Pseudomelanoma diagnosis in a tertiary ophthalmologic centre in Spain.

BACKGROUND: The purpose of this study was to determine the types and frequency of lesions that can be misdiagnosed as choroidal or ciliary body melanomas (posterior uveal tract melanoma [PUM]). METHODS: This is a retrospective, descriptive study examining data from patients referred to Hospital La Paz in Madrid with the diagnosis of possible PUM between January 2005 and March 2020. All patients referred for PUM were studied. In collaboration with an oncology-specialized ophthalmologic centre, each patient underwent a full ophthalmic examination, ultrasonography, and optical coherence tomography, with agreed clinical criteria used to differentiate melanomas from pseudomelanomas. RESULTS: In our cohort of 715 patients, 48.9% had pseudomelanomas. Thirty-five different conditions were misdiagnosed as melanomas. The 5 most common conditions were choroidal nevus (40.5%), peripheral exudative hemorrhagic chorioretinopathy (12%), choroidal hemangioma (10.5%), choroidal metastasis (8%), and age-related macular degeneration (4%). CONCLUSIONS: Altering the diagnosis and changing the treatment and prognosis for patients can be difficult for a referral centre. Herein we present the largest European cohort investigated and highlight the importance of identifying the correct diagnosis to prevent mistreatment and possible overtreatment. These misdiagnoses can have an emotional effect on patients and their families, which could be avoided with a correct diagnosis. We analyze the most common pseudomelanoma diagnoses to help physicians better diagnose patients in their care.

First-in-Human Gene Therapy Trial of AAV8-hCARp.hCNGB3 in Adults and Children With CNGB3-associated Achromatopsia.

PURPOSE: To assess the safety and efficacy of AAV8-hCARp.hCNGB3 in participants with CNGB3-associated achromatopsia (ACHM). DESIGN: Prospective, phase 1/2 (NCT03001310), open-label, nonrandomized clinical trial. METHODS: The study enrolled 23 adults and children with CNGB3-associated ACHM. In the dose-escalation phase, adult participants were administered 1 of 3 AAV8-hCARp.hCNGB3 dose levels in the worse-seeing eye (up to 0.5 mL). After a maximum tolerated dose was established in adults, an expansion phase was conducted in children ≥3 years old. All participants received topical and oral corticosteroids. Safety and efficacy parameters, including treatment-related adverse events and visual acuity, retinal sensitivity, color vision, and light sensitivity, were assessed for 6 months. RESULTS: AAV8-hCARp.hCNGB3 (11 adults, 12 children) was safe and generally well tolerated. Intraocular inflammation occurred in 9 of 23 participants and was mainly mild or moderate in severity. Severe cases occurred primarily at the highest dose. Two events were considered serious and dose limiting. All intraocular inflammation resolved following topical and systemic steroids. There was no consistent pattern of change from baseline to week 24 for any efficacy assessment. However, favorable changes were observed for individual participants across several assessments, including color vision (n = 6/23), photoaversion (n = 11/20), and vision-related quality-of-life questionnaires (n = 21/23). CONCLUSIONS: AAV8-hCARp.hCNGB3 for CNGB3-associated ACHM demonstrated an acceptable safety and tolerability profile. Improvements in several efficacy parameters indicate that AAV8-hCARp.hCNGB3 gene therapy may provide benefit. These findings, with the development of additional sensitive and quantitative end points, support continued investigation.

Safety and effectiveness of pre-emptive diabetic vitrectomy in patients with severe, non-fibrotic retinal neovascularisation despite panretinal photocoagulation.

OBJECTIVES: To investigate the safety and effectiveness of pre-emptive vitrectomy in eyes with severe non-fibrotic proliferative diabetic retinopathy. METHODS: A multi-centre, retrospective, observational study. Pre-emptive vitrectomy was performed in non-fibrotic diabetic eyes with a visual acuity (VA) of 20/50 or better, where there was extensive persistent neovascularisation despite prior panretinal photocoagulation, and where the fellow eye had established sight loss despite vitrectomy for tractional complications. The primary outcome measure was the VA at last visit. RESULTS: Twenty patients were included. The mean age was 39 ± 14 years. Fifteen patients were Type 1 diabetic. The median baseline VA was 20/30 and remained stable at 20/28 at last visit (median follow-up period: 24 months). Eight eyes (40.0%) developed post-operative vitreous cavity haemorrhage; 4 of which required a vitreous cavity washout procedure. There were no post-operative retinal detachments. The index eye remained the significantly better eye at all time points bar one month post-surgery. Regression of retinopathy grading was observed in all eyes. CONCLUSION: In this pilot study, we found no sight loss with pre-emptive diabetic vitrectomy. Better eye status was maintained in this high-risk group. Further study with larger number of patients and longer-term follow-up is indicated.

"Delamination Plus": A Technique to Reduce Immediate Postoperative Diabetic Cavity Hemorrhage.

PURPOSE: To investigate the effectiveness of an intraoperative surgical technique to reduce the incidence of immediate postoperative cavity hemorrhage in patients undergoing vitrectomy for complications of proliferative diabetic retinopathy. METHODS: A single-center, prospective study of 20 consecutive patients who underwent vitrectomy for proliferative diabetic retinopathy-related complications. A standard 3-port pars plana vitrectomy with either 23 g or 25 g was performed. At the end of surgery, the infusion was switched off to create transient hypotony and endolaser photocoagulation with long-duration burns were applied to actively leaking blood vessel. RESULTS: The average age was 56.2 + 12.8 years. Eleven eyes had actively bleeding vessels at the end of surgery and received endolaser photocoagulation. No patients were found to have hypotony at Day 1 postoperative. Preoperative median visual acuity was 20/1,600 improving to 20/40 at a median of 2.3 weeks post-op (range 0.4-8.5 weeks). Two eyes (10%) had a small postoperative cavity hemorrhage with 20/40 vision, which did not require further intervention. CONCLUSION: The described technique was found to be effective in reducing the incidence of postoperative cavity hemorrhage from up to 75% reported in literature to 10% in our pilot study. Further study with a larger number of patients is required.

Diagnostic sensitivity of vitrectomy and vitreous biopsy for vitritis.

PURPOSE: To investigate sensitivity of diagnostic vitrectomy and vitreous biopsy for patients with vitritis of unknown aetiology. METHODS: Retrospective analysis of all vitrectomies and vitreous biopsies, performed at St Thomas' Hospital, London, UK, for vitritis between February 2001 and February 2019. Patients were identified using the VITREOR database and records were reviewed. Patients were categorised as infectious, non-infectious or masquerade based on final diagnosis. Sensitivity of both diagnostic pars plana vitrectomy (PPV) and vitreous cutter biopsy in each category was investigated. Furthermore, data on gender, age, and method of anaesthesia were also collected. RESULTS: In our cohort, 64 patients underwent PPV with a diagnostic sensitivity of 67% (43/64) overall and 60% (18/30), 56% (9/16) and 89% (16/18) for those with infectious, masquerade and non-infectious aetiologies, respectively. In comparison, 96 patients underwent a vitreous cutter biopsy with diagnostic sensitivity of 74% (71/96) overall and 71% (55/77), 67% (4/6) and 92% (12/13) for those with infectious, masquerade and non-infectious aetiologies, respectively. No statistically significant difference in sensitivity was identified between the vitrectomy and vitreous biopsy groups for either aetiology. Patients undergoing vitrectomy were noted to be older (p = 0.02) and more likely to undergo a general anaesthetic (p < 0.01). CONCLUSIONS: Herein we demonstrate similar diagnostic sensitivity of PPV and vitreous cutter biopsy in patients with vitritis of unknown aetiology.

Outcomes Following Pars Plana Vitrectomy for Severe Ocular Trauma.

PURPOSE: To investigate outcomes and presenting characteristics for subjects undergoing pars plana vitrectomy for ocular trauma. METHODS: Retrospective study of 113 patients who underwent pars plana vitrectomy for severe ocular trauma at [name deleted to maintain the integrity of the review process] between 1999 and 2018. Data were collected on age, gender, initial and final visual acuity (LogMAR), mode of injury, type of injury, number of surgeries performed, follow-up duration, type of tamponade, presence of phthisis, and retinal detachment. The Birmingham Eye Trauma Terminology System (BETTS) was employed. RESULTS: We identified assault and contusion injuries to be the most common mode and type of ocular injury in our cohort. Furthermore, through follow-up we noted a varied number of operations required by patients presenting with ocular trauma and a statistically significant improvement in visual acuity from 1.73 ( ± 0.86) LogMAR to 1.17 ( ± 1.03; p < 0.01) LogMAR. A statistically significant difference in final visual acuity was also noted between BETTS classified type of injury groups (p < 0.01). Notably, only 7.3% and 8.2% of patients developed phthisis or a persisting retinal detachment, respectively, during follow-up. CONCLUSION: Our study demonstrates that ocular trauma requiring pars plana vitrectomy can require a varied number of operations with a guarded visual prognosis. However, a small percentage will proceed to develop phthisis following intervention.

A NOVEL CASE SERIES OF NMNAT1-ASSOCIATED EARLY-ONSET RETINAL DYSTROPHY: EXTENDING THE PHENOTYPIC SPECTRUM.

PURPOSE: To report two siblings with NMNAT1-associated retinopathy presenting with a later onset and milder phenotype than previously described. METHODS: Retrospective case series of two siblings. The authors describe two cases of early-onset retinal dystrophy caused by disease-causing NMNAT1 variants. Visual acuity, clinical examination, and retinal imaging including color fundus photography, spectral domain optical coherence tomography, and fundus autofluorescence were performed. Both cases underwent full-field and pattern electroretinography incorporating the International standards. RESULTS: Two siblings were found to harbor the variants c.53A>G, p.(Asn18Ser) and c.769G>A, p.(Glu257Lys) in NMNAT1 after retinal dystrophy panel gene testing. Both had good visual acuity until the ages of 6 and 11 years, respectively, with subsequent gradual worsening into their twenties. At the ages of 10 and 16 years, respectively, electroretinograms indicated generalized rod and cone system dysfunction of moderate severity, with pattern electroretinography evidence of severe macular involvement. Repeat testing at the ages of 26 and 33 years revealed only mild worsening of rod photoreceptor function in both. CONCLUSION: NMNAT1-associated retinopathy has previously only been described as a typical form of Leber congenital amaurosis, with poor visual acuity from birth associated with nystagmus, characteristic macular atrophy, and intraretinal pigmentation from birth. Here, we present two siblings with a novel, later onset, and far milder phenotype. We suggest that this may be due to the two missense NMNAT1 variants resulting in milder reduction of NMNAT1 enzymatic activity. These cases extend the phenotypic spectrum associated with NMNAT1 and further highlight the clinical heterogeneity associated with inherited retinal diseases.

Safety of intracameral cefuroxime in pars plana vitrectomy.

BACKGROUND/OBJECTIVES: Postoperative endophthalmitis is a rare, but serious complication of pars plana vitrectomy (PPV). Subconjunctival cefuroxime injection has been the traditional choice for post vitrectomy endophthalmitis prophylaxis. Its effectiveness and safety in this context are however poorly understood and cases of retinal toxicity have been reported. The traditional standard subconjunctival antibiotic prophylaxis has been superceded in cataract surgery by intracameral antibiotic prophylaxis. SUBJECTS/METHODS: The primary aim of this three centre non-randomised retrospective database cohort study of 7,532 PPV procedures was to identify the rate of endophthalmitis in cohorts of patients treated with intracameral or subconjunctival cefuroxime. A secondary aim was to estimate the achieved intraocular antibiotic concentrations of cefuroxime in eyes with intracameral versus subconjunctival administration using mathematical modelling. RESULTS: The overall incidence of postoperative endophthalmitis was 0.07% (5/7532). There were no cases of endophthalmitis in eyes receiving intracameral cefuroxime alone or in combination with subconjunctival cefuroxime (0/5586). Patients receiving subconjunctival cefuroxime alone had a higher incidence of endophthalmitis (0.22%, 4/1835), and there was one case of endophthalmitis in eyes not receiving any perioperative antibiotics (0.9%, 1/111). No cases of cefuroxime toxicity were identified. With subconjunctival cefuroxime, in the presence of a sclerotomy leak, we estimated the vitreous drug concentration to be higher than that for intracameral cefuroxime and potentially toxic. CONCLUSIONS: Intracameral cefuroxime appears to be a safe and efficient choice for prophylaxis against endophthalmitis after PPV. Small eyes with intraocular tamponade seem to be at particular risk of drug toxicity if cefuroxime is administered via the subconjunctival route.

Long-Term Investigation of Retinal Function in Patients with Achromatopsia.

Purpose: To investigate the long-term natural history of retinal function of achromatopsia (ACHM). Methods: Subjects with molecularly confirmed ACHM were recruited in a prospective cohort study of mesopic microperimetry. Coefficient of repeatability and intraclass correlation coefficient (ICC) of mean sensitivity (MS) were calculated. Best-corrected visual acuity (BCVA), bivariate contour ellipse area (BCEA), contrast sensitivity (CS), MS, total volume (VTOT), and central field volume (V5°) from volumetric and topographic analyses were acquired. Correlation of functional parameters with structural findings from optical coherence tomography (OCT) was performed. Results: Eighteen subjects were recruited. Mean follow-up was 7.2 years. The MS test-retest repeatability coefficient was 1.65 decibels (dB), and the ICC was 0.973 (95% confidence interval, 0.837-0.98). Mean MS was similar for right and left eyes (16.97dB and 17.14dB, respectively). A negative significant correlation between logMAR BCVA and the retinal sensitivity indices (MS, VTOT, V5°) was found. A significant negative correlation between logCS and MS, VTOT, and V5° was also observed. BCVA and BCEA improved during follow-up. Mean CS, MS, VTOT, and V5° at final follow-up were similar to baseline. MS was similar between CNGA3- and CNGB3-ACHM. Patients with and without the presence of a foveal ellipsoid zone on OCT had similar MS (16.64 dB and 17.17 dB, respectively). Conclusions: We demonstrate a highly reproducible assessment of MS. Retinal function including MS, volumetric indices, and CS are stable in ACHM. Improvement of fixation stability and small changes of BCVA over time may be part of the natural history of the disease.

Validation of a Vision-Guided Mobility Assessment for RPE65-Associated Retinal Dystrophy.

Purpose: To validate a vision-guided mobility assessment for individuals affected by RPE65-associated retinal dystrophy (RPE65-RD). Methods: In this comparative cross-sectional study, 29 subjects, comprising 19 subjects with RPE65-RD and 10 normally-sighted subjects undertook three assessments of mobility: following a straight line, navigating a simple maze, and stepping over a sidewalk "kerb." Performance was quantified as the time taken to complete each assessment, number of errors made, walking speed, and percent preferred walking speed, for each assessment. Subjects also undertook assessments of visual acuity, contrast sensitivity, full-field static perimetry, and age-appropriate quality of life questionnaires. To identify the most relevant metric to quantify vision-guided mobility, we investigated repeatability, as well as convergent, discriminant, and criterion validity. We also measured the effect of illumination on mobility. Results: Walking speed through the maze assessment best discriminated between RPE65-RD and normally-sighted subjects, with both convergent and discriminant validity. Walking speed also approached statistical significance when assessed for criterion validity (P = 0.052). Subjects with RPE65-RD had quantifiably poorer mobility at lower illumination levels. A relatively small mean difference (-0.09 m/s) was identified in comparison to a relatively large repeatability coefficient (1.10 m/s). Conclusions: We describe a novel, quantifiable, repeatable, and valid assessment of mobility designed specifically for subjects with RPE65-RD. The assessment is sensitive to the visual impairment of individuals with RPE65-RD in low illumination, identifies the known phenotypic heterogeneity and will furthermore provide an important outcome measure for RPE65-RD. Translational Relevance: This assessment of vision-guided mobility, validated in a dedicated cohort of subjects with RPE65-RD, is a relevant and quantifiable outcome measure for RPE65-RD.

Retinal Structure in RPE65-Associated Retinal Dystrophy.

Purpose: RPE65-associated retinal dystrophy (RPE65-RD) is an early onset, progressive, severe retinal dystrophy. We sought to characterize the natural history of retinal degeneration in affected individuals. Methods: We performed cross-sectional and longitudinal quantitative and qualitative assessments of retinal architecture in RPE65-RD using spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) imaging. Twenty-six subjects (mean age, 14.8 years, range, 5-24 years) with RPE65-RD underwent SD-OCT and FAF imaging, of whom 14 subjects were followed up over time. Foveal thickness (FT), outer nuclear layer thickness (ONLT), ellipsoid zone width (EZW), and ellipsoid zone area (EZA) were calculated where possible. These were correlated with age, best corrected visual acuity (BCVA), and central 30° retinal sensitivity (V30). Intra-observer agreement, test-retest repeatability, and interocular symmetry were also investigated. Results: We identified structural interocular symmetry, the presence of autofluorescence in 46% (12/26) of subjects, and the presence of foveal hypoplasia (associated with significantly worse BCVA) in 50% of subjects. EZW and EZA were measurable in 67% (35/52) and 37% (19/52) of eyes, respectively, with both demonstrating good agreement on repeated measurement. The annual rate of progression using EZW was -300.63 µm/year, and -1.17 mm2/year in EZA. EZW was found to have a statistically significant correlation with BCVA and V30. Conclusions: We identified the presence of autofluorescence in half of our subjects, with foveal hypoplasia also noted in half of our cohort. EZW, and to a lesser extent EZA, were robust measures of retinal degeneration and represent valuable metrics to determine the impact of intervention. (ClinicalTrials.gov number NCT02714816.).

Detailed clinical characterisation, unique features and natural history of autosomal recessive RDH12-associated retinal degeneration.

BACKGROUND: Defects in retinol dehydrogenase 12 (RDH12) account for 3.4%-10.5 % of Leber congenital amaurosis and early-onset severe retinal dystrophy (EOSRD) and are a potential target for gene therapy. Clinical trials in inherited retinal diseases have unique challenges, and natural history studies are critical to successful trial design. The purpose of this study was to characterise the natural history of RDH12-associated retinal degeneration. METHODS: A retrospective chart review was performed in individuals with retinal degeneration and two likely disease-causing variants in RDH12. RESULTS: 57 subjects were enrolled from nine countries. 33 subjects had clinical records available from childhood. The data revealed an EOSRD, with average age of onset of 4.1 years. Macular atrophy was a universal clinical finding in all subjects, as young as 2 years of age. Scotopic and photopic electroretinography (ERG) responses were markedly reduced in all subjects, and a non-recordable ERG was documented as young as 1 year of age. Assessment of visual acuity, visual field and optical coherence tomography revealed severe loss of function and structure in the majority of subjects after the age of 10 years. Widefield imaging in 23 subjects revealed a unique, variegated watercolour-like pattern of atrophy in 13 subjects and sparing of the peripapillary area in 18 subjects. CONCLUSIONS: This study includes the largest collection of phenotypic data from children with RDH12-associated EOSRD and provides a comprehensive description of the timeline of vision loss in this severe, early-onset condition. These findings will help identify patients with RDH12-associated retinal degeneration and will inform future design of therapeutic trials.

Cross-Sectional and Longitudinal Assessment of the Ellipsoid Zone in Childhood-Onset Stargardt Disease.

PURPOSE: To evaluate the reliability of ellipsoid zone (EZ) loss width and area measurements from spectral-domain optical coherence tomography (SD-OCT) images and track disease progression in childhood-onset Stargardt disease (STGD1). METHODS: Children with molecularly confirmed STGD1 (n = 46, mean age 12.4 years) underwent SD-OCT for the measurement of the transverse (width) loss of the EZ and en face analysis to quantify the area of EZ loss. All scans were analyzed twice by two graders to evaluate reliability. The annual rate of EZ width and area loss were calculated. RESULTS: The intra- and intergrader reliability of transverse EZ loss and area of EZ loss measurements at baseline for both graders was 0.99. The mean annual rate of transverse EZ loss (±standard deviation) was 279.5 ± 259.9 µm/y. The mean rate of area of EZ loss (±standard deviation) was 1.20 ± 1.29 mm2/y. The percentage transverse EZ loss was 10.2 ± 9.9%/y, which was significantly lower than the area of EZ loss at 19.4 ± 16.3%/y. High degree of interocular symmetry was observed. CONCLUSIONS: This is a prospective study on the quantification of EZ loss in children with STGD1 and highlights the reliability of SD-OCT in measuring EZ loss. High intra- and intergrader reliability was observed, with good ability to detect changes over time. TRANSLATIONAL RELEVANCE: Measuring the area of EZ loss was more sensitive compared with transverse EZ width loss measurements and will be valuable for natural history studies and clinical trials requiring sensitive and reliable structural endpoints.

Adaptive Optics Retinal Imaging in CNGA3-Associated Achromatopsia: Retinal Characterization, Interocular Symmetry, and Intrafamilial Variability.

Purpose: To investigate retinal structure in subjects with CNGA3-associated achromatopsia and evaluate disease symmetry and intrafamilial variability. Methods: Thirty-eight molecularly confirmed subjects underwent ocular examination, optical coherence tomography (OCT), and nonconfocal split-detection adaptive optics scanning light ophthalmoscopy (AOSLO). OCT scans were used for evaluating foveal hypoplasia, grading foveal ellipsoid zone (EZ) disruption, and measuring outer nuclear layer (ONL) thickness. AOSLO images were used to quantify peak foveal cone density, intercell distance (ICD), and the coefficient of variation (CV) of ICD. Results: Mean (±SD) age was 25.9 (±13.1) years. Mean (± SD) best corrected visual acuity (BCVA) was 0.87 (±0.14) logarithm of the minimum angle of resolution. Examination with OCT showed variable disruption or loss of the EZ. Seven subjects were evaluated for disease symmetry, with peak foveal cone density, ICD, CV, ONL thickness, and BCVA not differing significantly between eyes. A cross-sectional evaluation of AOSLO imaging showed a mean (±SD) peak foveal cone density of 19,844 (±13,046) cones/mm2. There was a weak negative association between age and peak foveal cone density (r = -0.397, P = 0.102), as well as between EZ grade and age (P = 0.086). Conclusions: The remnant cone mosaics were irregular and variably disrupted, with significantly lower peak foveal cone density than unaffected individuals. Variability was also seen among subjects with identical mutations. Therefore, subjects should be considered on an individual basis for stratification in clinical trials. Interocular symmetry suggests that both eyes have comparable therapeutic potential and the fellow eye can serve as a valid control. Longitudinal studies are needed, to further examine the weak negative association between age and foveal cone structure observed here.

Cross-Sectional and Longitudinal Assessment of Retinal Sensitivity in Patients With Childhood-Onset Stargardt Disease.

PURPOSE: We assess cross-sectional and longitudinal microperimetry and full-field static perimetry-derived retinal sensitivity with conventional and volumetric indices of retinal function in childhood-onset Stargardt disease (STGD1). METHODS: Subjects with molecularly confirmed childhood-onset STGD1 underwent full-field static perimetry and/or microperimetry using custom designed grids. Mean sensitivity (MS) and total volume (VTOT) were computed for each microperimetry test. MS, VTOT, and central field volume (V30) were computed for each full-field static perimetry test. Subjects under 18 years old at baseline were classified as children and subjects 18 years or older as adults. RESULTS: A total of 43 children (mean age at baseline, 13.0 years; range, 8-17) and 13 adults (mean age at baseline, 23.1 years; range, 18-32) were included in the analysis. For full-field static perimetry and microperimetry for both subgroups, intraclass correlation coefficient results for MS and volumetric indices were good to excellent, indicating strong test-retest reliability. Interocular symmetry in terms of baseline measurements and the annual rate of progression was observed. A greater rate of progression was observed in childhood. CONCLUSIONS: To our knowledge, this is the first prospective study of retinal sensitivity in a large cohort of molecularly confirmed subjects with childhood-onset STGD1 demonstrating that children with STGD1 can reliably undertake detailed functional testing. Moreover, using custom designed grids and subsequent topographic analysis, volumetric indices of retinal function provide a reliable measure of retinal sensitivity. TRANSLATIONAL RELEVANCE: This study highlights the use of microperimetry and full-field static perimetry, as well as volumetric indices of retinal function, in monitoring disease progression.

Longitudinal Assessment of Retinal Structure in Achromatopsia Patients With Long-Term Follow-up.

Purpose: To longitudinally characterize structural retinal changes in achromatopsia (ACHM) over extended follow-up. Methods: Fifty molecularly confirmed ACHM subjects underwent serial spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) imaging. Foveal structure on SD-OCT was graded and compared for evidence of progression, and foveal total retinal thickness (FTRT) and outer nuclear layer (ONL) thickness were serially measured. FAF patterns were characterized and compared over time. Results: Mean SD-OCT follow-up was 61.6 months (age range at baseline, 6-52 years). Forty-five of the subjects had serial FAF (mean follow-up: 48.5 months). Only 6 (12%) of the subjects demonstrated qualitative change on serial foveal SD-OCT scans. Among the entire cohort, there was no statistically significant change over time in FTRT (P = 0.2459) or hyporeflective zone (HRZ) diameter (P = 0.3737). There was a small-but statistically significant-increase in ONL thickness (P = 0.0084). Three different FAF patterns were observed: centrally increased FAF (13/45), normal FAF (14/45), and well-demarcated reduced FAF (18/45), with the latter group displaying a small gradual increase in the area of reduced FAF of 0.055 mm2 over 43.4 months (P = 0.0011). Conclusions: This longitudinal study of retinal structure in ACHM represents the largest cohort and longest follow-up period to date. Our findings support the presiding notion that ACHM is essentially a stationary condition regarding retinal structure, and any change over time is likely to be small, slow, and variable across patients. This may potentially afford a wider window for therapeutic intervention.