Mitochondrial Damage in Traumatic CNS Injury

Laurie M. Davis and Patrick G. Sullivan

11.1 Traumatic Brain Injury

With over 1.5 million injuries every year, traumatic brain injury (TBI) has become an almost ubiquitous phenomenon in our country. As this disorder can be present without any outward sign of physical damage and the victims are usually cogni-tively impaired (i.e., not vocal), it has become a largely "silent epidemic" (Jennett 1998; Thurman et al. 1999; Jager et al. 2000; CDC 2003; Langlois et al. 2006). Current advancements in medicine have allowed patients who would have previously succumbed to their wounds, to survive long after their initial injury. Also, there is a growing population of individuals who sustain a mild to moderate TBI who do not seek treatment (~25%), and often develop prolonged and chronic neurological symptoms (CDC 2003). The growing injured population has presented our society with an enormous economic and social burden, as these patients are commonly unable to properly reintegrate in to their previous professional and social networks. They become exceedingly dependent on family and social outreach programs to live their daily lives which cause their health care costs to total tens of billion dollars per year (Langlois et al. 2006). Although there are limited treatment options designed to allow people to survive their injuries, consisting of minimizing acute brain edema, decreasing intracranial pressure, and the prevention of peripheral complications, there is no current treatment to attenuate or recover the loss of neural tissue (Hatton 2001).

Perhaps the most insidious aspect of TBI is that it can occur without obvious signs of injury to the patient's body. There have been recorded medical incidences of mysterious neurological disorders dating back to World War I (WWI). Physicians in the British armed forces had then given it the somewhat enigmatic label of "shell shock" (SS) (Jones et al. 2007). Although some cases could be attributed to psychosis, by 1917 SS was responsible for 14% of all discharges from the armed forces, and accounted for 33% of all discharges of non-wounded soldiers. It had become

L.M. Davis and P.G. Sullivan

The Spinal Cord & Brain Injury Research Center, The University of Kentucky Chandler College of Medicine, 741 South Limestone Street, Lexington, KY, USA

so prevalent throughout the armed forces and had such a wide array of presenting symptoms that it was highly debated whether or not it was a real condition, and the etiology and management was highly disputed during the early twentieth century. By the end of WWI the prevalence of SS began to incur a large financial burden upon the British armed forces, primarily due to the 32,000 pensions that had been awarded to "neurasthenic" soldiers suffering from SS with no obvious cerebral injury. The controversial definition of the disorder and its method of treatment, in addition to the development of public controversy and stigma over diagnosis, delayed the development of a treatment protocol and even caused the British army to ban the use of the term "shell shock" from medical reports.

During World War II (WWII) the British army banned the SS terminology in hopes of avoiding another epidemic of these cases, which they may or may not have viewed as physical disorders. However, with the start of the war it became readily apparent that disavowing the existence of this disorder did not prevent another epidemic. In response to the army regulations regarding this disorder, alternative terminology arose in its place, such as post-concussion syndrome (PS) or post-trauma concussion state (coined by Shaller). Eventually, physicians began to realize that many of the soldiers that suffered from this concussed state had been in close proximity of an explosion during battle. This led them to speculate that some force, that had no perceptible outward affect on the body, had a substantial effect on fragile neural tissues. In an attempt to, once again, clarify the etiology of this disorder, Denny-Brown suggested that it was the timeline of symptom presentation within the individual patient instead of the symptom type that was the key factor between severe head injury and PS. His etiological account indicated that severe head injury would present with immediate neurologic symptoms that would trend toward recovery, whereas PS would have delayed onset of neurologic symptoms with a trend toward worsening symptoms (Jones et al. 2007). It has been estimated that 50% of patients with a mild TBI can develop PS, consisting of dizziness, headaches, cognitive dysfunction, sleep disorders, and depression (CDC 2003; Langlois et al. 2006; Rapoport et al. 2006). This delayed development of symptoms in the mild to moderate patient populations is perhaps the most unfortunate aspect of this condition, as soldiers and civilians can often suffer immense psychiatric morbidity without realizing that they require medical treatment for a physical injury. A recent online polling study indicated that 42% of their respondents who suffered from TBI failed to seek medical care, which is considerably higher than the CDC estimate of 25%. It has been observed clinically that even mild or moderate TBI can require neurosurgical intervention, and any delay in treatment could prove to be costly in terms of cognitive and functional recovery (Setnik and Bazarian 2007).

Of the more than 1.5 million military personnel deployed since 2001 to the Middle East, approximately 25% of the injured service members have reported brain injury. Unpublished data from the Department of Defense indicates that blast injuries are the leading cause of TBI in war zones; and has been labeled as a signature injury of the current Middle Eastern conflicts (Hoge et al. 2008). Recently, the ravages of TBI has been documented through the unfortunate injury of network news anchor Bob Woodruff, which showed the grim reality of the recovery process of this disorder and its effects on patients' lives in terms of cognitive dysfunction and its impact on the family dynamics (Woodruff and Woodruff 2007). Although the TBI sustained by Woodruff was severe, mild and moderate injury have also become a long-term problem coupled with prolonged cognitive dysfunction within the armed forces population, with approximately 18% prevalence in various reports (Hoge et al. 2008). In addition to prolonged cognitive deficits, the injured population also has an increased predisposition to the development of post-traumatic stress disorder (PTSD). There is also a problem of failure to report due to a perceived stigma concerning psychological problems within the armed forces population, which could contribute to the development of chronic neurologic dysfunction due to physical injury within this population of injured patients (Hoge et al. 2004).

Within the civilian population of the United States ~2% of the population (5.3 million) is currently living with long-term disabilities resulting from TBI (Langlois et al. 2006). The leading causes of TBI (Fig. 11.1) are falls and motor vehicle accidents, followed closely by assault and "struck by/against" incidents (Langlois et al. 2006). There has also been an increasing population of pediatric (5-18 years) TBI cases resulting from sports-related injuries, which can often be misdiagnosed as the symptoms manifest as lethargy, irritability or fatigue (CDC 2003; Yang et al. 2008). TBI has a biphasic age distribution of incidence; occurring in young (<25) and elderly (>75) populations (Langlois et al. 2006; Rutland-Brown et al. 2006). Over 50,000 deaths are attributed to TBI each year, as well as 235,000 hospitalizations and 1,111,000 emergency department visits (Fig. 11.2). With such a high incidence and great propensity for the development of chronic symptoms, the total medical costs incurred by individuals currently living with TBI within the USA can reach $50 billion dollars per year. This figure increases to $60 billion when lost societal

Fig. 11.1 Traumatic brain injury causes

Traumatic Brain Injury Morbidity and Mortality

Fatal 3%

Traumatic Brain Injury Morbidity and Mortality

Fatal 3%

Fig. 11.2 Traumatic brain injury morbidity and mortality

productivity of these individuals is factored in; however, these figures do not factor in how this disorder impacts social and family dynamics (Langlois et al. 2006; Rutland-Brown et al. 2006). As such, there is a clear need for the development of neuroprotective therapies and effective protocols for the treatment of TBI.

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