Diffuse axonal injury (DAI) is a type of traumatic brain injury (TBI) that results from a blunt injury to the brain . In the United States, traumatic brain injury is a leading cause of death and disability among children and young adults. The Center for Disease Control and Prevention (CDC) estimates that there are over 1.5 million reported cases of traumatic brain injury every year in the United States. Traumatic brain injury is classified as mild, moderate, and severe based on Glasgow Coma Scale (GCS). Traumatic brain injury patients with GCS of 13 to 15 are classified to be mild, which includes the majority of traumatic brain injury patients. Patients with a GCS of nine to 12 are considered to have a moderate traumatic brain injury, while patients with GCS below eight are classified as having a severe traumatic brain injury.
The GCS measures the following three functions:
Diffuse axonal injury (DAI) primarily affects the white matter tracts in the brain. Clinically, patients with DAI can present in a spectrum of neurological dysfunction. This can range from clinically insignificant to a comatose state. However, most patients with DAI are identified to be severe and commonly have a GCS <8. A diffuse axonal injury is a clinical diagnosis.
The most common etiology of diffuse axonal injury involves high-speed motor vehicle accident. The most common mechanism involves an accelerating and decelerating motion that leads to shearing forces to the white matter tracts of the brain. This leads to microscopic and gross damage to the axons in the brain at the junction of the gray and white matter. Diffuse axonal injury commonly affects white matter tracts involved in the corpus callosum and brainstem. Interestingly, there is no association between diffuse axonal injury and underlying skull fractures.
The true incidence of DAI is unknown. However, it is estimated that roughly 10% of all TBI admitted to the hospital will have some degree of DAI. Of the patients with DIA, it is estimated roughly 25% will result in death. This statistic may be underestimated as patients with subdural hematomas, epidural hematomas, and other forms of TBI will not carry a true diagnosis of DAI. Postmortem studies have shown that patients with severe TBI have a significant incidence of diffuse axonal injury.
The primary insults of diffuse axonal injury lead to disconnection or malfunction of neurons interconnection . This affects numerous functional areas of the brain. Usually, patients with diffuse axonal injury present with bilateral neurological examination deficits frequently affecting the frontal and temporal white matter, corpus callosum, and brainstem. The Adams classification of diffuse axonal injury utilizes pathophysiological lesions in the white matter tracts and clinical presentation.
The Adams Diffuse Axonal Injury Classification:
Axonal portions of neurons have a mechanical disruption of cytoskeletons resulting in proteolysis, swelling, and other microscopic and molecular changes to the neuronal structure.
DAI is a clinical diagnosis. Typically, DAI is considered in patients with a GCS <8 for over six hours. The clinical presentation of patients with diffuse axonal injury relates to the severity of a diffuse axonal injury. For example, mild diffuse axonal injury patients present with signs and symptoms that reflect a concussive disorder. These symptoms most commonly include a headache. The other post-concussive symptoms can include dizziness, nausea, vomiting, and fatigue. However, patients with a severe diffuse axonal injury may also present with a loss of consciousness and remain in a persistent vegetative state. A very small number of those patients with severe diffuse axonal injury will regain consciousness in the first year after the injury.
Other common neurological manifestations include dysautonomia. Dysautonomic symptoms commonly include tachycardia, tachypnea, diaphoresis, vasoplegia, hyperthermia, abnormal muscle tone, and posturing.
In general, diffuse axonal injury is a severe form of traumatic brain injury . Therefore, implementation of an advanced trauma life support protocol is a standard of care for all head injured patients.
Definitive diagnosis of diffuse axonal injury can be made in postmortem pathologic examination of brain tissue. However, in clinical practice, a diagnosis of diffuse axonal injury is made by implementing clinical information and radiographic findings. Understanding the mechanism of head injury facilitates a differential diagnosis of DAI. Patients who experience rotational or acceleration-deceleration closed head injury should be suspected to have DAI. Generally, DAI is diagnosed after a traumatic brain injury with GCS <8 for more than six consecutive hours.
Radiographically, computed tomography (CT) head findings of small punctate hemorrhages to white matter tracts can indicate diffuse axonal injury in the setting of an appropriate clinical presentation. Overall, CT head has a low yield in detecting diffuse axonal injury related injuries. Currently, magnetic resonance imaging (MRI), specifically Diffuse Tensor Imaging (DTI), is the imaging modality of choice for diagnosis of diffuse axonal injury. A recent report suggests that acute gradient-recalled echo (GRD) MRI will enhance the detection of axonal injury in grade 3 diffuse axonal injury patients, suggesting that it is most likely a better diagnostic tool.
It should be of note that DAI should be strongly considered in patients that fail to improve after receiving surgical evacuation of subdural or epidural hematomas. Conversely, if patients drastically improve after surgical evacuation of a subdural or epidural hematoma DAI may not be present.
Currently, there are no laboratory tests for the diagnosis of DAI . However, there is current research on identifying molecular markers in the serum of traumatic brain injury patients to help aid the diagnosis of DAI.
Treatment of patients with diffuse axonal injury are geared toward prevention of secondary injuries and facilitating rehabilitation. It appears to be the secondary injuries that lead to increased mortality. These can include hypoxia with coexistent hypotension, edema, and intracranial hypertension. Therefore, prompt care to avoid hypotension, hypoxia, cerebral edema, and elevated intracranial pressure (ICP) is advised.
Initial treatment priority in traumatic brain injury is focused on resuscitation. In a non-neuro trauma center, trauma surgeons and emergency physicians may perform the initial resuscitation and neurologic treatment to stabilize and transport the patient to a designated neurotrauma center expeditiously. ICP monitoring is indicated in patients with GCS of less than 8 after consultation with neurosurgery. Other considerations for ICP monitoring include patients that cannot have continual neurologic evaluations. These are typically in patients receiving general anesthesia, narcotic analgesia, sedation, and prolonged paralysis for other injuries. Cerebral oxygen saturation monitoring can be used with ICP monitoring to assess the degree of oxygenation. Short-term, usually seven days, anticonvulsant treatment can be used to prevent early post-traumatic seizures. There is no evidence that this will prevent long-term post-traumatic seizures however. There is emerging evidence that progesterone treatment in acute traumatic brain injury may reduce morbidity and mortality. This cannot be routinely recommended at this time.
Overall, the goal of diffuse axonal injury patients' treatment is supportive care and prevention of secondary injuries.
Prognosis is considered to be poor in patients with severe DAI.
Postoperative care, if operative intervention is pursued, typically is aimed at reducing ICP and improving cerebral blood flow.
Patients and families should expect prolonged rehabilitative therapies after severe DAI. This can include physical, occupational, speech, and other psychosocial therapies.
Typically neurosurgery, neurology, trauma surgery, and intensive care can help guide therapies.
A diffuse axonal injury is a type of severe traumatic brain injury that affects patients and their families. Diffuse axonal injury patients have a range multiple neurological deficits that affect the physical and mental status of the patient. These changes usually compromise social reintegration, return to productivity, and quality of life of patients and their families. For most patients and families, the clinical status of diffuse axonal injury patients will continue to persist for a minimum of two years. Then, most patients and families will achieve and accept a new baseline. Recent, epidemiological studies indicate that the outcomes of diffuse axonal injury patients are associated with the number of lesions identified through imaging. There are emerging studies suggesting that during the acute phase of diffuse axonal injury, hypoxia, and hypotension are associated with increased mortality. Therefore, it is important to continue investigating the clinical, pathophysiological, and radiographic studies to advance the management of diffuse axonal injury patients.
Patients with DAI often have a severe brain injury and are best managed by a multidisciplinary team that includes a neurologist, ophthalmologist, physical and occupational therapist, speech therapist, intensivist, internist, ICU nurses, and a mental health nurse.  Diffuse axonal injury patients have a range of multiple neurological deficits that affect the physical and mental status of the patient. These changes usually compromise social reintegration, return to productivity, and quality of life of patients and their families. For most patients and families, the clinical status of diffuse axonal injury patients will continue to persist for a minimum of two years. 
The outcome for patients with DAI is generally poor. The recovery is long and complete recovery is usually not possible in cases of severe injury. For many, there is life long disability with a poor quality of life. (Level V)
|||Faul M,Coronado V, Epidemiology of traumatic brain injury. Handbook of clinical neurology. 2015; [PubMed PMID: 25702206]|
|||Traumatic Brain Injury-Related Emergency Department Visits, Hospitalizations, and Deaths - United States, 2007 and 2013., Taylor CA,Bell JM,Breiding MJ,Xu L,, Morbidity and mortality weekly report. Surveillance summaries (Washington, D.C. : 2002), 2017 Mar 17 [PubMed PMID: 28301451]|
|||Diffuse Axonal Injury: Epidemiology, Outcome and Associated Risk Factors., Vieira RC,Paiva WS,de Oliveira DV,Teixeira MJ,de Andrade AF,de Sousa RM,, Frontiers in neurology, 2016 [PubMed PMID: 27812349]|
|||Revisiting Grade 3 Diffuse Axonal Injury: Not All Brainstem Microbleeds are Prognostically Equal., Izzy S,Mazwi NL,Martinez S,Spencer CA,Klein JP,Parikh G,Glenn MB,Greenberg SM,Greer DM,Wu O,Edlow BL,, Neurocritical care, 2017 May 5 [PubMed PMID: 28477152]|
|||Traumatic axonal injury, a clinical-pathological correlation., Davceva N,Sivevski A,Basheska N,, Journal of forensic and legal medicine, 2017 May [PubMed PMID: 28437717]|
|||Post-acute brain injury urinary signature: a new resource for molecular diagnostics., Ottens AK,Stafflinger JE,Griffin HE,Kunz RD,Cifu DX,Niemeier JP,, Journal of neurotrauma, 2014 Apr 15 [PubMed PMID: 24372380]|
|||Celeghin A,Galetto V,Tamietto M,Zettin M, Emotion Recognition in Low-Spatial Frequencies Is Partly Preserved following Traumatic Brain Injury. BioMed research international. 2019; [PubMed PMID: 30809551]|
|||Iacono D,Lee P,Hallett M,Perl D, Possible Post-Traumatic Focal Dystonia Associated with Tau Pathology Localized to Putamen-Globus Pallidus. Movement disorders clinical practice. 2018 Sep-Oct; [PubMed PMID: 30637269]|
|||Hendricks HT,Heeren AH,Vos PE, Dysautonomia after severe traumatic brain injury. European journal of neurology. 2010 Sep; [PubMed PMID: 20298427]|
|||van Eijck MM,Schoonman GG,van der Naalt J,de Vries J,Roks G, Diffuse axonal injury after traumatic brain injury is a prognostic factor for functional outcome: a systematic review and meta-analysis. Brain injury. 2018; [PubMed PMID: 29381396]|
|||Weber MT,Arena JD,Xiao R,Wolf JA,Johnson VE, Clarity reveals a more protracted temporal course of axon swelling and disconnection than previously described following traumatic brain injury. Brain pathology (Zurich, Switzerland). 2018 Nov 16; [PubMed PMID: 30444552]|
|||Humble SS,Wilson LD,Wang L,Long DA,Smith MA,Siktberg JC,Mirhoseini MF,Bhatia A,Pruthi S,Day MA,Muehlschlegel S,Patel MB, Prognosis of diffuse axonal injury with traumatic brain injury. The journal of trauma and acute care surgery. 2018 Jul; [PubMed PMID: 29462087]|
|||Ma J,Zhang K,Wang Z,Chen G, Progress of Research on Diffuse Axonal Injury after Traumatic Brain Injury. Neural plasticity. 2016; [PubMed PMID: 28078144]|
|||Thomas TC,Colburn TA,Korp K,Khodadad A,Lifshitz J, Translational Considerations for Behavioral Impairment and Rehabilitation Strategies after Diffuse Traumatic Brain Injury 2015; [PubMed PMID: 26269926]|