Traumatic brain injury: Epidemiology, classification, and pathophysiology

INTRODUCTION — Traumatic brain injury (TBI) is a major source of health loss and disability worldwide. Globally, the annual incidence of TBI is variably estimated at 27 to 69 million [1,2]. Many survivors live with significant disabilities, resulting in major socioeconomic burden. In 2010, the economic impact of TBI in the United States was estimated to be $76.5 billion in direct and indirect costs [3,4].

The focus of this topic is on the epidemiology, pathophysiology, and classification of TBI. Other aspects of traumatic head injury are discussed separately. (See "Management of acute moderate and severe traumatic brain injury" and "Acute mild traumatic brain injury (concussion) in adults" and "Intracranial epidural hematoma in adults" and "Posttraumatic seizures and epilepsy" and "Subdural hematoma in adults: Etiology, clinical features, and diagnosis" and "Skull fractures in adults".)

EPIDEMIOLOGY

Definition of TBI — A simple, consistent definition of TBI is critical in estimating its burden. In 2010, the international interagency initiative toward common data elements for research in TBI and psychological health proposed a definition of TBI applicable across the spectrum of injury severity.

This definition states that TBI is an alteration in brain function, or other evidence of brain pathology, caused by an external force [5]. In this definition, the presence of confounding factors such as intoxication or medical illness does not preclude a diagnosis of TBI, although clinical judgment is used to decide whether the patient's symptoms are a consequence of the TBI. Additionally, this definition recognizes that clinical symptoms of brain injury may be delayed or absent, and that "other evidence of brain pathology" can include imaging or laboratory investigations. The focus of this definition is "brain" rather than "head" injury. The six categories of external force that may result in TBI include [5]:

●The head being struck by an object

●The head striking an object

●Acceleration/deceleration of the brain without direct external impact

●A foreign body penetrating the brain

●The force from a blast/explosion

●Other forces yet to be defined

Global trends — Estimating the global burden of TBI is challenging. For one, many patients with TBI, particularly with mild injury, do not seek medical attention. Also, high-quality epidemiologic data are mostly available from high-income countries, while the majority of the world's population resides in low- and middle-income countries. Existing data suggest, however, that the incidence of TBI varies substantially across countries and regions.

The Global Burden of Disease (GBD) study published the following estimates regarding TBI in 2016 [1]:

●Incidence – The global annual incidence was estimated at 27.08 million, with an age-standardized incidence rate of 369 per 100,000 population [1]. However, one study, which used open-source epidemiologic data on traffic injuries to model the incidence of TBI, estimated a worldwide annual TBI incidence of 69 million, higher than the GBD estimate [2].

●Prevalence – Global TBI prevalence was estimated at 55.5 million, with an age-standardized prevalence rate of 759 per 100,000 [1].

●Disability burden – TBIs were estimated to result in 8.1 million years of living with disability worldwide in 2016 (111 per 100,000, age standardized) [1].

●Causes – Overall, falls were the single most common cause of TBI, with road traffic injuries the second most common cause [1].

●Socio-demographic trends – Studies have reported somewhat conflicting data regarding socio-demographic trends.

Stratified by socio-demographic index (SDI), the age-standardized incidence rate was highest in the high-middle category at 468 per 100,000 [1]. While the incidence rate rose globally by 3.6 percent compared with 1990, it fell by 9.4 percent in countries with the highest SDI, rose by 21.8 percent in countries in the middle SDI category, and fell by 9.3 percent in the lowest SDI category. Falls were the single most common cause of TBI in every SDI category, with road traffic injuries the second most common cause. The reduction in TBI in high SDI countries is thought to be a result of road safety regulations.

In another study, the total burden of TBI was found to be three times greater in low- to middle-income countries compared with high-income countries [2]. In lower-income countries, 56 percent of TBIs were estimated to be due to traffic accidents compared with 25 percent in high-income countries. Other trends identified in other studies include a greater proportion of older TBI patients and falls as a mechanism of injury in high-income countries, compared with younger patients and traffic accidents as the primary mechanism of injury in lower-income countries [6-9].

Finally, in the Global Neurotrauma Outcomes Study, median age and mechanism of injury were strongly associated with human development index (HDI) tier across 57 countries [10]. Median patient age in low HDI tier countries was 28 years versus 54 years in very high HDI tier countries. In very high HDI tier countries, 27 percent of TBIs were due to road traffic collisions as opposed to 62 percent in medium tier and 37 percent in low tier countries.

United States — Few high-quality epidemiologic monitoring studies exist [6]. The GBD study estimates a TBI incidence of 1.11 million and prevalence of 2.35 million in the United States in 2016 [1]. Standardized for age, the incidence rate was 333 per 100,000 in 2016, a 3.3 percent reduction from 1990, while the prevalence rate was 605 per 100,000, a 5.7 percent reduction compared with 1990 [1].

The Centers for Disease Control and Prevention (CDC) estimates that in 2014 there were approximately 2.53 million emergency department (ED) visits, 288,000 hospitalizations, and 56,800 deaths related to TBI in the United States [11]. These numbers are thought to underestimate the burden of TBI, since they do not include patients who did not seek medical attention, received ambulatory care, were seen at Veterans Affairs centers, or were in the military.

Data from the CDC suggest that older adults bear the brunt of the morbidity and mortality associated with TBI [12]:

●The highest rates of TBI emergency visits were seen in older adults (≥75 years; 1682 per 100,000 population), the very young (0 to 4 years; 1619 per 100,000), and young adults (15 to 24 years; 1010 per 100,000).

●The highest rates of TBI-related hospitalizations occurred in the adults ≥75 years (471 per 100,000) compared with adults 65 to 74 years (146 per 100,000), and with adults 55 to 64 years (90 per 100,000). Rates of TBI-related deaths demonstrate similar age-related trends.

There was also evidence of a shift in the primary mechanism of TBI in the United States [4,11,12]. Compared with 2006, the rate of ED visits for TBI in 2014 increased 54 percent from 522 per 100,000 to 802 per 100,000. The largest increase (80 percent) was seen as a result of falls. Falls were the leading cause of TBI-related injuries, and over half of TBIs due to falls were in the youngest (0 to 4 years) and oldest (≥75 years) age groups. Rates of TBI-related deaths resulting from self-harm, including suicide, increased by 17 percent during the study period while age-adjusted rates of TBI-related hospitalizations due to traffic accidents fell. In adolescents, sports-related injuries account for a substantial proportion [13]. The proportion of TBI secondary to violence has risen over the past decade and now accounts for 7 to 10 percent of cases [14].

Lower socioeconomic status, alcohol and drug use, and underlying psychiatric and cognitive disorders are also risk factors for brain injury [13,15].

TBI is a major problem for the United States military; the Department of Defense reports that between 2000 and 2019, 413,858 military personnel suffered TBI [16], while 15,262 suffered TBI in the first three-quarters of 2019 [17].

Moderate and severe TBIs are associated with neurologic and functional impairments. The prevalence of long-term disability related to TBI in the United States is variably estimated to be between 3.2 to 5.3 million, or approximately 1 to 2 percent of the population [18,19].

Epidemiologic trends more specific to mild TBI are discussed separately. (See "Acute mild traumatic brain injury (concussion) in adults", section on 'Epidemiology'.)

CLASSIFICATION — TBI is a heterogeneous disease. There are many different ways to categorize patients in terms of clinical severity, mechanism of injury, and pathophysiology, each of which may impact prognosis and treatment.

The best prognostic models ideally include all of the factors described below, as well as age, medical comorbidity, and laboratory parameters [7,20,21]. However, treatment decisions are likely best informed by considering these variables individually rather than as a lump score. Further efforts at improved classification are ongoing, as these may help to refine treatment approaches [22].

Clinical severity scores — TBI has traditionally been classified using injury severity scores; the most commonly used is the Glasgow Coma Scale (GCS) (table 1), which should be measured in the emergency department (ED) following resuscitation and in the absence of sedation [23].

The GCS is universally accepted as a tool for TBI classification because of its simplicity, reproducibility, and predictive value for overall prognosis. However, it is limited by confounding factors such as medical sedation and paralysis, endotracheal intubation, and intoxication. These confounding issues are often particularly prominent in patients with a low GCS score [24,25].

An alternative scoring system, the Full Outline of UnResponsiveness (FOUR) Score, has been developed in order to attempt to obviate these issues, primarily by including a brainstem examination [26,27]. However, this lacks the long track record of the GCS in predicting prognosis and is somewhat more complicated to perform, which may be a barrier for non-neurologists [28].

Severity classification — A GCS score of 8 or less measured on admission represents severe TBI, a GCS score of 9 through 12 traditionally has represented moderate TBI, and a GCS score of 13 through 15 mild TBI.

However, the recognition that more than one-third of patients with TBI and a GCS score of 13 have potentially life-threatening intracranial lesions has led to a reevaluation of this classification [29,30]. While a revised classification has not been widely adopted, a GCS score of 9 through 13 likely best represents the TBI population at moderate risk for death or long-term disability (ie, "potentially severe"). The term "mild TBI" should be reserved for patients with a GCS score of 14 or 15 who have no major intracranial pathology on imaging. (See "Acute mild traumatic brain injury (concussion) in adults", section on 'Definitions'.)

The classification of severity based on the GCS reflects both the intensity of care required during acute hospitalization and long-term outcomes. Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) is a longitudinal observational study in the United States that investigated recovery from TBI extending from the acute hospitalization to several years following injury [31-33]. While most patients with severe (98 percent) and moderate (92 percent) TBI required initial admission to an intensive care unit, patients with severe TBI were hospitalized for a longer duration overall than patients with moderate TBI (mean 26 versus 15 days, p<0.001) [32]. By contrast, six months following injury, over 90 percent of patients with mild TBI and no evidence of intracranial pathology on computed tomography (CT) of the brain were completely independent within the home [31]. The prognosis of moderate and severe TBI is discussed in detail separately. (See "Management of acute moderate and severe traumatic brain injury", section on 'Outcomes'.)

Neuroimaging scales — TBI can lead to several pathologic injuries, most of which can be identified on neuroimaging [22]:

●Skull fracture

●Epidural hematoma (EDH)

●Subdural hematoma (SDH)

●Subarachnoid hemorrhage (SAH)

●Intraparenchymal hemorrhage

●Cerebral contusion

●Intraventricular hemorrhage

●Focal and diffuse patterns of axonal injury with cerebral edema

Two currently used CT-based grading scales are the Marshall scale and the Rotterdam scale:

●The Marshall scale uses CT findings to classify injuries in six different categories (table 2) [34]. It is widely used in neurotrauma centers and has been shown to predict the risk of increased intracranial pressure (ICP) and outcome in adults accurately, but it lacks reproducibility in patients with multiple types of brain injury.

●The Rotterdam scale is a more recent CT-based classification developed to overcome the limitations of the Marshall scale (table 3). It has shown promising early results but requires broader validation [35].

Other considerations — There are other important considerations for prognosis and treatment in individuals with severe TBI.

●Different disease mechanisms (eg, closed versus penetrating injuries, blast versus blunt trauma) may affect the type of pathologic brain injury.

●Extracranial injuries are present in approximately 35 percent of cases [36]. Multiple systemic traumatic injuries can further exacerbate brain injury because of associated blood loss, hypotension, hypoxia, and other related complications.

PATHOPHYSIOLOGY — The pathophysiology of TBI-related brain injury is divided into two separate but related categories: primary brain injury and secondary brain injury.

Current clinical approaches to the management of TBI center around these concepts of primary and secondary brain injury. Surgical treatment of primary brain injury lesions, particularly subdural and epidural hematomas, is central to the initial management of severe head injury. Likewise, the identification, prevention, and treatment of secondary brain injury is the principal focus of neurointensive care management for patients with severe TBI. (See "Management of acute moderate and severe traumatic brain injury".)

Primary brain injury — Primary brain injury occurs at the time of trauma. Common mechanisms include direct impact, rapid acceleration/deceleration, penetrating injury, and blast waves. Although these mechanisms are heterogeneous, they all result from external mechanical forces transferred to intracranial contents. The damage that results includes a combination of focal contusions and hematomas, as well as shearing of white matter tracts (diffuse axonal injury [DAI]) along with focal and global cerebral edema.

●Shearing mechanisms lead to DAI, which is visualized pathologically and on neuroimaging studies as multiple small lesions seen within white matter tracts (image 1). Patients with severe DAI may present with coma without elevated intracranial pressure (ICP). This typically involves the gray-white junction in the hemispheres, with more severe injuries affecting the corpus callosum and/or midbrain. Magnetic resonance imaging (MRI; in particular diffusion tensor imaging) is more sensitive than CT for detecting DAI, and the sensitivity of the test declines if delayed from the time of injury [37]. While some patients with DAI suffer a poor outcome, imaging evidence of DAI outside the brainstem is not a reliable predictor of poor outcome [38,39], and outcomes for DAI within the brainstem can vary substantially based on the degree of involvement of the ascending reticular activating system (ARAS) [40].

●Focal cerebral contusions are the most frequently encountered lesions. Contusions are commonly seen in the basal frontal and temporal areas, which are particularly susceptible due to direct impact on basal skull surfaces in the setting of acceleration/deceleration injuries (image 2). Coalescence of cerebral contusions or a more severe head injury disrupting intraparenchymal blood vessels may result in an intraparenchymal hematoma.

●Extra-axial (defined as outside the substance of the brain) hematomas are generally encountered when forces are distributed to the cranial vault and the most superficial cerebral layers. These include epidural, subdural, and subarachnoid hemorrhage.

•In adults, epidural hematomas (EDHs) are typically associated with torn dural vessels such as the middle meningeal artery and are almost always associated with a skull fracture. EDHs are lenticular shaped and tend not to be associated with underlying brain damage. For this reason, patients who are found to have EDHs only on CT scan may have a better prognosis than individuals with other traumatic hemorrhage types (image 3) [35]. (See "Intracranial epidural hematoma in adults" and "Intracranial epidural hematoma in children".)

•Subdural hematomas (SDHs) result from damage to bridging veins, which drain the cerebral cortical surfaces to dural venous sinuses, or from the blossoming of superficial cortical contusions. They tend to be crescent shaped and are often associated with underlying cerebral injury (image 4). Because cerebral atrophy causes stretching of the bridging veins, making them more susceptible to traumatic injury, SDHs may occur in response to no or minimal trauma in older adults. (See "Subdural hematoma in adults: Etiology, clinical features, and diagnosis" and "Intracranial subdural hematoma in children: Epidemiology, anatomy, and pathophysiology".)

•Subarachnoid hemorrhage (SAH) can occur with disruption of small pial vessels and commonly occurs in the sylvian fissures and interpeduncular cisterns. Intraventricular hemorrhage or superficial intracerebral hemorrhage may also extend into the subarachnoid space. (See "Nonaneurysmal subarachnoid hemorrhage".)

•Intraventricular hemorrhage is believed to result from tearing of subependymal veins, or by extension from adjacent intraparenchymal or subarachnoid hemorrhage. (See "Intraventricular hemorrhage".)

Approximately one-third of patients with severe TBI develop a coagulopathy, which is associated with an increased risk of hemorrhage enlargement, poor neurologic outcomes, and death [41-45]. While the coagulopathy may result from existing patient medications such as warfarin or antiplatelet agents, acute TBI is also thought to produce a coagulopathy through the systemic release of tissue factor and brain phospholipids into the circulation, leading to inappropriate intravascular coagulation and a consumptive coagulopathy [46].

Secondary brain injury — Secondary brain injury in TBI is usually considered as a cascade of molecular injury mechanisms that are initiated at the time of initial trauma and continue for hours or days. These mechanisms include [41,47-55]:

●Neurotransmitter-mediated excitotoxicity causing glutamate, free-radical injury to cell membranes

●Electrolyte imbalances

●Mitochondrial dysfunction

●Inflammatory responses

●Apoptosis

●Secondary ischemia from vasospasm, focal microvascular occlusion, vascular injury

These lead, in turn, to neuronal cell death as well as to cerebral edema and increased ICP that can further exacerbate the brain injury. This injury cascade shares many features of the ischemic cascade in acute stroke. These various pathways of cellular injury have been the focus of extensive preclinical work into the development of neuroprotective treatments to prevent secondary brain injury in TBI. No clinical trials of these strategies have demonstrated clear benefit in patients.

However, a critical aspect of ameliorating secondary brain injury after TBI is the avoidance of secondary brain insults, which would otherwise be well tolerated but can exacerbate neuronal injury in cells made vulnerable by the initial TBI. Examples include hypotension and hypoxia (which decrease substrate delivery of oxygen and glucose to injured brain), elevated ICP/decreased cerebral perfusion pressure (CPP), fever and seizures (which may further increase metabolic demand), and hyperglycemia (which may exacerbate ongoing injury mechanisms). (See "Management of acute moderate and severe traumatic brain injury".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Head injury in adults (The Basics)")

SUMMARY

●Definition – Traumatic brain injury (TBI) is defined as an alteration in brain function, or other evidence of brain pathology, caused by an external force. TBI encompasses a broad range of pathologic injuries to the brain of varying clinical severity that result from head trauma. (See 'Definition of TBI' above.)

●Epidemiology – The incidence rate of TBI varies across regions. TBI in high-income countries has trended toward an older age group, with falls as the primary mechanism of injury, while TBI in low- and middle-income countries trends toward a younger age group, with traffic accidents as the primary mechanism of injury. (See 'Epidemiology' above.)

●Causes – In the United States, TBI-related emergency department (ED) visits, hospitalizations, and deaths are most common in adults age ≥75 years. Falls have replaced traffic accidents as the most common mechanism for TBI-related ED visits, hospitalizations, and deaths, especially in older adults. Violence and self-harm have also become more common causes of TBI. (See 'Epidemiology' above.)

●Clinical severity classification – TBI is classically categorized using the Glasgow Coma Scale (GCS) (table 1) as mild (GCS score 14 through 15), moderate (GCS score 9 through 13), and severe (GCS score 3 through 8) according to clinical severity. (See 'Clinical severity scores' above.)

●Other classification schemes – TBI can also be classified according to the type and severity of neuroimaging findings, the mechanism of brain injury, and other variables. These factors individually, and in the aggregate, influence prognosis and treatment. (See 'Classification' above.)

●Pathophysiology – The pathophysiology of TBI includes primary and secondary brain injury:

•The pathoanatomic sequelae of primary TBI include intra- and extraparenchymal hemorrhages and diffuse axonal injury (DAI). (See 'Primary brain injury' above.)

•Secondary TBI results from a cascade of molecular injury mechanisms, which are initiated at the time of initial trauma and continue for hours or days. It is likely that secondary brain injury can be exacerbated by modifiable systemic events such as decreased cerebral perfusion pressure (CPP), hypoxia, fever, and seizures. (See 'Secondary brain injury' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Nicholas Phan, MD, FRCSC, FACS, and J Claude Hemphill, III, MD, MAS, who contributed to an earlier version of this topic review.