Acute macular neuroretinopathy following Valsalva manoeuvre: an insight into the pathophysiology.

Acute macular neuroretinopathy (AMN) affects the outer retina and is most likely induced by non-inflammatory ischaemia of the retinal deep capillary plexus and choriocapillaris. A man in his early 20s developed Valsalva retinopathy following weightlifting at the gym and presented with blurring of vision in the left eye 1 month after the initial retinal haemorrhages had resolved. A diffuse, purplish, donut-shaped, perifoveal lesion was seen on funduscopy and was well defined by an optical coherence tomography angiography (OCTA) en face image in the left eye. Outer retinal changes on optical coherence tomography (OCT) and a dense co-localised scotoma on a visual field (VF) examination confirmed the diagnosis of AMN, and the patient was started on a tapering dose of oral steroids. Improvement was seen in OCT, OCTA and VF during the 6-month follow-up visit. The use of OCTA en face imaging enabled the accurate identification of the lesion in the affected layers of the retina.

[Multimodal topographically oriented approach to the study of full-thickness macular holes]. / Mul'timodal'nyi topograficheski orientirovannyi podkhod k izucheniyu skvoznykh makulyarnykh razryvov.

PURPOSE: This article studies the relationship between structural changes according to the findings of optical coherence tomography (OCT) and OCT angiography (OCTA), microperimetry (MP), multifocal electroretinography (mfERG) parameters in topographically corresponding areas of the macular region in idiopathic full-thickness macular holes (FTMH). MATERIAL AND METHODS: OCT, OCTA, MP and mfERG were performed in 14 eyes with FTMH stages I-IV according to Gass. In 13 points at a distance of 0-2.5°, 2.5-5.0°, and 5.0-10.0° from the fixation point, the light sensitivity (LS), amplitude and latency of the P1 component were compared with the size of the hole, the area of cystic changes (CC) at the level of the inner nuclear layer (INL) and the outer plexiform layer and Henle fiber layer complex (OPL+HFL), vessel density in the superficial and deep capillary plexus (SCP and DCP). RESULTS: LS and P1 component amplitude were significantly reduced at a distance of up to 5.0° from the fixation point. LS correlates with the apical and basal diameter of the hole (R> -0.53), the area of CC in the INL (R> -0.62) and the OPL+HFL complex (R> -0.55), the density of vessels in the SCP at a distance of up to 2.5° from the fixation point (R>0.51) and in the DCP at a distance of up to 5° from the fixation point (R>0.49). The P1 amplitude correlates with the basal diameter of the hole (R= -0.38), the area of CC in the INL and the OPL+HFL complex (R> -0.33) and vessel density in the SCP (R=0.37) at a distance of up to 2.5° from the fixation point, as well as vessel density in the DCP at a distance of up to 5° from the fixation point (R=0.47). Vessel density in the DCP is significantly lower in the presence of CC in the retina (p<0.001). CONCLUSION: In FTMH, there is a relationship between bioelectrical activity and LS, and structural disorders, capillary perfusion in different layers of the retina. A multimodal topographically oriented approach allows studying the relationship between structural and functional parameters in individual points of the retina and can be used in monitoring of FTMH after surgical treatment.

Does collagen cross linking have any effect on retinal circulation in patients with keratoconus? An optical coherence tomography angiography (OCTA) study.

BACKGROUND: We aimed to employ Optical Coherence Tomography Angiography (OCTA) to comprehensively assess changes in the optic nerve head (ONH) and macular perfusion before and after the Corneal Collagen Cross-Linking (CCL) procedure in patients with keratoconus. METHODS: A total of 22 keratoconus patient's candidate for CCL procedures were included based on specific criteria, with meticulous exclusion criteria in place to minimize potential confounders. Participants underwent OCTA assessments of the ONH and macula using the Spectralis OCT (Heidelberg) before CCL, as well as at 1- and 3-months post-CCL. MATLAB software was utilized for image analysis. RESULTS: The mean age of the participants was 20.09 ± 6.11, including 59% male, and the mean intraocular pressure (IOP) before the surgery was 13.59 ± 2.85 mmHg. Peripapillary Retinal nerve fiber layer (ppRNFL) thickness and overall retinal thickness remained stable post-CCL. However, significant alterations were observed in macular vessel density, emphasizing regional variations in vascular response. For macular large vessel density (LVD), both superficial and deep vascular complex (SVC and DVC) demonstrated significant differences between before surgery and the 3 months post-surgery follow-up (p < 0.001 and p = 0.002, respectively). Optic nerve head markers demonstrated relative stability, except for changes in avascular complex density, which was 49.2 ± 2.2% before the surgery and decrease to 47.6 ± 1.7% three months after the operation (P-value = 0.005). CONCLUSION: While CCL appears to maintain the integrity of certain ocular structures, alterations in macular perfusion post-CCL suggest potential effects on retinal blood supply. Long-term monitoring is crucial to understand the implications of these changes, particularly in the context of conditions such as diabetes.

Choroidal and central macular thickness before and after treatment in post fever retinitis.

PURPOSE: To study the choroidal thickness (CT) and central macular thickness (CMT) in post-fever retinitis (PFR) and their correlation with visual acuity and treatment. METHODS: A retrospective, observational study of patients presenting with PFR from 2013 to 2021 and with spectral domain optical coherence tomography (SD-OCT) (Heidelberg®, SpectralisTM, Heidelberg, Germany) images were included. The CT and CMT were measured at presentation and at the final visit. The CT was measured subfoveally and at points 2000 µm superior, inferior, medial, and lateral from the fovea using the caliper tool. RESULTS: Seventy-nine eyes of 65 patients were included for this study. The mean age was 39.03 (±16.00) years with female preponderance of 53.84% (n = 35). Mean follow-up duration was 30 days. Mean CT at presentation and at follow-up was 254.12 µm and 241.51 µm, respectively. CT was decreased in majority of the eyes 67.1% (n = 53) from their baseline value. Mean CMTs at presentation and final visit were 454.8 µm and 223.7 µm, respectively. Best corrected visual acuity had a positive correlation with CMT (r = 0.340; P = 0.002) and negligible correlation with CT. A significant decrease in the mean CT was noted in patients who received doxycycline either alone or in combination with a steroid as compared to those who did not receive any treatment (P < 0.001). The significance of which is unknown presently. CONCLUSION: CMT has a greater role in determining the final visual outcome than CT. CT can be reduced post-treatment with no effect on vision.

Contribution of systemic factors on macular vessel density: a sex-specific population-based study.

PURPOSE: To evaluate the influence of systemic factors on macular vessel density in quantitative Optical Coherence Tomography Angiography (OCTA) by sex. STUDY DESIGN: A cross-sectional study. METHODS: A total of 2018 adults were recruited in this study. Participants were excluded (n=964) due to missing data, eye-related problems, or low OCTA scan quality. Macular vessel densities were measured with OCTA using split-spectrum amplitude decorrelation angiography algorithm. Only the data from the right eyes were selected for analysis. Multivariable linear regression analysis was performed to determine the associations between macular vessel density and obesity-related systemic factors in each gender group. RESULTS: The right eyes of 1054 participants (59.6% women) were enrolled. Men had significantly higher obesity parameters and associated risk factors. In multivariable linear regression analysis in men, older age and type 2 diabetes mellitus were independently associated with lower superficial retinal vessel density (ß = -0.37, p = 0.002; ß = -1.22, p = 0.03) and deep retinal vessel density, respectively (ß = -0.66, p < 0.001; ß = -1.76, p = 0.02); positive association was also observed between body mass index (BMI) and superficial retinal vessel density (ß = 0.56, p = 0.02). In women, only higher systolic blood pressure was independently associated with a lower deep retinal vessel density (ß = -0.50, p = 0.003). CONCLUSIONS: This large cross-sectional study shows that older age and type 2 diabetes mellitus are associated with lower superficial and deep retinal capillary vessel density in men. This may help clinicians better understand how systemic factors influence retinal vessel density in different genders and future studies can ascertain more potential sex differences.

Reduced macular thickness and vascular density in abnormal glucose metabolism patients: A meta-analysis of optical coherence tomography (OCT) and OCT angiography studies.

BACKGROUND: Alterations in macular thickness and vascular density before clinically visible diabetic retinopathy (DR) remain inconclusive. This study aimed to determine whether retinal manifestations in abnormal glucose metabolism (AGM) patients differ from those in the healthy individuals. METHODS: PubMed, Embase, and Web of Science were searched between 2000 and 2021. The eligibility criteria were AGM patients without DR. Primary and secondary outcomes measured by optical coherence tomography (OCT) and OCT angiography (OCTA) were analyzed and expressed as standardized mean differences (SMDs) with 95% confidence intervals (CIs). A random-effects model was used in the data synthesis. The potential publication bias for the variables was evaluated using Egger's test. RESULTS: A total of 86 observational studies involving 13,773 participants and 15,416 eyes were included. OCT revealed that compared to healthy controls, the total macular thickness of AGM patients was thinner, including the thickness of fovea (-0.24, 95% CI [-0.39, -0.08]; P  = 0.002, I2  = 87.7%), all regions of parafovea (-0.32, 95% CI [-0.54, -0.11]; P  = 0.003; I2  = 71.7%) and the four quadrants of perifovea; the thickness of peripapillary retinal nerve fiber layer (pRNFL), macular retinal nerve fiber layer (mRNFL), and ganglion cell layer (GCL) also decreased. OCTA indicated that the superficial and deep vascular density decreased, the foveal avascular zone (FAZ) area enlarged, and the acircularity index (AI) reduced in AGM individuals. CONCLUSIONS: Retinal thinning and microvascular lesions have occurred before the advent of clinically detectable DR; OCT and OCTA may have the potential to detect these preclinical changes. REGISTRATION: PROSPERO; http://www.crd.york.ac.uk/prospero/ ; No. CRD42021269885.

Linking Vascular Structure and Function: Image-Based Virtual Populations of the Retina.

Purpose: This study explored the relationship among microvascular parameters as delineated by optical coherence tomography angiography (OCTA) and retinal perfusion. Here, we introduce a versatile framework to examine the interplay between the retinal vascular structure and function by generating virtual vasculatures from central retinal vessels to macular capillaries. Also, we have developed a hemodynamics model that evaluates the associations between vascular morphology and retinal perfusion. Methods: The generation of the vasculature is based on the distribution of four clinical parameters pertaining to the dimension and blood pressure of the central retinal vessels, constructive constrained optimization, and Voronoi diagrams. Arterial and venous trees are generated in the temporal retina and connected through three layers of capillaries at different depths in the macula. The correlations between total retinal blood flow and macular flow fraction and vascular morphology are derived as Spearman rank coefficients, and uncertainty from input parameters is quantified. Results: A virtual cohort of 200 healthy vasculatures was generated. Means and standard deviations for retinal blood flow and macular flow fraction were 20.80 ± 7.86 µL/min and 15.04% ± 5.42%, respectively. Retinal blood flow was correlated with vessel area density, vessel diameter index, fractal dimension, and vessel caliber index. The macular flow fraction was not correlated with any morphological metrics. Conclusions: The proposed framework is able to reproduce vascular networks in the macula that are morphologically and functionally similar to real vasculature. The framework provides quantitative insights into how macular perfusion can be affected by changes in vascular morphology delineated on OCTA.

The long-term influence of perinatal factors on macular morphology and vessel density in preterm children.

BACKGROUND: Increased survival rate of extremely preterm children is associated with a higher risk of retinopathy of prematurity (ROP) and long-term sequelae, which implicate retinal changes. PURPOSE: To assess an influence of perinatal characteristics on morphology and retinal vascularity of the macula in preterm children. METHODS: A cohort of 123 preterm children at the age of 10.5 years (IQR: 8.12-12.77) was prospectively assessed. Optical coherence tomography angiography (OCTA) was performed using RTVueXR Avanti. Foveal thickness, parafoveal thickness, size of foveal avascular zone (FAZ), superficial and deep vessel density, central choroidal thickness (CCT) were analyzed. The associations between OCTA results and perinatal factors, including the presence of ROP and therapy requirements were assessed in preterm children. RESULTS: Significantly smaller FAZ, higher foveal thickness and vessel density were noted in children with ROP, Respiratory Distress Syndrome, Bronchopulmonary Dysplasia, required erythropoietin, transfusion or steroids. Foveal thickness was increased in children with ROP (p < 0.001) and following laser treatment (p < 0.05). Thinner CCT was noted in children with a history of sepsis (p < 0.05) and ROP required treatment (p < 0.05). Pregnancy bleeding was associated with higher superficial foveal vessel density (p < 0.05) and smaller FAZ (p < 0.05). CONCLUSION: Neonatal factors have a huge impact on retinal development, but the role of prenatal factors should not be neglected in preterm children.

Effect of mydriasis on macular and peripapillary metrics in swept-source optical coherence tomography angiography.

Introduction: The study aimed to evaluate the effect of mydriasis on macular and peripapillary metrics with swept-source optical coherence tomography angiography (SS-OCTA) in healthy subjects. Methods: Thirty-five healthy subjects were included. The macular region was scanned by the 3×3mm mode and 6×6mm mode, and the peripapillary region was scanned by the 4.5×4.5mm mode on both eyes with SS-OCTA before and after mydriasis. Macular and peripapillary metrics, including retinal vessel density (VD) and fundus thickness were measured by the built-in program. Data of the right eye were analyzed. Results: The signal strength of the scans was comparable before and after mydriasis (all P>0.05). There were no significant differences in foveal avascular zone (FAZ) parameters and retinal VD of most sectors in both macular and peripapillary areas (all P>0.05). Choroidal thickness was decreased, outer and whole retinal thickness was increased in most of the macular sectors after mydriasis (all P<0.05). Choroidal thickness was decreased in all the peripapillary sectors, but whole retinal thickness and GCC thickness were increased in some peripapillary sectors after mydriasis (all P<0.05). Conclusions: FAZ parameters and retinal VD in the most macular and peripapillary regions are not affected by mydriasis. The thickness of the choroid is decreased after mydriasis, while the thickness of retinal layers in some sectors may be increased after mydriasis.

Individual vs simultaneous macular and optic disc measurements with spectral domain optical coherence tomography in glaucoma and healthy eyes.

We assessed the repeatability and agreement of ganglion cell complex (GCC) in the macular area and the peripapillary retinal nerve fiber layer (ppRNFL) with individual and combined macula and disc scans. The macular GCC and ppRNFL thicknesses from 34 control eyes and 43 eyes with glaucoma were measured with the Canon Optical Coherence Tomography (OCT) HS-100. Two repeated measurements were performed with both scan modes. The repeatability limit (Rlim) and agreement analysis were performed. The individual scan showed better repeatability than the combined scan in both groups. However, the differences in the Rlim for the GCC in most sectors were lower than 3 µm (axial resolution of the OCT), and this was larger than 3 µm for most of the ppRNFL sectors. The mean differences in the thickness between both scan modes for the GCC and ppRNFL measurements were less than 3 and 6 µm, respectively. The interval of the limits of agreement was about 10 µm in some sectors for the GCC, and about 40 and 60 µm in some sectors in controls and glaucoma eyes, respectively. Both scan modes showed good repeatability in both groups. The agreement results suggest that the scan modes cannot be used interchangeably.

THE EFFECT OF INTERNAL LIMITING MEMBRANE PEELING ON THE INNER RETINAL LAYERS IN PATIENTS WITHOUT MACULAR PATHOLOGIC CONDITION.

BACKGROUND: To examine the effect of internal limiting membrane peeling on the inner retinal layers in patients without macular pathological condition. METHODS: A prospective nonrandomized trial of patients undergoing pars plana vitrectomy with internal limiting membrane peeling for pathologic condition outside the macula was performed. Optical coherence tomography including macular ganglion cell layer, inner plexiform layer, and peripapillary retinal nerve fiber layer imaging was performed before surgery, 1, 3, and 6 months postoperatively, and at the end of follow-up (ranges between 4 and 17 months). Patients with any macular pathological condition on optical coherence tomography before surgery were excluded. The main outcome measure was change in thickness of the ganglion cell layer and inner plexiform layer. RESULTS: Ten patients who underwent pars plana vitrectomy with internal limiting membrane peeling for macula-on retinal detachment were included in the analysis. The mean age was 55 years, and the mean follow up was 10.8 months. All patients completed at least two postoperative follow-up visits that included an optical coherence tomography as per the protocol (range 2-6 months). There was an immediate reduction in the global (G), inferotemporal, superotemporal, and superior (S) ganglion cell layer thickness at the first follow up as compared with the preoperative state ( P = 0.028, P = 0.027, P = 0.026, and P = 0.027 respectively). From the first follow-up visit onward until the final follow-up, the thinning persisted, although there was no further statistically significant thinning. CONCLUSION: Peeling of the internal limiting membrane causes significant ganglion cell layer thinning in maculae without pathologic condition before surgery. At up to 17 months of follow-up, this effect seems to be immediate and nonprogressive.

Closure Grading and Visual Outcome in Patients with Large Idiopathic Macular Holes: A Spectral-Domain Optical Coherence Tomography Observation.

INTRODUCTION: So far, there has been no closure grade system synthesizing morphological and microstructural features for large idiopathic macular holes (IMHs) treated by vitrectomy and internal limiting membrane (ILM) peeling. This study aimed to propose a concise one and explore its relevance with visual acuity and the related preoperative factors. METHODS: Consecutive patients with large IMHs (minimum diameter >400 µm), undergoing vitrectomy and ILM peeling, obtaining primary closure and regularly followed-up were enrolled. Preoperative clinical charts and spectral-domain optical coherence tomography (SD-OCT) parameters were reviewed. SD-OCT images and best corrected visual acuity (BCVA) were assessed at 1, 4, and 10 months postoperatively. SD-OCT features at last visit were categorized by BCVA significance, and preoperative risk factors were analyzed. RESULTS: Sixty-eight eyes from 64 patients were enrolled. The 10-month postoperative SD-OCT images were categorized into closure grade 1, 2, and 3 with successively decreased BCVA (p < 0.001). During early follow-up, part of grades 2 and 3 could evolve into the upper grade, respectively, but grade 3 could never evolve into grade 1 and exhibited the least satisfactory long-term BCVA. Binary logistic regression showed that large minimum linear diameter (MLD) was a risk factor for grade 3 occurrence (p < 0.001), with a cutoff value of 625.5 µm from the receiver operating characteristic curve for MLD predicting grade 3 occurrence (p = 0.001). CONCLUSION: Long-term closure status of large IMHs could be categorized into three grades with BCVA significance. Large horizontal MLD is a risk factor for occurrence of grade 3 closure with unsatisfactory visual recovery.

Sensitivity and specificity of SS-OCT for detecting macular pathologies vs SD-OCT.

PURPOSE: To evaluate the sensitivity and specificity of swept-source optical coherence tomography (SS-OCT) biometer compared with the gold standard spectral-domain optical coherence tomography (SD-OCT) for detecting macular pathology in patients with cataract. SETTING: Eye Centers of Tennessee, Crossville, TN. DESIGN: Prospective, cross-sectional, observational, examiner-masked. METHODS: The study included 132 participants aged 50 years and older, who underwent precataract surgery work-up. All participants underwent fixation check retinal scans using SS-OCT biometer (IOLMaster 700) as well as full macular scans using Cirrus SD-OCT. 3 independent masked examiners evaluated the scans if they were normal or had a suspected pathology. Different measures of diagnostic accuracy were calculated for 3 examiners. RESULTS: True positive rate (sensitivity) ranged from 71.1% (32/45) to 79.2% (42/53), and false negative rate was between 20.8% (11/53) and 28.9% (13/45) for the 3 examiners. True negative rate (specificity) ranged from 86.8% (59/68) to 94.1% (64/68), and false positive rate was between 5.9 (4/68) and 13.2% (9/68). The fitted receiver operating characteristic area ranged from 0.83 to 0.95. CONCLUSIONS: Using retinal SS-OCT biometer scans as a replacement of the dedicated macular SD-OCT for screening or diagnosing macular health would not be appropriate because of its low sensitivity. SS-OCT biometer may potentially fail to identify approximately one-fourth of patients who actually have the disease. Therefore, the final decision on macular health should be based on the gold standard SD-OCT scans. When full macular SD-OCT scans are not accessible, the limited retinal scan information from SS-OCT biometer may still provide useful insights into the macular health.

Subclinical macular vessel density alterations in patients with juvenile systemic lupus erythematosus.

OBJECTIVE: The aim is to evaluate subclinical alterations of macular microvasculature in patients with juvenile systemic lupus erythematosus (JSLE). METHODS: This is a cross-sectional study of 29 eyes of 29 patients diagnosed with JSLE and 29 eyes of 29 healthy controls. The vessel density (VD) of the superficial capillary plexus (SCP), intermediate capillary plexus (ICP), deep capillary plexus (DCP), choriocapillaris (CC), and area of foveal avascular zone (FAZ) was measured using optical coherence tomography angiography (OCTA). A multiple linear regression analysis was performed to evaluate the effects of disease duration and activity on OCTA parameters. RESULTS: The VD of total (p = .007) and the superior (p = .014) and inferior (p = .004) quadrants in SCP was significantly lower in children with JSLE. The VD of total and all quadrants in ICP decreased (p = .015, p = .0045, p = .015, p = .033), except that of the temporal quadrant (p = .366). The total (p = .011) and superior quadrant (p<.01) DCP-VD showed a significant decrease in children with JSLE. The decrease in VD in the total (p = .003) and nasal quadrant (p = .017) of CC was also remarkable. No significant difference in the FAZ area was found between the two groups (p = .774). Multiple linear regression analyses adjusted for age, spherical equivalent, and intraocular pressure were conducted. No contributing factor to OCTA parameters was found. CONCLUSIONS: We demonstrated decreased VD in all layers of the retina and CC in patients with JSLE without ocular involvement. Early screening and close follow-up were recommended.

An Evaluation of the Repeatability of Visual Function Following Surgical Repair of Macula-Off Rhegmatogenous Retinal Detachment.

Purpose: To evaluate the reliability and reproducibility of visual function assessments for patients with macula-off rhegmatogenous retinal detachment (RRD). Methods: This prospective study included patients with unilateral macula-off RRD of <10-day duration successfully treated with a single, uncomplicated surgery at least 1 year following repair. Visual function assessments were performed at time of enrollment and 1 month later. Testing included Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), low-contrast visual acuity (VA) 2.5% and 5%, contrast sensitivity assessment with Mars and Gabor patches, reading speed (acuity, speed, and critical print size), color vision testing (protan, deutan, and tritan), and microperimetry. Spectral-domain ocular coherence tomography (SD-OCT) was performed. Paired t-statistics were used to compare values between visits and between the study and fellow eyes. Results: Fourteen patients (9 male, 5 female) with a mean age of 69 years at time of surgery were evaluated. Correlation coefficients across the two visits were highest for ETDRS BCVA (0.97), tritan color vision testing (0.96), and low-contrast VA 5% (0.96), while the average t-statistic was largest for low-luminance deficit (4.2), ETDRS BCVA (4.1), and reading speed critical print size (3.7). ETDRS BCVA did not correlate with SD-OCT findings. Conclusions: ETDRS BCVA can be considered a highly reliable and reproducible outcome measure. LLVA, protan color discrimination, contrast sensitivity, and reading speed may be useful secondary outcome measures. Translational Relevance: This study provides guidance on the selection of visual function outcome measures for clinical trials of patients with macula-off RRD.

Quantification of choroidal hyperreflective layer: A swept-source optical coherence tomography study.

PURPOSE: To investigate variation in reflectivity of choroidal layers in normal eyes. METHODS: From the swept-source optical coherence tomography database, we retrospectively included eyes with a normal fundus. Choroidal reflectivity was measured on the horizontal and vertical B-scan optical coherence tomography images. The optical barrier of the choroid was defined as the first hill in the middle of the reflectance graph from the retinal pigment epithelium-Bruch's membrane complex to the chorioscleral junction. RESULTS: The optical barrier of the choroid was identified in 91 eyes of 91 individuals. The amplitude of peak reflectivity of the optical barrier of the choroid at macular center (142.85 ± 15.04) was greater than those in superior (136.12 ± 14.08) or inferior macula (135.30 ± 16.13) (P = 0.028, P = 0.008, respectively). Latency between the peak of the retinal pigment epithelium-Bruch's membrane complex and the optical barrier of the choroid at macular center (48.11 ± 13.78 µm) was shorter than those in nasal macula (55.58 ± 19.21 µm) (P = 0.021). The amplitude of the peak reflectivity of the optical barrier of the choroid in the center negatively correlated with the latency between the retinal pigment epithelium-Bruch's membrane complex and the optical barrier of the choroid (P < 0.001). CONCLUSION: An optical barrier exists in the inner choroid of the normal eye. Its depth depends on the location within the macula. Further studies are mandatory to evaluate variations in the barrier in the eyes with chorioretinal disease.