Secondary prevention comprises minimizing the biological injury arising from the immediate physical trauma and maximizing the biological potential for tertiary prevention. Although concepts of tertiary prevention are now being incorporated into the early management of traumatic brain injury, secondary prevention is the primary focus of prehospital and acute health care delivery. Central to these efforts are 2 assumptions: there are evolving and delayed biological injuries following trauma (“secondary injury”); and interventions directed at secondary injury can make a difference. Certainly the most dramatic evidence for the first concept is a patient who, following traumatic brain injury, “talks and dies” — that is a patient who, at first, is able to verbalize sensibly but subsequently deteriorates, typically because of delayed or evolving intracranial hemorrhage, and dies from rapidly progressive raised intracranial pressure. The early removal of various types of traumatic intracranial hematoma can change the outcome for these patients. Over the last few decades, we have learned much about factors associated with worse outcomes following traumatic brain injury, such as hypotension and hypoxia. It is likely that advances in prehospital care or transport as well as advances in critical care, which have resulted in the reduction of hypoxia and hypotension, may be the reason for the improved outcomes we have witnessed following severe traumatic brain injury.
There is a substantial body of work that has analyzed other systemic and intracranial physiologically targeted interventions that might reduce secondary injury and make a difference in outcomes. These include the analysis of prehospital factors, choice of fluid for resuscitation, blood-pressure management, temperature management, intracranial pressure management, oxygenation parameters and ventilation techniques. These have resulted in the publication of practice guidelines for severe traumatic brain injury.16
Similarly, there is literature that involves the early clinical identification and diagnosis of mild traumatic brain injury and its early and ongoing management. However, much of this work is aimed at the early initiation of strategies for tertiary prevention.
In addition to clinical systemic approaches and those directed by intracranial physiology, clinical studies of interventions targeted at reducing secondary injury arising from discrete subcellular processes (e.g., toxicity due to reactive oxygen species, overstimulation of glutamate receptors, excessive influx of calcium and inflammatory upregulation) have not resulted in a standard drug treatment. This likely reflects both the complexity of the mechanisms of secondary injury as well as issues of drug dosing and timing and the lack of specificity of drug effects.17,18
In the last 10 years, further exploration into the mechanisms underlying the failure of subcellular treatments for secondary injury has revealed a greater than anticipated complexity of molecular processes, but it has also revealed novel targets with higher probabilities of success. Bridging these knowledge gaps is paramount to developing effective future treatments.
Basic biological mechanisms
Although primary injury comprises the initial tear, shear or hemorrhage, the mechanisms of secondary injury can dramatically exacerbate the initial injury. However, the delayed process of secondary injury allows hope for meaningful intervention. Secondary injuries are multiple, parallel, interacting and interdependent cascades of biological reactions caused by primary injury. The major known pathways are summarized in and some clinical manifestations are illustrated in .
Figure 1: The major pathways associated with the progression of secondary injury after a traumatic brain injury. Microcirculatory derangements involve stenosis (1) and loss of microvasculature, and the blood–brain barrier may break down as a result (more ...)
Figure 2: Computed tomography scans of the brain of a 35-year-old man showing normal anatomy and normal-sized ventricles (left) and a 25-year-old man involved in a motor vehicle crash (right), showing frontal contusions, a depressed skull fracture and (more ...)
In general, the ongoing sequelae of damage to nervous tissue is perpetuated by the early failure of neuronal energy, glial injury and dysfunction (swelling of astrocytic foot processes, reversal of neurotransmitter reuptake and reactive astrocytosis), inflammation (invasion of the injury site by microglia and release of proinflammatory cytokines), destruction and stenosis of microvasculature, excitotoxicity and aberrant ionic homeostasis in neurons, and progressive white matter deterioration ().
White matter injury
White matter — the part of the brain that provides long connections between different parts of the grey matter or cortex — exhibits different patterns of deterioration compared with grey matter. Traumatic axonal injury is a common occurrence in both focal and diffuse brain trauma regardless of injury severity.19–22
Traumatic axonal injury has proven to be a reliable predictor of poor survival or poor long-term outcome23–26
yet it is frequently underdiagnosed, particularly in mild traumatic brain injury owing to a lack of tools with sufficient thresholds of detection. Importantly, we now understand that there are mechanisms leading to delayed white matter injury beyond the direct initial consequence of shear forces generated at the moment of initial trauma. Following trauma to the head, especially with rotational forces, it is possible to identify axonal shearing from primary injury. However, a greater number of axons undergo disconnection, or secondary axotomy, at later times.27
Immunohistochemical markers of axonal injury, advanced imaging technologies and serum biomarkers have demonstrated that white matter injury is in fact a progressive and delayed degenerative process. This occurs in both severe and mild traumatic brain injuries.
Abnormal calcium homeostasis is a critical component of the progression of secondary injury in both grey and white matter. In neuronal cell injury, it is associated with excitotoxic cell death, initiation of programmed cell death and postsynaptic receptor modifications. In axonal injury, calcium initiates a cascade of events culminating in axonal disconnection. In both neuronal and axonal injury, calcium overload is linked to early mitochondrial swelling.28,29
Excessive sequestration of calcium by mitochondria causes its membrane depolarization, the opening of membrane permeability transition pores and the release of initiating factors of programmed cell death.30,31
The loss of mitochondrial function not only eliminates calcium buffering capacity but also contributes to the influx of calcium resulting from bioenergetic failure of ATP-dependent ion pumps. For example, cyclosporin A, an immunosuppressant and inhibitor of the mitochondrial membrane-permeability-transition pore, has been shown to reduce both axonal pathology and neuronal cell loss, thus illustrating the importance of this process.32–35
White matter injury is increasingly recognized as central to the impact on the quality of life of patients with either severe or mild traumatic brain injury. After severe injury, damage to the major white matter tracts is devastating and, despite normal intracranial pressure, it can be the determinant of death or persistent disability (). Following mild traumatic brain injury, white matter lesions may be the determinant of ongoing symptoms as well as patients' increased susceptibility to future traumatic events.
Figure 3: Magnetic resonance images of the brain of a 38-year-old woman (left) and 35-year-old male passenger in a motor vehicle crash (right) with extensive injury to the corpus callosum (a major tract of white matter between the left and right cerebral (more ...)
The important secondary injury of white matter involves the axonal membrane becoming “leaky” (a state permitting an influx of extracellular calcium).36–38
As a result of increased calcium concentrations in the axon, enzymes that degrade key structural proteins become activated and destroy proteins responsible for the maintenance of shape and transport in axons. These events cause the accumulation of transported proteins, axonal swelling and, ultimately, disconnection39
Activation of protein-targeting enzymes after trauma can result in the production of distinct protein fragments. The identification of these signature markers through proteomic screening technologies has high diagnostic potential for determining the nature and severity of injury as well as potential therapeutic targets.40
One family of ubiquitous enzymes, calpains, has received considerable attention as key mediators of axonal injury. Given the profound protection conferred by pharmacologic antagonists in animal models, these enzymes may also be potential therapeutic targets for white matter injury.41–43
Under normal physiologic conditions (low intracellular calcium), calpains have a wide range of targets with numerous regulatory functions.44,45
Under pathophysiological conditions, however, calpains target axonal proteins responsible for structure and transport.45–47
A particular axonal protein expressed exclusively in the brain, αII-spectrin, provides an example of how the diagnosis of white matter injury may be aided by proteomic technologies. Calpain-mediated breakdown of αII-spectrin results in the production of 2 specific fragments (150 kDa and 145 kDa).48,49
In contrast, caspase-3 cleavage (typically associated with programmed cell death) of αII-spectrin results in a 150 kDa and a 120 kDa fragment.48
This distinction allows the dominant process to be determined and holds potential for diagnosis and directed drug design.
Several conventional histologic markers used to characterize traumatic injury to axons include the degradation of several intra-axonal cytoskeletal proteins and the accumulation of transported proteins, such as β-amyloid precursor protein.50–52
As an increasing number of markers of white matter injury are elucidated, it is becoming evident that histologic examination of a few select markers does not reflect the full extent of axonal injury because of the diverse spectrum of mechanisms that can occur as a function of injury severity, location and tissue type. A key stumbling block in the development of treatments for white matter injury is identifying the mechanisms that are most damaging or, more realistically, interventions that can be applied within a reasonable time frame.
Although histologic markers can be used to characterize the pathological events that occur in white matter, the effective translation of basic research findings into meaningful clinical therapy ultimately depends on the functional outcome of white matter. In this regard, electrophysiological assessments in experimental laboratories have shed light on interventions that translate to functionally measurable outcomes. These experimental techniques have been used to track the functional deterioration of white matter after trauma, to identify subpopulations of axons that are more vulnerable than others and to evaluate potential therapeutic treatments for the deterioration of white matter.53–56
Studies have revealed that white matter trauma is an active progressive process. Following trauma, white matter exhibits active lesions of inflammation, cytoskeletal breakdown and, finally, axonal disconnection. It is a phenomenon known to occur across a range of injury severities. Further complicating the issue is the finding that all axons are not created equal, with varying susceptibilities dependent on subcellular make-up. We are beginning to recognize that white matter lesions may be responsible for more symptoms than previously thought and that they may be the source of the ongoing neuro-cognitive issues that affect patients following mild traumatic brain injury.