Retinitis Pigmentosa Masquerades: Case Series and Review of the Literature.

Retinitis pigmentosa (RP) displays a broad range of phenotypic variations, often overlapping with acquired retinal diseases. Timely recognition and differentiation of RP masquerades is paramount due to the treatable nature of many such conditions. This review seeks to present examples of pseudo-RP cases and provide a comprehensive overview of RP masquerades. We first present two pseudo-RP cases, including comprehensive clinical histories and multimodal retinal imaging, to highlight the important role of accurate diagnoses that subsequently steered effective intervention. Subsequently, we conduct an in-depth review of RP masquerades to provide valuable insights into their key distinguishing features and management considerations. The recent approval of ocular gene therapy and the development of investigational gene-based treatments have brought genetic testing to the forefront for RP patients. However, it is important to note that genetic testing currently lacks utility as a screening tool for inherited retinal diseases (IRDs), including RP. The integrity of a precise clinical assessment remains indispensable for the diagnosis of both RP and RP masquerade conditions, thereby facilitating prompt intervention and appropriate management strategies.

Current Management Options for Patients with Retinitis Pigmentosa.

With an estimated prevalence of 1 in 4000 worldwide [1], retinitis pigmentosa (RP) comprises a spectrum of progressive inherited retinal disorders that can lead to blindness as early as age 30 [2]. Despite its relatively high prevalence and devastating consequences, RP does not have a definitive cure. Therapeutic attempts have been made with nutritional supplementation, but these strategies only have proven benefit in a limited number of patients with rare forms of RP. Thus, current standards of care involve regular follow-up, management of associated ocular pathology such as macular edema and cataracts, and genetic counseling and low vision rehabilitation. In recent years, gene therapy, visual prostheses, and stem cell therapy have emerged as FDA-approved treatments for RP, but these options are not yet widely used. Herein, this chapter will discuss the therapeutic strategies listed above that comprise the current standards of care and briefly discuss some emerging options.

Detecting Progression in Advanced Glaucoma: Are Optical Coherence Tomography Global Metrics Viable Measures?

SIGNIFICANCE: Optical coherence tomography (OCT) summary measures have been suggested as a way to detect progression in eyes with advanced glaucoma. Here, we show that these measures have serious flaws largely due to segmentation errors. However, inspection of the images and thickness maps can be clinically useful. PURPOSE: This study aimed to test the hypothesis that recently suggested global OCT measures for detecting progression in eyes with advanced progression are seriously affected by segmentation mistakes and other errors that limit their clinical utility. METHODS: Forty-five eyes of 38 patients with a 24-2 mean deviation worse than -12 dB had at least two spectral domain OCT sessions (0.8 to 4.4 years apart) with 3.5-mm circle scans of the disc and cube scans centered on the fovea. Average (global) circumpapillary retinal nerve fiber layer thickness, GcRNFL, and ganglion cell plus inner plexiform layer thickness, GGCLP, were obtained from the circle and cube scan, respectively. To evaluate progression, ΔGcRNFL was calculated for each eye as the GcRNFL value at time 2 minus the value at time 1, and ΔGGCLP was calculated in a similar manner. The b-scans of the six eyes with the highest and lowest ΔGcRNFL and ΔGGCLP values were examined for progression as well as segmentation, alignment, and centering errors. RESULTS: Progression was a major factor in only 7 of the 12 eyes with the most negative values of either ΔGcRNFL or ΔGGCLP, whereas segmentation played a role in 8 eyes and was the major factor in all 12 eyes with the largest positive values. In addition, alignment (one eye) and other (three eyes) errors played a secondary role in four of the six eyes with the most negative ΔGcRNFL values. CONCLUSIONS: For detecting the progression of advanced glaucoma, common summary metrics have serious flaws largely due to segmentation errors, which limit their utility in clinical and research settings.

An Evaluation of a New 24-2 Metric for Detecting Early Central Glaucomatous Damage.

PURPOSE: We sought to test the hypothesis that a recently proposed pattern standard deviation (PSD) metric, based upon the 24-2 visual field (VF) test, as well as the PSD of the 10-2 VF, will miss central glaucomatous damage confirmed with an objective structure-function method. DESIGN: Cross-sectional study. METHODS: A glaucoma (G) group (70 eyes/patients) diagnosed with glaucoma and a 24-2 mean deviation better than -6 dB and a healthy (H) group (45 eyes/patients) had 24-2 and 10-2 VFs and optical coherence tomography (OCT) scans twice within 4 weeks. The PSD(C24-2), based upon the central 12 points of the 24-2, was compared with the PSD(10-2). To evaluate central damage (CD) in G eyes with normal PSD(C24-2) values, a post hoc analysis was combined with a CD reference standard (CD-RS), which was based upon an objective, topographic comparison between abnormal points on the 10-2 VF and OCT probability maps. RESULTS: The 115 PSD(C24-2) and PSD(10-2) values were significantly correlated (Spearman correclation coefficient: rho = 0.55; P < .001) and the number of G eyes (19) identified as abnormal by the PSD(C24-2) was not significantly different from the number (22) identified by the PSD(10-2) (P = .15). However, based upon the CD-RS, 44 of 70 G eyes were classified as abnormal. The PSD(C24-2) missed 27 (61%) of these 44 eyes, and the PSD(10-2) missed 23 (52%) of these eyes. Post hoc analysis revealed clear CD in most of these eyes. CONCLUSION: Neither the PSD(C24-2) nor the PSD(10-2) metric is good measure of early CD. Instead we recommend a topographic approach based upon OCT probability maps and a 10-2 VF.

Local Glaucomatous Defects of the Circumpapillary Retinal Nerve Fiber Layer Show a Variety of Patterns of Progression.

PRECIS: The region of glaucomatous progression, seen on optical coherence tomography (OCT) images of the circumpapillary retinal nerve fiber layer (cRNFL), increases in width and depth in all eyes, but shows a variety of different patterns of loss across eyes. PURPOSE: The purpose of this study was to examine the patterns of cRNFL loss secondary to glaucomatous progression in a region associated with the superior hemifield of the 24-2/30-2 visual field (VF). METHODS: Twenty-four eyes (20 patients) with a diagnosis of glaucoma and evidence of progression on OCT had OCT disc cube scans on at least 3 separate visits (mean follow-up 7.4 y; range: 3.9 to 11.4). Circumpapillary b-scans were derived after enface images were aligned to assure that the study region (ie, 0 to -135 degrees, where 0 degree is 9 o'clock, on a right eye) coincided. Within this region, a region of progression (ROP) was defined based on the loss in cRNFL thickness between the first and subsequent visits. The width of the ROP was determined, along with the locations of its leading (close to fixation) and trailing edges. In addition, for each ROP, the location and depth at the point of maximal loss, total loss, and average remaining retinal nerve fiber layer were measured. RESULTS: The ROP proceeded both toward and away from fixation. Across eyes, the ROP varied widely in width (32 to 131 degrees, mean 82.7 degrees), location, and loss at point of deepest loss (22 to 99 µm, mean 52.9 µm), as well as total cRNFL loss. CONCLUSIONS: All eyes showed a widening and deepening of the ROP, but a variety of different patterns of progressive cRNFL loss. Thus, one should expect considerable variation in patterns of VF loss. Furthermore, conventional metrics (global or quadrant cRNFL thickness) do not fully depict the progressive changes that can be appreciated by inspecting OCT images.

Qualitative evaluation of neuroretinal rim and retinal nerve fibre layer on optical coherence tomography to detect glaucomatous damage.

PURPOSE: To understand the added value of Bruch's membrane opening-minimum rim width (BMO-MRW) measurements to conventional circumpapillary retinal nerve fibre layer (cpRNFL) thickness measurements on optical coherence tomography (OCT) imaging for discriminating between perimetric glaucoma and healthy eyes, evaluated through a qualitative evaluation. METHODS: 384 healthy eyes and 188 glaucoma eyes were evaluated, and glaucoma eyes were categorised as perimetric (n=107) based on a history of ≥3 consecutive abnormal 24-2 visual field tests or suspected glaucoma if they did not (n=81). OCT-derived BMO-MRW and cpRNFL reports were qualitatively evaluated by two experienced graders in isolation at first, and then by using both reports combined. The diagnostic performance (sensitivity at 95% specificity, total and partial area under the receiver operating characteristic curve) of detecting perimetric glaucoma with each method were compared. RESULTS: All diagnostic performance measures for detecting perimetric glaucoma eyes were not significantly different when using either the cpRNFL or BMO-MRW reports alone compared with using both reports combined (p≥0.190), nor when comparing the use of each report in isolation (p≥0.500). CONCLUSIONS: Experienced graders exhibited no difference in discriminating between perimetric glaucoma and healthy eyes when using a cpRNFL report alone, the BMO-MRW report alone or the two reports combined. Therefore, either OCT imaging report of the neuroretinal tissue could be used effectively for detecting perimetric glaucoma, but further studies are needed to determine whether there are specific advantages of each method, or the combination of both, when evaluating eyes that have a greater degree of diagnostic uncertainty.

Comparison of Widefield and Circumpapillary Circle Scans for Detecting Glaucomatous Neuroretinal Thinning on Optical Coherence Tomography.

PURPOSE: Our purpose was to compare the effectiveness of detecting progressive retinal nerve fiber layer (RNFL) thickness changes using widefield scans compared to circumpapillary circle scans derived from optic disc volume scans when using a manual region-of-interest (ROI) approach. METHODS: In a prospective observational study, a total of 125 eyes diagnosed clinically with glaucoma or suspected glaucoma that had both widefield (12 × 9 mm) and optic disc (6 × 6 mm) scans obtained at least one year apart were included. Changes in the RNFL thickness between the two visits were evaluated within region(s) of observed or suspected glaucomatous damage, which were manually outlined after reviewing key features from each scan on the second visit (described as a manual ROI approach). Within ROI(s), changes in the widefield and circumpapillary RNFL thickness (wfRNFLROI and cpRNFLROI), as well as in the global circumpapillary RNFL thickness (cpRNFLG), were determined. The performance of these three methods for detecting progressive changes was compared using longitudinal signal-to-noise ratios (SNRs), whereby the rate of change determined by each method was normalized by individualized estimates of measurement variability and age-related change. RESULTS: On average, the longitudinal SNRs for the wfRNFLROI, cpRNFLROI, and cpRNFLG methods were -0.57, -0.38, and -0.23 y-1, respectively, being significantly more negative for the wfRNFLROI than the latter two methods (P ≤ 0.009). CONCLUSIONS: Progressive RNFL thickness changes were more effectively detected on widefield optical coherence tomography (OCT) scans using a manual ROI approach compared to conventional derived circumpapillary circle scans. TRANSLATIONAL RELEVANCE: Widefield OCT scans show promise for improving the detection of glaucomatous progression.

Evaluation of a Qualitative Approach for Detecting Glaucomatous Progression Using Wide-Field Optical Coherence Tomography Scans.

PURPOSE: To determine the effectiveness of detecting glaucomatous progression by a qualitative evaluation of wide-field (12 × 9 mm) scans on optical coherence tomography imaging. This method was compared to a conventional quantitative analysis of the global circumpapillary retinal nerve fiber layer (cpRNFL) thickness. METHODS: A total of 409 eyes with a clinical diagnosis of glaucoma or suspected glaucoma for which two wide-field scans were obtained at least 1 year apart (n = 125) and within one session (n = 284) were included to determine the sensitivity of detecting progression at 95% specificity. Qualitative OCT evaluation was performed in a similar manner to flicker chronoscopy by superimposing the two scans, and the progression probability was graded. A quantitative event-based analysis of the global cpRNFL thickness also was performed. RESULTS: Thirty-three and 25 eyes were deemed to have progressed based on qualitative and quantitative approaches, respectively (P = 0.152). A post hoc review of cases where the two methods disagreed revealed that all eyes missed by the quantitative analysis had established glaucomatous damage that appeared to show characteristic patterns of progression. All eyes missed by the qualitative evaluation appeared to be free of such established damage, and instead showed a generalized reduction in cpRNFL thickness. CONCLUSIONS: Qualitative evaluation of OCT imaging information more frequently detected change consistent with known patterns of glaucomatous progression than global cpRNFL thickness, warranting further studies to evaluate its value. TRANSLATIONAL RELEVANCE: A framework for qualitatively evaluating progressive glaucomatous changes on OCT imaging clinically shows promise.

Evaluation of a Region-of-Interest Approach for Detecting Progressive Glaucomatous Macular Damage on Optical Coherence Tomography.

PURPOSE: To evaluate a manual region-of-interest (ROI) approach for detecting progressive macular ganglion cell complex (GCC) changes on optical coherence tomography (OCT) imaging. METHODS: One hundred forty-six eyes with a clinical diagnosis of glaucoma or suspected glaucoma with macular OCT scans obtained at least 1 year apart were evaluated. Changes in the GCC thickness were identified using a manual ROI approach (ROIM), whereby region(s) of observed or suspected glaucomatous damage were manually identified when using key features from the macular OCT scan on the second visit. Progression was also evaluated using the global GCC thickness and an automatic ROI approach (ROIA), where contiguous region(s) that fell below the 1% lower normative limit and exceeded 288 µm2 in size were evaluated. Longitudinal signal-to-noise ratios (SNRs) were calculated for progressive changes detected by each of these methods using individualized estimates of test-retest variability and age-related changes, obtained from 303 glaucoma and 394 healthy eyes, respectively. RESULTS: On average, the longitudinal SNR for the global thickness, ROIA and ROIM methods were -0.90 y-1, -0.91 y-1, and -1.03 y-1, respectively, and was significantly more negative for the ROIM compared with the global thickness (P = 0.003) and ROIA methods (P = 0.021). CONCLUSIONS: Progressive glaucomatous macular GCC changes were optimally detected with a manual ROI approach. TRANSLATIONAL RELEVANCE: These findings suggests that an approach based on a qualitative evaluation of OCT imaging information and consideration of known patterns of damage can improve the detection of progressive glaucomatous macular damage.

Detecting Glaucomatous Progression With a Region-of-Interest Approach on Optical Coherence Tomography: A Signal-to-Noise Evaluation.

PURPOSE: To compare two region-of-interest (ROI) approaches and a global thickness approach for capturing progressive circumpapillary retinal nerve fiber layer (cpRNFL) changes on optical coherence tomography (OCT) imaging. METHODS: Progressive cpRNFL thickness changes were evaluated in 164 eyes with a clinical diagnosis of glaucoma or suspected glaucoma; all eyes underwent optic disc OCT imaging on two visits at least 1 year apart. Such changes were evaluated with a manual ROI approach (ROIM), which involved manual identification of region(s) of observed or suspected glaucomatous damage. The ROIM was compared with an automatic ROI approach (ROIA), where regions were automatically identified if the cpRNFL thickness fell below the 1% lower normative limits, and to global cpRNFL thickness. These methods were compared using longitudinal signal-to-noise ratios (SNRs), calculated based upon individualized estimates of measurement variability and age-related changes for each ROI, obtained from 321 glaucoma eyes and 394 healthy eyes, respectively. RESULTS: The average longitudinal SNR of the ROIM, ROIA and global thickness methods were -0.46, -0.39, and -0.30 y-1, respectively. The average longitudinal SNR for the ROIM was significantly more negative compared with both the ROIA and global thickness methods (P = 0.005 for both). CONCLUSIONS: A manual ROI approach was the optimal method for detecting progressive cpRNFL loss compared with an automatic ROI approach and the global cpRNFL thickness measure. TRANSLATIONAL RELEVANCE: These findings highlight the potential advantages conferred by a careful qualitative evaluation of OCT imaging for detecting glaucoma progression.

24-2 Visual Fields Miss Central Defects Shown on 10-2 Tests in Glaucoma Suspects, Ocular Hypertensives, and Early Glaucoma.

PURPOSE: To investigate the prevalence of visual field defects in glaucomatous eyes, glaucoma suspects, and ocular hypertensives with 24-2 and 10-2 visual fields. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Patients with or suspected glaucoma tested with 24-2 and 10-2. Patients were classified into 3 groups on the basis of the presence of glaucomatous optic neuropathy (GON) and 24-2 visual field abnormalities: early glaucoma (GON and abnormal visual field, mean deviation >-6 decibels [dB]), glaucoma suspects (GON and normal visual field), and ocular hypertensives (normal disc, normal visual field, and intraocular pressure >22 mmHg). For the classification of visual field abnormalities, 24-2 and 10-2 tests performed on the same visit were analyzed. MAIN OUTCOME MEASURES: Comparison of the prevalence of abnormal 24-2 versus 10-2 visual field results based on cluster criteria in each diagnostic group. RESULTS: A total of 775 eyes (497 patients) were evaluated. A total of 364 eyes had early glaucoma, 303 eyes were glaucoma suspects, and 108 eyes were ocular hypertensives. In the glaucoma group, 16 of the 26 eyes (61.5%) classified as normal based on cluster criteria on 24-2 tests were classified as abnormal on 10-2 visual fields. In eyes with suspected glaucoma, 79 of the 200 eyes (39.5%) classified as normal on the 24-2 test were classified as abnormal on 10-2 visual fields. In ocular hypertensive eyes, 28 of the 79 eyes (35.4%) classified as normal on the 24-2 were classified as abnormal on the 10-2. Patients of African descent were more likely to have an abnormal 10-2 result (67.3 vs. 56.8%, P = 0.009). CONCLUSIONS: Central visual field damage seen on the 10-2 test is often missed with the 24-2 strategy in all groups. This finding has implications for the diagnosis of glaucoma and classification of severity.

Optical Coherence Tomography and Glaucoma Progression: A Comparison of a Region of Interest Approach to Average Retinal Nerve Fiber Layer Thickness.

PURPOSE: To determine whether the change in the retinal nerve fiber layer (RNFL) thickness in a region of interest (ROI) is a better measure of glaucoma progression than the change in average circumpapillary (cp) RNFL thickness. METHODS: Disc cube scans were obtained with frequency domain optical coherence tomography from 60 eyes of 60 patients (age, 61.7±12.7 y) with early or suspected glaucoma and controlled intraocular pressure. The average time between 2 test dates was 3.2±1.8 years. En-face images of the scans from the 2 tests were aligned based on the blood vessels, and cp images were derived for an annulus 100 µm wide and 3.4 mm in diameter, centered on the disc. An ROI was defined as the portion of the circumpapillary retinal nerve fiber layer (cpRNFL) plot within the temporal disc that extended below the 1% confidence interval for ≥5 degrees. Trend analysis using multilevel mixed-effects models was used to compare the rates of change between ROI width and average cpRNFL thickness. RESULTS: In total, 26 of the 60 eyes had a total of 33 ROIs. The ROI width significantly increased between the 2 test dates (median, 4.9 degrees; Q1=1.03 degrees, Q3=10.5 degrees). In comparison, the average cpRNFL thickness did not decrease significantly over the same period (median, -0.7 µm; Q1=-2.7 µm, Q3=2.7 µm). Mixed-effects linear models confirmed significant ROI progression (P=0.015), but not average cpRNFL (P=0.878). CONCLUSIONS: In this population, RNFL thinning in a ROI is a better measure of progression than is average cpRNFL thickness change.