Application of a Deep Machine Learning Model for Automatic Measurement of EZ Width in SD-OCT Images of RP.

Purpose: We applied a deep convolutional neural network model for automatic identification of ellipsoid zone (EZ) in spectral domain optical coherence tomography B-scans of retinitis pigmentosa (RP). Methods: Midline B-scans having visible EZ from 220 patients with RP and 20 normal subjects were manually segmented for inner limiting membrane, inner nuclear layer, EZ, retinal pigment epithelium, and Bruch's membrane. A total of 2.87 million labeled image patches (33 × 33 pixels) extracted from 480 B-scans were used for training a convolutional neural network model implemented in MATLAB. B-scans from a separate group of 80 patients with RP were used for testing the model. A local connected area searching algorithm was developed to process the model output for reconstructing layer boundaries. Correlation and Bland-Altman analyses were conducted to compare EZ width measured by the model to those by manual segmentation. Results: The accuracy of the trained model to identify inner limiting membrane, inner nuclear layer, EZ, retinal pigment epithelium, and Bruch's membrane patches in the test dataset was 98%, 89%, 91%, 94%, and 96%, respectively. The EZ width measured by the model was highly correlated with that by two graders (r = 0.97; P < 0.0001). Bland-Altman analysis revealed a mean EZ width difference of 0.30 mm (coefficient of repeatability = 0.9 mm) between the model and the graders, comparable to the mean difference of 0.34mm (coefficient of repeatability = 0.8 mm) between two graders. Conclusions: The results demonstrated the capability of a deep machine learning-based method for automatic identification of EZ in RP, suggesting that the method can be used to quantify structural deficits in RP for detecting disease progression and for evaluating treatment effect. Translational Relevance: A deep machine learning model has the potential to replace humans for grading spectral domain optical coherence tomography images in RP.

Regional Variations and Intra-/Intersession Repeatability for Scotopic Sensitivity in Normal Controls and Patients With Inherited Retinal Degenerations.

Purpose: Dark-adapted visual fields were obtained from patients with inherited retinal degeneration (IRD) and controls to evaluate the effect that age, retinal region, and disease had on scotopic sensitivity. Intra- and intersession test-retest repeatabilities for patients and controls were measured to establish significant change for longitudinal studies. Methods: A total of 41 patients with IRD and 30 controls had one eye dilated and dark-adapted for 40 minutes. Scotopic sensitivity was measured with a Medmont dark-adapted chromatic (DAC) perimeter (size V stimulus, 200-ms duration, background luminance < 0.0001 cd/m2, dynamic range 0-75 decibel [dB]). Mixed effects analysis was performed to analyze age, retinal eccentricity, and sensitivity. The intra-/intersession coefficients of repeatability (CR) were calculated for controls and patients with IRD. Results: Each additional year was associated with lower sensitivity (-0.22 dB) per year in normal controls over age 50 compared to younger controls (12-49 years). The superior field had lower sensitivity than the inferior, but the nasal field was not different compared to the temporal field in normal controls. The CR for intra- and intersession testing on mean sensitivity (MS)/pointwise sensitivity (PWS) were ±1.5/±8.5 and ±3.3/±9.8 dB, respectively, for patients with IRD. Control MS/PWS CR were ±1.5/±6.1 dB for intrasession and ±1.7/±6.8 dB for intersession DAC perimetry. Conclusions: The DAC perimeter is an important asset because it tests a wide field of scotopic vision. The CR are comparable to those of other perimetry devices. Effects of age and retinal region should be considered when assessing scotopic sensitivity measured with the DAC perimeter.

Dark-Adapted Chromatic Perimetry for Measuring Rod Visual Fields in Patients with Retinitis Pigmentosa.

PURPOSE: Although rod photoreceptors are initially affected in retinitis pigmentosa (RP), the full-field of rod vision is not routinely characterized due to the unavailability of commercial devices detecting rod sensitivity. The purpose of this study was to quantify rod-mediated vision in the peripheral field from patients with RP using a new commercially available perimeter. METHODS: Participants had one eye dilated and dark-adapted for 45 minutes. A dark-adapted chromatic (DAC) perimeter tested 80 loci 144° horizontally and 72° vertically with cyan stimuli. The number of rod-mediated loci (RML) were analyzed based on normal cone sensitivity (method 1) and associated with full-field electroretinography (ERG) responses by Pearson's r correlation and linear regression. In a second cohort of patients with RP, RML were identified by two-color perimetry (cyan and red; method 2). The two methods for ascribing rod function were compared by Bland-Altman analysis. RESULTS: Method 1 RML were correlated with responses to the 0.01 cd.s/m2 flash (P < 0.001), while total sensitivity to the cyan stimulus showed correlation with responses to the 3.0 cd.s/m2 flash (P < 0.0001). Method 2 detected a mean of 10 additional RML compared to method 1. CONCLUSIONS: Scotopic fields measured with the DAC detected rod sensitivity across the full visual field, even in some patients who had nondetectable rod ERGs. Two-color perimetry is warranted when sensitivity to the cyan stimulus is reduced to ≤20 dB to get a true estimation of rod function. TRANSLATIONAL RELEVANCE: Many genetic forms of retinitis pigmentosa (RP) are caused by mutations in rod-specific genes. However, treatment trials for patients with RP have relied primarily on photopic (cone-mediated) tests as outcome measures because there are a limited number of available testing methods designed to evaluate rod function. Thus, efficient methods for quantifying rod-mediated vision are needed for the rapidly increasing numbers of clinical trials.

North Carolina macular dystrophy (MCDR1) caused by a novel tandem duplication of the PRDM13 gene.

PURPOSE: To identify the underlying cause of disease in a large family with North Carolina macular dystrophy (NCMD). METHODS: A large four-generation family (RFS355) with an autosomal dominant form of NCMD was ascertained. Family members underwent comprehensive visual function evaluations. Blood or saliva from six affected family members and three unaffected spouses was collected and DNA tested for linkage to the MCDR1 locus on chromosome 6q12. Three affected family members and two unaffected spouses underwent whole exome sequencing (WES) and subsequently, custom capture of the linkage region followed by next-generation sequencing (NGS). Standard PCR and dideoxy sequencing were used to further characterize the mutation. RESULTS: Of the 12 eyes examined in six affected individuals, all but two had Gass grade 3 macular degeneration features. Large central excavation of the retinal and choroid layers, referred to as a macular caldera, was seen in an age-independent manner in the grade 3 eyes. The calderas are unique to affected individuals with MCDR1. Genome-wide linkage mapping and haplotype analysis of markers from the chromosome 6q region were consistent with linkage to the MCDR1 locus. Whole exome sequencing and custom-capture NGS failed to reveal any rare coding variants segregating with the phenotype. Analysis of the custom-capture NGS sequencing data for copy number variants uncovered a tandem duplication of approximately 60 kb on chromosome 6q. This region contains two genes, CCNC and PRDM13. The duplication creates a partial copy of CCNC and a complete copy of PRDM13. The duplication was found in all affected members of the family and is not present in any unaffected members. The duplication was not seen in 200 ethnically matched normal chromosomes. CONCLUSIONS: The cause of disease in the original family with MCDR1 and several others has been recently reported to be dysregulation of the PRDM13 gene, caused by either single base substitutions in a DNase 1 hypersensitive site upstream of the CCNC and PRDM13 genes or a tandem duplication of the PRDM13 gene. The duplication found in the RFS355 family is distinct from the previously reported duplication and provides additional support that dysregulation of PRDM13, not CCNC, is the cause of NCMD mapped to the MCDR1 locus.

Reliability of a Manual Procedure for Marking the EZ Endpoint Location in Patients with Retinitis Pigmentosa.

PURPOSE: We developed and evaluated a training procedure for marking the endpoints of the ellipsoid zone (EZ), also known as the inner segment/outer segment (IS/OS) border, on frequency domain optical coherence tomography (fdOCT) scans from patients with retinitis pigmentosa (RP). METHODS: A manual for marking EZ endpoints was developed and used to train 2 inexperienced graders. After training, an experienced grader and the 2 trained graders marked the endpoints on fdOCT horizontal line scans through the macula from 45 patients with RP. They marked the endpoints on these same scans again 1 month later. RESULTS: Intragrader agreement was excellent. The intraclass correlation coefficient (ICC) was 0.99, the average difference of endpoint locations (19.6 µm) was close to 0 µm, and the 95% limits were between -284 and 323 µm, approximately ±1.1°. Intergrader agreement also was excellent. The ICC values were 0.98 (time 1) and 0.97 (time 2), the average difference among graders was close to zero, and the 95% limits of these differences was less than 350 µm, approximately 1.2°, for both test times. CONCLUSIONS: While automated algorithms are becoming increasingly accurate, EZ endpoints still have to be verified manually and corrected when necessary. With training, the inter- and intragrader agreement of manually marked endpoints is excellent. TRANSLATIONAL RELEVANCE: For clinical studies, the EZ endpoints can be marked by hand if a training procedure, including a manual, is used. The endpoint confidence intervals, well under ±2.0°, are considerably smaller than the 6° spacing for the typically used static visual field.

Worldwide Argus II implantation: recommendations to optimize patient outcomes.

BACKGROUND: A position paper based on the collective experiences of Argus II Retinal Prosthesis System investigators to review strategies to optimize outcomes in patients with retinitis pigmentosa undergoing retinal prosthesis implantation. METHODS: Retinal surgeons, device programmers, and rehabilitation specialists from Europe, Canada, Middle East, and the United States were convened to the first international Argus II Investigator Meeting held in Ann Arbor, MI in March 2015. The recommendations from the collective experiences were collected. Factors associated with successful outcomes were determined. RESULTS: Factors leading to successful outcomes begin with appropriate patient selection, expectation counseling, and preoperative retinal assessment. Challenges to surgical implantation include presence of staphyloma and inadequate Tenon's capsule or conjunctiva. Modified surgical technique may reduce risks of complications such as hypotony and conjunctival erosion. Rehabilitation efforts and correlation with validated outcome measures following implantation are critical. CONCLUSIONS: Bringing together Argus II investigators allowed the identification of strategies to optimize patient outcomes. Establishing an on-line collaborative network will foster coordinated research efforts to advance outcome assessment and rehabilitation strategies.

Docosahexaenoic Acid Slows Visual Field Progression in X-Linked Retinitis Pigmentosa: Ancillary Outcomes of the DHAX Trial.

PURPOSE: Docosahexaenoic acid (DHA) was supplemented in a single-site, placebo-controlled, randomized clinical trial designed to slow vision loss associated with X-linked retinitis pigmentosa (XLRP); the DHAX Trial. We previously reported no significant differences between supplemented and placebo groups in intent-to-treat analysis of primary ERG outcomes. Assessed herein are hypothesis-generating measures of ancillary visual function outcomes in participants fully adhering to trial protocol. METHODS: Male participants with XLRP (range, 7-31 years) received 30 mg DHA/kg/d (n = 29) or placebo (n = 22) for 4 years. Visual outcomes were measured annually and red blood cell (RBC) DHA determined every 6 months. RESULTS: Oral DHA supplementation increased mean RBC-DHA levels by 4-fold (P < 0.0001) over placebo. No group differences in progression were found for visual acuity (P = 0.11), shape discrimination (P = 0.18), or fundus appearance (P = 0.70). Optical coherence tomography (OCT) became available during year 2 of the trial; no group differences were seen in ellipsoid zone constriction (P = 0.87) over 2 years. Yearly rates of progression were reduced for dark-adapted thresholds (P = 0.06) and visual field sensitivity for foveal, macular, peripheral, total, and ellipsoid zone regions by DHA supplementation (P = 0.039, P = 0.031, P < 0.0001, P < 0.0001, and P = 0.033). Rates of visual field sensitivity decline were dependent on RBC-DHA (P = 0.046 to <0.0001). CONCLUSIONS: Supplementation of DHA significantly elevated blood DHA levels and reduced the rate of progression in final dark-adapted thresholds and visual field sensitivity. From the relationship between RBC-DHA and the rate of field sensitivity loss, we can extrapolate that an RBC-DHA level of 17% could minimize the decline in field sensitivity. (ClinicalTrials.gov number, NCT00100230.)

Rates of decline in regions of the visual field defined by frequency-domain optical coherence tomography in patients with RPGR-mediated X-linked retinitis pigmentosa.

PURPOSE: To determine whether annual decline in visual field sensitivity is greater in the transition zone at the edge of the frequency-domain optical coherence tomography (fdOCT) inner segment ellipsoid zone (EZ) than at other locations in the visual field. DESIGN: Prospective, longitudinal, observational study. PARTICIPANTS: Forty-four patients with X-linked retinitis pigmentosa (XLRP) resulting from a mutation in the RPGR gene. METHODS: Static perimetric fields (Humphrey 30-2; Carl Zeiss Meditec, Dublin, CA) were obtained annually for 4 years. Beginning with year 2, fdOCT scans were obtained annually with a Heidelberg Spectralis HRA + OCT (Heidelberg Engineering, Heidelberg, Germany). MAIN OUTCOME MEASURES: The rate of visual field decline at locations near the edge of the EZ compared with the rates for the macula and in the mid periphery. RESULTS: Sensitivity just inside and outside the edge of the EZ declined at rates of 0.84 and 0.92 dB/year, respectively. By comparison, average sensitivity in the macula and mid periphery declined by 0.38 and 0.61 dB/year, respectively. CONCLUSIONS: The edge of the EZ in each patient with XLRP indicates a transition zone between relatively healthy and relatively degenerate retina. The annual loss of sensitivity in the transition zone is more rapid than it is elsewhere in the retina.

A comparison of progressive loss of the ellipsoid zone (EZ) band in autosomal dominant and x-linked retinitis pigmentosa.

PURPOSE: In patients with retinitis pigmentosa (RP), the inner segment ellipsoid zone (EZ; also known as the inner segment/outer segment [IS/OS] border) is a marker of the usable visual field at a given point in time and of the progression of the disease over time. Here we compare the change in the width per year of the EZ band in patients with autosomal dominant (ad) and x-linked (xl) RP. METHODS: Using optical coherence tomography (OCT), 9-mm horizontal and vertical line scans through the fovea were obtained for one eye of 26 xlRP patients and 33 adRP patients. Scans were repeated on average 2.0 years later (range, 0.6-4.8 years). Using a manual segmentation procedure, the EZ band was delineated and its horizontal width (HW) and vertical width (VW) were determined. RESULTS: The adRP and xlRP patients had similar initial EZ HW (xlRP: 11.8 ± 5.4°, adRP: 12.4 ± 6.3°, P = 0.69) and VW (xlRP: 8.5 ± 4.9°, adRP: 11.4 ± 7.1°, P = 0.09). However, between visits the absolute loss and percent loss of the EZ width per year was significantly greater for xlRP than adRP for both HW (xlRP: 1.0 ± 0.6°/y, 9.6 ± 5.6%/y; adRP: 0.4 ± 0.5°/y, 3.4 ± 5.4%/y; P < 0.001) and VW (xlRP: 0.8 ± 0.8°/y, 9.2 ± 8.9%/y; adRP: 0.3 ± 0.5°/y, 4.2 ± 6.4%/y; P < 0.01). There was a weak correlation between the loss of EZ width per year and the initial width for xlRP (r(2) = 0.17, P = 0.036), but no correlation for adRP (r(2) = 0.004, P = 0.73). The test-retest difference of EZ HW was 0.2 ± 0.5°. CONCLUSIONS: The OCT data here support a faster rate of loss per year in the case of xlRP. (ClinicalTrials.gov number, NCT00100230.).

Four-year placebo-controlled trial of docosahexaenoic acid in X-linked retinitis pigmentosa (DHAX trial): a randomized clinical trial.

IMPORTANCE: X-linked retinitis pigmentosa is a severe inherited retinal degenerative disease with a frequency of 1 in 100,000 persons. Because no cure is available for this orphan disease and treatment options are limited, slowing of disease progression would be a meaningful outcome. OBJECTIVE: To determine whether high-dose docosahexaenoic acid (DHA), an ω-3 polyunsaturated fatty acid, slows progression of X-linked retinitis pigmentosa measured by cone electroretinography (ERG). DESIGN, SETTING, AND PARTICIPANTS: A 4-year, single-site, randomized, placebo-controlled, double-masked phase 2 clinical trial at a research center specializing in medical retina. Seventy-eight male patients diagnosed as having X-linked retinitis pigmentosa were randomized to DHA or placebo. Data were omitted for 2 patients with non-X-linked retinitis pigmentosa and 16 patients who were unable to follow protocol during the first year. The remaining participants were tested annually and composed a modified intent-to-treat cohort (DHA group, n = 33; placebo group, n = 27). INTERVENTIONS: All participants received a multivitamin and were randomly assigned to oral DHA (30 mg/kg/d) or placebo. MAIN OUTCOMES AND MEASURES: The primary outcome was the rate of loss of cone ERG function. Secondary outcomes were rod and maximal ERG amplitudes and cone ERG implicit times. Capsule counts and red blood cell DHA levels were assessed to monitor adherence. RESULTS: Average (6-month to 4-year) red blood cell DHA levels were 4-fold higher in the DHA group than in the placebo group (P < .001). There was no difference between the DHA and placebo groups in the rate of cone ERG functional loss (0.028 vs 0.022 log µV/y, respectively; P = .30). No group differences were evident for change in rod ERG (P = .27), maximal ERG (P = .65), or cone implicit time (no change over 4 years). The rate of cone loss (ie, event rate) was markedly reduced compared with rates in previous studies. No severe treatment-emergent adverse events were found. CONCLUSIONS AND RELEVANCE: Long-term DHA supplementation was not effective in slowing the loss of cone or rod ERG function associated with X-linked retinitis pigmentosa. Participant dropout and lower-than-expected disease event rate limited power to detect statistical significance. A larger sample size, longer trial, and attainment of a target blood DHA level (13%) would be desirable. While DHA supplementation at 30 mg/kg/d does not present serious adverse effects, routine monitoring of gastrointestinal tolerance is prudent. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00100230.

A Comparison of Methods for Tracking Progression in X-Linked Retinitis Pigmentosa Using Frequency Domain OCT.

PURPOSE: To compare the efficacy of frequency domain optical coherence tomography (fdOCT)-derived outer retinal measures in tracking disease progression in x-linked (xl) retinitis pigmentosa (RP) patients. METHODS: Macular volume scans and line scans (Spectralis) were obtained from 27 xlRP patients (15.3 ± 6.4 years) at two visits approximately 2 years apart. Changes in average outer retinal layer thicknesses across the volume scan were compared to changes detected by measures derived from the edge of the inner segment ellipsoid zone (EZ) band, that is, where the EZ band (also known as inner segment/outer segment border) disappears. Repeatability was tested on an independent set of 18 RP patients (43.5 ± 18.0 years). RESULTS: Average outer segment (OS) and outer nuclear layer (ONL) thickness showed marginally significant annual changes (P < 0.05), while total receptor (TR) thickness showed a greater change (P < 0.01). All measures derived from the edge of the EZ band significantly decreased (P < 0.01). Mean ± SD for test-retest differences in horizontal widths was 0.01 ± 0.06 mm. CONCLUSIONS: Measures of the EZ band are more effective in detecting disease progression than are thickness measures. Given the similar effectiveness of line and volume scans, manually marking the EZ band edge on vertical and/or horizontal line scans can be useful in tracking progression. TRANSLATIONAL RELEVANCE: Because disease progression in RP can be relatively slow, annual changes can be difficult to monitor during the course of a clinical trial. Here we suggest a quick, effective, and reliable method for detecting subtle changes.

Spectral-domain optical coherence tomography measures of outer segment layer progression in patients with X-linked retinitis pigmentosa.

IMPORTANCE: Determining the annual rate of change in the width of the inner segment ellipsoid zone (EZ; ie, inner/outer segment border) in the context of short-term variability should allow us to better understand the value of this measure for future treatment trials in X-linked retinitis pigmentosa (XLRP). OBJECTIVES: To identify the width of the central region showing an EZ and to determine the short-term repeat variability and the annual rate of change in the width of the EZ from spectral-domain optical coherence tomography (SD-OCT) measures in RP. DESIGN: Patients with recessive or simplex RP (age range, 8-65 years; mean age, 40.5 years) underwent scanning twice on the same day to evaluate test-retest variability. Patients with XLRP (age range, 8-27 years; mean age, 15.2 years) from a larger group participating in an ongoing double-blind treatment trial (docosahexaenoic acid vs placebo; clinicaltrials.gov NCT00100230) underwent spectral-domain optical coherence tomography line scanning across the horizontal meridian at 3 yearly intervals. SETTING: Research center specializing in medical retina. PARTICIPANTS: Forty-eight patients with RP, including 20 with recessive or simplex RP and 28 with XLRP, and 23 healthy control subjects. MAIN OUTCOME AND MEASURE: Widths of the EZ calculated and compared among the 3 annual visits. RESULTS: Test-retest differences were normally distributed, and the magnitude of the difference was independent of mean EZ width. The mean (SD) for test-retest differences in EZ width was 0.08° (0.22°) (range, -0.30° to 0.60°). Thus, 95% of all test-retest differences fall within ± 0.43° (124 µm). Of the 28 patients with XLRP, 27 showed a significant decrease in EZ width after 2 years. Patients with XLRP showed a mean annual decrease in EZ width of 0.86° (248 µm, or 7%). CONCLUSIONS AND RELEVANCE: The mean rate of decline in EZ width (7%) translates into a mean rate of change of 13% for the equivalent area of functioning retina. This rate of change is consistent with that reported for visual fields and full-field electroretinograms. Unlike visual fields and electroretinograms, however, the repeat variability is less than the annual rate of change. These results support the validity of EZ width as an outcome measure in prospective clinical trials in RP.

Phenotypic characterization of 3 families with autosomal dominant retinitis pigmentosa due to mutations in KLHL7.

OBJECTIVE: To characterize the visual phenotype caused by mutations in the BTB-Kelch protein, KLHL7, responsible for the RP42 form of autosomal dominant retinitis pigmentosa (RP). METHODS: Comprehensive ophthalmic testing included visual acuity, static visual field, kinetic visual field, dark adaptometry, full-field electroretinography, spectral-domain optical coherence tomography, and fundus photography. Longitudinal visual function data (range, 15-27 years) were available for some of the affected individuals. RESULTS: We report a phenotypic assessment of 3 unrelated families, each harboring different KLHL7 mutations (c.458C>T, c.449G>A, and c.457G>A). The fundi showed classic signs of RP. Best-corrected visual acuity was 20/50 or better in at least one eye up to age 65 years. Static and kinetic visual fields showed concentric constriction to central 10° to 20° by age 65 years; 2 patients with Goldmann perimetry exhibited bilateral visual field retention in the far periphery. Both rod and cone full-field electroretinographic amplitudes were substantially lower than normal, with a decline rate of 3% per year in cone 31-Hz flicker response. Rod and cone activation and inactivation variables were abnormal. Spectral-domain optical coherence tomography indicated retention of foveal inner segment-outer segment junction through age 65 years. CONCLUSIONS: Mutations in KLHL7 are associated with a late-onset form of autosomal dominant retinal degeneration that preferentially affects the rod photoreceptors. Full-field electroretinographic findings, including recovery kinetics, are consistent with those observed in other forms of autosomal dominant RP. CLINICAL RELEVANCE: The phenotypes are similar among patients with 3 types of KLHL7 mutations (c.458C>T, c.449G>A, and c.457G>A). Strong retention of foveal function and bilateral concentric constriction of visual fields with far periphery sparing may guide mutation screening in autosomal dominant RP.

ApoER2 function in the establishment and maintenance of retinal synaptic connectivity.

The cellular and molecular mechanisms responsible for the development of inner retinal circuitry are poorly understood. Reelin and apolipoprotein E (apoE), ligands of apoE receptor 2 (ApoER2), are involved in retinal development and degeneration, respectively. Here we describe the function of ApoER2 in the developing and adult retina. ApoER2 expression was highest during postnatal inner retinal synaptic development and was considerably lower in the mature retina. Both during development and in the adult, ApoER2 was expressed by A-II amacrine cells. ApoER2 knock-out (KO) mice had rod bipolar morphogenic defects, altered A-II amacrine dendritic development, and impaired rod-driven retinal responses. The presence of an intact ApoER2 NPxY motif, necessary for binding Disabled-1 and transducing the Reelin signal, was also necessary for development of the rod bipolar pathway, while the alternatively spliced exon 19 was not. Mice deficient in another Reelin receptor, very low-density lipoprotein receptor (VLDLR), had normal rod bipolar morphology but altered A-II amacrine dendritic development. VLDLR KO mice also had reductions in oscillatory potentials and delayed synaptic response intervals. Interestingly, age-related reductions in rod and cone function were observed in both ApoER2 and VLDLR KOs. These results support a pivotal role for ApoER2 in the establishment and maintenance of normal retinal synaptic connectivity.

Rod photoreceptor temporal properties in retinitis pigmentosa.

One of the characteristic signs of retinitis pigmentosa (RP) is the progressive loss of night vision. We have previously shown that the gain of rod photoreceptor activation is moderately reduced in some patients with RP, but this decrease in activation kinetics is not sufficient to account for the night blindness. Recently, single rod recording from animal models of RP showed rods under degeneration remain saturated for shorter periods than normal rods; i.e. are less able to sustain the rod photoresponse. Using paired-flash ERG, here we determine whether rod phototransduction inactivation parameters might also be abnormal in patients with RP. Inactivation parameters were derived from 13 subjects with normal vision, 16 patients with adRP, and 16 patients with autosomal recessive/isolate (rec/iso) RP. The adRP cases included 9 patients with rhodopsin mutations and 7 patients with peripherin/RDS mutations. The inactivation phase was derived using a double-flash paradigm, with a test flash of 2.7 log scot td-s followed at varying intervals by a 4.2 log scot td-s probe flash. Derived rod photoresponses to this just-saturating test flash in normal subjects exhibit a critical time to the initiation of recovery (T(sat)) of 525 ± 90 (SD) ms. The values of T(sat) were 336 ± 104 (SD) ms in patients with adRP (P < 0.001) and 271 ± 45 (SD) ms (P < 0.001) in patients with rec/iso RP. When T(sat) values were categorized by mutations, the values were 294 ± 91 (SD) ms (P < 0.001) for rhodopsin mutations, and 389 ± 100 (SD) ms (p = 0.01) for peripherin/RDS mutations. Overall, T(sat) in patients with RP was significantly correlated with the amplitude of ISCEV standard rod response (r = 0.56; P < 0.001) and the gain of the activation phase of phototransduction (r = 0.6, P < 0.001). T(sat) may be a useful marker for therapeutic efficacy in future clinical trials in RP.

The transition zone between healthy and diseased retina in patients with retinitis pigmentosa.

PURPOSE: To describe the structural changes in the transition zone from relatively healthy retinal regions to severely affected regions in patients with retinitis pigmentosa (RP) using frequency domain optical coherence tomography (fdOCT). METHODS: FdOCT line scans of the horizontal meridian were obtained from one eye of 13 patients with RP and 30 control subjects. The patients had normal or near normal foveal sensitivities and visual field diameters ≥10°. Using a computer-aided manual segmentation procedure, the locations at which the outer segment (OS) and outer nuclear layer plus outer plexiform layer (ONL+) thicknesses fell below the 95% confidence interval of the controls were measured, as were the locations at which the OS layer disappeared and the locations at which the ONL+ was reduced to an asymptotically small thickness. RESULTS: The progression from healthy to severely affected regions followed a common pattern in most patients. Region A, the central region including the foveal center, had normal OS and ONL+ thickness. Region B had abnormal OS but normal ONL+ thickness. Region C had abnormal but measurable OS and ONL+ thicknesses. In Region D, the OS layer disappeared, as did the IS/OS line, and the ONL+ thickness decreased further. In Region E, the ONL+ reached an asymptotic thickness. CONCLUSIONS: The structural changes in the transition zone followed an orderly progression from a thinning of the OS layer, to a thinning of the ONL+, to a loss of the OS layer, to an ONL+ reduced to an asymptotically small level.

A comparison of visual field sensitivity to photoreceptor thickness in retinitis pigmentosa.

PURPOSE: To explore the relationship between visual field sensitivity and photoreceptor layer thickness in patients with retinitis pigmentosa (RP). METHODS: Static automated perimetry (central 30-2 threshold program with spot size III; Humphrey Field Analyzer; Carl Zeiss Meditec, Inc., Dublin, CA) and frequency domain optical coherence tomography (Fd-OCT) scans (Spectralis HRA+OCT; Heidelberg Engineering, Vista, CA) were obtained from 10 age-matched normal control subjects and 20 patients with RP who had retained good central vision (better than 20/32). The outer segment (OS+) thickness (the distance between retinal pigment epithelium [RPE])/Bruch's membrane [BM] to the photoreceptor inner-outer segment junction), outer nuclear layer (ONL), and total retinal thickness were measured at locations corresponding to visual field test loci up to 21 degrees eccentricity. RESULTS: The average OS+ thickness in the control eyes was 63.1 +/- 5.2 microm, varying from approximately 69 microm in the foveal center to 56 microm at 21 degrees eccentricity. In patients with RP, OS+ thickness was below normal limits outside the fovea, and thickness decreased with loss in local field sensitivity, reaching an asymptotic value of 21.5 microm at approximately -10 dB. The ONL thickness also decreased with local field sensitivity loss. Although relative OS thickness was linearly related to visual field loss at all locations examined, a slightly better correlation was found between the product of OS and ONL thickness and visual field loss. CONCLUSIONS: In patients with RP with good foveal sensitivity, the OS thickness and the product of OS thickness and ONL thickness (assumed to represent the number of photoreceptors) decreases linearly with loss of local field sensitivity. In general, in regions where perimetric sensitivity loss is -10 dB or worse, the OS+ thickness approaches the thickness of the RPE/BM complex.

Macular atrophy in birdshot retinochoroidopathy: an optical coherence tomography and multifocal electroretinography analysis.

PURPOSE: The purpose of this study was to evaluate macular atrophy by frequency-domain optical coherence tomography (OCT) in patients with birdshot retinochoroidopathy and to compare the resulting thickness measures with visual acuity and multifocal electroretinography (mfERG). METHODS: Measures were obtained from 14 eyes of 7 patients with birdshot retinochoroidopathy and 23 normal eyes. Optical coherence tomography-3 measures of macular thinning were related to visual acuity, mfERG response density, and time since diagnosis. Horizontal midline frequency-domain OCT scans identified which layers of the retina were primarily responsible for macular thinning. RESULTS: All eyes with a history of birdshot retinochoroidopathy for >10 years had abnormal mfERG response densities. Compared with those without anatomic thinning (n = 8), eyes with anatomic thinning (n = 6) had significantly lower visual acuity (P = 0.0006), foveal response density (P = 0.006), and overall mfERG response density (P = 0.009). Segmentation of retinal layers on frequency-domain OCT scans showed that anatomic thinning was as a result of reduction in the receptor 1 layer (REC+), the thickness of the segment extending from the proximal border of the outer plexiform layer to the Bruch membrane-choroid interface. CONCLUSION: Macular atrophy, as reflected in OCT evidence of macular thinning and mfERG evidence of macular function, occurs in patients with long-standing birdshot retinochoroidopathy. Measures of retinal layer thicknesses by frequency-domain OCT suggest that the atrophy occurs primarily in the outer retina.