Six-year cumulative treatment effect and treatment efficacy of a dual focus myopia control contact lens.

PURPOSE: Accumulated axial growth observed during a 6-year clinical trial of a dual focus myopia control contact lens was used to explore different approaches to assess treatment efficacy. METHODS: Axial length measurements from 170 eyes in a 6-year clinical trial of a dual focus myopia control lens (MiSight 1 day, CooperVision) were analysed. Treatment groups comprised one having undergone 6 years of treatment and the other (the initial control group) having 3 years of treatment after 3 years of wearing a single vision control lens. Efficacy was assessed by comparing accumulated ocular growth during treatment to that expected of untreated myopic and emmetropic eyes. The impact of treatment on delaying axial growth was quantified by comparing the increased time required to reach criterion growths for treated eyes and survivor analysis approaches. RESULTS: When compared to the predicted accumulated growth of untreated eyes, 6 years of treatment reduced growth by 0.52 mm, while 3 years of treatment initiated 3 years later reduced growth by 0.19 mm. Accumulated differences between the growth of treated and untreated myopic eyes ranged between 67% and 52% of the untreated myopic growth, and between 112% and 86% of the predicted difference in growth between untreated myopic and age-matched emmetropic eyes. Treated eyes took almost 4 years longer to reach their final accumulated growth than untreated eyes. Treatment increased the time to reach criterion growths by 2.3-2.7 times. CONCLUSION: Estimated growth of age-matched emmetropic and untreated myopic eyes provided evidence of an accumulated slowing in axial elongation of 0.52 mm over 6 years, and the treated growth remained close to that expected of emmetropic eyes. Six years of dual focus myopia control delayed the time to reach the final growth level by almost 4 years.

Myopia Control Dose Delivered to Treated Eyes by a Dual-focus Myopia-control Contact Lens.

PURPOSE: This study examined the optical impact of a DF contact lens during near viewing in a sample of habitual DF lens wearing children. METHODS: Seventeen myopic children aged 14 to 18 years who had completed 3 or 6 years of treatment with a DF contact lens (MiSight 1 Day; CooperVision, Inc., San Ramon, CA) were recruited and fit bilaterally with the DF and a single-vision (Proclear 1 Day; CooperVision, Inc.) contact lens. Right eye wavefronts were measured using a pyramidal aberrometer (Osiris; CSO, Florence, Italy) while children accommodated binocularly to high-contrast letter stimuli at five target vergences. Wavefront error data were used to compute pupil maps of refractive state. RESULTS: During near viewing, children wearing single-vision lenses accommodated on average to achieve approximate focus in the pupil center but, because of combined accommodative lag and negative spherical aberration, experienced up to 2.00 D of hyperopic defocus in the pupil margins. With DF lenses, children accommodated similarly achieving approximate focus in the pupil center. When viewing three near distances (0.48, 0.31, and 0.23 m), the added +2.00 D within the DF lens treatment optics shifted the mean defocus from +0.75 to -1.00 D. The DF lens reduced the percentage of hyperopic defocus (≥+0.75 D) in the retinal image from 52 to 25% over these target distances, leading to an increase in myopic defocus (≤-0.50 D) from 17 to 42%. CONCLUSIONS: The DF contact lens did not alter the accommodative behavior of children. The treatment optics introduced myopic defocus and decreased the amount of hyperopically defocused light in the retinal image.

Comparing low-coherence interferometry and A-scan ultrasonography in measuring ocular axial dimensions in young rhesus monkeys.

We investigated a commercial low-coherence interferometer (LenStar LS 900 optical biometer) in measuring young rhesus monkey ocular dimensions. Ocular biometry data obtained using a LenStar and an A-scan ultrasound instrument (OPT-scan 1000) from 163 rhesus monkeys during 20-348 days of age were compared by means of coefficients of concordance and 95% limits of agreement. Linear regression was employed to examine and analyze the inter-instrument discrepancies. In young rhesus monkeys, the test-retest reliability of the LenStar was equal to or exceeded that of A-scan ultrasound (intraclass correlation = 0.86 to 0.93). The inter-instrument agreement was strong for vitreous chamber depth and axial length (coefficient of concordance = 0.95 and 0.86, respectively) and moderate for anterior chamber depth and lens thickness (coefficient of concordance = 0.74 and 0.63, respectively). The LenStar systematically underestimated ocular dimensions when compared to A-scan ultrasound (mean magnitude of difference = 0.11-0.57 mm). This difference could be minimized using linear calibration functions to equate LenStar data with ultrasound data. When this method was applied, the values between instruments were in excellent absolute agreement (mean magnitude of difference = 0.004-0.01 mm). In conclusion, the LenStar reliably measured ocular dimensions in young monkeys. When an appropriate calibration function is applied, the LenStar can be used as a substitute for A-scan ultrasonography.

Long-term Effect of Dual-focus Contact Lenses on Myopia Progression in Children: A 6-year Multicenter Clinical Trial.

SIGNIFICANCE: Treatment of myopic children with a dual-focus soft contact lens (DFCL; MiSight 1 day) produced sustained slowing of myopia progression over a 6-year period. Significant slowing was also observed in children switched from a single vision control to treatment lenses (3 years in each lens). PURPOSE: This study aimed to evaluate the effectiveness of DFCLs in sustaining slowed progression of juvenile-onset myopia over a 6-year treatment period and assess myopia progression in children who were switched to a DFCL at the end of year 3. METHODS: Part 1 was a 3-year clinical trial comparing DFCLs with a control contact lens (Proclear 1 day) at four investigational sites. In part 2, subjects completing part 1 were invited to continue for 3 additional years during which all children were treated with MiSight 1 day DFCLs (52 and 56 from the initially treated [T6] and control [T3] groups, respectively). Eighty-five subjects (45 [T3] and 40 [T6]) completed part 2. Cyclopleged spherical equivalent refractive errors (SEREs) and axial lengths (ALs) were monitored, and a linear mixed model was used to compare their adjusted change annually. RESULTS: Average ages at part 2 baseline were 13.2 ± 1.3 and 13.0 ± 1.5 years for the T6 and T3 groups, respectively. Slowed myopia progression in the T6 group observed during part 1 was sustained throughout part 2 (mean ± standard error of the mean: change from baseline SERE [in diopters], -0.52 ± 0.076 vs. -0.51 ± 0.076; change in AL [in millimeters], 0.28 ± 0.033 vs. 0.23 ± 0.033; both P > .05). Comparing progression rates in part 2 for the T6 and T3 groups, respectively, indicates that prior treatment does not influence efficacy (SERE, -0.51 ± 0.076 vs. -0.34 ± 0.077; AL, 0.23 ± 0.03 vs. 0.18 ± 0.03; both P > .05). Within-eye comparisons of AL growth revealed a 71% slowing for the T3 group (3 years older than part 1) and further revealed a small subset of eyes (10%) that did not respond to treatment. CONCLUSIONS: Dual-focus soft contact lenses continue to slow the progression of myopia in children over a 6-year period revealing an accumulation of treatment effect. Eye growth of the initial control cohort with DFCL was slowed by 71% over the subsequent 3-year treatment period.

Axial length targets for myopia control.

PURPOSE: Both emmetropic and myopic eyes elongate throughout childhood. The goals of this study were to compare axial elongation among untreated progressing myopes, progressing myopes treated with a myopia control contact lens and emmetropes, in order to place axial elongation in the context of normal eye growth in emmetropic children, and to consider whether normal physiological eye growth places limits on what might be achieved with myopia control. METHODS: Axial elongation data were taken from the 3-year randomised clinical trial of a myopia control dual-focus (MiSight® 1 day) contact lens. These were compared with data for myopic and emmetropic children in two large cohort studies: the Orinda Longitudinal Study of Myopia (OLSM) and the Singapore Cohort Study of the Risk Factors for Myopia (SCORM). Each study's published equations were used to calculate annual axial elongation. Four virtual cohorts-myopic and emmetropic for each model-were created, each with the same age distribution as the MiSight clinical trial subjects and the predicted cumulative elongation calculated at years 1, 2 and 3 for myopes and emmetropes using both the OLSM and SCORM models. RESULTS: The untreated control myopes in the MiSight clinical trial showed mean axial elongation over 3 years (0.62 mm) similar to the virtual cohorts based on the OLSM (0.70 mm) and SCORM (0.65 mm) models. The predicted 3-year axial elongation for the virtual cohorts of emmetropes was 0.24 mm for both the OLSM and SCORM models-similar to the mean 3-year elongation in MiSight-treated myopes (0.30 mm). CONCLUSIONS: The 3-year elongation in MiSight-treated myopes approached that of virtual cohorts of emmetropes with the same age distribution. It is hypothesised that myopic axial elongation is superimposed on an underlying physiological axial elongation observed in emmetropic eyes, which reflects increases in body stature. We speculate that optically based myopia control treatments may minimise the myopic axial elongation but retain the underlying physiological elongation observed in emmetropic eyes.

Adenosine receptor distribution in Rhesus monkey ocular tissue.

Adenosine receptor (ADOR) antagonists, such as 7-methylxanthine (7-MX), have been shown to slow myopia progression in humans and animal models. Adenosine receptors are found throughout the body, and regulate the release of neurotransmitters such as dopamine and glutamate. However, the role of adenosine in eye growth is unclear. Evidence suggests that 7-MX increases scleral collagen fibril diameter, hence preventing axial elongation. This study used immunohistochemistry (IHC) and reverse-transcription quantitative polymerase chain reaction (RT-qPCR) to examine the distribution of the four ADORs in the normal monkey eye to help elucidate potential mechanisms of action. Eyes were enucleated from six Rhesus monkeys. Anterior segments and eyecups were separated into components and flash-frozen for RNA extraction or fixed in 4% paraformaldehyde and processed for immunohistochemistry against ADORA1, ADORA2a, ADORA2b, and ADORA3. RNA was reverse-transcribed, and qPCR was performed using custom primers. Relative gene expression was calculated using the ΔΔCt method normalizing to liver expression, and statistical analysis was performed using Relative Expression Software Tool. ADORA1 immunostaining was highest in the iris sphincter muscle, trabecular meshwork, ciliary epithelium, and retinal nerve fiber layer. ADORA2a immunostaining was highest in the corneal epithelium, trabecular meshwork, ciliary epithelium, retinal nerve fiber layer, and scleral fibroblasts. ADORA2b immunostaining was highest in corneal basal epithelium, limbal stem cells, iris sphincter, ciliary muscle, ciliary epithelium, choroid, isolated retinal ganglion cells and scattered scleral fibroblasts. ADORA3 immunostaining was highest in the iris sphincter, ciliary muscle, ciliary epithelium, choroid, isolated retinal ganglion cells, and scleral fibroblasts. Compared to liver mRNA, ADORA1 mRNA was significantly higher in the brain, retina and choroid, and significantly lower in the iris/ciliary body. ADORA2a expression was higher in brain and retina, ADORA2b expression was higher in retina, and ADORA3 was higher in the choroid. In conclusion, immunohistochemistry and RT-qPCR indicated differential patterns of expression of the four adenosine receptors in the ocular tissues of the normal non-human primate. The presence of ADORs in scleral fibroblasts and the choroid may support mechanisms by which ADOR antagonists prevent myopia. The potential effects of ADOR inhibition on both anterior and posterior ocular structures warrant investigation.

Narrow-band, long-wavelength lighting promotes hyperopia and retards vision-induced myopia in infant rhesus monkeys.

The purpose of this investigation was to determine the effects of narrow band, long-wavelength lighting on normal refractive development and the phenomena of lens compensation and form-deprivation myopia (FDM) in infant rhesus monkeys. Starting at 24 and continuing until 151 days of age, 27 infant rhesus monkeys were reared under long-wavelength LED lighting (630 nm; illuminance = 274 ± 64 lux) with unrestricted vision (Red Light (RL) controls, n = 7) or a +3 D (+3D-RL, n = 7), -3 D (-3D-RL, n = 6) or diffuser lens (From Deprivation (FD-RL), n = 7) in front of one eye and a plano lens in front of the fellow eye. Refractive development, corneal power, and vitreous chamber depth were measured by retinoscopy, keratometry, and ultrasonography, respectively. Comparison data were obtained from normal monkeys (Normal Light (NL) controls, n = 39) and lens- (+3D-NL, n = 9; -3D-NL, n = 18) and diffuser-reared controls (FD-NL, n = 16) housed under white fluorescent lighting. At the end of the treatment period, median refractive errors for both eyes of all RL groups were significantly more hyperopic than that for NL groups (P = 0.0001 to 0.016). In contrast to fluorescent lighting, red ambient lighting greatly reduced the likelihood that infant monkeys would develop either FDM or compensating myopia in response to imposed hyperopic defocus. However, as in the +3D-NL monkeys, the treated eyes of the +3D-RL monkeys exhibited relative hyperopic shifts resulting in significant anisometropias that compensated for the monocular lens-imposed defocus (P = 0.001). The red-light-induced alterations in refractive development were associated with reduced vitreous chamber elongation and increases in choroidal thickness. The results suggest that chromatic cues play a role in vision-dependent emmetropization in primates. Narrow-band, long-wavelength lighting prevents the axial elongation typically produced by either form deprivation or hyperopic defocus, possibly by creating direction signals normally associated with myopic defocus.

Effects of local myopic defocus on refractive development in monkeys.

PURPOSE: Visual signals that produce myopia are mediated by local, regionally selective mechanisms. However, little is known about spatial integration for signals that slow eye growth. The purpose of this study was to determine whether the effects of myopic defocus are integrated in a local manner in primates. METHODS: Beginning at 24 ± 2 days of age, seven rhesus monkeys were reared with monocular spectacles that produced 3 diopters (D) of relative myopic defocus in the nasal visual field of the treated eye but allowed unrestricted vision in the temporal field (NF monkeys). Seven monkeys were reared with monocular +3 D lenses that produced relative myopic defocus across the entire field of view (FF monkeys). Comparison data from previous studies were available for 11 control monkeys, 8 monkeys that experienced 3 D of hyperopic defocus in the nasal field, and 6 monkeys exposed to 3 D of hyperopic defocus across the entire field. Refractive development, corneal power, and axial dimensions were assessed at 2- to 4-week intervals using retinoscopy, keratometry, and ultrasonography, respectively. Eye shape was assessed using magnetic resonance imaging. RESULTS: In response to full-field myopic defocus, the FF monkeys developed compensating hyperopic anisometropia, the degree of which was relatively constant across the horizontal meridian. In contrast, the NF monkeys exhibited compensating hyperopic changes in refractive error that were greatest in the nasal visual field. The changes in the pattern of peripheral refractions in the NF monkeys reflected interocular differences in vitreous chamber shape. CONCLUSIONS: As with form deprivation and hyperopic defocus, the effects of myopic defocus are mediated by mechanisms that integrate visual signals in a local, regionally selective manner in primates. These results are in agreement with the hypothesis that peripheral vision can influence eye shape and potentially central refractive error in a manner that is independent of central visual experience.

Corrigendum: Long-term narrowband lighting influences activity but not intrinsically photosensitive retinal ganglion cell-driven pupil responses.

[This corrects the article DOI: 10.3389/fphys.2021.711525.].

The M4 muscarinic antagonist MT-3 inhibits myopia in chick: evidence for site of action.

PURPOSE: It is well established that the broad-band muscarinic antagonist, atropine is effective at inhibiting the progression of myopia and does so by preventing the elongation of the vitreous chamber of the eye. However, uncertainty remains as to whether this effect occurs through a receptoral mechanism and, if so, which muscarinic receptor subtype mediates this effect. Previous work, in avian and mammalian models of myopia, implicates the M1 and M4 receptors as potential targets. The current study used physiologically relevant concentrations of highly selective muscarinic antagonists (MT-3 and MT-7) to further characterise the role of the M4 receptor in the control of myopia in the chick model of refractive development. METHODS: Nine groups of week-old chicks underwent 5 days of monocular deprivation, with a translucent occluder, to induce myopia. These animals had either no injection, scleral puncture with a needle, or daily intravitreal injections of MT-3 (M4-selective), MT-7 (M1-selective) or vehicle. Three concentrations of each antagonist were delivered (250 nm, 2.5 µm and 10 µm). After the treatment period, keratometry, retinoscopy and A-Scan ultrasound were used to assess ocular biometry. RESULTS: MT-3 treatment produced a significant dose-dependent reduction in relative myopia (treated-control eye) compared to vehicle treatment (vehicle -10.1 ± 1.1 D vs 10 µm MT-3 -4.0 ± 1.5 D, p < 0.01). The majority of this effect was due to reduced relative vitreous chamber elongation in drug treated eyes (vehicle +0.26 ± 0.04 mm, 10 µm MT-3 +0.08 ± 0.07 mm, p < 0.05). In contrast, MT-7 had no significant effect on the development of myopia (MT-7 10 µm: myopia, -12.1 ± 0.8 D and vitreous chamber depth, +0.23 ± 0.07 mm). Calculations indicate that the experimentally achieved concentrations of MT-3 at intraocular receptors necessary to inhibit 50% of myopia development (between 5 and 50 nm) were consistent with published in vitro affinity constants for the M4 receptor and below those for the M1 receptor. Histology demonstrated that MT-3 at the doses used had no gross effects on the retina, indicating a non-toxic mode of action. CONCLUSIONS: In the chick, which lacks a homologue of the mammalian M1 receptor, the above findings represent compelling evidence that muscarinic antagonists prevent myopia progression through an M4-receptor mediated mechanism, most likely located in the retina.

The effects of reduced ambient lighting on lens compensation in infant rhesus monkeys.

Although reduced ambient lighting (~50 lx) does not increase the degree of form-deprivation myopia (FDM) in chickens or infant monkeys, it does reduce the probability that monkeys will recover from FDM and that the normal age-dependent reduction in hyperopia will occur in monkeys reared with unrestricted vision. These findings suggest that low ambient lighting levels affect the regulatory mechanism responsible for emmetropization. To study this issue, infant rhesus monkeys (age ~ 24 days) were reared under dim light (55 ± 9 lx) with monocular -3D (dim-light lens-induced myopia, DL-LIM, n = 8) or +3D spectacle lenses (dim-light lens-induced hyperopia, DL-LIH, n = 7) until approximately 150 days of age. Refractive errors, ocular parameters and sub-foveal choroidal thickness were measured periodically and compared with normal-light-reared, lens-control monkeys (NL-LIM, n = 16; NL-LIH, n = 7). Dim light rearing significantly attenuated the degree of compensatory anisometropias in both the DL-LIM (-0.63 ± 0.77D vs. -2.11 ± 1.10D in NL-LIM) and DL-LIH treatment groups (-0.18 ± 1.93D vs. +1.71 ± 0.39D in NL-LIH). These effects came about because the treated and fellow control eyes had a lower probability of responding appropriately to the eye's effective refractive state. Vision-induced interocular differences in choroidal thickness were only observed in monkeys that exhibited compensating refractive changes, suggesting that failures in detecting the relative magnitude of optical errors underlay the abnormal refractive responses. Our findings suggest that low ambient lighting levels reduce the efficacy of the vision-dependent mechanisms that regulate refractive development.

The development of and recovery from form-deprivation myopia in infant rhesus monkeys reared under reduced ambient lighting.

Although reduced ambient lighting ("dim" light) can cause myopia in emmetropizing chicks, it does not necessarily lead to myopic changes in emmetropizing rhesus monkeys. Because myopia is rarely spontaneous, a question remained whether dim light would hasten the progression of visually induced myopia. To determine the effects of dim light on the development of and recovery from form-deprivation myopia (FDM), seven 3-week-old infant rhesus monkeys were reared under dim light (mean ± SD = 55 ± 9 lx) with monocular diffuser spectacles until ~154 days of age, then maintained in dim light with unrestricted vision until ~337 days of age to allow for recovery. Refractive errors, corneal powers, ocular axial dimensions and sub-foveal choroidal thicknesses were measured longitudinally and compared to those obtained from form-deprived monkeys reared under typical laboratory lighting (504 ± 168 lx). Five of the seven subjects developed FDMs that were similar to those observed among their normal-light-reared counterparts. The average degree of form-deprivation-induced myopic anisometropia did not differ significantly between dim-light subjects (-3.88 ± 3.26D) and normal-light subjects (-4.45 ± 3.75D). However, three of the five dim-light subjects that developed obvious FDM failed to exhibit any signs of recovery and the two monkeys that were isometropic at the end of the treatment period manifest abnormal refractive errors during the recovery period. All refractive changes were associated with alterations in vitreous chamber elongation rates. It appears that dim light is not a strong myopiagenic stimulus by itself, but it can impair the optical regulation of refractive development in primates.

Long-Term Narrowband Lighting Influences Activity but Not Intrinsically Photosensitive Retinal Ganglion Cell-Driven Pupil Responses.

Purpose: Light affects a variety of non-image forming processes, such as circadian rhythm entrainment and the pupillary light reflex, which are mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs). The purpose of this study was to assess the effects of long- and short-wavelength ambient lighting on activity patterns and pupil responses in rhesus monkeys. Methods: Infant rhesus monkeys were reared under either broadband "white" light (n = 14), long-wavelength "red" light (n = 20; 630 nm), or short-wavelength "blue" light (n = 21; 465 nm) on a 12-h light/dark cycle starting at 24.1 ± 2.6 days of age. Activity was measured for the first 4 months of the experimental period using a Fitbit activity tracking device and quantified as average step counts during the daytime (lights-on) and nighttime (lights-off) periods. Pupil responses to 1 s red (651 nm) and blue (456 nm) stimuli were measured after approximately 8 months. Pupil metrics included maximum constriction and the 6 s post-illumination pupil response (PIPR). Results: Activity during the lights-on period increased with age during the first 10 weeks (p < 0.001 for all) and was not significantly different for monkeys reared in white, red, or blue light (p = 0.07). Activity during the 12-h lights-off period was significantly greater for monkeys reared in blue light compared to those in white light (p = 0.02), but not compared to those in red light (p = 0.08). However, blue light reared monkeys exhibited significantly lower activity compared to both white and red light reared monkeys during the first hour of the lights-off period (p = 0.01 for both) and greater activity during the final hour of the lights-off period (p < 0.001 for both). Maximum pupil constriction and the 6 s PIPR to 1 s red and blue stimuli were not significantly different between groups (p > 0.05 for all). Conclusion: Findings suggest that long-term exposure to 12-h narrowband blue light results in greater disruption in nighttime behavioral patterns compared to narrowband red light. Normal pupil responses measured later in the rearing period suggest that ipRGCs adapt after long-term exposure to narrowband lighting.

Effects of low intensity ambient lighting on refractive development in infant rhesus monkeys (Macaca mulatta).

Studies in chickens suggest low intensity ambient lighting causes myopia. The purpose of this experiment was to examine the effects of low intensity ambient lighting (dim light) on normal refractive development in macaque monkeys. Seven infant rhesus monkeys were reared under dim light (room illumination level: ~55 lx) from 24 to ~310 days of age with otherwise unrestricted vision. Refractive error, corneal power, ocular axial dimensions, and choroidal thickness were measured in anesthetized animals at the onset of the experiment and periodically throughout the dim-light-rearing period, and were compared with those of normal-light-reared monkeys. We found that dim light did not produce myopia; instead, dim-light monkeys were hyperopic relative to normal-light monkeys (median refractive errors at ~155 days, OD: +3.13 D vs. +2.31 D; OS: +3.31D vs. +2.44 D; at ~310 days, OD: +2.75D vs. +1.78D, OS: +3.00D vs. +1.75D). In addition, dim-light rearing caused sustained thickening in the choroid, but it did not alter corneal power development, nor did it change the axial nature of the refractive errors. These results showed that, for rhesus monkeys and possibly other primates, low ambient lighting by itself is not necessarily myopiagenic, but might compromise the efficiency of emmetropization.

Eccentricity-dependent effects of simultaneous competing defocus on emmetropization in infant rhesus monkeys.

Dual-focus lenses that impose simultaneous competing myopic defocus over the entire visual field produce axial hyperopic shifts in refractive error. The purpose of this study was to characterize the effects of eccentricity on the ability of myopic defocus signals to influence central refractive development in infant monkeys. From 24 to 152 days of age, rhesus monkeys were reared with binocular, dual-focus lenses that had central, zero-powered zones surrounded by alternating concentric annular power zones of +3D and zero power. Between subject groups the diameter of the central, zero-powered zone was varied from 2 mm to 8 mm in 2 mm steps (+3D/pl 2 mm, n = 6; +3D/pl 4 mm, n = 6; +3D/pl 6 mm, n = 8, or + 3D/pl 8 mm, n = 6). For the treatment lens with 2, 4, 6 and 8 mm central zones, objects at eccentricities beyond 11°, 16°, 19° and 23°, respectively, were imaged exclusively through the dual-power peripheral zones. Refractive status (retinoscopy), corneal power (keratometry) and axial dimensions (ultrasonography) were measured at two-week intervals. Comparison data were obtained from monkeys reared with binocular, single-vision +3D full-field lenses (+3D FF, n = 6) and 41 normal control monkeys reared with unrestricted vision. At the end of the rearing period, with the exception of the +3D/pl 8 mm group (median = +3.64 D), the ametropias for the other lens-reared groups (medians: FF = +4.39 D, 2 mm = +5.19 D, 4 mm = +5.59 D, 6 mm = +3.50 D) were significantly more hyperopic than that for the normal monkeys (+2.50 D). These hyperopic errors were associated with shallower vitreous chambers. The key finding was that the extent and consistency of these hyperopic ametropias varied with the eccentricity of the dual-focus zones. The results confirm that myopic defocus in the near periphery can slow axial growth, but that imposed defocus beyond about 20° from the fovea does not consistently alter central refractive development.

The Adenosine Receptor Antagonist, 7-Methylxanthine, Alters Emmetropizing Responses in Infant Macaques.

Purpose: Previous studies suggest that the adenosine receptor antagonist, 7-methylxanthine (7-MX), retards myopia progression. Our aim was to determine whether 7-MX alters the compensating refractive changes produced by defocus in rhesus monkeys. Methods: Starting at age 3 weeks, monkeys were reared with -3 diopter (D; n = 10; 7-MX -3D/pl) or +3D (n = 6; 7-MX +3D/pl) spectacles over their treated eyes and zero-powered lenses over their fellow eyes. In addition, they were given 100 mg/kg of 7-MX orally twice daily throughout the lens-rearing period (age 147 ± 4 days). Comparison data were obtained from lens-reared controls (-3D/pl, n = 17; +3D/pl, n = 9) and normal monkeys (n = 37) maintained on a standard diet. Refractive status, corneal power, and axial dimensions were assessed biweekly. Results: The -3D/pl and +3D/pl lens-reared controls developed compensating myopic (-2.10 ± 1.07 D) and hyperopic anisometropias (+1.86 ± 0.54 D), respectively. While the 7-MX +3D/pl monkeys developed hyperopic anisometropias (+1.79 ± 1.11 D) that were similar to those observed in +3D/pl controls, the 7-MX -3D/pl animals did not consistently exhibit compensating myopia in their treated eyes and were on average isometropic (+0.35 ± 1.96 D). The median refractive errors for both eyes of the 7-MX -3D/pl (+5.47 D and +4.38 D) and 7-MX +3D/pl (+5.28 and +3.84 D) monkeys were significantly more hyperopic than that for normal monkeys (+2.47 D). These 7-MX-induced hyperopic ametropias were associated with shorter vitreous chambers and thicker choroids. Conclusions: In primates, 7-MX reduced the axial myopia produced by hyperopic defocus, augmented hyperopic shifts in response to myopic defocus, and induced hyperopia in control eyes. The results suggest that 7-MX has therapeutic potential in efforts to slow myopia progression.

Immunotoxin-Induced Ablation of the Intrinsically Photosensitive Retinal Ganglion Cells in Rhesus Monkeys.

Purpose: Intrinsically photosensitive retinal ganglion cells (ipRGCs) contain the photopigment melanopsin, and are primarily involved in non-image forming functions, such as the pupillary light reflex and circadian rhythm entrainment. The goal of this study was to develop and validate a targeted ipRGC immunotoxin to ultimately examine the role of ipRGCs in macaque monkeys. Methods: An immunotoxin for the macaque melanopsin gene (OPN4), consisting of a saporin-conjugated antibody directed at the N-terminus, was prepared in solutions of 0.316, 1, 3.16, 10, and 50 µg in vehicle, and delivered intravitreally to the right eye of six rhesus monkeys, respectively. Left eyes were injected with vehicle only. The pupillary light reflex (PLR), the ipRGC-driven post illumination pupil response (PIPR), and electroretinograms (ERGs) were recorded before and after injection. For pupil measurements, 1 and 5 s pulses of light were presented to the dilated right eye while the left pupil was imaged. Stimulation included 651 nm (133 cd/m2), and 4 intensities of 456 nm (16-500 cd/m2) light. Maximum pupil constriction and the 6 s PIPR were calculated. Retinal imaging was performed with optical coherence tomography (OCT), and eyes underwent OPN4 immunohistochemistry to evaluate immunotoxin specificity and ipRGC loss. Results: Before injection, animals showed robust pupil responses to 1 and 5 s blue light. After injection, baseline pupil size increased 12 ± 17%, maximum pupil constriction decreased, and the PIPR, a marker of ipRGC activity, was eliminated in all but the lowest immunotoxin concentration. For the highest concentrations, some inflammation and structural changes were observed with OCT, while eyes injected with lower concentrations appeared normal. ERG responses showed better preserved retinal function with lower concentrations. Immunohistochemistry showed 80-100% ipRGC elimination with the higher doses being more effective; however this could be partly due to inflammation that occurred at the higher concentrations. Conclusion: Findings demonstrated that the OPN4 macaque immunotoxin was specific for ipRGCs, and induced a graded reduction in the PLR, as well as, in ipRGC-driven pupil response with concentration. Further investigation of the effects of ipRGC ablation on ocular and systemic circadian rhythms and the pupil in rhesus monkeys will provide a better understanding of the role of ipRGCs in primates.

Observations on the relationship between anisometropia, amblyopia and strabismus.

We investigated the potential causal relationships between anisometropia, amblyopia and strabismus, specifically to determine whether either amblyopia or strabismus interfered with emmetropization. We analyzed data from non-human primates that were relevant to the co-existence of anisometropia, amblyopia and strabismus in children. We relied on interocular comparisons of spatial vision and refractive development in animals reared with 1) monocular form deprivation; 2) anisometropia optically imposed by either contact lenses or spectacle lenses; 3) organic amblyopia produced by laser ablation of the fovea; and 4) strabismus that was either optically imposed with prisms or produced by either surgical or pharmacological manipulation of the extraocular muscles. Hyperopic anisometropia imposed early in life produced amblyopia in a dose-dependent manner. However, when potential methodological confounds were taken into account, there was no support for the hypothesis that the presence of amblyopia interferes with emmetropization or promotes hyperopia or that the degree of image degradation determines the direction of eye growth. To the contrary, there was strong evidence that amblyopic eyes were able to detect the presence of a refractive error and alter ocular growth to eliminate the ametropia. On the other hand, early onset strabismus, both optically and surgically imposed, disrupted the emmetropization process producing anisometropia. In surgical strabismus, the deviating eyes were typically more hyperopic than their fellow fixating eyes. The results show that early hyperopic anisometropia is a significant risk factor for amblyopia. Early esotropia can trigger the onset of both anisometropia and amblyopia. However, amblyopia, in isolation, does not pose a significant risk for the development of hyperopia or anisometropia.