Definition of Traumatic Brain Injury

Traumatic brain injury (TBI) is defined as injury to the brain caused by external forces. These types of injuries result from a jolt or blow to the head, or are caused by an object penetrating the skull and injuring the brain. Examples of sources of TBI include motor vehicle accidents, falls, assaults, and gunshot wounds. TBI should be differentiated from other types of acquired injuries to the brain, such as those caused by tumor or stroke, because of the significant differences in mechanisms, treatments, and outcomes between traumatic and nontraumatic injury. TBI should also be differentiated from the term head injury, which is defined as a blow to the head or laceration and may occur without causing injury to the brain. A TBI can further be defined as either open or closed. An open, or penetrating, TBI occurs when the head is hit by an object that breaks the skull and enters the brain. A closed TBI occurs when the brain is injured but the skull remains intact. A diagnosis of TBI is often established through an evaluation of clinical symptoms, as well as positive neurologic signs and neuroimaging findings.

Defining Severity of Injury

TBI is often categorized as mild, moderate, or severe. The Glasgow Coma Scale (GCS) has become the most widely used primary initial assessment tool for determining the severity of injury (Box 49-1).⁴²⁶ During the initial stages of diagnosis in the field or emergency facility, TBI is suspected or indicated if there has been a significant blow to the head and/or there is an alteration of or loss of consciousness at the time of injury. An initial GCS score is obtained through clinical evaluation. As indicated in Box 49-1, the score is obtained by rating the best visual, verbal, and motor responses. The total score is simply a sum of these ratings, with scores ranging from 3 to 15. A score of 3T is given if the score obtained is due to medically induced chemical paralysis associated with intubation.

Generally accepted guidelines identify three levels of severity based on GCS scores: mild (GCS = 13 to 15), moderate (GCS = 9 to 12), and severe (GCS = 3 to 8). Individuals scoring in the mild TBI range should be evaluated at an emergency facility but might require minimal or no hospitalization. For more severe injuries involving loss of consciousness, the GCS is a widely accepted measure indicating the depth of coma and is generally serially measured until emergence from coma. However, the GCS has limited applicability to young children. The Pediatric Glasgow Coma Scale (PGCS) is a modified version of the GCS for use with pediatric TBI patients.³⁰⁹

Severity of injury is also defined by the duration of loss of consciousness/coma and the severity of symptoms. Individuals with mild TBI can experience brief loss of consciousness and transient confusion and neurologic symptoms. They might also experience a brief period of posttraumatic amnesia (PTA). PTA is generally characterized by a loss of memory for events surrounding the injury, disorientation, confusion, and significant cognitive impairment. Although there has been some discrepancy in the literature regarding the diagnosis of mild TBI, some general consensus among measures has been established and will be discussed later in this chapter. The terms complicated mild injury and postconcussive syndrome are often used to refer to cases in which diagnosis falls in the mild range but additional signs or symptoms of injury are present. Some examples include situations in which positive neuroimaging findings indicate injury to the brain, and/or where symptoms such as headache, dizziness, and cognitive dysfunction persist for a significant period after mild injury. Individuals sustaining moderate to severe TBI often have a more prolonged loss of consciousness, or coma. On emerging from coma, these individuals might initially be inconsistent in responding to environmental stimuli. As they become increasingly able to consistently respond, they might continue to exhibit symptoms of PTA for a significant period. Increased duration of coma and PTA have been associated with poorer prognosis and outcomes (to be discussed further in the outcomes section of this chapter). Some individuals with severe injuries do not regain consciousness, remaining in a “vegetative” state, whereas others emerge only to a minimally conscious state. The evaluation and care for individuals along the spectrum of injury and recovery will also be discussed in later sections of this chapter.

United States and Worldwide

Approximately 1.7 million TBIs occur each year in the United States.²⁴⁵ Of these, approximately 52,000 result in death and 1.365 million are mild injuries (often referred to as concussions), for which individuals are treated and released from the emergency room. This leaves approximately 275,000 individuals who survive moderate to severe TBI, generally requiring significant medical care and hospital stays. Many are left with long-term disability as a result of these injuries.²⁴⁵ According to one study, 40% of individuals hospitalized because of TBI reported at least one ongoing issue at 1 year after injury, with improvement of memory and problem solving listed as one of the most frequently unmet needs.⁸⁶ Such cognitive impairments, in addition to physical and medical issues, have significant impact on the ability of an individual to perform everyday activities. In fact, it is estimated by the Centers for Disease Control and Prevention that at least 5.3 million Americans currently have a need for long-term or lifelong assistance with activities of daily living (ADLs) as a result of TBI.⁴³⁵

Globally, TBI is a leading cause of death and disability. Although exact worldwide statistics are difficult to obtain, a fairly recent review estimated approximately 775,000 new TBI hospitalizations per year in Europe.⁴²² Available information suggests that the epidemiology of TBI on a global scale is similar to trends found in the United States. Incidence of TBI by age and gender varies slightly across regions but overall appears to follow patterns similar to those found in the United States.²⁰¹ For example, the distribution of mild, moderate, and severe TBI is consistent across the United States, Europe, Australia, and Asia: 80% of injuries are mild TBI, whereas moderate and severe TBI each account for 10% of injuries.⁴²²

Causes of Injury

The leading causes of TBI in the United States include falls (35.2%), traffic-related crashes (17.3%), struck by/against events (sports) (16.5%), assaults (10%), and other injuries (21%).²⁴⁵ Sports injuries account for 1.6 to 3.8 million TBIs a year, although most of these are mild injuries that are not treated in the hospital or emergency department.²⁴⁶ It should be noted that these statistics vary with age, gender, geographic location within and between countries, and with group membership as a result of multiple factors, as explained below.

What is known of the global etiology of TBI is similar to U.S. rates, with a few notable exceptions. Sixty percent of TBIs in Europe are due to road traffic injuries.¹⁶⁷ This figure is distributed evenly across most regions, suggesting that road traffic-related injuries are not associated only with high income countries. Twenty to 30% of injuries are due to falls, 10% violence, and 10% sports or work related.¹⁶⁷ India has the highest reported rate of TBI related to falls.^201,422 Latin America, Caribbean, and sub-Saharan Africa have the highest reported TBI rates as a result of road traffic incidents and violence.²⁰¹

Associated Costs

The costs of TBI including direct medical costs and lost productivity in the United States were estimated to total $60 billion dollars in 2000.¹²⁷ Worldwide statistics are less easily obtained. The costs associated with TBI go well beyond just the cost of medical care. The societal costs, or indirect costs, associated with the potential loss of productive work years for those who have been injured, as well as family members or others who might need to care for them, must also be considered. TBI also results in significant alterations in personal roles and responsibilities for the injured individual and family members. Reduced participation in complex leisure or recreational activities is also often a personal cost associated with TBI.

Demographics and Risk Factors

Primary Injury

TBI occurs in conjunction with mechanical forces that cause disruption to the brain tissue. Closed head injuries can occur as a result of mechanical forces that shear axons, as well as by forces at the site of the impact or at the point opposite the impact.¹⁴⁰ Contact forces occur when the head is prevented from moving after it is struck. Inertial forces occur when the head is set into motion and accelerates.¹⁷⁸

Inertial forces associated with angular acceleration result in diffuse axonal injury (DAI). This is a process that causes tensile strains resulting in microscopic disruption of axons, cerebral edema, and neuronal disconnection. In angular acceleration, the brain’s center of gravity moves over a center of angulation, or fulcrum, located in the lower to middle cervical region.¹⁴³ The severity of DAI depends on the duration, magnitude, direction of the angular acceleration, and associated impact.¹⁴³ In severe cases of DAI, more than just superficial axons and deeper white matter structures are affected. The gray–white matter junction is also particularly vulnerable to DAI. Midline brain structures, such as the corpus callosum, are often affected by DAI, and DAI is also associated with loss of consciousness and coma. Recovery from DAI is gradual and can be linked to the duration of coma.¹⁷⁸ Violent shaking associated with child abuse generates significant acceleration–deceleration forces, which result in shearing injury to brain tissue, disruption of blood vessels, and retinal bleeding.¹³⁰

Inertial forces associated with translational acceleration result in a head movement that is in line with the brain’s center of gravity. The resulting differential movement of the brain relative to the skull causes focal injuries such as contusions. Cortical contusions often occur on gyral crests, particularly on the undersurface of the frontal and anterior temporal lobes, where bony prominences located in the basilar skull can create tissue and vascular disruption. Contusions can occur under the impact site (coup injury) and result from a rapid skull distortion during impact.¹⁴³ Contusions remote from the injury site and opposite of the impact are contrecoup injuries and occur as a result of negative pressure generated from the impact, and are associated with translational acceleration.³²⁸ Patients with significant TBI can have one or more contusions, and deficits observed with cerebral contusions are linked with the lesion location and size.

DAI and focal contusions can result in neuronal disconnection, or diaschisis. The concept of diaschisis was first proposed by Constantin von Monakow in 1905 and refers to neurons remote from a site of injury, but anatomically connected to the damaged area, becoming functionally depressed. Because every structure in the brain is directly or indirectly connected to all other structures, the basic idea generated from this concept is that damage to one structure will be disruptive to other structures. Imaging studies suggest that diaschisis can result in the metabolic depression of areas both regionally associated and remote from the site of injury.^121,295 Others suggest that focal cortical lesions can affect contralateral cortical functioning by way of intercallosal connections¹⁰² and can affect the function of subcortical structures, including the striatum.¹²¹ Resolution of diaschisis is one of several theories for recovery of function.^121,295

Epidural hematomas (EDHs) result from local impact and subsequent laceration of underlying dural veins and arteries. The meningeal artery is commonly the source of EDHs, and damage to dural sinuses can also cause EDH. When an EDH develops from a disrupted artery, a neurologic emergency occurs because the EDH quickly expands and rapidly causes neurologic deterioration.¹⁷⁸

Subdural hematomas (SDHs) result from inertial forces and the tearing of bridging veins.³²⁸ Bridging veins are susceptible to shear and rupture from brief high-velocity angular accelerations associated with falls.¹⁴¹ Traumatic subarachnoid hemorrhage (SAH) occurs when angular acceleration shears vessels located in the subarachnoid space.¹⁷⁸

Secondary Injury

Secondary injury develops over the hours and days after the initial impact and is associated with disruption of cerebral blood flow and metabolism, massive release of neurochemicals, cerebral edema, and disruption of ion homeostasis leading to cellular injury and eventual cell death. Much of what is known about secondary injury is derived from postmortem analyses of human brain tissues, blood, cerebrospinal fluid (CSF), and parenchymal microdialysate fluid obtained early after clinical TBI. Much of the work exploring secondary injury has also used in vivo experimental models of TBI and in vitro injury methods. Experimental models of TBI produce one or more types of primary injury, which lead to the development of secondary injury cascades that closely resemble observations made in the human condition.^104,276,404

Brain swelling occurs in response to the initial injury and early events involved with secondary injury and results in elevated intracranial pressure (ICP) and decreased cerebral perfusion pressure (CPP). If severe enough, brain swelling can lead to herniation, which has potentially fatal consequences. In some cases, elevated ICP is due to the development of focal extraaxial lesions like SDH and EDH described above. In other cases, elevated ICP and intracranial hypertension result from global mechanisms occurring on a cellular level that lead to brain edema. Some mechanisms that affect brain edema include vasogenic edema, increased tissue osmolarity, and vascular dysregulation resulting from increased cerebral blood volume. However, brain edema resulting from neuronal and astrocyte swelling secondary to increased glutamate metabolism after excitotoxic insult might impart the most damage.²³¹

Excitatory amino acids (EAAs) like glutamate and aspartate are ubiquitous and important neurotransmitters for normal brain function. After TBI, excess excitatory amino acid levels are present in extracellular microdialysate fluid and CSF.^53,452 Excess EAA release occurs, in part, from the mechanical stresses associated with stretch injury of axons. Elevations in extracellular glutamate levels after TBI contribute to excitotoxic injury by affecting other paths of secondary head injury through two primary mechanisms. By binding their target receptors, excess EAAs can trigger an influx of sodium and chloride that leads to acute neuronal and astrocytic swelling. Excess EAA levels can also lead to an intracellular calcium influx and the release of Ca⁺⁺ from intracellular stores, leading to delayed cellular damage or death.^70,415 EAA-mediated, Ca⁺⁺-dependent production of nitric oxide, superoxide, and free radical damage to DNA and cellular membranes leads to cell death.²⁶⁵ Regional differences in the distribution of EAA-sensitive receptors contribute to selective vulnerability of some regions to excitotoxic injury like the hippocampus, a critical region for learning and memory.³⁰⁰

Lactate is the end product of glycolysis, and in neurons, lactate is converted to pyruvate for oxidative metabolism. Lactate/pyruvate ratios reflect the cellular energy balance and the cytosolic oxidation–reduction state.³⁹⁸ Increased metabolic demand after TBI is due, in part, to increased astrocytic glutamate uptake and results in increased lactate. Reduced cerebral blood flow, including pericontusional hypoperfusion, has been documented in both experimental models¹⁸⁷ and in humans⁴⁰⁹ early after TBI and results in ischemic injury. Elevations in lactate/pyruvate have been measured in pericontusional tissue in humans⁴⁴⁸ and are associated with other aspects of secondary injury, including increased ICP and mitochondrial dysfunction.

Although extracellular lactate has classically been a marker for anaerobic metabolism with hypoxic injury, newer research indicates that lactate is also used by brain tissue during an insult as an important energy source in oxidative metabolism.³⁵⁶ Evidence supports a dichotomous role of lactate in which it is produced by the astrocyte via glycolytic metabolism, to be directly consumed by the neuron after uptake through lactate transporters,^89,356 Physiologically³³⁷ and after TBI,³⁵⁶ excitatory amino acids are likely triggers to this metabolic process. After injury, estrogen facilitates lactate production for neuronal use by modulating lactate transporters.²⁹³ Experimental studies suggest that lactate is used as a neuronal energy substrate after TBI, and lactate administration after TBI is neuroprotective and decreases cognitive deficits.³⁶⁰

Mitochondrial dysfunction is often the result of energy failure and excitotoxic insult and results in the formation of highly reactive free radicals and subsequent oxidative damage to cell membranes and DNA. Hydroxyl radicals and other reactive oxygen species (ROS) react with many molecules found in living cells, including DNA, membrane lipids, and carbohydrates. Central nervous system (CNS) tissue is particularly vulnerable to oxidative injury because of the high rate of oxidative metabolic activity, the nonreplicating nature of neurons, high levels of transition metals, and a high membrane/cytoplasm ratio in neurons.¹⁰ Superoxide radicals are a principal mediator of the microvascular damage after TBI.²⁴² Free-reactive iron generated from hemorrhage catalyzes the formation of free radicals.²³¹ ROS production may also be a downstream effect of caspase-mediated cell death (apoptosis).¹²⁶

Cell death in CNS tissues after brain trauma falls into two primary categories: (1) cellular necrosis and (2) apoptosis or programmed cell death. Necrotic cells display cellular and nuclear swelling as well as disruption of cellular membranes. In contrast, apoptotic cells are characterized by cellular shrinkage, nuclear condensation, and DNA fragmentation.²¹⁶ Apoptosis is accompanied by a cascade of events required for cell death to occur.⁴¹⁰ Cell death patterns in TBI often reflect a combination of both necrosis and apoptosis.

Apoptosis can be initiated through either extracellular or intracellular signaling pathways. Cysteine-aspartic acid proteases (caspases) play an essential role in cell death via both pathways. Extracellular binding of cell surface death receptors, including tumor necrosis factor (TNF)-α receptor and Fas ligand receptor, initiates apoptotic signals that include caspase-8 and caspase-3 within seconds of ligand binding. Intracellular signaling is initiated by mitochondrial dysfunction in response to disturbances in cellular energy balance, oxidative injury, and changes in ionic homeostasis. This mitochondrial stress leads to the opening of the mitochondrial transition pore and cytochrome c release. Cytosolic cytochrome c release induces multiple caspases, including caspase-9 and caspase-3, which leads to the cleavage of key cellular elements like cytoskeletal proteins and DNA repair proteins as well as the activation of endonucleases.⁷⁷ In addition to this intracellular caspase-dependent process for apoptosis, intracellular apoptosis signaling can also occur via a caspase-independent pathway with apoptosis-inducing factor (AIF). AIF is released from the mitochondria and results in DNA fragmentation. The mitochondria house prosurvival and prodeath proteins that are both members of the BCL-2 protein family,² each of which can be manipulated experimentally to effect cell survival. As an example, estrogen enhances BCL-2 expression and cell survival after CNS injury.¹⁹⁹

Inflammation after TBI is characterized by complex cascades that largely include cytokines, or signaling molecules, that communicate with resident and infiltrating inflammatory cells. Cytokines like interleukin (IL)-1β and TNF are well studied in TBI. They are synthesized by peripheral cells and CNS neurons and glia, and are increased early after injury. IL-1β and other cytokines are also synthesized by activated microglia. IL-1β has potent leukocyte signaling properties that lead to cellular inflammatory responses after TBI. Cytokines generally can facilitate blood–brain barrier (BBB) disruption, cerebral edema, and cell death. Specifically, IL-1β and TNF can mediate synthesis of neurotoxic compounds such as arachidonic acid and are implicated in excitotoxic components of secondary injury.³⁷⁴

Cytokines are expressed in the brain and promote neuronal differentiation and survival under normal conditions. Cytokines play a dual role in secondary injury with TBI, and inflammatory cascades can either enhance cellular injury or provide neuroprotection. Some cytokines support neuroprotection and neurorepair through their effects on neurotrophin production, excitotoxicity, and antiinflammatory properties.^223,307 Some studies suggest that cytokine effects might be dose dependent, with higher levels more likely to be associated with detrimental effects and lower levels being neuroprotective. Cytokine effects might also be time dependent, with beneficial effects more likely at delayed or chronic time points after injury.³⁰⁸ TNF is an example in which time-dependent functions have been demonstrated,³⁸⁷ with TNF expression being protective at later time points after injury.

Aside from BCL-2 and the prosurvival components of neuroinflammation, other CNS compounds serve as endogenous neuroprotectants after TBI. Adenosine is a purine ribonucleoside and is ubiquitous in the brain, where it largely functions as a major neuroinhibitory molecule. After experimental brain injury, extracellular adenosine levels increase by 50- to 100-fold compared with baseline,²⁷ a phenomenon that is implicated as an endogenous neuroprotective mechanism. Adenosine functions as a neuroinhibitory molecule through its primary target, the A1 receptor. A1 receptor activation is a key local regulator of excitatory amino acid release during ischemia and trauma.¹² Adenosine can also hyperpolarize neuronal membranes and attenuate intracellular Ca⁺⁺ accumulation. Neurotrophins might also have a neuroprotective role after TBI, particularly because early increases in neurotrophin expression have been reported in experimental TBI.^193,492

Concomitant Injury

TBIs (especially the more severe cases) often are not an isolated injury. High-speed vehicular crashes and active combat frequently result in multiple injuries that can affect outcome.²³⁰ In civilians, associated injuries are linked with more disability even 1 year after the injury.⁴⁵⁵ TBIs associated with multiple other injuries are also associated with longer acute care lengths of stay and need for rehabilitation resources.⁴⁵³ In addition to increased functional deficits, rehabilitation needs, and more disability, concomitant injuries can directly affect secondary injury and associated pathology, and these phenomena have received some attention in the TBI literature. For example, experimental models incorporating TBI and hemorrhagic shock show increased hippocampal injury compared with TBI alone, a phenomenon likely associated with increased secondary ischemia.⁹²

Military Blast Injury

With the ongoing military conflicts in Iraq and Afghanistan, TBI is not only a common problem in the civilian population but also is a major problem for active combat military personnel. The frequent use of improvised explosive devices in these conflicts has resulted in a large number of military personnel (see previous epidemiology sections) sustaining TBI from blast injury. Blast injury can result in both blunt and penetrating trauma and follows a specific nomenclature (Box 49-2). Explosives can be categorized as high-order explosives (HE) or low-order explosives (LE), and each can cause a distinct injury pattern. HE produces a supersonic overpressurization shock wave that is associated with “primary injury.”⁴⁴¹ In addition to middle ear damage, brain injury can occur from primary blast injury without overt evidence of injury. The rapid pressure changes generated from the overpressure wave result in shear and stress forces that lead to trauma such as concussion, SDH, and DAI.^94,421 Penetrating head injury from flying debris is the result of secondary blast injury. Both HE and LE can result in tertiary blast injury from being physically thrown by a blast wind into the ground or other objects. Quaternary injury includes asphyxia or inhalation of toxic chemicals that can also contribute to brain injury. Many patients suffer from TBI induced from more than one facet of blast injury.

Research is increasingly being conducted to develop relevant blast injury models of TBI to examine and characterize mechanisms of primary and secondary injury for blast TBI and to assess behavioral effects.^21,60,264 The clinical difficulties after blast TBI of any severity can include headache, insomnia, decreased memory and attention, slower thinking, irritability, and depression.⁹¹ Additional research is focused on clinical symptom screening and outcomes, as well as physiologic markers and biomarkers associated with this type of TBI.^7,418,436

Repair, Regeneration, and Recovery

Acute mechanisms of secondary injury heavily influence the degree and type of injury and deficits that those with TBI experience. The chronic period after injury is characterized by multiple neurotransmitter deficits and cellular dysfunction. During this period, however, research demonstrates that the brain is amenable to neuroplasticity, repair, and recovery, and the potential for these processes can be augmented using relevant rehabilitation strategies.

One mechanism by which TBI recovery occurs is through the reversal of diaschisis. Contemporary thought on the concept of diaschisis suggests that the functional effects of diaschisis can be either reversible or permanent. The mechanisms by which diaschisis resolves, however, are poorly understood and likely multifactorial. The resolution of cerebral edema¹⁸¹ and blood flow regulation¹²¹ can contribute to early recovery.²³³ Later during the course, the alleviation of diaschisis might involve factors like synaptic plasticity,^295,365 axonal sprouting,³⁷² and cortical reorganization.²³⁸ Diaschisis after brain injury can be manipulated by both behavioral experience (rehabilitation) and pharmacologic intervention.^325,392 For example, depressed thalamic metabolism after cortical infarction was reversed with administration of neurostimulants such as amphetamine.³⁴²

Experimental and clinical research suggests that DA systems are key pathways involved in attention, task salience, and cognition, and that these pathways are chronically impaired after TBI.²⁰ Alterations in both presynaptic and postsynaptic dopaminergic proteins in the striatum and frontal cortex have been documented, including important proteins involved in DA synthesis and uptake.^{20,451,462,491} Decreases in striatal DAT expression, a key protein in regulating the extracellular half-life of DA, have been documented in humans.¹⁰⁷ Further research demonstrates that striatal neurotransmission is impaired, and this might be the result of TBI-induced changes in DA protein functionality.^451,462

Noradrenergic systems affect arousal, sleep–wake cycles, vigilance, and cognition, and the NET appears to affect NE neurotransmission, as well as interact with DA systems to affect DA neurotransmission.⁴⁶⁵ Noradrenergic function is impaired early after TBI. Previous reports suggest that cortical NE levels are decreased within 24 hours after brain injury, and adrenergic receptors are altered after injury.^348,349 NE augmentation early after TBI is neuroprotective, however, and NE agonists aid in neurorecovery.^37,108 It is important to remember that NE is critical for governing cortical plasticity and facilitating recovery post-TBI. By stimulating adrenergic systems with amphetamine and L-threo-dihydroxyphenylserine (or L-DOPS), a precursor of NE, neuronal damage after TBI can be minimized and sprouting is promoted.^{153,154,217,414,416}

Cholinergic systems are important for memory and cognition, and evidence suggests chronic impairments can occur after TBI. Hippocampus expression of the vesicular acetylcholine transporter is increased; however, evoked release of acetylcholine in neocortex and hippocampus is reduced after experimental TBI.^100,106,393 Daily local application of nerve growth factor also enhanced memory and hippocampal neuron function after experimental TBI.¹⁰¹

In addition to acute protection and cholinergic function, other studies support a role for neurotrophin administration in promoting long-term recovery. In contrast to acute increases in neurotrophin production, other work suggests that hippocampal brain-derived neurotrophic factor (BDNF) is decreased during chronic recovery from experimental TBI.⁶⁶ An enriched environment can reverse these decreases,⁶⁶ but chronic pericontusional administration of BDNF does not improve behavioral outcome or hippocampal cell survival.³² Intraparenchymal administration of both basic fibroblast growth factor and nerve growth factor reduces cognitive deficits in experimental TBI.^289,402 With these positive studies, improved recovery might be secondary to stimulation of brain repair and neuroplasticity.

Management of Mild Traumatic Brain Injury (Concussion)

Like more severe injuries, concussion results in significant alterations in brain physiology. After an initial increase in glucose use, brain metabolism is impaired and associated with the development of energy crisis, oxidative injury, and the initiation of biochemical cell death pathways. These derangements can occur for up to weeks after the concussion and persist even with a normal GCS score and general neurologic examination.¹⁵¹

There are several criteria and scoring systems for classifying degree or severity of mild TBI. The World Health Organization Collaborating Centre Task Force on Mild TBI states that key criteria for identifying persons with a mild TBI should include (1) at least one of the following: confusion, disorientation, loss of consciousness for less than 30 minutes, PTA for less than 24 hours, or other transient focal neurologic abnormalities, and (2) GCS score of 13 to 15 after 30 minutes or presentation to a health care facility. Findings with these criteria should be made in the absence of illicit drugs, alcohol, medications with sedating side effects, or other injuries or problems.⁵⁸ Patients with uncomplicated TBI typically do not have associated abnormalities on standard imaging tests like computer tomography (CT). Concussion severity nomenclature has been developed for the purposes of injury characterization and injury management. Some examples of concussion are provided in Table 49-1.^57,81,215

Table 49-1 Concussion Grading Scales

Patients with concussion frequently complain of any number of associated symptoms, including memory loss, poor concentration, impaired emotional control, posttraumatic headaches, sleep disorders, fatigue, irritability, dizziness, changes in visual acuity, depression, anxiety, personality changes, and seizures.^9,481 These problems can affect ADLs, social relationships, and abilities in the workplace. For most individuals with mild TBI, the symptoms resolve over time. A subset of patients, however, will have persistent symptoms classified as postconcussional syndrome and can require outpatient follow-up evaluation. The types of symptoms, proportion of patients who have persistent symptoms, and the duration of symptoms required to define symptoms as persistent have been widely debated. Reports of symptom duration to define persistent deficits can range between 3 and 12 months. The fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) suggests that individuals showing objective evidence of cognitive deficits, as well as three or more subjective symptoms, that represent a change in baseline function for at least 3 months can be classified with postconcussional disorder. Other classification systems, such as the International Classification of Diseases, 10th edition (ICD-10), do not include objective evidence of cognitive deficits.⁴⁸¹ Despite variability in definitions and classification, some studies suggest that females are more likely to have postconcussional syndrome.³⁴⁶

Athletes comprise a large portion of the population who sustain mild TBI, and many of these athletes are children. Special issues arise with this population with regard to “on site” concussion screening tools, determining the most effective algorithm for return to play, safety equipment use, management and prevention of recurrent injuries, and academic performance. As a general rule, athletes should be free of postconcussive symptoms before returning to competition. One report shows that 30% of high school football players return to play the same day of injury.¹⁶⁸ Many return-to-play guidelines, however, outline that athletes with a grade 1 or 2 concussion have a minimum of a 7-day period free of symptoms before returning to play.¹⁶⁹ Same-season injuries often occur within 7 to 10 days of the initial injury, a timeframe in which there is increased vulnerability to damage with the second insult.¹⁵¹ Most return-to-play algorithms emphasize a graded protocol for reintroducing the athlete to physical exertion. Recent studies, however, suggest that academic and cognitive exertion can affect postconcussive symptoms and cognitive testing performance and should be considered when developing return-to-play protocols for athletes.²⁷¹ Several guidelines recommend termination of sports participation for the remainder of the season if an athlete sustains a third concussion within that season.^57,358 Athletes who have one concussion are at increased risk for subsequent concussion,¹⁶⁹ and making a return to contact sports even after a single concussion is a decision that requires careful thought and consideration.

Acute Medical Management of Moderate to Severe Traumatic Brain Injury

The care of the patient with TBI begins in the field. Evidence-based guidelines put forth by the Brain Trauma Foundation and the American Association of Neurological Surgeons support a regional organized trauma care system that addresses prehospital care and triage. Direct transport of a patient with severe TBI to a Level 1 or 2 trauma center is associated with decreased mortality compared with indirect transport.¹⁸³ Facilities defined by the Guidelines for Prehospital Management of Traumatic Brain Injury as being appropriate facilities for transport include those offering CT scanning, neurosurgical care, ICP monitoring, and treatment capabilities. These facilities can provide 24-hour neurosurgical care, and intensive care treatment ICP monitors are routinely used. Each state can designate trauma facilities based on the availability of such care. Although treatment guidelines for initial management are not specific, the recommendations include complete and rapid physiologic resuscitation. Correction of hypoxia, including intubation, is appropriate. Sedation and neuromuscular blockade might need to be used to optimize the transport of the head injury patient.⁴¹

ICP has been the mainstay of monitoring after severe TBI. ICP can be monitored using a ventriculostomy, which is the procedure of choice because it allows therapeutic CSF drainage. ICP monitoring is appropriate in those patients with a GCS score of 8 or less after resuscitation, head CT showing contusions or edema, or systolic blood pressure less than 90 mm Hg.³¹⁶ ICP monitoring can also be considered in patients with severe TBI and a negative head CT if they are more than age 40, posturing, and/or have systolic blood pressure less than 90 mm Hg.⁴⁰ Elevated ICP is defined as 20 to 25 mm Hg in clinical practice. Maneuvers to decrease ICP include elevating the head of the bed 30 degrees, treatment of hyperthermia, mannitol administration, sedation, and brief hyperventilation. Prolonged chronic hyperventilation can negatively affect cerebral blood flow.³⁹

CPP is defined as the mean arterial pressure minus ICP and is the pressure gradient driving cerebral blood flow. Studies have documented worsened clinical outcomes in TBI patients with episodes of low CPP.⁶⁹ The current therapeutic recommendation is that CPP be maintained at more than 60 mm Hg in adults.⁴² Measurement of cerebral oxygen tension allows the practitioner to directly measure ischemia, rather than rely on the indirect measurement of CPP or ICP. Tissue oxygenation monitors, directly placed in brain tissue via an external ventricular drain (EVD), can detect focal ischemic changes that can go undetected with global measures. Interventions are then tailored to the cause of the decrease in tissue oxygenation. Studies have shown reduction in mortality with addition of this monitoring.⁴¹¹

Other treatment interventions have been studied in acute care clinical trials. A multicenter trial evaluating the role of corticosteroids in management of acute TBI showed an increase in mortality 2 weeks after TBI compared with placebo.³⁶⁷ Elevated CSF cortisol levels in severely injured patients might contribute to this outcome.³⁶⁸ Progesterone is a drug with pleiotropic neuroprotective properties identified in several preclinical studies occurring over decades.⁴⁰⁸ Recent clinical trials have shown its safety, and progesterone appears to have potential as a therapeutic agent.^482,487

Animal studies have evaluated the protective use of hypothermia, with several showing positive results.^76,96 Clinical trials using moderate hypothermia have shown some reduction in excitotoxic insult^274,452 and neurologic impairment; however, the results have not been consistent. For example, a large multicenter trial of hypothermia did not show improved outcomes in those patients with severe TBI.⁷⁸ To transition this treatment to routine human use, factors such as treatment window, rewarming rates, and type of anesthesia must be defined.⁴⁰⁷ Gender effects on treatment efficacy and physiologic response to treatment should also be considered.^23,417,452

Surgical treatment of TBI is indicated when intracerebral fluid collections exert a significant mass effect. Mass effect can be gauged by degree of midline shift on neuroimaging, and the decision to intervene can require serial neurologic examinations and CT scans.⁵² Depressed skull fractures greater than the thickness of the skull should be elevated to decrease the risk for infection, especially in the setting of a dural laceration. Surgical treatment can also be used to lower ICP. The use of decompressive craniectomy to decrease ICP is an accepted intervention, although the reduction of morbidity and mortality has not been proven.⁴⁷⁷

Secondary complications occurring in the intensive care unit (ICU) can also negatively affect TBI outcomes. Elevated glucose levels are associated with increased mortality after TBI, presumably as a result of increased lactic acid production leading to ischemia and impaired phosphorus metabolism.³⁷⁵ Sodium imbalance can potentiate risks for seizure, as well as worsen level of consciousness. Sodium imbalance is directly related to volume status. Hyponatremia can be exacerbated by the use of excessive volumes of intravenous fluids. This occurs even in the setting of normal saline or lactated Ringer’s solution used for fluid resuscitation, making monitoring of electrolytes and volume status important in preventing secondary complications. Prevention and aggressive treatment of infections are also important. Hyperthermia is another source of acceleration of secondary insults to brain parenchyma, increasing ischemia.²⁷³

Early initiation of nutrition is vitally important in the TBI patient. Metabolic rates can increase 40% during the early stages after injury. Guidelines recommend replacement of 140% of resting metabolism expenditure (100% of resting metabolism expenditure in paralyzed patients). The use of the gastrointestinal tract is preferred to maintain nutritional status. The goal of treatment is to maintain a positive nitrogen balance, although this is difficult to achieve. Measures such as nitrogen balance via a metabolic cart study, prealbumin levels, and liver functions should be followed in the ICU. Delaying nutrition replacement is associated with increased mortality.¹⁸⁴

The physiatrist plays a role in evaluating patients who have sustained TBI. The early assessment includes prevention of orthopedic and immobility complications. Early consultation can result in improved mobility, improved functional outcomes, and decreased acute care length of stay. In this model, rehabilitation assessment is a portion of the acute medical care, providing education and support for patients, families, and caregivers.⁴⁵³

Physiologic Measurements During Acute Care

Somatosensory-evoked potentials (SSEPs) are recorded from the scalp after stimulation of a sensory or mixed nerve in the peripheral nervous system. SSEPs are often used in severe TBI cases to predict survival and evaluate posttraumatic coma and persistent vegetative states. In some cases, SSEP testing is used as an adjunct to the clinical examination in determining brain death.¹⁷⁴ Cant et al.⁵⁶ found that bilateral loss of the median SSEP was indicative of impending death, and asymmetric findings observed in the cortical response were indicative of severe residual deficits. Their study indicated that serial SSEPs often change through the hospital course, and each study does not always correlate well with the ultimate outcome.

Like other neurologic evaluations, electroencephalography (EEG) can be beneficial when assessing TBI patients to detect injury severity and depth of coma.³⁷⁸ Degree of unconsciousness can quickly change, and continuous EEG (cEEG) monitoring can detect electrophysiologic signs of clinical deterioration.¹⁷⁵ Initial EEG recordings taken within 24 hours of injury, however, are generally more abnormal and of less prognostic significance than those performed after 24 to 48 hours.⁴¹⁹ cEEG is a standard part of care at some Level 1 trauma centers, and cEEG can be used to effectively identify subclinical electrographic seizures, which are associated with other physiologic factors that contribute to poor outcome, such as ICP elevations and increases in metabolic stress.⁴⁴⁷

Pupillary reflexes have been used not only as clinical indicators of surgical emergencies and complications in TBI associated with edema and herniation but also as a tool in determining lesion location, mortality, and global outcome after injury. The presence or absence of pupillary reflexes and degrees of anisocoria have been used in models predicting the probability of intracerebral hematoma and lesion location.⁶⁸

Although not yet used routinely at the bedside, biomarkers have considerable potential as adjunctive tools in TBI diagnosis, prognosis, and monitoring treatment effect. Protein biomarkers that have been studied in TBI include either (1) markers of structural damage or (2) markers reflective of the cellular and molecular cascades observed with secondary injury and repair. Protein biomarkers have also been studied in both CSF and serum. CSF biomarker studies are valuable in that measured levels are largely a reflection of CNS pathology. CSF collection is only routine, however, in severely injured patients who require an extraventricular drain for management of ICP. Serum markers are attractive because of their potential application to mild and severe cases of TBI, but serum biomarker levels are often limited by the extent of BBB permeability present after the injury. Markers of acute injury have been much more thoroughly studied compared with chronic markers of injury.