Biomarkers
Introduction
Domain 13: Biomarkers - Neuroimaging
Introduction:
Recommendations
LEVEL OF EVIDENCE 
A = Consistent, good-quality, patient-oriented evidence (example: at least one large randomized control trial, meta-analysis or systematic review with homogeneity, or large, high- quality, multi-centre cohort study)
B = Inconsistent or limited-quality patient-oriented evidence (example: smaller cohort studies, case studies or control trials with limitations)
C = Consensus, usual practice, opinion or weaker-level evidence
13.1
At this stage, advanced neuroimaging biomarkers are not yet ready for clinical implementation/management.
Level of Evidence: 
Biomarkers such as functional MRI (fMRI), diffusion tensor imaging (DTI), magnetic resonance spectroscopy (MRS), arterial spin labeling (ASL), cerebrovascular-reactivity mapping (CVR), quantitative susceptibility based susceptibility weighted imaging (qSWI), electroencephalography/event-related potential (EEG/ERP), transcranial magnetic stimulation (TMS), while potentially useful as research tools, are not ready for clinical implementation.
13.2
When conventional MRI is performed in the clinical management of concussion patients, the inclusion of susceptibility-weighted images (SWI) sequences could be considered as it may be useful for detecting small hemorrhages. The clinical significance of small hemorrhages on SWI is not clear at present.
Level of Evidence:
See Recommendation 2.1c for more information on when to consider diagnostic brain or cervical spine imaging.
Tools and Resources
References
Research papers that support the present guideline recommendations:
Babcock, L., Yuan, W., Leach, J., Nash, T., & Wade, S. (2015). White matter alterations in youth with acute mild traumatic brain injury. Journal of Pediatric Rehabilitation Medicine, 8(4), 285–296. https://doi.org/10.3233/PRM-150347
Beauchamp, M. H., Beare, R., Ditchfield, M., Coleman, L., Babl, F. E., Kean, M., … Anderson, V. (2013). Susceptibility weighted imaging and its relationship to outcome after pediatric traumatic brain injury. Cortex, 49(2), 591–598. https://doi.org/10.1016/j.cortex.2012.08.015
Bonow, R. H., Friedman, S. D., Perez, F. A., Ellenbogen, R. G., Browd, S. R., Mac Donald, C. L., … Rivara, F. P. (2017). Prevalence of Abnormal Magnetic Resonance Imaging Findings in Children with Persistent Symptoms after Pediatric Sports-Related Concussion. Journal of Neurotrauma, 34(19), 2706–2712. https://doi.org/10.1089/neu.2017.4970
Chamard, E., & Lichtenstein, J. D. (2018). A systematic review of neuroimaging findings in children and adolescents with sports-related concussion. Brain Injury, 32(7), 816–831. https://doi.org/10.1080/02699052.2018.1463106
Dona, O., Noseworthy, M. D., DeMatteo, C., & Connolly, J. F. (2017). Fractal analysis of brain blood oxygenation level dependent (BOLD) signals from children with mild traumatic brain injury (mTBI). PLoS ONE, 12(1). https://doi.org/10.1371/journal.pone.0169647
Ellis, M. J., Leiter, J., Hall, T., McDonald, P. J., Sawyer, S., Silver, N., … Essig, M. (2015). Neuroimaging findings in pediatric sports-related concussion. Journal of Neurosurgery: Pediatrics, 16(3), 241–247. https://doi.org/10.3171/2015.1.PEDS14510
Fakhran, S., Yaeger, K., Collins, M., & Alhilali, L. (2014). Sex Differences in White Matter Abnormalities after Mild Traumatic Brain Injury: Localization and Correlation with Outcome. Radiology, 272(3), 815–823. https://doi.org/10.1148/radiol.14132512
Faris, G., Byczkowski, T., Ho, M., & Babcock, L. (2016). Prediction of Persistent Postconcussion Symptoms in Youth Using a Neuroimaging Decision Rule. Academic Pediatrics, 16(4), 336–342. https://doi.org/10.1016/j.acap.2015.10.007
Genc, S., Anderson, V., Ryan, N. P., Malpas, C. B., Catroppa, C., Beauchamp, M. H., & Silk, T. J. (2017). Recovery of White Matter following Pediatric Traumatic Brain Injury Depends on Injury Severity. Journal of Neurotrauma, 34(4), 798–806. https://doi.org/10.1089/neu.2016.4584
Iyer, K. K., Barlow, K. M., Brooks, B., Ofoghi, Z., Zalesky, A., & Cocchi, L. (2019). Relating brain connectivity with persistent symptoms in pediatric concussion. Annals of Clinical and Translational Neurology, 6(5), 954–961. https://doi.org/10.1002/acn3.764
Keightley, M. L., Singh Saluja, R., Chen, J.-K., Gagnon, I., Leonard, G., Petrides, M., & Ptito, A. (2014). A Functional Magnetic Resonance Imaging Study of Working Memory in Youth after Sports-Related Concussion: Is It Still Working? Journal of Neurotrauma, 31(5), 437–451. https://doi.org/10.1089/neu.2013.3052
King, R., Grohs, M. N., Kirton, A., Lebel, C., Esser, M. J., & Barlow, K. M. (2019). Microstructural neuroimaging of white matter tracts in persistent post-concussion syndrome: A prospective controlled cohort study. NeuroImage: Clinical, 23(April), 101842. https://doi.org/10.1016/j.nicl.2019.101842
King, R., Kirton, A., Zewdie, E., Seeger, T. A., Ciechanski, P., & Barlow, K. M. (2019). Longitudinal assessment of cortical excitability in children and adolescents with mild traumatic brain injury and persistent post-concussive symptoms. Frontiers in Neurology, 10(MAY), 8–18. https://doi.org/10.3389/fneur.2019.00451
Lancaster, M. A., Olson, D. V., McCrea, M. A., Nelson, L. D., LaRoche, A. A., & Muftuler, L. T. (2016). Acute white matter changes following sport-related concussion: A serial diffusion tensor and diffusion kurtosis tensor imaging study. Human Brain Mapping, 37(11), 3821–3834. https://doi.org/10.1002/hbm.23278
Mac Donald, C. L., Barber, J., Wright, J., Coppel, D., De Lacy, N., Ottinger, S., … Temkin, N. (2019). Longitudinal Clinical and Neuroimaging Evaluation of Symptomatic Concussion in 10-to 14-year-old Youth Athletes. Journal of Neurotrauma, 36(2), 264–274. https://doi.org/10.1089/neu.2018.5629
Manning, K. Y., Schranz, A., Bartha, R., Dekaban, G. A., Barreira, C., Brown, A., … Menon, R. S. (2017). Multiparametric MRI changes persist beyond recovery in concussed adolescent hockey players. Neurology, 89(21), 2157–2166. https://doi.org/10.1212/WNL.0000000000004669
Mayer, A. R., Hanlon, F. M., & Ling, J. M. (2015). Gray Matter Abnormalities in Pediatric Mild Traumatic Brain Injury. Journal of Neurotrauma, 32(10), 723–730. https://doi.org/10.1089/neu.2014.3534
Morgan, C. D., Zuckerman, S. L., King, L. E., Beaird, S. E., Sills, A. K., & Solomon, G. S. (2015). Post-concussion syndrome (PCS) in a youth population: defining the diagnostic value and cost-utility of brain imaging. Child’s Nervous System, 31(12), 2305–2309. https://doi.org/10.1007/s00381-015-2916-y
Murdaugh, D. L., King, T. Z., Sun, B., Jones, R. A., Ono, K. E., Reisner, A., & Burns, T. G. (2018). Longitudinal Changes in Resting State Connectivity and White Matter Integrity in Adolescents with Sports-Related Concussion. Journal of the International Neuropsychological Society, 24(8), 781–792. https://doi.org/10.1017/S1355617718000413
Mutch, W. A. C., Ellis, M. J., Ryner, L. N., McDonald, P. J., Morissette, M. P., Pries, P., … Fisher, J. A. (2018). Patient-specific alterations in CO2 cerebrovascular responsiveness in acute and sub-acute sports-related concussion. Frontiers in Neurology, 9(JAN), 1–11. https://doi.org/10.3389/fneur.2018.00023
Mutch, W. A. C., Ellis, M. J., Ryner, L. N., Morissette, M. P., Pries, P. J., Dufault, B., … Fisher, J. A. (2016). Longitudinal Brain Magnetic Resonance Imaging CO2 Stress Testing in Individual Adolescent Sports-Related Concussion Patients: A Pilot Study. Frontiers in Neurology, 7(July), 1–8. https://doi.org/10.3389/fneur.2016.00107
Mutch, W. Alan C. Ellis, Michael J. Ryner, Lawrence N. Graham, Ruth. Dufault, Brenden. Gregson, Brian. Hall, Thomas. Bunge, Martin. Essig, M. (2015). Brain magnetic resonance imaging CO2 stress testing in adolescent post-concussion syndrome: pCASL findings. Journal of Neurosurgery, 125(September), 1–13. https://doi.org/10.3171/2015.6.JNS15972.
Newsome, M. R., Li, X., Lin, X., Wilde, E. A., Ott, S., Biekman, B., … Levin, H. S. (2016). Functional connectivity is altered in concussed adolescent athletes despite medical clearance to return to play: A preliminary report. Frontiers in Neurology, 7(JUL), 1–9. https://doi.org/10.3389/fneur.2016.00116
Orr, C. A., Albaugh, M. D., Watts, R., Garavan, H., Andrews, T., Nickerson, J. P., … Hudziak, J. J. (2016). Neuroimaging Biomarkers of a History of Concussion Observed in Asymptomatic Young Athletes. Journal of Neurotrauma, 33(9), 803–810. https://doi.org/10.1089/neu.2014.3721
Rose, S. C., Schaffer, C. E., Young, J. A., McNally, K. A., Fischer, A. N., & Heyer, G. L. (2017). Utilization of conventional neuroimaging following youth concussion. Brain Injury, 31(2), 260–266. https://doi.org/10.1080/02699052.2016.1235285
Saluja, R. S., Chen, J.-K., Gagnon, I. J., Keightley, M., & Ptito, A. (2015). Navigational Memory Functional Magnetic Resonance Imaging: A Test for Concussion in Children. Journal of Neurotrauma, 32(10), 712–722. https://doi.org/10.1089/neu.2014.3470
Schmidt, J., Hayward, K. S., Brown, K. E., Zwicker, J. G., Ponsford, J., Van Donkelaar, P., … Boyd, L. A. (2018). Imaging in pediatric concussion: A systematic review. Pediatrics, 141(5). https://doi.org/10.1542/peds.2017-3406
Sinopoli, K. J., Chen, J.-K., Wells, G., Fait, P., Ptito, A., Taha, T., & Keightley, M. (2014). Imaging “Brain Strain” in Youth Athletes with Mild Traumatic Brain Injury during Dual-Task Performance. Journal of Neurotrauma, 31(22), 1843–1859. https://doi.org/10.1089/neu.2014.3326
Stephens, J. A., Liu, P., Lu, H., & Suskauer, S. J. (2018). Cerebral Blood Flow after Mild Traumatic Brain Injury: Associations between Symptoms and Post-Injury Perfusion. Journal of Neurotrauma, 35(2), 241–248. https://doi.org/10.1089/neu.2017.5237
Urban, K. J., Barlow, K. M., Jimenez, J. J., Goodyear, B. G., & Dunn, J. F. (2015). Functional Near-Infrared Spectroscopy Reveals Reduced Interhemispheric Cortical Communication after Pediatric Concussion. Journal of Neurotrauma, 32(11), 833–840. https://doi.org/10.1089/neu.2014.3577
Urban, K. J., Riggs, L., Wells, G. D., Keightley, M., Chen, J.-K., Ptito, A., … Sinopoli, K. J. (2017). Cortical Thickness Changes and Their Relationship to Dual-Task Performance following Mild Traumatic Brain Injury in Youth. Journal of Neurotrauma, 34(4), 816–823. https://doi.org/10.1089/neu.2016.4502
Van Beek, L., Ghesquière, P., Lagae, L., & De Smedt, B. (2015). Mathematical Difficulties and White Matter Abnormalities in Subacute Pediatric Mild Traumatic Brain Injury. Journal of Neurotrauma, 32(20), 1567–1578. https://doi.org/10.1089/neu.2014.3809
Van Beek, L., Vanderauwera, J., Ghesquière, P., Lagae, L., & De Smedt, B. (2015). Longitudinal changes in mathematical abilities and white matter following paediatric mild traumatic brain injury. Brain Injury, 29(13–14), 1701–1710. https://doi.org/10.3109/02699052.2015.1075172
Wang, Y., Nelson, L. D., LaRoche, A. A., Pfaller, A. Y., Nencka, A. S., Koch, K. M., & McCrea, M. A. (2016). Cerebral Blood Flow Alterations in Acute Sport-Related Concussion. Journal of Neurotrauma, 33(13), 1227–1236. https://doi.org/10.1089/neu.2015.4072
Wang, Y., West, J. D., Bailey, J. N., Westfall, D. R., Xiao, H., Arnold, T. W., … McDonald, B. C. (2015). Decreased cerebral blood flow in chronic pediatric mild TBI: An MRI perfusion study. Developmental Neuropsychology, 40(1), 40–44. https://doi.org/10.1080/87565641.2014.979927
Westfall, D. R., West, J. D., Bailey, J. N., Arnold, T. W., Kersey, P. A., Saykin, A. J., & McDonald, B. C. (2015). Increased brain activation during working memory processing after pediatric mild traumatic brain injury (mTBI). Journal of Pediatric Rehabilitation Medicine, 8(4), 297–308. https://doi.org/10.3233/PRM-150348
Wu, T., Merkley, T. L., Wilde, E. A., Barnes, A., Li, X., Chu, Z. D., … Levin, H. S. (2017). A preliminary report of cerebral white matter microstructural changes associated with adolescent sports concussion acutely and subacutely using diffusion tensor imaging. Brain Imaging and Behavior, 1–12. https://doi.org/10.1007/s11682-017-9752-5
Last update: November 16, 2019
Domain 14: Biomarkers - Serologic
Introduction:
Recommendations
LEVEL OF EVIDENCE A = Consistent, good-quality, patient-oriented evidence (example: at least one large randomized control trial, meta-analysis or systematic review with homogeneity, or large, high- quality, multi-centre cohort study)B = Inconsistent or limited-quality patient-oriented evidence (example: smaller cohort studies, case studies or control trials with limitations)C = Consensus, usual practice, opinion or weaker-level evidence
14.1
The use of serologic biomarkers is not clinically indicated. Presently there is no validated “concussion blood test” that can be used to accurately detect concussion in children/adolescents.
Level of Evidence:
At this stage, newer serologic and other clinical biomarkers, while potentially useful as research tools, are not ready for clinical implementation/management.
Tools and Resources
References
Research papers that support the present guideline recommendations:
Babcock, L., Byczkowski, T., Wade, S. L., Ho, M., & Bazarian, J. J. (2013). Inability of S100B to predict postconcussion syndrome in children who present to the emergency department with mild traumatic brain injury: A brief report. Pediatric Emergency Care, 29(4), 458–461. https://doi.org/10.1097/PEC.0b013e31828a202d
Bazarian, J. J., Blyth, B. J., He, H., Mookerjee, S., Jones, C., Kiechle, K., … Khan, J. (2013). Classification Accuracy of Serum Apo A-I and S100B for the Diagnosis of Mild Traumatic Brain Injury and Prediction of Abnormal Initial Head Computed Tomography Scan. Journal of Neurotrauma, 30(20), 1747–1754. https://doi.org/10.1089/neu.2013.2853
Białuńska, A., & Salvatore, A. P. (2017). The auditory comprehension changes over time after sport-related concussion can indicate multisensory processing dysfunctions. Brain and Behavior, 7(12), 1–8. https://doi.org/10.1002/brb3.874
Broglio, S. P., Williams, R., Lapointe, A., Rettmann, A., Moore, B., Meehan, S. K., & Eckner, J. T. (2017). Brain network activation technology does not assist with concussion diagnosis and return to play in football athletes. Frontiers in Neurology, 8(JUN). https://doi.org/10.3389/fneur.2017.00252
Delefortrie, Q., Lejeune, F., Kerzmann, B., Levy, R., Adam, J. F., Sottiaux, T., … Hachimi-Idrissi, S. (2018). Evaluation of the Roche® Elecsys and the Diasorin® Liaison S100 kits in the management of mild head injury in the emergency room. Clinical Biochemistry, 52(November 2017), 123–130. https://doi.org/10.1016/j.clinbiochem.2017.11.004
Kraus, N., Thompson, E. C., Krizman, J., Cook, K., White-Schwoch, T., & LaBella, C. R. (2016). Auditory biological marker of concussion in children. Scientific Reports, 6(August), 1–10. https://doi.org/10.1038/srep39009
Little, C. E., Emery, C., Scott, S. H., Meeuwisse, W., Palacios-Derflingher, L., & Dukelow, S. P. (2016). Do children and adolescent ice hockey players with and without a history of concussion differ in robotic testing of sensory, motor and cognitive function? Journal of NeuroEngineering and Rehabilitation, 13(1), 1–19. https://doi.org/10.1186/s12984-016-0195-9
Lugones, M., Parkin, G., Bjelosevic, S., Takagi, M., Clarke, C., Anderson, V., & Ignjatovic, V. (2018). Blood biomarkers in paediatric mild traumatic brain injury: a systematic review. Neuroscience and Biobehavioral Reviews, 87(January), 206–217. https://doi.org/10.1016/j.neubiorev.2018.02.006
Manzano, S., Holzinger, I. B., Kellenberger, C. J., Lacroix, L., Klima-Lange, D., Hersberger, M., … Staubli, G. (2016). Diagnostic performance of S100B protein serum measurement in detecting intracranial injury in children with mild head trauma. Emergency Medicine Journal, 33(1), 42–46. https://doi.org/10.1136/emermed-2014-204513
Meier, T. B., Nelson, L. D., Huber, D. L., Bazarian, J. J., Hayes, R. L., & McCrea, M. A. (2017). Prospective Assessment of Acute Blood Markers of Brain Injury in Sport-Related Concussion. Journal of Neurotrauma, 1, neu.2017.5046. https://doi.org/10.1089/neu.2017.5046
Munia, T. T. K., Haider, A., Schneider, C., Romanick, M., & Fazel-Rezai, R. (2017). A Novel EEG Based Spectral Analysis of Persistent Brain Function Alteration in Athletes with Concussion History. Scientific Reports, 7(1), 1–13. https://doi.org/10.1038/s41598-017-17414-x
Oris, C., Pereira, B., Durif, J., Simon-Pimmel, J., Castellani, C., Manzano, S., … Bouvier, D. (2018). The biomarker s100b and mild traumatic brain injury: A meta-analysis. Pediatrics, 141(6). https://doi.org/10.1542/peds.2018-0037
Papa, L., Mittal, M. K., Ramirez, J., Ramia, M., Kirby, S., Silvestri, S., … Zonfrillo, M. R. (2016). In Children and Youth with Mild and Moderate Traumatic Brain Injury, Glial Fibrillary Acidic Protein Out-Performs S100β in Detecting Traumatic Intracranial Lesions on Computed Tomography. Journal of Neurotrauma, 33(1), 58–64. https://doi.org/10.1089/neu.2015.3869
Papa, L., Mittal, M. K., Ramirez, J., Silvestri, S., Giordano, P., Braga, C. F., … Zonfrillo, M. R. (2017). Neuronal Biomarker Ubiquitin C-Terminal Hydrolase Detects Traumatic Intracranial Lesions on Computed Tomography in Children and Youth with Mild Traumatic Brain Injury. Journal of Neurotrauma, 34(13), 2132–2140. https://doi.org/10.1089/neu.2016.4806
Papa, L., Zonfrillo, M. R., Welch, R. D., Lewis, L. M., Braga, C. F., Tan, C. N., … Mittal, M. K. (2019). Evaluating glial and neuronal blood biomarkers GFAP and UCH-L1 as gradients of brain injury in concussive, subconcussive and non-concussive trauma: a prospective cohort study. BMJ Paediatrics Open, 3(1), e000473. https://doi.org/10.1136/bmjpo-2019-000473
Parkin, G. M., Clarke, C., Takagi, M., Hearps, S., Babl, F. E., Davis, G. A., … Ignjatovic, V. (2019). Plasma Tumor Necrosis Factor Alpha Is a Predictor of Persisting Symptoms Post-Concussion in Children. Journal of Neurotrauma, 36(11), 1768–1775. https://doi.org/10.1089/neu.2018.6042
Reches, A., Kutcher, J., Elbin, R. J., Or-Ly, H., Sadeh, B., Greer, J., … Kontos, A. P. (2017). Preliminary investigation of Brain Network Activation (BNA) and its clinical utility in sport-related concussion. Brain Injury, 31(2), 237–246. https://doi.org/10.1080/02699052.2016.1231343
Rhine, T., Babcock, L., Zhang, N., Leach, J., & Wade, S. L. (2016). Are UCH-L1 and GFAP promising biomarkers for children with mild traumatic brain injury? Brain Injury, 30(10), 1231–1238. https://doi.org/10.1080/02699052.2016.1178396
Studer, M., Goeggel Simonetti, B., Heinks, T., Steinlin, M., Leichtle, A., Berger, S., & Joeris, A. (2015). Acute S100B in serum is associated with cognitive symptoms and memory performance 4 months after paediatric mild traumatic brain injury. Brain Injury, 29(13–14), 1667–1673. https://doi.org/10.3109/02699052.2015.1075250
Tylicka, M., Matuszczak, E., Dȩbek, W., Hermanowicz, A., & Ostrowska, H. (2014). Circulating proteasome activity following mild head injury in children. Child’s Nervous System, 30(7), 1191–1196. https://doi.org/10.1007/s00381-014-2409-4
Last update: November 16, 2019