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Diffuse axonal injury (DAI)

Widespread axonal damage in the aftermath of acute/repetitive traumatic brain injury (TBI), leading to deficits in cerebral connectivity that may or may not recover over time.

Widespread axonal damage in the aftermath of acute/repetitive traumatic brain injury (TBI), leading to deficits in cerebral connectivity that may or may not recover over time.

History:

DAI was first described in comatose trauma subjects who demonstrated scattered axonal injury in the cerebrum, cerebellum, and brainstem on postmortem examination. Advances in histopathology during the 1950s further revealed the extent of axonal injury associated with DAI at the cellular level. Through the 1960s additional studies would describe an early histopathological pattern of scattered axonal injury characterized by worsening swelling and distortion of normal architecture into retraction bulbs and helical structures. Extensive characterization of these histologic findings in trauma victims subject to large acceleration/deceleration forces led to the initial definitions of “diffuse axonal injury” described in 1982 by Adams and colleagues.


Etiopathogenesis

Traumatic brain injury (TBI):

Traumatic brain injury (TBI) is one of the world’s leading causes of morbidity and mortality among young individuals. TBI applies powerful rotational and translational forces to the brain parenchyma, which results in a traumatic diffuse axonal injury (DAI) responsible for brain swelling and neuronal death.

Most common causes of diffuse axonal injury
Most common causes of diffuse axonal injury. Listed from the highest to the lowest occurrence. | Diffuse Axonal Injury: A Devastating Pathology | IntechOpen. (n.d.). Retrieved November 12, 2021, from https://www.intechopen.com/chapters/58454

The most common mechanism involves an accelerating and decelerating motion that leads to shearing forces to the white matter tracts of the brain. This leads to microscopic and gross damage to the axons in the brain at the junction of the gray and white matter. Diffuse axonal injury commonly affects white matter tracts involved in the corpus callosum and brainstem. This affects numerous functional areas of the brain. Usually, patients with diffuse axonal injury present with bilateral neurological examination deficits frequently affecting the frontal and temporal white matter, corpus callosum, and brainstem.

Gradient-echo MRI show multiple small hemorrhagic foci on the hemispheric white matter
Gradient-echo magnetic resonance images show multiple small hemorrhagic foci on the hemispheric white matter (A), corpus callosum (B), and brain stem (C). | Park, S. J., Hur, J. W., Kwon, K. Y., Rhee, J. J., Lee, J. W., & Lee, H. K. (2009). Time to recover consciousness in patients with diffuse axonal injury : assessment with reference to magnetic resonance grading. Journal of Korean Neurosurgical Society, 46(3), 205–209. https://doi.org/10.3340/jkns.2009.46.3.205

Interestingly, there is no association between diffuse axonal injury and underlying skull fractures.

Adams DAI Classification:

Utilizes pathophysiological lesions in the white matter tracts and clinical presentation.
  • Grade 1: A mild diffuse axonal injury with microscopic white matter changes in the cerebral cortex, corpus callosum, and brainstem
  • Grade 2: A moderate diffuse axonal injury with gross focal lesions in the corpus callosum
  • Grade 3: A severe diffuse axonal injury with finding as Grade 2 and additional focal lesions in the brainstem

Histopathology:

Definitive diagnosis of diffuse axonal injury can be made in the postmortem pathologic examination of brain tissue. However, in clinical practice, a diagnosis of diffuse axonal injury is made by implementing clinical information and radiographic findings. Understanding the mechanism of head injury facilitates a differential diagnosis of DAI.
Immunohistochemistry and Stainings
(A) Scattered axonal retraction balls stained with Congo Red (arrows), scale bar: ×250; (B) diffuse β-APP positivity expression in the corpus callosum is an indicator of axonal injury (grade II), scale bar: ×80; (C) β-APP (brown reactions) reaction exhibited a strong positive reaction typically occurring in the dorsolateral quadrant or quadrants adjacent to a superior cerebellar peduncle (grade III), scale bar: ×100; (D) morphological features of neuronal apoptosis (green) associated with marked condensation of chromatin and its fragmentation into discrete bodies (arrows), scale bar: ×250. | Frati, A., Cerretani, D., Fiaschi, A. I., Frati, P., Gatto, V., La Russa, R., Pesce, A., Pinchi, E., Santurro, A., Fraschetti, F., & Fineschi, V. (2017). Diffuse Axonal Injury and Oxidative Stress: A Comprehensive Review. International journal of molecular sciences, 18(12), 2600. https://doi.org/10.3390/ijms18122600

Epidemiology:

The true incidence of DAI is unknown. However, it is estimated that roughly 10% of all TBI admitted to the hospital will have some degree of DAI. Of the patients with DIA, it is estimated that roughly 25% will result in death. This statistic may be underestimated as patients with subdural hematomas, epidural hematomas, and other forms of TBI will not carry a true diagnosis of DAI. Postmortem studies have shown that patients with severe TBI have a significant incidence of diffuse axonal injury.


Presentation

Clinically, patients with DAI can present in a spectrum of neurological dysfunction. This can range from clinically insignificant to a comatose state. However, most patients with DAI are identified to be severe and commonly have a GCS of less than 8. A diffuse axonal injury is a clinical diagnosis.

Mild diffuse axonal injury (DAI):

Patients with mild diffuse axonal injury present with signs and symptoms that reflect a concussive disorder.
  • Concussive symptoms: Headache (M/C)
  • Other post-concussive symptoms: Dizziness, nausea, vomiting, and fatigue

Severe diffuse axonal injury (DAI):

Patients with a severe diffuse axonal injury may also present with a loss of consciousness and remain in a persistent vegetative state. A very small number of those patients with severe diffuse axonal injury will regain consciousness in the first year after the injury.

Dysautonomic symptoms:

Other common neurological manifestations include dysautonomia
  • Tachycardia, tachypnea
  • Diaphoresis
  • Vasoplegia, hyperthermia
  • Abnormal muscle tone, and posturing

Diagnosis

Glasgow coma scale (GCS) classification:

Traumatic brain injury is classified as mild, moderate, and severe based on the Glasgow coma scale (GCS).
  • Mild traumatic brain injury (TBI): GCS 13-15
  • Moderate traumatic brain injury (TBI): GCS 9-12
  • Severe traumatic brain injury (TBI): GCS < 8
Glasgow Coma Scale range
Glasgow Coma Scale range

Currently, there are no laboratory tests for the diagnosis of DAI.

Computed tomography (CT):

Overall, CT head has a low yield in detecting diffuse axonal injury related injuries.
  • Small punctate hemorrhages to white matter tracts can indicate diffuse axonal injury in the setting of an appropriate clinical presentation.
CT at 6 h after the trauma
CT at 6 h after the trauma: (A) Absence of the basal cisterns (arrow); and (B) massive brain edema and intraventricular hemorrhage (arrow); MRI scan of the same patient 5 days after the trauma: (C) DWI sequence disclosing the axonal injury of the corpus callosum (arrow); and (D) injury of the dorsal aspect of the pons (arrow) (FLAIR). | Frati, A., Cerretani, D., Fiaschi, A. I., Frati, P., Gatto, V., La Russa, R., Pesce, A., Pinchi, E., Santurro, A., Fraschetti, F., & Fineschi, V. (2017). Diffuse Axonal Injury and Oxidative Stress: A Comprehensive Review. International journal of molecular sciences, 18(12), 2600. https://doi.org/10.3390/ijms18122600

Magnetic resonance imaging (MRI):

MRI, specifically diffuse tensor imaging (DTI), is the imaging modality of choice for diagnosis of diffuse axonal injury.
MRI imaging of a 2-year-old patient with DAI after being ejected from a motor vehicle
MRI imaging of a 2-year-old patient with DAI after being ejected from a motor vehicle: T2-weighted FLAIR imaging appears on the left, with corresponding susceptibility weighted imaging (SWI) slice appearing on right. Punctate areas of increased T2 signal appear in the white matter of the right frontal and parietal lobes on the left, with some corresponding dotlike areas of signal loss in the right frontal white matter on the SWI image (arrows). | Su E, Bell M. Diffuse Axonal Injury. In: Laskowitz D, Grant G, editors. Translational Research in Traumatic Brain Injury. Boca Raton (FL): CRC Press/Taylor and Francis Group; 2016. Chapter 3. Available from: https://www.ncbi.nlm.nih.gov/books/NBK326722/

Management

DAI should be strongly considered in patients that fail to improve after receiving surgical evacuation of subdural or epidural hematomas. Conversely, if patients drastically improve after surgical evacuation of a subdural or epidural hematoma DAI may not be present.

In general, diffuse axonal injury is a severe form of traumatic brain injury. Therefore, the implementation of an advanced trauma life support protocol is a standard of care for all head-injured patients.

Resuscitative measures:

Initial treatment priority in traumatic brain injury is focused on resuscitation. In a non-neuro trauma center, trauma surgeons and emergency physicians may perform the initial resuscitation and neurologic treatment to stabilize and transport the patient to a designated neurotrauma center expeditiously.
  • ICP monitoring: Indicated in GCS < 8 after consultation with neurosurgery
  • Cerebral oxygen saturation monitoring: Used with ICP monitoring to assess the degree of oxygenation

Anticonvulsant therapy:

Short-term, usually seven days, anticonvulsant treatment can be used to prevent early post-traumatic seizures. There is no evidence that this will prevent long-term post-traumatic seizures, however.

Treatment of patients with diffuse axonal injury is geared toward the prevention of secondary injuries and facilitating rehabilitation. It appears to be the secondary injuries that lead to increased mortality. These can include hypoxia with coexistent hypotension, edema, and intracranial hypertension. Therefore, prompt care to avoid hypotension, hypoxia, cerebral edema, and elevated intracranial pressure (ICP) is advised.

Overall, the goal of the treatment of patients with diffuse axonal injury is supportive care and prevention of secondary injuries.

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