Circulating inflammatory monocytes oppose microglia and contribute to cone cell death in retinitis pigmentosa.

Retinitis pigmentosa (RP) is an intractable inherited disease that primarily affects the rods through gene mutations followed by secondary cone degeneration. This cone-related dysfunction can lead to impairment of daily life activities, and ultimately blindness in patients with RP. Paradoxically, microglial neuroinflammation contributes to both protection against and progression of RP, but it is unclear which population(s) - tissue-resident microglia and/or peripheral monocyte-derived macrophages (mφ) - are implicated in the progression of the disease. Here we show that circulating blood inflammatory monocytes (IMo) are key effector cells that mediate cone cell death in RP. Attenuation of IMo and peripherally engrafted mφ by Ccl2 deficiency or immune modulation via intravenous nano-particle treatment suppressed cone cell death in rd10 mice, an animal model of RP. In contrast, the depletion of resident microglia by a colony-stimulating factor 1 receptor inhibitor exacerbated cone cell death in the same model. In human patients with RP, IMo was increased and correlated with disease progression. These results suggest that peripheral IMo is a potential target to delay cone cell death and prevent blindness in RP.

RECURRENCE RATE OF CYSTOID MACULAR EDEMA WITH TOPICAL DORZOLAMIDE TREATMENT AND ITS RISK FACTORS IN RETINITIS PIGMENTOSA.

PURPOSE: To investigate the rate of the recurrence of cystoid macular edema (CME) secondary to retinitis pigmentosa (RP) after the initiation of topical dorzolamide and the recurrence risk factors. METHODS: We retrospectively analyzed the data of RP patients at Kyushu University Hospital. We included patients who showed a treatment response to 1.0% topical dorzolamide. The day of treatment initiation was set as the baseline. Topical dorzolamide treatment was continued during the follow-up. The recurrence of CME (defined as a >20% increase in central subfield thickness compared to previous visit, or a central subfield thickness value that exceed baseline value) was evaluated at each follow-up visit. Risk factors for RP-CME recurrence were analyzed by Cox proportional hazards modeling. A Kaplan-Meier survival analysis was used to evaluate the time to recurrent RP-CME. RESULTS: Forty RP-CME patients showed a treatment response to topical dorzolamide. During the mean 3.9-year follow-up, 14 patients exhibited recurrence; its rate was 15.6%, 34.7%, and 48.7% at 1, 3, and 5 years, respectively. A high baseline central subfield thickness was significantly associated with recurrent (hazard ratio 1.11, 95% CI: 1.05-1.18, P = 0.0004). CONCLUSION: The recurrence rate of RP-CME increased with time. A high baseline central subfield thickness value was a risk factor for recurrence.

Changes of Serum Inflammatory Molecules and Their Relationships with Visual Function in Retinitis Pigmentosa.

Purpose: Retinal degeneration involves neuroinflammation, and pro-inflammatory cytokines/chemokines are markedly increased in the eyes of patients with retinitis pigmentosa (RP). In this study, we investigated the changes of serum cytokines/chemokines in RP, and their relationships with visual parameters. Methods: Forty-five consecutive patients with typical RP aged 20 to -39 years and 28 age-matched and gender-matched controls were included. Fifteen cytokines (interleukin [IL]-1α, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p70, IL-13, 1L-15, IL-17, IL-23, interferon [IFN]-γ, and tumor necrosis factor [TNF]-α, TNF-ß) and 9 chemokines (eotaxin, growth-related oncogene [GRO]-α, I-309, IL-8, IFN-γ-inducible protein [IP]-10, monocyte chemotactic protein [MCP]-1, MCP-2, regulated activation normal T-cell expressed and secreted [RANTES], and thymus and activated regulated chemokine [TARC]) in the serum were simultaneously measured by a multiplexed immunoarray (Q-Plex). Relationships between these cytokines/chemokines and indices of central vision, such as visual acuity (VA), the values of static perimetry tests (Humphrey Field analyzer, the central 10-2 program), and optical coherence tomography measures were analyzed in the patients with RP. Results: Among the 15 cytokines and 9 chemokines, serum IL-8 and RANTES levels were significantly increased in patients with RP compared with controls (IL-8: P < 0.0001; RANTES: P < 0.0001). Among the elevated cytokines/chemokines, the levels of IL-8 were negatively correlated with VA (ρ = 0.3596 and P = 0.0165), and the average retinal sensitivity of four central points (ρ = -0.3691 and P = 0.0291), and 12 central points (ρ = -0.3491 and P = 0.0398), as well as the central subfield thickness (ρ = -0.3961 and P = 0.0094), and ellipsoid zone width (ρ = -0.3841 and P = 0.0120). Conclusions: Peripheral inflammatory response may be activated and serum IL-8 levels are associated with central vision in patients with RP.

Aqueous Flare and Progression of Visual Field Loss in Patients With Retinitis Pigmentosa.

Purpose: To investigate the association between aqueous flare and progression of visual field loss using the Humphrey Field Analyzer in patients with retinitis pigmentosa (RP). Methods: We examined a total of 101 eyes of 101 patients who were diagnosed with typical RP. Sixty-one percent of the patients were female, and the mean age of the total group was 47.4 years. Aqueous flare, visual field (by an Humphrey Field Analyzer, the central 10-2 SITA-Standard program), and optical coherence tomography measurements were obtained for all patients. The slope, which was derived from serial values of mean deviation, macular sensitivity, or foveal sensitivity for each eye with univariate linear regression, was used for analysis. Results: Aqueous flare values were significantly correlated with the mean deviation slope (r = -0.20, P = 0.046), macular sensitivity slope (r = -0.28, P = 0.005) and foveal sensitivity slope (r = -0.20, P = 0.047). The values of the retinal sensitivity slope significantly decreased as the aqueous flare level increased (all P < 0.05). These associations remained unchanged after adjustment for age, sex, and posterior subcapsular cataract, and epiretinal membrane. Conclusions: Elevation of aqueous flare is a risk factor for the decline of central visual function in RP. Aqueous flare may be a useful marker for disease progression in RP.

Direct comparison of retinal structure and function in retinitis pigmentosa by co-registering microperimetry and optical coherence tomography.

PURPOSE: To evaluate the retinal structure-function relationships in the macula of retinitis pigmentosa (RP) patients by comparing microperimetry-3 (MP-3) images with co-registered optical coherence tomography (OCT) images. METHODS: Thirty patients with typical RP were recruited from our hospital. The maculae of patients were examined with MP-3 and OCT. The retinal sensitivity was measured by MP-3 at 40 testing points arranged concentrically in a 16° diameter of the central retina, and we divided the 40 points into four zones according to degree from the fovea (2°, 4°, 6°, and 8°). We analyzed the correlation coefficients between the retinal sensitivity and the total retinal thickness (TRT), the length from the inner limiting membrane to the retinal pigment epithelium (RPE), and between the retinal sensitivity and the outer retinal thickness (ORT), the length from the outer plexiform layer to the RPE at each stimulus point. RESULTS: TRT showed moderate correlations with the retinal sensitivity at 2° (median ρ = 0.59 interquartile range (IQR) [0.38-0.72]), 4° (ρ = 0.59 [0.55-0.68]) and 6° (ρ = 0.60 [0.54-0.63]), and TRT was weakly-to-moderately related to the retinal sensitivity at 8° (ρ = 0.27 [0.19-0.48]). ORT exhibited strong correlations at 2° (ρ = 0.72 [0.60-0.81]), 4° (ρ = 0.71 [0.75-0.67]) and 6° (ρ = 0.70 [0.54-0.74]), and a weak-to-moderate correlations at 8° (ρ = 0.34 [0.29-0.53]). ORT was more strongly correlated with the retinal sensitivity compared to TRT (p = 0.018). CONCLUSION: ORT, rather than TRT, within 6° eccentricity was strongly correlated with the retinal sensitivity, suggesting that measuring ORT in those areas will help evaluate the macular status and progression in RP.

Relationships Between Serum Antioxidant and Oxidant Statuses and Visual Function in Retinitis Pigmentosa.

Purpose: To investigate the serum changes of antioxidant/oxidant markers and the relationship between these factors and visual function in patients with retinitis pigmentosa (RP). Methods: Fifty-two RP patients <40 years old and 25 controls were included. Serum samples were analyzed for superoxide dismutase 3 (SOD3) activity, glutathione peroxidase (GPx), potential antioxidant (PAO), and hexanoyl-lysine (HEL). The relationships between these markers and visual parameters, including best-corrected visual acuity (BCVA), mean deviation (MD), and average retinal sensitivity of 4 or 12 central points on static perimetry tests (Humphrey Field Analyzer, the central 10-2 program) were examined in the RP patients. Results: Although there was no significant difference in the serum SOD3 activity between RP patients and controls, serum SOD3 activity in the severe degeneration group with macular involvement (16.3 ± 11.3 U/mL) was significantly lower compared with those in the mild degeneration group (those with midperipheral scotomas; 28.5 ± 16.6 U/mL, P = 0.0459). SOD3 was significantly related to visual acuity (r = -0.3701, P = 0.0069) and the average retinal sensitivity of four central points (r = 0.3463, P = 0.0137) in RP patients. The linear trends of these two parameters across SOD3 levels were also significant (P = 0.0264 and 0.0172, respectively). There was no consistent correlation between other serum antioxidant/oxidant markers and visual parameters. Conclusions: Lower serum SOD3 activity was associated with the severe retinal degeneration in RP patients. Our results suggest that serum SOD3 activity may be related to disease severity in RP.

Early detection of cone photoreceptor cell loss in retinitis pigmentosa using adaptive optics scanning laser ophthalmoscopy.

PURPOSE: The purpose of the study was to investigate the characteristics of the parafoveal cone density changes in patients with retinitis pigmentosa (RP) using adaptive optics scanning laser ophthalmoscopy (AO-SLO). METHODS: A total of 14 eyes of RP patients and 10 eyes of control subjects were examined. High-resolution images of cone photoreceptor cells were obtained with a Canon AO-SLO system in the four retinal regions of the superior, inferior, temporal, and nasal areas located 1.0 mm from the central fovea. The relationships of cone density with optical coherence tomography (OCT) findings and the visual sensitivity of the static perimetry tests were analyzed in RP patients. RESULTS: The averaged cone densities in RP patients were decreased at 1.0 mm eccentricity from the fovea (11,899 cells/mm2) compared with those in control subjects (16,647 cells/mm2; P < 0.01). The cone density was substantially decreased even in RP patients with an intact interdigitation zone at the examined area (12,865 cells/mm2; P < 0.01 vs. controls) and preserved visual sensitivity with > 35 dB (13,019 cells/mm2; P < 0.001 vs. controls). CONCLUSIONS: In RP, cone photoreceptor cell loss occurred in the parafoveal region with a preserved EZ/IZ or visual sensitivity. AO-SLO may be a useful modality to detect early changes of cone photoreceptor cells in RP patients.

Night-vision aid using see-through display for patients with retinitis pigmentosa.

PURPOSE: From an early stage, retinitis pigmentosa (RP) patients suffer from night blindness which causes nocturnal mobility difficulties. We created a wearable visual aid that uses a high-performance see-through display, and added a high-sensitivity camera with a complementary metal-oxide-semiconductor sensor. Here, we evaluate the device's efficacy for helping night-blindness sufferers walk in the dark. STUDY DESIGN: Prospective clinical study. METHODS: Twenty-eight subjects underwent binocular visual acuity testing in the dark without (power off) and with (power on) the device. The test was carried out in a darkened room. We recorded the number of trial errors and the time it took each subject to arrive at the goal both with and without the aid of our device. RESULTS: Our device effectively assists walking in RP patients with mobility problems in the dark. CONCLUSION: Binocular visual acuity in the dark was significantly improved with the aid of our device. In the walking test, the number of errors decreased greatly with the device, and the travel time was significantly shortened.

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). Spearman's 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 mother's 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.

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

PURPOSE: 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). METHODS: We measured the area of the foveal avascular zone (FAZ) and the foveal and parafoveal flow density (FFD and PFD, respectively) in the superficial (S) and deep (D) retinal plexus by OCTA (AngioVue) and compared these values between 73 RP patients and 36 healthy controls. We analysed the relationships between these microvasculature measurements and central visual functions such as visual acuity (VA) and the values of static perimetry tests (Humphrey Field Analyzer, the central 10-2 program) in the RP patients. RESULTS: The FFD-S, PFD-S and PFD-D were significantly decreased in the RP patients compared to the controls (all p < 0.05), whereas there was no significant difference in the FAZ-S, FAZ-D or FFD-D (all p > 0.05). A subgroup analysis showed that the RP patients with VA <20/20 had increased FAZ-S compared to the controls and RP patients with VA ≥20/20 (p = 0.01 and p = 0.007, respectively). Spearman rank testing demonstrated that PFD-S and PFD-D were significantly correlated with all of the central visual parameters (all p < 0.01). The FAZ-S and FFD-S were significantly correlated with VA, and FAZ-D and FFD-D showed no significant correlation. CONCLUSION: Both the superficial and deep layers of the parafoveal microvasculature are attenuated in RP and correlated with reduced central visual function. The foveal microvasculature, especially in the deep layer, was relatively preserved until mild-to-moderately advanced stages.

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.