusted for age and possible risk factors that can elevate IOP. RESULTS The mean IOP ± SD was 13.7 ± 2.7 mm Hg in the right eye and 13.6 ± 2.7 mm Hg in the left eye. After adjusting for age, sex, systolic blood pressure, diabetes, total cholesterol, high-density lipoprotein cholesterol, body mass index, waist circumference, smoking habits, alcohol intake, and regular exercise, increased HOMA-IR levels were significantly associated with increasing IOP (P < 0.05). In the subgroup analyses based on the presence or absence of possible confounding risk factors, there was no evidence of heterogeneity between all subgroups (P for heterogeneity > 0.08). CONCLUSIONS The HOMA-IR is independently associated with elevated IOP levels after adjustment for confounding factors.

Prevalence and Risk Factors for Polypoidal Choroidal Vasculopathy in a General Japanese Population: The Hisayama Study

ABSTRACT Purpose: To estimate the prevalence and risk factors for polypoidal choroidal vasculopathy (PCV) in a general Japanese population. Methods: This population-based, cross-sectional study was conducted in 2007 with subjects from the Hisayama Study. Of the 3,648 residents in Hisayama, Japan, 2,663 who were ≥ 50 years old were enrolled in this study. The characteristics of PCV were determined by fundus examination or based on indocyanine green and fluorescein angiographic findings. We evaluated the contributions of the risk factors for PCV. Results: Among the 207 participants with age-related macular degeneration (AMD), 174 (6.5%) had early AMD, and 33 (1.2%) had late AMD, including 10 participants with PCV (0.4%). Male and smoking habit were significant risk factors for the development of PCV. Conclusions: The prevalence of PCV is higher among Japanese subjects than Caucasians in Western countries. Male gender and smoking habit were significant risk factors for PCV in a general Japanese population.

Assessment of central visual function in patients with retinitis pigmentosa

In order to clarify the disease progression in retinitis pigmentosa (RP) and its related factors, reliable data on the changes in central visual function in RP are needed. In this longitudinal study, we examined 118 patients who were diagnosed with typical RP. Visual acuity (VA), visual field using a Humphrey Field Analyzer with the central 10-2 SITA-Standard program, and optical coherence tomography measurements were obtained. The slopes, which were derived from serial values of mean deviation (MD), macular sensitivity (MS), or foveal sensitivity (FS) obtained for each eye by a linear mixed model, were used for analysis. MS and FS were calculated as the average retinal sensitivity of 12 and 4 central points respectively. There were statistically significant interactions of times with levels of the central subfield thickness (CST) on the slopes of MS and FS. Compared to the eyes without macular complications, the eyes with macular complications had steeper MD, MS and FS slopes, and this interaction was no significant, but marginal trend for the MS or FS slope (P = 0.10, 0.05, respectively). The central retinal sensitivity (i.e., MS and FS) slopes calculated were effective indices of the progression of central visual function in RP.

Relations Among Foveal Blood Flow, Retinal-Choroidal Structure, and Visual Function in Retinitis Pigmentosa

Purpose To investigate the relationships between foveal blood flow as measured by laser speckle flowgraphy (LSFG), the retinal-choroidal structure in enhanced depth imaging-optical coherence tomography (EDI-OCT), and central visual function in patients with retinitis pigmentosa (RP). Methods We studied 52 consecutive typical RP patients ≤50 years old and 21 age- and sex-matched controls. The mean blur rate (MBR), which represents the blood flow volume, was calculated in a 2.4-mm2 area centered on the fovea by LSFG. Subfoveal horizontal EDI-OCT images were recorded, and the choroidal area, choroidal hyporeflective area, and choroidal hyperreflective area were analyzed in the central 2.4-mm-wide region. The central foveal thickness (CFT), subfoveal choroidal thickness (SCT), and ellipsoid zone (EZ) width were also measured. Visual acuity (VA) and retinal sensitivity (Humphrey 10-2 program) were measured in the RP patients. Results The MBR, choroidal area, hyporeflective area, hyperreflective area, and SCT were significantly decreased in the RP patients (all P < 0.001, versus controls). Spearmans rank testing demonstrated no significant correlation between the MBR and the choroidal structural parameters in the RP patients. Decreased MBR was significantly associated with reductions in VA, retinal sensitivity, CFT, and EZ width (all P < 0.05). The choroidal structural parameters did not correlate with central visual function, and the choroidal area, hyperreflective area, and SCT were inversely associated with CFT (all P < 0.05). Conclusions These results demonstrated the divergence between the choroidal structure and blood function, and suggest that decreased choroidal flow, rather than the structural alteration, is closely associated with foveal degeneration in RP.

Discovery of a Cynomolgus Monkey Family With Retinitis Pigmentosa

Purpose To accelerate the development of new therapies, an inherited retinal degeneration model in a nonhuman primate would be useful to confirm the efficacy in preclinical studies. In this study, we describe the discovery of retinitis pigmentosa in a cynomolgus monkey (Macaca fascicularis) pedigree. Methods First, screening with fundus photography was performed on 1443 monkeys at the Tsukuba Primate Research Center. Ophthalmic examinations, such as indirect ophthalmoscopy, ERGs using RETeval, and optic coherent tomography (OCT) measurement, were then performed to confirm diagnosis. Results Retinal degeneration with cystoid macular edema was observed in both eyes of one 14-year-old female monkey. In her examinations, the full-field ERGs were nonrecordable and the outer layer of the retina in the parafoveal area was not visible on OCT imaging. Moreover, less frequent pigmentary retinal anomalies also were observed in her 3-year-old nephew. His full-field ERGs were almost nonrecordable and the outer layer was not visible in the peripheral retina. His father was her cousin (the son of her mothers older brother) and his mother was her younger half-sibling sister with a different father. Conclusions The hereditary nature is highly probable (autosomal recessive inheritance suspected). However, whole-exome analysis performed identified no pathogenic mutations in these monkeys.