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Brain injury

A brain injury, also known as acquired brain injury (ABI), refers to any damage to the brain that occurs after birth and is not due to congenital, degenerative, or perinatal conditions, resulting in disruptions to brain function that can affect cognition, movement, sensation, and behavior.^[1] These injuries are broadly classified into two categories: traumatic brain injury (TBI), which stems from external mechanical forces such as blows to the head, and non-traumatic brain injury, which arises from internal physiological disruptions like vascular events or infections.^[1] TBI specifically involves immediate primary damage from the impact and potential secondary damage from swelling, bleeding, or oxygen deprivation, while non-traumatic forms may develop more gradually.^[2] Common causes of brain injuries vary by type but frequently include falls, motor vehicle accidents, assaults, and sports-related impacts for TBI, accounting for the majority of cases in younger populations.^[2] Non-traumatic brain injuries often result from strokes, brain tumors, hypoxic events (such as drowning or cardiac arrest), infections like encephalitis, or toxic exposures including alcohol and drug abuse.^[1] Globally, there were approximately 21 million incident cases of TBI in 2021, making it a leading cause of disability and death, particularly among children, adolescents, and older adults.^[3] Symptoms of brain injury depend on the location, severity, and type but commonly include physical effects like headaches, nausea, seizures, and loss of consciousness; cognitive impairments such as memory loss, confusion, and difficulty concentrating; and behavioral or emotional changes including irritability, depression, or personality alterations.^[2] Mild injuries may resolve with rest, while severe cases can lead to coma, long-term disability, or fatality, with outcomes influenced by factors like age and prompt medical intervention.^[1] Diagnosis typically involves clinical assessments, such as the Glasgow Coma Scale for severity evaluation, alongside imaging techniques like CT scans or MRI to detect structural damage, and neuropsychological testing to gauge functional deficits.^[2] Treatment focuses on stabilization, symptom management, and rehabilitation; for acute cases, this may include surgery to reduce intracranial pressure or medications for seizures, followed by multidisciplinary therapy to address lasting impairments.^[1] Prevention strategies, including helmet use and fall-proofing environments, play a crucial role in reducing incidence, especially for TBI.^[2]

Introduction and Classification

Definition and Types

An acquired brain injury (ABI) refers to any damage to the brain tissue occurring after birth, resulting from external or internal forces and not due to congenital, degenerative, or perinatal conditions, which can lead to temporary or permanent impairments in cognitive, physical, sensory, or emotional functions.^[4] This damage disrupts normal brain activity and may affect overall neurological function, ranging from mild disruptions to severe, life-altering deficits.^[1] ABIs are broadly classified into two main categories: traumatic brain injury (TBI), caused by external mechanical forces such as impacts or penetrations, and non-traumatic brain injury, resulting from internal factors like reduced blood flow, infections, or other physiological disruptions.^[5] TBI is distinguished by its origin in sudden external trauma, while non-traumatic brain injury arises from non-mechanical events occurring after birth.^[6] Traumatic brain injury accounts for the majority of brain injury cases among young adults, often due to its association with accidents and violence.^[2] Subtypes of TBI include closed head injuries, where the skull remains intact and no external object penetrates the brain, and open (or penetrating) injuries, where the skull is breached, allowing direct damage to brain tissue.^[7] TBI can also be categorized as focal, involving localized damage to specific brain regions, or diffuse, affecting widespread areas such as through shearing forces that disrupt axons across the brain.^[8] For non-traumatic brain injuries, key subtypes encompass hypoxic-ischemic injuries from oxygen deprivation, infectious causes like meningitis or encephalitis, toxic or metabolic disorders from poisoning or electrolyte imbalances, and neoplastic injuries from brain tumors.^[9]^[1] Severity of brain injuries, particularly TBI, is often initially graded using the Glasgow Coma Scale (GCS), which assesses eye opening, verbal response, and motor response for a total score from 3 to 15.^[5] Mild injuries score 13-15, indicating brief alterations in consciousness; moderate injuries score 9-12, with more prolonged effects; and severe injuries score 3-8, associated with coma and high risk of long-term disability.^[8] This scale provides a standardized measure for acute assessment but does not predict long-term outcomes alone.^[10]

Traumatic vs. Non-Traumatic Brain Injury

Traumatic brain injury (TBI) is defined as an alteration in brain function or pathology caused by an external mechanical force, such as a bump, blow, jolt, or penetrating injury to the head or body.^[5] This force can lead to immediate mechanical damage through mechanisms like acceleration-deceleration forces, which produce coup-contrecoup injuries—contusions occurring both at the site of impact (coup) and on the opposite side of the brain (contrecoup) due to the brain's movement within the skull—or direct penetrating wounds that breach the skull and dura.^[11] Common examples of TBI include motor vehicle accidents, falls from heights, assaults, and sports-related concussions, which collectively account for the majority of cases.^[12] In contrast, non-traumatic brain injury results from internal physiological disruptions without any external physical force, often involving systemic or vascular insults that impair brain function over time.^[13] These injuries arise from events such as vascular disruptions like ischemic or hemorrhagic stroke, anoxia following cardiac arrest that deprives the brain of oxygen, or metabolic disturbances including severe hypoglycemia leading to neuronal damage.^[1]^[14]^[15] The key differences between traumatic and non-traumatic brain injuries lie in their onset and nature: TBI typically causes abrupt, focal mechanical disruption to brain tissue, while non-traumatic injuries involve more insidious, diffuse processes driven by oxygen deprivation, metabolic failure, or vascular compromise.^[16] Although both can result in overlapping secondary effects like cerebral edema, their pathophysiological implications diverge, with TBI prevention emphasizing external safety interventions (e.g., helmets, seatbelts) and non-traumatic management focusing on cardiovascular health and metabolic control.^[14] Severity classification for both types often relies on tools like the Glasgow Coma Scale to assess initial impairment.^[5]

Epidemiology

Incidence and Prevalence

Traumatic brain injury (TBI) is estimated to result in 20.8 million incident cases worldwide annually (as of 2021), representing a significant portion of all brain injuries.^[17] Non-traumatic brain injuries, such as ischemic or hemorrhagic strokes (approximately 12 million new cases each year globally as of 2021), add substantially to the overall burden.^[18]^[19] In the United States, prevalence data indicate that around 5.3 million people live with long-term disability attributable to prior TBI.^[12] The lifetime prevalence of mild TBI, often referred to as concussion, reaches up to 20% in the general adult population, based on self-reported surveys and health records analyzed by the Centers for Disease Control and Prevention (CDC).^[20] These figures highlight the enduring impact of brain injuries, with GBD studies estimating 37.9 million prevalent TBI cases worldwide in 2021.^[17] Epidemiological trends show a rising incidence of TBI in low- and middle-income countries, driven largely by road traffic accidents and limited preventive infrastructure.^[21] In contrast, high-income regions have experienced declines due to enhanced safety regulations, such as seatbelt laws and helmet mandates; for instance, age-adjusted TBI-related hospitalization rates in the US decreased by about 8% from 2006 to 2014.^[22] Globally, the GBD 2021 data reflect a 22.6% increase in TBI incident cases from 1990 to 2021, though age-standardized rates have stabilized in developed areas.^[23] Age-specific rates of TBI are highest among children aged 0-4 years and young adults aged 15-24 years, groups particularly vulnerable to falls and motor vehicle crashes, per CDC surveillance.^[24] These patterns are corroborated by WHO and GBD analyses, which emphasize the need for targeted interventions in pediatric and adolescent populations.^[25] Non-traumatic brain injuries show distinct epidemiological patterns; for example, strokes have increased 70% in incident cases since 1990, with over 7 million deaths annually (as of 2021), predominantly affecting older adults and low- to middle-income countries. Anoxic brain injuries from events like cardiac arrest or drowning contribute an estimated 1-2 million cases yearly, while infections such as encephalitis or meningitis add around 2.5 million global cases.^[19]^[26]

Risk Factors and Demographics

Traumatic brain injury (TBI) exhibits distinct demographic patterns, with males nearly twice as likely to be hospitalized for TBI compared to females, based on age-adjusted rates of 79.9 per 100,000 for males versus 43.7 for females. This disparity persists across age groups and is attributed to higher exposure to high-risk activities among males. Additionally, TBI incidence follows a bimodal age distribution, with peaks occurring among children and young adults (ages 15–24) due to activities like sports and motor vehicle incidents, and among the elderly (ages 65 and older) primarily from falls.^[24]^[27]^[28] Age serves as a key risk factor, with elderly individuals facing elevated vulnerability from falls, which account for the majority of TBI-related hospitalizations and deaths in those over 75. In contrast, youth and young adults experience higher rates linked to sports participation and interpersonal violence. Socioeconomic status also influences TBI risk, with individuals in low-income or deprived areas showing significantly higher incidence, particularly among children with co-existing mental health conditions or epilepsy, due to limited access to safety measures and higher exposure to hazardous environments. Military personnel and veterans represent another high-risk group, where blast exposures from improvised explosive devices and other combat-related incidents are a leading cause of mild to severe TBI.^[29]^[30]^[31]^[32] Modifiable risk factors include alcohol and substance abuse, which substantially elevate TBI likelihood, with intoxication present in up to 50% of cases and serving as one of the strongest predictors of injury occurrence. Lack of helmet use during sports and cycling further compounds risk, as helmets have been shown to reduce the likelihood of TBI by 53% and head injuries by 48%. Non-modifiable factors encompass genetic predispositions, such as variants of the APOE ε4 allele, which are associated with poorer functional outcomes and increased neurobehavioral impairments following TBI.^[33]^[34]^[35]^[36] Globally, TBI rates reveal stark disparities, with low- and middle-income countries bearing over 90% of trauma-related fatalities, largely driven by road traffic injuries amid inadequate infrastructure and vehicle safety standards. Occupational hazards exacerbate these patterns, particularly in construction, where workers face the highest TBI fatality rates—accounting for one-quarter of all construction deaths from 2003 to 2010—due to falls from heights and struck-by incidents.^[37]^[38]^[39]

Causes

Traumatic Causes

Traumatic brain injury (TBI) arises from external mechanical forces that disrupt brain function, distinguishing it from non-traumatic causes like strokes that stem from internal vascular events.^[12] The leading causes of non-fatal TBI in the United States include falls, which account for about 40-51% of cases depending on setting (e.g., 51% of hospitalizations as of 2018) and are particularly prevalent among children and older adults.^[27] Falls represent over 50% of TBIs in individuals over 65 years old (as of 2024).^[12] Motor vehicle crashes contribute to 14-25% of non-fatal TBIs (as of 2018), often involving high-speed impacts that generate substantial kinetic energy.^[27] Assaults and violence account for about 10-11% of TBIs, frequently resulting in penetrating injuries from firearms or blunt objects.^[40] Globally, road traffic injuries are a leading cause of TBI among younger populations, while falls predominate among older adults.^[1] In sports and recreation, concussions from contact activities such as football and boxing are common, with an estimated 1.6 to 3.8 million sports- and recreation-related concussions occurring annually in the United States (recent estimates).^[41] Military personnel face risks from blast injuries, which can be primary—caused by the direct overpressure wave from explosions—or tertiary, resulting from being thrown by the blast force.^[42]^[43] Other notable causes include workplace accidents, which pose elevated risks in occupations like construction and emergency response due to falls from heights, impacts from objects, or vehicle collisions.^[44] Child abuse, particularly shaken baby syndrome (also known as abusive head trauma), leads to 600–1,400 cases of TBI each year in the United States, typically from violent shaking or impact in infants.^[45] These causes operate through mechanisms such as direct impact to the head, rotational forces that induce diffuse axonal injury (DAI), or skull fractures that precipitate hematomas.^[46]

Non-Traumatic Causes

Non-traumatic brain injuries result from endogenous physiological, metabolic, infectious, or toxic processes that disrupt brain function without external mechanical force, in contrast to traumatic injuries caused by physical impact. These injuries encompass a range of conditions leading to neuronal damage, including vascular events, oxygen deprivation, infections, toxicities, metabolic derangements, iatrogenic complications, and progressive neurodegenerative changes. Globally, non-traumatic causes contribute substantially to the burden of acquired brain injury, with vascular disorders being among the most prevalent.^[1] Vascular causes primarily involve strokes, where ischemic strokes—resulting from thrombotic or embolic occlusion of cerebral arteries—account for approximately 87% of all strokes and represent a leading global cause of brain injury due to reduced blood flow and subsequent tissue necrosis.^[47] Hemorrhagic strokes, caused by vessel rupture and bleeding into brain tissue, comprise the remaining 13%, while cerebral aneurysm ruptures can trigger subarachnoid hemorrhage and focal brain damage.^[47] These events often lead to widespread infarction or compression of brain structures, with ischemic strokes alone causing over 10 million new cases annually worldwide.^[48] Hypoxic-ischemic brain injuries occur when inadequate oxygen delivery impairs cerebral metabolism, commonly following cardiac arrest, where survivors face a high risk of neurological deficits ranging from cognitive impairment to coma.^[49] Approximately 50% of cardiac arrest survivors experience significant long-term neurological dysfunction due to selective vulnerability in regions like the hippocampus and basal ganglia.^[50] Other triggers include drowning, which causes global anoxia, and carbon monoxide poisoning, leading to delayed encephalopathy from toxin binding to hemoglobin and cytochrome oxidase.^[51] Infectious causes such as encephalitis and meningitis involve direct pathogen invasion or inflammatory response damaging brain parenchyma, with viral encephalitis affecting roughly 7 cases per 100,000 people annually in the United States and higher rates in regions with endemic infections or immunocompromised populations.^[52] Bacterial meningitis similarly incurs brain injury through meningeal inflammation and abscess formation, while viral forms like herpes simplex encephalitis target temporal lobes, causing necrosis. Toxic etiologies include chemotherapy-induced neurotoxicity, impacting up to 50% of patients receiving neurotoxic agents like platinum compounds or taxanes, resulting in peripheral and central nervous system damage.^[53] Wernicke-Korsakoff syndrome, stemming from thiamine deficiency in chronic alcoholics, manifests as acute encephalopathy followed by amnesia due to mammillary body atrophy.^[54] Metabolic derangements, such as severe hypoglycemia, deprive neurons of glucose and provoke excitotoxic injury, potentially leading to irreversible deficits even after correction.^[55] Liver failure induces hepatic encephalopathy through ammonia accumulation and cerebral edema, exacerbating brain injury in acute settings. Iatrogenic causes arise from medical interventions, including post-surgical complications like ischemia from vascular manipulation or infection during neurosurgery. In neurodegenerative contexts, advanced dementia—such as in Alzheimer's disease—involves progressive amyloid and tau accumulation, culminating in chronic neuronal loss akin to ongoing brain injury.^[56]^[57] Strokes constitute a major portion of non-traumatic brain injuries globally, while infectious causes predominate in immunocompromised populations.^[48]

Pathophysiology

Primary Injury Mechanisms

Primary injury mechanisms refer to the initial biomechanical or pathophysiological damage to brain tissue occurring at the moment of insult, which is generally considered irreversible and sets the foundation for subsequent pathological processes. In traumatic brain injury (TBI), these mechanisms arise from external mechanical forces such as impact, acceleration-deceleration, or penetration, leading to either focal or diffuse damage.^[5] Focal injuries involve localized structural disruptions, while diffuse injuries affect broader neural networks without gross macroscopic changes.^[58] Focal injuries include contusions, which are bruises to the brain parenchyma resulting from direct impact against the skull, often occurring at the site of force application (coup injury) or the opposite side (contrecoup injury) due to rebound.^[5] Lacerations represent tears in brain tissue, typically from penetrating objects or severe skull fractures that breach the dura.^[5] Hematomas form as collections of blood from vascular rupture, categorized as epidural (between the skull and dura, often arterial), subdural (between dura and arachnoid, venous), or intracerebral (within parenchyma).^[5] These injuries directly compromise local tissue integrity and vascular supply.^[59] Diffuse injuries encompass concussion and diffuse axonal injury (DAI). Concussion involves transient functional disruption without evident structural alteration, characterized by brief loss of consciousness or altered mental status following mild impact.^[5] DAI, a more severe form, results from widespread shearing of axons in white matter tracts, leading to disconnection of neural circuits and often coma.^[58] This microscopic damage includes beta-amyloid accumulation in affected axons, impairing transport and contributing to long-term dysfunction.^[60] Biomechanically, primary TBI damage stems from linear acceleration, rotational forces, or blast waves. Linear acceleration causes the brain to shift within the skull, generating compressive and tensile strains that produce contusions and focal hemorrhages.^[58] Rotational acceleration induces angular momentum, twisting the brain and creating shear stresses that disproportionately affect axons at gray-white matter interfaces, thresholds exceeding 10,000 rad/s² often sufficient for DAI.^[61] Blast waves from explosions propagate pressure gradients through tissue, disrupting microtubules and causing diffuse shearing similar to rotational injury.^[58] In non-traumatic brain injury, primary mechanisms differ, focusing on vascular or metabolic insults. Ischemic necrosis occurs when vessel occlusion, as in stroke, deprives tissue of oxygen and glucose, leading to rapid cell death in the affected arterial territory.^[1] Excitotoxicity arises from massive glutamate release during energy failure, overactivating NMDA and AMPA receptors, causing calcium influx and necrotic breakdown of neurons.^[62] These processes, like their traumatic counterparts, initiate irreversible cellular destruction at the onset of injury.^[63]

Secondary Injury and Inflammatory Response

Secondary injury in traumatic brain injury (TBI) refers to the cascade of biochemical and cellular events that follow the initial mechanical insult, exacerbating neuronal damage through processes such as excitotoxicity, oxidative stress, and apoptosis. Excitotoxicity arises from excessive glutamate release, leading to overactivation of N-methyl-D-aspartate (NMDA) receptors and subsequent calcium influx into neurons, which disrupts cellular homeostasis and triggers downstream destructive pathways.^[64] This calcium dysregulation propagates mitochondrial dysfunction and enzymatic activation, contributing significantly to neuronal death in the hours following the primary injury.^[65] Oxidative stress complements this by generating reactive oxygen species (ROS) and free radicals, which damage lipids, proteins, and DNA, further compromising cellular integrity and amplifying tissue loss.^[66] Apoptosis, or programmed cell death, ensues as a result of these stressors, involving caspase activation and DNA fragmentation, leading to selective elimination of damaged neurons and glia without the inflammatory hallmarks of necrosis.^[67] The inflammatory response forms a critical component of secondary injury, initiated by microglial activation—the brain's resident immune cells—which rapidly respond to the primary trauma by proliferating and adopting a pro-inflammatory phenotype. Activated microglia release cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α), which recruit peripheral immune cells and perpetuate a cycle of inflammation that can worsen tissue damage.^[68] This response also compromises the blood-brain barrier (BBB) through endothelial tight junction disruption and matrix metalloproteinase activity, allowing plasma proteins and immune mediators to infiltrate the brain parenchyma, resulting in vasogenic edema and increased intracranial pressure.^[69] Systemic factors like hypotension, hypoxia, and seizures further amplify secondary injury by reducing cerebral perfusion and oxygenation or inducing metabolic demands that exceed supply, as seen in ischemia-reperfusion injury where restored blood flow paradoxically generates additional ROS and inflammation.^[70]^[71]^[72] Recent research as of 2025 has highlighted the role of neurovascular disturbances in secondary injury, including endothelial dysfunction and impaired glymphatic clearance, which contribute to chronic inflammation and amyloid deposition. Additionally, advances in understanding the immunological landscape reveal dysregulated T-cell responses and complement activation as key drivers of long-term neurodegeneration following TBI.^[73]^[74] The time course of secondary injury typically peaks between 24 and 72 hours post-trauma, when excitotoxic, oxidative, and inflammatory processes reach maximal intensity, leading to widespread cell death and edema.^[75] In cases of repetitive mild TBI, this evolves into chronic neuroinflammation, characterized by persistent microglial activation and cytokine elevation, which is implicated in the pathogenesis of chronic traumatic encephalopathy (CTE).^[76] A key therapeutic window exists in the first 4-6 hours after injury, during which interventions targeting these cascades can mitigate progression and preserve viable tissue.^[77]

Signs and Symptoms

Acute Signs and Symptoms

Signs and symptoms of brain injury vary depending on whether the injury is traumatic (e.g., from external impact) or non-traumatic (e.g., from stroke, hypoxia, or infection), but often overlap in disrupting neurological function. Acute manifestations typically emerge shortly after onset, within hours to days. For traumatic brain injury (TBI), the Glasgow Coma Scale (GCS) assesses level of consciousness, with scores from 3 (deep coma) to 15 (fully alert). Non-traumatic injuries may not involve GCS but present with cause-specific signs, such as sudden focal weakness in stroke or global confusion and seizures in hypoxic-ischemic events.^[78] Physical symptoms often dominate initial presentations in both types. In TBI, loss of consciousness (LOC) is common, with duration varying by severity: brief (under 30 minutes) in milder cases, prolonged (30 minutes to 24 hours) in moderate injuries, and extended (over 24 hours) in severe ones.^[79] Persistent or worsening headache, nausea, and repeated vomiting frequently occur due to intracranial pressure changes or meningeal irritation.^[7] Early post-traumatic seizures, appearing within the first week, affect approximately 10-25% of severe TBI patients and may manifest as convulsions or subtle events; in non-traumatic cases like encephalitis, seizures can also occur early due to inflammation.^[80] Cognitive symptoms involve immediate mental status alterations. Confusion and disorientation are prevalent across injury types, impairing orientation to time, place, or person. Post-traumatic amnesia—retrograde (pre-injury memory loss) and anterograde (inability to form new memories)—is typical in TBI, with duration correlating to severity; similar memory issues can arise in non-traumatic injuries like transient global amnesia from hypoxia.^[81] Neurological symptoms include focal deficits based on affected regions, such as hemiparesis or sensory loss from contusions in TBI or ischemia in stroke. Pupillary changes, like unequal or dilated pupils, signal potential herniation and require urgent attention in any acute brain injury. Frontal lobe injuries can disrupt executive function and behavior acutely.^[5]^[78] Severity in TBI is classified as: mild (GCS 13-15) with transient confusion and no prolonged LOC; moderate (GCS 9-12) with LOC 30 minutes to 24 hours; severe (GCS 3-8) with deep coma over 24 hours. Non-traumatic severity depends on underlying cause, such as infarct size in stroke. Non-localizing symptoms like fatigue and dizziness commonly accompany these, alongside vital sign abnormalities like Cushing's triad (hypertension, bradycardia, irregular respirations) indicating elevated intracranial pressure, particularly in TBI or mass lesions.^[79]^[82]

Chronic and Long-Term Effects

Chronic and long-term effects of brain injury persist beyond initial recovery and affect psychological, physiological, cognitive, and social domains, varying by injury type, severity, location, and individual factors. While much research focuses on traumatic brain injury (TBI), similar sequelae occur in non-traumatic cases, such as cognitive decline after stroke or chronic fatigue post-hypoxic injury. Survivors of moderate to severe TBI frequently face lifelong challenges, with outcomes differing widely.^[83] Psychological impacts are prominent, including depression, anxiety, and post-traumatic stress disorder (PTSD). Depression affects 30-50% of TBI individuals in the first year, linked to neurochemical and psychosocial factors; comparable rates occur post-stroke.^[84] Anxiety disorders are common, with adjusted odds ratios of 1.81 for generalized anxiety in military mTBI cohorts, and PTSD prevalence of 19.2% at six months in civilian TBI cases; anxiety and adjustment disorders also rise after non-traumatic events like tumors.^[84] Personality changes, such as irritability from frontal damage, contribute to affective instability.^[84] Physiologically, risks include epilepsy, sleep disturbances, and sensory deficits. Post-traumatic epilepsy develops in 10-20% of severe TBI cases, highest in the first year; seizure disorders can persist after infections or vascular events.^[85] Sleep disorders (insomnia, hypersomnia) affect 30-70% of TBI patients due to hypothalamic disruptions, similarly common post-stroke.^[86] Anosmia occurs in 10-15% overall (moderate 8-19%, severe 25-30%), from olfactory nerve shearing in TBI; olfactory loss can also follow non-traumatic cranial nerve damage.^[87] Cognitively, memory impairment and executive dysfunction hinder functioning, affecting 15-30% persistently beyond one year in TBI due to axonal injury; analogous deficits, like aphasia post-stroke, impact daily life and may progress to neurodegeneration, with TBI linked to 2-4 times higher Alzheimer's risk via inflammation.^[83]^[88] Social consequences include 50% unemployment in moderate-severe TBI a decade post-injury and family dysfunction in 33-78% of households from behavioral changes; similar strains occur in non-traumatic cases with dependency needs.^[89]^[90] In children, TBI heightens developmental delay risks, with up to 50% showing behavioral problems and 28% low developmental scores at one year, affecting milestones; pediatric non-traumatic injuries like near-drowning yield comparable long-term issues.^[91] Repetitive mild TBI in athletes can lead to chronic traumatic encephalopathy (CTE), a tauopathy in 41.4% of young contact sport participants postmortem, with cognitive/mood changes from axonal damage.^[92]

Diagnosis

Clinical Assessment

The clinical assessment of brain injury begins with a thorough history-taking to establish the context and potential severity of the injury. Key elements include the mechanism of injury, such as falls, motor vehicle collisions, or assaults, which help differentiate traumatic from non-traumatic causes. The duration of loss of consciousness (LOC), if present, is critical, as LOC lasting less than 30 minutes typically indicates mild injury, while longer durations suggest moderate to severe cases. Pre-hospital interventions, including airway management or immobilization, and witness accounts are essential, particularly when the patient is unable to provide details, to inform initial triage and estimate the Glasgow Coma Scale (GCS) score retrospectively.^[5] The physical examination focuses on a systematic neurological evaluation to identify focal deficits and signs of increased intracranial pressure. This includes assessment of cranial nerves for abnormalities like pupillary asymmetry or oculomotor dysfunction, motor and sensory function to detect hemiparesis or sensory loss, and reflexes to evaluate for hyperreflexia or Babinski signs indicative of upper motor neuron involvement. Vital signs are monitored closely for indicators of herniation, such as bradycardia, hypertension, and irregular respirations (Cushing's triad), which signal urgent deterioration. A general trauma survey is integrated to rule out associated injuries, but the neurological components guide immediate prioritization.^[93]^[5] Severity is quantified using standardized scales for objective evaluation and communication. The Glasgow Coma Scale (GCS), developed in 1974, remains the gold standard, comprising three components: eye opening (1-4 points: 1=no response, 4=spontaneous), verbal response (1-5 points: 1=no response, 5=oriented), and motor response (1-6 points: 1=no response, 6=obeys commands), with total scores ranging from 3 (deep coma) to 15 (fully alert); scores of 13-15 indicate mild injury, 9-12 moderate, and 3-8 severe. For rapid pre-hospital or emergency triage, the AVPU scale is employed as a simpler alternative: Alert (A), responds to Voice (V), responds to Pain (P), or Unresponsive (U), correlating roughly with GCS thresholds (A ≥15, V 13-14, P 9-12, U ≤8). These tools facilitate consistent assessment across settings.^[94]^[78]^[95] Mental status evaluation complements the GCS by assessing cognitive function beyond basic responsiveness. This involves testing orientation to person, place, and time; immediate and delayed recall for memory; and attention through serial subtraction or digit span tasks, often using simplified versions of the Mini-Mental State Examination (MMSE) adapted for acute settings. Impairments in these areas may reveal subtle diffuse axonal injury even in patients with normal vital signs.^[96]^[5] In special populations, assessments require adaptations to account for developmental or age-related factors. For pediatrics, the Pediatric GCS modifies verbal and motor components for children under 2 years, such as cooing or smiling for verbal response (2-5 points) and withdrawal to touch for motor (4-6 points), to improve accuracy in non-verbal infants; scores below 9 warrant aggressive monitoring. In the elderly, comorbidities like dementia or polypharmacy can mask symptoms, leading to underestimation of severity, so baseline cognitive function and frailty indices must be considered to avoid delayed recognition of deterioration.^[78]^[97]

Neuroimaging and Laboratory Tests

Computed tomography (CT) is the primary neuroimaging modality for initial evaluation of suspected traumatic brain injury (TBI), valued for its rapid acquisition, widespread availability, and high sensitivity in detecting acute abnormalities such as intracranial hemorrhages, skull fractures, and mass effects that may require urgent intervention.^[98] Non-contrast CT is recommended as the first-line imaging for patients with moderate to severe TBI, with sensitivity approaching 100% for identifying lesions necessitating neurosurgical intervention, such as epidural or subdural hematomas.^[99] According to the Brain Trauma Foundation guidelines, a head CT should be obtained for all patients with severe TBI (Glasgow Coma Scale [GCS] score of 3-8) following resuscitation.^[100] The National Institute for Health and Care Excellence (NICE) guidelines specify CT imaging within 1 hour for adults (≥16 years) with GCS less than 13 or children (<16 years) with GCS less than 14 on initial emergency department assessment, or for those with GCS less than 15 at 2 hours post-injury (on the appropriate scale), particularly if accompanied by clinical features like amnesia, repeated vomiting, or focal neurological deficits.^[101] Magnetic resonance imaging (MRI) provides superior soft tissue contrast compared to CT and is indicated when initial CT is negative but clinical suspicion persists, or for detailed characterization in subacute or chronic phases.^[102] MRI excels at identifying diffuse axonal injury (DAI), non-hemorrhagic contusions, and brainstem lesions, with diffusion-weighted imaging (DWI) particularly sensitive for detecting ischemic changes and cytotoxic edema associated with DAI.^[103] Susceptibility-weighted imaging (SWI) sequences on MRI can reveal microhemorrhages and vascular injuries not visible on CT.^[102] Advanced modalities like positron emission tomography (PET) and single-photon emission computed tomography (SPECT) assess cerebral metabolism, perfusion, and glucose utilization, offering insights into functional deficits in TBI, though they remain primarily investigational rather than routine diagnostic tools.^[98] Electroencephalography (EEG) is used to detect subclinical seizures or epileptiform activity, which occur in approximately 17% of severe TBI cases and can complicate acute management.^[104] Laboratory tests support neuroimaging by identifying systemic factors that influence TBI evaluation and management. Coagulation studies, including prothrombin time (PT) and international normalized ratio (INR), are essential to detect coagulopathy, which affects up to 35% of severe TBI patients and increases hemorrhage risk.^[105] Electrolyte panels evaluate for imbalances such as hyponatremia or hypokalemia, common in TBI due to hypothalamic-pituitary dysfunction or cerebral salt wasting.^[106] Blood-based biomarkers like S100 calcium-binding protein B (S100B) and glial fibrillary acidic protein (GFAP) are emerging aids for mild TBI, with validated S100B levels below 0.1 μg/L (using Roche Diagnostics assay) helping to rule out intracranial injury and avoid unnecessary CT scans in low-risk cases.^[107] GFAP shows promise in predicting MRI abnormalities in CT-negative mild TBI, with ongoing validation in 2020s studies supporting its integration into guidelines.^[108]

Diagnosis of Non-Traumatic Brain Injury

Diagnosis of non-traumatic brain injury varies by underlying cause and typically integrates clinical history, targeted laboratory tests, and advanced imaging. For vascular events such as ischemic stroke, non-contrast CT rules out hemorrhage, while MRI with diffusion-weighted imaging confirms infarction; CT or MR angiography identifies vessel occlusion.^[109] Infections like encephalitis or meningitis often require lumbar puncture for cerebrospinal fluid analysis, including cell count, protein, glucose, and cultures or PCR for pathogens.^[110] Hypoxic-ischemic injuries, resulting from events like cardiac arrest or drowning, are diagnosed through clinical context and MRI showing diffuse cortical or basal ganglia changes. Brain tumors are primarily diagnosed using contrast-enhanced MRI to delineate lesions and guide biopsy if needed.^[111] Across etiologies, neuropsychological testing evaluates cognitive and functional deficits.^[1]

Management

Acute Management

The acute management of brain injury prioritizes rapid stabilization to prevent secondary injury, focusing on the first hours to days following the event. Initial resuscitation follows the airway, breathing, and circulation (ABCs) protocol adapted for trauma patients. Airway protection is critical, with endotracheal intubation recommended for patients with a Glasgow Coma Scale (GCS) score less than 8 or those at risk of aspiration, using agents like ketamine to maintain hemodynamic stability.^[112] Breathing is optimized by ensuring adequate oxygenation (PaO₂ >60 mmHg) while avoiding routine hyperventilation, which can cause cerebral vasoconstriction; brief hyperventilation (PaCO₂ 30-35 mmHg) is reserved for signs of herniation.^[113] Circulation involves fluid resuscitation to maintain age-specific systolic blood pressure thresholds of ≥110 mmHg for patients aged 15–49 years and ≥70 years, and ≥100 mmHg for those aged 50–69 years, to preserve cerebral perfusion pressure (CPP), using isotonic fluids or blood products while avoiding hypotension or excessive crystalloids.^[112] Intracranial pressure (ICP) management is a cornerstone for severe traumatic brain injury (TBI), targeting ICP below 20-22 mmHg and CPP of 60-70 mmHg to mitigate ischemia and edema. Non-invasive measures include elevating the head of the bed to 30-45 degrees and maintaining normothermia. Pharmacologic interventions involve hyperosmolar therapy, such as mannitol (0.25-1 g/kg) or hypertonic saline (e.g., 3% NaCl), to reduce cerebral edema, with monitoring for serum osmolality and sodium levels. Surgical options, including craniotomy for evacuation of epidural hematomas exceeding 30 mL, or acute subdural hematomas with thickness greater than 10 mm or causing midline shift greater than 5 mm, are indicated based on CT findings and clinical deterioration. External ventricular drainage for cerebrospinal fluid diversion is recommended in patients with GCS 3-8 and abnormal CT scans.^[113]^[112]^[114] Seizure prophylaxis is standard in severe TBI to prevent early post-traumatic seizures (within 7 days), which occur in up to 25% of cases. A 7-day course of phenytoin (loading dose 15-20 mg/kg IV, maintenance 5 mg/kg/day) is recommended, as it reduces early seizure incidence by approximately 50% without affecting late seizures or overall mortality. Levetiracetam is an alternative with fewer drug interactions, though evidence for superiority is limited.^[115]^[113] The Brain Trauma Foundation (BTF) guidelines provide tiered recommendations for severe TBI management, emphasizing evidence-based interventions to reduce mortality by up to 50% when implemented. Level I evidence contraindicates steroids, as high-dose methylprednisolone increases mortality risk by 18% without improving outcomes, based on the CRASH trial involving over 10,000 patients. Therapeutic hypothermia (target 32-35°C for 48 hours) yields mixed results; while it may temporarily lower ICP, large trials like Eurotherm3235 show no functional benefit and potential harm from complications like pneumonia, so it is not routine but considered for refractory ICP.^[100]17188-2/fulltext)^[116] For non-traumatic brain injuries, such as acute ischemic stroke, acute management includes thrombolysis with intravenous alteplase within 4.5 hours of symptom onset in eligible patients (e.g., NIHSS score ≥4, no hemorrhage on CT), improving outcomes by 30% relative to placebo in pivotal trials. Blood pressure is managed below 185/110 mmHg pre-thrombolysis to minimize bleeding risk.^[117] For hypoxic-ischemic brain injury following events like cardiac arrest, targeted temperature management at 32–36°C for 24 hours is recommended to provide neuroprotection and improve neurological outcomes.^[118] In cases of infectious causes such as encephalitis, prompt administration of antimicrobials (e.g., acyclovir for herpes simplex virus) alongside supportive care is essential, guided by cerebrospinal fluid analysis and clinical presentation.^[119]

Rehabilitation and Chronic Care

Rehabilitation for brain injury typically begins following acute stabilization and progresses through structured phases aimed at restoring function and independence. The initial acute rehabilitation phase often occurs inpatient, focusing on intensive interventions such as physical therapy to improve mobility, occupational therapy to enhance daily living skills, and speech therapy to address communication and swallowing difficulties.^[120] These therapies are tailored to the individual's deficits and may last several weeks, with evidence from systematic reviews indicating that early initiation within days of injury optimizes recovery by promoting neuroplasticity and preventing secondary complications like muscle atrophy.^[121] Transitioning to community reintegration involves outpatient or home-based programs, including vocational training to facilitate return to employment or productive activities, emphasizing skills like time management and workplace adaptation.^[122] A multidisciplinary team coordinates care, comprising neurologists for ongoing medical oversight, psychologists to manage cognitive and emotional challenges, physical and occupational therapists for functional restoration, speech-language pathologists for communication support, and social workers to address socioeconomic barriers.^[123] This collaborative approach ensures holistic treatment, with family education integrated to empower caregivers in supporting recovery and recognizing signs of deterioration.^[120] Key therapeutic approaches include cognitive behavioral therapy (CBT) to alleviate psychological issues such as anxiety and depression, which affect up to 50% of survivors; randomized controlled trials demonstrate CBT's efficacy in improving emotional regulation and quality of life when delivered individually over 8-12 sessions.^[124] Emerging neurostimulation techniques, like transcranial direct current stimulation (tDCS), show promise in enhancing cognitive and motor recovery by modulating neural excitability, particularly when combined with traditional therapy in chronic phases.^[125] Assistive devices further support independence, ranging from low-tech options like canes and adaptive utensils to high-tech solutions such as voice recognition software and powered wheelchairs, which mitigate mobility and cognitive limitations.^[126] In chronic care, ongoing management targets persistent symptoms, with medications like oral or intrathecal baclofen serving as a first-line treatment for spasticity, reducing muscle tone and associated pain in 60-80% of responsive patients according to clinical guidelines.^[127] Pain management may involve adjunctive analgesics or antispasmodics, tailored to avoid sedation that could exacerbate cognitive impairments.^[128] Regular monitoring for complications like posttraumatic hydrocephalus is essential, involving serial neuroimaging and clinical assessments to detect ventricular enlargement early, as untreated cases can worsen cognitive outcomes in up to 20% of severe injury survivors.^[129] Intensive rehabilitation yields measurable benefits, with systematic reviews of randomized controlled trials reporting return-to-work rates of 30-65% at one to two years post-injury among those receiving specialized vocational interventions, compared to lower rates without such support.^[130] Evidence from RCTs also supports early mobilization protocols, which improve functional independence and reduce ICU length of stay by promoting physical activity and mitigating deconditioning.^[131]

Prognosis

Outcome Prediction

Outcome prediction in brain injury involves the use of standardized scales and prognostic models to forecast survival, functional recovery, and long-term disability, primarily in traumatic cases but with adaptations for other etiologies. These tools integrate clinical, radiographic, and laboratory data to guide clinical decision-making, family counseling, and resource allocation, though their accuracy varies by injury type and timing of assessment. Recent advances include AI and machine learning models that predict outcomes after moderate to severe traumatic brain injury (TBI), achieving accuracies up to 95% for in-hospital mortality and functional recovery.^[132]^[133] The Glasgow Outcome Scale (GOS), developed in 1975, remains a cornerstone for evaluating global disability six months post-injury, categorizing outcomes into five levels: death, persistent vegetative state, severe disability (conscious but disabled, unable to live independently), moderate disability (disabled but independent), and good recovery (resumption of normal life).^[134]^[135] The extended version, known as the Glasgow Outcome Scale-Extended (GOSE), refines this into eight categories by subdividing moderate and severe disability levels, enhancing sensitivity for detecting nuanced recovery in mild to moderate traumatic brain injury (TBI).^[136]^[137] Complementing the GOS, the Disability Rating Scale (DRS) assesses disability across eight items spanning arousal, cognitive function for self-care, dependency, and psychosocial employability, providing a continuous score from 0 (no disability) to 29 (extreme vegetative state) to track recovery from coma to community reintegration.^[138]^[139] Prognostic models like the IMPACT calculator, derived from large TBI databases, predict six-month mortality and unfavorable outcomes by combining core variables such as age, Glasgow Coma Scale (GCS) score, pupil reactivity, and computed tomography (CT) findings (e.g., hematoma volume, midline shift) with optional laboratory data like hemoglobin and glucose levels.^[140] This model achieves 70-80% accuracy for mortality prediction, with area under the curve (AUC) values typically ranging from 0.77 to 0.82, though it may overestimate risks in contemporary cohorts due to advances in care.^[141] Early clinical factors strongly influence these predictions; for instance, fixed or non-reactive pupils on admission signal increased intracranial pressure and correlate with higher mortality rates, while episodes of hypotension (systolic blood pressure <90 mmHg) independently double the risk of adverse outcomes by exacerbating secondary brain injury.^[142]^[143] Biomarkers such as ubiquitin C-terminal hydrolase-L1 (UCH-L1) aid prognosis, particularly in mild TBI, where elevated serum levels within 12 hours indicate neuronal damage and help stratify risk for poor recovery; the U.S. Food and Drug Administration approved UCH-L1 testing in 2019 for ruling out intracranial lesions in GCS 13-15 patients, with prognostic utility in predicting six-month outcomes when combined with glial fibrillary acidic protein (GFAP).^[144] Short-term predictions focus on 30-day mortality, which reaches 30-40% in severe TBI (GCS ≤8), driven by initial injury severity and secondary insults.^[145] Long-term forecasts emphasize one-year functional independence, where only about 33% of severe TBI survivors achieve minimal disability (DRS 0-3), with recovery plateauing after six months but varying by age and rehabilitation access.^[146] Limitations arise in non-traumatic brain injuries, such as stroke or anoxic events, where TBI-specific models like IMPACT show reduced applicability due to differing pathophysiology; instead, stroke scales like the National Institutes of Health Stroke Scale (NIHSS) better predict outcomes by emphasizing focal deficits over global trauma metrics, highlighting the need for etiology-tailored tools.^[147]

Complications and Quality of Life

Brain injury survivors are at heightened risk for various medical complications that can arise during acute care and persist long-term. Infections, particularly pneumonia, are prevalent among those requiring mechanical ventilation, affecting 40-50% of patients with severe traumatic brain injury (TBI).^[148] Thromboembolic events, including deep vein thrombosis and pulmonary embolism, also occur frequently due to immobility and hypercoagulability, contributing to morbidity in up to 20% of severe cases with prophylaxis.^[149] Endocrine disruptions, such as pituitary dysfunction, manifest in 25-50% of severe TBI patients, often involving growth hormone deficiency or hypogonadism that requires ongoing hormone replacement.^[150] Neurological complications further compound the challenges, with posttraumatic hydrocephalus developing in approximately 10% of severe TBI cases, leading to increased intracranial pressure and necessitating shunt placement.^[151] Paroxysmal disorders, including paroxysmal sympathetic hyperactivity, affect 8-33% of severe TBI survivors, characterized by episodic tachycardia, hypertension, and hyperthermia that can mimic sepsis or seizures.^[152] In athletic contexts, second impact syndrome represents a rare but catastrophic complication, where a subsequent head injury before full recovery from an initial concussion triggers rapid cerebral edema and potentially fatal brain herniation.^[153] The quality of life for brain injury survivors is profoundly impacted, with reduced life expectancy 9 years shorter post-severe TBI due to heightened mortality from secondary conditions.^[154] Social isolation is common, as cognitive and behavioral changes limit participation in relationships and activities, with up to 70% reporting deterioration in their social networks.^[155] Financial burdens are substantial, with annual U.S. costs for TBI exceeding $100 billion as of 2023, encompassing medical care, lost productivity, and long-term support needs.^[156] Health-related quality of life is often assessed using tools like the SF-36 survey, which reveals persistent deficits in physical and mental domains among survivors.^[157] Patient-reported outcomes indicate that around 40% of those with moderate TBI express dissatisfaction with life at 6-12 months post-injury, linked to ongoing symptoms like pain and emotional distress.^[158] Rehabilitation interventions play a key role in addressing these issues but do not fully eliminate them; for instance, while collaborative care programs can reduce pain interference by up to 30%, chronic pain persists in 46-60% of moderate-to-severe TBI cases.^[159]

History

Early Recognition and Milestones

The recognition of brain injury traces its origins to ancient civilizations, where early observations laid the groundwork for understanding head trauma. Around 400 BCE, Hippocrates documented symptoms of head injuries in his treatise On Injuries of the Head, including convulsions, hemiplegia, sensory loss, and coma, which he linked directly to brain dysfunction rather than supernatural causes. He recommended trephination—a procedure involving drilling or scraping holes in the skull—to evacuate accumulated fluids or fragments from fractures, aiming to relieve intracranial pressure and prevent fatal complications such as epilepsy or death. This approach, detailed across 48 case studies with 27 involving head trauma, represented the first systematic medical account of neurosurgical intervention for such injuries.^[160]^[161] The 19th century brought significant progress through anatomical and clinical studies that emphasized brain localization and functional assessment. In 1861, French surgeon Paul Broca examined patients like "Tan" (Leborgne), who exhibited expressive aphasia following a lesion in the posterior inferior frontal gyrus of the left hemisphere, establishing a foundational link between specific brain regions and language production. This lesion-based approach revolutionized neurology by shifting from holistic views of the brain to modular theories of function. Concurrently, 19th-century neurologists developed rudimentary classifications of consciousness levels in comatose patients—such as grading stupor, delirium, and deep coma based on responsiveness to stimuli—which served as conceptual precursors to standardized tools like the Glasgow Coma Scale introduced later in the 20th century.^[162]^[163] In the early 20th century, insights into physiological mechanisms advanced recognition further. During his 1900–1901 studies in Europe, Harvey Cushing pioneered biophysical understandings of intracranial pressure (ICP), demonstrating through animal experiments how elevated ICP from trauma could lead to brain herniation and systemic responses like the Cushing reflex (hypertension and bradycardia). His work translated into surgical practices for ICP monitoring and decompression, improving outcomes in acute head injuries. By 1928, pathologist Harrison Martland described "punch drunk" syndrome in boxers, characterizing it as a progressive neurological disorder from repeated mild concussions, with symptoms including slurred speech, unsteady gait, and mental dullness—marking the first formal acknowledgment of concussion as a cumulative syndrome rather than transient.^[164]^[165]^[166] Key diagnostic milestones emerged mid-century. In the 1940s, electroencephalography (EEG) became a vital tool for evaluating brain injury, with early applications by researchers like Glaser and Sjaardema revealing abnormal electrical patterns—such as slowed waves or epileptiform discharges—in traumatic cases, enabling non-invasive detection of diffuse dysfunction beyond visible lesions. The 1970s saw Thomas Gennarelli coin the term "diffuse axonal injury" (DAI) through primate acceleration-deceleration models, identifying widespread white matter shearing as a primary cause of traumatic coma and persistent deficits, even without gross hemorrhage or contusion.^[167]^[8] Post-World War II veteran care played a crucial social role in highlighting long-term brain injury effects. With wartime advances in triage and antibiotics reducing mortality from head wounds to about 12%, more survivors faced chronic issues like cognitive impairment, personality changes, and epilepsy, prompting expanded rehabilitation programs through the U.S. Department of Veterans Affairs and underscoring the need for lifelong support.^[168]

Modern Advances in Research and Treatment

In the realm of diagnostics, computed tomography (CT) scanning became routinely integrated into traumatic brain injury (TBI) assessment by the 1980s, revolutionizing the detection of acute hemorrhages and mass lesions that were previously reliant on invasive methods.^[169] Magnetic resonance imaging (MRI), particularly diffusion tensor imaging variants, emerged in the 1990s as a superior tool for identifying diffuse axonal injury (DAI), which CT often misses, enabling earlier characterization of microstructural damage.^[170] By the 2010s, blood-based biomarkers such as glial fibrillary acidic protein (GFAP), often in combination with ubiquitin C-terminal hydrolase-L1 (UCH-L1), received FDA clearance in 2019 for aiding in the identification of intracranial injuries, with GFAP showing high sensitivity across TBI severities.^[107] Treatment advancements have been guided by evidence-based protocols from the Brain Trauma Foundation, whose initial guidelines for severe TBI management were published in 1995, emphasizing intracranial pressure monitoring and hyperosmolar therapy to mitigate secondary injury.^[171] Neuroprotective strategies, such as progesterone administration, advanced to phase III trials in the 2010s but ultimately failed to demonstrate clinical benefits in large randomized studies, highlighting challenges in translating preclinical promise to human outcomes.^[172] More recently, stem cell therapies have progressed to phase II clinical trials in the 2020s, with autologous mesenchymal stem cells showing potential in reducing lesion volume and improving motor deficits in chronic TBI patients during double-blind, placebo-controlled evaluations.^[173] Key research milestones include the 2005 identification of chronic traumatic encephalopathy (CTE) by neuropathologist Bennet Omalu, linking repetitive head trauma in athletes to tau protein accumulation and neurodegeneration, which spurred widespread studies on long-term brain health.^[174] Genomic investigations in the 1990s established associations between the apolipoprotein E ε4 (APOE ε4) allele and poorer recovery outcomes following TBI, influencing amyloid-beta deposition and Alzheimer's risk in affected individuals.^[175] In the 2020s, artificial intelligence models, including deep learning algorithms applied to CT scans and clinical data, have achieved up to 95% accuracy in predicting in-hospital mortality and functional outcomes, enhancing prognostic precision beyond traditional scales.^[176] Policy developments have emphasized prevention, with U.S. states enacting mandatory motorcycle helmet laws starting in the 1980s, which reduced head injury-related hospitalizations by up to 53% in adopting regions like California by 1991.^[177] In sports, the National Football League (NFL) implemented standardized concussion protocols in the 2010s, mandating sideline evaluations and prohibiting return-to-play until symptom resolution, contributing to a 7.6% decline in documented concussions per game from prior decades.^[178] Recent studies from 2020 to 2025 have illuminated links between COVID-19 and hypoxic-ischemic brain injury, with autopsy findings revealing widespread microhemorrhages and leukoencephalopathy in severe cases, often without direct viral invasion, attributed to systemic hypoxia and inflammation.^[179] These investigations underscore the pandemic's role in exacerbating TBI-like sequelae, prompting integrated neurocritical care approaches for post-acute recovery.^[180]

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Microglia in the TBI Brain: The Good, The Bad, And The Dysregulated
Microglia play a critical role in neuroinflammation following a traumatic brain injury (TBI). In the injured brain microglia can produce neuroprotective ...
[71]
Blood–Brain Barrier Pathophysiology following Traumatic Brain Injury
BBB disruption is a pathological hallmark of severe TBI and is associated with neuroinflammatory events contributing to brain edema and cell death.BLOOD–BRAIN BARRIER... · TRAUMATIC BRAIN INJURY... · IMPORTANCE IN...
[72]
Post-Traumatic Hypoxia Is Associated with Prolonged Cerebral ...
Hypoxia (Hx) and hypotension are frequent secondary insults aggravating brain damage, and both have been correlated with worse outcome.
[73]
Neuronal injury and death following focal mild brain injury - NIH
Our data indicated that seizure occurrence following mild TBI aggravates cell injury and death via activation of neuroinflammatory processes and may increase ...
[74]
Ischemia-reperfusion Injury in the Brain: Mechanisms and Potential ...
Ischemia-reperfusion injury is a common feature of ischemic stroke, which occurs when blood supply is restored after a period of ischemia.
[75]
Pathophysiology and Treatment of Cerebral Edema in Traumatic ...
Cerebral edema (CE) and resultant intracranial hypertension are associated with unfavorable prognosis in traumatic brain injury (TBI).
[76]
Current understanding of neuroinflammation after traumatic brain ...
This review provides an overview of recent understanding of neuroinflammation in TBI and preclinical cell-based therapies that target neuroinflammation and ...
[77]
Current Clinical Trials in Traumatic Brain Injury - PMC - NIH
Since secondary injury characteristics develop progressively, a therapeutic window of opportunity exists in order to protect further loss of neurons and glia ...
[78]
Glasgow Coma Scale - StatPearls - NCBI Bookshelf
Jun 23, 2025 · The Glasgow Coma Scale (GCS) is a cornerstone tool in the neurological assessment of patients with acute brain injury and impaired consciousness.Continuing Education Activity · Introduction · Clinical Significance · Other Issues
[79]
Table 1, Criteria used to classify TBI severity - NCBI Bookshelf
Post-traumatic Amnesia, 0–1 day, >1 and <7 days, >7 days. Glasgow Coma Scale (best available score in 24 hours), 13–15, 9–12, 3–8. TBI = traumatic brain injury.
[80]
Early seizures and temporal lobe trauma predict post-traumatic ... - NIH
ICU cEEG studies have shown a high incidence (18–30%) of early seizures within 7 days after TBI, most of which are nonconvulsive seizures (Vespa et al., 1999; ...
[81]
What are common symptoms of traumatic brain injury (TBI)? | NICHD
Nov 24, 2020 · Headache · Confusion · Lightheadedness · Dizziness · Blurred vision · Ringing in the ears, also known as tinnitus · Tiredness or sleepiness · A bad ...Missing: acute | Show results with:acute
[82]
Increased Intracranial Pressure - StatPearls - NCBI Bookshelf - NIH
Sep 14, 2025 · Cushing triad—characterized by hypertension, bradycardia, and irregular respirations—is a late and ominous sign of impending herniation.
[83]
Epidemiology of Chronic Effects of Traumatic Brain Injury - PMC
Males account for a significantly greater proportion of all TBIs than females, with annual incidence rates being 388 per 100,000 males versus 195 per 100,000 ...
[84]
Mental health consequences of traumatic brain injury - PMC - NIH
Moderate and severe TBI can cause personality changes including impulsivity, severe irritability, affective instability, and apathy.Missing: physiological | Show results with:physiological
[85]
Risk Factors and Incidence of Epilepsy after Severe Traumatic Brain ...
Risk for PTE is highest after severe TBI, defined as a post-resuscitation Glasgow Coma Scale (GCS) score of <=8,4 developing in 10-20% of patients who survive ...Missing: credible source
[86]
Traumatic Brain Injury and Sleep Disorders - PMC - PubMed Central
Sleep disturbance is common following traumatic brain injury (TBI), affecting 30–70% of individuals, many occurring after mild injuries. Insomnia, fatigue and ...
[87]
Post-traumatic olfactory dysfunction: a scoping review of assessment ...
Jul 12, 2023 · Bratt et al. (3) found that 8% of patients with moderate or severe TBI had anosmia, and 14% had olfactory dysfunctions lasting years after the ...
[88]
[PDF] Traumatic Brain Injury and Cognitive Decline - Alzheimer's Association
These include chronic neuroimmune activation, structural injury that results in cumulative neuronal and cellular dysfunction, and the disruption of the blood- ...Missing: unemployment developmental delays
[89]
Employment Probability Trajectories Up To 10 Years After Moderate ...
Dec 5, 2018 · The employment rate dropped from 82% pre-injury to 53% at 1 year follow-up and thereafter remained fairly stable up to 10 years (48, 55, and 50% ...
[90]
Traumatic Brain Injury - an overview | ScienceDirect Topics
According to different studies, between 33% and 78% of families report dysfunction after TBI (Gan, Campbell, Gemeinhardt, & McFadden, 2006; Testa, Malec, ...
[91]
The effect of pediatric traumatic brain injury on behavioral outcomes
Findings showed that up to 50% of brain-injured children are at risk for presenting with behavioral problems and disorders.
[92]
Neuropathologic and Clinical Findings in Young Contact Sport ...
Aug 28, 2023 · Importance Young contact sport athletes may be at risk for long-term neuropathologic disorders, including chronic traumatic encephalopathy (CTE) ...
[93]
Trauma Neurological Exam - StatPearls - NCBI Bookshelf
Feb 24, 2024 · The test is performed by holding the patient's eyes open and rotating the head from side to side or up and down. The normal response is eye ...Continuing Education Activity · Technique or Treatment · Clinical Significance
[94]
https://pubmed.ncbi.nlm.nih.gov/4136544/
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AVPU Scale - StatPearls - NCBI Bookshelf
Apr 3, 2023 · Health care professionals within a hospital utilize this scale during patient assessment for any patients at risk of having an abnormal level of ...
[96]
How To Assess Mental Status - Neurologic Disorders - Merck Manuals
The mental status examination is used to evaluate the patient's level of consciousness and the content of consciousness.
[97]
Geriatric Head Injury - StatPearls - NCBI Bookshelf - NIH
Aug 8, 2023 · The initial evaluation of a geriatric patient begins with the standard trauma primary survey of the airway, breathing, circulation, disability, ...Continuing Education Activity · Pathophysiology · History and Physical · Evaluation
[98]
Imaging Evidence and Recommendations for Traumatic Brain Injury
Neuroimaging plays a critical role in the evaluation of patients with traumatic brain injury, with NCCT as the first-line of imaging for patients with traumatic ...
[99]
External Validation of the Canadian CT Head Rule and the New ...
Sep 28, 2005 · Sensitivity for neurosurgical intervention was 100% for both the CCHR and the NOC. The NOC had a higher sensitivity for neurocranial traumatic ...
[100]
Guidelines for the Management of Severe TBI, 3rd Edition
May 1, 2007 · ... (TBI; Glasgow Coma Scale [GCS] score of 3-8 after resuscitation) and an abnormal computed tomography (CT) scan. An abnormal CT scan of the head ...Missing: imaging | Show results with:imaging
[101]
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May 18, 2023 · This guideline covers assessment and early management of head injury in babies, children, young people and adults.Recommendations · Head injury · Tools and resources · Update information
[102]
Neuroimaging Update on Traumatic Brain Injury - NCBI - NIH
Feb 11, 2024 · The recommended protocol includes using a multidetector CT (MDCT) with axial views, head tilt/gantry angling to reduce ocular lens radiation ...Introduction · Imaging Use and Techniques · Extra-Axial Lesions · Vascular Injury
[103]
Neuroimaging of Traumatic Brain Injury - PMC - PubMed Central - NIH
Dec 20, 2018 · The purpose of this article is to review conventional and advanced neuroimaging techniques performed in the setting of traumatic brain injury (TBI).
[104]
Development of Seizures Following Traumatic Brain Injury - MDPI
Sep 12, 2024 · The incidence was 1.5% in patients with mild TBI, 2.9% for moderate TBI, and 17% for severe TBI [18]. A review of the available literature ...
[105]
Detecting Traumatic Brain Injury-Induced Coagulopathy - NIH
Jan 1, 2023 · Among these tests, prothrombin time (PT) and its derivative, the international normalization ratio (INR), are widely used in clinical settings ...
[106]
Electrolyte Imbalance in Acute Traumatic Brain Injury
Aug 30, 2024 · Electrolyte disturbances are common in patients with traumatic brain injury (TBI), particularly affecting sodium, potassium, chloride, and calcium levels.
[107]
GFAP and S100B: What You Always Wanted to Know and Never ...
Mar 21, 2022 · S100B (cutoff <0.1 ug/L when measured with Roche Diagnostics system) can be used as part of the guideline algorithm to rule out the need for ...
[108]
Blood biomarkers for traumatic brain injury: A narrative review of ...
Application of S100B led to reduction of head CT scans. GFAP may also predict magnetic resonance imaging (MRI) abnormalities in CT-negative cases of TBI.
[109]
Acute Management of Traumatic Brain Injury - PMC - PubMed Central
Management strategies must therefore focus on preventing secondary injury by avoiding hypotension and hypoxia and maintaining appropriate cerebral perfusion ...
[110]
[PDF] Guidelines for the Management of Severe Traumatic Brain Injury
Abbreviations: CPP=cerebral perfusion pressure, CT=computed tomography, GCS=Glasgow Coma Scale,. GOS=Glasgow Outcome Scale, ICP=intracranial pressure ...
[111]
A Randomized, Double-Blind Study of Phenytoin for the Prevention ...
Aug 23, 1990 · Phenytoin exerts a beneficial effect by reducing seizures only during the first week after severe head injury.
[112]
Guidelines for the Management of Severe TBI, 4th Edition
Sep 30, 2016 · Guidelines for the Management of Severe TBI, 4th Edition · View the complete Guidelines, including methods and detailed evidence review here.Missing: imaging | Show results with:imaging
[113]
Hypothermia for Intracranial Hypertension after Traumatic Brain Injury
Oct 7, 2015 · In patients with traumatic brain injury, hypothermia can reduce intracranial hypertension. The benefit of hypothermia on functional outcome is unclear.
[114]
Guidelines for the Early Management of Patients With Acute ...
Oct 30, 2019 · Obtain a follow-up CT or MRI scan at 24 h after IV alteplase before starting anticoagulants or antiplatelet agents. Expand Table. AIS indicates ...
[115]
Rehabilitation and Long-Term Care Needs After Traumatic Brain Injury
Targeted rehabilitation may include cognitive rehabilitation, speech-language pathology services, physical or occupational therapy, vestibular and oculomotor ...
[116]
A comprehensive review of rehabilitation approaches for traumatic ...
Jun 12, 2025 · This comprehensive review critically examines key rehabilitation strategies for TBI, including neuropsychological assessments, cognitive and neuroplasticity- ...
[117]
After Brain Injury Rehabilitation - Shepherd Center
This phase is about overcoming challenges, embracing opportunities, and reintegrating into your community with confidence. Continuing your recovery journey.
[118]
Interdisciplinary Management of Traumatic Brain Injury - Physiopedia
Teamwork is one of the most fundamental factors in traumatic brain injury rehabilitation and an essential element of comprehensive patient care.
[119]
Cognitive Behavioral Therapy (CBT) - Brainline.org
Mar 16, 2021 · CBT has also been shown to have effectiveness in treating symptoms of depression and anxiety that develop following traumatic brain injury. One ...
[120]
A map of evidence using transcranial direct current stimulation ...
May 11, 2023 · Transcranial direct current stimulation (tDCS) is a low-cost, non-invasive brain stimulation intervention that improves cognitive function in ...Abstract · Introduction · Results · Discussion
[121]
Assistive Technology for People Living with Brain Injury
Some types of devices include wheelchairs, hearing aids, computer software (e.g., voice recognition programs, screen readers, etc.), and cellphone apps to help ...
[122]
Baclofen Pump: What It Is, Side Effects & Complications
Baclofen is a skeletal muscle relaxant medication. It's a common medication to treat spasticity (muscle stiffness) and other spinal cord conditions. Within ...
[123]
Baclofen in the Therapeutic of Sequele of Traumatic Brain Injury
Baclofen is a muscle relaxant used to treat spasticity and improve mobility in patients with spinal cord injuries, relieving pain and muscle stiffness.
[124]
Posttraumatic hydrocephalus: Recent advances and new ...
Nov 16, 2023 · Patients might be monitored in the intensive care unit (ICU) and given the previously discussed medications to maintain an adequate ICP.
[125]
Early, specialist vocational rehabilitation to facilitate return to work ...
A systematic review identified that only 41% (range 30–65%) of people who were in work prior to their TBI were working at 1 and 2 years post injury. Those who ...
[126]
Effect of a generalized early mobilization and rehabilitation protocol ...
Jul 30, 2025 · The general EMRP for trauma patients improved physical activity levels early after ICU admission and may have reduced the risk of complications ...
[127]
A Manual for the Glasgow Outcome Scale-Extended Interview - PMC
The GOSE can be used to assess the consequences of general trauma, including polytrauma, and in this case the effects of all kinds of injury are included. The ...
[128]
[PDF] The Glasgow Outcome Scale: 40 years of application and refinement
Aug 3, 2016 · The Glasgow Outcome Scale (GOS) was first published in 1975 by Brian Jennett and. Michael Bond, and, with over 4,000 citations to the ...
[129]
Glasgow Outcome Scale - Medscape Reference
Jan 13, 2023 · The Glasgow Outcome Scale (GOS) categorizes the outcomes of patients after traumatic brain injury, as follows: Death. Persistent vegetative ...<|separator|>
[130]
Glasgow Outcome Scale - Extended - Shirley Ryan AbilityLab
Jun 1, 2019 · The GOS-E classifies global outcomes in TBI survivors. It is primarily intended to describe outcome in groups of cases for research purposes.
[131]
Disability Rating Scale (DRS) | Centre for Neuro Skills
This established scale was developed as a method of rating the effects of traumatic brain injury to determine how long recovery might take.
[132]
Clinical utility and psychometric properties of the Disability Rating ...
The DRS is an 8-item scale assesses four domains, including level of consciousness, cognitive functioning related to self-care, level of dependence, and ...
[133]
Prognostic calculator | TBI-IMPACT.org
Based on extensive prognostic analysis the IMPACT investigators have developed prognostic models for predicting 6 month outcome in adult patients with moderate ...
[134]
Performance of the IMPACT and CRASH prognostic models for ...
Mar 15, 2024 · Overall, IMPACT models overestimated mortality and reasonably estimated unfavorable outcome, whereas CRASH models overestimated mortality and ...
[135]
Early Pupil Abnormality Frequency Predicts Poor Outcomes ... - NIH
Apr 29, 2025 · A higher frequency of abnormal pupil measurements within the first 72 hours is associated with unfavorable outcomes and significantly enhances ...
[136]
Hypotension and Adverse Outcomes in Moderate to Severe ...
Nov 11, 2024 · Hypotension has been established as a significant contributor to adverse outcomes, including mortality, disability, poor neurological function, ...
[137]
Diagnostic Performance of GFAP, UCH-L1, and MAP-2 Within 60 ...
Sep 4, 2024 · Blood-based biomarkers GFAP and UCH-L1 were approved by the US Food and Drug Administration (FDA) for clinical use in adult patients with mild ...
[138]
Prognostication of Mortality and Long-Term Functional Outcomes ...
The mortality rate in moderate and severe TBI patients at 6 months post-injury is 40.3% in adults (16–65 years) and rises to 50.0% in the elderly (>65 years).
[139]
Functional Outcomes Over the First Year After Moderate to Severe ...
Jul 6, 2021 · Among the severe TBI group, we found that 19% had no disability (DRS score 0) and another 14% had only mild disability (DRS scores 1-3) at 12 ...
[140]
Validation and comparison of two stroke prognostic models for ... - NIH
We aimed to validate and compare two clinical prognostic models for mortality which include the National Institutes of Health Stroke Scale (NIHSS); ...Missing: traumatic brain injury
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Systemic complications after head injury: a clinical review - Lim - 2007
Apr 18, 2007 · Pneumonia is the commonest non-neurological complication of severe TBI, occurring in 40–65% of patients [3, 6, 35], with those with the lowest ...Missing: thromboembolism prevalence
[142]
Traumatic brain injuries induced pituitary dysfunction: a call for ...
The prevalence of PTHP among patients with a history of TBI is estimated to be 15–68% (10, 11, 12). Symptoms may present at any time after the inflicting trauma ...
[143]
Hydrocephalus Following Severe Traumatic Brain Injury
Feb 15, 2022 · The purpose of this study was to identify the rate of occurrence of PTH in severe TBI patients both with and without DHC, determine predictors of hydrocephalus,
[144]
Paroxysmal Sympathetic Hyperactivity After Acquired Brain Injury
Nov 10, 2023 · In patients with severe TBI, the prevalence of PSH ranges from 8 to 33%, and the risk of developing PSH after TBI may be higher in adolescents ...
[145]
Second Impact Syndrome - StatPearls - NCBI Bookshelf - NIH
Second impact syndrome is a condition in which an individual experiences a second head injury before completely recovering from a prior head injury.
[146]
Chronic impact of traumatic brain injury on outcome and quality of life
Jun 21, 2016 · The global burden is such that TBI survivors have a lower life expectancy than the general population [4].
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Loneliness after a Brain or Spinal Cord Injury - Neuropraxis
Of those suffering from a traumatic brain injury, 70 percent have seen a deterioration in their social life, with a similar percentage feeling that people in ...Missing: prevalence | Show results with:prevalence<|control11|><|separator|>
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The costs of traumatic brain injury: a literature review - PMC - NIH
Jun 26, 2013 · The medical savings were estimated to be $11,280 per patient compared to the estimated cost to society of $164,951. They estimated the total ...
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Quality of life after traumatic brain injury: a cross-sectional analysis ...
Oct 17, 2020 · SF-36: Short Form (36) Health Survey: a 36-item patient-reported questionnaire regarding health status, used in medical outcome studies. TBI:.Missing: dissatisfaction | Show results with:dissatisfaction
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Satisfaction with Life after Mild Traumatic Brain Injury: A TRACK-TBI ...
A prospective study of 375 Emergency Department (ED) patients with mTBI found that roughly 45% reported dissatisfaction with life at 6 months post-injury, ...
[151]
Collaborative Care for Chronic Pain After Traumatic Brain Injury
Jun 3, 2024 · In a study of moderate-to-severe TBI, approximately 46% of 3804 participants endorsed current chronic pain, with back pain occurring most ...
[152]
Hippocrates: a pioneer in the treatment of head injuries - PubMed
Trepanation, a neurosurgical procedure still in practice today, is presented in detail. As a whole, the treatise, the first written work in medical history ...
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Hippocrates, Galen, and the uses of trepanation in the ancient ...
According to Hippocrates, injuries that require trepana- tion include cases of fissured fractures, bone contusion with or without associated fracture, and hedra ...
[154]
Paul Broca's historic cases: high resolution MR imaging of the brains ...
Apr 2, 2007 · In 1861, the French surgeon, Pierre Paul Broca, described two patients who had lost the ability to speak after injury to the posterior ...
[155]
Cerebral localization of higher functions: The period between ... - NIH
Pierre-Paul Broca Broca studied patients with speech loss (1861-1865) - his two initial cases, Leborgne (Tan) and Lelong, were examined in life, and their ...
[156]
Harvey Cushing's Wanderjahr (1900–1901) - PMC - NIH
Cushing devised an intricate pulley system to apply precise pressure to the exposed canine cerebrum. He created small craniectomy defects in experimental ...Missing: concepts | Show results with:concepts
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modern neurosurgery's definitive development in Harvey Cushing's ...
In the years 1901 through 1905, the implications of his research on the “Cushing reflex” were quickly translated into surgical techniques for controlling ICP.
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Dr Harrison Martland and the history of punch drunk syndrome | Brain
Dec 28, 2017 · In 1928, pathologist Harrison Martland published a paper entitled 'Punch Drunk', in which he proposed a link between neurological symptoms ...Pivotal work on punch drunk... · Legacy of Martland's work
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Chapter 7. Electrophysiological Assessment - Psychiatry Online
Electroencephalography (EEG) was the first clinical diagnostic tool to provide evidence of abnormal brain function due to TBI (Glaser and Sjaardema 1940) and ...
[160]
Military Traumatic Brain Injury: The History, Impact, and Future - PMC
Jul 21, 2022 · Mortality from brain wounds dropped to ∼12%, which meant more casualties in need of rehabilitation.
[161]
The Neuropsychology of Traumatic Brain Injury: Looking Back ...
Dec 4, 2017 · Introduced in the 1970s, computed tomography (CT) was the first imaging modality to characterize the heterogeneity in pathophysiology of acute ...
[162]
Advances in neuroimaging of traumatic brain injury and ...
For TBI, we focus on findings and advances in neuroimaging that hold promise for better detection, characterization, and monitoring of objective brain changes ...
[163]
A Clinical Trial of Progesterone for Severe Traumatic Brain Injury
Dec 10, 2014 · Progesterone has been associated with robust positive effects in animal models of traumatic brain injury (TBI) and with clinical benefits in two phase 2 ...
[164]
DoD-Funded Stem Cell Trial Expands in Texas to Treat Traumatic ...
Sep 16, 2025 · Enrollment has opened at UTHealth San Antonio for a 51-participant, FDA-authorized double-blind placebo-controlled Phase II clinical trial ...
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Study: New cases of CTE in players - ESPN
Dec 1, 2012 · Researchers at Boston University have discovered 28 new cases of chronic brain damage in deceased football players -- including 15 who played in the NFL.
[166]
Genetic Influences in Traumatic Brain Injury - NCBI - NIH
From this meta-analysis, the authors concluded that the presence of the APOE4 allele is not associated with the initial severity of brain injury but is ...
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Traumatic Brain Injury and Artificial Intelligence: Shaping the Future ...
Mar 7, 2025 · AI models have been developed to predict in-hospital mortality of TBI patients up to an accuracy of 95.6%. Furthermore, AI enhances neuroimaging ...
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[PDF] Motorcycle Helmet Laws: The Facts, What Can Be Done to Jump ...
California passed a universal helmet law in 1991,104 and in that first year, the number of motorcyclists hospitalized with a brain injury dropped by 53%.105 In ...
[169]
Twelve Years of National Football League Concussion Data - PMC
There were 0.38 documented concussions per NFL game in 2002-2007—7.6% lower than the 0.42 in the earlier period (1996-2001). The injury rate was lower in ...
[170]
Covid-19–associated diffuse posthypoxic leukoencephalopathy and ...
In our case, CSF analysis demonstrated mixed elevated CSF protein which likely reflect brain injury secondary to microhemorrhages and brain-blood barrier ...
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COVID Collection | Brain - Oxford Academic
Widespread hypoxic injury and microglial activation were seen in brain tissue, but little to no viral RNA or protein, suggesting that the neurological ...