Chronic Traumatic Encephalopathy: Should We Be Worried?

[[{"type":"media","view_mode":"media_crop","fid":"23959","attributes":{"alt":"","class":"media-image media-image-right","id":"media_crop_9186395842139","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"2007","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"width: 185px; height: 199px; float: right;","title":" ","typeof":"foaf:Image"}}]]Sensational media attention continues to surround the subject of traumatic brain injury (TBI) more generally, and chronic traumatic encephalopathy (CTE) more specifically. A recent round of media attention was sparked late in 2013 with headlines declaring Major League Baseball’s first victim of CTE and the suggestion that CTE may have contributed to a death by suicide.¹ Recognition of the consequences of repetitive brain trauma dates back to the initial description of “punch drunk” boxers in 1928, involving cases of chronic TBI endured throughout a boxing career (during an era in which the sport was considerably more brutal).

The term “CTE” was introduced more recently to describe progressive neuropathological changes and diffuse clinical neuropsychiatric symptoms associated with a history of TBI, and following considerably more modest degrees of TBI exposure than that associated with the initial case descriptions involving boxers. Particularly alarming are recent descriptions of CTE that suggest that even a single (mild) TBI may be enough to trigger a progressive and devastating neurodegenerative illness.^2,3 Suppositions of this kind have understandably generated widespread alarm, expanding the purported at-risk population.

“Should I be worried about CTE?”

The expansive and nonspecific emerging syndrome profile proposed for CTE spans an extraordinarily broad array of extremely common physical complaints and cognitive, emotional, and/or behavior problems.³ Many of these symptoms feature in psychiatric conditions that commonly occur in the general population (eg, depression, anxiety, and/or substance abuse/dependence) as well as in neurodegenerative conditions (eg, Alzheimer disease, Parkinson disease).

The proposed syndrome profile for CTE overlaps with a wide array of neuropsychiatric conditions. Given that overlap, and the frequency with which mild TBI occurs, psychiatrists and other mental health professionals will likely encounter patients with clinical presentations that are superficially consistent with CTE literature. Clinicians need to be prepared to thoughtfully navigate these clinical encounters and to answer the question: “Should I be worried about CTE?”

Both the public’s and clinicians’ understanding of CTE has been chiefly shaped by mass media. Unfortunately, many news reports provide a somewhat unbalanced picture of CTE research. The media often present scientific theory as medical fact and seldom elaborate on significant methodological limitations.

Questioning the evidence

While each newly identified case of CTE seems to generate numerous headlines, calls for more cautious interpretation of CTE research based on a relatively small sample and experimental designs of modest evidentiary value seldom receive the same degree of media attention. This has yielded an environment wherein common neuropsychiatric symptoms and exceptionally rare behavioral events (eg, murder, suicide) are often reduced to complications of TBI and CTE. Meanwhile, alternative neuropsychiatric explanations, many of which are both common and treatable, are being overlooked.

A number of reports have emerged that call for caution and consideration when determining the extent to which we should be worried about CTE. While detailed review of each of these publications is beyond the scope of this article, it is worth reflecting on the common points of concern.

Granier and colleagues⁴ were among the first to publish a call for restraint in interpreting CTE research and advised against “leaping too far too soon.” The researchers identified media sensationalism, high-profile cases, and financial pressures surrounding sports (professional and collegiate) as generating widespread interest. They noted a lack of well-designed, prospective, large-sample, randomized clinical trials that examined the effect of concussions on long-term neuropsychiatric health. They argued that sweeping change predicated on inconclusive data is “neither scientifically supported nor ethically responsible.”

Differences between clinical case definitions and neuropathological criteria for CTE persist among leading CTE researchers (compare the definitions and criteria used by the Center for the Study of Traumatic Encephalopathy with that endorsed by the Brain Injury Research Institute). These differences reveal the premature nature of the conclusions to date. There is some convergence between the CTE definitions regarding the presence of neurofibrillary tangles and/or threads, yet the requisite volume and location of the tangles and threads remain incompletely defined.³

McKee and colleagues⁵ observed that “7 of 18 control brains were completely negative for p-tau [hyperphosphorylated tau] neurofibrillary tangles,” revealing that, to some extent, 61% were positive for p-tau neurofibrillary tangles. Hence, the modest specificity of neurofibrillary tangles as a diagnostic marker for CTE should mandate considerable caution when relying on this neuropathological criterion.⁶

Particularly informative is a systematic review of CTE recently published by Gardner and colleagues.⁷ The authors reflect on the relatively limited number of cases to date and study methodologies of modest evidentiary value. They identified only 158 autopsy cases examined for CTE in the medical literature and noted important differences between the original descriptions of dementia pugilistica and more recent cases of CTE. The researchers pointed out “critical differences in age of onset, progression, clinical features, pathological findings, and diagnostic criteria.” These differences caused Gardner and colleagues to distinguish between “classic CTE” and “modern CTE.” Such findings are not unlike the disparate clinical presentations featured in some of the more modern CTE literature itself.⁸

The discrepancies between the old and the new variants of CTE complicate our efforts to understand the nature of these proposed neuropsychiatric entities. Only 85 reported autopsies were conducted in the past decade: 20% featured “pure” CTE neuropathology, 52% had CTE in addition to other neuropathologies, 5% had neuropathology but no CTE, and 24% had no neuropathology. Gardner and colleagues point out that the spectrum of neuropathology for cognitively intact older adults, as well as for those with neurological illness, is diverse. That reality and the above-described autopsy data (which also suffer from prominent case-selection bias) suggest challenges for establishing clinicopathological correlations between the neuropathology of CTE and various clinical presentations.

In addition, meaningful consideration for “differential diagnoses, mediating variables, moderating variables, or multifactorial neuropathological processes” is lacking from the CTE literature. Little is known about the neuropathological findings potentially associated with other common medical and neuropsychiatric conditions that appear with some regularity among patients with CTE and similar at-risk populations. These conditions (eg, drug and/or steroid abuse, alcohol abuse, chronic psychiatric illness, cardiovascular disease, cerebrovascular disease) may yield neuropathological findings similar or identical to those attributed to CTE. These conditions (alone or in combination with other neurodegenerative conditions) might also account for much of the clinical phenomenology ascribed to CTE.

“The strongly presented causal assumptions in the literature relating to concussive and subconcussive brain impact exposure derived from case studies are scientifically premature, especially given the absence of cross-sectional, epidemiological, prospective, or longitudinal studies on the topic.”⁷ In short, the existing data establish neither a causal relationship between TBI and CTE nor a causal relationship between neuropathological findings of CTE and clinical presentations.

CTE and neuropsychiatric mortality

The existing epidemiological data derived from the study of health status among football players are not consistent with a lethal CTE epidemic. Of particular importance is a study that examined mortality among 3439 retired professional football players.⁹ Contrary to notions of devastating health consequences resulting from careers in the NFL, study data showed lower than expected mortality. Moreover, there were fewer deaths caused by neuropsychiatric conditions than anticipated.

Deaths due to “mental, psychoneurotic, and personality disorders” were calculated at 11.7, but only 4 such deaths were actually observed. Other noteworthy examples of less than expected causes of death included violence (48.3 expected; 13 observed), intentional self-harm (21.8 expected; 9 observed), assault and homicide (26.4 expected; 4 observed), and symptoms and illdefined conditions (10 expected; 3 observed). Such data are contrary to assertions that NFL players are at high risk for violent and/or suicide deaths from any cause, including CTE.

If NFL players are actually at increased risk for CTE, the existing epidemiological data argue against CTE being a high-risk condition for violent and/or suicide deaths. This reminds us of the need for caution when embracing overly reductionist formulations for complex human behaviors. Violent acts, whether directed against oneself or others, seldom feature a singular cause and tend to be the consequence of multiple interacting neuropsychiatric and psychosocial factors.¹⁰

Nevertheless, allusions to causal relationships between CTE and suicide abound in the medical literature and popular press. But the evidence in support of such a relationship is particularly weak. Iverson¹¹ observes that there are no published cross-sectional, epidemiological, or prospective studies that show a correlation between participation in contact sports and suicide. He observes:

Finding evidence of the neuropathology of CTE in the brains of former athletes who complete suicide is a provocative but not statistically compelling source of evidence. The putative causal link in individual cases represents circular reasoning (ie, petitio principii). Given that there were only 9 reported deaths by suicide in former NFL players between 1960 and 2007, and there have been 6 reported suicides in the past 2 years, it is essential to carefully investigate the diverse array of risk factors for suicidality in former athletes-and not adopt a singular mechanistic assumption about proteinopathy as the primary explanation.

In a systematic review of the literature on CTE and suicide, only 2 case series were identified that met inclusion criteria.¹² Autopsies from 17 unique cases revealed only 5 that involved death from suicide. The case series failed to employ blinding, control cases, or systematic data collection regarding TBI exposure or medical/neuropsychiatric history. The overall quality of evidence regarding a relationship between CTE and suicide was rated as very low on the basis of Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria.¹³

Clinical approach to mild TBI and CTE

Much of the alarm surrounding CTE and the potential consequences stemming from a single mild TBI or a modest number of concussive injuries stems from literature that has marginalized the more developed medical science on TBI outcomes. When determining the extent to which we should be worried about a mild TBI in a typical clinical encounter, clinicians and patients are better served by relying on meta-analyses that examine outcomes from mild TBI rather than on CTE literature derived from a relatively small (nonrandom) sample of persons who are unlike most patients in terms of either TBI exposure or neuropsychiatric comorbidity.

The prognosis for a single mild TBI is very favorable, portending a full and fast recovery for the vast majority of patients.^14-16 Such findings are far more applicable to the overwhelming majority of patients who present with histories of mild TBI than to the case reports featured in the CTE literature.

Misapplication of CTE case series data creates the potential for unfortunate clinical consequences. Misunderstanding regarding the implications of the TBI and CTE research may foster maladaptive anxiety among patients, families, and health care professionals. Importantly, premorbid and concurrent psychiatric problems, and anxiety in particular, may influence postinjury symptoms more than mild TBI does.¹⁷ Hence, concerted efforts are needed to better educate medical and mental health professionals, as well as the public, regarding the state of the research on mild TBI and CTE.

It is important to avoid catastrophizing mild TBI and mitigate the collective anxiety that such practices engender, to reduce the likelihood of iatrogenic adverse outcomes after mild TBI. Persistent CTE-like symptoms in the wake of a mild TBI may be the impetus needed to explore and identify other neuropsychiatric illnesses that might better account for atypical clinical presentations.

Conclusion

Preliminary results derived from relatively small case series and methodologically problematic studies should not dictate policy over the more robustly established medical research on mild TBI. It remains somewhat unclear whether any of our patients need to be worried about CTE, but readily apparent that the overwhelming majority of them need not be.

Disclosures:

Dr Wortzel is Director of Neuropsychiatric Consultation Services, Veterans Integrated Service Network (VISN) 19 Mental Illness, Research, Education and Clinical Center, Denver Veterans Hospital, Denver; and Michael K. Cooper Professor of Neurocognitive Disease, Assistant Professor of Psychiatry, Neurology, and Physical Medicine & Rehabilitation, University of Colorado School of Medicine, Aurora. He reports no conflicts of interest concerning the subject matter of this article.

Disclaimer-This article is based on work supported, in part, by the Department of Veterans Affairs, but does not necessarily represent the views of the Department of Veterans Affairs or the United States Government.

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