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.

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.

Intraocular kinetics of pathological ATP after photoreceptor damage in rhegmatogenous retinal detachment.

PURPOSE: Extracellular Adenosine triphosphate (ATP) released by dying cells may cause a secondary cell death in neighboring cells in retinal degeneration. We investigated intraocular ATP kinetics to gain mechanical insights into the pathology in rhegmatogenous retinal detachment (RRD). STUDY DESIGN: Retrospective clinical study. METHODS: Vitreous or subretinal fluids (SRF) were obtained from patients with RRD (n=75), macular hole (MH; n=20), and epiretinal membrane (ERM; n=35) during vitrectomy. ATP levels in those samples were measured by luciferase assay. RESULTS: Mean ATP levels in the vitreous from RRD patients were significantly higher compared to those from MH and ERM patients (2.3 and 0.3 nM, respectively. P<0.01). Mean ATP levels in the SRF from RRD (11.7 nM) were higher than those in the vitreous from RRD (P<0.01). Mean ATP levels in the vitreous with short durations (1-8 days) of RRD were higher compared to those with long durations (>8 days) (3.2 and 1.4 nM, respectively. P<0.05). Similarly, ATP in SRF with short durations were higher than those with long durations (23.8 and 3.6 nM, respectively. P<0.05). Furthermore, the concentrations of ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1), a major ATP degradative enzyme, in the vitreous from RRD were higher than those from MH/ERM (1.2 and 0.2 ng/ml, respectively. P<0.01). ENTPD1 expression was localized in the cytoplasm of CD11b-positive infiltrating cells in the vitreous and retinal cells. CONCLUSION: ATP increased in the vitreous and SRF in RRD and decreased over time with an upregulation of ENTPD1. The kinetics indicate the pathological mechanism of the excessive extracellular ATP after RRD.

Comparison of Microperimetry and Static Perimetry for Evaluating Macular Function and Progression in Retinitis Pigmentosa.

Purpose: To compare the usefulness of microperimetry and static automated perimetry in patients with retinitis pigmentosa (RP), using macular anatomical metrics as a reference. Design: Prospective observational study. Participants: Forty-eight eyes of 48 patients with RP in Kyushu University Hospital who underwent microperimetry-3 (MP-3) and Humphrey Field Analyzer (HFA) 10-2 testing ≥3 times during ≥2 years were included. Methods: Macular anatomy (ellipsoid zone [EZ] length) was assessed by OCT, and macular function was assessed by MP-3 (mean retinal sensitivity at radii 2°, 4°, and 8°) and HFA10-2 program (mean retinal sensitivity at radii 2°, 4°, and 8°). Correlations between functional and anatomical parameters were analyzed cross sectionally at baseline and longitudinally by comparing the rate of progression. Main Outcome Measures: Correlation coefficients between anatomical and functional metrics. Results: The mean age at baseline was 50.1 ± 12.3 years, and the mean follow-up period was 2.8 ± 0.7 years. At baseline, EZ length was significantly correlated with MP-3 mean retinal sensitivity at radii 2°, 4°, and 8° (Spearman's ρ = 0.65, 0.84, 0.89; all P < 0.005) and HFA10-2 mean retinal sensitivity at radii 2°, 4°, and 8° (Spearman's ρ = 0.61, 0.73, 0.78; all P < 0.005). Longitudinal analysis showed that the slope of EZ length (-88.92 µm/year) was significantly correlated with the slope of MP-3 retinal sensitivity at 8° radius (-0.62 decibels [dB]/year; Spearman's ρ = 0.31, P=0.03) and the slope of HFA retinal sensitivity at 8° radius (-0.60 dB/year; Spearman's ρ = 0.43, P < 0.005). Conclusions: Both MP-3 and HFA values were cross sectionally well-correlated with EZ length in patients with patients; however, these associations became weaker in the longitudinal analysis. This highlights the need for researchers to explore additional or more sensitive parameters to better monitor RP progression. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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.

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.

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.