Diffuse axonal injury

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Diffuse axonal injury
Classification and external resources

Susceptibility weighted image (SWI) of diffuse axonal injury

in trauma at 1.5 teslas (right)
eMedicine radio/216
MeSH D020833

Diffuse axonal injury (DAI) is one of the most common and devastating types of traumatic
brain injury,[1], 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.[2] It occurs in about half of all
cases of severe head trauma and also occurs in moderate and mild brain injury.[3]

The outcome is frequently coma, with over 90% of patients with severe DAI never regaining
consciousness.[2] 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 may be a milder type of diffuse axonal injury.[7]

Contents
[hide]

• 1 Mechanism
• 2 Characteristics
o 2.1 Histological characteristics
o 2.2 Cytoskeleton disruption
o 2.3 Calcium influx
• 3 Diagnosis and treatment
• 4 Potential Treatments
• 5 History
 • 6 See also
• 7 References

• 8 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; it can also occur
as the result of child abuse[11] such as in 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.[2] Two thirds of DAI lesions occur in areas where grey and white matter meet.[2]

[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.[2] DAI most commonly affects
white matter in areas including the brain stem, the corpus callosum, and the cerebral
hemispheres.[3] 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
axons are not typically torn upon impact; rather, secondary biochemical cascades, which occur in
response to the primary injury (which occurs as the result of mechanical forces at the moment of
trauma) and take place hours to days after the initial injury, are largely responsible for the
damage to axons.[3][8][15]

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.[17] 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.[2]

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.[18] The axolemma disintegrates,[18]
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),[19] and nearby cells begin phagocytic activity, engulfing
debris.[20]

[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.[18][21] An increase in Ca2+ and Na+ levels and a drop in K+ levels is found within the
axon directly after injury.[8][18] 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,[22] 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.[23][18] Excess Ca2+ can also lead to damage to the blood brain
barrier and swelling of the brain.[22]

One of the proteins activated by the presence of calcium in the cell is calpain, a Ca2+-dependent
non-lysosomal protease.[23] About 15 minutes to half an hour after the onset of injury, a process
called calpain-mediated spectrin proteolysis, or CMSP, begins to occur.[24] 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][24] Other molecules that can be degraded by calpains are microtubule
subunits, microtubule-associated proteins, and neurofilaments.[23]
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".[24]

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.[25] After the injury,
astrocytes can shrink, causing parts of the brain to atrophy.[2]

[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.[2] However, there are characteristics
typical of DAI that may or may not show up on a CT scan.[3] Diffuse injury has more
microscopic injury than macroscopic injury and is difficult to detect with CT and MRI, but its
presence can be inferred when small bleeds are visible in the corpus callosum or the cerebral
cortex.[26] MRI is more useful than CT for detecting characteristics of diffuse axonal injury in the
subacute and chronic time frames.[27] Newer studies such as Diffusion Tensor Imaging are able to
demonstrate the degree of white matter fiber tract injury even when the standard MRI is
negative. 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.[2]

MRI is more sensitive than CT scans,[3] but MRI may also miss DAI, because it identifies the
injury using signs of edema, which may not be present.[25]

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.[28]

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] Potential Treatments

Polyethylene glycol acts as a membrane sealant, and may serve to prevent the aforementioned
devastating calcium influx. Rats treated with polyethylene glycol immediately following DAI
induction showed no cytotoxic edema on diffusion weighted MRI 7 days later unlike controls.[29]

[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.[30] Strich first proposed the idea
in 1956, calling it diffuse degeneration of white matter, but that was too long so they just call it,
"Diffuse axonal injury", or DAI for short.[31] Strich was researching the relationship between
dementia and head trauma[30] and asserted in 1956 that DAI played an integral role in the
eventual development of dementia due to head trauma.[11] The term DAI was introduced in the
early 1980s.[32]