Skip to main content

Revisiting Grade 3 Diffuse Axonal Injury: Not All Brainstem Microbleeds are Prognostically Equal

Neurocritical Care volume 27, pages 199–207 (2017)Cite this article

Abstract

Background

Recovery of functional independence is possible in patients with brainstem traumatic axonal injury (TAI), also referred to as “grade 3 diffuse axonal injury,” but acute prognostic biomarkers are lacking. We hypothesized that the extent of dorsal brainstem TAI measured by burden of traumatic microbleeds (TMBs) correlates with 1-year functional outcome more strongly than does ventral brainstem, corpus callosal, or global brain TMB burden. Further, we hypothesized that TMBs within brainstem nuclei of the ascending arousal network (AAN) correlate with 1-year outcome.

Methods

Using a prospective outcome database of patients treated for moderate-to-severe traumatic brain injury at an inpatient rehabilitation hospital, we retrospectively identified 39 patients who underwent acute gradient-recalled echo (GRE) magnetic resonance imaging (MRI). TMBs were counted on the acute GRE scans globally and in the dorsal brainstem, ventral brainstem, and corpus callosum. TMBs were also mapped onto an atlas of AAN nuclei. The primary outcome was the disability rating scale (DRS) score at 1 year post-injury. Associations between regional TMBs, AAN TMB volume, and 1-year DRS score were assessed by calculating Spearman rank correlation coefficients.

Results

Mean ± SD number of TMBs was: dorsal brainstem = 0.7 ± 1.4, ventral brainstem = 0.2 ± 0.6, corpus callosum = 1.8 ± 2.8, and global = 14.4 ± 12.5. The mean ± SD TMB volume within AAN nuclei was 6.1 ± 18.7 mm3. Increased dorsal brainstem TMBs and larger AAN TMB volume correlated with worse 1-year outcomes (R = 0.37, p = 0.02, and R = 0.36, p = 0.02, respectively). Global, callosal, and ventral brainstem TMBs did not correlate with outcomes.

Conclusions

These findings suggest that dorsal brainstem TAI, especially involving AAN nuclei, may have greater prognostic utility than the total number of lesions in the brain or brainstem.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

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

Fig. 1
Fig. 2

References

  1. Strich SJ. Diffuse degeneration of the cerebral white matter in severe dementia following head injury. J Neurol Neurosurg Psychiatry. 1956;19:163–85.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Adams H, Mitchell DE, Graham DI, Doyle D. Diffuse brain damage of immediate impact type. Its relationship to ‘primary brain-stem damage’ in head injury. Brain. 1977;100:489–502.

    CAS  Article  PubMed  Google Scholar 

  3. Firsching R, Woischneck D, Klein S, et al. Brain stem lesions after head injury. Neurol Res. 2002;24:145–6.

    Article  PubMed  Google Scholar 

  4. Crompton MR, Teare RD, Bowern DA. Prolonged coma after head injury. Lancet. 1966;2:938–40.

    CAS  Article  PubMed  Google Scholar 

  5. Adams JH, Doyle D, Ford I, et al. Diffuse axonal injury in head injury: definition, diagnosis and grading. Histopathology. 1989;15:49–59.

    CAS  Article  PubMed  Google Scholar 

  6. Gennarelli TA, Thibault LE, Adams JH, et al. Diffuse axonal injury and traumatic coma in the primate. Ann Neurol. 1982;12:564–74.

    CAS  Article  PubMed  Google Scholar 

  7. Smith DH, Nonaka M, Miller R, et al. Immediate coma following inertial brain injury dependent on axonal damage in the brainstem. J Neurosurg. 2000;93:315–22.

    CAS  Article  PubMed  Google Scholar 

  8. Maas AI, Steyerberg EW, Butcher I, et al. Prognostic value of computerized tomography scan characteristics in traumatic brain injury: results from the IMPACT study. J Neurotrauma. 2007;24:303–14.

    Article  PubMed  Google Scholar 

  9. Crash Trial Collaborators MRC, Perel P, Arango M, et al. Predicting outcome after traumatic brain injury: practical prognostic models based on large cohort of international patients. BMJ. 2008;336:425–9.

    Article  Google Scholar 

  10. Hashimoto T, Nakamura N, Richard KE, Frowein RA. Primary brain stem lesions caused by closed head injuries. Neurosurg Rev. 1993;16:291–8.

    CAS  Article  PubMed  Google Scholar 

  11. Gentry LR. Imaging of closed head injury. Radiology. 1994;191:1–17.

    CAS  Article  PubMed  Google Scholar 

  12. Gentry LR, Godersky JC, Thompson B, Dunn VD. Prospective comparative study of intermediate-field MR and CT in the evaluation of closed head trauma. AJR Am J Roentgenol. 1988;150:673–82.

    CAS  Article  PubMed  Google Scholar 

  13. Skandsen T, Kvistad KA, Solheim O, et al. Prevalence and impact of diffuse axonal injury in patients with moderate and severe head injury: a cohort study of early magnetic resonance imaging findings and 1-year outcome. J Neurosurg. 2010;113:556–63.

    Article  PubMed  Google Scholar 

  14. Aguas J, Begue R, Diez J. Brainstem injury diagnosed by MRI. An epidemiologic and prognostic reappraisal. Neurocirugia (Astur). 2005;16:14–20.

    CAS  Article  Google Scholar 

  15. Wedekind C, Hesselmann V, Lippert-Gruner M, Ebel M. Trauma to the pontomesencephalic brainstem-a major clue to the prognosis of severe traumatic brain injury. Br J Neurosurg. 2002;16:256–60.

    CAS  Article  PubMed  Google Scholar 

  16. Mannion RJ, Cross J, Bradley P, et al. Mechanism-based MRI classification of traumatic brainstem injury and its relationship to outcome. J Neurotrauma. 2007;24:128–35.

    Article  PubMed  Google Scholar 

  17. Parvizi J, Damasio A. Consciousness and the brainstem. Cognition. 2001;79:135–60.

    CAS  Article  PubMed  Google Scholar 

  18. Edlow BL, Takahashi E, Wu O, et al. Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders. J Neuropathol Exp Neurol. 2012;71:531–46.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Rappaport M, Hall KM, Hopkins K, et al. Disability rating scale for severe head trauma: coma to community. Arch Phys Med Rehabil. 1982;63:118–23.

    CAS  PubMed  Google Scholar 

  20. Hall KM, Bushnik T, Lakisic-Kazazic B, et al. Assessing traumatic brain injury outcome measures for long-term follow-up of community-based individuals. Arch Phys Med Rehabil. 2001;82:367–74.

    CAS  Article  PubMed  Google Scholar 

  21. Greenberg SM, Vernooij MW, Cordonnier C, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol. 2009;8:165–74.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Hall K, Cope DN, Rappaport M. Glasgow outcome scale and disability rating scale: comparative usefulness in following recovery in traumatic head injury. Arch Phys Med Rehabil. 1985;66:35–7.

    CAS  PubMed  Google Scholar 

  23. Wang JY, Bakhadirov K, Devous MD Sr, et al. Diffusion tensor tractography of traumatic diffuse axonal injury. Arch Neurol. 2008;65:619–26.

    PubMed  Google Scholar 

  24. Perlbarg V, Puybasset L, Tollard E, et al. Relation between brain lesion location and clinical outcome in patients with severe traumatic brain injury: a diffusion tensor imaging study using voxel-based approaches. Hum Brain Mapp. 2009;30(12):3924–33.

    Article  PubMed  Google Scholar 

  25. Martinez-Ramirez S, Romero JR, Shoamanesh A, et al. Diagnostic value of lobar microbleeds in individuals without intracerebral hemorrhage. Alzheimers Dement. 2015;11:1480–8.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Firsching R, Woischneck D, Klein S, et al. Classification of severe head injury based on magnetic resonance imaging. Acta Neurochir (Wien). 2001;143:263–71.

    CAS  Article  Google Scholar 

  27. Gentry LR, Godersky JC, Thompson B. MR imaging of head trauma: review of the distribution and radiopathologic features of traumatic lesions. AJR Am J Roentgenol. 1988;150:663–72.

    CAS  Article  PubMed  Google Scholar 

  28. Gentry LR, Thompson B, Godersky JC. Trauma to the corpus callosum: MR features. AJNR Am J Neuroradiol. 1988;9:1129–38.

    CAS  PubMed  Google Scholar 

  29. Iwamura A, Taoka T, Fukusumi A, et al. Diffuse vascular injury: convergent-type hemorrhage in the supratentorial white matter on susceptibility-weighted image in cases of severe traumatic brain damage. Neuroradiology. 2012;54:335–43.

    Article  PubMed  Google Scholar 

  30. Edlow BL, McNab JA, Witzel T, Kinney HC. The structural connectome of the human central homeostatic network. Brain Connect. 2016;6:187–200.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Scheid R, Preul C, Gruber O, et al. Diffuse axonal injury associated with chronic traumatic brain injury: evidence from T2*—weighted gradient-echo imaging at 3 T. AJNR Am J Neuroradiol. 2003;24:1049–56.

    PubMed  Google Scholar 

  32. Scheid R, Walther K, Guthke T, et al. Cognitive sequelae of diffuse axonal injury. Arch Neurol. 2006;63:418–24.

    Article  PubMed  Google Scholar 

  33. Lee H, Wintermark M, Gean AD, et al. Focal lesions in acute mild traumatic brain injury and neurocognitive outcome: CT versus 3T MRI. J Neurotrauma. 2008;25:1049–56.

    Article  PubMed  Google Scholar 

  34. Niogi SN, Mukherjee P, Ghajar J, et al. Extent of microstructural white matter injury in postconcussive syndrome correlates with impaired cognitive reaction time: a 3T diffusion tensor imaging study of mild traumatic brain injury. AJNR Am J Neuroradiol. 2008;29:967–73.

    CAS  Article  PubMed  Google Scholar 

  35. Weiss N, Galanaud D, Carpentier A, et al. A combined clinical and MRI approach for outcome assessment of traumatic head injured comatose patients. J Neurol. 2008;255:217–23.

    Article  PubMed  Google Scholar 

  36. Newcombe V, Chatfield D, Outtrim J, et al. Mapping traumatic axonal injury using diffusion tensor imaging: correlations with functional outcome. PLoS ONE. 2011;6:e19214.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. Rosenblum WI. Immediate, irreversible, posttraumatic coma: a review indicating that bilateral brainstem injury rather than widespread hemispheric damage is essential for its production. J Neuropathol Exp Neurol. 2015;74:198–202.

    Article  PubMed  Google Scholar 

  38. Ricciardi MC, Bokkers RP, Butman JA, et al. Trauma-specific brain abnormalities in suspected mild traumatic brain injury patients identified in the first 48 h after injury: a blinded magnetic resonance imaging comparative study including suspected acute minor stroke patients. J Neurotrauma. 2016;34:23–30.

    Article  Google Scholar 

  39. Kenney K, Amyot F, Haber M, et al. Cerebral vascular injury in traumatic brain injury. Exp Neurol. 2016;275(Pt 3):353–66.

    Article  PubMed  Google Scholar 

  40. Parikh G, R-C A, Latour L. Evidence of primary vascular injury after acute head trauma in the traumatic head injury neuroimaging classification (THINC) study. Neurology. 2013;80:E205.

    Google Scholar 

  41. Geurts BH, Andriessen TM, Goraj BM, Vos PE. The reliability of magnetic resonance imaging in traumatic brain injury lesion detection. Brain Inj. 2012;26:1439–50.

    Article  PubMed  Google Scholar 

  42. Tomlinson BE. Brain-stem lesions after head injury. J Clin Pathol Suppl (R Coll Pathol). 1970;4:154–65.

    CAS  Article  Google Scholar 

  43. Tong KA, Ashwal S, Holshouser BA, et al. Hemorrhagic shearing lesions in children and adolescents with posttraumatic diffuse axonal injury: improved detection and initial results. Radiology. 2003;227:332–9.

    Article  PubMed  Google Scholar 

  44. Scheid R, Ott DV, Roth H, et al. Comparative magnetic resonance imaging at 1.5 and 3 Tesla for the evaluation of traumatic microbleeds. J Neurotrauma. 2007;24:1811–6.

    Article  PubMed  Google Scholar 

  45. Muehlschlegel S, Carandang R, Ouillette C, et al. Frequency and impact of intensive care unit complications on moderate-severe traumatic brain injury: early results of the outcome prognostication in traumatic brain injury (OPTIMISM) study. Neurocrit Care. 2013;18:318–31.

    Article  PubMed  Google Scholar 

  46. Izzy S, Compton R, Carandang R, et al. Self-fulfilling prophecies through withdrawal of care: do they exist in traumatic brain injury, too? Neurocrit Care. 2013;19:347–63.

    Article  PubMed  Google Scholar 

  47. Edlow BL, Copen WA, Izzy S, et al. Longitudinal diffusion tensor imaging detects recovery of fractional anisotropy within traumatic axonal injury lesions. Neurocrit Care. 2016;24:342–52.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Institutes of Health (R25NS065743, K23NS094538), the American Academy of Neurology/American Brain Foundation, the James S. McDonnell Foundation, and the National Institute on Disability, Independent Living, and Rehabilitation Research, Administration for Community Living, US Department Health and Human Services to Spaulding Rehabilitation Hospital (H133A120085). However, the contents of this manuscript do not necessarily represent the policy of the Department of Health and Human Services and endorsement by the Federal Government should not be assumed.

Author information

Authors and Affiliations

  1. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Saef Izzy, Sergi Martinez, Camille A. Spencer, Steven M. Greenberg & Brian L. Edlow

  2. Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA

    Saef Izzy & Joshua P. Klein

  3. Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Joshua P. Klein

  4. Department of Physical Medicine and Rehabilitation, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Nicole L. Mazwi

  5. Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Nicole L. Mazwi & Mel B. Glenn

  6. Program in Trauma, Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA

    Gunjan Parikh

  7. Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, USA

    Ona Wu & Brian L. Edlow

  8. Department of Neurology, Yale-New Haven Hospital, Yale School of Medicine, New Haven, CT, USA

    David M. Greer

  9. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Ona Wu

Authors
  1. Saef Izzy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicole L. Mazwi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sergi Martinez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Camille A. Spencer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joshua P. Klein
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gunjan Parikh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mel B. Glenn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Steven M. Greenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. David M. Greer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ona Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Brian L. Edlow
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Saef Izzy.

Ethics declarations

Conflict of interest

No competing financial interests exist.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PPTX 2400 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Izzy, S., Mazwi, N.L., Martinez, S. et al. Revisiting Grade 3 Diffuse Axonal Injury: Not All Brainstem Microbleeds are Prognostically Equal. Neurocrit Care 27, 199–207 (2017). https://doi.org/10.1007/s12028-017-0399-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12028-017-0399-2

Keywords

  • Traumatic brain injury
  • Traumatic axonal injury
  • Diffuse axonal injury
  • Gradient-recalled echo MRI
  • Traumatic microbleed
  • Brainstem