Measurement of pupillary light reflex could serve as expedient biomarker for concussion

Adolescents with sports-related concussion had different pupillary light reflex (PLR) responses than healthy controls, a prospective observational cohort study showed.

Of nine metrics measured with a handheld dynamic infrared pupillometer, eight were significantly greater in young people diagnosed with concussion, reported Christina Master, MD, of Children’s Hospital of Philadelphia, and coauthors.

“Quantitative metrics of the pupillary light reflex are enhanced in adolescent sport-related concussion and distinguish athletes with concussion from healthy control individuals and may serve as a fast, portable, objective physiologic biomarker for adolescent sport concussion,” they wrote in JAMA Ophthalmology.

“Enhancement of PLR metrics characterizes acute concussion, with larger pupil sizes and increased average and peak constriction/dilation velocities,” they added. “The association of concussion with PLR metrics appears robust, with significant differences between athletes with concussion and control participants in all metrics except for latency.”

Measurements were significantly greater in concussed adolescents versus controls in:

  • Maximum pupil diameter (steady-state pupil size before light stimulus): 4.83 mm versus 4.01 mm, difference 0.82; 99.44% CI 0.53-1.11.
  • Minimum pupil diameter (pupil size after maximum constriction in response to light stimulus): 2.96 mm versus 2.63 mm, difference 0.33; 99.4% CI 0.18-0.48).
  • Percentage pupil constriction: 38.23% versus 33.66%, difference 4.57; 99.4% CI 2.60-6.55.
  • Peak constriction velocity: 4.88 mm/s versus 3.91 mm/s, difference 0.97, 99.4% CI 0.63-1.31.
  • Average constriction velocity: 3.08 mm/s versus 2.50 mm/s, difference 0.58; 99.4% CI 0.36-0.81.
  • Average dilation velocity: 1.32 mm/s versus 1.22 mm/s, difference 0.10; 99.4% CI 0.00-0.20.
  • T75 (time to 75% pupillary redilation): 1.81 seconds versus 1.51 seconds, difference 0.30; 99.4% CI 0.10-0.51.
  • Peak dilation velocity: 1.83 mm/s versus 1.64 mm/s, difference 0.19; 99.4% CI 0.07-0.32.

Receiver operating characteristic curves for each metric showed maximum pupil diameter and peak constriction velocity had the greatest area under the curve (0.78 for both) for distinguishing athletes with concussion from controls.

A ninth measurement, latency (time to maximum constriction in response to light stimulus), did not differ between groups.

“We accounted for multiplicity by calculating Bonferroni corrections for the nine PLR metrics; we present the 99.44% CIs around the mean values and the mean differences between comparison groups,” the researchers noted.

In an accompanying editorial, Wesley Beaulieu, PhD, and Adam Glassman, MS, both of the Jaeb Center for Health Research in Tampa, Florida, wrote: “We were happy to see that the authors of this study used an appropriate method for controlling the false-positive rate, given that several interconnected outcomes were analyzed in their study.

“We agree with their conclusion that PLR metrics show promise as an objective, reproducible biomarker for sports related concussion in adolescent athletes,” they added. “Future prospective studies that evaluate individuals before and after sports-related concussion onset are needed to establish the utility of PLR in diagnosing concussion.”

Multiple imaging, blood, and cerebrospinal fluid biomarkers have been investigated in traumatic brain injury of varying origin and severity, but a practical, objective measure for rapid assessment of sports-related concussion has proven elusive. Pupillary reflex abnormalities after concussion reflect one form of autonomic dysfunction due to concussion, with the light reflex involving both parasympathetic constriction and sympathetic dilation.

Dynamic infrared pupillometry using a handheld device is objective, rapid and automated, and has been studied in adults after traumatic brain injury with mixed results regarding which measures change and their timing. One study comparing PLR after TBI in military adults with civilian controls during 2-8 week subacute phase found longer latency, lower average constriction and dilation velocities, and increased pupillary re-dilation (T75) versus controls.

To study pupillary measures in adolescent athletes, Master and colleagues prospectively enrolled high school athletes ages 12 to 18 diagnosed with sports-related concussion from August 2017 to December 2018. Average age of concussed athletes was 15.7; 56% were female, and 51% had history of prior concussion. This group did not have pre-injury pupillometry; assessment was done a median 12 days after injury.

Healthy controls were also identified and had pupillary assessments before the start of their high school sports season (mean age 15.3, 58% female, and 26% with history of prior concussion).

The analysis reported on 134 controls and 98 adolescents with concussion. Athletes with concussion within 1 month of injury (or pre-injury assessment), ongoing chronic post-concussion symptoms, and with any ocular or neurologic condition or taking medication that could affect pupillary responses were excluded.

Exploratory analysis by sex showed prolongation of T75 in girls with concussion. The finding lends support to “previously described sex-based differences following concussion reflecting differential adverse effects of trauma on the sympathetic system,” the authors wrote.

A largely white population that was 12-18 years old limits the study’s generalizability. “Owing to potential developmental differences in the PLR, our results should not be extrapolated to either younger pediatric or older adult populations until more is understood about neurodevelopmental and aging factors associated with the PLR,” the researchers wrote.

  1. Adolescents with sports-related concussion had different pupillary light reflex responses than healthy controls.

  2. Of nine metrics measured with a handheld dynamic infrared pupillometer, eight were significantly greater in adolescents diagnosed with concussion.

Paul Smyth, MD, Contributing Writer, BreakingMED™

This work was supported in part by the NIH’s National Institute of Neurological Disorders and Stroke and the Pennsylvania Department of Health.

The researchers reported no conflicts of interest.

Beaulieu reports receipt of grants to his institution from the National Eye Institute, Genentech, and Regeneron. Glassman reports receipt of grants from the National Eye Institute, Regeneron, and Genentech.

Cat ID: 474

Topic ID: 82,474,737,474,138,192,925