Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders.

PURPOSE: To identify genetic etiologies and genotype/phenotype associations for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs). METHODS: We coupled phenotyping with exome or genome sequencing of 467 probands (550 affected and 1108 total individuals) with genetically unsolved oCCDDs, integrating analyses of pedigrees, human and animal model phenotypes, and de novo variants to identify rare candidate single nucleotide variants, insertion/deletions, and structural variants disrupting protein-coding regions. Prioritized variants were classified for pathogenicity and evaluated for genotype/phenotype correlations. RESULTS: Analyses elucidated phenotypic subgroups, identified pathogenic/likely pathogenic variant(s) in 43/467 probands (9.2%), and prioritized variants of uncertain significance in 70/467 additional probands (15.0%). These included known and novel variants in established oCCDD genes, genes associated with syndromes that sometimes include oCCDDs (e.g., MYH10, KIF21B, TGFBR2, TUBB6), genes that fit the syndromic component of the phenotype but had no prior oCCDD association (e.g., CDK13, TGFB2), genes with no reported association with oCCDDs or the syndromic phenotypes (e.g., TUBA4A, KIF5C, CTNNA1, KLB, FGF21), and genes associated with oCCDD phenocopies that had resulted in misdiagnoses. CONCLUSION: This study suggests that unsolved oCCDDs are clinically and genetically heterogeneous disorders often overlapping other Mendelian conditions and nominates many candidates for future replication and functional studies.

In vivo quasi-elastic light scattering detects molecular changes in the lenses of adolescents with Down syndrome.

Down syndrome (DS) is the most common chromosomal disorder in humans. DS is associated with increased prevalence of several ocular sequelae, including characteristic blue-dot cerulean cataract. DS is accompanied by age-dependent accumulation of Alzheimer's disease (AD) amyloid-ß (Aß) peptides and amyloid pathology in the brain and comorbid early-onset Aß amyloidopathy and colocalizing cataracts in the lens. Quasi-elastic light scattering (QLS) is an established optical technique that noninvasively measures changes in protein size distributions in the human lens in vivo. In this cross-sectional study, lenticular QLS correlation time was decreased in adolescent subjects with DS compared to age-matched control subjects. Clinical QLS was consistent with alterations in relative particle hydrodynamic radius in lenses of adolescents with DS. These correlative results suggest that noninvasive QLS can be used to evaluate molecular changes in the lenses of individuals with DS.

The Incidence of Strabismus After Upper and Lower Blepharoplasty in the United States.

PURPOSE: To compare the incidence of strabismus after upper and lower blepharoplasty in the United States. METHODS: Retrospective cohort study of adults (age ≥18 years) in the IRIS Registry (Intelligent Research in Sight) who underwent blepharoplasty between January 1, 2013 and December 31, 2020. The primary outcome was the Kaplan-Meier estimated cumulative incidence of strabismus diagnosis and surgery within 3 years of blepharoplasty. Multivariable Cox regression was used to determine the association of blepharoplasty type with strabismus diagnosis and surgery, adjusting for patient age, sex, and geographic region. RESULTS: Blepharoplasty was performed in 368,623 patients (median [interquartile range] age, 69 [63-75] years, and 69% female). Compared with those undergoing upper eyelid blepharoplasty, patients treated with lower eyelid blepharoplasty were slightly younger (median age, 66 vs. 69 years; p < 0.001) and more likely to be female (71% vs. 69%; p < 0.001). There was a greater 3-year incidence of strabismus diagnosis (2.0% vs. 1.5%; p < 0.001) and a greater 3-year incidence of strabismus surgery (0.15% vs. 0.06%; p = 0.003) for individuals undergoing lower vs. upper blepharoplasty. After adjusting for age, sex, and geographic region, lower blepharoplasty was associated with a higher 3-year risk of strabismus diagnosis (HR, 1.49; 95% CI, 1.23-1.81; p < 0.001) and surgery (HR, 2.53; 95% CI, 1.27-5.03; p = 0.008). CONCLUSIONS: This registry-based analysis found that individuals undergoing lower eyelid blepharoplasty were at higher risk of strabismus compared with those undergoing upper eyelid blepharoplasty. Using large databases to understand the incidence of complications of frequently performed procedures may improve ophthalmologists' ability to provide data-driven counseling on surgical risks prior to intervention.

Challenges in management of congenital enophthalmos due to anomalous accessory orbital extraocular muscle bands.

INTRODUCTION: Congenital enophthalmos is a rare condition characterized by posterior displacement of the globe, often associated with bony orbital anomalies or whole globe development defects. The purpose of this report is to present two unrelated cases of congenital enophthalmos secondary to anomalous accessory orbital bands and to describe characteristics of orbital imaging that differentiate this condition from the other causes. METHODS: The case records of two patients who presented with congenital enophthalmos and were discovered to have anomalous accessory orbital extraocular muscle bands were reviewed. The clinical features, initial diagnosis, high resolution magnetic resonance imaging (MRI) findings, and surgical outcomes were noted. A 3-dimensional reconstruction model was used to understand the approach and surgical management in one of the cases. RESULTS: Both patients presented with unilateral severe enophthalmos, globe retraction, and restricted ocular motility in all directions since birth. High-resolution MRI of the orbits revealed a short anomalous band, isointense to the muscle, arising from a rectus muscle belly and attaching to the posteroinferior part of the globe adjacent to the optic nerve. The caliber of the extraocular muscles and ocular motor nerves was normal. In one patient, surgery was not pursued due to the extreme posterior location of the band with proximity to the optic nerve. In the other patient, the deviation did not improve, despite successfully severing the accessory band, due to extensive scarring. CONCLUSION: Anomalous accessory orbital extraocular muscle bands are a rare and often overlooked cause of congenital enophthalmos when associated with limited ocular motility. Imaging the orbit can aid in diagnosis and help differentiate it from other causes. Safe surgical approaches to address the problem are limited, and available approaches may not be effective. These two cases highlight that the management of accessory extraocular muscle bands causing enophthalmos can be extremely challenging and difficult to improve even with intensive surgical intervention.

Factors associated with the use of botulinum toxin injections for adult strabismus in the IRIS Registry.

This cross-sectional study used data from a large nationwide registry to describe the factors associated with use of botulinum toxin injections for adults with strabismus in the United States. Botulinum toxin injections were performed on 3.1% of adults undergoing an intervention for strabismus between 2013 and 2020. Adults treated with botulinum toxin injections were more likely to be older and female. Compared to non-Hispanic White patients, non-Hispanic Black patients were three times less likely to receive treatment with botulinum toxin after adjusting for age, sex, geographic region, and type of insurance. Efforts to understand the factors contributing to disparities in the use of botulinum toxin for strabismus may lead to opportunities for more equitable access to this intervention.

Correlation of Strabismus Surgical Outcomes Graded by Goal-Determined Metric With Patient Satisfaction Survey.

PURPOSE: Although strabismus surgery outcomes can be objectively measured, patient perception of results may differ. We present surgical outcomes graded by a prospective, "goal-determined metric" and compare these outcomes to results of a patient satisfaction survey. DESIGN: Validity analysis comparing a clinical "goal-determined metric" to patient satisfaction. METHODS: Goal-determined metric outcomes (2018-2021) for 2 surgeons treating esotropia or exotropia for diplopia control or reconstructive goals were collected. Inclusion required completion of postoperative examination 2-6 months after surgery and a satisfaction survey. RESULTS: Record review identified 275 patients; 228 (median age 41 years [interquartile range 13-59]) met inclusion criteria. For the entire cohort, 87% were graded as "excellent" outcomes, and 78% of patients were overall "very satisfied." Agreement between patients' and surgeons' grading was 75% to 79% for all reconstructive surgery and for treatment of diplopia from esotropia. Agreement was lower, although not statistically different, for treatment of diplopia from exotropia (64%, 95% CI 43%-80%; P = .184). Preoperative risk factors, concurrent vertical or oblique surgery, and sex did not affect outcomes or satisfaction. Performance of activities requiring distance viewing improved more than performance of activities at near after esotropia-diplopia surgery (odds ratio 3.0, 95% CI 1.5-6.4; P = .004). For reconstructive cases achieving "much better" eye alignment, 62% and 72% (previously esotropic and exotropic) reported enhanced self-confidence. CONCLUSIONS: Outcomes graded by goal-determined metric correlated well with many aspects of patient satisfaction. Patient-perceived improvement in appearance was important regardless of goal. Greater improvement in performance of activities requiring distance rather than near viewing characterized treatment of diplopia from esotropia.

Peripheral Binocular Imbalance in Anisometropic and Strabismic Amblyopia.

Purpose: Individuals with amblyopia experience central vision deficits, including loss of visual acuity, binocular vision, and stereopsis. In this study, we examine the differences in peripheral binocular imbalance in children with anisometropic amblyopia, strabismic amblyopia, and typical binocular vision to determine if there are systematic patterns of deficits across the visual field. Methods: This prospective cohort study recruited 12 participants with anisometropic amblyopia, 10 with strabismic amblyopia, and 10 typically sighted controls (age range, 5-18 years). Binocular imbalance was tested at 0°, 4°, and 8° eccentricities (4 angular locations each) using band-pass filtered Auckland optotypes (5 cycles per optotype) dichoptically presented with differing contrast to each eye. The interocular contrast ratio was adjusted until the participant reported each optotype with equal frequency. Results: Participants with anisometropic and strabismic amblyopia had a more balanced contrast ratio, or decreased binocular imbalance, at 4° and 8° eccentricities as compared with central vision. Participants with strabismic amblyopia had significantly more binocular imbalance in the periphery as compared with individuals with anisometropic amblyopia or controls. A linear mixed effects model showed a main effect for strabismic amblyopia and eccentricity on binocular imbalance across the visual field. Conclusions: There is evidence of decreased binocularity deficits, or interocular suppression, in the periphery in anisometropic and strabismic amblyopia as compared with controls. Notably, those with strabismic amblyopia exhibited more significant peripheral binocular imbalance. These variations in binocularity across the visual field among different amblyopia subtypes may necessitate tailored approaches for dichoptic treatment.

Presence of Copy Number Variants Associated With Esotropia in Patients With Exotropia.

Importance: Strabismus is a common ocular disorder of childhood. There is a clear genetic component to strabismus, but it is not known if esotropia and exotropia share genetic risk factors. Objective: To determine whether genetic duplications associated with esotropia are also associated with exotropia. Design, Setting, and Participants: This was a cross-sectional study conducted from November 2005 to December 2023. Individuals with constant or intermittent exotropia of any magnitude or a history of surgery for exotropia were recruited from pediatric ophthalmic practices. Data were analyzed from March to December 2023. Exposure: Genetic duplication. Main Outcomes and Measures: Presence of genetic duplications at 2p11.2, 4p15.2, and 10q11.22 assessed by digital droplet polymerase chain reaction. Orthoptic measurements and history of strabismus surgery were performed. Results: A total of 234 individuals (mean [SD] age, 19.5 [19.0] years; 127 female [54.3%]) were included in this study. The chromosome 2 duplication was present in 1.7% of patients with exotropia (4 of 234; P = .40), a similar proportion to the 1.4% of patients with esotropia (23 of 1614) in whom it was previously reported and higher than the 0.1% of controls (4 of 3922) previously reported (difference, 1.6%; 95% CI, 0%-3.3%; P < .001). The chromosome 4 duplication was present in 3.0% of patients with exotropia (7 of 234; P = .10), a similar proportion to the 1.7% of patients with esotropia (27 of 1614) and higher than the 0.2% of controls (6 of 3922) in whom it was previously reported (difference, 2.8%; 95% CI, 0.6%-5.0%; P < .001). The chromosome 10 duplication was present in 6.0% of patients with exotropia (14 of 234; P = .08), a similar proportion to the 4% of patients with esotropia (64 of 1614) and higher than the 0.4% of controls (18 of 3922) in whom it was previously reported (difference, 5.6%; 95% CI, 2.5%-8.6%; P < .001). Individuals with a duplication had higher mean (SD) magnitude of deviation (31 [13] vs 22 [14] prism diopters [PD]; difference, 9 PD; 95% CI, 1-16 PD; P = .03), were more likely to have constant (vs intermittent) exotropia (70% vs 29%; difference, 41%; 95% CI, 20.8%-61.2%; P < .001), and had a higher rate of exotropia surgery than those without a duplication (58% vs 34%; difference, 24%; 95% CI, 3%-44%; P = .02). Conclusions and Relevance: In this cross-sectional study, results suggest that the genetic duplications on chromosomes 2, 4, and 10 were risk factors for exotropia as well as esotropia. These findings support the possibility that esotropia and exotropia have shared genetic risk factors. Whether esotropia or exotropia develops in the presence of these duplications may be influenced by other shared or independent genetic variants or by environmental factors.

The Association of Race, Ethnicity, and Insurance Status with the Visual Acuity of Retinoblastoma Survivors in the IRIS® Registry.

PURPOSE: To identify sociodemographic factors associated with the visual outcomes of retinoblastoma survivors. METHODS: Retrospective cohort study using a US-based clinical data registry. All individuals < 18 years of age with a history of retinoblastoma in the Intelligent Research in Sight (IRIS®) Registry (1/1/2013-12/31/2020). The primary outcome was visual acuity below the threshold for legal blindness (20/200 or worse) in at least one eye. Multivariable logistic regression was used to evaluate the association between visual outcomes and age, sex, laterality, race, ethnicity, type of insurance, and geographic location. RESULTS: This analysis included 1545 children with a history of retinoblastoma. The median length of follow-up was 4.1 years (IQR, 2.2-5.9 years) and the median age at most recent clinical visit was 12 years (IQR, 8-16 years). Retinoblastoma was unilateral in 54% of cases. Poor vision in at least one eye was identified in 78% of all children and poor vision in both eyes in 17% of those with bilateral disease. Poor visual outcomes were associated with unilateral diagnosis (OR, 1.55; 95% CI,1.13-2.12; p = .007), Black race (OR, 2.03; 95% CI, 1.19-3.47; p = .010), Hispanic ethnicity (OR, 1.65; 95% CI, 1.16-2.37; p = .006), and non-private insurance (OR, 1.47; 95% CI, 1.02-2.10; p = .037). CONCLUSIONS: Poor visual outcomes appear to be more common among Black, Hispanic, and publicly insured children with a history of retinoblastoma, raising concerns regarding healthcare inequities. Primary care physicians should ensure that young children receive red reflex testing during routine visits and consider retinoblastoma in the differential diagnosis of abnormal eye exams.

Risk of abducens nerve palsy following COVID-19 vaccination.

PURPOSE: To investigate the prevalence and risk of new-onset abducens nerve palsy and acute-onset diplopia following mRNA COVID-19 vaccination. METHODS: In this retrospective, population-based study, patient data from the COVID-19 Research Network of TriNetX was searched via the TriNetX Analytics platform for patients who received specific vaccinations based on Common Procedural Technology codes. We recorded instances of newly diagnosed abducens nerve palsy and diplopia within 21 days following each vaccination event. RESULTS: Of the 3,545,224 patients (mean age at vaccination, 46.2 ± 21.3 years) who received the mRNA COVID-19 vaccine, 12 (<0.0001%) patients had a new diagnosis of abducens nerve palsy and 453 (0.013%) had acute-onset diplopia within 21 days of first dose of COVID-19 vaccination. After propensity score matching, the relative risk for new abducens nerve palsy diagnosis after the first dose of COVID-19 vaccination was not significantly different from that after influenza (RR, 0.77), Tdap (RR, 1.0), or the second dose of the COVID-19 vaccinations (RR, 1.00). Furthermore, there was a lower risk of abducens nerve palsy diagnosis after the first dose of the COVID-19 vaccination compared with the risk after COVID-19 infection (RR, 0.15). CONCLUSIONS: The risk of a new abducens nerve palsy diagnosis following the first dose of the COVID-19 vaccine is lower than the risk associated with COVID-19 infection itself. There is no evidence to suggest a causal relationship between COVID-19 vaccination and the development of abducens nerve palsy.

Decreased scene-selective activity within the posterior intraparietal cortex in amblyopic adults.

Amblyopia is a developmental disorder associated with reduced performance in visually guided tasks, including binocular navigation within natural environments. To help understand the underlying neurological disorder, we used fMRI to test the impact of amblyopia on the functional organization of scene-selective cortical areas, including the posterior intraparietal gyrus scene-selective (PIGS) area, a recently discovered region that responds selectively to ego-motion within naturalistic environments (Kennedy et al., 2024). Nineteen amblyopic adults (10 female) and thirty age-matched controls (12 female) participated in this study. Amblyopic participants spanned a wide range of amblyopia severity, based on their interocular visual acuity difference and stereoacuity. The visual function questionnaire (VFQ-39) was used to assess the participants' perception of their visual capabilities. Compared to controls, we found weaker scene-selective activity within the PIGS area in amblyopic individuals. By contrast, the level of scene-selective activity across the occipital place area (OPA), parahippocampal place area (PPA), and retrosplenial cortex (RSC)) remained comparable between amblyopic and control participants. The subjects' scores on "general vision" (VFQ-39 subscale) correlated with the level of scene-selective activity in PIGS. These results provide novel and direct evidence for amblyopia-related changes in scene-processing networks, thus enabling future studies to potentially link these changes across the spectrum of documented disabilities in amblyopia.

Using high-resolution functional MRI to differentiate impacts of strabismic and anisometropic amblyopia on evoked ocular dominance activity in humans.

We employed high-resolution functional MRI (fMRI) to distinguish the impacts of anisometropia and strabismus (the two most frequent causes of amblyopia) on the evoked ocular dominance (OD) response. Sixteen amblyopic participants (8 females), comprising 8 individuals with strabismus, 7 with anisometropia, 1 with deprivational amblyopia, along with 8 individuals with normal visual acuity (1 female), participated in this study for whom, we measured the difference between the response to stimulation of the two eyes, across early visual areas (V1-V4). In controls, as expected from the organization of OD columns, the evoked OD response formed a striped pattern that was mostly confined to V1. Compared to controls, the OD response in amblyopic participants formed larger fused patches that extended into downstream visual areas. Moreover, both anisometropic and strabismic participants showed stronger OD responses in V1, as well as in downstream visual areas V2-V4. Although this increase was most pronounced in V1, the correlation between the OD response level and the interocular visual acuity difference (measured behaviorally) was stronger in higher-level visual areas (V2-V4). Beyond these common effects, and despite similar densities of amblyopia between the anisometropic and strabismic participants, we found a greater increase in the size of V1 portion that responded preferentially to fellow eye stimulation in anisometropic compared to strabismic individuals. We also found a greater difference between the amplitudes of the response to binocular stimulation, in those regions that responded preferentially to the fellow vs. amblyopic eye, in anisometropic compared to strabismic subjects. In contrast, strabismic subjects demonstrated increased correlation between the OD responses evoked within V1 superficial and deep cortical depths, whereas anisometropic subjects did not. These results provide some of the first direct functional evidence for distinct impacts of strabismus and anisometropia on the mesoscale functional organization of the human visual system, thus extending what was inferred previously about amblyopia from animal models.

Ocular lichen planus as a cause of recurrent restrictive strabismus.

We report the case of an 80-year-old man with restrictive strabismus in lateral gaze following multiple oculoplastic procedures for idiopathic epiphora. Despite excellent initial response to nasal conjunctival recession with lysis of adhesions and a miminal recession of the medial rectus muscle, the patient suffered recurrence of diplopia associated with limitation of abduction due to aggressive, deep, subconjunctival scarring. Given the history of oral lichen planus (LP), the patient was diagnosed with ocular involvement of LP. He underwent a second conjunctival recession, this time accompanied by an intensive LP treatment regimen. Nine months after surgery, he remained diplopia free and orthophoric in primary gaze. Surgeons treating restrictive strabismus in patients with LP should consider implementing systemic and topical immunosuppressive treatment simultaneously with surgical management.

Refractive errors in patients with Bardet Biedl syndrome.

PURPOSE: Bardet-Biedl Syndrome (BBS) is a rare autosomal recessive ciliopathy. Within corneal development, primary cilia serve a critical role. We sought to investigate the association of BBS with corneal astigmatism among a cohort of patients with BBS. METHODS: This was a cross-sectional, retrospective study performed at a pediatric ophthalmology department of a tertiary hospital. The study enrolled 45 patients with genetically confirmed Bardet-Biedl syndrome, encompassing a total of 90 eyes observed from February 2011 to August 2021. Spherical and cylindrical refractive errors and keratometry outcome measures, including diopter (D) values at the flattest and steepest axes, were recorded. Corneal astigmatism of greater than 3D is considered extreme corneal astigmatism based on previously published data. RESULTS: Among 45 patients (M:26; F:19), the mean age was 16.4 ± 8.2 years, and the mean best-corrected visual acuity was 20/60. The most common molecular diagnosis was BBS1, seen in 24 of 45 (53.3%). Among all the patients, the mean spherical refractive error was -2.9 ± 3.8D. The mean cylindrical refractive error was 2.6 ± 1.5D. The mean keratometry values at the flattest axis was 43.5 ± 5.3D (39.4-75.0) and at the steepest axis was 47.2 ± 7.3D(41.5-84.0). Among all the patients with BBS, the mean corneal astigmatism was 3.7 ± 1.0D(0.5-7.1), which is considered extreme. CONCLUSION: A cohort of individuals with BBS demonstrated high corneal astigmatism. These results suggest an association between corneal astigmatism and primary ciliary dysfunction and may assist in clinical management and future therapeutic targets among BBS and other corneal disorders.

A Comparison of Chemodnervation to Incisional Surgery for Acute, Acquired, Comitant Esotropia: An International Study.

PURPOSE: To compare the efficacy of botulinum toxin injections to strabismus surgery in children with acute, acquired, comitant esotropia (ACE), and to investigate factors predicting success. DESIGN: International, multi-center nonrandomized comparative study METHODS: Setting: Cloud-based survey. STUDY POPULATION: Children aged 2 to 17 years who underwent a single surgical intervention for ACE. INTERVENTIONS: Botulinum toxin injection ("chemodenervation" group) or strabismus surgery ("surgery" group). MAIN OUTCOME MEASURES: Primary measure: success rate at 6 months in propensity-matched cohort, defined as total horizontal deviation of 10 prism diopters or less with evidence of binocular single vision. Secondary measure: Risk factors for poor outcomes in the full cohort. RESULTS: Surgeons from 19 centers contributed. There were 74 patients in the chemodenervation group and 97 patients in the surgery group. In the propensity-matched data (n = 98), success rate was not significantly different at 6 months (70.2% vs 79.6%; P = .2) and 12 months (62.9% vs 77.8%; P = .2), but was significantly lower in the chemodenervation group at 24 months (52% vs 86.4%; P = .015). Irrespective of treatment modality, treatment delay was associated with lower success rates at 6 months, with median time from onset to intervention 4.5 months (interquartile range (IQR): 2.1, 6.7) in the success group and 7.7 months (IQR: 5.6, 10.1) in the failure group (P < .001). CONCLUSIONS: In children with ACE, success rate after chemodenervation was similar to that of surgery for up to 12 months but lower at 24 months. Those with prompt intervention and no amblyopia had the most favorable outcomes, regardless of treatment modality.

Expanding the genetics and phenotypes of ocular congenital cranial dysinnervation disorders.

Purpose: To identify genetic etiologies and genotype/phenotype associations for unsolved ocular congenital cranial dysinnervation disorders (oCCDDs). Methods: We coupled phenotyping with exome or genome sequencing of 467 pedigrees with genetically unsolved oCCDDs, integrating analyses of pedigrees, human and animal model phenotypes, and de novo variants to identify rare candidate single nucleotide variants, insertion/deletions, and structural variants disrupting protein-coding regions. Prioritized variants were classified for pathogenicity and evaluated for genotype/phenotype correlations. Results: Analyses elucidated phenotypic subgroups, identified pathogenic/likely pathogenic variant(s) in 43/467 probands (9.2%), and prioritized variants of uncertain significance in 70/467 additional probands (15.0%). These included known and novel variants in established oCCDD genes, genes associated with syndromes that sometimes include oCCDDs (e.g., MYH10, KIF21B, TGFBR2, TUBB6), genes that fit the syndromic component of the phenotype but had no prior oCCDD association (e.g., CDK13, TGFB2), genes with no reported association with oCCDDs or the syndromic phenotypes (e.g., TUBA4A, KIF5C, CTNNA1, KLB, FGF21), and genes associated with oCCDD phenocopies that had resulted in misdiagnoses. Conclusion: This study suggests that unsolved oCCDDs are clinically and genetically heterogeneous disorders often overlapping other Mendelian conditions and nominates many candidates for future replication and functional studies.

Gaps in the Vision Screening Pathway for School-Aged US Children.

This cross-sectional study uses a nationally representative survey of the US pediatric population to identify gaps in the vision screening pathway.