Optic disk anatomical features of children with central retinal vein occlusion.

PURPOSE: To report a case series of children with central retinal vein occlusion (CRVO) showing a high prevalence of crowded optic disks with minimal cupping. METHODS: We retrospectively reviewed the medical records of children diagnosed with CRVO from 2008 to 2019 at a single tertiary care pediatric hospital. Clinical records, fundus photographs, and optical coherence tomography (OCT) images were reviewed. Optic disk anatomical parameters of the unaffected fellow eyes, including OCT-measured optic disk area and vertical cup:disk ratio, were collected and analyzed. RESULTS: Six patients with unilateral CRVO were identified. All patients were female. Age at presentation ranged between 9 and 17 years. Five patients were otherwise healthy, with negative systemic investigations (idiopathic group). The remaining patient had a known systemic risk factor of active Takayasu arteritis. Within the idiopathic group, "disk-at-risk" optic nerve configuration, defined as a cup:disk ratio of 0.2 or smaller, was identified in the fellow eye of all 5 patients. In the unaffected eyes, mean OCT-measured optic disk area was 1.67 ± 0.13 mm2 and mean cup:disk ratio was 0.19 ± 0.12. The patient with Takayasu arteritis had normal OCT disk area of 2.1 mm2 and cup:disk ratio of 0.61. CONCLUSIONS: We observed a high prevalence of anatomical features potentially consistent with a constrictive optic disk configuration in pediatric patients with CRVO.

Investigation of light-induced lacrimation and pupillary responses in episodic migraine.

The purpose of this pilot study was to investigate the light-induced pupillary and lacrimation responses mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs) in migraine. Ten participants with episodic migraine and normal tear production, as well as eleven visually normal controls participated in this study. Following an initial baseline trial (no light flash), participants received seven incremental and alternating red and blue light flashes. Pupillometry recording of the left eye and a 1-min anesthetized Schirmer's test of the right eye (using 0.5% proparacaine) were performed simultaneously. Intrinsic and extrinsic ipRGC photoactivities did not differ between migraine participants and controls across all intensities and wavelengths. Migraine participants, however, had significantly lower lacrimation than controls following the highest blue intensity. A positive correlation was found between melanopsin-driven post-illumination pupillary responses and lacrimation following blue stimulation in both groups. Our results show that participants with self-reported photophobia have normal ipRGC-driven responses, suggesting that photophobia and pupillary function may be mediated by distinct ipRGC circuits. The positive correlation between melanopsin-driven pupillary responses and light-induced lacrimation suggests the afferent arm of the light-induced lacrimation reflex is melanopsin-mediated and functions normally in migraine. Lastly, the reduced melanopsin-mediated lacrimation at the highest stimulus suggests the efferent arm of the lacrimation reflex is attenuated under certain conditions, which may be a harbinger of dry eye in migraine.

Severe obstructive sleep apnea diagnosed after non-arteritic anterior ischaemic optic neuropathy in a young man.

Non-arteritic anterior ischaemic optic neuropathy (NAION) is the most common acute optic neuropathy in older individuals but may also occur in younger patients. A 30-year-old man presented with a 2-day history of right eye painless vision loss and was found to have right optic disc oedema and a left 'disc-at-risk'. He was diagnosed with right NAION and review of symptoms revealed witnessed apnea at night and episodes where he woke up gasping for air, concerning for obstructive sleep apnea (OSA). A formal sleep study revealed severe OSA and he was treated with continuous positive airway pressure to reduce his risk of fellow eye involvement and reduce his overall cardiovascular risk. OSA should be considered in every patient with NAION, especially in younger patients without any additional risk factors.

Binocular Summation in Postillumination Pupil Response Driven by Melanopsin-Containing Retinal Ganglion Cells.

Purpose: To investigate how melanopsin-mediated intrinsically photosensitive retinal ganglion cell (ipRGC) signals are integrated binocularly using chromatic pupillometry. We hypothesized that if the melanopsin system is summative, there will be a greater postillumination pupillary response (PIPR) under binocular conditions after viewing bright blue light. Methods: Pupillary responses in 10 visually normal participants were recorded with an eye tracker following full-field stimulation of red (long wavelength) and blue (short wavelength) light of equal intensity (dim: 0.1 cd [candela]/m2, bright: 60 cd/m2) and duration (400 ms). Individual monocular (left eye) pupil responses were measured first, followed by binocular responses. Each participant repeated the same protocol on 3 separate days, at similar times of day. PIPR was recorded for bright red and blue conditions only, whereas maximum pupillary constriction (MPC) was measured under both bright and dim conditions during red and blue light stimulation. Results: Bright blue light stimulation induced greater PIPR under binocular than monocular viewing conditions (F(1,9) = 79.52, P < 0.001). Bright red light stimulation induced minimal PIPR and showed no significant difference between viewing conditions post Bonferroni correction (F(1,9) = 5.49, P = 0.04). MPC was greater during binocular than monocular viewing conditions for all light stimuli, but was greatest following blue compared to red light stimulation. Conclusions: A larger PIPR was induced using a binocular than a monocular full-field stimulus of equal intensity and duration, demonstrating that melanopsin-mediated ipRGC signals are summated binocularly. This study expands our current understanding of the melanopsin system and may be used as an additional marker to stratify diseases according to their etiologies.

Ocular Topical Anesthesia Does Not Attenuate Light-Induced Discomfort Using Blue and Red Light Stimuli.

Purpose: To investigate whether melanopsin-containing ophthalmic trigeminal ganglion cells provide significant input to mediate light-induced discomfort. This is done by studying the effect of ocular topical anesthesia on light-induced discomfort threshold to blue light and red light stimuli using a psychophysical approach. Method: Ten visually normal participants completed the experiment consisting of two trials: an anesthesia trial in which light stimuli were presented to both eyes following 0.5% proparacaine eye drops administration, and a placebo trial in which normal saline drops were used. In each trial, a randomized series of 280 blue and red light flashes were presented over seven intensity steps with 20 repetitions for each color and light intensity. Participants were instructed to report whether they perceived each stimulus as either "uncomfortably bright" or "not uncomfortably bright" by pressing a button. The proportion of "uncomfortable" responses was pooled to generate individual psychometric functions, from which 50% discomfort thresholds (defined as the light intensity at which the individuals perceived the stimulus to be uncomfortably bright/unpleasant 50% of the time) were calculated. Results: When blue light was presented, there was no significant difference in the light-induced discomfort thresholds between anesthesia and placebo trials (P = 0.44). Similarly, when red light was used, no significant difference in threshold values was found between the anesthesia and placebo trials (P = 0.28). Conclusions: Ocular topical anesthesia does not alter the light-induced discomfort thresholds to either blue or red light, suggesting that the melanopsin-containing ophthalmic trigeminal ganglion cells provide little or no significant input in mediating light-induced discomfort under normal physiologic conditions.

A Novel Visual Psychometric Test for Light-Induced Discomfort Using Red and Blue Light Stimuli Under Binocular and Monocular Viewing Conditions.

Purpose: To develop an objective psychophysical method to quantify light-induced visual discomfort, and to measure the effects of viewing condition and stimulus wavelength. Methods: Eleven visually normal subjects participated in the study. Their pupils were dilated (2.5% phenylephrine) before the experiment. A Ganzfeld system presented either red (1.5, 19.1, 38.2, 57.3, 76.3, 152.7, 305.3 cd/m2) or blue (1.4, 7.1, 14.3, 28.6, 42.9, 57.1, 71.4 cd/m2) randomized light intensities (1 s each) in four blocks. Constant white-light stimuli (3 cd/m2, 4 s duration) were interleaved with the chromatic trials. Participants reported each stimulus as either "uncomfortably bright" or "not uncomfortably bright." The experiment was done binocularly and monocularly in separate sessions, and the order of color/viewing condition sequence was randomized across participants. The proportion of "uncomfortable" responses was used to generate individual psychometric functions, from which 50% discomfort thresholds were calculated. Results: Light-induced discomfort was higher under blue compared with red light stimulation, both during binocular (t(10) = 3.58, P < 0.01) and monocular viewing (t(10) = 3.15, P = 0.01). There was also a significant difference in discomfort between viewing conditions, with binocular viewing inducing more discomfort than monocular viewing for blue (P < 0.001), but not for red light stimulation. Conclusions: The light-induced discomfort characteristics reported here are consistent with features of the melanopsin-containing intrinsically photosensitive retinal ganglion cell light irradiance pathway, which may mediate photophobia, a prominent feature in many clinical disorders. This is the first psychometric assessment designed around melanopsin spectral properties that can be customized further to assess photophobia in different clinical populations.

The Relation Between Light-Induced Lacrimation and the Melanopsin-Driven Postillumination Pupil Response.

Purpose: To investigate the chromatic characteristics and intensity-response function of light-induced reflex lacrimation and its correlation with the melanopsin-driven postillumination pupil response (PIPR). Methods: Eleven visually normal participants completed the experiment. Lacrimation was measured in one eye by placing a calibrated filter paper strip in the conjunctival sac over a 1 minute-interval (Schirmer's test) during which participants received either no light stimulation (baseline trial) or one flash of blue or red light stimuli presented binocularly with a Ganzfeld stimulator, while the pupil response was recorded simultaneously from the fellow eye by using an eye tracker. Light stimulation trials were presented in alternating fashion at seven incremental intensity steps (0.1, 1, 3.16, 10, 31.6, 100, and 400 cd/m2). Postillumination pupil response was defined as the mean pupil constriction from 10 to 30 seconds post illumination. Results: The amount of lacrimation in response to 10 to 400 cd/m2 blue light was significantly greater than baseline and increased monotonically with increasing light intensity. Red light did not induce significant reflex lacrimation until the brightest stimulation at 400 cd/m2. There was a positive linear correlation between PIPR and lacrimation in response to blue light (r = 0.74, P < 0.001) but not to red light (r = 0.13, P = 0.25). Conclusions: The chromatic characteristics and intensity-response of light-induced lacrimation are highly consistent with the features of melanopsin phototransduction. This finding is the first in vivo evidence in humans, supporting the hypothesis that light-induced reflex lacrimation is mediated primarily by melanopsin photoactivity, and provides new insight into the putative mechanisms of photophobia.

Dataset of red light induced pupil constriction superimposed on post-illumination pupil response.

We collected and analyzed pupil diameter data from of 7 visually normal participants to compare the maximum pupil constriction (MPC) induced by "Red Only" vs. "Blue+Red" visual stimulation conditions. The "Red Only" condition consisted of red light (640±10 nm) stimuli of variable intensity and duration presented to dark-adapted eyes with pupils at resting state. This condition stimulates the cone-driven activity of the intrinsically photosensitive retinal ganglion cells (ipRGC). The "Blue+Red" condition consisted of the same red light stimulus presented during ongoing blue (470±17 nm) light-induced post-illumination pupil response (PIPR), representing the cone-driven ipRGC activity superimposed on the melanopsin-driven intrinsic activity of the ipRGCs ("The Absence of Attenuating Effect of Red light Exposure on Pre-existing Melanopsin-Driven Post-illumination Pupil Response" Lei et al. (2016) [1]). MPC induced by the "Red Only" condition was compared with the MPC induced by the "Blue+Red" condition by multiple paired sample t-tests with Bonferroni correction.

The absence of attenuating effect of red light exposure on pre-existing melanopsin-driven post-illumination pupil response.

It has been proposed that after activation by blue light, activated melanopsin is converted back to its resting state by long wavelength red light exposure, a putative mechanism of melanopsin chromophore recovery in vivo. We tested this hypothesis by investigating whether red light attenuates the ongoing post-illumination pupil response (PIPR) induced by melanopsin-activating blue light. Pupillary light responses were tested using "Blue+Red" double flashes and "Blue Only" single flash stimuli in 10 visually normal subjects. For "Blue+Red" conditions, PIPR was induced with an intense blue flash, followed by experimental red light exposure of variable intensity and duration (Experiment 1) immediately or 9s after the offset of the blue flash (Experiment 2). For "Blue Only" conditions, only the PIPR-inducing blue stimuli were presented (reference condition). PIPR was defined as the mean pupil size from 10 to 30s (Experiment 1) and from 25 to 60s (Experiment 2) after the offset of blue light stimuli. The results showed that PIPR from "Blue+Red" conditions did not differ significantly from those of "Blue Only" conditions (p=0.55) in Experiment 1. The two stimulation conditions also did not differ in Experiment 2 (p=0.38). We therefore conclude that red light exposure does not alter the time course of PIPR induced by blue light. This finding does not support the hypothesis that long wavelength red light reverses activated melanopsin; rather it lends support to the hypothesis that the wavelengths of stimuli driving both the forward and backward reactions of melanopsin may be similar.

Efficacy and safety of dexamethasone intravitreal implant for refractory macular edema in children.

OBJECTIVE: To evaluate the efficacy and safety of dexamethasone (DEX) intravitreal implant (Ozurdex) in pediatric patients with cystoid macular edema (CME) refractory to conventional treatment. DESIGN: This study is a retrospective chart review. PARTICIPANTS: Four pediatric patients (5 eyes) with CME caused by uveitis, type I idiopathic macular telangiectasia (IMT), or Coats disease treated with DEX intravitreal implant. METHODS: Medical records of the 4 pediatric patients (5 eyes) with CME included in this study were reviewed. Data collected included details of the underlying diseases, treatments, and pretreatment and post-treatment central retinal thickness (CRT) measured by time-domain optical coherence tomography, visual acuity (VA), intraocular pressure (IOP), and lens status. The median follow-up time was 65 weeks (range, 59-93 weeks). RESULTS: Fifteen DEX intravitreal implants were injected into 5 eyes over the follow-up period. Reduction of CME was achieved in all eyes within 12 weeks after the initial injection. VA improved in 4 eyes and was unchanged in 1 eye at 12 weeks; VA improved in 2 eyes, decreased in 2 eyes, and was unchanged in 1 eye at 52 weeks. Three of 5 eyes experienced IOP elevation ≥ 10 mm Hg during the follow-up period. IOP was ultimately controlled medically in all eyes. Significant lens opacification was documented in 2 eyes. CONCLUSIONS: DEX intravitreal implant can be considered as an effective adjunctive off-label treatment to pediatric macular edema caused by uveitis or IMT/Coats disease; the safety profile of repeated treatment is acceptable.

Test-retest reliability of hemifield, central-field, and full-field chromatic pupillometry for assessing the function of melanopsin-containing retinal ganglion cells.

PURPOSE: We evaluated the test-retest reliability of current methods of inducing the melanopsin-driven postillumination pupil response (PIPR) under hemifield, central-field, and full-field stimulation conditions. METHODS: Pupil response was recorded with an eye tracker in 10 visually normal participants. Light stimuli were presented using a Ganzfeld screen with a custom-built device that allows specific regions of the retina to be stimulated. Blue light stimulation at 400 cd/m(2) intensity was presented for 400 ms to the lower and upper halves of the central 30° fields (hemifields), central 30° field (central-field), and full-field to induce PIPR. Red light full-field stimulation also was presented with the same intensity and duration as a control condition. Test-retest reliability of the PIPR measures was assessed by calculating the intraclass correlation coefficient (ICC) of six repetitions for lower and upper hemifield stimulation, and three repetitions for central-field and full-field stimulation. RESULTS: Hemifield, central-field, and full-field blue light stimulation induced increasingly greater PIPR in ascending order, while full-field red light stimulation induced no PIPR. Mean lower and upper hemifield PIPR was highly symmetric. Mean ICC of blue light PIPR was 0.87 for lower hemifield, 0.88 for upper hemifield, 0.95 for central-field, and 0.94 for full-field stimulation. CONCLUSIONS: We validated a new and repeatable method to measure PIPR induced by hemifield, central-field, and full-field light stimulation. Good PIPR measurement reliability was obtained under all conditions. This practical and reliable protocol will facilitate the clinical application of PIPR testing in different disease populations.

Full-field chromatic pupillometry for the assessment of the postillumination pupil response driven by melanopsin-containing retinal ganglion cells.

PURPOSE: The postillumination pupil response (PIPR) is produced by intrinsically photosensitive retinal ganglion cells (ipRGCs). We aimed to refine the testing conditions for PIPR by investigating whether a greater PIPR can be induced using full-field light stimuli of shorter duration and lower intensity than that produced by existing protocols that use central-field stimuli. METHODS: Pupil response was recorded with an eye tracker in 10 visually-normal subjects. Red and blue light stimuli were presented using a Ganzfeld system. In Experiment 1 (intensity trials), PIPR was induced using 1-second full-field stimuli of increasing intensities from 0.1 to 400 cd/m(2) (11 steps). For comparison, PIPR also was induced using a 60° × 90° central-field blue stimulus of 400 cd/m(2). In Experiment 2 (duration trials), PIPR was induced using 100 and 400 cd/m(2) full-field stimulus of increasing duration from 4 to 1000 ms (10 steps). RESULTS: Results indicated that PIPR increased monotonically with increasing stimulus intensity. Full-field stimulation using blue light at 400 cd/m(2) intensity induced significantly more sustained PIPR than central-field stimulation (P = 0.001). In addition, PIPR increased as the stimulus duration increased from 4 to 200 ms; however, no further increase in PIPR was observed when the duration increased from 400 to 1000 ms. CONCLUSIONS: Compared to existing central-field protocols, larger PIPR can be induced with a full-field stimulus with lower intensity and shorter duration, indicating that PIPR is a function of stimulus intensity, stimulus duration, and retinal area stimulated. The testing protocol can be refined with this new knowledge to target particular clinical populations.