Autopsy & forensics
General
Traumatic axonal injury
Authors: Michel Tawil, M.D., Christine E. Fuller, M.D.
Editorial Board Member: Lorenzo Gitto, M.D.
Last author update: 3 January 2024
Last staff update: 3 January 2024
Copyright: 2023-2024, PathologyOutlines.com, Inc.
PubMed Search: Traumatic axonal injury
Table of Contents
Definition / general | Essential features | Terminology | Epidemiology | Pathophysiology | Autopsy findings | Gross images | Microscopic (histologic) images | Board review style question #1 | Board review style answer #1Cite this page: Tawil M, Fuller CE. Traumatic axonal injury. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/forensicsneuropathologytai.html. Accessed December 16th, 2024.
Definition / general
- Subgroup of traumatic brain injury caused by angular or rotational acceleration / deceleration of the head, leading to a pattern of widespread injury to neurons, specifically to their axons (Trends Neurosci 2016;39:311)
- Acceleration / deceleration in the coronal plane in particular is associated with shearing force injuries
- Subdural hematoma (via tearing of bridging veins)
- Traumatic axonal injury
- Spectrum of injury ranges from subclinical to that of severe diffuse damage resulting in persistent vegetative state and death
Essential features
- Axonal injury (traumatic or otherwise) can only be directly diagnosed by microscopic examination; axonal swellings / retraction balls (also known as spheroids) are characteristic of axonal injury
- Lesions of traumatic axonal injury most frequent in parasagittal white matter, corpus callosum, dorsolateral rostral brainstem
- B amyloid precursor protein (APP) immunostain is helpful for detection of axonal damage
Terminology
- Axonal injury is a nonspecific term
- May be focal or diffuse (diffuse axonal injury [DAI])
- May be traumatic or nontraumatic etiology (especially secondary to hypoxic / ischemic injury)
- Traumatic axonal injury (TAI): axonal injury with trauma as the underlying etiology
- May be focal or diffuse
Epidemiology
- TAI occurs with high frequency in the context of motor vehicle accidents; only in ~10% of fall injuries
- Head trauma victims who die with TAI tend to have a lower incidence of lucid interval, skull fracture, contusive injury or intracranial hematoma compared to those with fatal head injury without TAI (Ann Neurol 1982;12:557)
Pathophysiology
- Morphological manifestation of a traumatic brain injury typically due to strain or shearing force (Acta Neuropathol 2002;104:79)
- Axonal swellings are the result of axonal transport leading to accumulation of material (including heat shock protein, amyloid precursor protein) proximal to the site of axonal tear / axotomy (Exp Neurol 2012;233:364)
- Pathologic grading system for the severity of TAI has been previously proposed (Ann Neurol 1982;12:557, Histopathology 1989;15:49, PLoS One 2015;10:e0122329)
- Grade 1: axonal swellings seen only microscopically with no obvious macroscopic lesions are clinically associated with mild or moderate posttraumatic coma
- Grade 2: axonal swellings and macroscopic focal lesions in the corpus callosum are associated with moderate posttraumatic coma and severe disability
- Grade 3: axonal swellings, macroscopic focal lesions in both corpus callosum and brainstem are associated experimentally with the poorest outcome
- Correlation with clinical presentation and outcomes is unclear (J Forensic Leg Med 2017:48:35)
- Absence of validation in substantial human studies to directly correlate MRI findings with histopathologic findings complicates the interpretation of the TAI grade in clinical practice (Acta Neurochir (Wien) 2021;163:31)
- In diffuse axonal injuries, it is not only the magnitude of acceleration but also the time over which the acceleration occurs that produces the injury (DiMaio: Forensic Pathology, 2nd Edition, 2001)
- Diffuse vascular injury (J Forensic Sci 2003;48:626)
- Often accompanies moderate to severe TAI; it is likely that vascular damage is secondary to the same deformative forces
- Diffuse petechial hemorrhages may also be the result of fat emboli to the CNS
Autopsy findings
- Macroscopic findings (Int J Curr Res 2017;9:48426, Sud Med Ekspert 2022;65:24)
- Grossly evident lesions may accompany more severe injuries with TAI, including
- Petechial or more confluent hemorrhagic lesions in deep white matter structures like the corpus callosum, internal capsule and superior cerebellar peduncles
- Gliding contusions of frontal lobe white matter
- Deep cerebral hemorrhages of the basal ganglia
- Cerebral surface contusions or other hemorrhages (epidural / subdural / subarachnoid) are often not present
- Grossly evident lesions may accompany more severe injuries with TAI, including
- Diffuse vascular injury (J Forensic Sci 2003;48:626)
- Typically multiple petechial hemorrhages in the centrum ovale region of the frontal lobe or other regions where TAI is frequent
- Microscopic findings
- Histologic examination is needed for detection of TAI; it does not by itself result in grossly evident lesions
- Histologic findings are dependent upon survival time postinjury
- Sampling of regions including cerebral parasagittal white matter, corpus callosum, other long tracts (internal capsule, etc.) and brainstem should be performed in all cases where TAI suspected
- Shortly after traumatic brain injury, there is often a notable, singular swelling known as an axonal bulb (previously termed a retraction ball), which is indicative of probable complete axonal disconnection (Exp Neurol 2013;246:35)
- Amyloid precursor protein axonal accumulations may be detected within a few hours of injury, well before axonal spheroids would be visible by routine stains (Leg Med (Tokyo) 2009:11:S171)
- β amyloid precursor protein (APP) is the gold standard to detect axonal injury (J Lab Physicians 2023;15:399)
- By 24 hours, axonal spheroids visible by H&E stained sections
- Focal increase in calcium concentration in an axon precedes and can result in the development of axonal spheroids (Trends Neurosci 2016;39:311)
- Spheroids may persist for 1 - 2 months and may be highlighted by silver stains or immunostains for neurofilament or APP
- At 2 weeks postinjury, microglial clusters become evident in damaged areas; these may persist for multiple months (Neural Plast 2021;2021:5554824)
- Wallerian degeneration with fiber tract degeneration will occur over months and years postinjury (Curr Opin Neurol 2019;32:786)
- Differentiation of TAI from axonal injury secondary to ischemia may be difficult (Jenny: Child Abuse and Neglect - Diagnosis, Treatment and Evidence, 1st Edition, 2010)
- Features that favor the latter include microscopic evidence of necrotic neurons and geographic accumulations of APP
- Findings of widely scattered APP staining, APP staining in caudal brainstem and lesions of vascular injury in the corpus callosum or dorsolateral brainstem would favor TAI
- Note that both of these processes can co-occur
Gross images
Contributed by Michel Tawil, M.D.
Petechial hemorrhage
Microscopic (histologic) images
Contributed by Michel Tawil, M.D.
Axonal spheroids
Board review style question #1
A 35 year old woman was brought to the emergency room after a high speed automobile accident. She was found unresponsive at the scene, with little external evidence of trauma. Severe brain injury was suspected. She was pronounced dead upon arrival at the ER. Autopsy revealed petechial hemorrhages within the corpus callosum and superior cerebellar peduncles. What other finding is most likely to be encountered in this patient?
- Diffuse axonal injury
- Diffuse subarachnoid hemorrhage
- Epidural hematoma
- Skull fracture
- Subdural hematoma
Board review style answer #1
A. Diffuse axonal injury. Gross findings of petechial hemorrhages within the corpus callosum and dorsolateral rostral brainstem / superior cerebellar peduncles may be seen in association with severe traumatic diffuse axonal injury.
Answer B is incorrect because diffuse subarachnoid hemorrhage most often accompanies ruptured saccular aneurysm. Answers C and D are incorrect because epidural hematoma arises from laceration of the middle meningeal artery, most frequently due to skull fracture. Answer E is incorrect because subdural hematoma most frequently arises secondary to tearing of bridging veins; it may at times accompany diffuse axonal injury, which would be grossly evident radiographically as well as at autopsy (as would subarachnoid hemorrhage, epidural hematoma and skull fracture).
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Reference: Traumatic axonal injury
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Reference: Traumatic axonal injury
