Ocular and visual perceptive factors associated with treatment outcomes in patients with anisometropic amblyopia.

BACKGROUND: The aim of this observational study was to identify ocular and visual perceptive risk factors related to treatment results following refractive correction and patching in children with anisometropic amblyopia, who were between the ages of 4 to 14 years old. METHODS: One-hundred and two children with newly diagnosed anisometropic amblyopia were recruited. Successful treatment of amblyopia was defined as the final best corrected visual acuity (BCVA) better than or equal to 0.1 logMAR and amblyopic eye BCVA within 1 line of the sound eye BCVA by the end of the treatment period. BCVA, cycloplegic refraction, stereoacuity, perceptual eye position (PEP) and interocular suppression were measured. RESULTS: Of these patients, 45.10% achieved successful treatment of amblyopia after refractive correction and patching for 10.5 months. The mean age was not significantly different between patients who were successfully and unsuccessfully treated (5.50 ± 1.59 years vs 6.14 ± 2.19 years, respectively). Patients who failed treatment had significantly larger interocular difference of BCVA at the time of initial treatment (successful group: 0.33 ± 0.29 logMAR, unsuccessful group: 0.65 ± 0.35 logMAR) and after refractive adaptation (successful group: 0.15 ± 0.13 logMAR, unsuccessful group: 0.42 ± 0.35 logMAR). They also had higher spherical equivalent (SE) of amblyopic eyes (successful group: 3.08 ± 3.61 D, unsuccessful group: 5.27 ± 3.38 D), bigger interocular difference of SE (successful group: 0.94 ± 2.71 D, unsuccessful group: 3.09 ± 3.05 D), worse stereoacuity (successful group: 2.32 ± 0.37 log seconds of arc, unsuccessful group: 2.75 ± 0.32 log seconds of arc), larger vertical PEP deviation (successful group: 6.41 ± 6.08 pixel, unsuccessful group: 19.07 ± 24.96 pixel) and deeper interocular suppression (successful group: 21.7 ± 19.7%, unsuccessful group: 37.8 ± 27.1%) than those of successfully treated patients. The most influential treatment failure risk factors were larger vertical PEP deviation [adjusted odds ratio (OR) (95% confidence interval) 1.12 (1.02-1.22)] and worse stereoacuity [adjusted odds ratio (OR) (95% confidence interval) 7.72 (1.50-39.85)] in multiple logistic regression analysis. CONCLUSIONS: Larger vertical PEP deviation and worse stereoacuity were the most influential treatment failure risk factors in children with anisometropic amblyopia. The vertical PEP deviation and stereoacuity, which can reflect interocular interaction, may be useful in predicting the response to therapy.

Allelic heterogeneity contributes to variability in ocular dysgenesis, myopathy and brain malformations caused by Col4a1 and Col4a2 mutations.

Collagen type IV alpha 1 and 2 (COL4A1 and COL4A2) are present in nearly all basement membranes. COL4A1 and COL4A2 mutations are pleiotropic, affecting multiple organ systems to differing degrees, and both genetic-context and environmental factors influence this variable expressivity. Here, we report important phenotypic and molecular differences in an allelic series of Col4a1 and Col4a2 mutant mice that are on a uniform genetic background. We evaluated three organs commonly affected by COL4A1 and COL4A2 mutations and discovered allelic heterogeneity in the penetrance and severity of ocular dysgenesis, myopathy and brain malformations. Similarly, we show allelic heterogeneity in COL4A1 and COL4A2 biosynthesis. While most mutations that we examined caused increased intracellular and decreased extracellular COL4A1 and COL4A2, we identified three mutations with distinct biosynthetic signatures. Reduced temperature or presence of 4-phenylbutyrate ameliorated biosynthetic defects in primary cell lines derived from mutant mice. Together, our data demonstrate the effects and clinical implications of allelic heterogeneity in Col4a1- and Col4a2-related diseases. Understanding allelic differences will be valuable for increasing prognostic accuracy and for the development of therapeutic interventions that consider the nature of the molecular cause in patients with COL4A1 and COL4A2 mutations.

Correlation of Serial Scleral and Corneal Pneumatonometry.

PURPOSE: To evaluate the usefulness of scleral pneumatonometry as an alternative for corneal measurements of intraocular pressure (IOP) over a broad range of IOPs. DESIGN: Prospective, observational cohort study. PARTICIPANTS: The study was conducted in the University of California, San Francisco, Retina Clinic between August and November 2013 in 33 adult patients (age range, 34-94 years; mean ± standard deviation, 74.1±13.4 years) receiving anti-vascular endothelial growth factor intravitreal injections, which transiently increase IOP. METHODS: Corneal pachymetry and serial corneal and temporal scleral pneumatonometry (baseline, immediately after, and 10, 20, and 30 minutes after injection) were collected. One-time baseline corneal and scleral pneumatonometry readings were obtained in the noninjected eye. MAIN OUTCOME MEASURES: Correlation analysis and a Bland-Altman plot were used to evaluate reliability and agreement between scleral and corneal measurements of IOP. A linear mixed model was used to determine the relationship between measurements and to perform covariate analyses. RESULTS: Scleral and corneal pneumatonometry showed nearly 1:1 linear correlation, although scleral pneumatonometry was biased toward higher values (r = 0.94; P < 0.001). Scleral pneumatonometry averaged 9.0 mmHg higher than corneal pneumatonometry (95% limits of agreement, -1.5 to 19.5 mmHg). A linear mixed model resulted in the following equation: corneal IOP = 1.04 × scleral IOP - 10.37. Age, central corneal thickness, laterality, and glaucoma and lens status did not impact this relationship. The difference between corneal and scleral pneumotonometry was correlated between the two eyes of individual patients (r = 0.75; P < 0.001). CONCLUSIONS: Differences between serial scleral measurements reflect differences between serial corneal measurements. Scleral pneumatonometry should be considered as an alternative to corneal pneumatonometry for following patients in whom corneal measurements are unreliable or unobtainable.

COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets.

Heterotrimers composed of collagen type IV alpha 1 (COL4A1) and alpha 2 (COL4A2) constitute one of the most abundant components of nearly all basement membranes. Accordingly, mutations in COL4A1 or COL4A2 are pleiotropic and contribute to a broad spectrum of disorders, including myopathy, glaucoma and hemorrhagic stroke. Here, we summarize the contributions of COL4A1 and COL4A2 mutations in human disease, integrate knowledge gained from model organisms and evaluate the implications for pathogenic mechanisms and therapeutic approaches.

Agreement of Serial iCare HOME2 and Goldmann Applanation Tonometry.

PURPOSE: To assess agreement of iCare HOME2 and Goldmann applanation tonometry over a wide range of intraocular pressure (IOP). DESIGN: A prospective, observational cohort study. SUBJECTS: Twenty-six adult patients undergoing intravitreal injection, which temporarily raises IOP, were recruited from the Palo Alto Medical Foundation Retina Clinic between October 2022 and February 2023. METHODS: Subjects had serial iCare HOME2 (IOPI) and Goldmann applanation (IOPG) IOP measurements before and at 0 and 5 to 10 minutes after injection. Baseline IOPs and pachymetry were taken in both eyes. MAIN OUTCOME MEASURES: Correlation between IOPI and IOPG was tested by within-subjects intraclass correlation coefficient (ICC) for repeated measures. Agreement between IOPI and IOPG was evaluated by a Bland-Altman plot with correction for multiple measurements. The difference between IOPI and IOPG was evaluated between eyes at baseline (Pearson's r) and within the injected eye over different timepoints (ICC for absolute agreement). Linear regression was used to evaluate the effects of age, sex, glaucoma, and corneal thickness. RESULTS: The mean IOPI and IOPG were 25.3 (range: 9-55) and 23.5 (range: 8-56) mmHg, respectively. The correlation between IOPI and IOPG was 0.99 (P < 0.001). The mean difference (IOPG - IOPI) was 2.2 mmHg (95% limits of agreement: -3.4 to 7.8 mmHg). The bias in measurements was correlated between eyes (r, 0.68; P < 0.001) and in the injected eye across all timepoints (ICC, 0.86; 95% CI, 0.75-0.93), but did not show a relationship with age, sex, glaucoma, or corneal thickness. CONCLUSIONS: IOPI and IOPG showed excellent correlation; however, there was a stable bias toward IOPG being higher than IOPI over a large range of IOP. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

A Health-Related Quality of Life Measure for Patients Who Undergo Minimally Invasive Glaucoma Surgery.

PURPOSE: To develop a patient-reported outcome measure to assess the impact of glaucoma and treatment, including minimally invasive glaucoma surgery (MIGS). DESIGN: Observational study before and after concomitant cataract and Food and Drug Administration-approved implantable MIGS device surgery. SETTING: Survey administration was on a computer, iPad, or similar device. PATIENT POPULATION: 184 adults completed the baseline survey, 124 a survey 3 months after surgery, and 106 the 1-month test-retest reliability survey. The age range was 37 to 89 (average age = 72). Most were female (57%), non-Hispanic White (81%), and had a college degree (56%). MAIN OUTCOME MEASURES: The Glaucoma Outcomes Survey (GOS) assesses functional limitations (27 items), vision-related symptoms (7 items), psychosocial issues (7 items), and satisfaction with microinvasive glaucoma surgery (1 item). These multiple-item scales were scored on a 0 to 100 range, with a higher score indicating worse health. RESULTS: Internal consistency reliability estimates ranged from 0.75 to 0.93, and 1-month test-retest intraclass correlations ranged from 0.83 to 0.92 for the GOS scales. Product-moment correlations among the scales ranged from 0.56 to 0.60. Improvement in visual acuity in the study eye from baseline to the 3-month follow-up was significantly related to improvements in GOS functional limitations (r = 0.18, P = .0485), vision-related symptoms (r = 0.19, P = .0386), and psychosocial concerns (r = 0.18, P = .0503). Responders to treatment ranged from 17% for vision-related symptoms to 48% for functional limitations. CONCLUSIONS: This study supports using the GOS for ophthalmic procedures such as MIGS. Further evaluation of the GOS in different patient subgroups and clinical settings is needed.

Controlling the number of melanopsin-containing retinal ganglion cells by early light exposure.

A small percentage of retinal ganglion cells (RGCs) express melanopsin and are intrinsically photosensitive (ipRGCs). Whether light can affect the development of ipRGCs is not clear. In the rat retina, we found constant light exposure during the first postnatal week significantly increased the number of melanopsin immunopositive ipRGCs. This increase was durable and specific for melanopsin immunopositive ipRGCs. BrdU labeling showed no proliferation of the melanopsin immunopositive ipRGCs during constant light exposure. Retrograde labeling from the superior colliculus showed that no other types of RGCs were induced to express melanopsin. Light exposure was effective in increasing melanopsin immunopositive ipRGCs only when it coincided with the apoptotic phase of RGC development. However, daily intravitreous injection of tetrodotoxin, blocking action potentials, abolished the light induced increase of melanopsin immunopositive ipRGCs. These findings indicate that early light exposure can increase the number of melanopsin immunopositive ipRGCs through a process dependent on intrinsic photosensitive spiking activity. Furthermore, the increase of melanopsin immunopositive ipRGCs is potentially induced by apoptosis suppression in ipRGCs or enhanced expression of melanopsin.

Normal-Tension Glaucoma Masqueraders: Detection Using Optical Coherence Tomography.

PURPOSE: Optical coherence tomography (OCT) has become an important tool in the diagnosis and management of glaucoma; however, there can be overlap in the OCT findings between glaucoma and other diseases. We describe the clinical examination finings and interpretation of OCT imaging that led to the diagnosis of glaucoma masqueraders in a clinical case series. MATERIALS AND METHODS: Four adult patients seen in the glaucoma clinic at the Duke Eye Center were included in a retrospective observational case series. Clinical presentation, history, examination, and testing (visual fields, scanning laser ophthalmoscopy, and spectral-domain OCT imaging) were reviewed. RESULTS: We report a case series of 4 patients and their spectral-domain OCT findings with retinal disease or nonglaucomatous optic neuropathy, who presented for evaluation of suspected or previously diagnosed normal-tension glaucoma. The first patient showed marked diffuse retinal nerve fiber layer (RNFL) and macular thinning on OCT due to cancer-associated retinopathy. The second patient, who demonstrated deep focal inferotemporal RNFL loss with a corresponding arc of macular thinning on OCT, had a previous branch retinal artery occlusion. The third patient's OCT showed global RNFL and macular thinning from optic nerve hypoplasia. The last patient had bilateral, symmetric superior and temporal RNFL thinning on OCT with corresponding inferior arcuate defects, consistent with superior segmental optic nerve hypoplasia. CONCLUSIONS: In light of the clinical context and examination, optic nerve and macular OCT can be beneficial in distinguishing between glaucoma and glaucoma mimics.

Characterization of a variant of gap junction protein α8 identified in a family with hereditary cataract.

PURPOSE: Congenital cataracts occur in isolation in about 70% of cases or are associated with other abnormalities such as anterior segment dysgenesis and microphthalmia. We identified a three-generation family in the University of California San Francisco glaucoma clinic comprising three individuals with congenital cataracts and aphakic glaucoma, one of whom also had microphthalmia. The purpose of this study was to identify a possible causative mutation in this family and to investigate its pathogenesis. METHODS: We performed exome sequencing and identified a putative mutation in gap junction protein α8 (GJA8). We used PCR and DNA sequencing of GJA8 in affected and unaffected members of the pedigree to test segregation of the variant with the phenotype. We tested cellular distribution and function of the variant protein by immunofluorescence and intercellular transfer of Neurobiotin in transiently transfected HeLa cells. RESULTS: Exome sequencing revealed a variant in GJA8 (c.658A>G) encoding connexin50 (Cx50) that resulted in a missense change (p.N220D) in transmembrane domain 4. The variant was present in all three affected family members, but was also present in the proband's grandfather who was reported to be unaffected. The mutant protein localized to the plasma membrane and supported intercellular Neurobiotin transfer in HeLa cells. CONCLUSIONS: We identified a variant in transmembrane domain 4 of Cx50 in a family with autosomal dominant congenital cataracts. This variant has been previously identified in other cataract cohorts, but it is also present in unaffected individuals. Our study demonstrates that the mutant protein localized to the plasma membrane and formed functional intercellular channels. These data suggest that GJA8 c.658A>G is most likely a benign rare variant.

Orbital compartment syndrome following retrobulbar injection of amphotericin B for invasive fungal disease.

PURPOSE: To describe a complication of retrobulbar amphotericin B injections in the treatment of invasive rhino-orbital asperigillosis. OBSERVATIONS: 27 year-old renal transplant recipient presented with a two-week history of headache, binocular diplopia and proptosis of the left eye. Endonasal biopsy on hospital day 3 confirmed the diagnosis of rhino-orbital invasive Aspergillus fumigatus involving the left orbital apex.In addition to systemic antifungal treatment and cessation of immunosuppression, retrobulbar amphotericin B injections (3.5 mg/1 ml) combined with endoscopic local debridement were initiated when the patient developed progressive visual loss. Retrobulbar injections were administered on hospital days 8, 10, 14, 17, and 20. Endoscopic debridement occurred on hospital days 10 and 16.After the fifth retrobulbar amphotericin B injection, the patient developed acute orbital compartment syndrome with intraocular pressures ranging from 47 to 86 mmHg and vision declined to 20/200, requiring emergent lateral canthotomy and superior and inferior cantholysis. Close observation without further intervention resulted in return of vision to 20/20 and normalization of intraocular pressure. CONCLUSION AND IMPORTANCE: Retrobulbar amphotericin B in combination with local debridement may be considered an alternative to exenteration for invasive aspergillosis secondary to reversible immunosuppression. To the authors' knowledge, orbital compartment syndrome secondary to retrobulbar amphotericin B administration has not previously been reported. Patients should be counseled on the risk of severe local inflammation due to amphotericin B. More research is needed to establish the most appropriate dosing, frequency, and duration of retrobulbar amphotericin B injections in the treatment of life-threatening Aspergillus infections.

The short-term effects of exercise on intraocular pressure, choroidal thickness and axial length.

PURPOSE: To explore ocular changes in healthy people after exercise. METHODS: Twenty five volunteers underwent exercise for 15 minutes on a treadmill. Measurements of choroidal thickness, intraocular pressure (IOP), ocular biometry, and blood pressure were taken before and after exercise. Enhanced Depth Imaging optical coherence tomography (EDI-OCT) was used to measure choroidal thickness at the fovea. Intraocular pressure (IOP) was measured by Goldmann applanation tonometry. Ocular biometric measures were collected using A scan ultrasound. Blood pressure was measured concurrently with the acquisition of the scans. RESULTS: Twenty five volunteers (25 eyes) with a mean age of 25.44±3.25 years were measured. There was a significant increase in systolic and diastolic pressure after exercise (P<0.05). The IOP showed a significant decrease after exercise (P<0.05). However there was no significant difference in the mean choroidal thickness, ocular axial length, anterior chamber depth, lens thickness, or vitreous length before and after exercise measurements (P>0.05). CONCLUSION: There was a significant decrease in IOP from exercise without a change in choroidal thickness and ocular biometric measures. IOP and choroidal thickness were not correlated, suggesting that the IOP decrease from exercise is not due to changes in choridal thickness.

COL4A2 mutation associated with familial porencephaly and small-vessel disease.

Familial porencephaly, leukoencephalopathy and small-vessel disease belong to the spectrum of disorders ascribed to dominant mutations in the gene encoding for type IV collagen alpha-1 (COL4A1). Mice harbouring mutations in either Col4a1 or Col4a2 suffer from porencephaly, hydrocephalus, cerebral and ocular bleeding and developmental defects. We observed porencephaly and white matter lesions in members from two families that lack COL4A1 mutations. We hypothesized that COL4A2 mutations confer genetic predisposition to porencephaly, therefore we sequenced COL4A2 in the family members and characterized clinical, neuroradiological and biochemical phenotypes. Genomic sequencing of COL4A2 identified the heterozygous missense G1389R in exon 44 in one family and the c.3206delC change in exon 34 leading to frame shift and premature stop, in the second family. Fragmentation and duplication of epidermal basement membranes were observed by electron microscopy in a c.3206delC patient skin biopsy, consistent with abnormal collagen IV network. Collagen chain accumulation and endoplasmic reticulum (ER) stress have been proposed as cellular mechanism in COL4A1 mutations. In COL4A2 (3206delC) fibroblasts we detected increased rates of apoptosis and no signs of ER stress. Mutation phenotypes varied, including porencephaly, white matter lesions, cerebellar and optic nerve hypoplasia and unruptured carotid aneurysm. In the second family however, we found evidence for additional factors contributing to the phenotype. We conclude that dominant COL4A2 mutations are a novel major risk factor for familial cerebrovascular disease, including porencephaly and small-vessel disease with reduced penetrance and variable phenotype, which might also be modified by other contributing factors.

Congenital solitary eyelid trichoepithelioma.

Trichoepitheliomas are unusual, benign tumors of hair follicle origin. They may present in children and adults as acquired lesions on the body and face, but they rarely involve the eyelids. Solitary trichoepitheliomas have not previously been reported in infants. We present a first report of congenital solitary eyelid trichoepithelioma in an infant and review the classification of trichoepitheliomas.

Inactivation of Cdc13p triggers MEC1-dependent apoptotic signals in yeast.

Inactivation of the budding yeast telomere binding protein Cdc13 results in abnormal telomeres (exposed long G-strands) and activation of the DNA damage checkpoint. In the current study, we show that inactivation of Cdc13p induces apoptotic signals in yeast, as evidenced by caspase activation, increased reactive oxygen species production, and flipping of phosphatidylserine in the cytoplasmic membrane. These apoptotic signals were suppressed in a mitochondrial (rho(o)) mutant. Moreover, mitochondrial proteins (e.g. MTCO3) were identified as multicopy suppressors of cdc13-1, suggesting the involvement of mitochondrial functions in telomere-initiated apoptotic signaling. These telomere-initiated apoptotic signals were also shown to depend on MEC1, but not TEL1, and were antagonized by MRE11. Our results are consistent with a model in which single-stranded G-tails in the cdc13-1 mutant trigger MEC1-dependent apoptotic signaling in yeast.