The Utility of Pupillary Light Reflex Metrics as a Physiologic Biomarker for Adolescent Sport-Related Concussion | Adolescent Medicine | JN Learning | AMA Ed Hub [Skip to Content]
[Skip to Content Landing]

Utility of Pupillary Light Reflex Metrics as a Physiologic Biomarker for Adolescent Sport-Related Concussion

Educational Objective
To determine the potential utility of pupillary light reflex metrics as physiological biomarkers for concussion.
1 Credit CME
Key Points

Question  Do quantitative metrics of the pupillary light reflex (PLR) distinguish athletes with concussion from healthy control individuals?

Findings  In this cohort study, 8 PLR metrics (maximum and minimum pupillary diameter, percentage constriction, peak and average constriction velocity, peak and average dilation velocity, and time to 75% pupillary redilation) were greater among adolescent athletes with concussion compared with healthy control individuals.

Meaning  These results suggest that 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.

Abstract

Importance  Concussion diagnosis remains clinical, without objective diagnostic tests available for adolescents. Known deficits in visual accommodation and autonomic function after concussion make the pupillary light reflex (PLR) a promising target as an objective physiological biomarker for concussion.

Objective  To determine the potential utility of PLR metrics as physiological biomarkers for concussion.

Design, Setting, and Participants  Prospective cohort of adolescent athletes between ages 12 and 18 years recruited between August 1, 2017, and December 31, 2018. The study took place at a specialty concussion program and private suburban high school and included healthy control individuals (n = 134) and athletes with a diagnosis of sport-related concussion (SRC) (n = 98). Analysis was completed June 30, 2020.

Exposures  Sports-related concussion and pupillometry assessments.

Main Outcomes and Measures  Pupillary light reflex metrics (maximum and minimum pupillary diameter, peak and average constriction/dilation velocity, percentage constriction, and time to 75% pupillary redilation [T75]).

Results  Pupillary light reflex metrics of 134 healthy control individuals and 98 athletes with concussion were obtained a median of 12.0 days following injury (interquartile range [IQR], 5.0-18.0 days). Eight of 9 metrics were significantly greater among athletes with concussion after Bonferroni correction (maximum pupil diameter: 4.83 mm vs 4.01 mm; difference, 0.82; 99.44% CI, 0.53-1.11; minimum pupil diameter: 2.96 mm vs 2.63 mm; difference, 0.33; 99.4% CI, 0.18-0.48; percentage constriction: 38.23% vs 33.66%; difference, 4.57; 99.4% CI, 2.60-6.55; average constriction velocity: 3.08 mm/s vs 2.50 mm/s; difference, 0.58; 99.4% CI, 0.36-0.81; peak constriction velocity: 4.88 mm/s vs 3.91 mm/s; difference, 0.97; 99.4% CI, 0.63-1.31; average dilation velocity, 1.32 mm/s vs 1.22 mm/s; difference, 0.10; 99.4% CI, 0.00-0.20; peak dilation velocity: 1.83 mm/s vs 1.64 mm/s; difference, 0.19; 99.4% CI, 0.07-0.32; and T75: 1.81 seconds vs 1.51 seconds; difference, 0.30; 0.10-0.51). In exploratory analyses, sex-based differences were observed, with girls with concussion exhibiting longer T75 (1.96 seconds vs 1.63 seconds; difference, 0.33; 99.4% CI, 0.02-0.65). Among healthy control individuals, diminished PLR metrics (eg, smaller maximum pupil size 3.81 mm vs 4.22 mm; difference, −0.41; 99.4% CI, −0.77 to 0.05) were observed after exercise.

Conclusions and Relevance  These findings suggest that enhancement of PLR metrics characterize acute adolescent concussion, while exercise produced smaller pupil sizes and overall slowing of PLR metrics, presumably associated with fatigue. Quantifiable measures of the PLR may serve in the future as objective physiologic biomarkers for concussion in the adolescent athlete.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Corresponding Author: Christina L. Master, MD, Sports Medicine and Performance Center, Children’s Hospital of Philadelphia, 3401 Civic Center Blvd, 2nd Floor Wood Building, Philadelphia, PA 19104 (masterc@email.chop.edu).

Accepted for Publication: July 28, 2020.

Published Online: September 24, 2020. doi:10.1001/jamaophthalmol.2020.3466

Author Contributions: Dr Master had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Master, Podolak, Ciuffreda, Metzger, Joshi, McDonald, Grady, Arbogast.

Acquisition, analysis, or interpretation of data: Master, Podolak, Ciuffreda, Metzger, Joshi, McDonald, Margulies, Arbogast.

Drafting of the manuscript: Master, Podolak, Ciuffreda, Metzger, Margulies.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Master, Ciuffreda, Metzger, Joshi.

Obtained funding: Master, Margulies, Arbogast.

Administrative, technical, or material support: Master, Podolak, Ciuffreda, Grady.

Supervision: Master, Ciuffreda, Arbogast.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported in part by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (grant R01NS0975NIH) and the Pennsylvania Department of Health (grant SAP4100077078).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentations: Preliminary data from this analysis were presented in part at the following conferences: National Neurotrauma Symposium, Toronto, Ontario, Canada, 2018; 3rd International Pediatric Brain Injury Society Meeting, Belfast, Ireland, 2018; American Academy of Pediatrics National Conference and Exhibit, Orlando, Florida, 2018; University of Pennsylvania Center for Brain Injury and Repair Retreat, Swarthmore, Pennsylvania, 2018; Children’s Hospital of Philadelphia Biomedical Postdoctoral Research Symposium, Philadelphia, Pennsylvania, 2018; Pediatric Research in Sports Medicine Annual Meeting, Atlanta, Georgia, 2019; Pediatric Academic Societies Meeting, Baltimore, MD, 2019; Pediatric Research in Sports Medicine Annual Meeting, Glendale, Arizona, 2020.

Additional Contributions: We thank Ronni S. Kessler, MS, Fairuz Mohammed, MS, MPH, Ari Fish, BS, Shelly Sharma, BA, and Julia Vanni, BS, of Children’s Hospital of Philadelphia for their contribution to data collection for this study. In addition, we thank the students and parents from the Shipley School for their participation. We appreciate the support from the Shipley School administration, faculty and athletic department: Steve Piltch, MEd, EdD, Mark Duncan, MEd, Katelyn Taylor, BS, Dakota Carroll, MS, Kimberly Shaud, BS, Kayleigh Jenkins, BS, and Michael Turner, MEd, without whose support this research would not have been possible.

References
1.
Master  CL , Scheiman  M , Gallaway  M ,  et al.  Vision diagnoses are common after concussion in adolescents.   Clin Pediatr (Phila). 2016;55(3):260-267. doi:10.1177/0009922815594367PubMedGoogle ScholarCrossref
2.
Leddy  JJ , Kozlowski  K , Fung  M , Pendergast  DR , Willer  B .  Regulatory and autoregulatory physiological dysfunction as a primary characteristic of post concussion syndrome: implications for treatment.   NeuroRehabilitation. 2007;22(3):199-205. doi:10.3233/NRE-2007-22306PubMedGoogle ScholarCrossref
3.
Dalecki  M , Gorbet  DJ , Macpherson  A , Sergio  LE .  Sport experience is correlated with complex motor skill recovery in youth following concussion.   Eur J Sport Sci. 2019;19(9):1257-1266. doi:10.1080/17461391.2019.1584249PubMedGoogle ScholarCrossref
4.
Swanson  MW , Weise  KK , Dreer  LE ,  et al.  Academic difficulty and vision symptoms in children with concussion.   Optom Vis Sci. 2017;94(1):60-67. doi:10.1097/OPX.0000000000000977PubMedGoogle ScholarCrossref
5.
Master  CL , Master  SR , Wiebe  DJ ,  et al.  Vision and vestibular system dysfunction predicts prolonged concussion recovery in children.   Clin J Sport Med. 2018;28(2):139-145. doi:10.1097/JSM.0000000000000507PubMedGoogle ScholarCrossref
6.
Storey  EP , Master  SR , Lockyer  JE , Podolak  OE , Grady  MF , Master  CL .  Near point of convergence after concussion in children.   Optom Vis Sci. 2017;94(1):96-100. doi:10.1097/OPX.0000000000000910PubMedGoogle ScholarCrossref
7.
Taylor  WR , Chen  JW , Meltzer  H ,  et al.  Quantitative pupillometry, a new technology: normative data and preliminary observations in patients with acute head injury: technical note.   J Neurosurg. 2003;98(1):205-213. doi:10.3171/jns.2003.98.1.0205PubMedGoogle ScholarCrossref
8.
Ciuffreda  KJ , Joshi  NR , Truong  JQ .  Understanding the effects of mild traumatic brain injury on the pupillary light reflex.   Concussion. 2017;2(3):CNC36. doi:10.2217/cnc-2016-0029PubMedGoogle ScholarCrossref
9.
Rickmann  A , Waizel  M , Kazerounian  S , Szurman  P , Wilhelm  H , Boden  KT .  Digital pupillometry in normal subjects.   Neuroophthalmology. 2016;41(1):12-18. doi:10.1080/01658107.2016.1226345PubMedGoogle ScholarCrossref
10.
Boev  AN , Fountas  KN , Karampelas  I ,  et al.  Quantitative pupillometry: normative data in healthy pediatric volunteers.   J Neurosurg. 2005;103(6)(suppl):496-500.PubMedGoogle Scholar
11.
Winston  M , Zhou  A , Rand  CM ,  et al.  Pupillometry measures of autonomic nervous system regulation with advancing age in a healthy pediatric cohort.   Clin Auton Res. 2019.PubMedGoogle Scholar
12.
Capó-Aponte JE, Urosevich TG, Walsh DV, Temme LA, Tarbett AK. Pupillary light reflex as an objective biomarker for early identification of blast-induced mTBI. J Spine. 2013;S4:004. doi:10.4172/2165-7939.S4-004.
13.
Thiagarajan  P , Ciuffreda  KJ .  Pupillary responses to light in chronic non-blast-induced mTBI.   Brain Inj. 2015;29(12):1420-1425. doi:10.3109/02699052.2015.1045029PubMedGoogle ScholarCrossref
14.
Truong  JQ , Ciuffreda  KJ .  Comparison of pupillary dynamics to light in the mild traumatic brain injury (mTBI) and normal populations.   Brain Inj. 2016;30(11):1378-1389. doi:10.1080/02699052.2016.1195922PubMedGoogle ScholarCrossref
15.
Ting  W , Topolovec-Vranic  J , McGowan  M ,  et al.  A pilot study exploring pupil response measurement in mild traumatic brain injury.   Can J Neurol Sci. 2015;42(1):S40-S40.Google ScholarCrossref
16.
Capó-Aponte  JE , Beltran  TA , Walsh  DV , Cole  WR , Dumayas  JY .  Validation of visual objective biomarkers for acute concussion.   Mil Med. 2018;183(1)(suppl_1):9-17.PubMedGoogle ScholarCrossref
17.
Joseph  JR , Swallow  JS , Willsey  K ,  et al.  Pupillary changes after clinically asymptomatic high-acceleration head impacts in high school football athletes.   J Neurosurg. 2019;(November):1-6. doi:10.3171/2019.7.JNS191272PubMedGoogle Scholar
18.
McCrory  P , Meeuwisse  W , Dvořák  J ,  et al.  Consensus statement on concussion in sport-the 5th international conference on concussion in sport held in Berlin, October 2016.   Br J Sports Med. 2017;51(11):838-847.PubMedGoogle Scholar
19.
Truong  JQ , Ciuffreda  KJ .  Objective pupillary correlates of photosensitivity in the normal and mild traumatic brain injury populations.   Mil Med. 2016;181(10):1382-1390. doi:10.7205/MILMED-D-15-00587PubMedGoogle ScholarCrossref
20.
Armstrong  RA .  When to use the Bonferroni correction.   Ophthalmic Physiol Opt. 2014;34(5):502-508. doi:10.1111/opo.12131PubMedGoogle ScholarCrossref
21.
Zou  KH , O’Malley  AJ , Mauri  L .  Receiver-operating characteristic analysis for evaluating diagnostic tests and predictive models.   Circulation. 2007;115(5):654-657. doi:10.1161/CIRCULATIONAHA.105.594929PubMedGoogle ScholarCrossref
22.
Mayer  AR , Wertz  C , Ryman  GS ,  et al. Neurosensory deficits vary as a function of point of care in pediatric mild traumatic brain injury. J Neurotrauma. 2018;35(10):1178-1184. doi:10.1089/neu.2017.5340
23.
Bin Zahid  A , Hubbard  ME , Lockyer  J ,  et al.  Eye tracking as a biomarker for concussion in children.   Clin J Sport Med. 2018;(August):1. doi:10.1097/JSM.0000000000000639PubMedGoogle Scholar
24.
Howell  DR , Brilliant  AN , Storey  EP , Podolak  OE , Meehan  WP  III , Master  CL .  Objective eye tracking deficits following concussion for youth seen in a sports medicine setting.   J Child Neurol. 2018;33(12):794-800. doi:10.1177/0883073818789320PubMedGoogle ScholarCrossref
25.
Kozlowski  KF , Graham  J , Leddy  JJ , Devinney-Boymel  L , Willer  BS .  Exercise intolerance in individuals with postconcussion syndrome.   J Athl Train. 2013;48(5):627-635. doi:10.4085/1062-6050-48.5.02PubMedGoogle ScholarCrossref
26.
Nyström  P , Gliga  T , Nilsson Jobs  E ,  et al.  Enhanced pupillary light reflex in infancy is associated with autism diagnosis in toddlerhood.   Nat Commun. 2018;9(1):1678. doi:10.1038/s41467-018-03985-4PubMedGoogle ScholarCrossref
27.
Esterov  D , Greenwald  BD .  Autonomic dysfunction after mild traumatic brain injury.   Brain Sci. 2017;7(8):E100. doi:10.3390/brainsci7080100PubMedGoogle Scholar
28.
Marion  CM , Radomski  KL , Cramer  NP , Galdzicki  Z , Armstrong  RC .  Experimental traumatic brain injury identifies distinct early and late phase axonal conduction deficits of white matter pathophysiology, and reveals intervening recovery.   J Neurosci. 2018;38(41):8723-8736. doi:10.1523/JNEUROSCI.0819-18.2018PubMedGoogle ScholarCrossref
29.
Baker  JG , Leddy  JJ , Darling  SR , Shucard  J , Makdissi  M , Willer  BS .  Gender differences in recovery from sports-related concussion in adolescents.   Clin Pediatr (Phila). 2016;55(8):771-775. doi:10.1177/0009922815606417PubMedGoogle ScholarCrossref
30.
Filipe  JA , Falcão-Reis  F , Castro-Correia  J , Barros  H .  Assessment of autonomic function in high level athletes by pupillometry.   Auton Neurosci. 2003;104(1):66-72. doi:10.1016/S1566-0702(02)00268-0PubMedGoogle ScholarCrossref
31.
Tekin  K , Sekeroglu  MA , Kiziltoprak  H , Doguizi  S , Inanc  M , Yilmazbas  P .  Static and dynamic pupillometry data of healthy individuals.   Clin Exp Optom. 2018;101(5):659-665. doi:10.1111/cxo.12659PubMedGoogle ScholarCrossref
32.
Maugans  TA , Farley  C , Altaye  M , Leach  J , Cecil  KM .  Pediatric sports-related concussion produces cerebral blood flow alterations.   Pediatrics. 2012;129(1):28-37. doi:10.1542/peds.2011-2083PubMedGoogle ScholarCrossref
33.
Meier  TB , Bellgowan  PSFF , Singh  R , Kuplicki  R , Polanski  DW , Mayer  AR .  Recovery of cerebral blood flow following sports-related concussion.   JAMA Neurol. 2015;72(5):530-538. doi:10.1001/jamaneurol.2014.4778PubMedGoogle ScholarCrossref
34.
Lam  BL , Thompson  HS , Corbett  JJ .  The prevalence of simple anisocoria.   Am J Ophthalmol. 1987;104(1):69-73. doi:10.1016/0002-9394(87)90296-0PubMedGoogle ScholarCrossref
35.
Sharma  S , Baskaran  M , Rukmini  AV ,  et al.  Factors influencing the pupillary light reflex in healthy individuals.   Graefes Arch Clin Exp Ophthalmol. 2016;254(7):1353-1359. doi:10.1007/s00417-016-3311-4PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close