AANS Neurosurgeon | Volume 26, Number 2, 2017

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Point: Chronic Traumatic Encephalopathy: A Real Disease, but Not a New One

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Chronic traumatic encephalopathy (CTE) is a term applied to a chronic, progressive neurodegenerative illness occurring in some individuals who have experienced repeated concussive or sub-concussive traumatic brain injuries (1-4). The term and the diagnosis have come to considerable public attention and ignited controversy because of the description of CTE cases in former athletes who played American football professionally in the U.S. or who played professional hockey in the National Hockey League (NHL) (1-5). It is also now an important consideration among armed services members subjected to repeated concussions in training or in combat. 

After denying any such connection for a considerable time, the National Football League (NFL) only recently acknowledged the causal relationship after litigation, and the NHL Commissioner is still denying any such connection. This has created a controversy, which given the popularity of football and hockey as spectator sports, and given the very large amounts of money at stake, excite comments from the public as a whole. This has been dramatized in a Hollywood film, “Concussion,” relating the story of Bennet Omalu, MD, MBA, MPH, who first published cases of CTE in former NFL players.

Historical Background
CTE is not a “new” disease as some have thought or stated. The appearance of dementia with or without an associated parkinsonian movement disorder was known to occur in boxers back into the 19th century. The first formal medical article describing this is likely that of pathologist Harrison S. Martland (6). He noted that for years, neurologists and other “experts” denied the existence of a “punch drunk” neurological syndrome even though fighters, fight promoters and the public that followed boxing knew it was a real syndrome (6). An understanding of the disorder developed only gradually with the maturation of neuropathology as a discipline. It was quickly understood that the brains of boxers who exhibited the clinical syndrome of being “punch drunk” had some of the changes associated with Alzheimer’s disease (AD), and this caused significant confusion because AD itself was poorly understood neuropathologically until at least the 1970s.

By 1976, the second edition of Greenfield’s Neuropathology stated, “It is well established that persons subjected to repeated concussive or sub-concussive blows, such as boxers and footballers (presumably she meant rugby players), may develop neurological signs and progressive dementia, the ‘punch-drunk’ syndrome(7). This description noted neuropathologically that numerous neurons had neurofibrillary tangles, especially in the temporal lobes, without many or any senile plaques, thus separating the neuropathological features from those of AD, and this clinical-neuropathological entity was termed “dementia pugilistica.”

As will become apparent from the description of the “modern” pathology of CTE, what has become known as CTE is dementia pugilistica in another patient population. It is highly interesting to note that this disorder also was recognized in the older literature in rugby players. The neuropathological descriptions of the disorder are now more sophisticated and involve immunohistochemical stains for microtubule-associated protein tau, beta-amyloid, TAR-DNA binding protein (TDP-43) and other potentially relevant antigens.

Neuropathology
The brains of possible CTE patients are often not visibly atrophic but some are. They typically lack overt evidence of blunt head trauma: there are no old contusions, no membranes left from organized old subdural hematomas and no deep white matter cavities from old hemorrhages. A striking number have a cyst of the cavum septum pellucidum, and those cysts are often ruptured; in other cases, the septum is torn. This damage to the septum was also reported in boxers by Corsellis et al. (8).

When a relatively young person (an athlete, ex-athlete, soldier or someone who has been both) has a progressive neurological syndrome that fits the description of clinical problems of CTE and then dies, the neuropathological examination must establish if there are brain changes of any of a range of disease entities, including CTE.

The larger series of such cases that have been accumulated and reported also emphasize that the tau-immunopositive abnormalities are frequently perivascular as well as at the depths of sulci, and neither distribution is typical of AD. They are also mostly in the upper cortex, the opposite of what is most often seen in AD (4,5), and they are not distributed in the spatial and temporal pattern typical for AD, in which tangles are first found in the entorhinal cortices, then in the hippocampi, and only last in neocortex (9). Cases which fit these descriptions are the least controversial, especially when they lack beta-amyloid plaques, at least among neuropathologists. Reflecting this, the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke (NINDS) sponsored a conference that resulted in a consensus on neuropathological criteria regarding CTE (5). For the neuropathology community, CTE is a real disorder that has been identified in a considerable number of former athletes who participated in contact sports with a high risk of “minor” head injury, such as football, hockey and rugby, as well as boxing.

Diagnosing CTE
Unfortunately, a significant number of persons who may have CTE die from suicide, homicide or unexpected other disease such as cardiovascular disease and are either then not subjected to autopsy or are autopsied by forensic pathologists without the necessary neuropathological expertise or interest. Forensic pathologists are highly goal-directed to find the cause and manner of death and not to further investigate other co-morbid conditions. Thus, many of these cases are either not investigated or are inadequately sampled. 

Causation Versus Association
Critics of the claim that CTE is a consequence of repetitive minor head trauma, sufficient to cause a concussion in some cases but not in others, argue that the number of cases examined is relatively small compared to the potential populations at risk in such sports or in the military; and that there are almost no controls (since those at risk are relatively young, the general autopsy rate is low and young people who die of drug overdoses, other forms of suicide, homicide, etc., are not usually subjected to detailed neuropathological examination).

It is completely true that these are not controlled observations, and no prospective clinical trial is possible. The original case reports by Omalu could be dismissed as anecdotes, albeit disturbing ones. However, the accumulated experience reported by others is impressive: for example, a 2013 study found that 68 out of 85 autopsies of individuals potentially at risk for CTE had brain changes associated with that diagnosis. Thus, this issue would seem to be largely settled: there is a characteristic pathology associated with a clinical syndrome, and these together are sufficient to establish a clinicopathological entity of CTE, the cause of which is repetitive “minor” head trauma. That the neuropathological changes match those of dementia pugilistica, a disorder unequivocally induced by repeated head trauma, only adds to this consensus.

We all make choices in our daily lives that balance the risk of an activity versus its reward (think driving to work, flying, eating unhealthful foods, getting too little sleep, etc.). Participating in contact sports, or enjoying the public performances of them, or benefiting from the advancement of the national interest that armed services members give in combat, may likewise be desired. We should understand that the rewards of such activity or spectating exposes these highly skilled young people to the risk of an insidious, crippling, irreversible, and sometimes lethal brain disorder.


References
1. Omalu, B.I., DeKosky, S.T., Minster, R.L., Kamboh, M.I., Hamilton, R.L., & Wecht, C.H. (2005). Chronic traumatic encephalopathy in a National Football League player. Neurosurgery, 57(1), 128-134.

2. Omalu, B.I., DeKosky, S.T., Hamilton, R.L., Minster, R.L., Kamboh, M.I., Shakir, A.M., & Wecht, C.H. (2006). Chronic traumatic encephalopathy in a national football league player: part II. Neurosurgery, 59(5), 1086-1093.

  1. 3. McKee, A.C., Cantu, R.C., Nowinsky, C.J., Hedley-Whyte, E.T., Gavett, B.E., Budson, A.E., … & Stern, R.A. (2009). Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. Journal of Neuropathology & Experimental Neurology, 68(7), 709-735.

    4. McKee, A.C., Stern, R.A., Nowinski, C.J., Stern, R.A., Daneshvar, D.H., Alvarez, V.E., … & Riley, D.O. (2013). The spectrum of disease in chronic traumatic encephalopathy. Brain, 136(1), 43-64.

    5. McKee, A.C., Cairns, N.J., Dickson, D.W., Folkerth, R.D., Keene, C.D., Litvan, I., … & Tripodis, Y. (2016). The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta neuropathologica, 131(1), 75-86.

    6. Martland, H.S. (1928). Punch drunk. Journal of the American Medical Association, 91(15), 1103-1107.

    7. Strich, S.J. Cerebral trauma. In Blackwwood W, Corsellis JAN, eds, Greenfield’s Neuropathology, 3rd edition (London; Edward Arnold), 1976, p. 349.

    8. Corsellis, J.A.N., Bruton, C.J., & Freeman-Browne, D. (1973). The aftermath of boxing. Psychological medicine, 3(3), 270-303.

    9. Braak, H., & Braak, E. (1991). Neuropathological staging of Alzheimer-related changes. Acta neuropathologica, 82(4),239-259.

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Douglas C Miller MD,PhD | September 12, 2016 at 9:46 am

Some of this became a bit garbled during the editing process. The “second edition of Greenfield’s” referred to in the text is the third edition. The author of the chapter, whose name got omitted in editing to make the article small enough, was Sabena Strich. I apologize for not catching these, but then I didn’t see a final pdf before on-line publication.