Diffuse axonal injury

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Diffuse axonal injury
Compare SWI and GRE Trauma.png
Two MRI images of a patient with diffuse axonal injury resulting from trauma, at 1.5 tesla field strength. Left: conventional gradient recalled echo (GRE). Right: Susceptibility weighted image (SWI).
Specialty Neurology

Diffuse axonal injury (DAI) is a brain injury in which scattered lesions occur over a widespread area in white matter tracts as well as grey matter. [1] [2] [3] [4] [5] [6] [7] DAI is one of the most common and devastating types of traumatic brain injury [8] and is a major cause of unconsciousness and persistent vegetative state after severe head trauma. [9] It occurs in about half of all cases of severe head trauma and may be the primary damage that occurs in concussion. The outcome is frequently coma, with over 90% of patients with severe DAI never regaining consciousness. [9] Those who awaken from the coma often remain significantly impaired. [10]

Contents

DAI can occur across the spectrum of traumatic brain injury (TBI) severity, wherein the burden of injury increases from mild to severe. [11] [12] Concussion may be a milder type of diffuse axonal injury. [12] [13]

Mechanism

DAI is the result of traumatic shearing forces that occur when the head is rapidly accelerated or decelerated, as may occur in car accidents, falls, and assaults. [14] Vehicle accidents are the most frequent cause of DAI; it can also occur as the result of child abuse [15] such as in shaken baby syndrome. [16]

Immediate disconnection of axons may be observed in severe brain injury, but the major damage of DAI is delayed secondary axon disconnections, slowly developed over an extended time course. [2] Tracts of axons, which appear white due to myelination, are referred to as white matter. Lesions in both grey and white matter are found in postmortem brains in CT and MRI exams. [9]

Besides mechanical breakage of the axonal cytoskeleton, DAI pathology also includes secondary physiological changes, such as interrupted axonal transport, progressive swellings known as axonal varicosities, and degeneration. [17] Recent studies have linked these changes to twisting and misalignment of broken axon microtubules, as well as tau protein and amyloid precursor protein (APP) deposition. [17] [18]

Characteristics

Lesions typically are found 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 pattern. [9] DAI most commonly affects white matter in areas including the brain stem, the corpus callosum, and the cerebral hemispheres.

The lobes of the brain most likely to be injured are the frontal and temporal lobes. [19] Other common locations for DAI include the white matter in the cerebral cortex, the superior cerebral peduncles, [16] basal ganglia, thalamus, and deep hemispheric nuclei.[ clarification needed ] [20] These areas may be more easily damaged because of the difference in density between them and the other regions of the brain. [20]

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 by a process known as Wallerian degeneration. While it was once thought that the main cause of axonal separation was tearing due to mechanical forces during the trauma event, 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. [21] [22] [23]

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. [24] It also opens sodium channels in the axolemma, which causes voltage-gated calcium channels to open and Ca2+ to flow into the cell. [24] The intracellular presence of Ca2+ triggers 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. [21]

Cytoskeleton disruption

Immunoreactive axonal profiles are observed as either granular (B, G, H) or more elongated, fusiform (F) swellings in the corpus callosum and the brain stem (H) at 24h post traumatic brain injury. Example of APP immunoreactive neurons (arrow heads) observed in the cortex underneath the impact site (E, G). No APP staining was observed in healthy control animals (D). APP immunostaining in a mouse brain after traumatic brain injury.png
Immunoreactive axonal profiles are observed as either granular (B, G, H) or more elongated, fusiform (F) swellings in the corpus callosum and the brain stem (H) at 24h post traumatic brain injury. Example of APP immunoreactive neurons (arrow heads) observed in the cortex underneath the impact site (E, G). No APP staining was observed in healthy control animals (D).

Axons are normally elastic, but when rapidly stretched they become brittle, and the axonal cytoskeleton can be broken. 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. [25] When this swelling becomes large enough, it can tear the axon at the site of the cytoskeleton break, causing it to draw back toward the cell body and form a bulb. [11] This bulb is called a "retraction ball", the histological hallmark of diffuse axonal injury. [9]

When the axon is torn, Wallerian degeneration, in which the part of the axon distal to the break degrades, takes place within one to two days after injury. [26] The axolemma disintegrates, [26] myelin breaks down and begins to detach from the cell in an anterograde direction (from the body of the cell toward the end of the axon), [27] and nearby cells begin phagocytic activity, engulfing the cellular debris. [28]

Calcium influx

While sometimes only the cytoskeleton is disturbed, frequently disruption of the axolemma occurs as well, causing the influx of Ca2+ ions into the cell and unleashing a variety of degradational processes. [26] [29] An increase in Ca2+ and Na+ levels and a drop in K+ levels are found within the axon immediately after injury. [21] [26] Possible routes of Ca2+ entry include sodium channels, pores formed in the membrane during stretch, and failure of ATP-dependent transporters due to mechanical blockage or lack of available metabolic energy. [21] High levels of intracellular Ca2+, the major cause of post-injury cell damage, [30] destroy mitochondria, [11] and trigger phospholipases and proteolytic enzymes that damage Na+ channels and degrade or alter the cytoskeleton and the axoplasm. [31] [26] Excess Ca2+ can also lead to damage to the blood–brain barrier and swelling of the brain. [30]

One of the proteins activated by the presence of calcium in the cell is calpain, a Ca2+-dependent non-lysosomal protease. [31] About 15 minutes to half an hour after the onset of injury, a process called calpain-mediated spectrin proteolysis, or CMSP, begins to occur. [32] 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. [31] [32] Other molecules that can be degraded by calpains are microtubule subunits, microtubule-associated proteins, and neurofilaments. [31]

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 "programmed cell death". [32]

Mitochondria, dendrites, and parts of the cytoskeleton damaged in the injury have a limited ability to heal and regenerate, a process which occurs over two or more weeks. [33] After the injury, astrocytes can shrink, causing parts of the brain to atrophy. [9]

Diagnosis

Diffuse axonal injury after a motorcycle accident. MRI after 3 days: on T1-weighted images the injury is barely visible. On the FLAIR, DWI and T2*-weighted images a small bleed is identifiable. Diffuse axonal injury- cMRT nach 3 Tagen.jpg
Diffuse axonal injury after a motorcycle accident. MRI after 3 days: on T1-weighted images the injury is barely visible. On the FLAIR, DWI and T2*-weighted images a small bleed is identifiable.

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. [9] However, there are characteristics typical of DAI that may or may not show up on a CT scan. 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. [34] MRI is more useful than CT for detecting characteristics of diffuse axonal injury in the subacute and chronic time frames. [35] 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. [9]

MRI is more sensitive than CT scans, but is still liable to false negatives because DAI is identified by looking for signs of edema, which may not always be present. [33]

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. [36]

Treatment

DAI currently lacks specific treatment beyond that for any type of head injury, which includes stabilizing the patient and trying to limit increases in intracranial pressure (ICP).

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 sustained head trauma years before. [37] Strich first proposed the idea in 1956, calling it diffuse degeneration of white matter; however, the more concise term "diffuse axonal injury" came to be preferred. [38] Strich was researching the relationship between dementia and head trauma [37] and asserted in 1956 that DAI played an integral role in the eventual development of dementia due to head trauma. [15] The term DAI was introduced in the early 1980s. [39]

Notable examples

See also

Related Research Articles

<span class="mw-page-title-main">Axon</span> Long projection on a neuron that conducts signals to other neurons

An axon or nerve fiber is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action potentials away from the nerve cell body. The function of the axon is to transmit information to different neurons, muscles, and glands. In certain sensory neurons, such as those for touch and warmth, the axons are called afferent nerve fibers and the electrical impulse travels along these from the periphery to the cell body and from the cell body to the spinal cord along another branch of the same axon. Axon dysfunction can be the cause of many inherited and acquired neurological disorders that affect both the peripheral and central neurons. Nerve fibers are classed into three types – group A nerve fibers, group B nerve fibers, and group C nerve fibers. Groups A and B are myelinated, and group C are unmyelinated. These groups include both sensory fibers and motor fibers. Another classification groups only the sensory fibers as Type I, Type II, Type III, and Type IV.

<span class="mw-page-title-main">Myelin</span> Fatty substance that surrounds nerve cell axons to insulate them and increase transmission speed

Myelin is a lipid-rich material that surrounds nerve cell axons to insulate them and increase the rate at which electrical impulses pass along the axon. The myelinated axon can be likened to an electrical wire with insulating material (myelin) around it. However, unlike the plastic covering on an electrical wire, myelin does not form a single long sheath over the entire length of the axon. Rather, myelin ensheaths the axon segmentally: in general, each axon is encased in multiple long sheaths with short gaps between, called nodes of Ranvier. At the nodes of Ranvier, which are approximately one thousandth of a mm in length, the axon's membrane is bare of myelin.

<span class="mw-page-title-main">Head injury</span> Serious trauma to the cranium

A head injury is any injury that results in trauma to the skull or brain. The terms traumatic brain injury and head injury are often used interchangeably in the medical literature. Because head injuries cover such a broad scope of injuries, there are many causes—including accidents, falls, physical assault, or traffic accidents—that can cause head injuries.

<span class="mw-page-title-main">Brain injury</span> Destruction or degeneration of brain cells

Brain injury (BI) is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors. In general, brain damage refers to significant, undiscriminating trauma-induced damage.

<span class="mw-page-title-main">Wallerian degeneration</span> Biological process of axonal degeneration

Wallerian degeneration is an active process of degeneration that results when a nerve fiber is cut or crushed and the part of the axon distal to the injury degenerates. A related process of dying back or retrograde degeneration known as 'Wallerian-like degeneration' occurs in many neurodegenerative diseases, especially those where axonal transport is impaired such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. Primary culture studies suggest that a failure to deliver sufficient quantities of the essential axonal protein NMNAT2 is a key initiating event.

<span class="mw-page-title-main">Traumatic brain injury</span> Injury of the brain from an external source

A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity ranging from mild traumatic brain injury (mTBI/concussion) to severe traumatic brain injury. TBI can also be characterized based on mechanism or other features. Head injury is a broader category that may involve damage to other structures such as the scalp and skull. TBI can result in physical, cognitive, social, emotional and behavioral symptoms, and outcomes can range from complete recovery to permanent disability or death.

Closed-head injury is a type of traumatic brain injury in which the skull and dura mater remain intact. Closed-head injuries are the leading cause of death in children under 4 years old and the most common cause of physical disability and cognitive impairment in young people. Overall, closed-head injuries and other forms of mild traumatic brain injury account for about 75% of the estimated 1.7 million brain injuries that occur annually in the United States. Brain injuries such as closed-head injuries may result in lifelong physical, cognitive, or psychological impairment and, thus, are of utmost concern with regards to public health.

<span class="mw-page-title-main">Astrogliosis</span> Increase in astrocytes in response to brain injury

Astrogliosis is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons from central nervous system (CNS) trauma, infection, ischemia, stroke, autoimmune responses or neurodegenerative disease. In healthy neural tissue, astrocytes play critical roles in energy provision, regulation of blood flow, homeostasis of extracellular fluid, homeostasis of ions and transmitters, regulation of synapse function and synaptic remodeling. Astrogliosis changes the molecular expression and morphology of astrocytes, in response to infection for example, in severe cases causing glial scar formation that may inhibit axon regeneration.

In cellular neuroscience, an axotomy is the cutting or otherwise severing of an axon. This type of denervation is often used in experimental studies on neuronal physiology and neuronal death or survival as a method to better understand nervous system diseases.

<span class="mw-page-title-main">Spectrin</span> Cytoskeletal protein

Spectrin is a cytoskeletal protein that lines the intracellular side of the plasma membrane in eukaryotic cells. Spectrin forms pentagonal or hexagonal arrangements, forming a scaffold and playing an important role in maintenance of plasma membrane integrity and cytoskeletal structure. The hexagonal arrangements are formed by tetramers of spectrin subunits associating with short actin filaments at either end of the tetramer. These short actin filaments act as junctional complexes allowing the formation of the hexagonal mesh. The protein is named spectrin since it was first isolated as a major protein component of human red blood cells which had been treated with mild detergents; the detergents lysed the cells and the hemoglobin and other cytoplasmic components were washed out. In the light microscope the basic shape of the red blood cell could still be seen as the spectrin-containing submembranous cytoskeleton preserved the shape of the cell in outline. This became known as a red blood cell "ghost" (spectre), and so the major protein of the ghost was named spectrin.

<span class="mw-page-title-main">Calpain</span> Protease enzyme present in mammals and other organisms

A calpain is a protein belonging to the family of calcium-dependent, non-lysosomal cysteine proteases expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of protease clan CA in the MEROPS database. The calpain proteolytic system includes the calpain proteases, the small regulatory subunit CAPNS1, also known as CAPN4, and the endogenous calpain-specific inhibitor, calpastatin.

Gliosis is a nonspecific reactive change of glial cells in response to damage to the central nervous system (CNS). In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells, including astrocytes, microglia, and oligodendrocytes. In its most extreme form, the proliferation associated with gliosis leads to the formation of a glial scar.

<span class="mw-page-title-main">Nerve injury</span> Damage to nervous tissue

Nerve injury is an injury to a nerve. There is no single classification system that can describe all the many variations of nerve injuries. In 1941, Seddon introduced a classification of nerve injuries based on three main types of nerve fiber injury and whether there is continuity of the nerve. Usually, however, nerve injuries are classified in five stages, based on the extent of damage to both the nerve and the surrounding connective tissue, since supporting glial cells may be involved.

Neuroregeneration involves the regrowth or repair of nervous tissues, cells or cell products. Neuroregenerative mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Neuroregeneration differs between the peripheral nervous system (PNS) and the central nervous system (CNS) by the functional mechanisms involved, especially in the extent and speed of repair. When an axon is damaged, the distal segment undergoes Wallerian degeneration, losing its myelin sheath. The proximal segment can either die by apoptosis or undergo the chromatolytic reaction, which is an attempt at repair. In the CNS, synaptic stripping occurs as glial foot processes invade the dead synapse.

<span class="mw-page-title-main">Coup contrecoup injury</span> Type of head injury

In head injury, a coup injury occurs under the site of impact with an object, and a contrecoup injury occurs on the side opposite the area that was hit. Coup and contrecoup injuries are associated with cerebral contusions, a type of traumatic brain injury in which the brain is bruised. Coup and contrecoup injuries can occur individually or together. When a moving object impacts the stationary head, coup injuries are typical, while contrecoup injuries are produced when the moving head strikes a stationary object.

A cerebral laceration is a type of traumatic brain injury that occurs when the tissue of the brain is mechanically cut or torn. The injury is similar to a cerebral contusion; however, according to their respective definitions, the pia-arachnoid membranes are torn over the site of injury in laceration and are not torn in contusion. Lacerations require greater physical force to cause than contusions, but the two types of injury are grouped together in the ICD-9 and ICD-10 classification systems.

Primary and secondary brain injury are ways to classify the injury processes that occur in brain injury. In traumatic brain injury (TBI), primary brain injury occurs during the initial insult, and results from displacement of the physical structures of the brain. Secondary brain injury occurs gradually and may involve an array of cellular processes. Secondary injury, which is not caused by mechanical damage, can result from the primary injury or be independent of it. The fact that people sometimes deteriorate after brain injury was originally taken to mean that secondary injury was occurring. It is not well understood how much of a contribution primary and secondary injuries respectively have to the clinical manifestations of TBI.

<span class="mw-page-title-main">Focal and diffuse brain injury</span> Medical condition

Focal and diffuse brain injury are ways to classify brain injury: focal injury occurs in a specific location, while diffuse injury occurs over a more widespread area. It is common for both focal and diffuse damage to occur as a result of the same event; many traumatic brain injuries have aspects of both focal and diffuse injury. Focal injuries are commonly associated with an injury in which the head strikes or is struck by an object; diffuse injuries are more often found in acceleration/deceleration injuries, in which the head does not necessarily contact anything, but brain tissue is damaged because tissue types with varying densities accelerate at different rates. In addition to physical trauma, other types of brain injury, such as stroke, can also produce focal and diffuse injuries. There may be primary and secondary brain injury processes.

<span class="mw-page-title-main">Chromatolysis</span> Dissolution of a neurons Nissl bodies

In cellular neuroscience, chromatolysis is the dissolution of the Nissl bodies in the cell body of a neuron. It is an induced response of the cell usually triggered by axotomy, ischemia, toxicity to the cell, cell exhaustion, virus infections, and hibernation in lower vertebrates. Neuronal recovery through regeneration can occur after chromatolysis, but most often it is a precursor of apoptosis. The event of chromatolysis is also characterized by a prominent migration of the nucleus towards the periphery of the cell and an increase in the size of the nucleolus, nucleus, and cell body. The term "chromatolysis" was initially used in the 1940s to describe the observed form of cell death characterized by the gradual disintegration of nuclear components; a process which is now called apoptosis. Chromatolysis is still used as a term to distinguish the particular apoptotic process in the neuronal cells, where Nissl substance disintegrates.

<span class="mw-page-title-main">SARM1</span> Protein-coding gene in the species Homo sapiens

Sterile alpha and TIR motif containing 1 Is an enzyme that in humans is encoded by the SARM1 gene. It is the most evolutionarily conserved member of the Toll/Interleukin receptor-1 (TIR) family. SARM1's TIR domain has intrinsic NADase enzymatic activity that is highly conserved from archaea, plants, nematode worms, fruit flies, and humans. In mammals, SARM1 is highly expressed in neurons, where it resides in both cell bodies and axons, and can be associated with mitochondria.

References

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  37. 1 2 Pearce JM (2007). "Observations on concussion. A review". European Neurology. 59 (3–4): 113–9. doi: 10.1159/000111872 . PMID   18057896. S2CID   10245120.
  38. ↑ Gennarelli GA, Graham DI (2005). "Neuropathology". In Silver JM, McAllister TW, Yudofsky SC (eds.). Textbook Of Traumatic Brain Injury. Washington, DC: American Psychiatric Association. p. 34. ISBN   978-1-58562-105-7 . Retrieved 2008-06-10.
  39. ↑ Granacher RP (2007). Traumatic Brain Injury: Methods for Clinical & Forensic Neuropsychiatric Assessment, Second Edition. Boca Raton: CRC. pp. 26–32. ISBN   978-0-8493-8138-6 . Retrieved 2008-07-06.
  40. ↑ "The story of Roberto Guerrero".
  41. ↑ "Jules Bianchi: Family confirms Formula One driver sustained traumatic brain injury in Japanese GP crash" . Retrieved 8 October 2014.
  42. ↑ "F1 driver Jules Bianchi dies from crash injuries". BBC Sport. BBC. 2015-07-18. Retrieved 18 July 2015.
  43. ↑ "Frank Muller, The Fight of his Life". 2006. Retrieved December 14, 2017.
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