WITH THE INCREASED use of improvised explosive devices, rocket-propelled grenades, land mines, and other high explosives, traumatic brain injury (TBI) has become the “signature injury” of current warfare. Almost daily, men and women of the US Armed Forces and allied coalition personnel encounter attacks with high explosives while deployed in both Operation Iraqi Freedom and Operation Enduring Freedom. With the protection of modern body armor and helmets, many military personnel who would have died in the past from equivalent explosive exposure are actually surviving, with TBI. Unfortunately, multiple exposures to high explosives with subsequent nonfatal brain injuries have become extremely common among service members, especially with the current reality of repeated deployments.
Traumatic brain injury may be divided into mild, moderate, and severe forms. Of all combat-related TBIs, mild TBI (mTBI), also known as concussion, is the most common form suffered by service members at present. Defense and Veterans Brain Injury Center1 statistics show that, over the past decade, there have been 220 430 documented TBIs, with approximately 75% classified as mTBI. Postdeployment surveys indicate that 15% to 20% of service members returning from Operation Iraqi Freedom experienced at least 1 TBI. With newly enacted guidelines mandating the documentation and reporting of combat-related TBIs (Directive-Type Memorandum [DTM]-09-033), data now suggest that an even higher percentage of service members in Operation Enduring Freedom have endured 1 or more TBIs, the number of episodes occasionally reaching more than 15 per individual.
In the military context, the Department of Veteran Affairs and the Department of Defense define TBI as a “traumatically induced structural injury and/or physiological disruption of brain function as a result of an external force,” indicated by at least 1 of the following clinical signs: decreased level of consciousness, loss of memory immediately before or after the injury, alteration in mental state, neurologic deficits, or intracranial lesion. The definition for mTBI incorporates the specific parameters of loss of consciousness fewer than 30 minutes, alteration in mental state fewer than 24 hours, and posttraumatic amnesia for less than a day. The Glasgow Coma Scale should be almost normal with scores between 13 and 15 within the first 24 hours. For mTBI, structural imaging such as computed tomography and magnetic resonance imaging should also be normal. Yet, although standard computed tomography and magnetic resonance imaging brain scans show no abnormalities, military personnel with mTBIs often suffer from persistent headache, sleep disturbance, concentration and memory problems, irritability, dizziness, disequilibrium, vision change, or excessive fatigue,1 suggesting pathologic abnormalities on a microscopic level.
Remarkably, there currently exists a paucity of detailed neuropathology studies to characterize either the acute or long-term effects of TBI on the brains of military personnel. With lack of neuropathology studies on human cases, we still do not know the extent and nature of damage to the human brain induced by explosive blasts.
HISTORY OF MEDICAL RESPONSE TO HIGH EXPLOSIVES IN MILITARY CONFLICTS
In 1863, trinitrotoluene, the prototype high explosive, was originally synthesized by the German chemist Julius Wilbrand. It was a bright yellow color and pragmatically employed as a dye for many years until its explosive properties were finally recognized. Trinitrotoluene was first incorporated into artillery shells in 1902, but not extensively used until World War I (1914-1918), especially in the trench warfare along the Western Front. During these lengthy battles, soldiers huddled in their trenches and endured unrelenting bombardment by high-energy explosive artillery fire. In the extensive trench battles of Verdun, Somme and Ypres, both armies exchanged millions of artillery shells. After living through such bombardments in the trenches, many troops began developing an unknown, bizarre condition, in time recognized as “NYDN (Not Yet Diagnosed, Neurologic),” “neurasthenia,” or “shell shock.”2 Although a clinical definition of shell shock was never formally accepted, these soldiers typically presented with persistent headache, amnesia, inability to concentrate, difficulty sleeping and mood disturbance, including periods of depression and despondency. Frequently, these soldiers killed themselves.
The number of cases of shell shock increased rapidly, and it became clear that most affected individuals were no longer able to perform their military duties. Accordingly, many British shell shock patients returned to England and underwent hospitalization for further evaluation and treatment. Among the major British institutions working with shell shock patients was the Maudsley Hospital, a research psychiatric hospital recently opened outside London.2,3 Major Frederick Mott, trained in both neurology and pathology, served as the medical director. In response to the lack of knowledge in treating the growing number of soldiers with shell shock, Mott proposed to perform postmortem studies to elucidate the neuroanatomical pathology underlying this medical condition. In the Lettsonian Lectures, Mott discussed the immediate effects of high explosives on the central nervous system. In 1916, his lectures were summarized in 2 articles published in The Lancet. 4,5 Within these and other writings,6 Mott reported neuropathologic findings on 2 soldiers who had died soon after exposure to an explosive blast while serving on the Western Front during World War I. In neither of these cases was there physical evidence of external trauma to the head, penetrating injury, or damage to the skull. Examination of the brains revealed multiple petechial hemorrhages, mostly within the white matter of centrum semiovale, corpus callosum and internal capsule, and extravasation of blood into the subarachnoid space. Mott surmised the blast wave from the explosion had caused death.
The Maudsley Hospital simply did not have the capacity to handle the substantial number of shell shock cases returning to Great Britain from the battlefield. Hence, the Moss Side Military Hospital at Maghull, a sizeable medical facility near Liverpool, started accepting patients.2,3
As an unintentional outcome of caring for soldiers with shell shock in the 2 different hospitals, incongruent views on the afflictions of the human mind became blatantly obvious. Prior to World War I, physicians diagnosed and treated patients with both neurologic and psychiatric problems under the medical discipline of neurology. By the time of the Great War, psychiatry began emerging from neurology to establish itself as an independent clinical specialty. Psychiatrists of that era turned to the writings of Freud, Jung, and others for their understanding of diseases of the mind and employed these concepts in devising approaches to diagnosis and treatment.
For the medical personnel at the Maudsley Hospital with principally a neurologic focus, the shell shock patients were most likely suffering from a poorly understood organic disorder, possibly related to unknown physical changes caused by explosive blast and/or toxic exposure. For the medical personnel at the Moss Side Military Hospital at Maghull with predominantly psychiatric guidelines, shell shock was a functional disorder, a “psychoneurosis,” related to insidious emotional turmoils and repressed memories compromising patients' psychosocial adaptations to the stresses of combat. The debates must have been heated. Nevertheless, ultimately a governmental committee of enquiry gave final voice to these issues for decades to come.
Following the end of World War I, the British government convened a commission to investigate the nature of shell shock and determine how to deal with the thousands of surviving veterans with that diagnosis. The Commission was called the “War Office Committee of Enquiry into ‘Shell Shock',” or simply the Southborough Committee.7 They took testimony from numerous prominent physicians with clinical experience and expertise in shell shock. Subsequent to deliberations, the Southborough Committee issued its report, declaring shell shock as “a convenient evasion of duty, if not disguised malingering.” Furthermore, they concluded that “No case of psycho-neurosis or of mental breakdown, even when attributed to a shell explosion or the effect thereof, should be classified as a battle casualty.” Finally, the committee members recommended that “Shell shock was not a valid diagnostic entity and the use of the term should therefore be banned.” Ensuing this declaration, the term “shell shock” was abandoned, and any idea that exposure to an explosive blast might produce lasting pathology in the brain was no longer considered worthy of investigation. The field of psychiatry had won the dispute over shell shock.
In subsequent military conflicts of the twentieth century, behavioral/psychiatric symptomatology continued to be noted in military personnel with combat experience. During World War II and the Korean War, such cases were identified and diagnosed as “combat or battle fatigue.” During and following the Vietnam War, psychiatrists worked with many combatants, especially on return to the United States, with neuropsychiatric symptoms such as anxiety, depression, mood swings, sleep disturbance, substance abuse, and suicide. This problem was thought unique to those fighting in the Vietnam conflict; thus, the term “Vietnam Syndrome” was originally proposed. It followed that several psychiatrists, who were also anti-Vietnam war activists, led a lobbying effort mainly directed at the writers of the third edition of the Diagnostic and Statistical Manual of Mental Disorders. Because of their efforts, the DSM III was finally published in 1980 with the introduction of a new psychiatric condition that, although not specific for combat experience in Vietnam, was primarily derived from that military conflict. It was called posttraumatic stress disorder (PTSD). The term persists to present day.
Other than the 2 cases reported by Mott, we found no other studies describing the acute effects of blast on the human brain. In 1949, Cramer et al8 reported massive intracerebral hemorrhage in a World War II veteran who had died 2 months after exposure to an explosion. With the exception of a case report published this past month, no additional medical literature addresses the long-term neuropathologic sequelae in the human brain after exposure to an explosive blast. For this reason, we review literature pertaining to the long-term consequences of repeated head trauma associated with sports to provide potential insight.
THE LONG-TERM CONSEQUENCES OF REPEATED HEAD TRAUMA ASSOCIATED WITH SPORTS
In 1928, the American pathologist Harrison S. Martland9 published an article titled “Punch Drunk,” putting forth for the first time in the medical literature the concept that boxers with repeated head injuries could suffer from a debilitating medical condition, termed punch-drunk syndrome, dementia pugilistica, and eventually chronic traumatic encephalopathy (CTE).10,11 Martland9 described its early symptoms as flopping of the foot or leg with staggering and disequilibrium. Sometimes the boxer was mentally confused and showed signs of slowed muscular movement. Ironically, referees would at times stop the fight, believing the boxer actually intoxicated, while knowledgeable boxing fans referred to the phenomenon as “cuckoo,” “goofy,” or “slug nutty.” At late stages, frequently long after retirement from the ring, former fighters would develop parkinsonism, with rest tremor, unsteadiness of gate, and masked facies. This was commonly accompanied by a degree of cognitive dysfunction and, at times, frank dementia. Martland9 hypothesized that a progressive neurodegenerative process caused this clinical paradigm. Furthermore, he urged the medical community to establish or refute definitively the existence of punch-drunk syndrome with statistical data and deliberate neurologic examinations. In addition, he encouraged neuropathologists at neurologic clinics and asylums, to which these men were not infrequently committed, to study their brains.9
In 1967, the Royal College of Physicians of London appointed Dr A. H. Roberts to study the late neurologic sequelae of professional boxing.12 Within 2 years, he interviewed and examined almost all of the 250 retired boxers randomly selected from 16 781 professionals registered with the British Boxing Board of Control between the years 1929 and 1955. Of the 224 former boxers examined, 37 participants showed clinical evidence of lasting severe central nervous system impairment. He acknowledged the wide spectrum of clinical presentations among individuals, yet ascribed to a composite clinical paradigm for traumatic encephalopathy primarily involving the cerebellar and extrapyramidal systems. The neurologic syndrome ranged from mild forms with dysarthria, asymmetric pyramidal lesions, and perhaps, disequilibrium to severe disability with ataxias, rigidity, tremor, and dementia. Roberts estimated the prevalence of traumatic encephalopathy, as he defined it, at approximately 17%, with increased occupational exposure (eg, number of fights, number of knockouts) correlating positively with the extent of neurologic dysfunction. He found the evidence insufficient to support observations in previous publications of either neurodegeneration or neuropsychiatric problems, such as personality change, as a medical consequence to boxing.12 Unfortunately, neuropathologic studies were not part of the follow-up to Roberts's cohort.
Eventually, the brains of deceased former boxers were examined at autopsy. In a classic article published in 1973, Corsellis and coworkers13 reported a detailed investigation of the brains of 15 retired boxers, correlating antemortem clinical symptoms recounted by surviving family members with neuropathologic examinations. Cerebral atrophy was noted as a general trend. In addition, the brains often displayed enlarged lateral ventricles with fenestrated cavum septum pellucidum, atrophied fornices, and a thinned corpus callosum. The cerebellum showed scarring, particularly in the tonsillar regions with demyelination and loss of Purkinje cells. Most notable, many neuronal populations displayed extensive neurofibrillary tangle (NFT) formation, aggregates of misfolded, hyperphosphorylated tau proteins associated with several neurodegenerative diseases. Frequently, the substantia nigra pars compacta was depigmented, with neuronal loss and NFTs within surviving nigral neurons. Lewy bodies, indicative of Parkinson's disease, were absent. Neurofibrillary tangles were noted in the hippocampus and were widely distributed in the cerebral cortex, with preferential deposition in the medial temporal gray matter and accompanying extensive neuronal loss. In stark contrast to Alzheimer disease, senile (ie, neuritic) plaques were rarely observed,13,14 and if present, in scanty amounts, with the exception of one patient who died at 57 years. The authors concluded that several neurologic features of the boxers directly corresponded to structural changes in their brains; for example, those with memory loss showed disruption of the limbic pathways (eg, hippocampus, medial temporal lobe, fornix) and with parkinsonism, involvement of the substantia nigra. The authors further contemplated the propensity for traumatic brain damage to produce outbursts of rage or aggression, although ultimately concluded that they were unable to identify a specific anatomical site to account for these symptoms.13
With the publishing of these and other seminal articles, CTE has been characterized as a distinct progressive neurodegenerative disease entity associated with widespread intraneuronal accumulation of the protein tau, thus categorizing it as a form of tauopathy.10 Normally, tau proteins stabilize microtubules within neurons, aiding with transport of essential components in the axons necessary for cell function and survival. In tauopathies, tau proteins disassociate from microtubules, become hyperphosphorylated, misfold and aggregate to form NFTs, a process that presumably serves as the instigator of toxicity and cell death by unknown mechanisms. Chronic traumatic encephalopathy has been confirmed at autopsy in athletes who had played football, soccer, ice hockey, and other contact sports with an inherent risk of subconcussive or concussive injuries.10 The clinical onset of CTE can range from the second to the seventh decades of life, with early symptoms more typically detected in approximately the fourth decade.
Characteristic of neurodegenerative disease, neurologic deficits progressively exacerbate and expand in symptomatology, often over several decades. Clinically, patients show prominent behavioral abnormalities, often formerly uncharacteristic to the person, such as abrupt mood swings with explosive rage, depression, impulsive acts, and substance abuse. Other complaints include chronic headache, difficulty sleeping, memory impairment, poor concentration and decision making, slurring of speech, signs and symptoms of parkinsonism, and at late stages, dementia. Not infrequently, these patients commit suicide without apparent premeditation or they die as a consequence of engaging in life-threatening, poorly conceived, high-risk behavior. At autopsy, the brain is typically of normal gross appearance, but can show mild global atrophy, with thinning of the corpus callosum and enlarged ventricles and cavum septum pellucidum. There also exists a distribution pattern of NFTs that is characteristic of CTE. Neurofibrillary tangles tend to aggregate in the medial temporal cortex, hippocampus and parahippocampal gyrus, thalamus, mammillary bodies, amygdala, hypothalamus, and substantia nigra. Neurofibrillary tangles also preferentially amass in the depths of sulci and surround small penetrating cerebral cortical blood vessels in an irregular, patchy distribution.15 In the neocortex, NFTs concentrate in the superficial layers II and III, differing from Alzheimer disease in which NFTs predominate in the deeper layers V and VI.16 Also unlike Alzheimer disease, there is a general absence of neuritic (ie, senile) plaques in CTE.13,14
THE NEUROPATHOLOGY OF TBI IN THE MILITARY: WHAT DO WE (REALLY) KNOW?
Since the beginning of military engagements in 2001, more than 2 million US military personnel have been deployed to Iraq and Afghanistan, many serving multiple tours of duty, with thousands being exposed to explosions. Approximately, 220 000 service members have returned to the United States reporting at least 1 TBI, a number that most likely underrepresents its true prevalence. Service members with mTBI often complain of headache, irritability, memory problems, difficulty concentrating, and sleep disturbance, similar to military personnel with head injuries of past wars and, as we have noted, athletes with CTE confirmed at autopsy. These observations raise the question whether a proportion of service members with TBI due to blast exposure are actually suffering from CTE.
In support of this hypothesis, Omalu et al17 recently published a case report of a 27-year-old US Marine Corps veteran. During his 2 deployments in Iraq, he experienced combat and was exposed to multiple blasts, sometimes being within 50 meters of detonation. After his second deployment, he developed progressive cognitive impairment, memory disturbances, and behavioral and mood disorders, while abusing alcohol. He was diagnosed with PTSD before he finally took his life by hanging. At autopsy, his brain appeared grossly normal, but microscopic examination revealed NFTs in anatomical locations that are consistent with a diagnosis of CTE.
Given the prominent behavioral components of the neurodegenerative disease CTE and high likelihood of its existence in the military, we again return to the divisive medical question originating in the early twentieth century. Are behavioral anomalies evident after combat experience due to a psychiatric response to the emotional stresses of war or rather due to a neurologic disturbance, such as CTE? In a recent study, Hoge et al18 noted the association between mTBI and PTSD in modern warfare. The authors surveyed 2525 US Army infantry soldiers after deployment to Iraq for a year to determine clinical sequelae to mTBI, especially after exposure to blast. The authors reported that 44% of the soldiers with mTBI and subsequent loss of consciousness met criteria for PTSD, in comparison with those with mTBI and altered mental status (27%), injuries other than TBI (16%), and no injuries (9%). Mott himself suggested that prolonged active service in warfare may heighten the susceptibility to a “neurasthenic condition,”4,6 a concept supported by the estimated 9% of soldiers with PTSD and no reported injuries18 and further bolstered by the introduction of PTSD as a medical entity in 1980. Nonetheless, the study also underscores the increased probability of a PTSD diagnosis with a history of mTBI, particularly with loss of consciousness, which hints at an underlying organic disturbance.
Despite the use of high explosives in warfare for at least 100 years, there have been no detailed neuropathology studies to characterize the sequelae of TBI in the human brain after blast exposure. The hypothesis that particular behavioral anomalies and cognitive impairments may be secondary to organic changes in the brain after blast will now be systematically and extensively tested. Under the auspices of the congressionally mandated Center for Neuroscience and Regenerative Medicine19 and in collaboration with the Armed Forces Medical Examiner System, we are about to embark on a major study to document the neuropathology of TBI in the military—both the acute effects and the long-term consequences. Professor Frederick Mott was never able to undertake such a study, although he essentially proposed doing so in 1916. He was later knighted for his activities as a hospital administrator, not as a visionary neuropathologist.20 Hopefully, Sir Frederick would be pleased that his hypothesis, that shell shock is primarily an organic disorder, is finally being tested, with the prospect that our findings will foster a concomitant remerging of the disciplines of neurology and psychiatry. It is remarkable that it has taken almost a century for this to happen.