Skip to main content

Advertisement

SpringerLink
Log in

Neurostereologic Lesion Volumes and Spreading Depolarizations in Severe Traumatic Brain Injury Patients: A Pilot Study

  • Original Work
  • Published:
Neurocritical Care Aims and scope Submit manuscript

An Invited Editorial Commentary to this article was published on 15 March 2019

Abstract

Background

Spreading depolarizations (SDs) occur in 50–60% of patients after surgical treatment of severe traumatic brain injury (TBI) and are independently associated with unfavorable outcomes. Here we performed a pilot study to examine the relationship between SDs and various types of intracranial lesions, progression of parenchymal damage, and outcomes.

Methods

In a multicenter study, fifty patients (76% male; median age 40) were monitored for SD by continuous electrocorticography (ECoG; median duration 79 h) following surgical treatment of severe TBI. Volumes of hemorrhage and parenchymal damage were estimated using unbiased stereologic assessment of preoperative, postoperative, and post-ECoG serial computed tomography (CT) studies. Neurologic outcomes were assessed at 6 months by the Glasgow Outcome Scale-Extended.

Results

Preoperative volumes of subdural and subarachnoid hemorrhage, but not parenchymal damage, were significantly associated with the occurrence of SDs (P’s < 0.05). Parenchymal damage increased significantly (median 34 ml [Interquartile range (IQR) − 2, 74]) over 7 (5, 8) days from preoperative to post-ECoG CT studies. Patients with and without SDs did not differ in extent of parenchymal damage increase [47 ml (3, 101) vs. 30 ml (− 2, 50), P = 0.27], but those exhibiting the isoelectric subtype of SDs had greater initial parenchymal damage and greater increases than other patients (P’s < 0.05). Patients with temporal clusters of SDs (≥ 3 in 2 h; n = 10 patients), which included those with isoelectric SDs, had worse outcomes than those without clusters (P = 0.03), and parenchymal damage expansion also correlated with worse outcomes (P = 0.01). In multivariate regression with imputation, both clusters and lesion expansion were significant outcome predictors.

Conclusions

These results suggest that subarachnoid and subdural blood are important primary injury factors in provoking SDs and that clustered SDs and parenchymal lesion expansion contribute independently to worse patient outcomes. These results warrant future prospective studies using detailed quantification of TBI lesion types to better understand the relationship between anatomic and physiologic measures of secondary injury.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Maas AI, Stocchetti N, Bullock R. Moderate and severe traumatic brain injury in adults. Lancet Neurol. 2008;7:728–41.

    Article  PubMed  Google Scholar 

  2. Langlois JA, Rutland-Brown W, Wald MM. The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil. 2006;21:375–8.

    Article  PubMed  Google Scholar 

  3. Menon DK, Schwab K, Wright DW, Maas AI. Position statement: definition of traumatic brain injury. Arch Phys Med Rehabil. 2010;91:1637–40.

    Article  PubMed  Google Scholar 

  4. Dreier JP. The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease. Nat Med. 2011;17:439–47.

    Article  CAS  PubMed  Google Scholar 

  5. de Crespigny A, Rother J, van Bruggen N, Beaulieu C, Moseley ME. Magnetic resonance imaging assessment of cerebral hemodynamics during spreading depression in rats. J Cereb Blood Flow Metab. 1998;18:1008–17.

    Article  PubMed  Google Scholar 

  6. Murphy TH, Li P, Betts K, Liu R. Two-photon imaging of stroke onset in vivo reveals that NMDA-receptor independent ischemic depolarization is the major cause of rapid reversible damage to dendrites and spines. J Neurosci. 2008;28:1756–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Risher WC, Croom D, Kirov SA. Persistent astroglial swelling accompanies rapid reversible dendritic injury during stroke-induced spreading depolarizations. Glia. 2012;60:1709–20.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Dreier JP, Lemale CL, Kola V, Friedman A, Schoknecht K. Spreading depolarization is not an epiphenomenon but the principal mechanism of the cytotoxic edema in various gray matter structures of the brain during stroke. Neuropharmacology 2017.

  9. Hartings JA, Shuttleworth CW, Kirov SA, et al. The continuum of spreading depolarizations in acute cortical lesion development: examining Leao’s legacy. J Cereb Blood Flow Metab. 2017;37:1571–94.

    Article  PubMed  Google Scholar 

  10. Lauritzen M, Dreier JP, Fabricius M, Hartings JA, Graf R, Strong AJ. Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. J Cereb Blood Flow Metab. 2011;31:17–35.

    Article  PubMed  Google Scholar 

  11. Dreier JP, Fabricius M, Ayata C, et al. Recording, analysis, and interpretation of spreading depolarizations in neurointensive care: review and recommendations of the COSBID research group. J Cereb Blood Flow Metab. 2017;37:1595–625.

    Article  PubMed  Google Scholar 

  12. Hartings JA, Bullock MR, Okonkwo DO, et al. Spreading depolarisations and outcome after traumatic brain injury: a prospective observational study. Lancet Neurol. 2011;10:1058–64.

    Article  PubMed  Google Scholar 

  13. Hartings JA, Watanabe T, Bullock MR, et al. Spreading depolarizations have prolonged direct current shifts and are associated with poor outcome in brain trauma. Brain. 2011;134:1529–40.

    Article  PubMed  Google Scholar 

  14. Hinzman JM, Wilson JA, Mazzeo AT, Bullock MR, Hartings JA. Excitotoxicity and metabolic crisis are associated with spreading depolarizations in severe traumatic brain injury patients. J Neurotrauma. 2016;33:1775–83.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Hinzman JM, Andaluz N, Shutter LA, et al. Inverse neurovascular coupling to cortical spreading depolarizations in severe brain trauma. Brain 2014.

  16. Hartings JA, Vidgeon S, Strong AJ, et al. Surgical management of traumatic brain injury: a comparative-effectiveness study of 2 centers. J Neurosurg. 2014;120:434–46.

    Article  PubMed  Google Scholar 

  17. von Bornstadt D, Houben T, Seidel JL, et al. Supply-demand mismatch transients in susceptible peri-infarct hot zones explain the origins of spreading injury depolarizations. Neuron. 2015;85:1117–31.

    Article  CAS  Google Scholar 

  18. Hartings JA, Dreier JP. Real-time detection of lesion development in acute brain injury. J Cereb Blood Flow Metab. 2017;37:1550–2.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Nakamura H, Strong AJ, Dohmen C, et al. Spreading depolarizations cycle around and enlarge focal ischaemic brain lesions. Brain. 2010;133:1994–2006.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Drenckhahn C, Winkler MK, Major S, et al. Correlates of spreading depolarization in human scalp electroencephalography. Brain. 2012;135:853–68.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Hartings JA, York J, Carroll CP, et al. Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction. Brain. 2017;140:2673–90.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Dreier JP, Woitzik J, Fabricius M, et al. Delayed ischaemic neurological deficits after subarachnoid haemorrhage are associated with clusters of spreading depolarizations. Brain. 2006;129:3224–37.

    Article  PubMed  Google Scholar 

  23. Luckl J, Lemale CL, Kola V, et al. The negative ultraslow potential, electrophysiological correlate of infarction in the human cortex. Brain 2018.

  24. Hartings JA, Strong AJ, Fabricius M, et al. Spreading depolarizations and late secondary insults after traumatic brain injury. J Neurotrauma. 2009;26:1857–66.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Strong AJ, Fabricius M, Boutelle MG, et al. Spreading and synchronous depressions of cortical activity in acutely injured human brain. Stroke. 2002;33:2738–43.

    Article  PubMed  Google Scholar 

  26. Fabricius M, Fuhr S, Bhatia R, et al. Cortical spreading depression and peri-infarct depolarization in acutely injured human cerebral cortex. Brain. 2006;129:778–90.

    Article  PubMed  Google Scholar 

  27. Eriksen N, Rostrup E, Andersen K, et al. Application of stereological estimates in patients with severe head injuries using CT and MR scanning images. Br J Radiol. 2010;83:307–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gundersen HJ, Jensen EB, Kieu K, Nielsen J. The efficiency of systematic sampling in stereology–reconsidered. J Microsc. 1999;193:199–211.

    Article  CAS  PubMed  Google Scholar 

  29. Hartings JA, Watanabe T, Dreier JP, Major S, Vendelbo L, Fabricius M. Recovery of slow potentials in AC-coupled electrocorticography: application to spreading depolarizations in rat and human cerebral cortex. J Neurophysiol. 2009;102:2563–75.

    Article  PubMed  Google Scholar 

  30. Jimenez-Roldan L, Alen JF, Gomez PA, et al. Volumetric analysis of subarachnoid hemorrhage: assessment of the reliability of two computerized methods and their comparison with other radiographic scales. J Neurosurg. 2013;118:84–93.

    Article  PubMed  Google Scholar 

  31. Chastain CA, Oyoyo UE, Zipperman M, et al. Predicting outcomes of traumatic brain injury by imaging modality and injury distribution. J Neurotrauma. 2009;26:1183–96.

    Article  PubMed  Google Scholar 

  32. Yuh EL, Cooper SR, Ferguson AR, Manley GT. Quantitative CT improves outcome prediction in acute traumatic brain injury. J Neurotrauma. 2012;29:735–46.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Clatterbuck RE, Sipos EP. The efficient calculation of neurosurgically relevant volumes from computed tomographic scans using Cavalieri’s Direct Estimator. Neurosurgery. 1997;40:339–42 (discussion 43).

    Article  CAS  PubMed  Google Scholar 

  34. Stocchetti N, Croci M, Spagnoli D, Gilardoni F, Resta F, Colombo A. Mass volume measurement in severe head injury: accuracy and feasibility of two pragmatic methods. J Neurol Neurosurg Psychiatry. 2000;68:14–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Eriksen N, Rostrup E, Fabricius M, et al. Early focal brain injury after subarachnoid hemorrhage correlates with spreading depolarizations. Neurology 2018 (in press).

  36. Krenzlin H, Jussen D, Plath M, et al. Occurrence of spontaneous cortical spreading depression is increased by blood constituents and impairs neurological recovery after subdural hematoma in rats. J Neurotrauma. 2019;36:395–402.

    Article  PubMed  Google Scholar 

  37. Karabiyikoglu M, Keep R, Hua Y, Xi G. Acute subdural hematoma: new model delineation and effects of coagulation inhibitors. Neurosurgery. 2005;57:565–72 discussion -72.

    Article  PubMed  Google Scholar 

  38. Lapilover EG, Lippmann K, Salar S, et al. Peri-infarct blood-brain barrier dysfunction facilitates induction of spreading depolarization associated with epileptiform discharges. Neurobiol Dis. 2012;48:495–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dreier JP, Korner K, Ebert N, et al. Nitric oxide scavenging by hemoglobin or nitric oxide synthase inhibition by N-nitro-l-arginine induces cortical spreading ischemia when K+ is increased in the subarachnoid space. J Cereb Blood Flow Metab. 1998;18:978–90.

    Article  CAS  PubMed  Google Scholar 

  40. Alahmadi H, Vachhrajani S, Cusimano MD. The natural history of brain contusion: an analysis of radiological and clinical progression. J Neurosurg. 2010;112:1139–45.

    Article  PubMed  Google Scholar 

  41. Flint AC, Manley GT, Gean AD, Hemphill JC 3rd, Rosenthal G. Post-operative expansion of hemorrhagic contusions after unilateral decompressive hemicraniectomy in severe traumatic brain injury. J Neurotrauma. 2008;25:503–12.

    Article  PubMed  Google Scholar 

  42. Stiver SI. Complications of decompressive craniectomy for traumatic brain injury. Neurosurg Focus. 2009;26:E7.

    Article  PubMed  Google Scholar 

  43. Loane DJ, Kumar A, Stoica BA, Cabatbat R, Faden AI. Progressive neurodegeneration after experimental brain trauma: association with chronic microglial activation. J Neuropathol Exp Neurol. 2014;73:14–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Oertel M, Kelly DF, McArthur D, et al. Progressive hemorrhage after head trauma: predictors and consequences of the evolving injury. J Neurosurg. 2002;96:109–16.

    Article  PubMed  Google Scholar 

  45. Agrawal A, Timothy J, Pandit L, Manju M. Post-traumatic epilepsy: an overview. Clin Neurol Neurosurg. 2006;108:433–9.

    Article  PubMed  Google Scholar 

  46. Hukkelhoven CW, Steyerberg EW, Habbema JD, et al. Predicting outcome after traumatic brain injury: development and validation of a prognostic score based on admission characteristics. J Neurotrauma. 2005;22:1025–39.

    Article  PubMed  Google Scholar 

  47. Maas AI, Hukkelhoven CW, Marshall LF, Steyerberg EW. Prediction of outcome in traumatic brain injury with computed tomographic characteristics: a comparison between the computed tomographic classification and combinations of computed tomographic predictors. Neurosurgery. 2005;57:1173–82 discussion -82.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Claus Holst at Frederiksberg Hospital, Copenhagen, Denmark, for statistical advice and Dr. Achala Vagal at the University of Cincinnati Medical Center, OH, USA, for radiologic guidance.

Author Contributions

NE performed stereologic assessments, analyzed data, and drafted the manuscript. BP and ER conceived the project, advised on design and methods, supervised CT analysis, and edited and approved the manuscript. DOO, DM, LAS, AJS, JW, and CP recruited subjects into the study, provided associated data, and edited and approved the manuscript. JPD performed data analysis, contributed to writing and interpretation, and edited and approved the manuscript. PM performed the primary statistical analyses and edited and approved the manuscript. MJL conceived and supervised the project, and edited and approved the manuscript. MF performed data analysis, contributed to writing, and edited and approved the manuscript. JAH recruited subjects into the study, organized data, prepared figures, and drafted and approved the manuscript.

Source of Support

Research was supported by the US Army CDMRP PH/TBI Research Program (Contract No. W81XWH-08-2-0016), the Agnes and Poul Friis´Foundation, the Aase and Ejnar Danielsens Foundation, the Dagmar Marshall’s Foundation, Deutsche Forschungsgemeinschaft (DFG DR 323/5-1), Bundesministerium für Bildung und Forschung (BMBF CSB 01 EO 0801) and FP7 No. 602150 CENTER-TBI.

Conflicts of Interest

The authors report no conflicts of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author information

Authors and Affiliations

  1. Research Laboratory for Stereology and Neuroscience, Bispebjerg-Frederiksberg Hospital, Copenhagen, Denmark

    Nina Eriksen & Bente Pakkenberg

  2. Institute of Clinical Medicine, Faculty of Health, University of Copenhagen, Copenhagen, Denmark

    Bente Pakkenberg

  3. Department of Diagnostics, Glostrup Hospital and Centre for Healthy Aging, University of Copenhagen, Copenhagen, Denmark

    Egill Rostrup

  4. Department of Clinical Neurophysiology, Rigshospitalet, Copenhagen, Denmark

    Martin J. Lauritzen

  5. Department of Neuroscience and Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark

    Martin J. Lauritzen

  6. Department of Clinical Neuroscience, King’s College Hospital, London, UK

    Anthony J. Strong & Clemens Pahl

  7. Department of Neurosurgery, Charité University Medicine, Berlin, Germany

    Johannes Woitzik

  8. Department of Neurosurgery, Medical College of Virginia, Richmond, VA, USA

    Bruce Mathern

  9. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    David O. Okonkwo & Lori A. Shutter

  10. Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Lori A. Shutter

  11. Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Lori A. Shutter

  12. Department of Neurophysiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Martin Fabricius

  13. Institute for Clinical Epidemiology and Applied Biostatistics, University of Tübingen, Tübingen, Germany

    Peter Martus

  14. Center for Stroke Research Berlin, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany

    Johannes Woitzik & Jens P. Dreier

  15. Department of Neurology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany

    Jens P. Dreier

  16. Department of Experimental Neurology, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany

    Jens P. Dreier

  17. Bernstein Center for Computational Neuroscience Berlin, Berlin, Germany

    Jens P. Dreier

  18. Einstein Center for Neurosciences Berlin, Berlin, Germany

    Jens P. Dreier

  19. Department of Neurosurgery, University of Cincinnati (UC) College of Medicine, and UC Gardner Neuroscience Institute, Cincinnati, OH, USA

    Jed A. Hartings

Authors
  1. Nina Eriksen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bente Pakkenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Egill Rostrup
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David O. Okonkwo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bruce Mathern
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lori A. Shutter
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anthony J. Strong
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Johannes Woitzik
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Clemens Pahl
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jens P. Dreier
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Peter Martus
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Martin J. Lauritzen
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Martin Fabricius
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Jed A. Hartings
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jed A. Hartings.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Eriksen, N., Pakkenberg, B., Rostrup, E. et al. Neurostereologic Lesion Volumes and Spreading Depolarizations in Severe Traumatic Brain Injury Patients: A Pilot Study. Neurocrit Care 30, 557–568 (2019). https://doi.org/10.1007/s12028-019-00692-w

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12028-019-00692-w

Keywords

Search

Navigation