“He Was Never Quite ‘Himself’ after that Accident”: Exploring the Long-term Consequences of Mild Traumatic Brain Injury
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* Grant Sinson

Patients seek medical care after traumatic brain injury (TBI) roughly 2 million times per year in the United States. Eighty percent of these injuries can be classified as “mild”. The real incidence of TBI is, however, unknown, because victims of mild TBI often do not see a physician. Having your “bell rung” or “seeing stars” is an experience that a high percentage of us could talk about from personal experience. During athletics, these are injuries that fall into the “shake it off” category. In this issue, Hofman et al (page 441) report their study of victims of mild TBI, which used MR imaging, single-photon emmission CT (SPECT), and formal neurocognitive testing. Seventy-seven percent of these patients had abnormalities seen on MR or SPECT studies or both. The question is: can you “shake off” such abnormalities manifested by brain imaging and physiological changes?

One would think that we should know the answer to this question, but there is little science to support an adequate response. What we do know about the clinical consequences of mild TBI is that a poorly defined subset of patients will have persistent symptoms that often are referred to as the “postconcussive syndrome”. In some cases, headaches, difficulties with memory or concentration, and behavioral changes can be quite debilitating. We also know that for people who carry the apolipoprotein-e4 allele, mild TBI is a risk factor for the development of Alzheimer disease (1). What are the implications of this when we learn that every high school football team in America averages almost two mild TBIs per season (2)? The annual national estimate of mild TBI among 10 high school sports (boys' sports: baseball, basketball, football, soccer, wrestling; girls' sports: basketball, field hockey, softball, soccer, volleyball) is 66,816 cases (2).

One difficulty with studying these patients is that they tend to “fall through the cracks” in clinical science. Head-injured patients are often cared for by neurosurgeons, because an early risk to these patients is the development of a delayed hematoma. Consequently, most studies of clinical management are focused on more severe TBI. Patients with mild TBI and few outward signs of injury often have difficulty finding an experienced physician interested in treating them after the risk of developing a delayed hematoma has passed. Therefore, those researchers who have an interest in mild TBI come from a wide range of backgrounds including psychiatry, rehabilitation medicine, neurology, neuropsychology, neurosurgery, traumatology (general surgery), critical care (anesthesiology), and radiology. The result can be disjointed research efforts that are not well communicated to others studying the same problem. For example, neurosurgical research tends to document well the mechanism of injury and imaging findings, but long-term outcome information can be lacking. Alternatively, physiatrists can have difficulty finding information on a patient's mechanism of injury to correlate with poor outcomes.

The laboratory study of TBI has focused primarily on moderate and severe injuries. Only recently have studies been initiated that evaluate the effects of more mild injury. Provocative studies have shown ongoing cell death by apoptotic pathways in the days, weeks, and even months after experimental TBI. Do the abnormalities on MR and SPECT images that are seen in studies like Hofman et al's signify the initiation of a long-term destructive process within the brains of these patients?

To study the effects of TBI better, we must define the disease process better. I believe that the treatment of cancer represents an appropriate analogy. Most of us learned about cancer as children by witnessing friends or family fighting this serious disease. To simplify the issue, adults taught us about cancer as a single disease. Most cancers share the attributes of causing pain and suffering, requiring aggressive treatment, and many types result in death. Few effective treatments for any cancer could have been discovered if the many different diseases that are called “cancer” were not defined as separate diseases. “Traumatic brain injury” must be viewed as a very nonspecific label for a group of pathophysiological events that share only their initiating event and require different treatments. TBI is many pathophysiological processes occurring at different times and in different patients. Some of the different mechanisms that contribute to damage in various models of TBI include: apoptotic cell death, calcium-mediated excitotoxicity, direct pressure from expanding hematomas, breakdown of the axonal cytoskeleton, cellular edema, mitochondrial dysfunction, and ischemia. In the study of a drug that prevents apoptotic cell death after TBI, efficacy cannot be demonstrated if many of the patients entered into the study do not have any apoptotic cell death. The analogy would be performing lung resections for cancer but not knowing if there was any tumor in the lung. Even if lung resections were effective for some patients, the study design could not answer the question.

MR imaging, spectroscopy, and other novel radiographic tests offer the power to provide data concerning both anatomic and biochemical changes in the brain after TBI noninvasively. I believe that radiologists working with other interested researchers will enable us to better classify TBI early after the injury, well within the therapeutic window for many types of secondary injury. This information will permit more appropriate evaluation of new treatment paradigms and improve our ability to provide important prognostic information to patients. Additionally, if we confirm that some mild TBI can have long-term cognitive consequences in certain people, the manner in which we permit ourselves or our loved ones to be exposed to the risk of mild TBI could be altered significantly.

## References

1.  Mayeux R, Ottman R, Maestre G, et al. **Synergistic effects of traumatic head injury and apolipoprotein-e4 in patients with Alzheimer's disease.** Neurol 1995;45:555-557
    
    [Abstract/FREE Full Text](http://www.ajnr.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6OToibmV1cm9sb2d5IjtzOjU6InJlc2lkIjtzOjg6IjQ1LzMvNTU1IjtzOjQ6ImF0b20iO3M6MTk6Ii9ham5yLzIyLzMvNDI1LmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

2.  Powell JW, Barber-Foss KD. **Traumatic brain injury in high school athletes.** JAMA 1999;282:958-963
    
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