Role of noninvasive ocular imaging as a biomarker in peripheral artery disease (PAD): A systematic review.

This study aimed to review the current literature exploring the utility of noninvasive ocular imaging for the diagnosis of peripheral artery disease (PAD). Our search was conducted in early April 2022 and included the databases Medline, Scopus, Embase, Cochrane, and others. Five articles were included in the final review. Of the five studies that used ocular imaging in PAD, two studies used retinal color fundus photography, one used optical coherence tomography (OCT), and two used optical coherence tomography angiography (OCTA) to assess the ocular changes in PAD. PAD was associated with both structural and functional changes in the retina. Structural alterations around the optic disc and temporal retinal vascular arcades were seen in color fundus photography of patients with PAD compared to healthy individuals. The presence of retinal hemorrhages, exudates, and microaneurysms in color fundus photography was associated with an increased future risk of PAD, especially the severe form of the disease. The retinal nerve fiber layer (RNFL) was significantly thinner in the nasal quadrant in patients with PAD compared to age-matched healthy individuals in OCT. Similarly, the choroidal thickness in the subfoveal region was significantly thinner in patients with PAD compared to controls. Patients with PAD also had a significant reduction in the retinal and choroidal circulation in OCTA compared to healthy controls. As PAD causes thinning and ischemic changes in retinal vessels, examination of the retinal vessels using retinal imaging techniques can provide useful information about early microvascular damage in PAD. Ocular imaging could potentially serve as a biomarker for PAD. PROSPERO ID: CRD42022310637.

Association between relative peripheral refraction and corresponding electro-retinal signals.

PURPOSE: Considering the potential role of the peripheral retina in refractive development and given that peripheral refraction varies significantly with increasing eccentricity from the fovea, we investigated the association between relative peripheral refraction (RPR) and corresponding relative peripheral multifocal electroretinogram (mfERG) responses (electro-retinal signals) from the central to the peripheral retina in young adults. METHODS: Central and peripheral refraction using an open-field autorefractor and mfERG responses using an electrophysiology stimulator were recorded from the right eyes of 17 non-myopes and 24 myopes aged 20-27 years. The relative mfERG N1, P1 and N2 components (amplitude density and implicit time) of a mfERG waveform were compared with the corresponding RPR measurements at the best-matched eccentricities along the principal meridians, that is at the fovea (0°), horizontal (±5°, ±10° and ± 25°) and vertical meridians (±10° and ± 15°). RESULTS: The mean absolute mfERG N1, P1 and N2 amplitude densities (nV/deg2 ) were maximum at the fovea in both non-myopes (N1: 57.29 ± 14.70 nV/deg2 , P1: 106.29 ± 24.46 nV/deg2 , N2: 116.41 ± 27.96 nV/deg2 ) and myopes (N1: 56.25 ± 15.79 nV/deg2 , P1: 100.79 ± 30.81 nV/deg2 , N2: 105.75 ± 37.91 nV/deg2 ), which significantly reduced with increasing retinal eccentricity (p < 0.01). No significant association was reported between the RPR and corresponding relative mfERG amplitudes at each retinal eccentricity (overall Pearson's correlation, r = -0.25 to 0.26, p ≥ 0.09). In addition, the presence of relative peripheral myopia or hyperopia at extreme peripheral retinal eccentricities did not differentially influence the corresponding relative peripheral mfERG amplitudes (p ≥ 0.24). CONCLUSIONS: Relative peripheral mfERG signals are not associated with corresponding RPR in young adults. It is plausible that the electro-retinal signals may respond to the presence of absolute hyperopia (and not relative peripheral hyperopia), which requires further investigation.

Associations between systemic melatonin and human myopia: A systematic review.

PURPOSE: Experimental models have implicated the role of melatonin circadian rhythm disruption in refractive error development. Recent studies have examined melatonin concentration and its diurnal patterns on refractive error with equivocal results. This systematic review aimed to summarise the literature on melatonin circadian rhythms in myopia. RECENT FINDINGS: PubMed, EMBASE, Web of Science, Scopus, ProQuest Central, LILACS, Cochrane and Medline databases were searched for papers between January 2010 and December 2022 using defined search terms. Seven studies measured melatonin and circadian rhythms in three biological fluids (blood serum, saliva and urine) in both myopes and non-myopes. Morning melatonin concentrations derived from blood serum varied significantly between studies in individuals aged 10-30 years, with a maximum of 89.45 pg/mL and a minimum of 5.43 pg/mL using liquid chromatography and mass spectrometry. The diurnal variation of salivary melatonin was not significantly different between myopes and emmetropes when measured every 4 h for 24 h and quantified with enzyme-linked immunosorbent assay. Significantly elevated salivary melatonin concentrations were reported in myopes compared with emmetropes, aged 18-30 years when measured hourly from evening until their habitual bedtime using liquid chromatography. However, the relationship between dim light melatonin onset and refractive group was inconsistent between studies. The 6-sulphatoxymelatonin concentration derived from overnight urine volume, measured using a double antibody radioimmunoassay, was found to be significantly lower in myopes (29.17 pg/mL) than emmetropes (42.51 pg/mL). SUMMARY: The role of melatonin concentration and rhythm in myopia has not been studied extensively. This systematic review confirms conflicting findings across studies, with potential relationships existing. Future studies with uniform methodological approaches are required to ascertain the causal relationship between melatonin dysregulation and myopia in humans.

Melanopsin modulates refractive development and myopia.

Myopia, or nearsightedness, is the most common form of refractive abnormality and is characterized by excessive ocular elongation in relation to ocular power. Retinal neurotransmitter signaling, including dopamine, is implicated in myopic ocular growth, but the visual pathways that initiate and sustain myopia remain unclear. Melanopsin-expressing retinal ganglion cells (mRGCs), which detect light, are important for visual function, and have connections with retinal dopamine cells. Here, we investigated how mRGCs influence normal and myopic refractive development using two mutant mouse models: Opn4-/- mice that lack functional melanopsin photopigments and intrinsic mRGC responses but still receive other photoreceptor-mediated input to these cells; and Opn4DTA/DTA mice that lack intrinsic and photoreceptor-mediated mRGC responses due to mRGC cell death. In mice with intact vision or form-deprivation, we measured refractive error, ocular properties including axial length and corneal curvature, and the levels of retinal dopamine and its primary metabolite, L-3,4-dihydroxyphenylalanine (DOPAC). Myopia was measured as a myopic shift, or the difference in refractive error between the form-deprived and contralateral eyes. We found that Opn4-/- mice had altered normal refractive development compared to Opn4+/+ wildtype mice, starting ∼4D more myopic but developing ∼2D greater hyperopia by 16 weeks of age. Consistent with hyperopia at older ages, 16 week-old Opn4-/- mice also had shorter eyes compared to Opn4+/+ mice (3.34 vs 3.42 mm). Opn4DTA/DTA mice, however, were more hyperopic than both Opn4+/+ and Opn4-/- mice across development ending with even shorter axial lengths. Despite these differences, both Opn4-/- and Opn4DTA/DTA mice had ∼2D greater myopic shifts in response to form-deprivation compared to Opn4+/+ mice. Furthermore, when vision was intact, dopamine and DOPAC levels were similar between Opn4-/- and Opn4+/+ mice, but higher in Opn4DTA/DTA mice, which differed with age. However, form-deprivation reduced retinal dopamine and DOAPC by ∼20% in Opn4-/- compared to Opn4+/+ mice but did not affect retinal dopamine and DOPAC in Opn4DTA/DTA mice. Lastly, systemically treating Opn4-/- mice with the dopamine precursor L-DOPA reduced their form-deprivation myopia by half compared to non-treated mice. Collectively our findings show that disruption of retinal melanopsin signaling alters the rate and magnitude of normal refractive development, yields greater susceptibility to form-deprivation myopia, and changes dopamine signaling. Our results suggest that mRGCs participate in the eye's response to myopigenic stimuli, acting partly through dopaminergic mechanisms, and provide a potential therapeutic target underling myopia progression. We conclude that proper mRGC function is necessary for correct refractive development and protection from myopia progression.

Electroretinogram responses in myopia: a review.

The stretching of a myopic eye is associated with several structural and functional changes in the retina and posterior segment of the eye. Recent research highlights the role of retinal signaling in ocular growth. Evidence from studies conducted on animal models and humans suggests that visual mechanisms regulating refractive development are primarily localized at the retina and that the visual signals from the retinal periphery are also critical for visually guided eye growth. Therefore, it is important to study the structural and functional changes in the retina in relation to refractive errors. This review will specifically focus on electroretinogram (ERG) changes in myopia and their implications in understanding the nature of retinal functioning in myopic eyes. Based on the available literature, we will discuss the fundamentals of retinal neurophysiology in the regulation of vision-dependent ocular growth, findings from various studies that investigated global and localized retinal functions in myopia using various types of ERGs.

Effects of mild- and moderate-intensity illumination on short-term axial length and choroidal thickness changes in young adults.

PURPOSE: Previous studies have shown that time spent outdoors is protective against myopia development in children. In this study, we examined the effects of 500 and 1000 lux of illumination to the eye on axial length (AL) and choroidal thickness (CT) changes in young adults. METHODS: Fifteen participants (mean age, 21.60 years [2.16]) with a mean refraction of -0.34 D (0.37) were exposed to 500 and 1000 lux of illumination for 120 min in a dark room on two different days, using a pair of light-emitting glasses. Ocular measurements were repeated on an additional day in darkness (~5 lux). Ocular biometrics and CT were measured and analysed in the right eye before the light exposure (0 min), after 30, 60 and 120 min of exposure and 30 min after light offset to measure recovery using the Lenstar biometer and the Cirrus optical coherence tomographer, respectively. RESULTS: Exposure to 500 and 1000 lux of illumination resulted in a significant reduction in AL at 30, 60 and 120 min compared to darkness (AL change at 120 min: darkness, +0.020 mm [0.004]; 500 lux, -0.006 mm [0.004]; 1000 lux, -0.013 mm [0.004]; p < 0.001). Exposure to 500 and 1000 lux caused a significant overall thickening of the subfoveal choroid compared to darkness (CT change across 120 min: darkness, -0.010 mm [0.007]; 500 lux, +0.006 mm [0.005]; 1000 lux, +0.009 mm [0.003], p = 0.02). Ocular changes were not significantly different between the two illumination levels (p > 0.05) and returned to baseline within 30 min of light offset. CONCLUSIONS: Exposure to mild- or moderate-intensity illumination on the eye can induce a significant short-term reduction in AL and an increase in CT in young adults. Future studies on larger cohorts with varying light intensities are needed to better understand the effects of ocular illumination on AL changes in humans.

Influence of the time of day on axial length and choroidal thickness changes to hyperopic and myopic defocus in human eyes.

Research in animal models have shown that exposing the eye to positive or negative spectacle lenses can lead to predictable changes in eye growth. Recent research indicates that brief periods (1-2 h) of monocular defocus results in small, but significant changes in axial length and choroidal thickness of human subjects. However, the effects of the time of day on these ocular changes with defocus are not known. In this study, we examined the effects of monocular myopic and hyperopic defocus on axial length and choroidal thickness when applied in the morning (change between 10 a.m. and 12 p.m.) vs the evening (change between 5 and 7 p.m.) in young adult human participants (mean age, 23.44 ±â€¯4.52 years). A series of axial length (using an IOL Master) and choroidal thickness (using an optical coherence tomographer) measurements were obtained over three consecutive days in both eyes. Day 1 (no defocus) examined the baseline ocular measurements in the morning (10 a.m. and 12 p.m.) and in the evening (5 and 7 p.m.), day 2 investigated the effects of hyperopic and myopic defocus on ocular parameters in the morning (subjects wore a spectacle lens with +3 or -3 DS over the right eye and a plano lens over the left eye between 10 a.m. and 12 p.m.), and day 3 examined the effects of defocus in the evening (+3 or -3 DS spectacle lens over the right eye between 5 and 7 p.m.). Exposure to myopic defocus caused a significant reduction in axial length and thickening of the subfoveal choroid at both times; but, compared to baseline data from day 1, the relative change in axial length (-0.021 ± 0.009 vs +0.004 ± 0.003 mm, p = 0.009) and choroidal thickness (+0.027 ± 0.006 vs +0.007 ± 0.006 mm, p = 0.011) with defocus were significantly greater for evening exposure to defocus than for the morning session. On the contrary, introduction of hyperopic defocus resulted in a significant increase in axial length when given in the morning (+0.026 ± 0.006 mm), but not in the evening (+0.001 ± 0.003 mm) (p = 0.047). Furthermore, hyperopic defocus resulted in a significant thinning of the choroid (p = 0.005), but there was no significant influence of the time of day on choroidal changes associated with hyperopic defocus (p = 0.672). Exposure to hyperopic and myopic defocus at different times of the day was also associated with changes in the parafoveal regions of the choroid (measured across 1.5 mm nasal and temporal choroidal regions on either side of the fovea). Our results show that ocular response to optical defocus varies significantly depending on the time of day in human subjects. These findings represent a potential interaction between the signal associated with the eye's natural diurnal rhythm and the visual signal associated with the optical defocus, making the eye perhaps more responsive to hyperopic defocus (or 'go' signal) in the morning, and to myopic defocus (or 'stop' signal) in the latter half of the day.

Lack of cone mediated retinal function increases susceptibility to form-deprivation myopia in mice.

Retinal photoreceptors are important in visual signaling for normal eye growth in animals. We used Gnat2cplf3/cplf3 (Gnat2-/-) mice, a genetic mouse model of cone dysfunction to investigate the influence of cone signaling in ocular refractive development and myopia susceptibility in mice. Refractive development under normal visual conditions was measured for Gnat2-/- and age-matched Gnat2+/+ mice, every 2 weeks from 4 to 14 weeks of age. Weekly measurements were performed on a separate cohort of mice that underwent monocular form-deprivation (FD) in the right eye from 4 weeks of age using head-mounted diffusers. Refraction, corneal curvature, and ocular biometrics were obtained using photorefraction, keratometry and optical coherence tomography, respectively. Retinas from FD mice were harvested, and analyzed for dopamine (DA) and 3,4-dihydroxyphenylacetate (DOPAC) using high-performance liquid chromatography. Under normal visual conditions, Gnat2+/+ and Gnat2-/- mice showed similar refractive error, axial length, and corneal radii across development (p > 0.05), indicating no significant effects of the Gnat2 mutation on normal ocular refractive development in mice. Three weeks of FD produced a significantly greater myopic shift in Gnat2-/- mice compared to Gnat2+/+ controls (-5.40 ±â€¯1.33 D vs -2.28 ±â€¯0.28 D, p = 0.042). Neither the Gnat2 mutation nor FD altered retinal levels of DA or DOPAC. Our results indicate that cone pathways needed for high acuity vision in primates are not as critical for normal refractive development in mice, and that both rods and cones contribute to visual signalling pathways needed to respond to FD in mammalian eyes.

Circadian rhythms, refractive development, and myopia.

PURPOSE: Despite extensive research, mechanisms regulating postnatal eye growth and those responsible for ametropias are poorly understood. With the marked recent increases in myopia prevalence, robust and biologically-based clinical therapies to normalize refractive development in childhood are needed. Here, we review classic and contemporary literature about how circadian biology might provide clues to develop a framework to improve the understanding of myopia etiology, and possibly lead to rational approaches to ameliorate refractive errors developing in children. RECENT FINDINGS: Increasing evidence implicates diurnal and circadian rhythms in eye growth and refractive error development. In both humans and animals, ocular length and other anatomical and physiological features of the eye undergo diurnal oscillations. Systemically, such rhythms are primarily generated by the 'master clock' in the surpachiasmatic nucleus, which receives input from the intrinsically photosensitive retinal ganglion cells (ipRGCs) through the activation of the photopigment melanopsin. The retina also has an endogenous circadian clock. In laboratory animals developing experimental myopia, oscillations of ocular parameters are perturbed. Retinal signaling is now believed to influence refractive development; dopamine, an important neurotransmitter found in the retina, not only entrains intrinsic retinal rhythms to the light:dark cycle, but it also modulates refractive development. Circadian clocks comprise a transcription/translation feedback control mechanism utilizing so-called clock genes that have now been associated with experimental ametropias. Contemporary clinical research is also reviving ideas first proposed in the nineteenth century that light exposures might impact refraction in children. As a result, properties of ambient lighting are being investigated in refractive development. In other areas of medical science, circadian dysregulation is now thought to impact many non-ocular disorders, likely because the patterns of modern artificial lighting exert adverse physiological effects on circadian pacemakers. How, or if, such modern light exposures and circadian dysregulation contribute to refractive development is not known. SUMMARY: The premise of this review is that circadian biology could be a productive area worthy of increased investigation, which might lead to the improved understanding of refractive development and improved therapeutic interventions.

Association of Body Length with Ocular Parameters in Mice.

PURPOSE: To determine the association between changes in body length with ocular refraction, corneal radii, axial length, and lens thickness in two different mouse strains. METHODS: Body length, ocular refraction, corneal radii, axial length, and lens thickness were measured for two inbred mouse strains: 129S1/SvJ (n = 7) and C57BL/6 J (n = 10) from 4 to 12 weeks of age. Body length, from tip of nose to base of tail, was obtained using a digital camera. Biometric parameters, corneal radii, and refractions were measured using spectral-domain optical coherence tomography, automated keratometry, and infrared photorefraction, respectively. A mixed-model ANOVA was performed to examine the changes in ocular parameters as a function of body length and strain in mice controlling for age, gender, and weight over time. RESULTS: C57BL/6J mice had significantly longer body length (average body length at 10 weeks, 8.60 ± 0.06 cm) compared to 129S1/SvJ mice (8.31 ± 0.05 cm) during development (P < .001). C57BL/6J mice had significantly hyperopic refractions compared to 129S1/SvJ mice across age (mean refraction at 10 weeks, 129S1/SvJ: +0.99 ± 0.44D vs. C57BL/6J: +6.24 ± 0.38D, P < .001). Corneal radius of curvature, axial length, and lens thickness (except 10 weeks lens thickness) were similar between the two strains throughout the measurement. In the mixed-model ANOVA, changes in body length showed an independent and significant association with the changes in refraction (P = .002) and corneal radii (P = .016) for each mouse strain. No significant association was found between the changes in axial length (P = .925) or lens thickness (P = .973) as a function of body length and strain. CONCLUSIONS: Changes in body length are significantly associated with the changes in ocular refraction and corneal radii in different mouse strains. Future studies are needed to determine if the association between body length and ocular refraction are related to changes in corneal curvature in mice.

IRBP deficiency permits precocious ocular development and myopia.

PURPOSE: Interphotoreceptor retinoid-binding protein (IRBP) is abundant in the subretinal space and binds retinoids and lipophilic molecules. The expression of IRBP begins precociously early in mouse eye development. IRBP-deficient (KO) mice show less cell death in the inner retinal layers of the retina before eyelid opening compared to wild-type C57BL/6J (WT) controls and eventually develop profound myopia. Thus, IRBP may play a role in eye development before visually-driven phenomena. We report comparative observations during the course of the natural development of eyes in WT and congenic IRBP KO mice that suggest IRBP is necessary at the early stages of mouse eye development for correct function and development to exist in later stages. METHODS: We observed the natural development of congenic WT and IRBP KO mice, monitoring several markers of eye size and development, including haze and clarity of optical components in the eye, eye size, axial length, immunohistological markers of differentiation and eye development, visually guided behavior, and levels of a putative eye growth stop signal, dopamine. We conducted these measurements at several ages. Slit-lamp examinations were conducted at post-natal day (P)21. Fundus and spectral domain optical coherence tomography (SD-OCT) images were compared at P15, P30, P45, and P80. Enucleated eyes from P5 to P10 were measured for weight, and ocular dimensions were measured with a noncontact light-emitting diode (LED) micrometer. We counted the cells that expressed tyrosine hydroxylase (TH-positive cells) at P23-P36 using immunohistochemistry on retinal flatmounts. High-performance liquid chromatography (HPLC) was used to analyze the amounts of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) at P7-P60. Monocular form deprivation in the right eye was induced using head-mounted goggles from P28 to P56. RESULTS: Eye elongation and eye size in the IRBP KO mice began to increase at P7 compared to the WT mice. This difference increased until P12, and the difference was maintained thereafter. SD-OCT images in live mice confirmed previously reported retinal thinning of the outer nuclear layer in the IRBP KO mice compared to the WT mice from P15 to P80. Slit-lamp and fundoscopy examination outcomes did not differ between the WT and KO mice. SD-OCT measurements of the optical axis components showed that the only factor contributing to excess optical axis length was the depth of the vitreous body. No other component of optical axis length (including corneal thickness, anterior chamber depth, and lens thickness) was different from that of the WT mouse. The refractive power of the IRBP KO mice did not change in response to form deprivation. The number of retinal TH-positive cells was 28% greater in the IRBP KO retinas compared to the WT mice at P30. No significant differences were observed in the steady-state retinal DA or DOPAC levels or in the DOPAC/DA ratios between the WT and IRBP KO mice. CONCLUSIONS: The IRBP KO mouse eye underwent precocious development and rapid eye size growth temporally about a day sooner than the WT mouse eye. Eye size began to differ between the WT and KO mice before eyelid opening, indicating no requirement for focus-dependent vision, and suggesting a developmental abnormality in the IRBP KO mouse eye that precedes form vision-dependent emmetropization. Additionally, the profoundly myopic KO eye did not respond to form deprivation compared to the non-deprived contralateral eye. Too much growth occurred in some parts of the eye, possibly upsetting a balance among size, differentiation, and focus-dependent growth suppression. Thus, the loss of IRBP may simply cause growth that is too rapid, possibly due to a lack of sequestration or buffering of morphogens that normally would bind to IRBP but are unbound in the IRBP KO eye. Despite the development of profound myopia, the DA levels in the IRBP KO mice were not statistically different from those in the WT mice, even with the excess of TH-positive cells in the IRBP KO mice compared to the WT mice. Overall, these data suggest that abnormal eye elongation in the IRBP KO mouse is independent of, precedes, and is epistatic to the process(es) of visually-driven refractive development.

ON pathway mutations increase susceptibility to form-deprivation myopia.

The ON pathway mutation in nob mice is associated with altered refractive development, and an increased susceptibility to form-deprivation (FD) myopia. In this study, we used mGluR6-/- mice, another ON pathway mutant, to determine whether the nob phenotype was due to the Nyx mutation or abnormal ON pathway transmission. Refractive development under a normal visual environment for mGluR6-/- and age-matched wild-type (WT) mice was measured every 2 weeks from 4 to 16 weeks of age. The response to monocular FD from 4 weeks of age was measured weekly in a separate cohort of mice. Refraction and ocular biometry were obtained using a photorefractor and optical coherence tomography. Retinas were harvested at 16 weeks, and analyzed for dopamine (DA) and DOPAC using high-performance liquid chromatography. Under normal conditions, mGluR6-/- mice were significantly more myopic than their WT controls (refraction at 12 weeks; WT: 9.40 ± 0.16 D, mGluR6-/-: 6.91 ± 0.38 D). Similar to nob mice, two weeks of FD resulted in a significant myopic shift of -5.57 ± 0.72 D in mGluR6-/- mice compared to -1.66 ± 0.19 D in WT animals. No significant axial length changes were observed with either normal or FD visual conditions. At 16 weeks, mGluR6-/- retinas showed significantly lower DOPAC levels (111.2 ± 33.0 pg/mg) compared to their WT counterparts (197.5 ± 11.2 pg/mg). Retinal DA levels were similar between the different genotypes. Our results indicate that reduced retinal DA metabolism/turnover may be associated with increased susceptibility to myopia in mice with ON pathway defect mutations.

Comparison of refractive development and retinal dopamine in OFF pathway mutant and C57BL/6J wild-type mice.

PURPOSE: Proper visual transmission depends on the retinal ON and OFF pathways. We used Vsx1-/- mice with a retinal OFF visual pathway defect to determine the role of OFF pathway signaling in refractive development (RD) of the eye. METHODS: Refractive development was measured every 2 weeks in Vsx1-/-, Vsx1+/+ (both on 129S1/Sv background), and commonly used C57BL/6J mice from 4 to 12 weeks of age. Form deprivation (FD) was induced monocularly from 4 weeks of age using head-mounted diffuser goggles. Refractive state, corneal curvature, and ocular biometry were obtained weekly using photorefraction, keratometry, and 1310 nm spectral-domain optical coherence tomography. Retinal dopamine and its metabolite, 3,4-dihydroxyphenylacetate (DOPAC), were measured using high-performance liquid chromatography (HPLC). RESULTS: During normal development, the Vsx1-/- and Vsx1+/+ mice showed similar myopic refractions at younger ages (4 weeks, Vsx1-/-: -5.28±0.75 diopter (D); WT: -4.73±0.98 D) and became significantly hyperopic by 12 weeks of age (Vsx1-/-: 3.28±0.82 D; WT: 5.33±0.81 D). However, the C57BL/6J mice were relatively hyperopic at younger ages (mean refraction at 4 weeks, 3.40±0.43 D), and developed more hyperopic refractions until about 7 weeks of age (8.07±0.55 D) before stabilizing. Eight weeks of FD did not induce a myopic shift in the 129S1/Sv animals (0.16±0.85 D), as opposed to a significant shift of -4.29±0.42 D in the C57BL/6J mice. At 4 weeks of visual development, dopamine turnover (the DOPAC/dopamine ratio) was significantly greater in the 129S1/Sv mice compared to the C57BL/6J mice. FD did not alter the levels of dopamine between the goggled and opposite eyes for any genotype or strain. CONCLUSIONS: OFF pathway signaling may not be critically important for normal refractive development in mice. Elevated retinal dopamine turnover in early refractive development may prevent FD myopia in 129S1/Sv mice compared to C57BL/6J mice.

Refractive index measurement of the mouse crystalline lens using optical coherence tomography.

In recent years, there has been a growing interest for using mouse models in refractive development and myopia research. The crystalline lens is a critical optical component of the mouse eye that occupies greater than 50% of the ocular space, and significant increases in thickness with age. However, changes in refractive index of the mouse crystalline lens are less known. In this study, we examined the changes in thickness and refractive index of the mouse crystalline lens for two different strains, wild-type (WT) and a nyx mutant (nob) over the course of normal visual development or after form deprivation. Refractive index and lens thickness measurements were made on ex vivo lenses using spectral domain optical coherence tomography (SD-OCT). Comparison of refractive index measurements on 5 standard ball lenses using the SD-OCT and their known refractive indices (manufacturer provided) indicated good precision (intra-class correlation coefficient, 0.998 and Bland-Altman coefficient of repeatability, 0.116) of the SD-OCT to calculate mouse lens refractive index ex vivo. During normal visual development, lens thickness increased significantly with age for three different cohorts of mice, aged 4 (average thickness from both eyes; WT: 1.78 ± 0.03, nob: 1.79 ± 0.08 mm), 10 (WT: 2.02 ± 0.05, nob: 2.01 ± 0.04 mm) and 16 weeks (WT: 2.12 ± 0.06, nob: 2.09 ± 0.06 mm, p < 0.001). Lens thickness was not significantly different between the two strains at any age (p = 0.557). For mice with normal vision, refractive index for isolated crystalline lenses in nob mice was significantly greater than WT mice (mean for all ages; WT: 1.42 ± 0.01, nob: 1.44 ± 0.001, p < 0.001). After 4 weeks of form deprivation to the right eye using a skull-mounted goggling apparatus, a thinning of the crystalline lens was observed in both right and left eyes of goggled animals compared to their naïve controls (average from both the right and the left eye) for both strains (p = 0.052). In form deprived mice, lens refractive index was significantly different between the goggled animals and non-goggled naïve controls in nob mice, but not in WT mice (p = 0.009). Both eyes of goggled nob mice had significantly greater lens refractive index (goggled, 1.49 ± 0.01; opposite, 1.47 ± 0.03) compared to their naïve controls (1.45 ± 0.02, p < 0.05). The results presented here suggest that there are genetic differences in the crystalline lens refractive index of the mouse eye, and that the lens refractive index in mice significantly increase with form deprivation. Research applications requiring precise optical measurements of the mouse eye should take these lens refractive indices into account when interpreting SD-OCT data.

Critical appraisal of Australian and New Zealand paediatric vision screening clinical practice guidelines using the AGREE II tool.

CLINICAL RELEVANCE: Vision disorders in children impact health-related quality of life, with early detection and intervention improving outcomes and educational performance. Eye health professionals should be aware of paediatric vision screening guidelines and their development to understand the components of local programmes and the differences in sensitivity and specificity between protocols. BACKGROUND: High-quality clinical practice guidelines (CPGs) for vision screening enable the early detection of common vision disorders; however, they require rigorous development to ensure optimal accuracy in detecting vision disorders, enabling timely interventions. This study evaluated the quality of available vision screening CPGs on vision screening of children in Australia and New Zealand. METHODS: A systematic search of academic databases, guideline databases, professional associations and Google search engines was conducted to identify relevant paediatric vision screening CPGs. Four independent reviewers used the Appraisal of Guidelines, Research and Evaluation (AGREE II) instrument to assess the quality of individual guidelines and scores were aggregated and reported as the percentage of the total possible score across the six AGREE II domains: scope and purpose, stakeholder involvement, rigour of development, clarity of presentation, applicability, and editorial independence. RESULTS: Initial 2,999 items were evaluated, with seven guidelines included. AGREE-II quality score agreement ranged from 43.3% to 95.8%. All guidelines scored >60.0% in the scope and purpose, however, most had poor scores of <26.5% in the rigour of development and <3.3% in editorial independence domains. All guidelines recommended screening using measures of habitual distance vision. CONCLUSION: Of the guidelines developed for use in Australia and New Zealand, most guidelines scored poorly when assessed against the AGREE II tool, because of lack of editorial independence and rigour of development. Paediatric vision screening guidelines should prioritise systematic review of literature to inform practice and include statements regarding competing interests.

Delayed melatonin circadian timing, lower melatonin output, and sleep disruptions in myopic, or short-sighted, children.

STUDY OBJECTIVES: This study investigated the differences in melatonin circadian timing and output, sleep characteristics, and cognitive function in myopic and non-myopic (or emmetropic) children, aged 8-15 years. METHODS: Twenty-six myopes (refractive error [mean ±â€…standard error mean] -2.06 ±â€…0.23 diopters) and 19 emmetropes (-0.06 ±â€…0.04 diopters), aged 11.74 ±â€…2.31 years were recruited. Circadian timing was assessed using salivary dim-light melatonin onset (DLMO), collected half-hourly for 7 hours, beginning 5 hours before and finishing 2 hours after individual average sleep onset in a sleep laboratory. Nocturnal melatonin output was assessed via aMT6s levels from urine voids collected from 05:30 pm to 8:00 am the following morning. Actigraphy-derived objective sleep timing were acquired for a week prior to the sleep laboratory visit. Cognitive assessments of sustained attention (using psychomotor vigilance task [PVT]) and working memory (using digit spans) were performed on the night of sleep laboratory. RESULTS: Myopic children (9:07 pm ±â€…14 minutes) exhibited a DLMO phase-delay of 1 hour 8 minutes compared to emmetropes (7:59 pm ±â€…13 minutes), p = 0.002. aMT6s melatonin levels were significantly lower among myopes (18.70 ±â€…2.38) than emmetropes (32.35 ±â€…6.93, p = 0.001). Myopes also exhibited significantly delayed sleep onset, delayed wake-up time, poor and reduced sleep, and more evening-type diurnal preference than emmetropes (all p < 0.05). Finally, myopes showed a slower reaction time in the PVT (p < 0.05), but not digit span tasks at night. CONCLUSIONS: These findings suggest a potential association between circadian rhythm dysfunction and myopia in children.

Exploring the utility of retinal optical coherence tomography as a biomarker for idiopathic intracranial hypertension: a systematic review.

This study aimed to examine the existing literature that investigated the effectiveness of optical coherence tomography (OCT) and optical coherence tomography angiography (OCT-A) as a biomarker for idiopathic intracranial hypertension (IIH). Our search was conducted on January 17th, 2024, and included the databases, Medline, Scopus, Embase, Cochrane, Latin American and Caribbean Health Sciences Literature (LILACS), International Standard Randomized Controlled Trial Number (ISRCTN) registry, and the International Clinical Trials Registry Platform (ICTRP). Our final review included 84 articles. In 74 studies, OCT was utilized as the primary ocular imaging method, while OCT-A was employed in two studies including eight studies that utilized both modalities. Overall, the results indicated that IIH patients exhibited significant increases in retinal nerve fiber layer (RNFL) thickness, total retinal and macular thickness, optic nerve head volume, and height, optic disc diameter and area, rim area, and thickness compared to controls. A significant correlation was observed between cerebrospinal fluid (CSF) pressure and OCT parameters including RNFL thickness, total retinal thickness, macular thickness, optic nerve head volume, and optic nerve head height. Interventions aimed at lowering CSF pressure were associated with a substantial improvement in these parameters. Nevertheless, studies comparing peripapillary vessel density using OCT-A between IIH patients and controls yielded conflicting results. Our systematic review supports OCT as a powerful tool to accurately monitor retinal axonal and optic nerve head changes in patients with IIH. Future research is required to determine the utility of OCT-A in IIH.

Hyperopic defocus and diurnal changes in human choroid and axial length.

PURPOSE: To investigate the influence of monocular hyperopic defocus on the normal diurnal rhythms in axial length and choroidal thickness of young adults. METHODS: A series of axial length and choroidal thickness measurements (collected at ∼3 hourly intervals, with the first measurement at ∼9 am and the final measurement at ∼9 pm) were obtained for 15 emmetropic young adults over three consecutive days. The natural diurnal rhythms (day 1, no defocus), diurnal rhythms with monocular hyperopic defocus (day 2, -2.00 DS spectacle lens over the right eye), and the recovery from any defocus induced changes (day 3, no defocus) in diurnal rhythms were examined. RESULTS: Both axial length and choroidal thickness underwent significant diurnal changes on each of the three measurement days (p < 0.0001). The introduction of monocular hyperopic defocus resulted in significant changes in the diurnal variations observed in both parameters (p < 0.05). A significant (p < 0.001) increase in the mean amplitude (peak to trough) of change in axial length (mean increase, 0.016 ± 0.005 mm) and choroidal thickness (mean increase, 0.011 ± 0.003 mm) was observed on day 2 with hyperopic defocus compared to the two "no defocus" days (days 1 and 3). At the second measurement (mean time 12:10 pm) on the day with hyperopic defocus, the eye was significantly longer by 0.012 ± 0.002 mm compared to the other two days (p < 0.05). No significant difference was observed in the average timing of the daily peaks in axial length (mean peak time 12:12 pm) and choroidal thickness (21:02 pm) over the three days. CONCLUSIONS: The introduction of monocular hyperopic defocus resulted in a significant increase in the amplitude of the diurnal change in axial length and choroidal thickness that returned to normal the following day after removal of the blur stimulus.

Comparison of an open view autorefractor with an open view aberrometer in determining peripheral refraction in children.

PURPOSE: The aim of this study was to compare central and peripheral refraction using an open view Shin-Nippon NVision-K 5001 autorefractor and an open view COAS-HD VR aberrometer in young children. METHODS: Cycloplegic central and peripheral autorefraction was measured in the right eye of 123 children aged 8 to 16 years. Three measurements each were obtained with both Shin-Nippon NVision-K 5001 autorefractor and COAS-HD VR aberrometer along the horizontal visual field up to 30° (nasal and temporal) in 10° steps. The refraction from the autorefractor was compared with aberrometer refraction for pupil analysis diameters of 2.5-mm and 5.0-mm. RESULTS: The Shin-Nippon was 0.30 D more hyperopic than COAS-HD VR at 2.5-mm pupil and 0.50 D more hyperopic than COAS-HD VR at 5-mm pupil for central refraction. For both pupil sizes, the 95% limits of agreement were approximately 0.50 D for central refraction, and limits were wider in the nasal visual field compared to the temporal visual field. The mean difference for both J0 and J45 were within 0.15 D and the 95% limits of agreement within 0.90 D across the horizontal visual field. CONCLUSION: Defocus components were similar between the Shin-Nippon autorefractor and the COAS-HD VR aberrometer with a 2.5-mm pupil for most visual field angles. However, there was a significant difference in defocus component between the Shin-Nippon autorefractor and the COAS-HD VR aberrometer with a 5.0-mm pupil, wherein the autorefractor measured more hyperopia. The astigmatic components J0 and J45 were similar between instruments for both central and peripheral refraction.