Linear streaks associated with retinitis pigmentosa.

PURPOSE: To describe a phenotypical manifestation characterized by the identification of peripheral linear streaks associated with retinitis pigmentosa (RP). METHODS: Study design is a prospective observational case series. All consecutive patients affected by RP underwent a complete ophthalmological examination. The diagnosis of peripheral linear streaks was based on the identification of curvilinear atrophic streaks in the periphery of the retina. RESULTS: Overall, six out of 140 patients (4.2%) were affected by peripheral linear streaks associated with RP. A single patient showed also punched out chorioretinal lesions at the posterior pole, with macular neovascularization development over the follow-up, treated with ranibizumab injections. CONCLUSIONS: RP phenotypical manifestation characterized by peripheral linear streaks is infrequent and may provide additional evidence to support the contribution of inflammation in the pathogenesis of RP.

Inner retinal thickness in Stargardt disease.

PURPOSE: To analyze the alterations at the level of the inner retina in patients affected by Stargardt disease (STGD1). METHODS: Cross-sectional investigation involving STGD1 patients with genetically confirmed diagnosis, who underwent optical coherence tomography (OCT), optical coherence tomography angiography (OCTA), and microperimetry. RESULTS: Overall, 31 patients (62 eyes) with genetically confirmed STGD1 were included in the study. Mean inner retinal thickness, vessel density of plexa, and retinal sensitivity resulted significantly reduced in STGD patients, compared with healthy controls (p < 0.05), both in the outer and in the inner ETDRS rings. Overall, 43% of eyes revealed an inner retinal thinning, whereas 21% and 35% showed a thicker or within normal range inner retina. CONCLUSIONS: Inner retina is irregularly altered in STGD1, showing variable quantitative alterations as detected on OCT. Inner retinal status might represent a useful biomarker to better characterize STGD1 and to ascertain the effects of new treatment approaches.

The Retinal Phenotype Associated with the p.Pro101Thr BEST1 Variant.

PURPOSE: To describe the retinal phenotype associated with the p.Pro101Thr BEST1 variant. DESIGN: Retrospective, observational case series. PARTICIPANTS: Patients diagnosed with bestrophinopathies in which molecular genetic testing identified the p.Pro101Thr BEST1 as well as healthy carriers among their first-degree relatives. METHODS: Medical records were reviewed to obtain data on family history and ophthalmic examinations, including retinal imaging. The imaging protocol included OCT and fundus autofluorescence using Spectralis HRA + OCT (Heidelberg Engineering). Genetic analysis was performed by next-generation sequencing. MAIN OUTCOME MEASURES: Results of ophthalmic examinations and multimodal imaging features of retinal phenotypes. RESULTS: The c.301C>A, p.Pro101Thr BEST1 missense variant was identified as the causative variant in 8 individuals (all men) from 5 families, accounting for 13% of cases (8/61) and 10% of pathogenic alleles (9/93) in our cohort of patients affected by bestrophinopathies. Seven individuals (14 eyes) had the variant in heterozygous status: all eyes had a hyperopic refractive error (median spherical equivalent of + 3.75 diopters [D]) and 4 individuals had a macular dystrophy with mildly reduced visual acuity (median of 20/25 Snellen), whereas the other 3 were asymptomatic carriers. On multimodal retinal imaging, 5 (36%) out of 14 eyes had subclinical bestrophinopathy, 4 (29%) had typical findings of adult-onset foveomacular vitelliform dystrophy (AOFVD), and the remaining 5 (36%) displayed a pattern dystrophy-like phenotype. Follow-up data were available for 6 subjects, demonstrating clinical stability up to 11 years, in both subclinical and clinical forms. An additional patient with autosomal recessive bestrophinopathy was found to harbor the p.Pro101Thr variant in homozygosity. CONCLUSIONS: The p.Pro101Thr BEST1 variant is likely a frequent cause of bestrophinopathy in the Italian population and can result in autosomal dominant macular dystrophies with incomplete penetrance and mild clinical manifestations as well as autosomal recessive bestrophinopathy. The spectrum of autosomal dominant maculopathy includes the typical AOFVD and a pattern dystrophy-like phenotype. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Association of Circulating Antiretinal Antibodies With Clinical Outcomes in Retinitis Pigmentosa.

Purpose: To determine if circulating antiretinal antibodies (ARAs) differ between patients affected by retinitis pigmentosa (RP) and control participants and to assess whether ARAs are associated with clinical outcomes in patients with RP. Methods: Cross-sectional study involving a group of patients clinically diagnosed with RP and a control group of healthy participants. Serum autoantibodies against enolase, heat shock protein 70 (HSP70), and carbonic anhydrase II (CAII) were tested in all participants using Jess capillary Western blot. We compared ARA prevalence between the RP and control groups and investigated the association of serum ARA positivity with macular edema and vitreomacular disorders in patients affected by RP. Results: Thirty-six patients affected by RP and a control group of 39 healthy individuals were included. Overall, at least one ARA positivity was detected in 89% and 80% of participants in the RP and control groups, respectively. We observed a similar prevalence of anti-CAII and anti-enolase ARA between patients and controls (P = 0.87 and P = 0.35, respectively). Sera from patients with RP tested positive for anti-HSP70 ARAs more frequently than those from controls (53% vs. 36%), albeit without reaching statistical significance (P = 0.29). Among the 72 eyes with RP, 25% presented with macular edema (most often bilateral) and 33% with epiretinal membrane and/or lamellar macular hole. None of the three ARAs was associated with an increased risk of any macular complications in eyes affected by RP (all P > 0.05). Conclusions: The prevalence of circulating ARAs against enolase, HSP70, and CAII is similar between patients affected by RP and healthy individuals. Our results provide evidence against the association of ARAs with macular edema and vitreomacular interface disorders in RP.

Fixation Location and Stability in Best Vitelliform Macular Dystrophy.

Purpose: To analyze fixation location and stability in best vitelliform macular dystrophy (BVMD) and test their association with best-corrected visual acuity (BCVA). Design: Observational, cross-sectional study. Participants: Thirty patients (55 eyes) affected by genetically confirmed BVMD were followed up at the Retinal Heredodystrophies Unit of IRCCS San Raffaele Scientific Institute, Milan. Methods: Patients underwent testing with macular integrity assessment (MAIA) microperimeter. Fixation location was measured as distance in degrees (°) between preferred retinal locus (PRL) and estimated fovea location (EFL); fixation was defined as eccentric when the distance between PRL and EFL exceeded 2°. Fixation stability was graded as stable, relatively unstable, or unstable and expressed as bivariate contour ellipse area (BCEA, °2). Main Outcome Measures: Fixation location and stability. Results: The median distance of the PRL from the anatomic fovea was 0.7°, and fixation location was eccentric in 27% of eyes. Fixation was graded as stable in 64% of eyes, relatively unstable in 13%, and unstable in 24%, with a median 95% BCEA of 6.2°2. The atrophic/fibrotic stage was associated with worse fixation parameters (all P < 0.01). Both PRL eccentricity and fixation stability were linearly associated with BCVA: every 1° increase in PRL eccentricity was associated with a 0.07 logarithm of the minimum angle of resolution (logMAR) worse BCVA (P < 0.0001) while every 1°2 increase in 95% BCEA was associated with a 0.01 logMAR worse BCVA (P < 0.001). No significant intereye correlation was found for PRL eccentricity and fixation stability, as well as no association between the patient's age and fixation parameters. Conclusions: We demonstrated that most eyes affected by BVMD retain a central stable fixation and provided evidence that both fixation eccentricity and stability are strongly associated with visual acuity in BVMD. These parameters may serve as secondary end points for future clinical trials. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Characterizing macular edema in retinitis pigmentosa through a combined structural and microvascular optical coherence tomography investigation.

The aim of the study was to characterize macular edema (ME) in retinitis pigmentosa (RP) by means of quantitative optical coherence tomography (OCT)-based imaging. The study was designed as observational, prospective case series, with 1-year follow-up. All RP patients underwent complete ophthalmologic assessment, including structural OCT, OCT angiography, and microperimetry (MP). The primary outcome was the characterization through quantitative OCT-based imaging of RP eyes complicated by ME. A total of 68 RP patients' eyes (68 patients) and 68 eyes of 68 healthy controls were recruited. Mean BCVA was 0.14 ± 0.17 LogMAR at baseline and 0.18 ± 0.23 LogMAR at 1-year follow-up (p > 0.05). Thirty-four eyes (17 patients; 25%) showed ME, with a mean ME duration of 8 ± 2 months. Most of the eyes were characterized by recurrent ME. The ME was mainly localized in the inner nuclear layer in all eyes. LogMAR BCVA was similar in all RP eyes, whether with or without ME, although those with ME were associated with higher vessel density values, as well as thicker choroidal layers, than those without ME. In conclusion, the inner retina is closely involved in the pathogenesis of ME. The impairment of retinal-choroidal exchanges and Müller cell disruption might be a major pathogenic factor leading to the onset of ME in RP.

Outer retinal and choriocapillaris modifications in choroideremia: three differentially impaired retinal regions and the potential diagnostic role of the external limiting membrane.

BACKGROUND: The external limiting membrane (ELM) is formed by the apical processes of Müller cells attached to the inner segments of the photoreceptor cells. Both cells are implicated in the pathogenesis of choroideremia (CHM). The purpose of this study was to explore the diagnostic role of ELM in CHM. METHODS: The study was designed as observational case series. Sixteen CHM eyes were examined by multimodal imaging and were compared to healthy controls. The main outcome was the measurement of ELM thickness and reflectivity over the follow-up, and its relationship with other multimodal imaging quantitative parameters. RESULTS: Baseline ELM was characterized by 11 ± 1 µm of thickness and 0.68 ± 0.13 of reflectivity, resulting 8 ± 1 µm (p < 0.01) and 0.65 ± 0.14 (p > 0.05) at the last follow-up. Choriocapillaris (CC) analysis revealed 3 regions. The first was characterized by normal vessel density (VD). The second surrounding the partially preserved islet, showing significantly lower baseline VD and undergoing minor changes over the follow-up. The third was localized in the partially preserved islet, showing significantly lower VD at baseline, and resulted atrophic at the last follow-up. ELM reflectivity and ELM thickness correlated both with outer retinal atrophy progression and the CC status. CONCLUSIONS: ELM may be considered a useful imaging biomarker in CHM. Its assessment confirmed a primary role of Müller cells impairment in the pathogenesis of CHM.

Morphological and functional involvement of the inner retina in retinitis pigmentosa.

BACKGROUND: To investigate the morphological retinal parameters associated with retinal sensitivity status in retinitis pigmentosa (RP) through a quantitative multimodal imaging approach. METHODS: The study was designed as an observational, prospective case series, including RP patients and healthy controls. Multimodal imaging included fundus autofluorescence (FAF), structural optical coherence tomography (OCT), OCT angiography (OCTA) and microperimetry (MP). The follow-up lasted 12 months. For each imaging modality, we performed an overall quantitative analysis and a detailed investigation based on the ETDRS-9 sectors grid. Quantitative parameters included the thickness of each retinal and choroidal layer, vessel density (VD), choriocapillaris porosity (CCP), FAF intensity and MP retinal sensitivity. RESULTS: We included 40 eyes (40 patients) affected by RP and 40 healthy eyes (40 controls). Mean baseline BCVA was 0.14 ± 0.18 LogMAR, with 0.18 ± 0.24 LogMAR after 1-year of follow-up. RP eyes showed statistically significant alterations of retinal and choroidal layers on the ETDRS-9 sectors grid, significant reduction of VD values and MP retinal sensitivity, and significantly higher CCP than controls. The inner retinal layers proved closely associated with the functional integrity of the posterior pole. In addition, our ROC analysis provided quantitative cutoffs connected significantly with a high probability of observing a partial sparing of MP retinal sensitivity. CONCLUSIONS: The inner retinal layers are closely associated with the functional integrity of the posterior pole in RP. FAF intensity reduction may be interpreted as lipofuscin metabolism impairment inducing increased phototoxic distress for retinal structures. Vascular involvement contributes to the morpho-functional deterioration of the macular region in RP.

Clinical Correlation Between Optical Coherence Tomography Biomarkers and Retinal Sensitivity in Best Vitelliform Macular Dystrophy.

Purpose: To investigate the clinical and imaging features associated with retinal sensitivity in Best vitelliform macular dystrophy (BVMD). Methods: This was a cross-sectional, single-center, observational study. Each patient underwent optical coherence tomography (OCT), near-infrared fundus autofluorescence, and OCT angiography. Macular integrity assessment microperimetry under mesopic conditions was performed to obtain retinal sensitivity thresholds from 68 testing points in the central macula. Structural OCT was used to classify BVMD lesions into four types according to their composition: vitelliform, mixed, subretinal fluid, and atrophy. Multilevel, mixed-effects linear regression was used to determine the factors associated with retinal sensitivity. Results: The study included 57 eyes of 30 patients with BVMD, 48 of which (84%) were in a clinical stage. Mean retinal sensitivity varied according to the composition of the lesion: the vitelliform type registering the highest (22 ± 4.1 dB), followed by mixed (18.73 ± 2.7 dB), subretinal fluid (15.68 ± 4.2 dB), and atrophy types (11.85 ± 4.6 dB). The factors most strongly associated with mean retinal sensitivity in BVMD proved to be the OCT lesion type and outer nuclear layer thickness. Conclusions: Retinal sensitivity in BVMD is influenced by lesion composition and outer nuclear layer thickness. Further studies with long-term follow-up are warranted to examine retinal sensitivity over time and to validate retinal sensitivity changes as biomarkers for BVMD. Translational Relevance: Assessing retinal sensitivity in BVMD provides a new instrument in the clinical characterization of the disease and offers the opportunity to identify imaging biomarkers for use as outcome measures in future clinical trials.

OCT Predictors of 3-Year Visual Outcome for Type 3 Macular Neovascularization.

PURPOSE: To identify baseline OCT predictors of the 3-year visual outcome for type 3 (T3) macular neovascularization (MNV) secondary to age-related macular degeneration (AMD) treated by anti-vascular endothelial growth factor (VEGF) therapy. DESIGN: Retrospective longitudinal study. PARTICIPANTS: Forty eyes of 30 patients affected by exudative treatment-naive T3 MNV were enrolled. METHODS: Baseline best-corrected visual acuity (BCVA) and several baseline OCT features were assessed and included in the analysis. Univariate and multivariate analyses served to identify risk factors associated with the 3-year BCVA. MAIN OUTCOME MEASURES: Baseline OCT features that are associated with bad or good visual outcomes of T3 MNV treated by anti-VEGF injections. RESULTS: Mean baseline BCVA was 0.34 ± 0.28 logarithm of the minimum angle of resolution (LogMAR), which significantly decreased to 0.52 ± 0.37 LogMAR at the end of the 3-year follow-up (P = 0.002). In the univariate analysis, the following baseline features were associated with the 3-year BCVA outcome: baseline BCVA (P = 0.004), foveal involvement of exudation (P = 0.004), and presence of subretinal fluid (SRF; P = 0.004). In the multivariate model, baseline BCVA (P = 0.032), central macular thickness (P = 0.036), number of active T3 lesions (P = 0.034), and presence of SRF (P = 0.008) were associated with the 3-year BCVA outcome. Interestingly, 3-year BCVA was significantly lower in 19 eyes with SRF at the baseline (0.69 ± 0.42 LogMAR) than 21 eyes without SRF (0.37 ± 0.24 LogMAR; P = 0.004). CONCLUSION: We identified structural OCT features associated with BCVA outcome after 3-year treatment with anti-VEGF injections. In contrast to previous studies on neovascular AMD, in our series, the presence of SRF at baseline was the most significant independent negative predictor of functional outcomes. Current findings may be employed to identify less favorable T3 patterns potentially deserving a more intensive treatment.

Choroidal Modifications Preceding the Onset of Macular Neovascularization in Age-Related Macular Degeneration.

INTRODUCTION: Macular neovascularization (MNV) is a common complication of age-related macular degeneration (AMD). Although several biomarkers may help to estimate the risk of MNV onset, neovascular complication is difficult to predict. Previous studies showed that the quantitative assessment of choroidal and choriocapillaris changes is useful for the assessment of atrophy expansion. On the other hand, scant data are available regarding the role of this kind of assessment in the setting of MNV. The aim of the study is to analyze choroidal and choriocapillaris changes occurring before the onset of MNV in patients affected by AMD using quantitative optical coherence tomography (OCT) and OCT angiography (OCTA). METHODS: The study was designed as a retrospective case series. Patients affected by AMD, categorized in eyes complicated by MNV and eyes not developing MNV, were retrospectively analyzed for 1 year of follow-up. Choroidal thickness (CT), Sattler layer thickness (SLT) and Haller layer thickness (HLT) were measured on OCT scans. Vessel density (VD) and choriocapillaris (CC) porosity were quantified on OCTA reconstructions. The main outcome measure was the relationship between choroidal and CC parameters, and MNV onset. RESULTS: We included 50 eyes of 50 AMD patients (28 male; mean age 74 ± 5 years). Over the 1-year follow-up, 15/50 eyes developed MNV (9 type 1; 3 type 2; 3 mixed type 1-2). Mean best-corrected visual acuity (BCVA) was 0.15 ± 0.15 logMAR at baseline, remaining stable in eyes not developing MNV (0.15 ± 0.12 logMAR; p > 0.05), and worsening to 0.38 ± 0.20 logMAR in eyes developing MNV (p < 0.01). VD values were similar between eyes developing MNV and eyes not complicated by MNV at baseline, with significant worsening detected only in MNV eyes. CC porosity was significantly higher in MNV eyes already before the onset of MNV. Furthermore, SLT was significantly lower in eyes developing MNV. The onset of MNV was preceded by a significant increase in intraretinal hyperreflective foci, whereas choroidal hyperreflective foci showed no evident changes. CONCLUSIONS: The degeneration of CC and the SLT thinning represent early an biomarker of MNV onset in AMD.

Choroidal neovascularization complicating sclerochoroidal calcifications.

PURPOSE: Sclerochoroidal calcifications (SCC) are rare conditions characterized by unifocal or multifocal well-defined scleral deposits of calcium. The present study describes two cases of SCC complicated by the onset of choroidal neovascularization (CNV). METHOD: Five patients affected by SCC were enrolled in the study and two cases were complicated by CNV. Both patients underwent complete ophthalmic examination with multimodal imaging including optical coherence tomography angiography (OCTA). RESULTS: In the two patients with CNV (1 male), BCVA was 20/40 and 20/50 in the affected eyes. Fundus examination revealed an irregular yellow-white lesion close to the superotemporal arcade in both patients, with exudation. The diagnosis of CNV was performed by means of fluorescein angiography in one patient and OCTA in the other patient. The patients received a total of 3 and 9 ranibizumab injections respectively over a six-year follow-up, reaching a final BCVA of 20/25 in both patients with stabilization of the CNV. CONCLUSIONS: SCC may be complicated by CNV, with good management obtained by intravitreal anti-VEGF injections.

Volume rendered 3D OCTA assessment of macular ischemia in patients with type 1 diabetes and without diabetic retinopathy.

The aim of this study was to measure macular perfusion in patients with type 1 diabetes and no signs of diabetic retinopathy (DR) using volume rendered three-dimensional (3D) optical coherence tomography angiography (OCTA). We collected data from 35 patients with diabetes and no DR who had OCTA obtained. An additional control group of 35 eyes from 35 healthy subjects was included for comparison. OCTA volume data were processed with a previously presented algorithm in order to obtain the 3D vascular volume and 3D perfusion density. In order to weigh the contribution of different plexuses' impairment to volume rendered vascular perfusion, OCTA en face images were binarized in order to obtain two-dimensional (2D) perfusion density metrics. Mean ± SD age was 27.2 ± 10.2 years [range 19-64 years] in the diabetic group and 31.0 ± 11.4 years [range 19-61 years] in the control group (p = 0.145). The 3D vascular volume was 0.27 ± 0.05 mm3 in the diabetic group and 0.29 ± 0.04 mm3 in the control group (p = 0.020). The 3D perfusion density was 9.3 ± 1.6% and 10.3 ± 1.6% in diabetic patients and controls, respectively (p = 0.005). Using a 2D visualization, the perfusion density was lower in diabetic patients, but only at the deep vascular complex (DVC) level (38.9 ± 3.7% in diabetes and 41.0 ± 3.1% in controls, p = 0.001), while no differences were detected at the superficial capillary plexus (SCP) level (34.4 ± 3.1% and 34.3 ± 3.8% in the diabetic and healthy subjects, respectively, p = 0.899). In conclusion, eyes without signs of DR of patients with diabetes have a reduced volume rendered macular perfusion compared to control healthy eyes.

Outer retinal tubulation formation and clinical course of advanced age-related macular degeneration.

Outer retinal tubulations (ORT) are a relatively new finding characterizing outer retinal atrophy. The main aim of the present study was to describe ORT development in advanced age-related macular degeneration (AMD) and to assess its relationship with disease's severity. Patients with advanced AMD characterized either by macular neovascularization or geographic atrophy, showing signs of outer retinal disruption or retinal pigment epithelium atrophy on structural optical coherence tomography (OCT) at the inclusion examination were prospectively recruited. All the patients underwent complete ophthalmologic evaluation, structural OCT scans and fundus autofluorescence imaging. The planned follow-up was of 3-years. Main outcome measures were ORT prevalence, mechanism of ORT formation, mean time needed for complete ORT formation, best-corrected visual acuity (BCVA), definitely decreased autofluorescence (DDAF) area, questionably decreased autofluorescence (QDAF) area, retinal layer thickness, foveal sparing, number of intravitreal injections. We also assessed the possible role of external limiting membrane (ELM) and Müller cells in ORT pathogenesis. Seventy eyes (70 patients) were included; 43 showed dry AMD evolving to geographic atrophy, while 27 displayed the features of wet AMD. Baseline BCVA was 0.5 ± 0.5 LogMAR, decreasing to 0.9 ± 0.5 LogMAR at the 3-year follow-up (p < 0.01). We detected completely formed ORT in 26/70 eyes (37%), subdivided as follows: 20 eyes (77%) wet AMD and 6 eyes (23%) dry AMD (p < 0.01). ORT took 18 ± 8 months (range 3-35 months) to develop fully. We described the steps leading to ORT development, characterized by progressive involvement of, and damage to the photoreceptors, the ELM and the RPE. Eyes displaying ORT were associated with a smaller QDAF area, less retinal layers damage and lower rate of foveal sparing than eyes free of ORT (p < 0.01). We also described pigment accumulations simulating ORT, which were detected in 16/70 eyes (23%), associated with a greater loss of foveal sparing, increased DDAF area and smaller QDAF area at the 3-year follow-up (p < 0.01). In conclusion, this study provided a description of the steps leading to ORT development in AMD. ELM and Müller cells showed a role in ORT pathogenesis. Furthermore, we described a subtype of pigment hypertrophy mimicking ORT, evaluating its clinical utility.

Real-Life Management of Central and Branch Retinal Vein Occlusion: A Seven-Year Follow-Up Study.

Retinal vein occlusion is the second most common retinal vascular pathology after diabetic retinopathy and a major cause of vision impairment. Nowadays, both central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO) can be well-managed by intravitreal treatments. However, considering the long-life expectance of the patients, few data are present in the literature about the very long-term outcome of CRVO and BRVO. The present study was an interventional, retrospective analysis of the morphological and functional long-term outcome of CRVO and BRVO patients, followed in an Italian referral center. We collected data from 313 eyes (178 CRVO eyes and 135 BRVO eyes). Mean follow-up was 45 ± 25 months (range 12-84 months). Both CRVO and BRVO eyes experience a significant visual acuity improvement secondary to anti-vascular endothelial growth factor/dexamethasone treatments (from 0.57 ± 0.25 to 0.41 ± 0.24 LogMAR in CRVO and from 0.53 ± 0.42 to 0.30 ± 0.41 LogMAR in BRVO, respectively) (p < 0.01). Also, central macular thickness (CMT) resulted significant recovery at the end of the follow-up (from 585.54 ± 131.43 to 447.88 ± 245.07 µm in CRVO and from 585.54 ± 131.43 to 447.88 ± 245.07 µm in BRVO, respectively) (p < 0.01). CRVO eyes received a mean of 10.70 ± 4.76 intravitreal treatments, whereas BRVO underwent 9.80 ± 5.39 injections over the entire 7-year follow-up. Our analyses highlighted different time points indicating the best obtainable improvement. This was the first year for CRVO (12-month follow-up) and the second year for BRVO (24-month follow-up). After these two time points, both visual acuity and CMT resulted stable up to the end of the follow-up. Ischemia was associated with significantly worse outcome.