Ophthalmic manifestations in Costello syndrome caused by Ras pathway dysregulation during development.

BACKGROUND: Costello syndrome (CS) is a multisystem developmental disorder caused by germline pathogenic variants in HRAS resulting in dysregulation of the Ras pathway. A systematic characterization of ophthalmic manifestations provides a unique opportunity to understand the role of Ras signal transduction in ocular development and guide optimal ophthalmic care in CS individuals. METHODS: Visual function, ocular features and genotype/phenotype correlations were evaluated in CS individuals harboring HRAS pathogenic variants, by cross-sectional and retrospective studies, and were recruited through the Costello Syndrome Family Network (CSFN) between 2007 and 2020. RESULTS: Fifty-six molecularly diagnosed CS individuals including 34 females and 22 males, ages ranging from 0.5 to 37 years were enrolled. The most common ophthalmic manifestations in the cross-sectional study were lack of stereopsis (96%), refractive errors (83%), strabismus (72%), nystagmus (69%), optic nerve hypoplasia or pallor (55%) and ptosis (13.7%) with higher prevalence than in the retrospective data (refractive errors (41%), strabismus (44%), nystagmus (26%), optic nerve hypoplasia or pallor (7%) and ptosis (11%)). Visual acuities were found to ranged from 20/25 to 20/800 and contrast sensitivity from 1.6% to 44%. HRAS pathogenic variants included p.G12S (84%), p.G13C (7%), p.G12A (5.4%), p.G12C (1.8%) and p.A146V (1.8%). CONCLUSION: Majority of individuals with CS have refractive errors, strabismus, nystagmus, absent stereopsis, and optic nerve abnormalities suggesting that HRAS and the Ras pathway play a vital role in visual system development. Ptosis, refractive errors and strabismus are amenable to treatment and early ophthalmic evaluation is crucial to prevent long-term vision impairment and improve overall quality of life in CS.

Early visual-evoked potential acuity and future behavioral acuity in cortical visual impairment.

PURPOSE: Cortical Visual Impairment (CVI) is bilateral visual impairment caused by damage to the posterior visual pathway. Both preferential looking and sweep visual-evoked potential (VEP) can be used to measure visual acuity. The purpose of this study was to determine if an early VEP measure of acuity is related to a young patient's future behavioral acuity. METHODS: The visual acuity of 33 patients with CVI was assessed using the sweep VEP and a behavioral measure on two occasions. The median age of the patients at the initial visit was 4.8 years (range: 1.3 to 19.2 years), and they were followed for an average of 6.9 years (SD: 3.5 years). RESULTS: The mean initial VEP acuity was 20/135 (0.735 logMAR), and the mean initial behavioral acuity was 20/475 (1.242 logMAR). The average difference between the two initial measures of acuity was 0.55 log unit, with the behavioral measure reporting a poorer visual acuity in all patients. However, the mean final behavioral acuity was 20/150 (0.741 logMAR), and the average difference between the initial VEP acuity and the final behavioral acuity was only 0.01 log unit. Therefore, the initial VEP measure was not statistically different from the final behavioral measure (t = 0.11; dF = 32; p = 0.45). CONCLUSIONS: Even though the initial VEP measure was much better than the initial behavioral measure, the initial VEP measure was similar to the behavioral visual acuity measured approximately 7 years later. Sweep VEP testing can be used as a predictive tool for at least the lower limit of future behavioral acuity in young patients with CVI.

VEP vernier, VEP grating, and behavioral grating acuity in patients with cortical visual impairment.

PURPOSE: Cortical visual impairment (CVI) is a leading cause of bilateral vision impairment. Because many patients with CVI cannot perform an optotype test, their acuity is often measured with a grating stimulus using a preferential looking (PL) test or the visual-evoked potential (VEP) recording. The purpose of this study is to determine the relationship among VEP vernier acuity, VEP grating acuity, and behavioral grating acuity in patients with CVI. METHODS: Sweep VEP vernier acuity, sweep VEP grating acuity, and behavioral grating acuity (measured with PL cards) were measured in 29 patients with CVI. The patients ranged in age from 3.2 to 22.7 years (mean: 12.3; SD: 5.3). Because the measures of vernier acuity and grating acuity have different units, the results were expressed as the log deficit (with normal being 30 cycles per degrees and 0.5 arc min, respectively). RESULTS: VEP grating acuity loss and VEP vernier acuity loss were significantly related (r = 0.70) with a slope of 1.31, indicating that indicating that on average, vernier acuity showed a 0.2 log unit deficit compared with VEP grating acuity. Behavioral grating acuity loss and VEP grating acuity loss were also significantly related (r = 0.64) with a slope of 1.55, indicating that behavioral acuity was more reduced (by approximately 0.3 log unit). VEP vernier acuity loss and behavioral grating acuity loss were significantly related (r = 0.66) with a slope of 0.85, indicating that behavioral acuity and VEP vernier acuity showed a similar magnitude of reduction. A Bland-Altman comparison between the VEP vernier acuity method and the behavioral acuity method showed a flat slope (0.30), indicating that the two measures produce similar visual acuity measures across the range of acuity levels. CONCLUSIONS: In patients with CVI, VEP vernier acuity showed greater deficits than VEP grating acuity and was more similar to the behavioral measures of grating acuity.

Longitudinal quantitative assessment of vision function in children with cortical visual impairment.

PURPOSE: Cortical visual impairment (CVI) is bilateral visual impairment caused by damage to the posterior visual pathway, the visual cortex, or both. Current literature reports great variability in the prognosis of CVI. The purpose of this study was to evaluate change in vision function in children with CVI over time using a quantitative assessment method. METHODS: The visual acuity and contrast sensitivity of children with CVI were retrospectively assessed using the sweep visual evoked potential (VEP). Thirty-nine children participated in the visual acuity assessment and 34 of the 39 children participated in the contrast threshold assessment. At the time of the first VEP, the children ranged in age from 1 to 16 years (mean: 5.0 years). The time between measures ranged from 0.6 to 13.7 years (mean: 6.5 years). RESULTS: Forty-nine percent of the children studied showed significant improvement of visual acuity. The average improvement was 0.43 log unit (mean change: 20/205 to 20/76) in those who improved. The initial visual acuity was worse in those who improved compared with those who did not improve (p < 0.001). Forty-seven percent of the children studied showed significant improvement of contrast threshold. In those who improved, the average amount of improvement was 0.57 log unit (10 to 2.6% Michelson). The initial contrast threshold was significantly worse in those who improved compared with those who did not improve (p = 0.001). Also, the change in contrast threshold was related to age of the child (p = 0.017). CONCLUSIONS: Significant improvement in vision function can occur over time in children with CVI. In the present study, approximately 50% of the children improved and the remainder remained stable. No relation was found between etiology and improvement. Further investigation is warranted to better understand the prognosis for visual recovery in children with CVI.

Effect of myopia on visual acuity measured with laser interference fringes.

The aim was to determine how visual acuity is affected by myopia when optical factors of the eye are controlled. Grating acuity was measured with interference fringes to avoid the effects of aberrations, and ocular biometry was used to compensate for differences in retinal image size among subjects. Distance spectacle refractions ranged from +2.25 to -14.75 D. The retinal magnification factor (RMF) in mm/deg was computed for each eye from the distance refraction, central corneal power and ultrasound biometry. A forced-choice orientation discrimination method was used to measure acuity for high-contrast 543 nm laser interference fringes in three retinal locations: the fovea, and at 4 deg and 10 deg eccentricity in the temporal retina. Acuity, expressed in c/deg and adjusted for spectacle magnification, was not significantly correlated with refraction at any of the three retinal locations. When acuity was converted to retinal spatial frequency units (c/mm) via the RMF, acuity decreased with increasing myopia at all three retinal locations (significantly at the fovea and at 10 deg eccentricity). Retinal acuity values in highly myopic subjects (>6 D) are consistent with retinal sampling distances that are larger than published values of human cone or ganglion cell spacing. The results imply that a highly myopic eye has retinal neurons that are more widely spaced than normal, but the increased axial length enlarges the retinal image enough to compensate for the retinal stretching. The data are consistent with a retinal stretching model that primarily affects the posterior pole.

Age differences in emotion-regulation strategies in handling everyday problems.

We examined age differences in problem-focused and emotion-regulatory problem-solving strategy use for self-generated family problems. Young, middle-aged, and older participants generated family problem situations that were high and low in emotional salience. They were asked both how they solved the problem and how they managed emotions involved in the problem. We conducted analyses on three categories of problem-solving strategies: instrumental strategies, proactive emotion regulation, and passive emotion regulation. When regulating emotions, middle-aged adults used more proactive emotion-regulation strategies than older adults, and older adults used more passive emotion-regulation strategies than middle-aged adults. These effects were driven by the high emotional salience condition.