Diffuse axonal injury

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Diffuse axonal injury Classification and external resources
eMedicine	radio/216
MeSH	D020833

Diffuse axonal injury (DAI) is one of the most common and devastating types of traumatic brain injury,^[1] occurring in about half of all cases of severe head trauma and also occurring in moderate and mild brain injury.^[2] It is a type of diffuse brain injury, meaning that damage occurs over a more widespread area than in focal brain injury. DAI, which refers to extensive lesions in white matter tracts, is one of the major causes of unconsciousness and persistent vegetative state after head trauma.^[3]

Though diffuse axonal injury seldom kills, the outcome is frequently coma, with over 90% of patients with severe DAI never regaining consciousness.^[3] Those who do wake up often remain significantly impaired.^[4]

Nowadays, other authors state that DAI can occur in every degree of severity from (very) mild or moderate to (very) severe.^[5][6] Concussion is thought to be a milder type of diffuse axonal injury.^[7]

Contents 1 Mechanism 2 Characteristics 2.1 Histological characteristics 2.2 Cytoskeleton disruption 2.3 Calcium influx 3 Diagnosis and treatment 4 History 5 See also 6 References 7 External links

[edit] Mechanism

Unlike brain trauma that occurs due to direct impact and deformation of the brain, DAI is the result of traumatic shearing forces that occur when the head is rapidly accelerated or decelerated, as may occur in auto accidents, falls, and assaults.^[8] It usually results from rotational forces or severe deceleration.^[9][10] Vehicle accidents are the most frequent cause of DAI; other common causes include falls, assaults, and child abuse^[11] such as shaken baby syndrome.^[12]

The major cause of damage in DAI is the disruption of axons, the neural processes that allow one neuron to communicate with another. Tracts of axons, which appear white due to myelination, are referred to as white matter. Acceleration causes shearing injury, which refers to damage inflicted as tissue slides over other tissue. When the brain is accelerated, parts of differing densities and distances from the axis of rotation slide over one another, stretching axons that traverse junctions between areas of different density, especially at junctions between white and grey matter.^[3] Two thirds of DAI lesions occur in areas where grey and white matter meet.^[3]

[edit] Characteristics

Lesions typically exist in the white matter of brains injured by DAI; these lesions vary in size from about 1-15 mm and are distributed in a characteristic way.^[3] DAI most commonly affects white matter in areas including the brain stem, the corpus callosum, and the cerebral hemispheres.^[2] The lobes of the brain most likely to be injured are the frontal and temporal lobes.^[13] Other common locations for DAI include the white matter in the cerebral cortex, the corpus callosum, the superior cerebral peduncles,^[12] basal ganglia, thalamus, and deep hemispheric nuclei.^[14] These areas may be more easily damaged because of the difference in density between them and the rest of the brain.^[14]

[edit] Histological characteristics

DAI is characterized by axonal separation, in which the axon is torn at the site of stretch and the part distal to the tear degrades. While it was once thought that the main cause of axonal separation was tearing due to mechanical forces during the trauma, it is now understood that secondary biochemical cascades, which occur in response to the primary injury and take place hours to days after the initial injury, are largely responsible for the damage to axons.^[8][15] Axons are not typically torn at the time of injury; rather they usually become separated hours or days after the injury.^[2]

Though the processes involved in secondary brain injury are still poorly understood, it is now accepted that stretching of axons during injury causes physical disruption to and proteolytic degradation of the cytoskeleton.^[1] It also opens sodium channels in the axolemma, which causes voltage-gated calcium channels to open and Ca²⁺ to flow into the cell.^[1] The intracellular presence of Ca²⁺ unleashes several different pathways, including activating phospholipases and proteolytic enzymes, damaging mitochondria and the cytoskeleton, and activating secondary messengers, which can lead to separation of the axon and death of the cell.^[8]

[edit] Cytoskeleton disruption

Axons are normally elastic, but when rapidly stretched they become brittle, and the axonal cytoskeleton can be broken. It is thought that integrins connected to the extracellular matrix outside the cell and to the cytoskeleton within it can transmit forces from the matrix to the cytoskeleton and cause the latter to tear when the axon is stretched.^[16]

Misalignment of cytoskeletal elements after stretch injury can lead to tearing of the axon and death of the neuron. Axonal transport continues up to the point of the break in the cytoskeleton, but no further, leading to a buildup of transport products and local swelling at that point.^{[citation needed]} When it becomes large enough, swelling can tear the axon at the site of the break in the cytoskeleton, causing it to draw back toward the cell body and form a bulb.^[6] This bulb is called a retraction ball, the hallmark of diffuse axonal injury.^[3]

When the axon is transected, Wallerian degeneration, in which the part of the axon distal to the break degrades, takes place within one to two days after injury.^[17] The axolemma disintegrates,^[17] myelin breaks down and begins to detach from cells in an anterograde direction (from the body of the cell toward the end of the axon),^[18] and nearby cells begin phagocytic activity, engulfing debris.^[19]

[edit] Calcium influx

While sometimes only the cytoskeleton is disturbed, frequently disruption of the axolemma occurs as well, causing the influx of Ca²⁺ into the cell and unleashing a variety of degrading processes.^[17][20] An increase in Ca²⁺ and Na⁺ levels and a drop in K⁺ levels is found within the axon directly after injury.^[8][17] Possible routes of Ca²⁺ entry include sodium channels, pores torn in the membrane during stretch, and failure of ATP-dependent transporters due to mechanical blockage or lack of energy.^[8] High levels of intracellular Ca²⁺, the major cause of post-injury cell damage,^[21] destroy mitochondria,^[6] contribute to the generation of reactive oxygen species^[15] and trigger phospholipases and proteolytic enzymes that damage Na+ channels and degrade or alter the cytoskeleton and the axoplasm.^[22][17] Excess Ca²⁺ can also lead to damage to the blood brain barrier and swelling of the brain.^[21]

One of the proteins activated by the presence of calcium in the cell is calpain, a Ca²⁺-dependent non-lysosomal protease.^[22] About 15 minutes to half an hour after the onset of injury, a process called calpain-mediated spectrin proteolysis, or CMSP, begins to occur.^[23] Calpain breaks down a molecule called spectrin, which holds the membrane onto the cytoskeleton, causing the formation of blebs and the breakdown of the cytoskeleton and the membrane, and ultimately the death of the cell.^[23][22] Other molecules that can be degraded by calpains are microtubule subunits, microtubule-associated proteins, and neurofilaments.^[22]

Generally occurring one to six hours into the process of post-stretch injury, the presence of calcium in the cell initiates the caspase cascade, a process in cell injury that usually leads to apoptosis, or "cell suicide".^[23]

Mitochondria, dendrites, and parts of the cytoskeleton damaged in the injury have a limited ability to heal and regenerate, a process which occurs over 2 or more weeks.^[24] After the injury, astrocytes can shrink, causing parts of the brain to atrophy.^[3]

[edit] Diagnosis and treatment

DAI is difficult to detect since it does not show up well on CT scans or with other macroscopic imaging techniques, though it shows up microscopically.^[3] However, there are characteristics typical of DAI that may or may not show up on a CT scan.^[2] Since axonal damage in DAI is largely a result of secondary biochemical cascades, it has a delayed onset, so a person with DAI who initially appears well may deteriorate later. Thus injury is frequently more severe than is realized, and medical professionals should suspect DAI in any patients whose CT scans appear normal but who have symptoms like unconsciousness.^[3]

MRI is more sensitive than CT scans,^[2] but MRI may also miss DAI, because it identifies the injury using signs of edema, which may not be present.^[24]

DAI is classified into grades based on severity of the injury. In Grade I, widespread axonal damage is present but no focal abnormalities are seen. In Grade II, damage found in Grade I is present in addition to focal abnormalities, especially in the corpus callosum. Grade III damage encompasses both Grades I and II plus rostral brain stem injury and often tears in the tissue.^[25]

DAI currently lacks a specific treatment beyond what is done for any type of head injury, including stabilizing the patient and trying to limit increases in intracranial pressure (ICP).

[edit] History

The idea of DAI first came about as a result of studies by Sabina Strich on lesions of the white matter of individuals who had suffered head trauma years before.^[26] Strich first proposed the idea in 1956, calling it diffuse degeneration of white matter.^[27] She was researching the relationship between dementia and head trauma^[26] and asserted in 1956 that DAI played an integral role in the eventual development of dementia due to head trauma.^[11]

[edit] See also

• Brain injury
• Axoplasmic transport

[edit] References

[edit] External links

• Diffuse Axonal Injury MRI and CT Images

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