Structural and Functional Changes in Non-Paraneoplastic Autoimmune Retinopathy.

BACKGROUND: To describe longitudinal changes in patients with non-paraneoplastic autoimmune retinopathy (npAIR) by utilizing different diagnostic modalities/tests. METHODS: The index study is a retrospective longitudinal review of sixteen eyes of eight patients from a tertiary care eye hospital diagnosed with npAIR. Multiple diagnostic modalities such as wide-angle fundus photography (WAFP), WA fundus autofluorescence (WAFAF), spectral-domain optical coherence tomography (SD-OCT), Goldmann visual field (GVF) perimetry, microperimetry (MP), electrophysiologic testing, and adaptive optics scanning laser ophthalmoscopy (AOSLO) were reviewed and analyzed. RESULTS: At the baseline visits, anomalies were detected by multimodal diagnostic tests on all patients. Subjects were followed up for a median duration of 11.5 [3.0-18.7] months. Structural changes at the baseline were detected in 14 of 16 (87.5%) eyes on WAFP and WAFAF and 13 of 16 (81.2%) eyes on SD-OCT. Eight of the ten (80%) eyes that underwent AOSLO imaging depicted structural changes. Functional changes were detected in 14 of 16 (87.5%) eyes on GVF, 15 of 16 (93.7%) eyes on MP, and 11 of 16 (68.7%) eyes on full-field electroretinogram (ff-ERG). Multifocal electroretinogram (mf-ERG) and visual evoked potential (VEP) tests were performed in 14 eyes, of which 12 (85.7%) and 14 (100%) of the eyes demonstrated functional abnormalities, respectively, at baseline. Compared to all the other structural diagnostic tools, AOSLO had a better ability to demonstrate deterioration in retinal microstructures occurring at follow-ups. Functional deterioration at follow-up was detected on GVF in 8 of 10 (80%) eyes, mf-ERG in 4 of 8 (50%) eyes, and MP in 7 of 16 (43.7%) eyes. The ff-ERG and VEP were stable in the majority of cases at follow-up. CONCLUSIONS: The utilization of multimodal imaging/tests in the diagnosing and monitoring of npAIR patients can aid in identifying anomalous changes over time. Analysis of both the anatomical and functional aspects by these devices can be supportive of detecting the changes early in such patients. AOSLO shows promise as it enables the capture of high-resolution images demonstrating quantifiable changes to retinal microstructure.

Detection of visual field defects using Eye Movement Pediatric Perimetry in children with intracranial lesions: feasibility and applicability.

The study aimed at evaluating the feasibility of Eye Movement Pediatric Perimetry (EMPP) among children in detecting Visual Field Defects (VFDs) associated with Intracranial Lesions (IL). Healthy controls (n = 35) and patients diagnosed with IL (n = 19) underwent a comprehensive clinical evaluation followed by a Goldmann Visual Field (GVF) and a customised EMPP protocol. During EMPP, all the participants were encouraged to fixate on a central target and initiate Saccadic Eye Movement (SEM) responses towards randomly appearing peripheral stimuli. The SEM responses were recorded using an eye-tracking device and further inspected to calculate Performance Scores (PS), Saccadic Reaction Times (SRTs), and an EMPP Index (EMPI). The mean age (years) of the controls and cases were 7.3 (SD: 1.5) and 9.4 (SD: 2.4) respectively. Among the controls, the older children (≥7 years) showed statistically significantly faster SRTs (p = 0.008) compared to the younger group. The binocular EMPP measurements compared between the controls and the cases revealed no statistically significant differences in PS (p = 0.34) and SRT (p = 0.51). EMPP failed in 4 children because of data loss or unacceptably poor PS whereas GVF failed in 7 children due to unreliable subjective responses. Of the 16 reports, with regard to the central 30-degree VF, 63% of the outputs obtained from both methods were comparable. EMPP is a reliable method to estimate and characterise the central 30-degree VF in greater detail in children with IL. EMPP can supplement the conventional methods, especially in those children who fail to complete a long duration GVF test.

Cancer-Associated Retinopathy due to Clear Cell Renal Carcinoma.

An 84-year-old female presented with bilateral scotomas and progressive nyctalopia over 1 year. Best-corrected visual acuity was 20/50 in both eyes with reduced color vision. Goldmann visual field showed bilateral cecocentral scotomas and generalized constriction of the visual fields. This led to an electroretinogram showing an electronegative pattern consistent with autoimmune retinopathies. Infectious workup was negative. Anti-retinal antibodies were positive, leading to a presumed diagnosis of cancer-associated retinopathy (CAR). Imaging showed a previously unknown left renal lower pole mass, and she underwent a radical nephrectomy. Biopsy showed nuclear grade-3 clear cell renal carcinoma staged T1. The patient was treated with oral prednisone with no ocular improvement. We report on a rare case of clear cell renal carcinoma causing CAR. CAR is an important paraneoplastic syndrome to diagnose since the majority of ocular cases precede other manifestations of malignancy. Therefore, a timely diagnosis of CAR can be lifesaving or at least life-extending.

Clinical trial design for neuroprotection in RHO autosomal dominant retinitis pigmentosa; outcome measure considerations.

Purpose: To identify structural and functional outcome measures among patients with Rho-positive autosomal dominant Retinitis Pigmentosa (adRP) to aid neuroprotection trial design.Methods: This was a retrospective cohort study of 52 patients with Rho-positive adRP. We measured Goldmann Visual Fields (GVF) constriction in four sectors (nasal, temporal, inferior, superior), and sectoral Ellipsoid Zone (EZ) width degeneration using Spectral Domain Optical Coherence Tomography (OCT) scans. Disease progression trajectories were projected using mixed effects modeling.Results: Superior GVF was most constricted at presentation and had the shallowest trajectory (less steep negative slope); Inferior GVF was less constricted (corrected p < .001) and had a steeper negative slope (corrected p = .019) than superior GVF. Temporal EZ was most stable on OCT with a relatively shallow negative trajectory (corrected p = .011).Conclusions: Patients' superior visual fields presented with more constriction and subsequently had a shallow negative slope suggesting the corresponding inferior retina may be "burned out" at presentation. Targeted therapies for adRP will likely show a greater efficacy signal if delivered to the superior and nasal retina, which may demonstrate more change on OCT and GVF over the course of a neuroprotection trial.Translational Relevance: Mixed effects analysis of sectoral visual field constriction and EZ degeneration in Rho-positive adRP can prove useful in monitoring therapeutic efficacy and identifying targets for local therapies.

Retinitis Punctata Albescens and RLBP1-Allied Phenotypes: Phenotype-Genotype Correlation and Natural History in the Aim of Gene Therapy.

Purpose: To identify relevant criteria for gene therapy based on clinical and genetic characteristics of rod-cone dystrophy associated with RLBP1 pathogenic variants in a large cohort comprising children and adults. Design: Retrospective cohort study. Participants: Patients with pathogenic variants in RLBP1 registered in a single French reference center specialized in inherited retinal dystrophies. Methods: Clinical, multimodal imaging, and genetic findings were reviewed. Main Outcome Measures: Age of onset; visual acuity; ellipsoid line length; nasal, temporal, and foveal retinal thickness; and pathogenic variants and related phenotypes, including Newfoundland rod-cone and Bothnia dystrophies (NFRCDs), were reappraised. Results: Twenty-one patients (15 families) were included. The most frequent form was NFRCD with 12 patients (8 families) homozygous for the recurrent deletion of exons 7 through 9 in RLBP1 and 5 patients (4 families) with biallelic protein-truncating variants (2 novel: p.Gln16∗ and p.Tyr251∗). A novel combination of the p.Arg234Trp Bothnia variant with a nonsense variant in trans led to Bothnia dystrophy in 2 sisters. One proband carrying the p.Met266Lys Bothnia variant and in trans p.Arg121Trp and a second, with the p.Arg9Cys and p.Tyr111∗ combination, both demonstrated mild retinitis punctata albescens. Independently of genotype, all patients showed a visual acuity of worse than 20/200, an ellipsoid line width of less than 1000 µm, and a mean foveal thickness of less than 130 to 150 µm, with loss of both the interdigitation and ellipsoid lines. Conclusions: The eligibility for RLBP1 gene therapy first should be determined according to the biallelic variant combination using a robust classification as proposed herein. An ellipsoid line width of more than 1200 µm and a central thickness of more than 130 to 150 µm with detectable ellipsoid and interdigitation lines should be 2 prerequisite imaging indicators for gene therapy.

Mild form of Zellweger Spectrum Disorders (ZSD) due to variants in PEX1: Detailed clinical investigation in a 9-years-old female.

Peroxisomal biogenesis disorders (PBD) are rare autosomal recessive disorders with various degrees of severity caused by hypomorphic mutations in 13 different peroxin (PEX) genes. In this study, we report the clinical and molecular characterization of a 9-years-old female presenting an apparently isolated pre-lingual sensorineural hearing loss (SNHL) and early onset Retinitis Pigmentosa (RP) that may clinically overlap with Usher syndrome. Genetic testing by clinical exome sequencing identified two variants in PEX1: the missense variant c.274G > C; p.(Val92Leu) that was already reported in a PBD patient, and the variant c.2140_2145dup; p.(Ser714_Gln715dup) which is a novel, non-frameshift variant, absent in control databases. On the basis of the molecular analysis, a thorough clinical examination revealed nail and dental abnormalities, a mild cognitive impairment, learning disabilities and poor feeding, apart from the retinal and audiological features initially identified. The clinical and molecular findings led us to the diagnosis of a mild form of PBD. This study further emphasizes that mild forms of PBD can be a differential diagnosis of Usher syndrome and suggests that patients with mild cognitive impairment associated to visual and hearing loss should perform a comprehensive mutation screening that includes PEX genes.

Longevity of visual improvements following transcorneal electrical stimulation and efficacy of retreatment in three individuals with retinitis pigmentosa.

PURPOSE: A small-scale randomized controlled trial conducted by our group found that four of seven retinitis pigmentosa (RP) subjects who received six weekly Transcorneal Electrical Stimulation (TES) sessions developed significant improvements in visual acuity (VA), quick contrast sensitivity function (qCSF), and/or Goldmann visual fields (GVF). We longitudinally monitored three of these participants for declining visual function due to natural RP progression to determine the duration of their responses and administered retreatments. METHODS: Over a period of 29-35 months, repeated ETDRS VA, qCSF and/or GVF tests and three to six TES treatment courses consisting of six weekly sessions were administered in each eye of three RP participants every four to 16 months in an unmasked, prospective case series study. RESULTS: For two participants, there were significant VA improvements of 44-52 letters (0.88-1.04 logMAR) and 15-23 letters (0.3-0.46 logMAR) in the worse eye at baseline after each of three or four treatment courses of TES compared to initial baseline. They had no significant decreases from baseline for VA or qCSF over 29 to 35 months, The third participant had a significant mean improvement in VA in the eye with better baseline vision (p = 0.004) and binocularly (p < 0.001) following six treatment courses over the 29-month period. For the first two participants, mean annual rates of GVF change for each eye ranged from -5% to 0% with the V4e stimulus, and -26% to +33% the III4e stimulus. The third participant's mean annual GVF changes were +14 to +35%, with a statistically significant improvement across 29 months for both the V4e and III4e stimuli in the right eye (p = 0.045; p = 0.015) and the V4e stimulus in the left eye (p = 0.047). CONCLUSION: Following encouraging visual improvements after TES that lasted for several months, it appears it may be possible to restore and prevent slowly diminishing vision over time with retreatments, which requires confirmation in a large-scale randomized controlled trial.

Recording and Analysis of Goldmann Kinetic Visual Fields.

Goldmann kinetic perimetry is a commonly used method of evaluating the peripheral visual field. Ongoing gene therapy trials have targeted the central retina, but have nonetheless often included Goldmann kinetic perimetry as part of extensive preinterventional and postinterventional assessment. Future gene therapy trials may target the entire retina through intravitreal injections, as have drug therapeutic trials, further necessitating the evaluation of function across the entire retina. In the following pages, we will briefly review the necessary steps to perform and quantify the visual field, using the conventional Goldmann perimeter and the Field Digitizer software (version 4.20; Johns Hopkins Technology Ventures, Baltimore, USA), respectively.

Reliability of kinetic visual field testing in children with mutation-proven retinal dystrophies: Implications for therapeutic clinical trials.

PURPOSE: Kinetic visual field testing is used to monitor disease course in retinal dystrophy clinical care and treatment response in treatment trials, which are increasingly recruiting children. This study investigates Goldmann visual field (GVF) changes in young children with mutation-proven retinal dystrophies as they age and with progression of the retinal degeneration. METHODS: Retrospective review of children ≤ 17 years old with a mutation-proven retinal dystrophy. Objective clinical disease activity was assessed by a retinal degeneration specialist masked to GVF results. Digital quantification of GVF area was performed. RESULTS: Twenty-nine children (58 eyes), ages 5-16, were identified. GVF area increased with age despite progression in 20 children and clinical stability in nine children. Mean ± standard error increase in GVF area/year was 333 ± 130 mm2 (I4e, p = 0.012), 720 ± 155 mm2 (III4e, p < 0.001), and 759 ± 167 mm2 (IV4e, p < 0.001), with greater increases at earlier ages. Repeatability coefficients were 7381 mm2 (I4e), 9379 mm2 (III4e), and 10346 mm2 (IV4e), indicating a large variability. At 2.5 years after the baseline GVF the area increased ≥ 20%, the criterion for positive treatment outcome defined in recent published therapeutic trials, in 38% (I4e), 34% (III4e), and 33% (IV4e) of eyes. CONCLUSION: In a substantial proportion of children with mutation-proven retinal dystrophies, there is a significant increase in GVF area with age, particularly those < 12 years, despite progression or stability of disease. These findings suggest that change in GVF area in children with retinal dystrophies can be an unreliable measure of response to treatment and on which to base appropriate counseling about visual impairment.

Spatial agreement between Goldmann visual field defects and fundus autofluorescence in patients with birdshot chorioretinopathy.

BACKGROUND: The purpose of this paper is to study the spatial agreement between visual field defects and ultra-wide field (UWF) fundus autofluorescence (FAF) in patients with birdshot chorioretinopathy (BSCR). The study is a retrospective, cross-sectional analysis of a university uveitis practice. Eight (8) eyes of five (5) patients with BSCR were included. Inclusion criteria were ability to fixate reliably. Goldmann visual fields (GVF) and UWF FAF were obtained, digitalized, and standardized. Analysis was performed by measuring areas of overlap of hypo-autofluorescent FAF lesions and GVF scotomas within the central 60°. Overlap was calculated as a percentage of the total area of FAF and GVF, respectively. Average areas were also calculated. RESULTS: The mean age of the subjects was 51 ± 12.28 years (range 38-69 years). 14 ± 23 % of the total lesion area identified as hypo-autofluorescent on FAF overlapped with scotoma. 28 ± 41 % of the GVF scotomas overlapped with hypo-autofluorescent FAF lesions. Average area of FAF hypo-autofluorescence was much larger (15.19 disc areas) than GVF (3.45 disc areas). CONCLUSIONS: There appear to be larger total areas of hypo-autofluorescence on FAF than scotoma evidenced by GVF and only a small amount of overlap. The finding suggests that GVF is relatively insensitive to anatomic loss, which can be detected using FAF. Further studies are required to assess whether this finding holds true for automated white-on-white perimetry. In addition, more selective psychophysical stimuli may have higher sensitivity in detecting early functional loss that accompanies anatomic damage.