Diffuse axonal injury

History
 TAI was first described in mid-twentieth century, as diffuse
microscopic pathological changes to the brain tissue.
 These lesions were believed to be the direct result of mechanical
impact on brain tissue after trauma.
 At the start of the 1980s, the term DAI (diffuse axonal idiopathic injury,
nowadays called TAI) was introduced in consecutive studies by Adams
and Gennarelli.
Adams JH, Doyle D, Ford I, Gennarelli TA, Graham DI McLellan DR (1989) Diffuse axonal injury in head
injury: definition, diagnosis and grading. Histopathology 15:49–59
Gennarelli TA, Thibault LE, Adams JH, Graham DI, Thompson CJ, Marcincin RP (1982) Diffuse axonal injury
and traumatic coma in the primate. Ann Neurol 12:564–574

History
 The term DAI implicates that there is diffuse topographic distribution
of traumatic findings.
 However, studies showed that the distribution of traumatic lesions in
DAI has a predisposition for white matter tracts in the midline of the
brain, including
 the corpus callosum,
 internal capsule,
 cerebral peduncles,
 brainstem, and
 the grey-white junction of the cerebral cortex [5, 7].
Adams JH, Graham DI, Gennarelli TA, Maxwell WL (1991) Diffuse axonal injury in non-missile head
injury. J Neurol Neurosurg Psychiatry 54:481–483

Introduction
Traumatic axonal injury (TAI) is a condition characterized as
 multiple, scattered, small hemorrhagic, and/or nonhemorrhagic
lesions, alongside brain swelling,
 in a more confined white matter distribution on imaging studies,
 together with impaired axoplasmic transport, axonal swelling, and
disconnection
 with more than 3 such foci present on imaging studies
according to the National Institutes of Health Common Data Elements
NINDS Common Data Elements (2012) Traumatic brain injury: data standards.
https://www.commondataelements.ninds.nih.gov/ Traumatic Brain Injury. Accessed 12-09-2020

Introduction
 In the past, DAI (diffuse axonal injury) was defined as
prolonged (> 6 h) loss of consciousness (LOC), without a
visible mass lesion.
 Nowadays, the term TAI, or traumatic axonal injury, is
more accurate than the term DAI.

Grading
 Adams et al. suggested a grading system for TAI, dividing TAI into three
different subgroups.
 In clinical practice, this grading has been applied clinically using MRI
susceptibility-weighted (SW) imaging
 But no thorough external validation studies have been carried out to
confirm proper clinical use of the MRI grading
Adams JH, Doyle D, Ford I, Gennarelli TA, Graham DI McLellan DR (1989) Diffuse axonal injury in
head injury: definition, diagnosis and grading. Histopathology 15:49–59

Pathophysiology
 The pathophysiology is complex and lacking a unifying
theory.
 The assumption that TAI is primarily and solely caused by
direct mechanical force has been abandoned.
 Besides the primary damage, there is secondary damage
caused by chemical alterations and changes in neuronal
metabolism.

Trauma mechanism
 There are two major mechanisms involved in head trauma:
 direct impact
 and accelerative and decelerative (a/d) forces.
 Sudden head movement produces a force vector inside the
intracranial cavity,
 resulting in shearing and strain injury.
 Shear and tear of axonal fibers can cause axonal damage
 resulting in TAI.
Gennarelli TA (1993) Mechanisms of brain injury. J Emerg Med 11(Suppl 1):5–11
Gennarelli TA, Thibault LE, Adams JH, Graham DI, Thompson CJ, Marcincin RP (1982)
Diffuse axonal injury and traumatic coma in the primate. Ann Neurol 12:564–574

Trauma mechanism
• A/d forces in the coronal plane are primarily associated with the
occurrence of TAI.
 The duration of the a/d forces decides for the type of injury.
 Slower A/d forces with a relatively long duration (20– 25 ms) will
mainly cause TAI
 Whereas shorter duration of a/d forces will likely cause acute
subdural hematoma (ASDH) through shearing of bridging veins .
Yoganandan N, Gennarelli TA, Zhang J, Pintar FA, Takhounts E, Ridella SA(2009)Association
of contact loading in diffuse axonal injuries from motor vehicle crashes. J Trauma 66:309–315

Trauma mechanism
 The combination of translational, rotational and angular
acceleration has been suggested as the most prominent
cause of TAI.
 TAI can also be caused by traumas with relatively low rates
of acceleration
 This fact is of importance in forensic pathology.
 Deadly TAI can occur even if the initial impact force is not strong
enough.

Primary axotomy
1. Pure mechanical stretch due to traumatic acceleration or
deceleration alone
2. Leads to direct tearing of axonal fibers.
3. Subsequently to this tearing, the damaged axonal fibers would
retract
4. And form retraction bulbs, which are visible on pathological
examination.
This process of direct tearing is called primary axotomy.
Adams H,Mitchell DE,GrahamDI, Doyle D (1977) Diffuse brain damage of immediate impact
type. Its relationship to 'primary brain-stem damage' in head injury. Brain 100:489–502

Primary axotomy
 Gliding hemorrhages visible on neuroimaging right after trauma
suggest that primary axotomy that can occur directly after impact.
 Complete primary axotomy is nowadays considered a rare form of
damage
 that occurs in cases of massive, widespread axonal damage.
 Primary axotomy may also cause a decreased level of consciousness
through widespread CNS damage
 including the thalami and the reticular substance of the brainstem.

Secondary axotomy
 If the inertial forces are of low intensity and do not cause complete
primary axotomy,
 Then they can still be strong enough to cause partial damage to the
axon,
 triggering a molecular pathway resulting in what is nowadays called
secondary axotomy.
 It may create a potential window of opportunity for therapeutic
treatment.
 This window will probably only be a few hours.
Christman CW, Grady MS, Walker SA, Holloway KL, Povlishock JT (1994) Ultrastructural
studies of diffuse axonal injury in humans. J Neurotrauma 11:173–186
Povlishock JT, Jenkins LW(1995)Are the pathobiological changes evoked by traumatic brain
injury immediate and irreversible? Brain Pathol 5:415–426

Secondary axotomy
 Secondary axotomy is an inflammatory and apoptotic
event
 While the primary axotomy is a true mechanical event, caused by
shearing forces.
 Secondary axotomy can also be seen as a continuation of
primary axotomy,
 where the initial structural damage caused by the traumatic forces
forms the base for the entire molecular cascade, instead of as a
separate entity.

Secondary axotomy
The figure illustrates an axon upon which
shear and rotational forces act.
1. The microtubules (blue) become
progressively stiffer and eventually
break,
2. leading to a disruption of the axonal
transport of molecules.
3. Calcium accumulates in the cell (both
through the mechanical opening of
calcium channels, as well as through the
disruption of mitochondria).
4. Through hydrolyzation of calpastatin
(which normally inhibits calpain),
calpain is activated and it in turn
hydrolyzes the cytoskeleton and
microtubules.
5. This cascade leads to apoptosis and
axon disconnection

Secondary axotomy
 This combined action of MT stiffness on the one hand and calcium
overload with apoptosis and cell death on the other hand
 ultimately lead to neuron dysfunction and widespread loss of connectivity.
 Secondary axotomy is nowadays accepted as the mechanism of
neuronal dysfunction after TAI
 but the exact timing of events and the targeted treatment remain elusive.

CLINICAL FEATURES
 Loss of consciousness,
 Cognitive and memory deficits
 Sodium and free water derangements
Meythaler J.M. et al. Current concepts: Diffuse axonal injury-associated traumatic brain
injury. Arch Phys Med Rehabil. 2001;82(10):1461–1471.
Richmond E, Rogol A.D. Endocrine. 2013. Traumatic brain injury: Endocrine consequences in
children and adults.

Diagnosis: Histopathological
findings
 The traditional histological findings in TAI are large axonal dilations
caused by complete axotomy, referred to as retraction bulbs or axonal
bulbs.
 Axonal varicosities are another histological finding.
 These are dilations along the length of the axon, visible within
several hours after trauma
 the result of processes described above under secondary axotomy due
to axonal transport impairment and protein accumulation are present

Histopathological findings
 Traditionally, hematoxylin and eosin (HE), and several silver stains
were most widely used to detect pathological changes.
 Nowadays, immunohistochemical staining is more widely used.
 Accumulation of beta-amyloid precursor protein (β- APP) is a sensitive
marker for diagnosis of TAI [76–80].
 Accumulation of β-APP is visible within 2 h after trauma and shows
more extensive injury than HE or silver staining.
Sherriff FE, Bridges LR, Sivaloganathan S (1994) Early detection of axonal injury after human
head trauma using immunocytochemistry for beta-amyloid precursor protein. Acta
Neuropathol 87:55–62
Gultekin SH, Smith TW (1994) Diffuse axonal injury in craniocerebral trauma. A comparative
histologic and immunohistochemical study. Arch Pathol Lab Med 118:168–171

Radiographic features
Diffuse axonal injury is characterized by multiple focal lesions with a
characteristic distribution:
 typically located at the grey-white matter junction, in the corpus
callosum and in more severe cases in the brainstem
 CT is capable of identifying large TAI-related hemorrhage,
 but non-hemorrhagic lesions and small TAI hemorrhage are
virtually impossible to identify using CT.
 The slice thickness of a conventional trauma head CT is about 5–10
mm. Since TAI lesions may fall under this detection margin, they
can be easily missed using conventional CT.

CT
 Non-contrast CT is routine in head injuries.
 Unfortunately, it is not sensitive for diffuse axonal injury
 And some patients with relatively normal CT scans may have
significant unexplained neurological deficit.
 The appearance depends on whether the lesions are hemorrhagic or
not.
 Hemorrhagic lesions will be hyperdense and range in size from a few
millimeters to a few centimeters in diameter.
 When hemorrhages are large, then CT is quite sensitive.
 Non-hemorrhagic lesions are hypodense.
 They typically become more evident over the first few days as edema
develops around them.
 They may be associated with significant and disproportionate cerebral
swelling.

MRI
 Conventional MRI (cMRI) has a higher sensitivity in demonstrating
lesions in the brainstem and the deep white matter, making it more
sensitive for identifying axonal injury compared to CT
 The MRI gradient echo sequence (GRE) is able to detect heme and
heme breakdown products
 making it a suitable method for discovering small hemorrhagic
lesions.
Yanagawa Y, Tsushima Y, Tokumaru A, Un-no Y, Sakamoto T, Okada Y, Nawashiro H, Shima K
(2000) A quantitative analysis of head injury using T2*-weighted gradient-echo imaging. J Trauma
49:272–277

MRI
 Susceptibility weighted imaging (SWI)
 as a variant sequence of GRE imaging
 considered the “gold standard” for identifying TAI lesions.
 It has a higher sensitivity for hemorrhage than GRE ,
 more useful for early diagnosis of TAI [84, 90].
 SWI might overestimate the size of a lesion due to its high
sensitivity to heme products.
Tong KA, Ashwal S, Holshouser BA, Shutter LA, Herigault G, Haacke AM, Kido DK (2003)
Hemorrhagic shearing lesions in children and adolescents with posttraumatic diffuse axonal
injury: improved detection and initial results. Radiology 227:332–339

MRI
 Diffusion tensor imaging (DTI)
 is an improved form of DWI.
 It can be used to evaluate nerve alignment, white matter
microstructure and the morphology around nerve fibers .
 Within the first 24 h after trauma, DTI can detect white matter
regions with reduced anisotropy, making it an adequate technique
for detecting TAI

Right-sided focal areas of hyperintense T2 signal in the brainstem, splenium of the
corpus callosum, superior frontal gyrus on the left and middle frontal gyrus on the
right.
Focal areas of hyperintense FLAIR signal in the splenium of the corpus callosum as
well as the periventricular white matter, in the brainstem on the right and subcortical
in the middle temporal lobe on the left, in the superior frontal gyrus on the left and
middle frontal gyrus on the right.
Focal areas of restricted diffusion in the frontal white matter and splenium of the
corpus callosum.
Focal area of signal loss on SWI sequences in the superior frontal gyrus on the left, as
well as multiple punctate areas of signal loss bilaterally, indicating hemorrhagic
lesions

MRI
Right-sided focal areas of hyperintense T2 signal in the brainstem, splenium of the
corpus callosum, superior frontal gyrus on the left and middle frontal gyrus on the
right.
Focal areas of hyperintense FLAIR signal in the splenium of the corpus callosum as
well as the periventricular white matter, in the brainstem on the right and
subcortical in the middle temporal lobe on the left, in the superior frontal gyrus on
the left and middle frontal gyrus on the right.
Focal areas of restricted diffusion in the frontal white matter and splenium of the
corpus callosum.
Focal area of signal loss on SWI sequences in the superior frontal gyrus on the left,
as well as multiple punctate areas of signal loss bilaterally, indicating hemorrhagic

MR spectroscopy
 MRS can be of benefit in identifying patients with grade I
injury which may be inapparent on other sequences.
 Features typically demonstrate elevation of choline
peak and reduction of NAA

BIOMARKERS
 CALCIUM-DEPENDENT PROTEOLYSIS AND αII SPECTRIN
BREAKDOWN PRODUCTS
 NEUROFILAMENT MARKERS
 GLIAL FIBRILLARY ACIDIC PROTEIN
 MYELIN BASIC PROTEIN
 S-100β
 NEURON-SPECIFIC ENOLASE
 UBIQUITIN CARBOXY-TERMINAL HYDROXYLASE L1
Su E, Bell M. Diffuse axonal injury. Translational research in traumatic brain injury. 2016 Apr
21;57:41.

Treatment
 DAI currently lacks a specific treatment
 Stabilization of the patient
 Limit increases in intracranial pressure (ICP).
 Rehabilitation - The rehabilitation phase may include:
 Speech therapy
 Physical therapy
 Occupational therapy
 Recreational therapy
 Adaptive equipment training
 Counseling

Treatment
 Currently, there is no TAI-specific treatment available.
 Treatment is performed in comformity with the “Guidelines for the
Management of Severe Traumatic Brain Injury”
Carney N, Totten AM, O'Reilly S, Ullman JS, Hawryluk GWJ, Bell MJ, Bratton SL, Chesnut
R, Harris OA, Kissoon N, Rubiano AM, Shutter L, Tasker RC, Vavilala MS, Wilberger J,
Wright DW, Ghajar J (2017) Guidelines for the management of severe traumatic brain
injury, Fourth Edition. Neurosurgery 18:6–15

Treatment: preventing secondary
axotomy
 Ca-channel blocker nimodipine
 could play a role in preventing or minimizing secondary damage of
the axon.
 Preclinical studies showed a decreased expression of β-APP,
suppressed activity of calcineurin (CaN), and lessened
ultrastructural axonal damage
 Paclitaxel(Taxol) has possible effect on limiting axonal degeneration

Treatment: preventing secondary
axotomy
 Ciclosporin A (CsA)
 Inhibits CaN.
 By preventing a rise in mitchondrial membrane permeability,
 CsA abates swelling and disruption of mitochondria and
 thereby mitigates axonal damage
 It also antagonizes calcium-mediated cytoskeletal disruption, and
thereby secondary axotomy
 Others:
 EPO
 Hypothermia
 Progesterone

Treatment
 Treatment enhancing neuronal regeneration
Stem cell therapy

Diffuse axonal injury

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