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PURPOSE: Out-of-hospital cardiac arrest (OHCA) survivors face significant risks of complications and death from hypoxic-ischemic brain injury leading to withdrawal of life-sustaining treatment (WLST). Accurate multimodal neuroprognostication, including automated pupillometry, is essential to avoid inappropriate WLST. However, inconsistent study results hinder standardized threshold recommendations. We aimed to validate proposed pupillometry thresholds with no false predictions of unfavorable outcomes in comatose OHCA survivors. METHODS: In the multi-center BOX-trial, quantitative measurements of automated pupillometry (quantitatively assessed pupillary light reflex [qPLR] and Neurological Pupil index [NPi]) were obtained at admission (0 h) and after 24, 48, and 72 h in comatose patients resuscitated from OHCA. We aimed to validate qPLR < 4% and NPi ≤ 2, predicting unfavorable neurological conditions defined as Cerebral Performance Category 3-5 at follow-up. Combined with 48-h neuron-specific enolase (NSE) > 60 µg/L, pupillometry was evaluated for multimodal neuroprognostication in comatose patients with Glasgow Motor Score (M) ≤ 3 at ≥ 72 h. RESULTS: From March 2017 to December 2021, we consecutively enrolled 710 OHCA survivors (mean age: 63 ± 14 years; 82% males), and 266 (37%) patients had unfavorable neurological outcomes. An NPi ≤ 2 predicted outcome with 0% false-positive rate (FPR) at all time points (0-72 h), and qPLR < 4% at 24-72 h. In patients with M ≤ 3 at ≥ 72 h, pupillometry thresholds significantly increased the sensitivity of NSE, from 42% (35-51%) to 55% (47-63%) for qPLR and 50% (42-58%) for NPi, maintaining 0% (0-0%) FPR. CONCLUSION: Quantitative pupillometry thresholds predict unfavorable neurological outcomes in comatose OHCA survivors and increase the sensitivity of NSE in a multimodal approach at ≥ 72 h.

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PURPOSE: Automated pupillometry (AP) facilitates objective pupillary assessment. In this study, we aimed at assessing nursing perspective about the utility of AP in neurocritically ill children to understand acceptance and usage barriers to guide development of a standardized use protocol. METHODS: We conducted a web-based, cross-sectional, anonymous, Google™ survey of nurses at two independent pediatric ICUs which have been using AP over last four years. The survey included questions related to user-friendliness, barriers, acceptance, frequency of use, and method of documenting AP findings. RESULTS: A total of 31 nurses responded to the survey. A total of 25 nurses (80.6%) used the automated pupillometer and 19 (61.3%) nurses preferred to use the automated pupillometer on critically ill intubated patients. Respondents rated the pupillometer a median [IQR] frequency of use of 7/10 [4-9] and a mean user-friendliness of 8/10 [7-10]. Barriers to pupillometer use included pupillometer unavailability, technical issues, lack of perceived clinical significance, and infection control. CONCLUSION: Nurses have widely adopted the use of automated pupillometer in the PICU especially for critically ill intubated patients and rate it favorably for user-friendliness. Barriers against its use include limited resources, infection concerns, technical issues, and a lack of perceived clinical significance and training. Implementation of standardized PICU protocol for AP usage in critically ill children, may enhance the acceptance, increase usage and aid in objective assessments. PRACTICE IMPLICATIONS: These findings can be used to create a standardized protocol on implementing automated pupillometry in the PICU for critically ill children.

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The pupillary light reflex (PLR) adapts the amount of light reaching the retina, protecting it and improving image formation. Two PLR mechanisms have been described in vertebrates. First, the pretectum receives retinal inputs and projects to the Edinger-Westphal nucleus (EWN), which targets the ciliary ganglion through the oculomotor nerve (nIII). Postganglionic fibers enter the eye-globe, traveling to the iris sphincter muscle. Additionally, some vertebrates exhibit an iris-intrinsic PLR mechanism mediated by sphincter muscle cells that express melanopsin inducing muscle contraction. Given the high degree of conservation of the lamprey visual system, we investigated the mechanisms underlying the PLR to shed light onto their evolutionary origins. Recently, a PLR mediated by melanopsin was demonstrated in lampreys, suggested to be brain mediated. Remarkably, we found that PLR is instead mediated by direct retino-iridal cholinergic projections. This retina-mediated PLR acts synergistically with an iris-intrinsic mechanism that, as in other vertebrates, is mediated by melanopsin and has contribution of gap junctions between muscle fibers. In contrast, we show that lampreys lack the brain-mediated PLR. Our results suggest that two eye-intrinsic PLR mechanisms were present in early vertebrate evolution, whereas the brain-mediated PLR has a more recent origin.

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The red reflex test, performed using a direct ophthalmoscope, serves as a critical diagnostic tool in identifying various ocular conditions. These conditions encompass retinal anomalies (such as retinoblastoma, Coats disease, retinopathy of prematurity, familial exudative vitreoretinopathy, myelinated nerve fibers, ocular toxocariasis, ocular toxoplasmosis, retinochoroidal coloboma, astrocytic, and combined hamartoma), vitreous abnormalities (including persistent fetal vasculature), lens issues (like cataract), anterior chamber and corneal conditions (comprising dysgenesis of the anterior segment, congenital glaucoma, birth trauma), and tear film disturbances. During this examination, the presence of leukocoria, characterized by a white pupillary reflex, can suggest the presence of underlying conditions. Any suspicion of an abnormal red reflex test warrants immediate evaluation by a qualified ophthalmologist. This article primarily underscores the paramount importance of the red reflex examination, not only to identify potential sight-threateningbut also life-threatening conditions. It delves into the most common causes of leukocoria in childhood and offers insights into a comprehensive diagnostic approach. The target audience for this article includes pediatricians, primary care clinicians, and ophthalmologists, all of whom play a pivotal role in the early detection and intervention of these critical eye disorders.

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OBJECTIVE: Video-based eye tracking was used to investigate saccade, pupil, and blink abnormalities among patients with Huntington's disease (HD) who watched sequences of short videos. HD, an autosomal dominant neurodegenerative disorder resulting from a CAG mutation on chromosome 4, produces motor and cognitive impairments including slow or irregular eye movements, which have been studied using structured tasks. METHODS: To explore how HD affects eye movements under instruction free conditions, we assessed 22 HD patients and their age matched controls in a 10-minute video-based free viewing task. RESULTS: Patients with HD experienced a significant reduction in saccade exploration rate following video clip transitions, an increase in pupil reactions to luminance changes after clip transitions, and a significant higher blink rate throughout the task compared to the control group. CONCLUSIONS: These results show that HD has a significant impact on how patients visually explore and respond to their environment under unconstrained and ecologically natural conditions. SIGNIFICANCE: Eye tracking in HD patients revealed saccadic, pupil, and blink abnormalities in early HD patients, suggestive of brain circuitry abnormalities that probably involve brain stem deficits. Further research should explore the impact of these changes on the quality of life of the patients affected by the disease.

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BACKGROUND: In the mammalian retina, intrinsically-photosensitive retinal ganglion cells (ipRGC) detect light and integrate signals from rods and cones to drive multiple non-visual functions including circadian entrainment and the pupillary light response (PLR). Non-visual photoreception and consequently non-visual sensitivity to light may change across child development. The PLR represents a quick and reliable method for examining non-visual responses to light in children. The purpose of this study was to assess differences in the PLRs to blue and red stimuli, measured one hour prior to bedtime, between children and adolescents. METHODS: Forty healthy participants (8-9 years, n = 21; 15-16 years, n = 19) completed a PLR assessment 1 h before their habitual bedtime. After a 1 h dim-light adaptation period (< 1 lx), baseline pupil diameter was measured in darkness for 30 s, followed by a 10 s exposure to 3.0 × 1013 photons/cm2/s of either red (627 nm) or blue (459 nm) light, and a 40 s recovery in darkness to assess pupillary re-dilation. Subsequently, participants underwent 7 min of dim-light re-adaptation followed by an exposure to the other light condition. Lights were counterbalanced across participants. RESULTS: Across both age groups, maximum pupil constriction was significantly greater (p < 0.001, ηp2 = 0.48) and more sustained (p < 0.001, ηp2 = 0.41) during exposure to blue compared to red light. For adolescents, the post-illumination pupillary response (PIPR), a hallmark of melanopsin function, was larger after blue compared with red light (p = 0.02, d = 0.60). This difference was not observed in children. Across light exposures, children had larger phasic (p < 0.01, ηp2 = 0.20) and maximal (p < 0.01, ηp2 = 0.22) pupil constrictions compared to adolescents. CONCLUSIONS: Blue light elicited a greater and more sustained pupillary response than red light in children and adolescents. However, the overall amplitude of the rod/cone-driven phasic response was greater in children than in adolescents. Our findings using the PLR highlight a higher sensitivity to evening light in children compared to adolescents, and continued maturation of the human non-visual photoreception/system throughout development.

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INTRODUCTION: Pupillary unrest in ambient light (PUAL) describes the fluctuation of pupil diameter observed in normal, awake subjects under typical levels of indoor light. PUAL becomes low to absent in young healthy subjects during opioid intoxication. We sought to determine the age-related distribution of PUAL values in a random sample of ambulatory participants. METHODS: Subjects ≥18 years of age were recruited. All were identified by age range (18-29, 30-49, 50-69, and ≥70), and surveyed for diabetes, beta-blocker use, and prior 24-hour opioid use. Relationship between mean PUAL, age group, comorbidity and opioid use were examined by Kruskal Wallis test, and PUAL and was modeled using stepwise multilevel linear regression, including diabetes, beta blocker use, prior 24-hour opioid use, autonomic dysfunction, and pupil diameter as fixed effects and subject as random effect. RESULTS: Among 150 subjects, 17 reported diabetes, 12 reported beta-blocker use, 14 reported prior 24-hour opioid use, and 120 reported no comorbid conditions. PUAL declined in higher age categories (by 0.0307, P < 0.001), with diabetes (by 0.0481, P = 0.025), and with beta-blocker use (by 0.0616, P = 0.005). Opioid related PUAL decline was observed, but statistical significance varied by model. Among healthy subjects, no PUAL value fell within range indicating high likelihood of opioid toxicity based on previous data from healthy subjects undergoing opioid infusion. CONCLUSION: PUAL declined in higher age groups, diabetes and beta-blocker use, conditions associated with impaired autonomic function, and with opioid use but significance varied depending on the chosen model.

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In humans, the eye pupils respond to both physical light sensed by the retina and mental representations of light produced by the brain. Notably, our pupils constrict when a visual stimulus is illusorily perceived brighter, even if retinal illumination is constant. However, it remains unclear whether such perceptual penetrability of pupil responses is an epiphenomenon unique to humans or whether it represents an adaptive mechanism shared with other animals to anticipate variations in retinal illumination between successive eye fixations. To address this issue, we measured the pupil responses of both humans and macaque monkeys exposed to three chromatic versions (cyan, magenta, and yellow) of the Asahi brightness illusion. We found that the stimuli illusorily perceived brighter or darker trigger differential pupil responses that are very similar in macaques and human participants. Additionally, we show that this phenomenon exhibits an analogous cyan bias in both primate species. Beyond evincing the macaque monkey as a relevant model to study the perceptual penetrability of pupil responses, our results suggest that this phenomenon is tuned to ecological conditions because the exposure to a "bright cyan-bluish sky" may be associated with increased risks of dazzle and retinal damages.

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OBJECTIVE: This study aimed to determine the validity of quantitative pupillometry to predict the length of time for return to full activity/duty after a mild traumatic brain injury (mTBI) in a cohort of injured cadets at West Point. METHODS: Each subject received baseline (T0) quantitative pupillometry, in addition to evaluation with the Balance Error Scoring System (BESS), Standardized Assessment of Concussion (SAC), and Sport Concussion Assessment Tool 5th Edition Symptom Survey (SCAT5). Repeat assessments using the same parameters were conducted within 48 hours of injury (T1), at the beginning of progressive return to activity (T2), and at the completion of progressive return to activity protocols (T3). Pupillary metrics were compared on the basis of length of time to return to full play/duty and the clinical scores. RESULTS: The authors' statistical analyses found correlations between pupillometry measures at T1, including end-initial diameter and maximum constriction velocity, with larger change and faster constriction predicting earlier return to play. There was also an association with maximum constriction velocity at baseline (T0), predicting faster return to play. CONCLUSIONS: The authors conclude that that pupillometry may be a valuable tool for assessing time to return to duty from mTBI by providing a measure of baseline resiliency to mTBI and/or autonomic dysfunction in the acute phase after mTBI.

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Purpose: The purpose of this study was to evaluate pupillary light reflex (PLR) to chromatic flashes in patients with early-onset high-myopia (eoHM) without (myopic controls = M-CTRL) and with (female-limited myopia-26 = MYP-26) genetic mutations in the ARR3 gene encoding the cone arrestin. Methods: Participants were 26 female subjects divided into 3 groups: emmetropic controls (E-CTRL, N = 12, mean age = 28.6 ± 7.8 years) and 2 myopic (M-CTRL, N = 7, mean age = 25.7 ± 11.5 years and MYP-26, N = 7, mean age = 28.3 ± 15.4 years) groups. In addition, one hemizygous carrier and one control male subject were examined. Direct PLRs were recorded after 10-minute dark adaptation. Stimuli were 1-second red (peak wavelength = 621 nm) and blue (peak wavelength = 470 nm) flashes at photopic luminance of 250 cd/m². A 2-minute interval between the flashes was introduced. Baseline pupil diameter (BPD), peak pupil constriction (PPC), and postillumination pupillary response (PIPR) were extracted from the PLR. Group comparisons were performed with ANOVAs. Results: Dark-adapted BPD was comparable among the groups, whereas PPC to the red light was slightly reduced in patients with myopia (P = 0.02). PIPR at 6 seconds elicited by the blue flash was significantly weaker (P < 0.01) in female patients with MYP-26, whereas it was normal in the M-CTRL group and the asymptomatic male carrier. Conclusions: L/M-cone abnormalities due to ARR3 gene mutation is currently claimed to underlie the pathological eye growth in MYP-26. Our results suggest that malfunction of the melanopsin system of intrinsically photosensitive retinal ganglion cells (ipRGCs) is specific to patients with symptomatic MYP-26, and may therefore play an additional role in the pathological eye growth of MYP-26.

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OBJECTIVES: Delayed cerebral ischemia (DCI) is a major driver of morbidity after aneurysmal subarachnoid hemorrhage (aSAH). Quantitative pupillometry has been shown to be of prognostic value after acute neurological injury. However, the evidence for the use of pupillometric features for the detection of DCI has been conflicting. The aim of this study was to investigate the prognostic value of frequent pupillometric monitoring for DCI detection. DESIGN: Observational cohort study from a prospective aSAH registry. SETTING: Tertiary referral center. PATIENTS: Adult patients with confirmed aSAH admitted to the ICU between March 2019 and December 2023. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred fourteen patients were included, of which 31 (27.2%) suffered from DCI. All patients underwent frequent pupillometry (every 3 hr). We determined the absolute value of the neurological pupil index (NPi) and constriction velocity (CV), and their value normalized to the maximal recorded value between the admission and the pupillometry measure to account for personalized baselines. The association between pupillometry values and the occurrence of DCI within 6-24 hours was investigated. Normalized CV had the best discriminative performance to identify DCI within 8 hours, with an area under the receiver operating characteristic curve of 0.82 (95% CI, 0.69-0.91). NPi, as well as non-normalized metrics, were not significantly associated with DCI. CONCLUSIONS: Normalized CV has a clinically and statistically significant association with the occurrence of DCI after aSAH. Frequent quantitative pupillometry could improve the multimodal monitoring of patients after aSAH with the goal of improving the identification of patients likely to benefit from therapeutic interventions.

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ABSTRACT: BACKGROUND: Delirium is a common neurological complication in patients admitted to the intensive care unit (ICU) after moderate to severe traumatic brain injury (TBI). Although current clinical guidelines prioritize delirium prevention, no specific tool is tailored to detect early signs of delirium in TBI patients. This preliminary 2-phase observational study investigated the correlation between the pupillary light reflex (PLR), measured with a pupillometer during mechanical ventilation, and the development of postextubation delirium in TBI patients. METHODS: A convenience sample of 26 adults with moderate to severe TBI under mechanical ventilation was recruited during their ICU stay. In phase I, PLR measurements were performed in the first 3 days of ICU admission using automated infrared pupillometry. In phase II, 2 raters independently extracted delirium data in the 72 hours post extubation period from medical records. Delirium was confirmed with a documented medical diagnosis. Point-biserial correlations ( rpb ) were used to examine the association between PLR scores and the presence of postextubation delirium. Student t tests were also performed to compare mean PLR scores between patients with and without delirium. RESULTS: Ten TBI patients (38%) were diagnosed with postextubation delirium, whereas 16 (62%) were not. Significant correlations between delirium and 2 PLR variables were found: pupil constriction percentage ( rpb (24) = -0.526, P = .006) and constriction velocity ( rpb (24) = -0.485, P = .012). The t test also revealed a significant difference in constriction percentage and velocity scores between TBI patients with and without delirium ( P ≤ .01). CONCLUSION: Our findings suggest that the use of pupillometry in the first 3 days of mechanical ventilation during an ICU stay may help identify TBI patients at risk for delirium after extubation. Although further research is necessary to support its validity, this technological tool may enable ICU nurses to better screen TBI patients for delirium and prevent its development.

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BACKGROUND: Hypoxic ischemic brain injury (HIBI) induced by cardiac arrest (CA) seems to predominate in cortical areas and to a lesser extent in the brainstem. These regions play key roles in modulating the activity of the autonomic nervous system (ANS), that can be assessed through analyses of heart rate variability (HRV). The objective was to evaluate the prognostic value of various HRV parameters to predict neurological outcome after CA. METHODS: Retrospective monocentric study assessing the prognostic value of HRV markers and their association with HIBI severity. Patients admitted for CA who underwent EEG for persistent coma after CA were included. HRV markers were computed from 5 min signal of the ECG lead of the EEG recording. HRV indices were calculated in the time-, frequency-, and non-linear domains. Frequency-domain analyses differentiated very low frequency (VLF 0.003-0.04 Hz), low frequency (LF 0.04-0.15 Hz), high frequency (HF 0.15-0.4 Hz), and LF/HF ratio. HRV indices were compared to other prognostic markers: pupillary light reflex, EEG, N20 on somatosensory evoked potentials (SSEP) and biomarkers (neuron specific enolase-NSE). Neurological outcome at 3 months was defined as unfavorable in case of best CPC 3-4-5. RESULTS: Between 2007 and 2021, 199 patients were included. Patients were predominantly male (64%), with a median age of 60 [48.9-71.7] years. 76% were out-of-hospital CA, and 30% had an initial shockable rhythm. Neurological outcome was unfavorable in 73%. Compared to poor outcome, patients with a good outcome had higher VLF (0.21 vs 0.09 ms2/Hz, p < 0.01), LF (0.07 vs 0.04 ms2/Hz, p = 0.003), and higher LF/HF ratio (2.01 vs 1.01, p = 0.008). Several non-linear domain indices were also higher in the good outcome group, such as SD2 (15.1 vs 10.2, p = 0.016) and DFA α1 (1.03 vs 0.78, p = 0.002). These indices also differed depending on the severity of EEG pattern and abolition of pupillary light reflex. These time-frequency and non-linear domains HRV parameters were predictive of poor neurological outcome, with high specificity despite a low sensitivity. CONCLUSION: In comatose patients after CA, some HRV markers appear to be associated with unfavorable outcome, EEG severity and PLR abolition, although the sensitivity of these HRV markers remains limited.

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To isolate melanopsin contributions to retinal sensitivity measured by the post-illumination pupil response (PIPR), controlling for individual differences in non-melanopsin contributions including retinal irradiance is required. When methodologies to negate such differences present barriers, statistical controls have included age, baseline diameter, iris pigmentation, and circadian time of testing. Alternatively, the pupil light reflex (PLR) and calculations estimating retinal irradiance both reflect retinal irradiance, while the PLR also reflects downstream pathways. We reanalyzed data from an observational, correlational study comparing the PIPR across seasons in seasonal affective disorder (SAD) and controls. The PIPR was measured in 47 adults in Pittsburgh, Pennsylvania (25 SAD) over 50 seconds after 1 second of red and blue stimuli of 15.3 log photons/cm2/s. The PLR was within 1 second while PIPR was averaged over 10-40 seconds post-stimulus. Two raters ranked iris pigmentation using a published scale. We evaluated model fit using Akaike's Information Criterion (AIC) across different covariate sets. The best-fitting models included either estimated retinal irradiance or PLR, and circadian time of testing. The PLR is collected contemporaneously in PIPR studies and is an individually specific measure of nonspecific effects, while being minimally burdensome. This work extends the prior publication by introducing theoretically grounded covariates that improved analytic model fits based on AIC specific to the present methods and sample. Such quantitative methods could be helpful in studies which must balance participant and researcher burden against tighter methodological controls of individual differences in retinal irradiance.

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It is a challenge for conventional monocular-camera single-light source eye-tracking methods to achieve high-speed eye tracking. In this work, a dual-ring infrared lighting source was designed to achieve bright and dark pupils in high speed. The eye-tracking method used a dual-ring infrared lighting source and synchronized triggers for the even and odd camera frames to capture bright and dark pupils. A pupillary corneal reflex was calculated by the center coordinates of the Purkinje spot and the pupil. A map function was established to map the relationship between the pupillary corneal reflex and gaze spots. The gaze coordinate was calculated based on the mapping function. The average detection time of each gaze spot was 3.76 ms.

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BACKGROUND: Late-life depression (LLD) is a prevalent neuropsychiatric disorder in the older population. While LLD exhibits high mortality rates, depressive symptoms in older adults are often masked by physical health conditions. In younger adults, depression is associated with deficits in pupil light reflex and eye blink rate, suggesting the potential use of these responses as biomarkers for LLD. METHODS: We conducted a study using video-based eye-tracking to investigate pupil and blink responses in LLD patients (n = 25), older (OLD) healthy controls (n = 29), and younger (YOUNG) healthy controls (n = 25). The aim was to determine whether there were alterations in pupil and blink responses in LLD compared to both OLD and YOUNG groups. RESULTS: LLD patients displayed significantly higher blink rates and dampened pupil constriction responses compared to OLD and YOUNG controls. While tonic pupil size in YOUNG differed from that of OLD, LLD patients did not exhibit a significant difference compared to OLD and YOUNG controls. GDS-15 scores in older adults correlated with light and darkness reflex response variability and blink rates. PHQ-15 scores showed a correlation with blink rates, while MoCA scores correlated with tonic pupil sizes. CONCLUSIONS: The findings demonstrate that LLD patients display altered pupil and blink behavior compared to OLD and YOUNG controls. These altered responses correlated differently with the severity of depressive, somatic, and cognitive symptoms, indicating their potential as objective biomarkers for LLD.

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Purpose: Investigating influencing factors on the pupillary light response (PLR) as a biomarker for local retinal function by providing epidemiological data of a large normative collective and to establish a normative database for the evaluation of chromatic pupil campimetry (CPC). Methods: Demographic and ophthalmologic characteristics were captured and PLR parameters of 150 healthy participants (94 women) aged 18 to 79 years (median = 46 years) were measured with L-cone- and rod-favoring CPC protocols. Linear-mixed effects models were performed to determine factors influencing the PLR and optical coherence tomography (OCT) data were correlated with the pupillary function volume. Results: Relative maximal constriction amplitude (relMCA) and latency under L-cone- and rod-favoring stimulation were statistically significantly affected by the stimulus eccentricity (P < 0.0001, respectively). Iris color and gender did not affect relMCA or latency significantly; visual hemifield, season, and daytime showed only minor influence under few stimulus conditions. Age had a statistically significant effect on latency under rod-specific stimulation with a latency prolongation ≥60 years. Under photopic and scotopic conditions, baseline pupil diameter declined significantly with increasing age (P < 0.0001, respectively). Pupillary function volume and OCT data were not correlated relevantly. Conclusions: Stimulus eccentricity had the most relevant impact on relMCA and latency of the PLR during L-cone- and rod-favoring stimulation. Latency is prolonged ≥60 years under scotopic conditions. Considering the large study collective, a representative normative database for relMCA and latency as valid readout parameters for L-cone- and rod-favoring stimulation could be established. This further validates the usability of the PLR in CPC as a biomarker for local retinal function.

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