Section C:

Biomarkers

Introduction

icon imgDomain 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 2.1d for more information on when to consider diagnostic brain or cervical spine imaging.

Tools and Resources
There are no Tools or Resources for this Domain.
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

icon imgDomain 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
There are no Tools or Resources for this Domain.
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

Section A:

Concussion Recognition, Initial Medical Assessment, Management

Section B:

Managing Concussion Symptoms