Cumulative Effects of Repeated Mild Traumatic Brain Injury and Chronic Traumatic Encephalopathy

Philip H. Montenigro, Daniella C. Sisniega, and Robert C. Cantu

INTRODUCTION

A concussion is a form of mild traumatic brain injury (MTBI) caused by an impact to the head, face, or neck, or rapid acceleration/deceleration, which results in an impairment of brain function [1,2]. Repeated concussions occur in a variety of contexts, but are commonly observed in sports, particularly sports in which frequent head contact is inevitable, such as boxing or football. Additionally, these sports have a tendency to foster a culture of toughness; the athlete is encouraged to play through injury, placing them at risk for repetitive head trauma and potentially the development of clinical impairments later in life. More specifically, it has been demonstrated that repetitive head trauma even in the absence of concussion can result in neurologic changes, including changes in cognition, mood, behavior, and a neurodegenerative condition known as chronic traumatic encephalopathy (CTE) [1,3].

EPIDEMIOLOGY

• 1.7 million people are diagnosed with a concussion in the United States each year [2].

• 1.6 to 3.8 million concussions are estimated to occur in sports and recreational activities in the United States as reported by the Centers for Disease Control and Prevention [2].

• 73% of football players underestimate their concussion histories [4].

• 53% of high school student athletes report prior histories of concussions at the start of high school [5].

• 36% of all collegiate athletes report histories significant for multiple concussions [5].

• 71% of high school players suffering catastrophic brain injuries had previous concussions in the same season [6]. A “catastrophic” brain injury includes three categories: fatal, nonfatal (permanent neurological or functional disability), and serious (severe injury without permanent neurological or functional disability; for example, subdural hematoma treated surgically) [6].

• NFL players have neurodegenerative disease listed as their cause of death at three times the rate of the general population [7].

• The mean number of concussions reported among individuals with pathologically documented CTE is 17 [8].

• 16% of individuals with pathologically documented CTE had no reported history of concussion [8], highlighting the potential risks associated with repetitive asymptomatic blows to the head (i.e., subconcussive impacts) [1,3,8–10].

PHYSIOPATHOLOGY

When a concussion is experienced, there is an activation of the inflammatory response. This response causes a disrupted neuronal metabolic cascade characterized by an imbalance of ions across the membrane, mitochondrial dysfunction, an increase in excitatory amino acids, a dysregulation of neurotransmitter synthesis, and an increase in free radical production [1]. Even in the absence of a concussion, the cumulative effect of subconcussive impacts can result in axonal injury and damage to the blood–brain barrier [1,9,10]. Ultimately, these metabolic changes within the neuron make it more vulnerable to secondary ischemic injury and potentially to injury from repeated subconcussive impacts. Genetics may also play a role in the development of long-term neurological deficits. One study found the ApoE4 allele in combination with repeated concussions is more likely to result in dementia [11]. Another study noted a significantly higher frequency of ApoE4 homozygotes among CTE cases [12].

CLINICAL MANIFESTATIONS

Athletes who participate in contact sports have an increased likelihood of developing acute and long-term neurocognitive impairment, depression, emotional instability, executive dysfunction, memory impairment, and neurodegeneration later in life [1]. The cumulative effects of concussions can have a sustained impact on cognitive function, in particular, planning and memory. While the cumulative effects of two concussions can result in little or no difference in the symptoms experienced compared to a single concussion, patients with multiple concussions (i.e., three or more) often experience a longer recovery period [13,14]. Notably, those who experience head trauma while still symptomatic from a previous concussion are at a higher risk for developing postconcussion syndrome (PCS), or persistent postconcussion symptoms lasting beyond the expected acute injury period, and second impact syndrome (SIS), an acute concussion-related outcome that disrupts the autoregulation of constant blood flow to the brain and can result in brain herniation and death [1]. Signs or symptoms of functional impairment may also develop or worsen after the age of 50 [15]. The late onset of symptoms may be due to underlying mechanisms that allow a person to function normally up until a threshold level of neurological damage has accumulated or until underlying pathology has progressed [1,15].

DIAGNOSIS

A detailed history and physical exam are critical for the evaluation of a patient presenting with cumulative effects of concussion. Structural changes are difficult to detect via CT and MRI [1] unless specialized techniques such as diffusion tensor imaging or PET MRI are used; these techniques are typically reserved for research settings. The cumulative effect of repeated concussion and subconcussive impacts has been demonstrated through imaging after a single season of athletic contact sport exposure [3,16,17]. These changes are best noted in the corpus callosum, external capsule, inferior fronto-occipital fasciculus, dilated ventricular system, and cavum septum pellucidum [1,11]. Even after the resolution of symptoms, ultrastructural and functional brain alterations may be seen by susceptibility weighted MRI, fMRI, magnetic resonance spectroscopy MRI, and PET MRI [1,11]. Fractional anisotropy and mean diffusivity are abnormal changes that may be seen in diffusion tensor imaging (DTI) [1,11].

CHRONIC TRAUMATIC ENCEPHALOPATHY

CTE is a neurodegenerative disease that has only been reported in individuals exposed to brain trauma, indicating that brain trauma is a necessary factor for its development. Not everyone exposed to brain trauma develops CTE, suggesting its development is influenced by other factors (e.g., genotype) as well. CTE occurs most frequently in people with a history of repeated brain trauma, such as boxers, football players, and military personnel [18–20]. Since not everyone exposed to repetitive trauma necessarily develops CTE, the minimum amount of exposure required for initiation is not yet known. In CTE, hyperphosphorylated tau (p-tau) accumulates in a unique pattern as perivascular neurofibrillary tangles and neurites at the depths of the cerebral sulci. These neurofibrillary tangles and neurites eventually spread to the adjacent superficial cortical layers, mostly neocortical layers II and III [20]. This pattern is different in location and progression from that seen in normal aging and in Alzheimer’s disease [11,20]. Also unlike Alzheimer’s disease, beta-amyloid plaque deposition is not consistently present. Ultrastructurally, there is a diminished total brain volume, reduced hippocampal size, and degeneration of the medial temporal lobes, frontal lobes, diencephalon, mammillary bodies, brainstem, dilated ventricular system, and cavum septum pellucidum [20]. The symptoms of CTE typically present in one of four clinical domains (Table 56.1):

• Cognitive: decrease in memory, executive function, attention, learning, and dementia

• Mood: depression, anxiety, suicidal tendencies, irritability, hopelessness, and apathy.

• Behavioral: explosiveness, violence, impulsiveness, having a “short fuse,” and aggression.

• Motor: Parkinsonism, ataxia, and dysarthria.

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