Diffuse Axonal Injury

Etiology

DAI results from rapid rotational or translational head movements that place shear strain on white-matter tracts. These movements tear axons and small vessels at gray-white interfaces and within the corpus callosum and brainstem. Angular acceleration during high-speed deceleration is the principal inciting force. DAI arises when inertial forces act on the brain so rapidly that tissue deformation exceeds axonal tolerance. Angular or rotational acceleration in the coronal plane is the most efficient mechanism to cause this injury; translational forces alone produce DAI less reliably.[3] 

Longer deceleration pulses stretch axons, while shorter, sharper pulses more often tear bridging veins than white matter.[2] Situations that deliver these loads include high-speed vehicle collisions, falls from height, and blows that produce rapid deceleration without skull fracture.[4] DAI clusters in young adults because they experience the highest exposure to vehicular and occupational acceleration injuries.[5] Alcohol or sedative use indirectly contributes by increasing risk-taking behaviors that precipitate high-energy acceleration events. 

Epidemiology

DAI is one of the most frequent diffuse lesions after TBI and carries a major public health impact. A 2025 systematic review found that 60% of patients with severe TBI have DAI; these severe TBI and DAI patients have a 16% mortality.[6]

DAI shows a marked male predominance. In the same meta-analysis, men accounted for 81% of severe TBI patients with confirmed DAI, a pattern thought to stem from higher exposure to road traffic and occupational hazards. National registry data echo this trend. In the Israeli National Trauma Registry of blunt-trauma patients with DAI, 77% were male.[7] The same study showed that 24% of recorded DAI cases occurred in individuals younger than 15 years, with the remaining 76% in older patients. Age also modulates outcome as pediatric victims experience lower mortality, 13% versus 18% in adults, despite comparable injury mechanisms and radiologic patterns. The better outcome in pediatric patients might be due to the greater neuroplasticity that occurs during development. 

Road traffic collisions account for the majority of DAI across all age groups, reaching 80% among adults and 71% among children in the Israeli registry. Falls emerge as the second leading cause.

Pathophysiology

In DAI, the acceleration forces cause a rapid stretch of the axons. This rapid stretch initially disrupts microtubules, the stiffest axonal elements, and produces focal breaks known as primary axotomy.[4] Complete primary axotomy is uncommon; more often, axons sustain partial damage that impairs axoplasmic flow without immediate transection.[5] Transport failure causes intra-axonal accumulation of β-amyloid precursor protein within 2 to 3 hours, which is a sensitive histological marker.[2]

Mechanical membrane pores and dysregulation of sodium channels raise intracellular calcium levels. Calcium activates calpains that proteolyze spectrin and other cytoskeletal proteins. Mitochondrial permeability changes follow, depleting ATP and releasing pro-apoptotic factors that amplify cytoskeletal collapse and cause a delayed axotomy, known as secondary axotomy. Secondary axotomy involves inflammatory and apoptotic processes, and opportunities for therapeutic interventions to halt these processes may exist.

DAI affects numerous functional areas of the brain. Widespread disconnection of cortical and subcortical networks depresses consciousness. Greater brain-stem involvement lengthens coma and worsens outcome. The Adams classification [5] of DAI was built upon the primate DAI classification by Gennarelli [3] and recognizes the following 3 DAI grades:

• Grade 1: This grade is characterized solely by microscopic evidence of axonal damage in the cerebral white matter, most notably within the hemispheres and the corpus callosum, with occasional involvement of the brain stem and cerebellum.
• Grade 2: The histological findings of grade 1 are included in grade 2, with the addition of a discrete focal lesion in the corpus callosum.
• Grade 3: This grade includes grade 2 findings and adds additional focal lesions in the dorsolateral region of the rostral brain stem. When these brain-stem lesions are visible on gross examination, the injury is considered a severe grade 3.

More recent neuropathological criteria [2] require that axonal injury be multifocal and involve both supratentorial and infratentorial regions. Moreover, the pattern and distribution of damaged axons must be indicative of trauma.

Histopathology

DAI produces a pattern of histopathological lesions. Focal hemorrhages frequently appear in the corpus callosum, most often within the splenium or genu, and in the dorsolateral rostral brainstem. These foci may evolve from punctate hemorrhage to granular scars or cysts with time. Microscopically, the white matter of the hemispheres, brainstem, and occasionally cerebellum shows axonal bulbs created by sheared axons.

In short survivors, the bulbs predominate, in intermediate survivors, microglial clusters surround the damaged fibers, and in long survivors, Wallerian degeneration becomes conspicuous.[5] Routine hematoxylin–eosin staining detects these changes only after about 24 hours. Silver impregnation shortens this window to 12 to 18 hours, but immunostaining for β-amyloid precursor protein (β-APP) reveals injured axons within 2 to 3 hours and is regarded as the most sensitive method. β-APP immunostaining can distinguish traumatic from hypoxic axonopathy.[2]

History and Physical

Clinical Presentation

DAI is fundamentally a clinical diagnosis that is typically suspected whenever a patient sustains a high-energy, rotational-acceleration head trauma and remains comatose (GCS ≤8) for longer than 6 hours without a lucid interval, and without a mass lesion or midline shift on imaging. DAI is very unlikely to happen in falls from the patient's height. The deceleration in this case is not sufficient to cause DAI, but might lead to other types of TBI, eg, subdural hematomas and skull fractures. A lucid interval can occur in DAI, but its likelihood diminishes as histopathologic grade increases. In fact, Adams and colleagues reported that none of the patients with severe, macroscopically evident DAI exhibited a lucid interval.[5]

The clinical presentation of patients with DAI is related to the severity of the disorder. In milder cases, patients resemble concussion sufferers: they briefly lose consciousness or experience transient confusion and develop headache, dizziness, nausea, vomiting, and fatigue. By contrast, more extensive axonal shearing manifests as immediate, prolonged coma, with some individuals never recovering higher cortical function and entering a persistent vegetative state.

Physical Examination

On initial neurological examination, the GCS score reflects injury severity: scores of 13 to 15 indicate a mild injury, 9 to 12 indicate a moderate injury, and ≤ 8 indicate a severe DAI. In an ICU case series of DAI patients, 83.6% of patients had a GCS score of 3 to 8, 12.9% had a GCS score of 9 to 12, and 3.5% had a GCS score of 13 to 15. Pupillary abnormalities were frequent, including anisocoria in 33.9% of cases, bilateral mydriasis in 5.6%, bilateral miosis in 7% and other irregularities in 4%.

Approximately 4% of patients developed generalized seizures within the first 24 hours; when electroencephalography was performed in 45% of the patients and revealed diffuse cerebral dysfunction in almost all patients and subtle status epilepticus in 21% of those tested. Dysautonomia occurred in 24% of patients during the first day, while focal motor deficits were uncommon, observed in only 3% of cases.[8] 

Dysautonomic manifestations commonly include findings of tachycardia, tachypnea, diaphoresis, hyperthermia, abnormal muscle tone, and posturing. The combination of dysautonomic signs can vary. Hemiplegia is a rare deficit in DAI.[9] DAI can present with a delayed decrease in GCS (within 6 hours), even in patients who initially present with a GCS of 15.[10]

Evaluation

In general, DAI is a form of TBI that is usually severe.[11] Therefore, the implementation of an advanced trauma life support protocol is a standard of care for all head-injured patients. 

A definitive diagnosis of DAI can be made through postmortem pathological examination of brain tissue. However, in clinical practice, a diagnosis of DAI 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 of having DAI. Generally, DAI is diagnosed after a TBI with a GCS <8 for more than 6 consecutive hours.

Computed Tomography Imaging

Noncontrast computed tomography (CT) serves as the first-line imaging modality for TBI patients with reduced consciousness. CT can reveal direct signs of DAI, eg, punctate hemorrhages, and indirect markers, including intraventricular or perimesencephalic bleeding. DAI lesions can be hemorrhagic, nonhemorrhagic, or a combination of both. CT has limited sensitivity for nonhemorrhagic and small axonal lesions. Overall, CT scans of the head have a low yield in detecting DAI-related injuries.[12] 

CT suggests the diagnosis of DAI when small, nonexpansile hemorrhagic lesions are visible at the gray–white matter junction, when blood is present in the intraventricular spaces, or when diffuse cerebral edema is present. A systematic review showed that in a patient with a closed TBI whose early CT shows no traumatic subarachnoid or intraventricular hemorrhage, severe DAI is unlikely. The presence of intraventricular blood, however, indicates a more severe DAI with a less favorable prognosis. Prognosis also worsens as the number of affected ventricles increases. Moreover, blood within the interpeduncular cistern strongly suggests severe DAI, corresponding to grade II or III.[13]

Concurrent primary traumatic lesions often coexist with DAI on CT. In one series of DAI patients admitted to the intensive care unit (ICU), skull fractures were seen in 39% of cases, subarachnoid hemorrhage in 67%, intraventricular hemorrhage in 34%, cerebral contusions in 46%, cerebral edema in 31%, subdural hematomas in 25%, extradural hematomas in 12.9% and pneumocephalus in 8.9%.[8]

Magnetic Resonance Imaging 

Magnetic resonance imaging (MRI) provides superior detection and characterization of DAI. FLAIR and T2-weighted sequences are effective in detecting subcortical and posterior fossa lesions. Gradient-recalled echo (GRE) MRI will enhance the detection of DAI. Susceptibility-weighted imaging (SWI) is considered the most sensitive method for visualizing the small hemorrhagic foci of DAI, outperforming GRE for early lesion detection. Likewise, diffusion-weighted imaging (DWI) identifies cytotoxic edema early on, and diffusion-tensor imaging (DTI) can quantify white-matter tract disruption (reduced fractional anisotropy), changes that correlate with discharge functional scores. Whenever the patient’s condition allows, an MRI protocol that includes SWI, DWI, DTI, and FLAIR/T2 sequences should be obtained to maximize diagnostic yield and aid in prognostication.[4]

Gentry [14] adjusted the Adams classification to classify DAI on MRI into the following 3 stages:

• Stage I: Visible lesions confined to the lobar white matter
• Stage II: Involvement of the corpus callosum
• Stage III: Involvement of the brainstem

Abu Hamdeh et al proposed an extended MRI classification system for DAI that builds on the traditional Adams and Gentry grades by adding a grade 4 and incorporating both lesion location and patient age. In this scheme, DAI is divided into the following 4 stages:

• Stage I: Visible lesions confined to the lobar white matter
• Stage II: Involvement of the corpus callosum
• Stage III: Involvement of the brainstem
• Stage IV: Lesions in the substantia nigra or mesencephalic tegmentum

Each stage is further subdivided by age (younger than 30 years versus 30 years or older) to reflect the independent prognostic impact of older age on outcome. MRI sequences sensitive to hemorrhage (T2, GRE, SWI) and diffusion (DWI) are used to identify and stage lesions within these regions.[15]

Notably, DAI should be strongly considered in patients who 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.

Emerging Modalities

Multidimensional MRI captures a combined T1- to T2-diffusion signal that highlights tiny axonal injuries invisible to routine scans and appears promising in the DAI diagnosis.[16]

CT radiomics, combined with machine learning, analyzes texture and shape features from routine head CT scans. A trained algorithm detected DAI with accuracies comparable to expert neuroradiologists and could serve as an artificial intelligence-based screening test for DAI.[17]

Emerging molecular biomarkers show promise as noninvasive adjuncts to imaging. Although no serum or cerebrospinal fluid test has yet reached routine clinical use, a growing panel of axonal injury markers has been identified. The markers that have been explored include β-amyloid precursor protein (β-APP), neurofilament proteins, neuron-specific enolase, S-100β, myelin basic protein, and tau species. While these assays remain investigational, they may soon complement imaging, particularly in settings where MRI is delayed or inconclusive.[18]

Treatment / Management

Diffuse Axonal Injury Management

Treatment of patients with DAI is primarily geared toward the prevention of secondary injuries and facilitating rehabilitation, as secondary injuries appear to 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, following TBI management guidelines.[19]

Initial treatment priority in TBI is focused on resuscitation. In a non-neurotrauma center, trauma surgeons and emergency physicians may perform initial resuscitation and neurologic treatment to stabilize and transport the patient to a designated neurotrauma center as expeditiously as possible. ICP monitoring is indicated in patients with a GCS of <8 after consultation with the neurosurgery team.

Other considerations for ICP monitoring include patients who cannot have continual neurologic evaluations. These are typically in patients receiving general anesthesia, opioid 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 7 days, anticonvulsant treatment can be used to prevent early posttraumatic seizures. No evidence has demonstrated that this will prevent long-term posttraumatic seizures, however. 

In an ICU DAI case series, the management of DAI was entirely supportive, focusing on the prevention of secondary insults. Sedation with a midazolam–fentanyl infusion, endotracheal intubation, and mechanical ventilation were required in 97% of patients for a mean duration of 16 ±16 days. Hemodynamic support included fluid resuscitation in 58% and catecholamine infusion in 31%, with a mean arterial pressure maintained above 70 mm Hg. Osmotherapy with mannitol was administered in 54% of cases to treat cerebral edema, and blood transfusion was needed in 66%. Urgent neurosurgical intervention for concurrent mass lesions was performed in 27% of patients.[8](B3)

Autonomic dysregulation can complicate DAI. In a case series of dysautonomia in DAI, half of the patients required pharmacological treatment, most commonly opioids, benzodiazepines, β-blockers, baclofen, and clonidine. Hyperthermia was treated using external cooling blankets.[20]

Overall, the primary goal of treating patients with DAI is to provide supportive care and prevent secondary injuries. 

Investigational Treatments Targeting Secondary Axotomy

Secondary axotomy represents an inflammatory-apoptotic process triggered by cytoskeletal disruption and calcium overload. Preclinical studies have identified several agents that may blunt this cascade. Calcium-channel blockade with nimodipine and calcineurin inhibition by ciclosporin A both attenuate β-APP accumulation, preserve mitochondrial integrity, and reduce axonal swelling. Calpain inhibitors provide variable protection, while FK506 (tacrolimus) significantly limits cytoskeletal damage and, when combined with controlled hypothermia, may extend the therapeutic window. More recent agents, eg, SN-6 (NCX1 blocker) and dynasore (Drp1/dynamin inhibitor), mitigate stretch-induced varicosities, mitochondrial degradation, and oxidative injury, and microtubule stabilizers (eg, paclitaxel or Epothilone D) have been shown to forestall secondary depolymerization and swelling. However, blood–brain barrier penetration remains a challenge.[4](B3)

Differential Diagnosis

Differential diagnoses that should also be considered when evaluating DAI include:

• Hematoma: Subdural, epidural, or intraparenchymal hematomas, cerebral contusions, and petechial hemorrhages may produce coma and punctate lesions on CT or MRI. A careful review of CT/MRI and serial imaging helps distinguish evolving mass lesions from true shearing injuries.

• Hypoxic injury: Global hypoxia often yields more diffuse cortical and deep gray matter signal changes on diffusion-weighted MRI than the focal white matter and corpus callosum lesions characteristic of DAI.

• Fat embolism syndrome
  • In polytrauma with long-bone fractures, fat emboli produce multiple scattered microbleeds on T2 or susceptibility-weighted imaging; however, clinical features (eg, rash and pulmonary dysfunction) and the timing postinjury aid in differentiation.
  • In fat embolism, the cerebral edema is more extensive, and the microhemorrhages are smaller but more numerous.[21]

• Subarachnoid hemorrhage
  • Although tSAH and DAI arise from distinct mechanisms (cortical vessel tears versus shear-induced axonal disruption), they are not mutually exclusive. Each can occur in isolation, or they can coexist.
  • Patients with tSAH are commonly found in the setting of DAI. Conversely, when tSAH is confined to the midline interhemispheric fissure or peri-mesencephalic cisterns, this significantly increases the likelihood of concomitant severe DAI.[13]

• Ischemic and hemorrhagic cerebrovascular accident

• Concussion/postconcussive syndrome
  • Distinguishing DAI from concussion remains challenging, in part because the traditional 6-hour loss-of-consciousness (LOC) threshold lacks strong empirical support, and axonal lesions have been documented in patients with shorter LOC intervals.
  • Clinically, concussion is defined by transient symptoms (eg, headache, confusion, brief LOC of <6 hours) without radiographic abnormalities, whereas DAI is presumed when LOC exceeds 6 hours and is supported by white-matter lesions on imaging.
  • However, conventional MRI detects fewer than half of DAI lesions, many of which are microscopic or nonhemorrhagic and therefore occult on routine scans. DTI) and tractography significantly improve sensitivity by revealing microstructural disruptions in the corpus callosum, brainstem, and significant fiber tracts, but these findings may also occur in so-called “mild” TBI injuries.
  • Neither LOC duration nor standard MRI alone reliably separates concussion from DAI; integration of prolonged neurologic dysfunction, advanced diffusion imaging, and careful exclusion of confounders (sedation effects, prior injuries) is essential for accurate diagnosis.[22] However, clinicians should be aware that, for clinical purposes, the 2 conditions can overlap, and attempting to distinguish them does not currently have clinical significance.
• Hypoglycemia

Prognosis

Prognosis in DAI depends on injury severity, lesion location, and the presence of secondary insults. In a case series involving ICU patients with DAI, the mortality rate reached 42%.[8]

The likelihood of an unfavorable outcome increases with higher DAI grade: 17% in grade 1, 40% in grade 2, and 63% in grade 3.[23] Several prognostic factors have been identified, including patient age, pupillary reactivity, hemoglobin levels, coma duration, Marshall classification, autonomic dysregulation, hypotension, hypoxia, hyperglycemia, and the Injury Severity Score.[24][25]

Lesions involving the substantia nigra, mesencephalic tegmentum, genu of the corpus callosum, and nuclei within the ascending arousal network are linked to significantly poorer outcomes.[15][26][27] The neuron-specific enolase level-to-GCS score ratio, known as the NGR, also provides prognostic value. A continuous decline in the NGR over the first 5 days postinjury correlated with favorable outcomes, achieving an area under the curve (AUC) of 0.934 in a 2025 study.[28]

Pediatric DAI demonstrates substantial in-hospital mortality, estimated at 20.3%, with the highest rates observed in children aged 0 to 3 years. Independent mortality predictors in pediatric patients include severe TBI (ED GCS 3–8), systolic blood pressure under 90 mm Hg, and coma lasting longer than 24 hours. Interestingly, DAI grade 3 did not correlate with worse outcomes in the pediatric population.[29]

Complications

DAI is frequently complicated by a cascade of systemic, neurological, and autonomic derangements that exacerbate secondary brain injury and worsen outcomes. In a ICU DAI case series, 97% of DAI patients were reported to have developed at least 1 systemic insult within 24 hours of injury, most commonly coagulopathy (68%), hyperthermia (59%), hypotension (37%), hypoxia (16%), hyperglycemia (17%), and electrolyte disturbances (hyponatremia in 6.5 %).[8]

Clinically significant autonomic dysregulation is frequently encountered in DAI patients with features, eg, unexplained hypertension, tachycardia, diaphoresis, or posturing. Autonomic dysregulation predicts more extended ICU/hospital stays and higher rates of unfavorable functional recovery.[20]

An often-overlooked complication of DAI is the process of secondary axotomy, in which inflammatory and apoptotic cascades continue to sever axons hours to days after the initial insult. Although no targeted therapies currently exist to halt this delayed axonal loss, rigorous supportive management can limit its deleterious effects. Supportive care includes optimizing cerebral perfusion pressure, maintaining normoxia and normoglycemia, and preventing secondary insults (eg, fever and hypotension). In this sense, unrestrained secondary axotomy itself functions as a complication, underscoring the critical role of intensive neurocritical care in improving overall outcome.