A Retrospective Longitudinal Study of 460 Patients with ABCA4-Associated Retinal Disease.

PURPOSE: To investigate the distribution of genotypes and natural history of ABCA4-associated retinal disease in a large cohort of patients seen at a single institution. DESIGN: Retrospective, single-institution cohort review. PARTICIPANTS: Patients seen at the University of Iowa between November 1986 and August 2022 clinically suspected to have disease caused by sequence variations in ABCA4. METHODS: DNA samples from participants were subjected to a tiered testing strategy progressing from allele-specific screening to whole genome sequencing. Charts were reviewed, and clinical data were tabulated. The pathogenic severity of the most common alleles was estimated by studying groups of patients who shared 1 allele. Groups of patients with shared genotypes were reviewed for evidence of modifying factor effects. MAIN OUTCOME MEASURES: Age at first uncorrectable vision loss, best-corrected visual acuity, and the area of the I2e isopter of the Goldmann visual field. RESULTS: A total of 460 patients from 390 families demonstrated convincing clinical features of ABCA4-associated retinal disease. Complete genotypes were identified in 399 patients, and partial genotypes were identified in 61. The median age at first vision loss was 16 years (range, 4-76 years). Two hundred sixty-five families (68%) harbored a unique genotype, and no more than 10 patients shared any single genotype. Review of the patients with shared genotypes revealed evidence of modifying factors that in several cases resulted in a > 15-year difference in age at first vision loss. Two hundred forty-one different alleles were identified among the members of this cohort, and 161 of these (67%) were found in only a single individual. CONCLUSIONS: ABCA4-associated retinal disease ranges from a very severe photoreceptor disease with an onset before 5 years of age to a late-onset retinal pigment epithelium-based condition resembling pattern dystrophy. Modifying factors frequently impact the ABCA4 disease phenotype to a degree that is similar in magnitude to the detectable ABCA4 alleles themselves. It is likely that most patients in any cohort will harbor a unique genotype. The latter observations taken together suggest that patients' clinical findings in most cases will be more useful for predicting their clinical course than their genotype. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Surgical Management of Full-Thickness Macular Holes in Macular Telangiectasia Type 2: A Global Multicenter Study.

PURPOSE: To report on macular hole repair in macular telangiectasia type 2 (MacTel2). DESIGN: Global, multicenter, retrospective case series. PARTICIPANTS: Patients undergoing surgery for MacTel2-associated full-thickness macular hole (MTMH). METHODS: Standardized data collection sheet distributed to all surgeons. MAIN OUTCOME MEASURES: Anatomic closure and visual outcomes of MTMH. RESULTS: Sixty-three surgeries in 47 patients with MTMH were included from 30 surgeons. Mean age was 68.1 years, with 62% female, 72% White, 21% East or South Asian, 2% African American, and 2% Hispanic or Latino. Procedures included 34 internal limiting membrane (ILM) peeling alone, 22 ILM flaps, 5 autologous retinal transplantations (ARTs), 1 retinotomy, and 1 subretinal bleb. For ILM peeling, preoperative visual acuity (VA) was 0.667 ± 0.423 logarithm of the minimum angle of resolution (logMAR). Minimum hole diameter (MHD) was 305.5 ± 159.4 µm (range, 34-573 µm). Sixteen of 34 ILM peels (47%) resulted in MTMH closure. At postoperative month 6, VA was stable at 0.602 ± 0.516 logMAR (P = 0.65). VA improved by at least 2 lines in 43% and at least 4 lines in 24%. For ILM flaps, preoperative VA was 0.878 ± 0.552 logMAR. MHD was 440.8 ± 175.5 µm (range, 97-697 µm), which was significantly larger than for ILM peels (P < 0.01). Twenty of 22 ILM flaps (90%) resulted in MTMH closure, which was significantly higher than for ILM peels (P < 0.01). At postoperative month 6, VA improved to 0.555 ± 0.405 logMAR (P < 0.05). VA improved by at least 2 lines in 56% and at least 4 lines in 28%. For ARTs, preoperative VA was 1.460 ± 0.391 logMAR. MHD was 390.2 ± 203.7 µm (range, 132-687 µm). All 5 ARTs (100%) resulted in MTMH closure. At postoperative month 6, VA was stable at 1.000 ± 0.246 logMAR (P = 0.08). Visual acuity improved at least 2 lines in 25%. CONCLUSIONS: Surgical closure of macular holes improved VA in 57% of MTMHs. Internal limiting membrane flaps achieved better anatomic and functional outcomes than ILM peeling alone. Autologous retinal transplantation may be an option for refractory MTMHs. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Demonstration of the pathogenicity of a common non-exomic mutation in ABCA4 using iPSC-derived retinal organoids and retrospective clinical data.

Mutations in ABCA4 are the most common cause of Mendelian retinal disease. Clinical evaluation of this gene is challenging because of its extreme allelic diversity, the large fraction of non-exomic mutations, and the wide range of associated disease. We used patient-derived retinal organoids as well as DNA samples and clinical data from a large cohort of patients with ABCA4-associated retinal disease to investigate the pathogenicity of a variant in ABCA4 (IVS30 + 1321 A > G) that occurs heterozygously in 2% of Europeans. We found that this variant causes mis-splicing of the gene in photoreceptor cells such that the resulting protein contains 36 incorrect amino acids followed by a premature stop. We also investigated the phenotype of 10 patients with compound genotypes that included this mutation. Their median age of first vision loss was 39 years, which is in the mildest quintile of a large cohort of patients with ABCA4 disease. We conclude that the IVS30 + 1321 A > G variant can cause disease when paired with a sufficiently deleterious opposing allele in a sufficiently permissive genetic background.

Long-term functional and structural outcomes in X-linked retinoschisis: implications for clinical trials.

Introduction: X-linked retinoschisis (XLRS) is an inherited retinal disease (IRD) caused by pathogenic mutations in the retinoschisin gene, RS1. Affected individuals develop retinal layer separation, leading to loss of visual acuity (VA). Several XLRS gene therapy trials have been attempted but none have met their primary endpoints. An improved understanding of XLRS natural history and clinical outcomes may better inform future trials. Here, we report the long-term functional and structural outcomes of XLRS and the relevance of RS1 genotypes to the visual prognosis of affected individuals. Methods: A retrospective chart review of patients with molecularly confirmed X-linked retinoschisis was performed. Functional and structural outcomes, and RS1 genotype data, were included for analysis. Results: Fifty-two patients with XLRS from 33 families were included in the study. Median age at symptom onset was 5 years (range 0-49) and median follow-up was 5.7 years (range 0.1-56.8). Macular retinoschisis occurred in 103 of 104 eyes (99.0%), while peripheral retinoschisis occurred in 48 of 104 eyes (46.2%), most often in the inferotemporal quadrant (40.4%). Initial and final VA were similar (logMAR 0.498 vs. 0.521; p = 0.203). Fifty of 54 eyes (92.6%) developed detectable outer retinal loss by age 20, and 29 of 66 eyes (43.9%) had focal or diffuse outer retinal atrophy (ORA) by age 40. ORA but not central subfield thickness (CST) was associated with reduced VA. Inter-eye correlation was modest for VA (r-squared = 0.03; p = 0.08) and CST (r-squared = 0.15; p = 0.001). Carbonic anhydrase inhibitors (CAIs) improved CST (p = 0.026), but not VA (p = 0.380). Eight of 104 eyes (7.7%) had XLRS-related retinal detachment (RD), which was associated with poorer outcomes compared to eyes without RD (median final VA 0.875 vs. 0.487; p <0.0001). RS1 null genotypes had greater odds of at least moderate visual impairment at final follow-up (OR 7.81; 95% CI 2.17, 28.10; p = 0.002) which was independent of age at onset, initial CST, initial ORA, or previous RD. Discussion: Overall, long-term follow-up of XLRS patients demonstrated relatively stable VA, with presenting CST, development of ORA, and null RS1 mutations associated with poorer long-term visual outcomes, indicating a clinically relevant genotype-phenotype correlation in XLRS.

Retinal Sublayer Analysis in Autoimmune Retinopathy and Identification of New Optical Coherence Tomography Phenotypes.

PURPOSE: Autoimmune retinopathy (AIR) is a poorly characterized disease with a wide phenotypic spectrum, complicating investigations of its underlying pathophysiology. We sought to analyze optical coherence tomography (OCT) retinal thickness changes in AIR patients. METHODS: A retrospective chart review from 2007 to 2017 was performed evaluating AIR patients at a single academic, tertiary referral center. OCT retinal sublayer analysis was performed, and paradoxical thickening phenotypes were reviewed. RESULTS: Twenty-nine AIR patients with positive anti-retinal antibodies and OCT imaging were identified. Overall, AIR patients had thinner retinal sublayers compared to controls; however, 12 patients (41.4%) had paradoxical thickening of the outer plexiform layer (OPL). This revealed two distinct OCT phenotypes. No association was found between retinal sublayer thickness and specific antiretinal antibodies. CONCLUSIONS: While the pathogenicity of antiretinal antibodies remains unclear, the OCT phenotypes observed underscore the potential for identifying clues in the underlying disease processes and clinical diagnosis.

MACULAR ATROPHY AND PHENOTYPIC VARIABILITY IN AUTOSOMAL DOMINANT STARGARDT-LIKE MACULAR DYSTROPHY DUE TO PROM1 MUTATION.

PURPOSE: To describe the phenotypic variability and rates of progression of atrophy in patients with PROM1 -associated macular dystrophy. METHODS: Patients in this retrospective, longitudinal case series from a tertiary center had clinical examination and multimodal imaging performed. Areas of retinal pigment epithelium and ellipsoid zone loss over time by optical coherence tomography were calculated by two independent graders. RESULTS: Fifteen patients from five kindreds with an Arg373Cys mutation in PROM1 were studied. The average age was 39 years, and 80% were women. The visual acuity was 20/40 at presentation and 20/57 at last follow-up (average 4.8 years). Three distinct macular phenotypes were observed: 1) central geographic atrophy (13%), 2) multifocal geographic atrophy (20%), and 3) bull's eye maculopathy (67%). The overall rate of atrophy progression was 0.36 mm 2 /year, but the average rate of atrophy progression varied by macular phenotype: 1.08 mm 2 /year for central geographic atrophy, 0.53 mm 2 /year for multifocal geographic atrophy, and 0.23 mm 2 /year for bull's eye maculopathy. CONCLUSION: Patients with PROM1 -associated macular dystrophy demonstrate distinct phenotypes, with bull's eye maculopathy being the most common. The average rate of atrophy progression may be similar to reported rates for ABCA4 -related Stargardt disease and less than age-related macular degeneration. These results provide important measures for following treatment response in future gene and stem cell-based therapies.

The Ocular Trauma Score Underestimates Visual Recovery for the Most Severe Open-Globe Injuries.

PURPOSE: To compare visual outcomes after open-globe injury (OGI) with those predicted by the Ocular Trauma Score (OTS), and to investigate the effect of treatment with pars plana vitrectomy (PPV). DESIGN: Retrospective cohort study. SUBJECTS: Patients presenting with OGI to an academic United States ophthalmology department from 2017 to 2020. METHODS: Best-corrected visual acuity (VA) measurements at the most recent follow-up were compared with final VA predicted by the OTS, based on preoperative injury characteristics. The most recently measured VA of patients treated with PPV during initial OGI repair (primary PPV group) was compared with patients treated with PPV after initial OGI repair (secondary PPV group) and patients never treated with PPV (No PPV group). MAIN OUTCOME MEASURES: Best-corrected VA in the injured eye at last follow-up; secondary outcome measures included the occurrence of vitreous hemorrhage at any time, occurrence of retinal detachment at any time, rates of additional surgery, and rates of enucleation. RESULTS: One-hundred and thirty-three subjects with OGI were identified and analyzed. The overall rate of PPV was 32%. Predictors of worse VA at last follow-up included older age (P = 0.047) and worse presenting VA (P < 0.001). Visual acuity outcomes for eyes in OTS categories 2 to 5 did not significantly differ from OTS predictions. However, eyes in OTS category 1 had a higher likelihood of last follow-up VA of light perception (LP) to hand motion (46% in the study cohort vs. 15% predicted by the OTS, P = 0.004) and a lower likelihood of no LP (33% vs. 74%, P < 0.001). The secondary PPV group had the worst VA at presentation among the 3 groups (P = 0.016), but VA at last follow-up did not significantly differ between the study groups (P = 0.338). CONCLUSIONS: The most severe OGIs (i.e., OTS category 1) had better visual outcomes than predicted by the published OTS expectations, and secondary PPV was associated with significant visual improvement despite poor prognostic predictions. Evaluation by a vitreoretinal surgeon should be considered for all patients with severe OGI, especially those in OTS category 1. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Choroidal Neovascularization Is Common in Best Vitelliform Macular Dystrophy and Plays a Role in Vitelliform Lesion Evolution.

OBJECTIVE: Choroidal neovascularization (CNV) is usually considered to be a late-stage complication in Best vitelliform macular dystrophy (BVMD) and can be difficult to diagnose with fluorescein angiography. This study used swept-source (SS) OCT angiography (OCTA) to evaluate the prevalence of CNV in BVMD, identify structural features associated with CNV, and provide insight into the role of CNV in vitelliform lesion evolution. DESIGN: Institutional review board-approved, retrospective, cross-sectional, and longitudinal study. PARTICIPANTS: Patients with molecularly confirmed BVMD. METHODS: Charts from consecutive patients with BVMD imaged with SS-OCTA (PLEX Elite 9000, Carl-Zeiss Meditec Inc) at the University of Iowa from September 2017 to October 2021 were reviewed. Clinical data, including age, gender, best-corrected visual acuity (BCVA), and treatment with intravitreal anti-VEGF injections were recorded. The presence of CNV on SS-OCTA was determined by expert graders and correlated with structural features, such as interstitial fluid, subretinal fluid, nodular subretinal pillar, focal choroidal excavation (FCE), and subfoveal choroidal thickness, with a P value of < 0.05 considered statistically significant. MAIN OUTCOME MEASURES: Presence of CNV on SS-OCTA and correlation with structural features on SS-OCT. RESULTS: A total of 53 eyes from 27 patients (13 women; 48.1%) were included. The mean age was 45 years (range, 8-79 years), and the mean logarithm of the minimum angle of resolution BCVA was 0.38 (range, 0-1). Choroidal neovascularization was identified on SS-OCTA in 27 eyes (50.9%), of which 63.0% had a vitelliform (Gass stage 2) lesion. In 40.7% (11 of 27) of eyes, there was no prior clinical diagnosis of CNV. Other structural features associated with CNV included FCEs (15.1%, 8 of 53 eyes) and nodular pillars (15.1%, 8 of 53 eyes) (P < 0.01). Seven patients had available longitudinal imaging, and most of these patients had CNV visible on SS-OCTA (71.4%; 10 of 14 eyes). CONCLUSION: Choroidal neovascularization is common in BVMD, including in the early stages of the disease. The presence of FCEs or nodular pillars should heighten the clinical suspicion of CNV, which may accelerate vitelliform lesion evolution. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Total retinal thickness: a neglected factor in the evaluation of inner retinal thickness.

AIM: To determine whether macular retinal nerve fibre layer (mRNFL) and ganglion cell-inner plexiform layer (GC-IPL) thicknesses vary by ethnicity after accounting for total retinal thickness. METHODS: We included healthy participants from the UK Biobank cohort who underwent macula-centred spectral domain-optical coherence tomography scans. mRNFL and GC-IPL thicknesses were determined for groups from different self-reported ethnic backgrounds. Multivariable regression models adjusting for covariables including age, gender, ethnicity and refractive error were built, with and without adjusting for total retinal thickness. RESULTS: 20237 participants were analysed. Prior to accounting for total retinal thickness, mRNFL thickness was on average 0.9 µm (-1.2, -0.6; p<0.001) lower among Asians and 1.5 µm (-2.3, -0.6; p<0.001) lower among black participants compared with white participants. Prior to accounting for total retinal thickness, the average GC-IPL thickness was 1.9 µm (-2.5, -1.4; p<0.001) lower among Asians compared with white participants, and 2.4 µm (-3.9, -1.0; p=0.001) lower among black participants compared with white participants. After accounting for total retinal thickness, the layer thicknesses were not significantly different among ethnic groups. When considered as a proportion of total retinal thickness, mRNFL thickness was ~0.1 and GC-IPL thickness was ~0.2 across age, gender and ethnic groups. CONCLUSIONS: The previously reported ethnic differences in layer thickness among groups are likely driven by differences in total retinal thickness. Our results suggest using layer thickness ratio (retinal layer thicknesses/total retinal thickness) rather than absolute thickness values when comparing retinal layer thicknesses across groups.

Biocompatibility of Human Induced Pluripotent Stem Cell-Derived Retinal Progenitor Cell Grafts in Immunocompromised Rats.

Loss of photoreceptor cells is a primary feature of inherited retinal degenerative disorders including age-related macular degeneration and retinitis pigmentosa. To restore vision in affected patients, photoreceptor cell replacement will be required. The ideal donor cells for this application are induced pluripotent stem cells (iPSCs) because they can be derived from and transplanted into the same patient obviating the need for long-term immunosuppression. A major limitation for retinal cell replacement therapy is donor cell loss associated with simple methods of cell delivery such as subretinal injections of bolus cell suspensions. Transplantation with supportive biomaterials can help maintain cellular integrity, increase cell survival, and encourage proper cellular alignment and improve integration with the host retina. Using a pig model of retinal degeneration, we recently demonstrated that polycaprolactone (PCL) scaffolds fabricated with two photon lithography have excellent local and systemic tolerability. In this study, we describe rapid photopolymerization-mediated production of PCL-based bioabsorbable scaffolds, a technique for loading iPSC-derived retinal progenitor cells onto the scaffold, methods of surgical transplantation in an immunocompromised rat model and tolerability of the subretinal grafts at 1, 3, and 6 months of follow-up (n = 150). We observed no local or systemic toxicity, nor did we observe any tumor formation despite extensive clinical evaluation, clinical chemistry, hematology, gross tissue examination and detailed histopathology. Demonstrating the local and systemic compatibility of biodegradable scaffolds carrying human iPSC-derived retinal progenitor cells is an important step toward clinical safety trials of this approach in humans.

Age-Related Macular Degeneration Masquerade: A Review of Pentosan Polysulfate Maculopathy and Implications for Clinical Practice.

ABSTRACT: Pentosan polysulfate (PPS) sodium (Elmiron) is the only Food and Drug Administration (FDA)-approved oral medication to treat interstitial cystitis, also known as bladder pain syndrome. A symptomatic pigmentary maculopathy associated with PPS was reported in 2018. Since then, recognition of this unique drug toxicity has increased rapidly. This potentially sight-threatening side effect prompted the FDA in June 2020 to update the label for PPS to warn about "retinal pigmentary changes." A challenging feature of pentosan maculopathy is its ability to mimic many other retinal conditions, including inherited retinal dystrophies such as pattern dystrophy, mitochondrially inherited diabetes and deafness, and Stargardt disease, and age-related macular degeneration. In this review, we discuss the history of PPS maculopathy and its implications for thousands of at-risk interstitial cystitis patients. We use published literature and an illustrative case from our institution to highlight the importance of diagnosing PPS maculopathy. We also compare PPS maculopathy to age-related macular degeneration, explain why differentiating between the 2 is clinically important, and highlight avenues for further research. Finally, we highlight the paucity of data on patients of color and why this lack of understanding may impact patient care.

Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial.

CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 ( NCT03140969 ), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit-risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development.

Predominance of hyperopia in autosomal dominant Best vitelliform macular dystrophy.

BACKGROUND/AIMS: Patients with BEST1-associated autosomal dominant Best vitelliform macular dystrophy (AD-BVMD) have been reported to be hyperopic, but the prevalence of refractive error has not been described. This study aimed to characterise the type and degree of refractive error in a large cohort of patients with AD-BVMD compared with an age-similar group with ABCA4-associated Stargardt disease. METHODS: This was a retrospective chart review of consecutive patients with molecularly confirmed AD-BVMD and Stargardt macular dystrophy seen at a single academic centre. Demographic information, including age, gender and genotype were extracted from the chart. The best corrected visual acuity (BCVA), as well as type and degree of refractive error on manifest refraction for each eye on each visit, were recorded and compared. RESULTS: A total of 178 eyes from 89 patients with AD-BVMD (35 women, 54 men; mean age 36.6 years) and 306 eyes from 153 patients (94 women, 59 men, mean age 30.2 years) with Stargardt disease were included in the study. Mean BCVA was excellent for both AD-BVMD and Stargardt eyes (logMAR 0.23 vs logMAR 0.31, respectively; p=0.55). At initial refraction, 73.0% of AD-BVMD eyes (130/178) were hyperopic, with mean spherical equivalent (SE) +1.38 dioptres (median +0.88) whereas 80.7% of Stargardt eyes (247/306) were myopic, with mean SE of -1.76 dioptres (median -1.19) (p<0.001). CONCLUSION: Patients with AD-BVMD are predominantly hyperopic, whereas those with Stargardt disease are predominantly myopic. The findings provide further evidence of a role for BEST1 in ocular growth and development.

Long-Term Outcomes and Risk Factors for Severe Vision Loss in Autosomal Dominant Neovascular Inflammatory Vitreoretinopathy (ADNIV).

Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) is a rare disorder characterized by uveitis, retinal neovascularization, and retinal degeneration. We sought to describe the course of treated and untreated ADNIV and to identify risk factors for severe vision loss. DESIGN: Observational case series. METHODS: Clinical data from ADNIV patients from 4 families seen from 1967 through 2019 at a single academic, tertiary referral center were reviewed. The main outcome measures were visual acuity at baseline and follow-up, as well as risk factors for vision loss. RESULTS: A total of 130 eyes from 65 ADNIV patients (45 female, 20 male; mean age 40.8 years, range 6-77 years) were included. Mean best corrected visual acuity (BCVA) at presentation was LogMAR 0.59 (about Snellen 20/80). Longitudinal analysis included 84 eyes from 42 patients (31 female, 11 male), with mean follow-up of 17.3 years (range 2-43.6 years). Mean BCVA at last follow-up was LogMAR 1.48 (about Snellen 20/600). The disease accelerated in the fifth decade of life, during which the majority of eyes went from normal vision or mild vision loss to at least moderate vision loss (20/70 Snellen equivalent); 25 eyes from 16 patients (29.8%;) showed a steep trajectory of vision loss to no light perception. Tractional retinal detachment was the greatest risk factor for severe vision loss (BCVA <20/200) on multivariable analysis (P < .05). CONCLUSIONS: Patients with ADNIV have a high lifetime risk of severe vision loss. Tractional retinal detachment is an important risk factor for poor vision.

Automated segmentation of choroidal layers from 3-dimensional macular optical coherence tomography scans.

BACKGROUND: Changes in choroidal thickness are associated with various ocular diseases, and the choroid can be imaged using spectral-domain optical coherence tomography (SD-OCT) and enhanced depth imaging OCT (EDI-OCT). NEW METHOD: Eighty macular SD-OCT volumes from 80 patients were obtained using the Zeiss Cirrus machine. Eleven additional control subjects had two Cirrus scans done in one visit along with enhanced depth imaging (EDI-OCT) using the Heidelberg Spectralis machine. To automatically segment choroidal layers from the OCT volumes, our graph-theoretic approach was utilized. The segmentation results were compared with reference standards from two independent graders, and the accuracy of automated segmentation was calculated using unsigned/signed border positioning/thickness errors and Dice similarity coefficient (DSC). The repeatability and reproducibility of our choroidal thicknesses were determined by intraclass correlation coefficient (ICC), coefficient of variation (CV), and repeatability coefficient (RC). RESULTS: The mean unsigned/signed border positioning errors for the choroidal inner and outer surfaces are 3.39 ± 1.26 µm (mean ± standard deviation)/- 1.52 ± 1.63 µm and 16.09 ± 6.21 µm/4.73 ± 9.53 µm, respectively. The mean unsigned/signed choroidal thickness errors are 16.54 ± 6.47 µm/6.25 ± 9.91 µm, and the mean DSC is 0.949 ± 0.025. The ICC (95% confidence interval), CV, RC values are 0.991 (0.977-0.997), 2.48%, 14.25 µm for the repeatability and 0.991 (0.977-0.997), 2.49%, 14.30 µm for the reproducibility studies, respectively. COMPARISON WITH EXISTING METHOD(S): The proposed method outperformed our previous method using choroidal vessel segmentation and inter-grader variability. CONCLUSIONS: This automated segmentation method can reliably measure choroidal thickness using different OCT platforms.

Mitochondrial DNA A3243G variant-associated retinopathy: a meta-analysis of the clinical course of visual acuity and correlation with systemic manifestations.

PURPOSE: The mitochondrial DNA A3243G (m.3243A>G) variant causes a wide spectrum of phenotypes, with pigmentary retinopathy as the most common ocular finding. We undertook this meta-analysis to investigate the clinical course of visual acuity (VA) in patients with m.3243A>G variant and provide key clinical correlations with systemic manifestations. METHODS: A PubMed literature search was performed and studies were selected after satisfying pre-set inclusion criteria. Demographic and clinical data, including retinal findings and systemic manifestations were recorded. Cross-sectional and linear regression analyses were used to investigate the relationship between VA and age, as well as between the age at diagnosis of retinopathy and the mean ages at diagnosis of sensorineural hearing loss or diabetes. The age and prevalence of systemic manifestations among patients with and without retinopathy were studied using t-tests and Mann-Whitney U-tests (performed on binarized data). Likelihood ratios were computed. RESULTS: The mean VA (average of both eyes) of 90 patients (72.2% female; 65/90) were collected from 18 studies published between 1990 and 2018. The baseline mean age was 45.2 years (range 17 to 92). The mean logMAR VA was 0.10 (- 0.12 to 1.39). There was a statistically significant linear correlation between the logMAR VA and age (p = .008). The VA of patients less than or equal to 50 years of age was significantly better than that of patients older than 50 years (0.06 vs.0.18 logMAR, p = .002). 67 patients (74.4%) showed a characteristic pigmentary retinopathy with a mean age at diagnosis of 47.9 years (17 to 92) and VA of 0.14 logMAR (- 0.12 to 1.24). Age at diagnosis of retinopathy was linearly correlated with age at diagnosis of hearing loss or diabetes (p < .001). Patients with retinopathy were more likely to have hearing loss (83.6% vs. 56.5%, p = .03) or diabetes (56.7% vs. 17.4%, p = .001) than those without retinopathy. Those with both hearing loss and diabetes had an earlier onset of retinopathy than those without (46.4 vs. 60.4 years, p = .01). Patients without both hearing loss and diabetes were 5.3-fold less likely to develop a retinopathy. CONCLUSIONS: Patients with m.3243A>G variant pigmentary retinopathy maintain highly functional VA until around the fifth decade of life, after which significant visual decline ensues. Patients without hearing loss and diabetes have a lower likelihood of exhibiting a retinopathy, which tends to appear about one decade after hearing loss and diabetes are diagnosed.

The effect of retinal scaffold modulus on performance during surgical handling.

Emerging treatment strategies for retinal degeneration involve replacing lost photoreceptors using supportive scaffolds to ensure cells survive the implantation process. While many design aspects of these scaffolds, including material chemistry and microstructural cues, have been studied in depth, a full set of design constraints has yet to be established. For example, while known to be important in other tissues and systems, the influence of mechanical properties on surgical handling has not been quantified. In this study, photocrosslinked poly(ethylene glycol) dimethacrylate (PEGDMA) was used as a model polymer to study the effects of scaffold modulus (stiffness) on surgical handling, independent of material chemistry. This was achieved by modulating the molecular weight and concentrations of the PEGDMA in various prepolymer solutions. Scaffold modulus of each formulation was measured using photo-rheology, which enabled the collection of real-time polymerization data. In addition to measuring scaffold mechanical properties, this approach gave insight on polymerization kinetics, which were used to determine the polymerization time required for each sample. Scaffold handling characteristics were qualitatively evaluated using both in vitro and ex vivo trials that mimicked the surgical procedure. In these trials, scaffolds with shear moduli above 35 kPa performed satisfactorily, while those below this limit performed poorly. In other words, scaffolds below this modulus were too fragile for reliable transplantation. To better compare these results with literature values, the compressive modulus was measured for select samples, with the lower shear modulus limit corresponding to roughly 115 kPa compressive modulus. While an upper mechanical property limit was not readily apparent from these results, there was increased variability in surgical handling performance in samples with shear moduli above 800 kPa. Overall, the knowledge presented here provides important groundwork for future studies designed to examine additional retinal scaffold considerations, including the effect of scaffold mechanical properties on retinal progenitor cell fate.