Diffuse axonal injury 1212182 225147552 2008-07-12T03:34:38Z Arcadian 104523 nav {{Infobox_Disease | Name = Diffuse axonal injury | Image = | Caption = | DiseasesDB = | ICD10 = | ICD9 = | ICDO = | OMIM = | MedlinePlus = | eMedicineSubj = radio | eMedicineTopic = 216 | MeshID = D020833| }} '''Diffuse axonal injury''' (DAI) is one of the most common and devastating types of [[traumatic brain injury]],<ref name="Iwata">Iwata A., Stys P.K., Wolf J.A., Chen X.H., Taylor, A.G., Meaney D.F., and Smith D.H. (2004). [http://www.jneurosci.org/cgi/content/abstract/24/19/4605 Traumatic axonal injury induces proteolytic cleavage of the voltage-gated sodium channels modulated by tetrodotoxin and protease inhibitors]. ''The Journal of Neuroscience''. '''24''' (19): 4605—4613.<!--♦♦♦primary♦♦♦--></ref> occurring in about half of all cases of severe [[head injury|head trauma]] and also occurring in moderate and mild [[brain injury]].<ref name="VikKvistad"/> It is a type of [[focal and diffuse brain injury|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.<ref name="Wasserman"> Wasserman J. and Koenigsberg R.A. (2007). [http://www.emedicine.com/radio/topic216.htm Diffuse axonal injury]. Emedicine.com. Retrieved on [[2008-01-26]].</ref> Though diffuse axonal injury seldom kills, the outcome is frequently [[coma]], with over 90% of patients with severe DAI never regaining consciousness.<ref name="Wasserman"/> Those who do wake up often remain significantly impaired.<ref name="Vinas"> Vinas F.C. and Pilitsis J. (2006). [http://www.emedicine.com/med/topic2888.htm Penetrating head trauma]. Emedicine.com. Retrieved on [[2008-01-14]].</ref> Nowadays, other authors state that DAI can occur in every degree of severity from (very) mild or moderate to (very) severe.<ref name=Vik>Vik A., Kvistad, K.A., Skandsen, T. & Ingebritsen, T. (2006). Diffus aksonal skade ved hodetraume. Tiddskr. ''Nor. Lægeforen''. 126: 2940-2944.</ref><ref name="Smith">Smith, D.H. and Meaney D.F. (2000). [http://nro.sagepub.com/cgi/content/abstract/6/6/483 Axonal damage in traumatic brain injury]. ''The Neuroscientist''. 6 (6): 483—495. Retrieved on [[2008-01-14]]. </ref> [[Concussion]] is thought to be a milder type of diffuse axonal injury.<ref name=sivak> {{ cite journal |author=Sivák Š, Kurča E, Jančovič D, Petriščák Š, Kučera P |year=2005 |url=http://www.clsjep.cz/odkazy/clc0507_445.pdf |format=PDF |title=An outline of the current concepts of mild brain injury with emphasis on the adult population |journal=Časopis Lėkařů Českých |volume=144 |issue=7 |pages=445–450 }} </ref> ==Mechanism== Unlike [[traumatic brain injury|brain trauma]] that occurs due to direct impact and deformation of the [[brain]], DAI is the result of [[physical trauma|traumatic]] shearing forces that occur when the head is rapidly accelerated or decelerated, as may occur in auto accidents, falls, and assaults.<ref name="Wolf">Wolf J.A., Stys P.K., Lusardi T., Meaney D., and Smith, D.H. (2001). [http://www.jneurosci.org/cgi/content/abstract/21/6/1923 Traumatic axonal injury induces calcium influx modulated by tetrodotoxin-sensitive sodium channels]. ''Journal of Neuroscience''. '''21''' (6): 1923–1930 <!--♦♦♦primary♦♦♦--></ref> It usually results from rotational forces or severe [[acceleration|deceleration]].<ref name="Sanders">Sanders M.J. and McKenna K. 2001. ''Mosby’s Paramedic Textbook'', 2nd revised Ed. Chapter 22, "Head and Facial Trauma." Mosby. </ref><ref name="Shepherd">Shepherd S. 2004. [http://www.emedicine.com/med/topic2820.htm Head Trauma]. Emedicine.com. Retrieved on [[2008-01-17]]. </ref> Vehicle accidents are the most frequent cause of DAI; other common causes include falls, assaults, and child abuse<ref name="Hardman02"/> such as [[shaken baby syndrome]].<ref name="SmithGreenwald">Smith D. and Greenwald B. 2003.[http://web.archive.org/web/20050909140825/http://www.emedicine.com/pmr/topic213.htm Management and staging of traumatic brain injury]. Emedicine.com. Retrieved through web archive on [[2008-01-17]].</ref> 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 [[myelin|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]].<ref name="Wasserman"/> Two thirds of DAI lesions occur in areas where grey and white matter meet.<ref name="Wasserman"/> ==Characteristics== [[Lesion]]s 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.<ref name="Wasserman"/> DAI most commonly affects white matter in areas including the [[brain stem]], the [[corpus callosum]], and the [[cerebral hemisphere]]s.<ref name="VikKvistad"/> The [[lobes of the brain]] most likely to be injured are the frontal and temporal lobes.<ref name="boon">Boon R. and de Montfor G.J. 2002. [http://web.archive.org/web/20060903021119/http://home.iprimus.com.au/rboon/BrainInjury.htm Brain injury]. Learning Discoveries Psychological Services. Retrieved through web archive on [[2008-01-17]].<!--♦♦♦sketchy web ref♦♦♦--></ref> Other common locations for DAI include the white matter in the [[cerebral cortex]], the [[corpus callosum]], the superior [[cerebral peduncle]]s,<ref name="SmithGreenwald"/> [[basal ganglia]], [[thalamus]], and deep [[hemispheric nuclei]].<ref name="singh">Singh J and Stock A (September 25, 2006). [http://www.emedicine.com/ped/topic929.htm Head Trauma]. Emedicine.com. Retrieved on [[2008-01-17]].</ref> These areas may be more easily damaged because of the difference in density between them and the rest of the brain.<ref name="singh"/> === 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 cascade]]s, 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.<ref name="Wolf"/><ref name="Arundine">Arundine M., Aarts M., Lau A., and Tymianski M. (2004). [http://www.jneurosci.org/cgi/content/full/24/37/8106 Vulnerability of central neurons to secondary insults after in vitro mechanical stretch]. ''Journal of Neuroscience'' '''24''' (37): 8106—8123. PMID 15371512. <!--♦♦♦primary♦♦♦--></ref> Axons are not typically torn at the time of injury; rather they usually become separated hours or days after the injury.<ref name="VikKvistad"> {{ cite journal |author=Vik A, Kvistad KA, Skandsen T, Ingebrigtsen T |title=Diffuse axonal injury in traumatic brain injury |language=Norwegian |journal=Tidsskrift for den Norske Laegeforening |volume=126 |issue=22 |pages=2940–2944 |year=2006 |pmid=17117192 |doi= }} </ref> 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 [[proteolysis|proteolytic]] degradation of the [[cytoskeleton]].<ref name="Iwata"/> It also opens [[sodium channel]]s in the [[axolemma]], which causes voltage-gated calcium channels to open and Ca<sup>2+</sup> to flow into the cell.<ref name="Iwata"/> The intracellular presence of Ca<sup>2+</sup> unleashes several different pathways, including activating [[phospholipase]]s and proteolytic [[enzymes]], damaging [[mitochondria]] and the cytoskeleton, and activating [[secondary messenger]]s, which can lead to separation of the axon and death of the cell.<ref name="Wolf"/> ===Cytoskeleton disruption=== Axons are normally elastic, but when rapidly stretched they become brittle, and the axonal [[cytoskeleton]] can be broken. It is thought that [[integrin]]s 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.<ref name="Ochs">Ochs S., Pourmand R., and Jersild R.A. Jr. (1996). Origin of beading constrictions at the axolemma: Presence in unmyelinated axons and after beta, beta′-iminodipropionitrile degradation of the cytoskeleton. ''Neuroscience''. '''70''' (4): 1081—1096. PMID 8848169.<!--♦♦♦primary♦♦♦--></ref> 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.{{fact|date=January 2008}} 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.<ref name="Smith"/> This bulb is called a [[retraction ball]], the hallmark of diffuse axonal injury.<ref name="Wasserman"/> 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.<ref name="Lopachin">LoPachin R.M. and Lehning E.J. (1997). Mechanism of calcium entry during axon injury and degeneration. ''Toxicology and Applied Pharmacology''. '''143''' (2): 233—244. PMID 9144441.<!--♦♦♦primary? check♦♦♦--> </ref> The axolemma disintegrates,<ref name="Lopachin"/> 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),<ref name="Cowie">Cowie R.J. and Stanton G.B. (2005). [http://www.med.howard.edu/anatomy/gas/wk12/Lect.%2037_Axoplasmic%20Flow,%20injury.htm Axoplasmic transport and neuronal responses to injury]. Howard University College of Medicine. Retrieved on [[2008-01-17]]. <!--♦♦♦web♦♦♦--></ref> and nearby cells begin [[phagocytosis|phagocytic]] activity, engulfing debris.<ref>Hughes P.M., Wells G.M.A., Perry V.H., Brown M.C., and Miller K.M. (2002). Comparison of matrix metalloproteinase expression during wallerian degeneration in the central and peripheral nervous systems. ''Neuroscience''. '''113''' (2): 273—287. PMID 12127085.<!--♦♦♦primary? check♦♦♦--></ref> ===Calcium influx=== While sometimes only the cytoskeleton is disturbed, frequently disruption of the [[axolemma]] occurs as well, causing the influx of [[calcium|Ca<sup>2+</sup>]] into the cell and unleashing a variety of degrading processes.<ref name="Lopachin"/><ref name="Povlishock">Povlishock J.T. and Pettus E.H. (1996). Traumatically induced axonal damage: Evidence for enduring changes in axolemmal permeability with associated cytoskeletal change. ''Acta Neurochirurgica''. '''66''': 81—86. PMID 8780803.<!--♦♦♦primary♦♦♦--></ref> An increase in Ca<sup>2+</sup> and [[sodium|Na<sup>+</sup>]] levels and a drop in [[potassium|K<sup>+</sup>]] levels is found within the axon directly after injury.<ref name="Wolf"/><ref name="Lopachin"/> Possible routes of Ca<sup>2+</sup> entry include [[sodium ion channel|sodium channel]]s, [[membrane pore|pore]]s torn in the membrane during stretch, and failure of [[ATP-dependent transporter]]s due to mechanical blockage or lack of energy.<ref name="Wolf"/> High levels of intracellular Ca<sup>2+</sup>, the major cause of post-injury cell damage,<ref name="zhou">Zhou F., Xiang Z., Feng W.X., and Zhen L.X. (2001). Neuronal free Ca<sup>2+</sup> and BBB permeability and ultrastructure in head injury with secondary insult. ''Journal of Clinical Neuroscience''. '''8''' (6): 561—563. PMID 11683606.<!--♦♦♦primary? check♦♦♦--></ref> destroy mitochondria,<ref name="Smith"/> contribute to the generation of [[reactive oxygen species]]<ref name="Arundine"/> and trigger [[phospholipase]]s and proteolytic [[enzyme]]s that damage Na+ channels and degrade or alter the cytoskeleton and the [[axoplasm]].<ref name="Castillo">Castillo M.R. and Babson J.R. (1998). Ca<sup>2+</sup>-dependent mechanisms of cell injury in cultured cortical neurons. ''Neuroscience''. '''86''' (4): 1133—1144. PMID 9697120.<!--♦♦♦primary? check♦♦♦--></ref><ref name="Lopachin"/> Excess Ca<sup>2+</sup> can also lead to damage to the [[blood brain barrier]] and swelling of the brain.<ref name="zhou"/> One of the [[protein]]s activated by the presence of [[calcium]] in the cell is [[calpain]], a Ca<sup>2+</sup>-dependent non-[[lysosome|lysosomal]] [[protease]].<ref name="Castillo"/> About 15 minutes to half an hour after the onset of injury, a process called calpain-mediated spectrin proteolysis, or CMSP, begins to occur.<ref name="Büki">Büki A, Okonkwo D.O., Wang K.K.W., and Povlishock J.T. (2000). [http://www.jneurosci.org/cgi/content/full/20/8/2825 Cytochrome ''c'' release and caspase activation in traumatic axonal injury]. ''Journal of Neuroscience''. '''20''' (8): 2825—2834. PMID 10751434. <!--♦♦♦primary? check♦♦♦--></ref> Calpain breaks down a molecule called [[spectrin]], which holds the membrane onto the cytoskeleton, causing the formation of [[bleb]]s and the breakdown of the cytoskeleton and the membrane, and ultimately the death of the cell.<ref name="Büki"/><ref name="Castillo"/> Other molecules that can be degraded by calpains are [[microtubule]] subunits, [[microtubule-associated protein]]s, and [[neurofilament]]s.<ref name="Castillo"/> 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".<ref name="Büki"/> [[Mitochondria]], [[dendrite]]s, 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.<ref name="Corbo">Corbo J. and Tripathi P. 2004. Delayed presentation of diffuse axonal injury: A case report. ''Trauma''. '''44''' (1): 57–60. PMID 15226709. <!--♦♦♦primary♦♦♦--></ref> After the injury, [[astrocyte]]s can shrink, causing parts of the [[brain]] to atrophy.<ref name="Wasserman"/> ==Diagnosis and treatment== DAI is difficult to detect since it does not show up well on [[CT scan]]s or with other macroscopic imaging techniques, though it shows up microscopically.<ref name="Wasserman"/> However, there are characteristics typical of DAI that may or may not show up on a CT scan.<ref name="VikKvistad"/> Since axonal damage in DAI is largely a result of secondary [[biochemical cascade]]s, 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]].<ref name="Wasserman"/> [[MRI]] is more sensitive than CT scans,<ref name="VikKvistad"/> but MRI may also miss DAI, because it identifies the injury using signs of [[edema]], which may not be present.<ref name="Corbo"/> 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.<ref name="Bigler">Bigler, E.D. 2000. [http://web.archive.org/web/20041205062946/http://psych.byu.edu/work/tbi.pdf The Lesion(s) in Traumatic brain injury: Implications for clinical neuropsychology]. Retrieved through web archive on [[2008-01-17]].</ref> 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). ==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.<ref name="Pearce"> {{ cite journal |author=Pearce JM |title=Observations on concussion. A review |journal=European Neurology |volume=59 |issue=3-4 |pages=113–119 |year=2007 |pmid=18057896 |doi=10.1159/000111872 |url=http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=000111872 }} </ref> Strich first proposed the idea in 1956, calling it ''diffuse degeneration of white matter''.<ref name="Gennarelli04"> {{ cite book |author=Gennarelli GA, Graham DI |chapter=Neuropathology |editor= Silver JM, McAllister TW, Yudofsky SC |title=Textbook Of Traumatic Brain Injury |publisher=American Psychiatric Association |location=Washington, DC |year=2005 |pages= 34 | isbn=1-58562-105-6 |oclc= |doi= |accessdate=2008-06-10 |url = http://books.google.com/books?id=3CuM6MviwMAC&pg=PA47&dq=neurotrauma&lr=&client=firefox-a&sig=7kXGu4v_cHPiZRFPwo2j7uIT-og#PPA27,M1 }} </ref> Strich was researching the relationship between dementia and head trauma<ref name="Pearce"/> and asserted in 1956 that DAI played an integral role in the eventual development of dementia due to head trauma.<ref name="Hardman02"> {{ cite journal |author=Hardman JM, Manoukian A |title=Pathology of head trauma |journal=Neuroimaging Clinics of North America |volume=12 |issue=2 |pages=175–187, vii |year=2002 |pmid=12391630 |doi=10.1016/S1052-5149(02)00009-6 }} </ref> The term DAI was introduced in the early 1980s.<ref name="Granacher07"> {{ cite book |author=Granacher RP |title=Traumatic Brain Injury: Methods for Clinical & Forensic Neuropsychiatric Assessment, Second Edition |publisher=CRC |location=Boca Raton |year=2007 |pages= 26–32|isbn=0-8493-8138-X |oclc= |doi= |accessdate=2008-07-06 |url= http://books.google.com/books?id=xt1YFydzXKQC&pg=PA32&lpg=PA32&dq=focal+diffuse+brain+injury+&source=web&ots=w7wP6GHZlC&sig=QTuqyJSaHrbwZvlVFClvDtEpEQk&hl=en&sa=X&oi=book_result&resnum=9&ct=result#PPA26,M1 }} </ref> ==See also== * [[Brain injury]] * [[Axoplasmic transport]] == References == {{reflist|2}} == External links == * [http://rad.usuhs.edu/medpix/medpix.html?mode=image_finder&action=search&srchstr=axonal%20injury&srch_type=all&details=-1#top Diffuse Axonal Injury] MRI and CT Images {{Neurotrauma}} {{Injuries, other than fractures, dislocations, sprains and strains}} [[Category:Neurotrauma]] [[nl:Diffuse axonale beschadiging]] [[no:Diffus axonal skade]]