Traumatic brain injury (TBI) is the leading cause of death and disability in young adults in the United States; the total national cost of TBI is more than $39 billion a year.1 Elucidation of the pathophysiology of brain injury is an important challenge for physicians who care for TBI patients. Equally important are prevention and a better scientific understanding of recovery and rehabilitation.
TBI is now generally viewed as a multidimensional, dynamic process. It is not unusual for a patient with TBI who initially is relatively stable and awake or in a light coma to deteriorate rapidly. Delayed hematoma or expanding contusions that are amenable to surgery account for many such cases. Others are related to uncontrolled brain swelling that may not respond to conventional management. Delayed secondary injury at the cellular level is also a major contributor to brain swelling and tissue loss after TBI. The ultimate pathologic picture thus evolves during the first few hours and days after trauma, and the physiologic, clinical, and behavioral aspects of recovery can continue for years. For these reasons, therapy should be predicated on an understanding of the multidimensional pathology of TBI and its evolution.
TBI is traditionally classified by its severity [see Table 1], though the current definitions are imperfect and distinctions between mild, moderate, and severe head injury can be difficult to make in the acute period. For example, acute management of an unconscious patient with a moderate head injury may differ little from that of a comatose patient with a more severe head injury; or a patient with little or no initial loss of consciousness may harbor a more serious and even life-threatening pathology, such as a delayed hematoma. Nevertheless, the distinctions are generally useful in guiding the approach to the patient.
Etiology
Brain injury may be caused by any of several types of head trauma, including the more typical closed head injury (in which rapid acceleration or deceleration causes the brain to strike the inside of the skull), direct impact to the head, or penetration by a missile or other foreign object. Although some details of the pathology of these types of trauma may differ, acute and long-term management are similar in most cases.
Pathogenesis
The pathologic changes that occur in TBI may result less from the injury itself than from an uncontrolled vicious circle of biochemical and physiologic events set in motion by the trauma. These biochemical events include changes in arachidonic acid metabolites (e.g., the prostaglandins); the formation of oxygen free radicals and lipid peroxidation; and changes in electrolytes (e.g., calcium and magnesium) in excitotoxic neurotransmitters (e.g., glutamate) and changes in various kinins and cytokines.2 These events can result in progressive injury to otherwise viable brain tissue by altering vascular reactivity and producing further ischemia, by producing brain swelling (hyperemia, edema, or both), by injuring neurons and glia directly, or by activating macrophages that cause neuronal and glial injury. The patient with severe TBI also often has multiple systemic abnormalities—such as changes in nutrition, cardiopulmonary status,3 circulating catecholamines, and coagulation4— that may be directly related to the brain injury and may have a profound impact on treatment.
At least five parallel components of the pathology of closed head injury have been identified: (1) focal hematomas and contusions, (2) diffuse axonal injury, (3) diffuse microvascular injury with loss of autoregulation and acute brain swelling, (4) hypoxia-ischemia, and (5) selective neuronal loss (especially of thalamic reticular, hippocampal, and cerebellar neurons), possibly caused by excitotoxins. In addition, recent electrophysiologic evidence suggests that a diffuse neuronal (gray matter) dysfunction may be the most subtle and sensitive measure of mild TBI and concussion [see Diffuse Gray Matter Dysfunction, below]. Each component may have a different effect on the patient, depending on the patient’s premorbid status, the severity of the injury, the treatment given, and the time that has elapsed since injury.
Some of these pathologic processes, such as focal hematomas and microvascular injury with brain swelling, can result in the death of the patient soon after injury; others, such as diffuse ax-onal injury and excitotoxic injury, may result principally in the death of neuronal groups and thus have implications for long-term function. Evaluation of the clinical efficacy of specific therapies therefore depends on the particular pathology targeted by the treatment. For example, survival after TBI may be a good outcome measure of the efficacy of agents designed to limit sub-acute brain swelling, but it may not be a good measure for evaluating potentially neuron-sparing agents, such as certain gluta-mate antagonists and neurotrophins.
Focal injury
Focal injuries include intracerebral and extracerebral hematomas and focal contusions. Hematomas are most common after the rapid acceleration or deceleration that occurs as the result of a fall or another form of impact, especially in the elderly. Delayed hematomas, which can occur in patients who are initially at low risk but whose condition deteriorates rapidly, are particularly important. Small hematomas can be treated conservatively, but delaying the surgical removal of large hematomas for longer than 4 hours after injury significantly increases mortality and morbidity.
Table 1 Severity of Traumatic Brain Injury
|
Severity |
Admission GCS Score |
Duration of Unconsciousness |
Duration of Posttraumatic Amnesia |
CT/MRI |
|
Uncomplicated mild |
13-15 |
0-20 min |
< 24 hr |
Normal |
|
Complicated mild |
13-15 |
0-20 min |
< 24 hr |
Abnormal |
|
Moderate |
9-12 |
< 24 hr |
> 24 hr |
Usually abnormal |
|
Severe |
3-8 |
> 24 hr |
Weeks |
Abnormal |
GCS—Glasgow Coma Scale
Focal contusions may occur under the site of impact, but by far the most common locations after acceleration-deceleration injury are in the orbitofrontal and anterior temporal lobes, where the brain abuts the base of the skull. The most troubling clinical sequelae are usually behavioral and cognitive abnormalities referable to these areas of the brain. Contusions can undergo secondary expansion or result in delayed hematomas. Patients with such injuries require particularly close observation in the acute period. Both hematomas and contusions are also significant risk factors for the development of posttraumatic epilepsy [see 11:X1I Epilepsy].
Diffuse axonal injury
Diffuse axonal injury—a shearing injury of axons in the hemispheric white matter, corpus callosum, and brain stem5—is a significant cause of persistent, severe neurologic deficits in closed-head injury. When severe, the injury is manifested clinically by immediate and prolonged loss of consciousness. Petechial hemorrhages in the white matter or blurring of the gray matter-white matter junction is best seen on magnetic resonance imaging, especially in coronal slices. However, the only early abnormality may be microscopic focal cytoskeletal disruption. These changes lead to disturbance of axonal flow and the subsequent severing of axons, with the typical light microscopic picture appearing 12 to 24 hours later. If severe enough, such axonal injury can lead to wal-lerian degeneration and diffuse target deafferentation.6,7 It is possible that medical treatments can prevent total axonal disruption. Certain neurotrophins, such as brain-derived neurotrophic factor and perhaps insulinlike growth factor, may attenuate it.
Such axonal injury may also occur even after mild TBI (MTBI) and in the absence of morphopathologic change in any other vascular, neural, or glial element. Some of the cognitive changes seen after MTBI may relate to diffuse axonal injury.
Diffuse microvascular damage
Diffuse microvascular damage is a major component of both closed and penetrating TBI. Depending on the severity of the injury, early changes may include loss of cerebrovascular autoreg-ulation, with decreased responses to changes in carbon dioxide and perfusion pressure, and transient systemic hypertension. The loss of autoregulation makes the brain particularly susceptible to fluctuations in systemic blood pressure; otherwise tolerable hypotension can thus result in cerebral ischemic damage in the patient with TBI. In addition, altered vascular sensitivity to circulating catecholamines can lead to vasoconstriction and further focal ischemia or reperfusion injury. The microvascular pathology includes an endothelial change that probably involves oxygen free radical-induced decreases in endothelial nitric oxide, with a concomitant vasoconstriction, and an initial hyper-glycolysis with a dissociation of cerebral blood flow and metab-olism.9 Positron emission tomography has demonstrated these metabolic changes even in patients with MTBI.
Free radicals, including the superoxide radical peroxynitrite, and the process of lipid peroxidation play a critical role in secondary injury, not only by their effect on the microvasculature but also by their direct effects on tissue. The pharmacologic agents used to reduce the formation of free radicals or to scavenge those already formed include steroids to inhibit lipid perox-idation; a-tocopherol (vitamin E) and its analogues; a-lipoic acid; iron chelators, such as deferoxamine; and enzymes such as super-oxide dismutase. However, in phase III clinical studies, two such compounds—the 21-aminosteroid tirilazad mesylate and a polyethylene glycol-conjugated superoxide dismutase—failed to provide clear benefit to patients with acute, severe TBI.10,11
Hypoxia-ischemia
The classic pathology of hypoxia-ischemia primarily involves the hippocampus and the vascular border zones of the brain. It is often superimposed on other, more specific pathologies of TBI. The traumatized brain is particularly sensitive to hypoxia-ischemia, possibly because of the metabolic demands already placed on neurons by the trauma itself12 or by increasing vascular permeability.13 The most significant improvements in the survival of patients with TBI have resulted from recognition of the importance of this component and its prevention, largely through training of paramedics, the development of emergency transport systems, and immediate resuscitation protocols.
Selective neuronal vulnerability, excitotoxic injury, and neuronal energy failure
Selective vulnerability of certain neuronal groups, including hippocampal and thalamic reticular neurons that receive gluta-minergic afferents from the orbitofrontal cortex, occurs after head injury and appears to be caused by glutamate excitotoxici-ty.15 It also occurs after mild head injury in animal models and may be a cause of the fatigue, attention, and memory problems often seen in postconcussion syndrome in humans.
Excitotoxic injury may be one of the most important mechanisms of neuronal death after traumatic or ischemic injury. Excessive release of glutamate and other neurotransmitters unleashes a chain of cellular events that deplete neuronal energy stores, damage mitochondria, and result in cell death or apoptosis. Thus, glu-tamate antagonists or other neuroprotectants, such as dextror-phan, riluzole, memantine, and magnesium, may play a role in the acute treatment of TBI. However, because of the importance of glutamate in the brain, receptor blockade is usually accompanied by intolerable side effects; a number of clinical trials with such agents have failed to show a clear benefit.16 Alternatively, therapies that prevent depletion of neuronal metabolic stores or that enhance neuronal stores have also been shown to protect cells in models of glutamate toxicity. One related neuroprotective strategy that reduces glutamate release and appears to protect cellular energy metabolism is moderate systemic hypothermia. A controlled pilot study showed long-term benefit from treatment with hypothermia for patients surviving severe TBI.17 However, a larger multicenter study failed to confirm these findings.
A more direct approach may be to use agents that enhance neuronal energy metabolism and mitochondrial function after injury. Because it addresses a "final common path" in neuronal dysfunction, death, or both, this approach may protect against various stressors, including excitotoxic, oxidative, or calcium-induced injury.19 Depletion of neuronal energy can result because of the increased demands placed on neurons and their membrane pumps by the injury and because of a failure of adenosine triphosphate (ATP) production.
Mitochondrial dysfunction has been demonstrated after brain injury. One mechanism of mitochondrial dysfunction is the failure of the mitochondrial membrane, with consequent release of cytochrome-c into the cytoplasm and the subsequent activation of caspases and the apoptotic cascade. Similarly, it has been postulated that mitochondrial failure, including failure of the pyru-vate dehydrogenase pathways, may underlie the demonstrated uncoupling of blood flow and metabolism after TBI.
Cyclosporine has been demonstrated to have a neuroprotec-tive effect, which is achieved through stabilization of the mito-chondrial membrane.20,21 Both creatine and the three-carbon sugar pyruvate have been shown to have marked neuroprotective effects in animal models of TBI. As with cyclosporine, this effect is achieved through stabilization of the mitochondrial mem-brane.22,23 Pyruvate is not only the primary energy substrate in neuronal mitochondria but also a good scavenger of oxygen free radicals. Both pyruvate and creatine are inexpensive and nontox-ic; they are in early clinical trials for the treatment of brain injury.
Diffuse gray matter dysfunction
In addition to selective neuronal vulnerability, recent evidence from quantitative electroencephalograhic and quantitative MRI studies suggests that a very common effect of TBI may be a diffuse gray matter dysfunction that manifests itself primarily through changes in brain electrical activity, as measured by EEG coherence, phase, and power.24-27 These alterations may, in turn, reflect a relative loss of neuronal membrane electrical efficiency, probably as a consequence of the failure of neuronal energy metabolism and the ATP-driven neuronal ion pumps. Such failure would not be unexpected in the face of a probable diffuse excito-toxic challenge or other challenges in the early period after TBI. These alterations may be the only physiologic or pathologic evidence of MTBI or concussion. Although the pathology of this dysfunction is likely to be very subtle, there is a strong correlation between these changes and changes in the T2-weighted MRI signal in the gray matter, which in turn is thought to reflect the functional integrity of neuronal membranes (T2 refers to spin-spin, or transverse, relaxation time). These EEG changes have also been demonstrated to correlate with neuropsychological performance, suggesting that they could also be responsible for some of the cognitive changes that occur after MTBI. Restoration of neuronal energy metabolism might be expected to ameliorate these cognitive changes.
Mild Traumatic Brain Injury
With an incidence of 180 per 100,000 people, MTBI is more common than any other neurologic diagnosis except migraine. MTBI is variably defined as any TBI/concussion with loss of consciousness of 0 to 30 minutes, a Glasgow Coma Scale (GCS) score of 13 to 15 on admission [see Table 2], posttraumatic amnesia or confusion lasting less than 24 hours, and no evidence of contusion or hematoma on CT. Concussion can be further divided into grades I, II, and III. Grade I concussion is characterized by transient mental changes lasting longer than 15 minutes, with no loss of consciousness; in grade II concussion, transient mental changes last longer than 15 minutes, and there is no loss of consciousness; and grade III concussion is characterized by brief loss of consciousness. Although these distinctions, especially the distinction between grade I and grade II concussion, can be relatively subtle, they can serve as a useful guide for return to normal activity, especially in athletes or other active individuals.28 In any case, MTBI, even without loss of consciousness, has been repeatedly associated with measurable abnormalities in cognition, attention, and behavior, as well as documented quantitative EEG and neuropathologic changes.24,29 Abnormalities seen on assessments of cognitive task have been repeatedly documented after MTBI; these abnormalities usually include disturbances of attention, information processing, and memory.30-33As might be expected, MTBI also has a significant psychosocial impact.
Over 75% of MTBI patients report some somatic or cognitive symptoms over the first several weeks after injury; these can have important functional, social, and economic implications. Symptoms include headache, dizziness or vertigo, blurred vision, fatigue, sleep disturbance, irritability, depression, anxiety, and poor memory and concentration. Typically, these symptoms improve steadily and are largely cleared after the first 3 months after injury. However, some symptoms, especially the emotional symptoms, can persist longer. The term postconcus-sion syndrome is often applied when this complex of symptoms is persistent.
There has been increasing attention paid to MTBI in sports.34 The study of MTBI in athletes offers several advantages, including the generally high preinjury health and motivation of athletes, the ability to conduct preinjury testing, and the relative predictability of the time of the injury. In one study, college football players were examined before and after injury; significant attention deficits were found to persist for as long as 5 days after a minor "ding" that was not associated with loss of consciousness.35 Similar findings have been reported in soccer players.36
Pathogenesis
The pathology associated with MTBI or concussion is still unclear, but some evidence suggests that these injuries may be associated with a diffuse cortical neuronal dysfunction; selective vulnerability of certain neurons and a modest amount of diffuse axonal injury may also be factors. Microvascular injury with alterations in autoregulation and uncoupling of blood flow and metabolism has also been described in MTBI, especially with repeated MTBI—the so-called second impact syndrome—in pediatric and adolescent patients.9,37,38 Finally, hematomas occur with some frequency in patients who might otherwise be classified as having MTBI.
Table 2 Glasgow Coma Scale92
|
Test |
Response |
Score |
|
Eye opening |
Spontaneous |
4 |
|
To speech To pain |
3 2 |
|
|
None |
1 |
|
|
Best verbal response |
Oriented |
5 |
|
Confused |
4 |
|
|
Inappropriate |
3 |
|
|
Incomprehensible |
2 |
|
|
None |
1 |
|
|
Best motor response (arm) |
Obedience to commands |
6 |
|
Localization of pain |
5 |
|
|
Withdrawal response to pain |
4 |
|
|
Flexion response to pain |
3 |
|
|
Extension response to pain |
2 |
|
|
None |
1 |
Figure 1 (a) MRI in a 25-year-old man with mild to moderate traumatic brain injury and residual irritability, lability of affect, aggressivity, and occasional dyscontrol episodes initially seems normal but on closer scrutiny shows blurring of the gray matter-white matter junction in the left temporal lobe. (b) Positron emission tomography confirms decreased metabolism in the left temporal lobe.
