Robert C. Cantu

Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury

Since the 1920s, it has been known that the repetitive brain trauma associated with boxing may produce a progressive neurological deterioration, originally termed dementia pugilistica, and more recently, chronic traumatic encephalopathy (CTE). We review 48 cases of neuropathologically verified CTE recorded in the literature and document the detailed findings of CTE in 3 professionalathletes, 1 football player and 2 boxers. Clinically, CTE is associated with memory disturbances, behavioral and personality changes, parkinsonism, and speech and gait abnormalities. Neuropathologically, CTE is characterized by atrophy of the cerebral hemispheres, medial temporal lobe, thalamus, mammillary bodies, and brainstem, with ventricular dilatation and a fenestrated cavum septum pellucidum. Microscopically, there are extensive tau-immunoreactive neurofibrillary tangles, astrocytic tangles, and spindle-shaped and threadlike neurites throughout the brain. The neurofibrillary degeneration of CTE is distinguished from other tauopathies by preferential involvement of the superficial cortical layers, irregular patchy distribution in the frontal and temporal cortices, propensity for sulcal depths, prominent perivascular, periventricular, and subpial distribution, and marked accumulation of tau-immunoreactive astrocytes. Deposition of &bgr;-amyloid, most commonly as diffuse plaques, occurs in fewer than half the cases. Chronic traumatic encephalopathy is a neuropathologically distinct slowly progressive tauopathy with a clear environmental etiology.

The spectrum of disease in chronic traumatic encephalopathy

Chronic traumatic encephalopathy is a progressive tauopathy that occurs as a consequence of repetitive mild traumatic brain injury. We analysed post-mortem brains obtained from a cohort of 85 subjects with histories of repetitive mild traumatic brain injury and found evidence of chronic traumatic encephalopathy in 68 subjects: all males, ranging in age from 17 to 98 years (mean 59.5 years), including 64 athletes, 21 military veterans (86% of whom were also athletes) and one individual who engaged in self-injurious head banging behaviour. Eighteen age- and gender-matched individuals without a history of repetitive mild traumatic brain injury served as control subjects. In chronic traumatic encephalopathy, the spectrum of hyperphosphorylated tau pathology ranged in severity from focal perivascular epicentres of neurofibrillary tangles in the frontal neocortex to severe tauopathy affecting widespread brain regions, including the medial temporal lobe, thereby allowing a progressive staging of pathology from stages I-IV. Multifocal axonal varicosities and axonal loss were found in deep cortex and subcortical white matter at all stages of chronic traumatic encephalopathy. TAR DNA-binding protein 43 immunoreactive inclusions and neurites were also found in 85% of cases, ranging from focal pathology in stages I-III to widespread inclusions and neurites in stage IV. Symptoms in stage I chronic traumatic encephalopathy included headache and loss of attention and concentration. Additional symptoms in stage II included depression, explosivity and short-term memory loss. In stage III, executive dysfunction and cognitive impairment were found, and in stage IV, dementia, word-finding difficulty and aggression were characteristic. Data on athletic exposure were available for 34 American football players; the stage of chronic traumatic encephalopathy correlated with increased duration of football play, survival after football and age at death. Chronic traumatic encephalopathy was the sole diagnosis in 43 cases (63%); eight were also diagnosed with motor neuron disease (12%), seven with Alzheimers disease (11%), 11 with Lewy body disease (16%) and four with frontotemporal lobar degeneration (6%). There is an ordered and predictable progression of hyperphosphorylated tau abnormalities through the nervous system in chronic traumatic encephalopathy that occurs in conjunction with widespread axonal disruption and loss. The frequent association of chronic traumatic encephalopathy with other neurodegenerative disorders suggests that repetitive brain trauma and hyperphosphorylated tau protein deposition promote the accumulation of other abnormally aggregated proteins including TAR DNA-binding protein 43, amyloid beta protein and alpha-synuclein.

Summary and agreement statement of the 2nd International Conference on Concussion in Sport, Prague 2004

In November 2001, the 1st International Symposium on Concussion in Sport was held in Vienna, Austria to provide recommendations for the improvement of safety and health of athletes who suffer concussive injuries in ice hockey, football (soccer), and other sports. The 2nd International Symposium on Concussion in Sport was organised by the same group and held in Prague, Czech Republic in November 2004. It resulted in a revision and update of the Vienna consensus recommendations, which are presented here.

Summary and agreement statement of the first International Conference on Concussion in Sport, Vienna 2001

Recommendations for the improvement of safety and health of athletes who may suffer concussive injuries In November 2001, the first International Symposium on Concussion in Sport was held in Vienna, Austria. This symposium was organised by the International Ice Hockey Federation (IIHF), the Federation Internationale de Football Association Medical Assessment and Research Centre (FIFA, F-MARC), and the International Olympic Committee Medical Commission (IOC). The aim of the symposium was to provide recommendations for the improvement of safety and health of athletes who suffer concussive injuries in ice hockey, football (soccer), and other sports. To this end a range of experts were invited to address specific issues of epidemiology, basic and clinical science, grading systems, cognitive assessment, new research methods, protective equipment, management, prevention, and long term outcome, and to discuss a unitary model for understanding concussive injury. At the conclusion of the conference, a small group of experts were given a mandate by the conference delegates and organising bodies to draft a document describing the agreement position reached by those in attendance at that meeting. For the purpose of this paper, this group will be called the Concussion in Sport Group (CISG). This review seeks to summarise the findings of the Vienna conference and to provide a working document that will be widely applicable to sport related concussion. This document is developed for use by doctors, therapists, health professionals, coaches, and other people involved in the care of injured athletes, whether at the recreational, elite, or professional level. During the course of the symposium, a persuasive argument was made that a comprehensive systematic approach to concussion would be of potential benefit to aid the injured athlete and direct management decisions.1 This protocol represents a work in progress, and, as with all other guidelines or proposals, it must undergo revision …

Nontraumatic sports death in high school and college athletes.

Nontraumatic deaths occur each year in organized high school and college athletics, resulting in considerable public concern. We conducted a study of the frequency and causes of nontraumatic sports deaths in high school and college athletes in the USA through the National Center for Catastrophic Sports Injury Research to define the magnitude of this problem and its causes. Over a 10-yr period, July 1983-June 1993, nontraumatic sports deaths were reported in 126 high school athletes (115 males and 11 females) and 34 college athletes (31 males and 3 females). Estimated death rates in male athletes were fivefold higher than in female athletes (7.47 vs 1.33 per million athletes per year, P < 0.0001), and twofold higher in male college athletes than in male high school athletes (14.50 vs 6.60 per million athletes per year, P < 0.0001). Cardiovascular conditions were more common causes of death than noncardiovascular conditions. Hypertrophic cardiomyopathy and congenital coronary artery anomalies were the most common causes of death. In high school and college athletes, males are at increased risk for nontraumatic sports deaths compared with females even after adjustment for participation frequency; college males are at greater risk than high school males. In all groups the deaths were primarily due to cardiovascular conditions.

Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model

Blast exposure is associated with chronic traumatic encephalopathy, impaired neuronal function, and persistent cognitive deficits in blast-exposed military veterans and experimental animals. Blast Brain: An Invisible Injury Revealed Traumatic brain injury (TBI) is the “signature” injury of the conflicts in Afghanistan and Iraq and is associated with psychiatric symptoms and long-term cognitive disability. Recent estimates indicate that TBI may affect 20% of the 2.3 million U.S. servicemen and women deployed since 2001. Chronic traumatic encephalopathy (CTE), a tau protein–linked neurodegenerative disorder reported in athletes with multiple concussions, shares clinical features with TBI in military personnel exposed to explosive blast. However, the connection between TBI and CTE has not been explored in depth. In a new study, Goldstein et al. investigate this connection in the first case series of postmortem brains from U.S. military veterans with blast exposure and/or concussive injury. They report evidence for CTE neuropathology in the military veteran brains that is similar to that observed in the brains of young amateur American football players and a professional wrestler. The investigators developed a mouse model of blast neurotrauma that mimics typical blast conditions associated with military blast injury and discovered that blast-exposed mice also demonstrate CTE neuropathology, including tau protein hyperphosphorylation, myelinated axonopathy, microvascular damage, chronic neuroinflammation, and neurodegeneration. Surprisingly, blast-exposed mice developed CTE neuropathology within 2 weeks after exposure to a single blast. In addition, the neuropathology was accompanied by functional deficits, including slowed axonal conduction, reduced activity-dependent long-term synaptic plasticity, and impaired spatial learning and memory that persisted for 1 month after exposure to a single blast. The investigators then showed that blast winds with velocities of more than 330 miles/hour—greater than the most intense wind gust ever recorded on earth—induced oscillating head acceleration of sufficient intensity to injure the brain. The researchers then demonstrated that blast-induced learning and memory deficits in the mice were reduced by immobilizing the head during blast exposure. These findings provide a direct connection between blast TBI and CTE and indicate a primary role for blast wind–induced head acceleration in blast-related neurotrauma and its aftermath. This study also validates a new blast neurotrauma mouse model that will be useful for developing new diagnostics, therapeutics, and rehabilitative strategies for treating blast-related TBI and CTE. Blast exposure is associated with traumatic brain injury (TBI), neuropsychiatric symptoms, and long-term cognitive disability. We examined a case series of postmortem brains from U.S. military veterans exposed to blast and/or concussive injury. We found evidence of chronic traumatic encephalopathy (CTE), a tau protein–linked neurodegenerative disease, that was similar to the CTE neuropathology observed in young amateur American football players and a professional wrestler with histories of concussive injuries. We developed a blast neurotrauma mouse model that recapitulated CTE-linked neuropathology in wild-type C57BL/6 mice 2 weeks after exposure to a single blast. Blast-exposed mice demonstrated phosphorylated tauopathy, myelinated axonopathy, microvasculopathy, chronic neuroinflammation, and neurodegeneration in the absence of macroscopic tissue damage or hemorrhage. Blast exposure induced persistent hippocampal-dependent learning and memory deficits that persisted for at least 1 month and correlated with impaired axonal conduction and defective activity-dependent long-term potentiation of synaptic transmission. Intracerebral pressure recordings demonstrated that shock waves traversed the mouse brain with minimal change and without thoracic contributions. Kinematic analysis revealed blast-induced head oscillation at accelerations sufficient to cause brain injury. Head immobilization during blast exposure prevented blast-induced learning and memory deficits. The contribution of blast wind to injurious head acceleration may be a primary injury mechanism leading to blast-related TBI and CTE. These results identify common pathogenic determinants leading to CTE in blast-exposed military veterans and head-injured athletes and additionally provide mechanistic evidence linking blast exposure to persistent impairments in neurophysiological function, learning, and memory.

Recovery from mild concussion in high school athletes

OBJECT A computerized neuropsychological test battery was conducted to evaluate memory dysfunction and self-reporting of symptoms in a group of high school athletes who had suffered concussion. METHODS Neuropsychological performance prior to and following concussion was compared with the test performance of an age-matched control group. Potentially important diagnostic markers of concussion severity are discussed and linked to recovery within the 1st week of injury. CONCLUSIONS High school athletes who had suffered mild concussion demonstrated significant declines in memory processes relative to a noninjured control group. Statistically significant differences between preseason and postinjury memory test results were still evident in the concussion group at 4 and 7 days postinjury. Self-reported neurological symptoms such as headache, dizziness, and nausea resolved by Day 4. Duration of on-field mental status changes such as retrograde amnesia and posttraumatic confusion was related to the presence of memory impairment at 36 hours and 4 and 7 days postinjury and was also related to slower resolution of self-reported symptoms. The results of this study suggest that caution should be exercised in returning high school athletes to the playing field following concussion. On-field mental status changes appear to have prognostic utility and should be taken into account when making return-to-play decisions following concussion. Athletes who exhibit on-field mental status changes for more than 5 minutes have longer-lasting postconcussion symptoms and memory decline.

Cumulative effects of concussion in high school athletes.

OBJECTIVE A common assumption in sports medicine is that a history of concussion is predictive of a lower threshold for, as well as a worse outcome after, subsequent concussive injury. The current study was conducted to investigate the relationship between concussion history in high school athletes and the on-field presentation of symptoms after subsequent concussion. METHODS One hundred seventy-three athletes who experienced sports-related concussion composed the initial study group. Binary groups were subsequently created on the basis of concussion history. Sixty athletes with no concussion history were compared with 28 athletes with a history of three or more concussions. The groups were compared in terms of the on-field presentation of symptoms after an in-study concussion. Dependent variables included the postinjury presence of loss of consciousness, anterograde amnesia, retrograde amnesia, and confusion. RESULTS Athletes with three or more prior concussions were more likely to experience on-field positive loss of consciousness (&khgr;2 = 8.0, P = 0.005), anterograde amnesia (&khgr;2 = 5.5, P = 0.019), and confusion (&khgr;2 = 5.1, P = 0.024) after a subsequent cerebral concussion. An odds ratio revealed that athletes with a history of three concussions were 9.3 times more likely than athletes with no history of concussion to demonstrate three to four abnormal on-field markers of concussion severity. CONCLUSION This study is the first to suggest a cumulative effect of concussion in high school athletes. A more severe on-field presentation of concussion markers is evidenced in high school athletes with a pronounced history of concussion. This study’s findings highlight the need for more long-term outcome studies in high school athletes who sustain sports-related concussions.

SECOND-IMPACT SYNDROME

Second impact syndrome (SIS) occurs when an athlete who has sustained an initial head injury, most often a concussion, sustains a second head injury before symptoms associated with the first have fully cleared. While most commonly reported in football, the SIS can occur during any sport that can produce head blows. Any athlete still complaining of post-concussion symptoms after a head injury must not be allowed to return to play.

TDP-43 Proteinopathy and Motor Neuron Disease in Chronic Traumatic Encephalopathy

Epidemiological evidence suggests that the incidence of amyotrophic lateral sclerosis is increased in association with head injury. Repetitive head injury is also associated with the development of chronic traumatic encephalopathy (CTE), a tauopathy characterized by neurofibrillary tangles throughout the brain in the relative absence of &bgr;-amyloid deposits. We examined 12 cases of CTE and, in 10, found a widespread TAR DNA-binding protein of approximately 43kd (TDP-43) proteinopathy affecting the frontal and temporal cortices, medial temporal lobe, basal ganglia, diencephalon, and brainstem. Three athletes with CTE also developed a progressive motor neuron disease with profound weakness, atrophy, spasticity, and fasciculations several years before death. In these 3 cases, there were abundant TDP-43-positive inclusions and neurites in the spinal cord in addition to tau neurofibrillary changes, motor neuron loss, and corticospinal tract degeneration. The TDP-43 proteinopathy associated with CTE is similar to that found in frontotemporal lobar degeneration with TDP-43 inclusions, in that widespread regions of the brain are affected. Akin to frontotemporal lobar degeneration with TDP-43 inclusions, in some individuals with CTE, the TDP-43 proteinopathy extends to involve the spinal cord and is associated with motor neuron disease. This is the first pathological evidence that repetitive head trauma experienced in collision sports might be associated with the development of a motor neuron disease.