Diffuse axonal injury (DAI) is a severe form of traumatic brain injury characterized by widespread damage to myelinated axonal tracts, often resulting in significant neurological impairments. It is commonly caused by various trauma mechanisms such as falls, vehicular accidents, and assaults, with diagnosis typically guided by advanced imaging techniques like MRI and DTI. Treatment primarily focuses on patient stabilization and rehabilitation, with ongoing research into preventing secondary axonal damage.

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DIFFUSE AXONAL
INJURY
DR BIPUL THAKUR

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HEAD INJURIES
 Head injury is defined as any trauma to the head other than superficial
injuries to the face.
 Traumatic brain injury (TBI) is a nondegenerative , non congenital insult
to the brain from an external mechanical force , possibly leading to
permanent or temporary impairment of cognitive, physical and
psychosocial functions with an associated diminished or altered state of
consciousness.

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TYPES OF TRAUMATIC BRAIN INJURY
 PRIMARY BRAIN INJURY
Occurs at the time of trauma
Cortical contusions
Lacerations
Bone fragmentation
Diffuse axonal injuries
Brain contusions

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SECONDARY INJURIES:
 Develops subsequent to the initial injury
 Preventable
 It include injuries from the hematomas, edema, hypoxemia,
ischemia (primarily due to the elevated ICP), vasospasm

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Grading of head injury

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Diffuse axonal injury
 A form of post traumatic brain injury which occurs over a broad swath of
myelinated tracts of the CNS resulting in significant neurological events ranging
from loss of consciousness to persistent vegetative state.
 Primarily affects white matter tracts in the brain.
 Occurs in the 50 % of severely head injured patients and accounts for 35% of
death from head injury
 DAI is defined as prolonged > 6 hr loss of consciousness without visible mass or
ischemia. Now a days the term TIA (Traumatic axonal injury) is used.

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Causes of DAI
 Accidental falls
 Vehicular accidents
 Child abuse
 Assaults
 Gunshots
 Violent shaking of child
 Sport related injuries

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Clinical grading of diffuse axonal
injury
 Mild : coma > 6-24 hrs followed by mild to moderate memory
impairment, mild to moderate disabilities
 Moderate : coma > 24 hrs , followed by confusions and long lasting
amnesia, mild to severe memory , behavior and cognitive deficits
 Severe: coma lasting months with flexor and extensor posturing .
Cognitive, memory, speech, sensorimotor and personality deficits.
Dysautonomia may occur

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Adams diffuse axonal injury
 Grade 1 : mild axonal injuries with microscopic white matter
changes in cerebral cortex, corpus callosum , brainstem and less
commonly , cerebellum
 Grade 2: Moderate DAI with Gross focal lesions in the corpus
callosum in addition to above
 Grade 3: Severe DAI with focal lesion in the dorsolateral quadrant of
the rostral brainstem in addition to above

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Pathophysiology of DAI
 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.

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Trauma mechanism
 Two major mechanisms involved in head trauma:
direct impact
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.
 a/d forces in the coronal plane are primarily associated with the occurrence of TAI
 Slower A/d forces with a relatively long duration (20– 25 ms) will mainly cause TAI

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Primary axotomy
 Pure mechanical stretch due to traumatic acceleration or deceleration alone
 Leads to direct tearing of axonal fibers.
 Subsequently to this tearing, the damaged axonal fibers would retract
 forms retraction bulbs, which are visible on pathological examination
 This process of direct tearing is called primary axotomy.

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Secondary axotomy
 Is an inflammatory and apoptotic event
 If the inertial forces are of low intensity and do not cause complete primary
axotomy
 can still be strong enough to cause partial damage to the axon,
 trigger a molecular pathway resulting in secondary axotomy.

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 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.

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Secondary axotomy
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

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CLINICAL FEATURES
 Loss of consciousness
 Cognitive and memory deficits
 Sodium and free water derangements

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Diagnosis:
Histopathological findings
 Large axonal dilations caused by complete axotomy, referred to as retraction bulbs
or axonal bulbs.
 Axonal varicosities:
- are dilations along the length of the axon, visible within several hours
after trauma

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Histopathological findings
 Traditionally hematoxylin and eosin (HE), and several silver stains were most
widely used to detect pathological changes.
 immunohistochemical staining is more widely used now.
 Accumulation of beta-amyloid precursor protein (β- APP) - sensitive marker for
diagnosis of TAI
 Accumulation of β-APP is visible within 2 h after trauma and shows more
extensive injury than HE or silver staining.

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Radiographic features
 typically located at the grey-white matter junction, in the corpus callosum and in
more severe cases in the brainstem
 MRI is used for grading of TIA

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CT scan
 Non-contrast CT - routinely done in head injuries.
 Not sensitive for diffuse axonal injury
 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
 Non-hemorrhagic lesions are hypodense.

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 deep shearing-type injury in or near the white
matter of the left internal capsule (arrow).

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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.
 Diffusion weighted imaging can accurately examine non haemorrhagic lesions.
High signal DWI can be used in patient with early stage TAI . Lesions found
represent cellular swelling and cytoxic edema.

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(A) and (B). Axial FLAIR images showed some punctate
hyperintense foci in the subcortical white matter of the
right frontal lobe (arrow) and the splenium of the corpus
callosum.
(C) and (D). DWI and ADC maps indicated restricted
diffusion within the splenium of the corpus callosum
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571536/

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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
 SWI might overestimate the size of a lesion due to its high sensitivity
to heme products

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SWI
multiple hypointense foci of hemorrhagic lesions at the
grey-white matter junction of bilateral temporal lobes(A),
bilateral frontal lobes (B),
posterior limb of the left internal capsule (C),
the fornix commissure, and the splenium of the corpus
callosum (D)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571536/

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Diffusion tensor imaging (DTI)
 is an improved form of DWI.
 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

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disrupted white matter fibers in the posteroinferior aspect of
the splenium (arrow, A),
left crus of the fornix (arrow, B),
subcortical frontal tracts (circle C and arrow D
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571536/

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BIOMARKERS
 C tau levels in CSF
 NEUROFILAMENT MARKERS
 GLIAL FIBRILLARY ACIDIC PROTEIN
 MYELIN BASIC PROTEIN
 S-100β
 NEURON-SPECIFIC ENOLASE
 UBIQUITIN CARBOXY-TERMINAL HYDROXYLASE L1

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

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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

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Treatment: preventing secondary
axotomy
 Ciclosporin A (CsA) :Inhibits Calcineurin. By preventing a rise in
mitochondrial 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
 Enhancing neuronal regeneration stem cell therapy

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 Treatment is performed in conformity with the “Guidelines for the Management
of Severe Traumatic Brain Injury”
 RECOVERY TIME OF TIA : According to the grade
 Grade 1: 1 week
 Grade 2 : 2 week
 Grade 3 : 2 month

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PREVENTION
 The Centers for Disease Control and Prevention (CDC Trusted
Source recommend that people reduce the risk of sustaining a TBI
by :
 wearing a seatbelt whenever riding in or driving a vehicle
 avoiding driving when under the influence of drugs or alcohol
 wearing the appropriate protective gear or helmet for the sport or
activity
 evaluating an older adult’s risk of falling and taking steps to reduce
their risk
 keeping the home safe and clutter-free

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Reference
 Greenberg handbook of neurosurgery 10th edition
 Clinical outcome of diffuse axonal injury according to radiological
grade – journal of trauma and injury
 https://www.jtraumainj.org/journal/view.php?doi=10.20408/
jti.2018.31.2.51
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571536

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THANK
YOU