The pupillary light reflex (PLR) is an important biomarker for the detection and management of traumatic brain injury (TBI). We investigated the performance of PupilScreen, a smartphone-based pupillometry app, in classifying healthy control subjects and subjects with severe TBI in comparison to the current gold standard NeurOptics pupillometer (NPi-200 model with proprietary Neurological Pupil Index [NPi] TBI severity score). A total of 230 PLR video recordings taken using both the PupilScreen smartphone pupillometer and NeurOptics handheld device (NPi-200) pupillometer were collected from 33 subjects with severe TBI (sTBI) and 132 subjects who were healthy without self-reported neurological disease. Severe TBI status was determined by Glasgow Coma Scale (GCS) at the time of recording. The proprietary NPi score was collected from the NPi-200 pupillometer for each subject. Seven PLR curve morphological parameters were collected from the PupilScreen app for each subject. A comparison via t-test and via binary classification algorithm performance using NPi scores from the NPi-200 and PLR parameter data from the PupilScreen app was completed. This was used to determine how the frequently used NPi-200 proprietary NPi TBI severity score compares to the PupilScreen app in ability to distinguish between healthy and sTBI subjects. Binary classification models for this task were trained for the diagnosis of healthy or severe TBI using logistic regression, k-nearest neighbors, support vector machine, and random forest machine learning classification models. Overall classification accuracy, sensitivity, specificity, area under the curve, and F1 score values were calculated. Median GCS was 15 for the healthy cohort and 6 (interquartile range 2) for the severe TBI cohort. Smartphone app PLR parameters as well as NPi from the digital infrared pupillometer were significantly different between healthy and severe TBI cohorts; 33% of the study cohort had dark eye colors defined as brown eyes of varying shades. Across all classification models, the top performing PLR parameter combination for classifying subjects as healthy or sTBI for PupilScreen was maximum diameter, constriction velocity, maximum constriction velocity, and dilation velocity with accuracy, sensitivity, specificity, area under the curve (AUC), and F1 score of 87%, 85.9%, 88%, 0.869, and 0.85, respectively, in a random forest model. The proprietary NPi TBI severity score demonstrated greatest AUC value, F1 score, and sensitivity of 0.648, 0.567, and 50.9% respectively using a random forest classifier and greatest overall accuracy and specificity of 67.4% and 92.4% using a logistic regression model in the same classification task on the same dataset. The PupilScreen smartphone pupillometry app demonstrated binary healthy versus severe TBI classification ability greater than that of the NPi-200 proprietary NPi TBI severity score. These results may indicate the potential benefit of future study of this PupilScreen smartphone pupillometry application in comparison to the NPi-200 digital infrared pupillometer across the broader TBI spectrum, as well as in other neurological diseases.

Background: Quantitative pupillometry has been proposed as an objective means to diagnose acute sports-related concussion (SRC). Objective: To assess the diagnostic accuracy of a smartphone-based quantitative pupillometer in the acute diagnosis of SRC. Methods: Division I college football players had baseline pupillometry including pupillary light reflex (PLR) parameters of maximum resting diameter, minimum diameter after light stimulus, percent change in pupil diameter, latency of pupil constriction onset, mean constriction velocity, maximum constriction velocity, and mean dilation velocity using a smartphone-based app. When an SRC occurred, athletes had the smartphone pupillometry repeated as part of their concussion testing. All combinations of the seven PLR parameters were tested in machine learning binary classification models to determine the optimal combination for differentiating between non-concussed and concussed athletes. Results: 93 football athletes underwent baseline pupillometry testing. Among these athletes, 11 suffered future SRC and had pupillometry recordings repeated at the time of diagnosis. In the machine learning pupillometry analysis that used the synthetic minority oversampling technique to account for the significant class imbalance in our dataset, the best-performing model was a random forest algorithm with the combination of latency, maximum diameter, minimum diameter, mean constriction velocity, and maximum constriction velocity PLR parameters as feature inputs. This model produced 91% overall accuracy, 98% sensitivity, 84.2% specificity, area under the curve (AUC) of 0.91, and an F1 score of 91.6% in differentiating between baseline and SRC recordings. In the machine learning analysis prior to oversampling of our imbalanced dataset, the best-performing model was k-nearest neighbors using latency, maximum diameter, maximum constriction velocity, and mean dilation velocity to produce 82% accuracy, 40% sensitivity, 87% specificity, AUC of 0.64, and F1 score of 24%. Conclusions: Smartphone pupillometry in combination with machine learning may provide fast and objective SRC diagnosis in football athletes.

We would like to thank the authors for their interest in our recent manuscript. We agree that the effects of analgesic and sedative administration are among the most relevant complicating factors for the use of any form of pupillometry in the intensive care unit setting. As discussed extensively in the limitations section of our manuscript, a variety of studies have demonstrated the effects of opioid and sedative medications on the pupillary light reflex. To address these concerns, we have performed an additional review of the medication administration records for the patients with severe traumatic brain injury in our study. We reviewed opioid administration prior to pupillometry measurements in our study cohort. In 8 recordings, the last opioid given was hydromorphone. In 21 recordings, the last opioid given was oxycodone. In the remaining 69 recordings, the last opioid given was fentanyl. The median time from most recent opioid administration to pupillary light reflex recording was 1244 minutes (20.7 hours), with an interquartile range of 5484 minutes. Given the long latency period between most recent opioid administration and recording of the pupillary light reflex, their effects on our analysis of the pupillary light reflex are likely minimal.

Similarities between acute ischemic and hemorrhagic stroke make diagnosis and triage challenging. We studied a smartphone-based quantitative pupillometer for differentiation of acute ischemic and hemorrhagic stroke. Stroke patients were recruited prior to surgical or interventional treatment. Smartphone pupillometry was used to quantify components of the pupillary light reflex (PLR). A synthetic minority oversampling technique (SMOTE) was applied to correct sample size imbalance. Four binary classification model types were trained using all possible combinations of the PLR components with 10-fold cross validation stratified by cohort. Models were evaluated for accuracy, sensitivity, specificity, area under the curve (AUC), and F1 score. The three best-performing models were selected based on AUC. Shapley additive explanation plots were produced to explain PLR parameter impacts on model predictions. Eleven subjects with intraparenchymal hemorrhage and 22 subjects with acute ischemic stroke were enrolled. One way ANOVA demonstrated significant differences between healthy control data, AIS, and IPH in five out of seven PLR parameters. After SMOTE, each class had n=22 PLR recordings for model training. The best-performing model was random forest using a combination of latency, mean and maximum constriction velocity, and mean dilation velocity to discriminate between stroke types with 91.5% (95% confidence interval: 84.1-98.9) accuracy, 90% (82.9-97.1) sensitivity, 93.3% (83-100) specificity, 0.917 (0.847-0.987) AUC, and 90.7% (84.1-97.3) F1 score. Smartphone-based quantitative pupillometry could be useful in differentiating between acute ischemic and hemorrhagic stroke.