THE FORENSIC
NEUROPATHOLOGY OF
BLUNT FORCE TRAUMA OF
THE BRAIN
Part 5: Diffuse Traumatic Brain Injury
Bennet I. Omalu, M.D., M.P.H.
Forensic Pathologist/ Neuropathologist
DIFFUSE TRAUMATIC BRAIN INJURY
• The sine qua non of Diffuse Traumatic Brain Injury is Diffuse
Traumatic Axonal Injury
• Typically associated with diffuse inertial biomechanical
loading and acceleration-deceleration shearing forces
Axonal injury is not localized to a single region of the brain, it is
diffusely spread
• Para-sagittal structures of the brain are most vulnerable
especially the splenium of the corpus callosum
• Diffuse Traumatic Axonal Injury is associated with gliding
contusions
• Note that axonal injury may be associated with non-traumatic
causes like viral encephalitis, hypoxic injury and toxic
encephalopathies, traumatic axonal injury is solely caused by
trauma
DIFFUSE TRAUMATIC BRAIN INJURY
• There are three neuropathologic grades of diffuse
traumatic axonal injury:
• Adams Grade 1 DAI
Diffuse cytotoxic edema, + APP immunohistochemistry
• Adams Grade 2 DAI
Diffuse cytotoxic edema, petechial/ecchymotic
hemorrhages in corpus callosum, + APP
• Adams Grade 3 DAI
Diffuse cytotoxic edema, petechial/ ecchymotic
hemorrhages in corpus callosum and dorso-lateral
brainstem, + APP. Typically associated with loss of
consciousness at the scene
PATHOLOGIC DIAGNOSIS OF DIFFUSE AXONAL
INJURY
• Following gross grading of DAI, tissue immuno-histochemistry must be
performed using antibodies for Amyloid Precursor Protein [APP]
• Amyloid Precursor Protein [APP]
 A single-membrane spanning protein found in cell membranes and
membranous organelles of every cell
 Involved in diverse metabolic and regulatory cell pathways including cell
adhesion and inter-cellular signaling
 Encoded by APP gene on Chromosome 21
 Parent compound of Beta-Amyloid peptide of Alzheimer’s Disease
Synthesized in the perikaryon
Fast antero-grade and retro-grade axonal transport by microtubules
[100-400 mm/day]
Without axonal injury APP is not detected by tissue
immunohistochemistery
PATHOLOGIC DIAGNOSIS OF DIFFUSE AXONAL
INJURY
• Amyloid Precursor Protein [APP], cont’d
 Following axonal injury and disruption of the micro-tubule cytoskeleton, APP
accumulates both proximally and distally to point of axonal injury
 It takes APP 2 – 3 hours post injury to accumulate sufficiently to be detected
 This can shorten to 1 hour with antigen retrieval methods
 APP has been observed up to 99 days post injury [3 months]
APP associated with diffuse hypoxic-ischemic injury shows a
geographic pattern of immunopositivity
Trauma-induced DAI exhibits a diffuse focal pattern of APP+
Using silver impregnation and H&E stains, axonal injury can be
identified after 15 hours of injury, axonal spheroids of Cajal, axonal
viscosities and swellings may be seen
 APP immuno-histochemistry is an important tool in medico-legal
cases
DAI AND APP
*
Adams Grade 2 DAI with corpus callosal hemorrhages and a
small gliding contusion [*]
DAI AND APP
APP IMMUNOSTAIN
H&E
Axonal Spheroids and Varicosities
OTHER TYPES OF DIFFUSE BRAIN INJURY
• DIFFUSE VASCULAR INJURY
Presents immediately after trauma, usually fatal
Brain exhibits only peri-vascular petechial and micro-hemorrhages in
lobar cortical white matter
• DIFFUSE CEREBRAL FAT EMBOLISM
Associated with fractures of long bones with surgical
fixation/manipulation
Associated with extensive soft tissue and crush injuries
Presents 2 to 3 days after trauma
Manifests as diffuse cortical white matter petechial perivascular
hemorrhages
Fat stains show intra-luminal fat globules in penetrating parenchymal
vessels
Peri-vascular rarefaction and demyelination may follow