Automated Pupillometry Identifies Absence of Intracranial Pressure Elevation in Intracerebral Hemorrhage Patients.

INTRODUCTION: Although automated pupillometry is increasingly used in critical care settings, predictive value of automatically assessed pupillary parameters during different intracranial pressure (ICP) levels and possible clinical implications are unestablished. METHODS: This retrospective cohort study at the neurocritical care unit of the University of Erlangen-Nuremberg (2016-2018) included 23 nontraumatic supratentorial (intracerebral hemorrhage) ICH patients without signs of abnormal pupillary function by manual assessment, i.e., absent light reflex. We assessed ICP levels by an external ventricular drain simultaneously with parameters of pupillary reactivity [i.e., maximum and minimum apertures, light reflex latency (Lat), constriction and redilation velocities (CV, DV), and percentage change of apertures (per-change)] using a portable pupillometer (NeurOptics®). Computed tomography (CT) scans were analyzed to determine lesion location, size, intraventricular hemorrhage, hydrocephalus, midline shift, and compression or absence of the basal cisterns. We performed receiver operating characteristics analysis to investigate associations of ICP levels with pupillary parameters and to determine best cutoff values for prediction of ICP elevation. After dichotomization of assessments according to ICP values (normal: < 20 mmHg, elevated: ≥ 20 mmHg), prognostic performance of the determined cutoff parameters of pupillary function versus of CT-imaging findings was analyzed by calculating sensitivity, specificity, positive and negative predictive values (logistic regression, corresponding ORs with 95% CIs). RESULTS: In 23 patients (11 women, median age 59.0 (51.0-69.0) years), 1,934 assessments were available for analysis. A total of 74 ICP elevations ≥ 20 mmHg occurred in seven patients. Best discriminative thresholds for ICP elevation were: CV < 0.8 mm/s (AUC 0.740), per-change < 10% (AUC 0.743), DV < 0.2 mm/s (AUC 0.703), and Lat > 0.3 s (AUC 0.616). Positive predictive value of all four parameters to indicate ICP elevation ranged between 7.2 and 8.3% only and was similarly low for CT abnormalities (9.1%). We found high negative predictive values of pupillary parameters [CV: 99.2% (95% CI 98.3-99.6), per-change: 98.7% (95% CI 97.8-99.2), DV: 98.0% (95% CI 97.0-98.7), Lat: 97.0% (95% CI 96.0-97.7)], and CT abnormalities [99.7% (95% CI 99.2-99.9)], providing evidence that both techniques adequately identified ICH patients without ICP elevation. CONCLUSIONS: Our data suggest an association between noninvasively detected changes in pupillary reactivity and ICP levels in sedated ICH patients. Although automated pupillometry and neuroimaging seem not sufficient to noninvasively indicate ICP elevation, both techniques, however, adequately identified ICH patients without ICP elevation. This finding may facilitate routine management by saving invasive ICP monitoring or repeated CT controls in patients with specific automated pupillometry readings.

Neuromonitoring of delirium with quantitative pupillometry in sedated mechanically ventilated critically ill patients.

BACKGROUND: Intensive care unit (ICU) delirium is a frequent secondary neurological complication in critically ill patients undergoing prolonged mechanical ventilation. Quantitative pupillometry is an emerging modality for the neuromonitoring of primary acute brain injury, but its potential utility in patients at risk of ICU delirium is unknown. METHODS: This was an observational cohort study of medical-surgical ICU patients, without acute or known primary brain injury, who underwent sedation and mechanical ventilation for at least 48 h. Starting at day 3, automated infrared pupillometry-blinded to ICU caregivers-was used for repeated measurement of the pupillary function, including quantitative pupillary light reflex (q-PLR, expressed as % pupil constriction to a standardized light stimulus) and constriction velocity (CV, mm/s). The relationship between delirium, using the CAM-ICU score, and quantitative pupillary variables was examined. RESULTS: A total of 59/100 patients had ICU delirium, diagnosed at a median 8 (5-13) days from admission. Compared to non-delirious patients, subjects with ICU delirium had lower values of q-PLR (25 [19-31] vs. 20 [15-28] %) and CV (2.5 [1.7-2.8] vs. 1.7 [1.4-2.4] mm/s) at day 3, and at all additional time-points tested (p < 0.05). After adjusting for the SOFA score and the cumulative dose of analgesia and sedation, lower q-PLR was associated with an increased risk of ICU delirium (OR 1.057 [1.007-1.113] at day 3; p = 0.03). CONCLUSIONS: Sustained abnormalities of quantitative pupillary variables at the early ICU phase correlate with delirium and precede clinical diagnosis by a median 5 days. These findings suggest a potential utility of quantitative pupillometry in sedated mechanically ventilated ICU patients at high risk of delirium.

Quantitative pupillometry for the monitoring of intracranial hypertension in patients with severe traumatic brain injury.

BACKGROUND: Elevated intracranial pressure (ICP) is frequent after traumatic brain injury (TBI) and may cause abnormal pupillary reactivity, which in turn is associated with a worse prognosis. Using automated infrared pupillometry, we examined the relationship between the Neurological Pupil index (NPi) and invasive ICP in patients with severe TBI. METHODS: This was an observational cohort of consecutive subjects with severe TBI (Glasgow Coma Scale [GCS] < 9 with abnormal lesions on head CT) who underwent parenchymal ICP monitoring and repeated NPi assessment with the NPi-200® pupillometer. We examined NPi trends over time (four consecutive measurements over intervals of 6 h) prior to sustained elevated ICP > 20 mmHg. We further analyzed the relationship of cumulative abnormal NPi burden (%NPi values < 3 during total ICP monitoring time) with intracranial hypertension (ICHT)-categorized as refractory (ICHT-r; requiring surgical decompression) vs. non-refractory (ICHT-nr; responsive to medical therapy)-and with the 6-month Glasgow Outcome Score (GOS). RESULTS: A total of 54 patients were studied (mean age 54 ± 21 years, 74% with focal injuries on CT), of whom 32 (59%) had ICHT. Among subjects with ICHT, episodes of sustained elevated ICP (n = 43, 172 matched ICP-NPi samples; baseline ICP [T- 6 h] 14 ± 5 mmHg vs. ICPmax [T0 h] 30 ± 9 mmHg) were associated with a concomitant decrease of the NPi (baseline 4.2 ± 0.5 vs. 2.8 ± 1.6, p < 0.0001 ANOVA for repeated measures). Abnormal NPi values were more frequent in patients with ICHT-r (n = 17; 38 [3-96]% of monitored time vs. 1 [0-9]% in patients with ICHT-nr [n = 15] and 0.5 [0-10]% in those without ICHT [n = 22]; p = 0.007) and were associated with an unfavorable 6-month outcome (15 [1-80]% in GOS 1-3 vs. 0 [0-7]% in GOS 4-5 patients; p = 0.002). CONCLUSIONS: In a selected cohort of severe TBI patients with abnormal head CT lesions and predominantly focal cerebral injury, elevated ICP episodes correlated with a concomitant decrease of NPi. Sustained abnormal NPi was in turn associated with a more complicated ICP course and worse outcome.

Midline Shift is Unrelated to Subjective Pupillary Reactivity Assessment on Admission in Moderate and Severe Traumatic Brain Injury.

BACKGROUND: This study aims to determine the relationship between pupillary reactivity, midline shift and basal cistern effacement on brain computed tomography (CT) in moderate-to-severe traumatic brain injury (TBI). All are important diagnostic and prognostic measures, but their relationship is unclear. METHODS: A total of 204 patients with moderate-to-severe TBI, documented pupillary reactivity, and archived neuroimaging were included. Extent of midline shift and basal cistern effacement were extracted from admission brain CT. Mean midline shift was calculated for each ordinal category of pupillary reactivity and basal cistern effacement. Sequential Chi-square analysis was used to calculate a threshold midline shift for pupillary abnormalities and basal cistern effacement. Univariable and multiple logistic regression analyses were performed. RESULTS: Pupils were bilaterally reactive in 163 patients, unilaterally reactive in 24, and bilaterally unreactive in 17, with mean midline shift (mm) of 1.96, 3.75, and 2.56, respectively (p = 0.14). Basal cisterns were normal in 118 patients, compressed in 45, and absent in 41, with mean midline shift (mm) of 0.64, 2.97, and 5.93, respectively (p < 0.001). Sequential Chi-square analysis identified a threshold for abnormal pupils at a midline shift of 7-7.25 mm (p = 0.032), compressed basal cisterns at 2 mm (p < 0.001), and completely effaced basal cisterns at 7.5 mm (p < 0.001). Logistic regression revealed no association between midline shift and pupillary reactivity. With effaced basal cisterns, the odds ratio for normal pupils was 0.22 (95% CI 0.08-0.56; p = 0.0016) and for at least one unreactive pupil was 0.061 (95% CI 0.012-0.24; p < 0.001). Basal cistern effacement strongly predicted midline shift (OR 1.27; 95% CI 1.17-1.40; p < 0.001). CONCLUSIONS: Basal cistern effacement alone is associated with pupillary reactivity and is closely associated with midline shift. It may represent a uniquely useful neuroimaging marker to guide intervention in traumatic brain injury.

Reliability of standard pupillometry practice in neurocritical care: an observational, double-blinded study.

BACKGROUND: In critical care units, pupil examination is an important clinical parameter for patient monitoring. Current practice is to use a penlight to observe the pupillary light reflex. The result seems to be a subjective measurement, with low precision and reproducibility. Several quantitative pupillometer devices are now available, although their use is primarily restricted to the research setting. To assess whether adoption of these technologies would benefit the clinic, we compared automated quantitative pupillometry with the standard clinical pupillary examination currently used for brain-injured patients. METHODS: In order to determine inter-observer agreement of the device, we performed repetitive measurements in 200 healthy volunteers ranging in age from 21 to 58 years, providing a total of 400 paired (alternative right eye, left eye) measurements under a wide variety of ambient light condition with NeuroLight Algiscan pupillometer. During another period, we conducted a prospective, observational, double-blinded study in two neurocritical care units. Patients admitted to these units after an acute brain injury were included. Initially, nursing staff measured pupil size, anisocoria and pupillary light reflex. A blinded physician subsequently performed measurement using an automated pupillometer. RESULTS: In 200 healthy volunteers, intra-class correlation coefficient for maximum resting pupil size was 0.95 (IC: 0.93-0.97) and for minimum pupil size after light stimulation 0.87 (0.83-0.89). We found only 3-pupil asymmetry (≥ 1 mm) in these volunteers (1.5% of the population) with a clear pupil asymmetry during clinical inspection. The mean pupil light reactivity was 40 ± 7%. In 59 patients, 406 pupillary measurements were prospectively performed. Concordance between measurements for pupil size collected using the pupillometer, versus subjective assessment, was poor (Spearmen's rho = 0.75, IC: 0.70-0.79; P < 0.001). Nursing staff failed to diagnose half of the cases (15/30) of anisocoria detected using the pupillometer device. A global rate of discordance of 18% (72/406) was found between the two techniques when assessing the pupillary light reflex. For measurements with small pupils (diameters <2 mm) the error rate was 39% (24/61). CONCLUSION: Standard practice in pupillary monitoring yields inaccurate data. Automated quantitative pupillometry is a more reliable method with which to collect pupillary measurements at the bedside.

Trustworthiness judgments and pupil-size in individuals with schizophrenia.

Individuals with schizophrenia show aberrant processing of social cues. In the current study, we (1) compared trustworthiness ratings of faces between patients with schizophrenia and healthy controls, (2) compared pupillary reactivity between patients and controls (3) examined whether trustworthiness judgments in schizophrenia are related to pupil reactivity, (4) and examined associations between trustworthiness judgements and symptom severity, specifically paranoia. Patients with schizophrenia spectrum disorders (N = 48) and healthy controls (N = 33) completed a Trustworthiness Task, during which their pupil size was measured via an eye-tracking device. The mean baseline-corrected pupil size was calculated from 24 pictures of real neutral faces, each presented for 2500 ms. Self-reported psychotic experiences were measured by Community Assessment of Psychic Functioning (CAPE-42), and symptom severity was rated by Brief Psychiatric Rating Scale (BPRS). No group differences were found in trustworthiness ratings or pupil reactivity parameters during trustworthiness judgments. Separately, among patients, absolute difference in pupil-size change and dilation after reaching minimum size were related to more severe positive symptoms and self-reported paranoia. Our results did not show social cognitive biases in the stable outpatients with schizophrenia, or the role of pupil reactivity in trustworthiness judgments. Future studies should use longer stimuli for pupillary reactivity and control the type and dosage of utilized antipsychotic medication. Further studies are required to explore relationships in larger and more symptomatic groups of patients.

Pupillometry in the follow-up of patients undergoing EVT - prediction of space-occupying hemispheric infarction.

BACKGROUND: Despite benefits of endovascular treatment (EVT) for large vessel occlusion (LVO) ischemic stroke, space-occupying brain edema (BE) represents a detrimental complication. In critical-care settings, CT-imaging is needed for monitoring these patients. Yet, bed-side techniques with the potential to predict whether patients develop BE or not would facilitate a time- and cost-efficient patient care. We assessed clinical significance of automated pupillometry in the follow-up of patients undergoing EVT. METHODS: From 10/2018 to 10/2021, neurocritical-care-unit patients were retrospectively enrolled after EVT of anterior circulation LVO. We monitored parameters of pupillary reactivity [light-reflex-latency (Lat), constriction- and redilation-velocities (CV, DV), percentage-change-of-apertures (per-change); NeurOptics-pupilometer®] up to every hour on day 1-3 of ICU stay. BE was defined as midline shift ≥ 5 mm on follow-up imaging 3-5 days after EVT. We calculated mean values of intra-individual differences between successive pairs of parameters (mean-deltas), determined best discriminative cut-off values for BE development (ROC-analyses), and evaluated prognostic performance of pupillometry for BE development (sensitivity/specificity/positive-/negative-predictive-values). RESULTS: 3241 pupillary assessments of 122 patients [67 women, 73 years (61.0-85.0)] were included. 13/122 patients developed BE. Patients with BE had significantly lower CVs, DVs, and smaller per-changes than patients without BE. On day 1 after EVT mean-deltas of CV, DV, and per-changes were significantly lower in patients with than without BE. Positive-predictive-values of calculated thresholds to discriminate both groups were considerably low, yet, we found high negative-predictive-values for CV, DV, per-changes, and mean-deltas (max.: 98.4%). CONCLUSION: Our data suggest associations between noninvasively detected changes in pupillary reactivity and BE early after LVO-EVT. Pupillometry may identify patients who are unlikely to develop BE and may not need repetitive follow-up-imaging or rescue-therapy.

Phasic activity of the locus-coeruleus is not a mediator of the relationship between fitness and inhibition in college-aged adults.

Aerobic fitness is consistently and robustly associated with superior performance on assessments of cognitive control. One potential mechanism underlying this phenomenon is activation of the locus-coeruleus. Specifically, individuals with greater aerobic fitness may be better able to sustain engagement in a cognitively demanding task via a superior ability to meet the metabolic demands of this neural system. Accordingly, the present investigation examined 1) the relationship between aerobic fitness and phasic activation of the locus-coeruleus (indexed using pupillometry) and 2) the potential mediating influence of locus-coeruleus activity on the relationship between aerobic fitness and cognitive task performance. Participants performed an inhibition task while their pupillary responses were measured using an infrared eye tracker. A VO2max test was then performed to determine individuals' aerobic fitness levels. Consistent with previous research, higher levels of aerobic fitness were related to shorter reaction time. However, phasic activity of the locus-coeruleus did not mediate this relationship - nor did it relate to aerobic fitness level. These results suggest that aerobic fitness does not relate to differences in locus-coeruleus activity in the context of cognitive control in college-aged adults.

Atypical Pupil Reactions in Brain Dead Patients.

BACKGROUND: During routine diagnosis of brain death, changes in pupil diameter in response to the stimulation of peripheral nerves are sometimes observed. For example, pupillary dilation after diagnosed brain death is described in the literature as the ciliospinal reflex. However, pupil constriction creates diagnostic doubts. OBJECTIVE: The pupillometric analysis of pupil response to stimulation of the cervicothoracic spinal cord in patients with diagnosed brain death. METHODS: Instrumental tests to confirm the arrest of cerebral circulation were performed in 30 adult subjects (mean age 53.5 years, range 26-75 years) with diagnosed brain death. In addition, a pupillometer was used to measure the change in pupil diameter in response to neck flexion. INTERVENTION: Flexion of the neck and measuring the response in change of the pupil with the use of the pupillometer. RESULTS: The change in the pupil was observed in the examined group of patients. Difference in pupil size ≥ 0.2 mm was observed in 14 cases (46%). In five cases (17%), pupil constriction was found (from 0.2 to 0.7 mm). Measurement error was +/- 0.1 mm. CONCLUSIONS: Both pupillary constriction and dilatation may occur due to a ciliospinal reflex in patients with brain death. This phenomenon needs further research in order to establish its pathophysiology.

Eyeing ambiguity: Pupillary reactivity during early automatic interpretations in major depressive disorder.

Automatic interpretation biases (AIB) are theorized to be a risk factor for depression. However, documenting AIB in depressed persons has been challenging and the source (affective vs cognitive) of AIB remains unclear. We conducted a psychophysiological investigation of AIB in a sample of 25 clinical interview assessed individuals experiencing a current major depressive episode and 28 never-depressed control individuals. Participants completed the Word Sentence Association Paradigm for Depression while their pupil size was recorded. Repeated measures ANOVAs were used to examine behavioral response data and multilevel modeling was used to examine pupillary reactivity (change from trial baseline). Compared to controls, the depressed group was both more likely to endorse negative AIB (p = .001, d = 1.01) and less likely to endorse benign AIB (p = .011, d = 0.72). Further, the depressed group exhibited significantly increased pupil size while processing negative words when they endorsed a negative interpretation compared with controls (ps = .010-.037, ds = 0.69-0.87), but did not differ during other AIB trial types. Within group comparisons revealed greater differentiation between interpretations in the healthy control group in both reaction time and pupillary reactivity AIB measures. This depression-related pupillary reactivity pattern fits with an emotional salience-based explanation better than a cognitive effort-based hypothesis of negative AIB, while pupillary reactivity pattern within the control group is consistent with a benign bias. People with depression lack benign AIB and may be more emotionally engaged during negative AIB than healthy controls.

Pupil Dilation Progression Modulates Aberrant Social Cognition in Autism Spectrum Disorder.

Progression of pupil dilation (PD) in response to visual stimuli may indicate distinct internal processes. No study has been performed on PD progression during a social cognition task. Here, we describe PD progression during the Movie for the Assessment of Social Cognition (MASC) test in n = 23 adolescents with Autism Spectrum Disorder (ASD) and n = 24 age, IQ and sex-matched neurotypical controls (NTC). The MASC consists of 43 video sequences depicting human social interactions, each followed by a multiple-choice question concerning characters' mental states. PD progression data were extracted by eye tracking and controlled for fixation behavior. Segmenting PD progression during video sequences by principal component analysis, three sequential PD components were unveiled. In ASD compared with NTC, a distinct PD progression was observed with increased constriction amplitude, increased dilation latency, and increased dilation amplitude that correlated with PD progression components. These components predicted social cognition performance. The first and second PD components correlated positively with MASC behavioral performance in ASD but negatively in NTC. These PD components may be interpreted as indicators of sensory-perceptual processing and attention function. In ASD, aberrant sensory-perceptual processing and attention function could contribute to attenuated social cognition performance. This needs to be tested by additional studies combining the respective cognitive tests and the outlined PD progression analysis. Phasic activity of the locus coeruleus-norepinephrine system is discussed as putatively shared underlying mechanism. Autism Res2019. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: In adolescents with autism, we found an altered pupil dilation during watching scenes of human interactions. Early pupil dilation correlated positively with the number of correct answers to questions about the shown human interactions. Our findings suggest that aberrant sensory processing and attention function may contribute to altered social cognition in autism.

Quantitative versus standard pupillary light reflex for early prognostication in comatose cardiac arrest patients: an international prospective multicenter double-blinded study.

PURPOSE: To assess the ability of quantitative pupillometry [using the Neurological Pupil index (NPi)] to predict an unfavorable neurological outcome after cardiac arrest (CA). METHODS: We performed a prospective international multicenter study (10 centers) in adult comatose CA patients. Quantitative NPi and standard manual pupillary light reflex (sPLR)-blinded to clinicians and outcome assessors-were recorded in parallel from day 1 to 3 after CA. Primary study endpoint was to compare the value of NPi versus sPLR to predict 3-month Cerebral Performance Category (CPC), dichotomized as favorable (CPC 1-2: full recovery or moderate disability) versus unfavorable outcome (CPC 3-5: severe disability, vegetative state, or death). RESULTS: At any time between day 1 and 3, an NPi ≤ 2 (n = 456 patients) had a 51% (95% CI 49-53) negative predictive value and a 100% positive predictive value [PPV; 0% (0-2) false-positive rate], with a 100% (98-100) specificity and 32% (27-38) sensitivity for the prediction of unfavorable outcome. Compared with NPi, sPLR had significantly lower PPV and significantly lower specificity (p  < 0.001 at day 1 and 2; p  = 0.06 at day 3). The combination of NPi ≤ 2 with bilaterally absent somatosensory evoked potentials (SSEP; n = 188 patients) provided higher sensitivity [58% (49-67) vs. 48% (39-57) for SSEP alone], with comparable specificity [100% (94-100)]. CONCLUSIONS: Quantitative NPi had excellent ability to predict an unfavorable outcome from day 1 after CA, with no false positives, and significantly higher specificity than standard manual pupillary examination. The addition of NPi to SSEP increased sensitivity of outcome prediction, while maintaining 100% specificity.

Glasgow coma scale motor score and pupillary reaction to predict six-month mortality in patients with traumatic brain injury: comparison of field and admission assessment.

The Glasgow Coma Scale (GCS) and pupillary reactivity are well-known prognostic factors in traumatic brain injury (TBI). The aim of this study was to compare the GCS motor score and pupillary reactivity assessed in the field and at hospital admission and assess their prognostic value for 6-month mortality in patients with moderate or severe TBI. We studied 445 patients with moderate or severe TBI from Austria enrolled to hospital in 2009-2012. The area under the curve (AUC) and Nagelkerke's R(2) were used to evaluate the predictive ability of GCS motor score and pupillary reactivity assessed in the field and at admission. Uni- and multi-variable analyses-adjusting for age, other clinical, and computed tomography findings-were performed using combinations of field and admission GCS motor score and pupillary reactivity. Motor scores generally deteriorated from the field to admission, whereas pupillary reactivity was similar. GCS motor score assessed in field (AUC=0.754; R(2)=0.273) and pupillary assessment at admission (AUC=0.662; R(2)=0.214) performed best as predictors of 6-month mortality in the univariate analysis. This combination also showed best performance in the adjusted analyses (AUC=0.876; R(2)=0.508), but the performance of both predictors assessed at admission was not much worse (AUC=0.857; R(2)=0.460). Field GCS motor score and pupillary reactivity at hospital admission, compared to other combinations of these parameters, possess the best prognostic value to predict 6-month mortality in patients with moderate-to-severe TBI. Given that differences in prognostic performance are only small, both the field and admission values of GCS motor score and pupillary reaction may be reasonable to use in multi-variable prediction models to predict 6-month outcome.