Postconcussion Syndrome, SIS, and CTE
As stated previously, the neurological effects of SRCs are typically transient—approximately 90% of high school athletes are symptom free and back at their neurological baseline within 1 month of the traumatic event.[35,79,82,93,101] However, a small percentage of athletes will continue to experience symptoms months after the initial injury; this is termed PCS. Common symptoms of PCS are often vague and nonspecific, making the diagnosis difficult. The primary complaint of an athlete suffering from PCS can be any symptom of concussion; the most commonly reported symptoms are headache, dizziness, insomnia, exercise intolerance, cognitive intolerance, depressed mood, irritability, anxiety, memory loss, poor concentration and problem solving, fatigue, photo- and/or phonophobia, and psychiatric complaints.[1,63,73] These late disabilities from the concussive event are frequently self-reported and appear to be inversely related to the severity of the injury. To date no evidence exists that correlates PCS with severity of injury, structural damage to the brain, or disruption of neurotransmitter cascades.
Morgan et al. recently identified preinjury mood or psychiatric disorders, a family history of mood disorders, the number of previously sustained concussions, and delayed symptomatology (defined as symptom onset occurring more than 3 hours postinjury) as predictors of PCS development in high school athletes after an SRC. Interestingly, this multivariate model indicated that a history of a preinjury mood disorder was much more significant for predicting the development of PCS than the number of previous concussions. The results of this study support previous findings that children with high levels of stress in their lives, a history of mood disorders, and children whose parents have mood or anxiety disorders have an increased risk of prolonged problems after suffering mild head injury. Another study examining the health consequences of PCS in children found that there was a 3.3-fold increase in depression after head injury, and that this increases to 4.8-fold when a parent had a mental health diagnosis. Providers need to be aware that these postconcussion symptoms exist and know the risk factors for their development, identify patients who are at the greatest risk, and monitor them closely.
A current area of concern among providers is the effect of repetitive mTBIs, subconcussive head impacts or concussion-generating impacts, and the development of SIS and CTE in the injured athlete.
Second-impact syndrome is a feared complication of returning to play too early after a concussive event, and suffering a repeat injury, before symptoms from a previous injury have resolved.[15,16] This syndrome, which is also called "diffuse cerebral swelling," is thought to involve the loss of autoregulation of the brain's blood supply, leading to vascular engorgement and elevated cerebral blood volume, as well as a marked increase in intracranial pressure, and ultimately can cause a herniation event resulting in coma or death. It is still widely debated whether this phenomenon exists as a sequela of prior head injury or if it represents a separate pathophysiological process of malignant cerebral edema seen in younger athletes. The literature on this etiology is sparse and case reports often describe young athletes (< 18 years old), in whom the pathophysiology and clinical history presented occasionally does not support the diagnosis of SIS. Of the 17 case reports of SIS identified, only 5 involved repeat injuries, all of which occurred within 7 days of the initial injury.[93,96] However, whether or not SIS exists as classically defined, the association with early, repeat concussive injury warrants that the injured athlete not return to play before the symptoms of the concussion have completely resolved.
Apart from SIS, allowing an athlete to return to play prior to symptom resolution predisposes them to more severe injury from a subsequent concussion, with a prolonged duration and increased severity of symptoms. A previous concussion decreases the cognitive ability and reaction time of the individual, increasing the athlete's susceptibility to repeat injury due to their diminished ability to respond to the demands of the sport.[74,75,91,95,134,140] There theoretically exists a time window of increased brain vulnerability due to the impaired cellular energy metabolism, during which a repetitive injury would worsen these neurochemical and neurometabolic derangements, leading to more significant cognitive deficits and prolonged recovery.[62,78,133,143–145]
The growing concern over the consequences of repetitive concussive and subconcussive injuries among American athletes is evident in today's media. Subconcussion is due to a biomechanical force applied to the cranial contents that does not result in clinical signs or symptoms sufficient to diagnose a concussion. The mechanism of injury may be due to direct impact; acceleration-deceleration or rotation of the head; or the "slosh" phenomenon, which is described as acute acceleration or deceleration of the body, with resultant brain movement within the cranial vault leading to injury. Although no overt signs are present on the initial injury, the clinical consequence of subconcussions is manifested as a result of the athlete's cumulative exposure. Concussion-free college athletes participating in contact sports demonstrated lower scores on formal neuropsychological testing, notably in new learning and memory domains, than did control individuals.[60,87] Among athletes exposed to subconcussive injuries, some studies have shown that the deterioration in cognitive performance is directly proportional to their exposure burden, although other studies have failed to reproduce this phenomenon.[87,103] When nonconventional neuroimaging is used, athletes without observable symptoms of a concussion have demonstrated neurophysiological changes that are similar to those seen on fMRI activation during working memory tasks in control patients with known concussion.[12,142] These changes appear to be statistically correlated with the number of subconcussive hits sustained by the athlete.
Additionally, DTI has provided evidence of white matter damage in subconcussion brain injuries, although the clinical significance of these lesions has yet to be determined. Unfortunately, our knowledge of subconcussions remains in its infancy, and although data strongly suggest the presence of detrimental neurological consequences secondary to the repetitive exposure by athletes, further research is needed if we are to understand the true scope of this entity.
Chronic Traumatic Encephalopathy
Recent evidence suggests that CTE is a potential long-term neurological sequela of repetitive brain injury, although a direct, causal mechanistic linkage has yet to be discovered. Neurological and neurobehavioral symptoms in contact sports were first described in boxers in the 1920s and 1930s—initially referred to as "punch drunk" syndrome—who developed parkinsonism, dysarthria, and psychiatric disturbances[84,115] (which were also colloquially known as "traumatic encephalopathy," "dementia pugilistica," and "chronic traumatic encephalopathy"). In the 1970s, researchers began to examine and categorize the neuropathological changes they discovered in boxers diagnosed with dementia pugilistica, and in the late 1990s, the association between repetitive head injuries and neocortical neurofibrillary tangle formation and tau pathology was identified. In 2005, Omalu et al. reported the first case of CTE in a retired National Football League player, with a second case reported 1 year later. McKee et al. described 48 cases in the world literature as of 2009, and a few years later proposed a pathological staging system to categorize CTE.
However, despite multiple authors describing a similar syndrome, the exact clinical features and pathological findings that are necessary and sufficient to constitute CTE remains unanswered. For instance, suicidality is widely cited as a clinical feature of CTE; it was first described by Omalu et al. in 2010 after patients in 2 of the 3 cases examined committed suicide. However, in the exhaustive 2009 review by McKee et al., suicide was not reported in a single case, nor was it included in their description of CTE's clinical features.
The most widely accepted etiological description of CTE assumes an associative relationship with multiple concussions in sports;[100,111,136] however, a single TBI or multiple mTBIs in military personnel and civilians[100,111,136] have been identified as possible causes. Lately, the role of subconcussion and the development of CTE has come to the forefront of many investigators' endeavors, in which this "silent" epidemic is cited as possibly a larger problem than classically diagnosed concussions.[3,6,38,97]
The evolution of neuropathological and clinical descriptions of CTE continues to be refined. Omalu et al. originally described the clinical presentation of CTE as a progressive deterioration in social and cognitive functioning, mood and behavioral disorders, progressive deterioration in interpersonal relationships, violent behavior, substance abuse, headaches and/or body aches, and increasing religiosity. Additionally, some have described an insidious onset, often initially manifesting as disturbances in attention, difficulty concentrating, or depression, with or without headaches. Athletes often begin showing symptoms between the ages of 35 and 45 years (range 24–65 years), with a characteristic latent period of approximately 8 years between the last trauma and the development of symptoms. There are data that suggest CTE may present as one of three clinical pictures: CTE onset at younger age with predominant behavioral or mood disturbances; CTE onset later in life with predominantly cognitive impairment; or CTE with a mixed picture of both cognitive and behavioral and/or mood disturbances.[105,137] The onset and severity of CTE symptoms may be associated with the burden of hyperphosphorylated tau deposition, neuroinflammation, and axonal pathology in the injured patient.
Recent descriptions of the microscopic neuropathology include the following: localized neuronal and glial accumulation of tau in perivascular areas of the cerebral cortex, sulcal depths, and superficial cortical lamina; multifocal axonal varicosities in subcortical and deep white matter; variable and sometimes absent beta-amyloid deposits; and immunohistological TAR DNA-binding protein 43 (TDP-43)–positive inclusions and neurites.[6,38,99] These patho logical findings may also be found in other conditions including Alzheimer disease, frontotemporal dementia, progressive supranuclear palsy, and aging; however, the localization of tau as described above is considered unique and is a distinguishing characteristic for CTE.
McKee et al. proposed a 4-stage pathological description of CTE in 2013 that represents a progressive description of the disease, with symptom onset and evolution associated with the severity of macro- and microscopic changes observed in gross specimens.
Stage I is often asymptomatic or associated with onset of nonspecific symptoms such as headache, irritability, and decreased concentration. On pathological examination, the brain is grossly unremarkable. Microscopically, one or two isolated perivascular foci of tau deposition are identified, often at the depths of cerebral sulci in the frontal cortex and subpial astrocytes. Vascular amyloid deposits and beta-amyloid plaques are not found.
Athletes with Stage II CTE are often symptomatic and exhibit short-term memory difficulties, disorganization and difficulty planning, aggression, mood swings and/or depression, explosivity, and suicidality.[100,137] Half of the pathological specimens show macroscopic changes including mild enlargement of the lateral and third ventricles, cavum septum pellucidum, and pallor of the substantia nigra and locus coeruleus. Multiple foci of tau pathology are identified in sulcal depths throughout the supratentorial cortex, with neurofibrillary tangles found in superficial layers of adjacent cortex. Deep structures (thalamus, median and dorsal raphe, and substantia nigra) show mild neurofibrillary degeneration. Perivascular beta-amyloid and beta-amyloid plaques are rarely identified.
By Stage III, most athletes are cognitively impaired due to memory loss, executive dysfunction, and attention deficits, in addition to the previously mentioned symptoms in earlier stages.[51,71,98] Macroscopically, there is reduced brain weight; mild frontal and temporal atrophy; lateral and third ventricular enlargement; septum abnormalities; atrophy of mammillary bodies, thalamus, and hypothalamus; thinning of the corpus callosum; and pallor of the locus coeruleus and substantia nigra. Microscopically, neurofibrillary tangles are identified in the sulcal depths and perivascular areas throughout the frontal, temporal, and parietal cortices. Additionally, the hippocampus, amygdala, entorhinal cortex, nucleus basalis of Meynert, and locus coeruleus display extensive neurofibrillary tangles, with less prominent foci now identified in the hypothalamus and mammillary bodies. Beta-amyloid deposits and plaques continue to become more prominent.
Stage IV CTE is associated with severe executive dysfunction and memory loss with dementia. Most athletes suffer from profound loss of concentration and attention, language difficulties, paranoia, depression, difficulty with gait, visuospatial disturbance, aggression, and explosivity.[97,98,105] Macroscopically, there is significant frontal, lateral, and medial temporal, and also anterior thalamic atrophy. The mammillary bodies are darkly discolored and atrophied, the hypothalamic floor is thinned, and there is marked enlargement of the lateral and third ventricles, in addition to the findings described in Stage III. Microscopically, severe spongiosus of cortical layer 2 and neuronal loss is widespread. The white matter of the cerebral hemispheres displays marked myelin loss and astrocytosis, perivascular macrophage deposition, and severe tau clusters and neurofibrillary tangles throughout the frontal, temporal, and parietal cortices. The insula, septal area, temporal cortex, amygdala, hippocampus, entorhinal cortex, substantia nigra, and locus coeruleus show severe neurofibrillary degeneration.
Despite this exhaustive description of the pathological stages by McKee et al., other researchers found different pathological changes in patients identified as having CTE. Omalu et al. reported that CTE is not associated with cerebral atrophy, in contrast to the previously mentioned findings by McKee et al., in which it was a prominent characteristic. Additionally, McKee et al. described tau immunoreactive astrocytic tangles as a defining feature of CTE, but these were not present in the series published by Omalu et al.[100,111] Microscopically, there is a discrepancy regarding subependymal accumulation of tau, which was described by McKee et al., but again not identified by Omalu et al., although both agree on the characterization of CTE by tau deposition in sulcal depths and superficial cortical layers.[100,111]
It is important to appreciate that many cases identified as CTE also showed other nonspecific neuropathological changes, in addition to many cases meeting neuropathological criteria for the diagnosis of other neurodegenerative diseases such as frontotemporal dementia and Alzheimer disease. These objective findings, along with the frequent overlapping of similar symptoms, make distinguishing CTE from other disorders difficult.
Going forward, there are several important issues regarding CTE that must be addressed. A set of consensus-based, specific, sufficient, and reproducible criteria for the neuropathological diagnosis of CTE needs to be established, with which control subjects can be analyzed to understand what pathological changes are attributable to CTE as compared with other neurodegenerative disorders and/or the normal aging process. The lack of control subjects in the prior pathological studies of CTE should not be minimized. These criteria may enable us to better qualify to what degree and by what mechanism tau deposition might cause or reflect the progressive degeneration and/or clinical symptoms of CTE.
Other areas of debate include identifying a clinical methodology to determine to what extent a patient's symptoms are attributable to CTE versus other neurological, psychiatric, medical, and degenerative processes; identifying to what extent repetitive neurotrauma uniquely contributes to clinical symptoms of CTE;[6,38,97,100,110,112,137,138] and identifying whether the changes attributed thus far to repetitive neurotrauma represent a distinct disease process, or whether the repetitive injuries are associated with reductions in cerebral reserve that result in an increased vulnerability to earlier expression of late-life neurodegenerative disorders.[58,124,125] Until our knowledge of CTE becomes more complete, and causality is identified, our best management strategy remains prevention. If the data suggestive of neurotrauma as an inciting factor prove to be true, better equipment, rule changes, and increased awareness will, it is hoped, result in a reduction in incidence of CTE in the future.
Neurosurg Focus. 2016;40(4):e5 © 2016 American Association of Neurological Surgeons