It is now recognised that there is a spectrum of concussion disorders ranging from acute concussion at one end to various forms of brain degeneration at the other end. The spectrum includes acute concussion, second impact syndrome or acute cerebral swelling, postconcussion syndrome, depression or anxiety, chronic traumatic encephalopathy (CTE) and possibly other forms of central nervous system degeneration. It is essential to carefully evaluate the clinical and neuropathological correlations of CTE that have been published. This has been accomplished in an excellent paper on this subject by Gardner and colleagues in this issue. There have been significant advances in our knowledge of the clinical and neuropathological features of CTE in athletes in the past 10 years. However, we are just at the beginning of our appreciation of this entity due to the paucity of research and the inability to diagnose CTE during life. At present, it is not possible to assess the validity of the proposed methods of classification and grading of the severity of the disease. Additional studies of large numbers of at-risk athletes are essential, especially prospective longitudinal studies. Obviously, such studies would be even more effective if reliable in vivo biomarkers were discovered, especially non-invasive ones such as advanced MRI or MR spectroscopy or invasive ones such as blood or cerebrospinal fluid tests. The major questions that remain unanswered include the frequency of CTE in various collision sports, the causal or otherwise relationship between concussions and CTE, the number of concussions that need to be involved and their management.
- Head injuries
- Contact sports
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Definitions of concussion and their consequences: the concussion spectrum of disorders
Seminal chronological events in the concussion world were the First International Conference on Concussions in Sports in Vienna in 2001 and the Consensus Statement of 20021 because the clarification of the definition of concussion and the elimination of non-evidence-based grading and staging scales of concussion rank as major achievements in this field. Then, refinements of the definition and management guidelines emanated from subsequent conferences and consensus statements and confirmed the merits of this approach.1–4 Unfortunately, not all concussion practitioners involved in the acute and rehabilitation components of concussions due to non-sport causes including motor vehicle crashes, injuries at work and falls at home adopted the same definition and management guidelines.5 It is time to discontinue the use of less specific definitions of concussion such as mild-traumatic brain injury (mTBI), which is an oxymoron especially when applied to repetitive concussions that can be associated with lifelong symptoms as in postconcussion syndrome (PCS) or brain degeneration as in chronic traumatic encephalopathy (CTE). The most compelling reason for eliminating the mTBI term is its inclusion of more severe brain injuries including brain contusions and haemorrhages in patients with a Glasgow Coma Scale of 13 and 14.6 ,7 Outliers that qualify as mTBI are excluded from being ‘sport consensus concussions’ on the basis of either focal clinical neurological deficits or lesions seen on CTs and MRIs. The inclusion of these more severe brain injuries as mTBI's is highly undesirable because they have different outcomes from injuries with concussion and they muddy the essential research needed to solve problems such as CTE.
Importantly, it is now recognised that there is a spectrum of concussion disorders ranging from acute concussions at one end to various forms of brain degeneration at the other end. The spectrum includes acute concussions, second impact syndrome or acute cerebral swelling, PCS, depression or anxiety, CTE and other possible forms of central nervous system degeneration.8 It is highly advantageous to have these long-term consequences of concussions included in the work of the International Conferences on Concussions in Sports.
The article by Gardner et al9 in this issue is an excellent example of the superb scholarship in concussion research necessary to bring the knowledge of the consequences of concussions out of the shadows of anecdotes and case series into the clarity of evidence-based medicine. Unfortunately, we are not there yet with CTE, although the field has progressed beyond isolated case reports. Although almost everyone recovers from a single concussion, unfortunately not everyone recovers from repetitive concussions, and this can lead to profound consequences for the individual and also for society because of the frequency of concussions. Indeed, this is currently one of the most important issues in neurotrauma and the sport concussion field: who will develop PCS or CTE as a postconcussion complication, and how commonly does this happen among athletes in collision sports? Unfortunately, until recently, there has been too little scholarship about PCS and CTE. The article by Gardner et al9 brings clarity to CTE, and will be greatly appreciated by practitioners, researchers and the general public.
Neuropathology and clinical/pathological correlations of CTE
Since Martland's10 paper in 1928, it has been apparent that repeated blows to the head in boxers can cause clinical, cognitive and motor deficits and clinical evidence of brain degeneration. However, since then and until recently there has been insufficient clinical/neuropathological research into the relationship between repetitive blows to the head and brain degeneration, and there are major unanswered questions about the incidence of this condition not only in boxers in whom it was originally described, but now in participants of other collision or contact sports.
It is only since 2005 that publications have appeared that attempted to define the clinical/neuropathological correlation between repetitive concussions and brain degeneration in athletes other than boxers. The first group to report case series in non-boxers with neuropathological changes of CTE was led by Omalu et al,11 ,12 and the second group reporting the neuropathology of a large series of CTE cases beginning in 2009 was led by McKee et al.13 ,14 Also, Hazrati et al15 reported the neuropathological evidence of CTE in three of six Canadian Football League players, all of whom had repeated concussions. Notably, the three with CTE also had other types of brain degeneration. Using a defined literature search protocol Gardner et al9 documented all 158 autopsy cases examined to date for CTE including the above three series of cases: 85 were athletes in a variety of sports examined in the last 10 years of whom 20% had pure CTE; 52% had CTE plus other neuropathology; and about 5% had neuropathological features of CTE without clinical CTE features. Gardner et al9 also provided an excellent overview of the potential pitfalls in interpretation in an ageing population subject to the natural history of neurodegenerative disease in the absence of trauma, and which can mimic most of the clinical features of CTE. The authors also correctly advised caution in attempting to establish cause and effect in this population with incomplete longitudinal data to establish accurate clinical–pathological correlation.
As a result of these reports, the sports community is now aware that the issue of brain degeneration as a consequence of repetitive concussion is not confined to boxers and applies at least to hockey, football, wrestling and rugby. At this time, there is no neuropathological confirmation of CTE in other sports. It is apparent that there are many unanswered questions to be answered to determine how big a problem this is, especially the percentage of concussed athletes that will develop CTE. We do not know the exact relationship between concussions and brain degeneration. How many concussions are required to cause brain degeneration? Do subconcussive blows lead to the same clinical deficits and pathological changes as concussive blows? Can we recognise the antecedent clinical picture of CTE? For example, is PCS a prodrome to CTE? Are the neuropathological changes of repetitive concussion absolutely specific for concussion or are they similar to the neurodegenerative changes that occur in normal ageing or diseases of ageing, such as Alzheimer's disease, frontotemporal dementia, Lewy Body disease and Parkinson's disease? How many non-concussed athletes or non-athletes will have any of the neuropathological changes such as deposition of phosphorylated τ that is considered to be specific for CTE? There are two major reasons for these unanswered questions: the lack of any specific in vivo biomarker for early or late cases of CTE (blood, cerebrospinal fluid (CSF), imaging, electrophysiology, etc); and an incomplete picture of the clinical/neuropathological correlation in CTE.
Attempts to further define the clinical and neuropathological features of CTE through classification and grading
The reports described above represent significant advances in the delineation of the neuropathology of CTE. Several laboratories have now reported that CTE has reasonably consistent neuropathological features. There is now a much clearer picture of the neuropathology of CTE based on the distribution of phosphorylated τ demonstrated by immunohistochemistry. There is reasonable consistency among these reports showing immunoreactive τ in cortex, subcortical nuclei and white matter. As stated by Gardner et al9 “the pathophysiological hallmark of these cases is the presence of regionally specific τ-immunoreactive neurofibrillary tangles, astrocytic tangles, neuropil neurites observed in both cortical and subcortical regions.” Thus, the case has become more compelling that there is a distinct neuropathological entity in athletes after sustained repetitive concussions. Military cases after blast injuries are also becoming of concern.14 Unfortunately, the clinical picture of sports CTE is still quite variable, but that should be rectified as prospective, longitudinal studies followed by autopsies are performed. Urgently needed are large-scale prospective, longitudinal studies of concussed and non-concussed individuals with neuropathological examination of the brain to search for evidence of τ-immunoreactive changes. To date, the control groups of age-matched and sex-matched cases without a history of concussions have been far too small.14
The fact that most CTE cases worsen clinically over time and the long latency in most cases before florid clinical findings emerge will always mean that cases of pure CTE will be rare, and will be mixed with various other neurodegenerative conditions of ageing as occurred in our three cases of CTE, all of which had identified neuropthological comorbidities including vascular disease, Alzheimer's disease and metastatic cancer.15 The admixture of comorbidities, alcohol and drug use also require further research.
Recently, two systems of classification of CTE have been proposed to improve the correlation between the clinical symptomatology and the neuropathological features. However, too few cases have been reported to determine the validity and usefulness of the two staging/grading systems reported in 2011 by Omalu et al16 and in 2013 by McKee et al.14 Also, Gardner et al9 have hypothesised that there are two types of CTE, the ‘classic’ and the ‘modern’, with the chronological dividing line being 2005. However, the comparison is impaired by the lack of cases with only 185 cases being reported to date, especially the paucity of reports describing the neuropathology and biochemistry of the earlier, classic version. The authors argued that there are clinical features that differentiate the two such as the classic cases having more prominent movement disorders, and the modern cases showing more frequent neuropsychiatric and behavioural disorders, and progressive dementia. The classic cases were mainly boxers while the modern cases were participants in many sports and non-sports activities, including military action. The differences between these two types may reflect the differing severity of CTE, or differing comorbidities, drug or alcohol abuse or differing genetic predisposition. The validation of this hypothesis will require much more research.
There have been significant advances in our knowledge of the clinical and neuropathological features of CTE in athletes in the past 10 years. However, we are just at the beginning of our appreciation of this entity due to the paucity of research and the inability to diagnose CTE during life. With our present knowledge of the condition, it is not possible to assess the validity of either the classic-modern classification or the two grading/scoring systems for CTE. Longitudinal studies of large numbers of at-risk athletes are essential. Obviously, such studies would be even more effective if reliable in vivo biomarkers were discovered, especially non-invasive ones such as advanced MRI or MRS or invasive ones such as blood or CSF tests. Indeed there are now a multitude of studies describing various putative biomarkers including Positron emission tomography, EEG, eye tracking, magnetoencephalography and others. These potential biomarkers would facilitate prospective, longitudinal studies followed by detailed brain examination at autopsy in athletes.
Funding This work was supported by the Canadian Sports Concussion Project at the Toronto Western Hospital, Toronto, Ontario Canada.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.
▸ References to this paper are available online at http://bjsm.bmj.com
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