Neurocritical Care

, Volume 27, Issue 2, pp 199–207 | Cite as

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

  • Saef IzzyEmail author
  • Nicole L. Mazwi
  • Sergi Martinez
  • Camille A. Spencer
  • Joshua P. Klein
  • Gunjan Parikh
  • Mel B. Glenn
  • Steven M. Greenberg
  • David M. Greer
  • Ona Wu
  • Brian L. Edlow
Original Article



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.


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.


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.


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.


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



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.

Compliance with Ethical Standards

Conflict of interest

No competing financial interests exist.

Supplementary material

12028_2017_399_MOESM1_ESM.pptx (2.3 mb)
Supplementary material 1 (PPTX 2400 kb)


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Saef Izzy
    • 1
    • 2
    Email author
  • Nicole L. Mazwi
    • 4
    • 5
  • Sergi Martinez
    • 1
  • Camille A. Spencer
    • 1
  • Joshua P. Klein
    • 2
    • 3
  • Gunjan Parikh
    • 6
  • Mel B. Glenn
    • 5
  • Steven M. Greenberg
    • 1
  • David M. Greer
    • 8
  • Ona Wu
    • 7
    • 9
  • Brian L. Edlow
    • 1
    • 7
  1. 1.Department of NeurologyMassachusetts General Hospital, Harvard Medical SchoolBostonUSA
  2. 2.Department of NeurologyBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  3. 3.Department of RadiologyBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  4. 4.Department of Physical Medicine and RehabilitationMassachusetts General Hospital, Harvard Medical SchoolBostonUSA
  5. 5.Department of Physical Medicine and RehabilitationSpaulding Rehabilitation Hospital, Massachusetts General Hospital, Harvard Medical SchoolBostonUSA
  6. 6.Program in Trauma, Department of NeurologyUniversity of Maryland School of MedicineBaltimoreUSA
  7. 7.Athinoula A. Martinos Center for Biomedical ImagingMassachusetts General HospitalCharlestownUSA
  8. 8.Department of NeurologyYale-New Haven Hospital, Yale School of MedicineNew HavenUSA
  9. 9.Department of RadiologyMassachusetts General Hospital, Harvard Medical SchoolBostonUSA

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