Diffuse Axonal Injury (DAI), also referred to as Traumatic Axonal Injury (TAI), is a severe form of traumatic brain injury (TBI) that results from rapid acceleration or deceleration forces. It occurs when the brain shifts and rotates inside the skull due to a sudden external or physical assault. When the injury occurs, axons, the long connective tissues of the brain, are damaged due to shearing forces.
The damaged axons undergo biochemical changes disrupting neural transmission in the brain stem, corpus callosum, and cerebellum. The injury to the brain can be mild, causing concussion, or it may be a severe injury that can cause coma or even death. The damage to the brain can be focal or diffuse.¹
DAI is considered one of the common causes of morbidity and mortality in children and young adults. The changes in the brain are often very tiny and can be difficult to detect in Computer tomography (CT) and Magnetic resonance imaging (MRI) scans.

Pathophysiology of Diffuse Axonal Injury (DAI)

The injury to the brain can be a primary and secondary brain injury. Primary brain injury is sudden injury to the brain that occurs at the time of impact, like a gunshot, car accident, or physical violence. Secondary injuries involve changes after the primary injury over hours or days. The direct shearing forces cause axonal damage that disrupts and retracts axons, leading to edema and the formation of retraction bulbs. This process of direct axonal damage is called primary axotomy. The retraction bulbs hinder the transport of protein and electrolytes through the neuron membrane, resulting in secondary axonal damage. Secondary axonal injury causes mitochondrial damage, including swelling, calcium influx, changes in membrane permeability, and cell disruption—this cascade of events leads to cell death.
DAI also causes a glial reaction which is caused by glial scar formation at the site of brain injury. The glial cells in the scar secrete growth factors to limit neuronal death. The overstimulation of glial cells releases pro-inflammatory cells like TNFα, impairing microglia’s ability to eliminate glutamate, causing oxidative stress in brain tissue, and inducing neuron death.² Progressive neuron degeneration in DAI can trigger the development of Alzheimer’s disease, Parkinson’s disease, Motor neuron disease, and chronic traumatic encephalopathy.³

Etiology of Diffuse Axonal Injury (DAI)

Traumatic forces cause DAI by accelerating or decelerating the brain inside the bony skull.⁴
A few examples are:

Motorcycle or car accidents
High impact sudden fall
Violence attack
Sports injuries
Child abuse (shaking a child violently)
Blast injuries

Classification of Diffuse Axonal Injury (DAI)

The classification of DAI is based on the severity and extent of the injury, which doctors assess through clinical symptoms and imaging techniques.

Classification based on GCS Score:

Health professionals use the Glasgow Coma Scale (GCS) as a tool to determine disruptions in the nervous system based on the level of consciousness. It records scores from three categories of responsiveness. Eye response, Verbal response, and Motor response. The sum of these responses determines the level of neurological function with a score of 15 highest possible score, indicating the person is fully conscious with normal responses.⁵

Mild: GCS scores 13 and 15.
Moderate: GCS scores 9 and 12.
Severe: GCS scores less than 8.

Classification based on Histopathology:

The classification of DAI based on histopathology is based on the anatomical distribution of injury, which was proposed by J Hume Adams in 1989.

Grade 1:

This is a mild axonal injury with microscopic changes in the white matter of the cerebral hemisphere, which are predominant in parasagittal white matter.

Grade 2:

Moderate axonal injury with a focal lesion in the corpus callosum. Tissue hemorrhage, axonal lesion, and retraction bulbs were found in the corpus callosum along with the area included in Grade 1 of the white hemisphere. Microglia activation and astrocytosis are also present.

Grade 3:

Severe axonal injury with a focal lesion in the brainstem and corpus callosum, along with injuries seen in grade 1 and grade 2. Axonal swelling, retraction bulbs, microglia activation, and presence of secondary injuries.⁶

Symptoms of Diffuse Axonal Injury (DAI)

DAI symptoms vary depending on severity but commonly include:

Loss of consciousness (ranging from minutes to prolonged coma)
Post-traumatic amnesia (difficulty recalling events before or after the injury.
Neurological deficits (motor dysfunction, balance issues, and sensory impairment.
Cognitive impairment (attention deficits, memory loss, and difficulty problem-solving)
Autonomic dysfunction (abnormal heart rate, blood pressure fluctuations, and impaired temperature regulation)

How do we Diagnose Diffuse Axonal Injury (DAI)?

The definitive diagnosis of DAI can be made through a post-mortem examination of brain tissue. In clinical practice, however, DAI is diagnosed based on clinical symptoms and radiographic findings.

Clinical Diagnosis of DAI:

DAI causes impairment in brain function that leads to considerable cognitive, physical, and behavioral changes affecting their quality of life. The changes due to injury are long-lasting but gradually recovered through the remodeling of the brain connection by neural plasticity.
DAI is diagnosed clinically when a patient has a loss of consciousness at the time of injury, and a GCS score of less than 8 for more than 6 hours.
Physical symptoms include motor dysfunction and difficulty in walking and balancing.⁷
The mild case of DAI is often presented with concussive symptoms of headache, nausea, vomiting, dizziness, and fatigue.
Changes in the level of consciousness are usually present. In severe cases, the patient can undergo comatose conditions for days, weeks, or even longer.
Cognitive impairment includes amnesia and difficulty in recalling events before and after the injury. A significant problem in maintaining attention and concentration with impairment in organizational and problem-solving.
In severe cases, autonomic dysfunction can often occur which includes abnormalities in heart rate, blood pressure, and temperature regulation.

Radiographic Imaging:

Imaging plays an important role in the detection and assessment of DAI. CT scans and MRI are widely used in diagnosis with MRI being more sensitive to detect subtle changes associated with DAI.

CT Scans

A CT scan (computerized tomography) produces detailed body images through X-ray techniques. Doctors often use it as an investigation tool for patients with traumatic brain injury.
It is sensitive to large hemorrhagic lesions, and the damage is more likely greater if lesions are detected on a CT scan.
The shearing forces in DAI usually occur in the white matter tract, which generally cannot be detected in CT scans. Non-contrast CT scans are not sensitive enough to detect diffuse axonal injury with significant neural deficits.
Hemorrhagic lesions appear as hyper-dense areas ranging from a few millimeters to a few centimeters. Non-hemorrhagic lesions are hypo-dense areas in CT scans that become obvious with time as edema develops causing significant and disproportionate cerebral swelling.

MRI Scans

MRI (Magnetic Resonance Imaging) is a medical imaging technique that produces images of organs and tissue in your body by using magnetic fields and computer-generated radio waves. It is the choice of diagnostic test used to detect DAI even with patients with normal CT scans of the brain.

Conventional brain MRI can detect DAI lesions, which are usually punctate, round, or ovoid and range in size from 1mm to 15mm.
MRI with susceptibility-weighted imaging (SWI) is an advanced imaging technique that enhances the detection of brain injury related to DAI.
It is sensitive to blood products, calcium, and iron deposits and detects micro-hemorrhages and micro-bleeds at the gray-white matter junction, in the corpus callosum and the brainstem.
Fluid-attenuated inversion recovery (FLAIR) signal in MRI is an imaging technique useful in the detection of non-hemorrhagic lesions in DAI.

MRI with a high FLAIR signal detects chronic changes such as gliosis and scarring that develop with time after the initial injury.⁸

MR Spectroscopy:

Magnetic Resonance (MR) spectroscopy is a non-invasive diagnostic test to detect biochemical changes in the brain by comparing the chemical composition of normal brain tissue with abnormal brain tissue.

MRs can diagnose early injury by measuring metabolites mainly N-acetyl aspartate (NAA), Choline (Cho), Creatinine, lactate, and myo-inositol.
Reduced NAA levels indicate axonal injury while the elevation of the choline peak demonstrates membrane turnover and gliosis during brain injury.⁹

Differential Diagnosis of Diffuse Axonal Injury (DAI)

Clinically certain conditions can present similarly to DAI, such as concussion, contusions, and hematomas.

Concussion: A mild traumatic brain injury that may not show significant abnormalities in imaging but affects brain function. DAI causes damage to brain axons whereas concussion involves localized damage with a higher likelihood of recovery. Symptoms include headache, dizziness, and brief loss of consciousness.
Contusion: Brain contusions are bruises visible as focal lesions on imaging at the impact site. DAI causes axonal damage due to shearing forces leading to diffuse neurological impact whereas cerebral contusions cause focal neurological deficit.
Hematomas: Hematomas can be epidural or subdural and appear as focal hyper-densities on CT scans. DAI damages brain axons, while hematomas involve localized collection of blood due to rupture of blood vessels. Symptoms include headache, confusion hemiparesis, and altered consciousness

Treatment of Diffuse Axonal Injury (DAI)

The management of patients with DAI involves a multidisciplinary approach to manage symptoms and provide rehabilitation.

The treatment of patients with DAI aims to prevent secondary injuries, which usually lead to mortality. To facilitate treatment, healthcare providers should promptly undertake steps to minimize the risk of hypoxia, hypotension, cerebral edema, and elevated intracranial pressure.
For acute management, medical professionals ensure the stabilization of vitals and address any life-threatening concerns based on the advanced trauma life support (ATLS) protocol.
Doctors strictly advise intracranial pressure monitoring for patients with a GCS score of less than 8. They monitor the degree of saturation by recording cerebral oxygen saturation.
Continuous neurological monitoring includes the patient’s level of consciousness, pupillary response, motor function, and vital signs.

Medical Intervention

Medical intervention to manage intracranial hemorrhage either surgically or conservatively based on signs and severity of symptoms.

Sedatives and Pain Relievers: Used to reduce agitation and improve comfort.
Osmotic Agents (e.g., Mannitol, Hypertonic Saline): Help reduce cerebral edema.
Anticonvulsants: Given short-term to prevent post-traumatic seizures.
Neuroprotective Agents: Some studies suggest drugs like amantadine may help enhance cognitive recovery.

Nutritional support is provided to meet metabolic demands and promote recovery.¹⁰

Surgical Intervention

Unlike focal brain injuries, DAI is a diffuse condition, meaning there is usually no specific lesion to remove. However, surgery may be required in cases where hematomas or significant brain swelling develop.

Rehabilitation in Diffuse Axonal Injury (DAI)

The DAI greatly impacted patient functional ability and quality of life. The objective of rehabilitation is to enable the patient to achieve daily routine activities with less complexity.¹¹

Rehabilitation requires a multidisciplinary team of physicians, nurses, occupational therapists, physiotherapists, and speech therapists.
Changes in muscle tone and soft tissue contracture are frequently present in post-traumatic patients. The physiotherapist provides splints, and personalized orthotics with active and passive stretching techniques. The purpose of rehabilitation is to lengthen the contracted muscle and increase muscle tone.
The program includes stretching techniques to enhance joint flexibility and strengthening exercises to improve muscle power and endurance.
In the later stage of rehabilitation proprioceptive neuromuscular exercises (PNF) for the upper limb, coordination exercises, reach-out exercises, posture control, and gait training were provided to the patient.

Prognosis of Diffuse Axonal Injury (DAI)

The prognosis of DAI is highly variable and depends on the severity of the injury. Patients’ overall health and access to health care also play an important role in the recovery of the patient after injury. The impairment of brain tissue function, rather than its destruction, allows for the possibility that the brain can regain its normal function over time. The clinical condition stabilizes and neuronal connections are reconstructed with plasticity. Some of the patients may recover fully with time while others may develop lifetime disabilities. Long-term hospitalization and comprehensive rehabilitation can aid in better clinical and functional outcomes in survivors.¹²

Summary

Diffuse Axonal Injury (DAI) is a severe form of traumatic brain injury that can lead to significant neurological impairment. While there is no direct cure, early medical intervention, intensive rehabilitation, and supportive care play a crucial role in recovery. The prognosis varies depending on the severity of the injury, but advancements in neurocritical care and rehabilitation continue to improve outcomes for affected individuals.

Refrences

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Diffuse Axonal Injury- Etiology, Treatment and Prognosis

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