Bennet I. Omalu, M.D., M.P.H. Forensic Pathologist/ Neuropathologist 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 [*]

Axonal Spheroids and Varicosities 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