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更好地理解慢性创伤性脑病:第一例病例以及10年后

作者:陈亚云 编译 来源:医学论坛网 日期:2016-05-14
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         The Long Drive Ahead to Better Understanding Chronic Traumatic EncephalopathyFirst (Case) and 10 (Years Later) James M.Noble,MD, MS, CPH1 In this issue ofJAMA Neurology, Mez and colleagues1present a

关键字:  慢性创伤性脑病 

The Long Drive Ahead to Better Understanding Chronic Traumatic EncephalopathyFirst (Case) and 10 (Years Later)

James M. Noble, MD, MS, CPH1

In this issue of JAMA Neurology, Mez and colleagues1 present a case of a young former amateur football player diagnosed with chronic traumatic encephalopathy (CTE), identified pathologically at autopsy at age 25 years, following death due to complications of endocarditis. This athlete is just one in a series of former contact sports athletes, including those having played American football, with evidence of CTE at autopsy. Several of these former players were even younger—just teenagers at the time pathological findings were identified.2 What distinguishes this case from other similar cases was his inclusion in the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) study, with an evaluation that uniquely included neuropsychological testing within months of his young death. As noted by the authors, arguably a group in the best position to recognize CTE clinically, his history and profile did not clearly distinguish CTE from postconcussion syndrome or depression, particularly given the young age of presentation. The case, in its findings, uncertainties, and timing, offers an opportunity to highlight a number of important, ongoing developments in the field of concussion and CTE, but also underscores the many substantial, unresolved, and essential questions left unanswered in the field.

The case of this former collegiate football player appears 10 years after the first reported case of football-associated CTE, identified in a former professional athlete.3 That publication put the sport of American football under increasing scrutiny about the prevalence and long-term sequelae of head injury in the sport. Omalu and colleagues3 faced a now storied criticism and eventual external validation of the findings, which (1) placed the discussion of potential risks of professional football in print, television, and film, (2) led to acknowledgment of risks in a class action lawsuit, and (3) more broadly sparked a public national debate about football and other contact sports at youth, high school, and collegiate levels by players, parents, and institutions. Concomitantly over these 10 years, a field of research in CTE has emerged and concussion research has greatly expanded by refining concussion clinical definitions,4 clarifying concussion epidemiology in football by age,5and identifying an evolving set of imaging and fluid-based biomarkers aiming to establish objective evidence of concussion diagnosis and recovery periods.

Despite these important and essential developments in CTE and concussion, many more basic questions remain unanswered. First, regarding exposure: How often do concussions actually occur in sports? And, is it the number of hits, the quality/intensity of each hit, or a combination thereof that matters? Concussion has been a part of high-risk contact sports—including football—for decades. Even 20 years ago, in an era long before public awareness dramatically increased, an estimated 300 000 American sports-related brain injuries were diagnosed annually.6 However, sports-related concussion remains unreported in the majority of cases, at least in part related to player perceptions and competitive disincentives to report. State concussion education laws have likely improved awareness among teams but the overall effects on diagnostic rates of concussion in each state are yet to be determined. Moreover, inclusion of helmet-based accelerometry suggests some collegiate players have upwards of 1000 substantial head hits each season,7 but predicting which of the many strong rotational movements may cause concussion remains imprecise.8 A head “hit count” has been advocated in the concussion field and may be a step in the right direction beyond time-based athletic exposures (number of games/practices or absolute time in the field of play), but how such a value will be determined precisely and its relevance to player outcomes including concussion risk mitigation remains untested. Mez and colleagues1 report that the player had more than 10 concussions in his lifetime, but based on typical histories, he may have had far more unrecognized or unreported concussions, as well as subconcussive head injuries in his 16-year tackle football career before medical retirement in his junior year in college.

The second major unanswered question in concussion regards the near-term sequelae. Namely, who takes longer to recover and why? About 10% of concussed athletes take longer than the typical 1- to 2-week clinical recovery period as experienced by their peers,9 but the specific risk factors leading to prolonged recovery remain uncertain. Proposed or suspected mechanisms include genetic factors predicting resilience to and recovery from injury, personal or family medical history including migraines and mood disorders, and player physical conditioning factors prior to brain injury. Next, what biomarkers can establish a recent injury has occurred and, perhaps more importantly, provide assurance that recovery is complete? At present, players are clinically and empirically judged to have recovered from concussion once asymptomatic (and—for some athletes in highly coordinated programs—back to or near an established neuropsychological baseline) and without recurrence of symptoms when fully engaged in their sport. However, magnetic resonance imaging, including functional magnetic resonance imaging10 and diffusion tensor imaging,11 and emerging blood-based biomarkers of neuronal injury12 have encouragingly moved the field in a direction of identifying objective correlates of symptomatic recovery. These modalities have also helped identify physiologic evidence of brain injury even without clinical history of concussion,10,13 again underscoring that concussions are expressed, recognized, or reported in highly variable ways person to person.

Most relevant to this case: what are the long-term risks of playing in contact sports with high rates of concussion? From a public health perspective, with millions of current and former contact sports athletes, establishing the long-term neurologic risks in contact sports has become an increasingly important issue. Despite the descriptions of the cognitive sequelae of boxing, a combat sport with intentional and frequent brain injury, there remains no epidemiologic incidence study of neurodegenerative sequelae in boxing. In football, like boxing, autopsies of former (and mostly professional) athletes have provided the basis for case series of CTE,2 which allows for refinement of pathologic descriptions but typically provides limited epidemiologic inference if any. Moreover, without an a priori plan to collect clinical evidence and emerging biomarkers of disease, clinicopathological correlations of CTE changes, particularly when pathologically mild, have been uncertain.

Only until the exposure to brain injury and concussion frequency can be refined, and clinical or biomarker profiles for CTE pathology are established in living patients, can an epidemiologic study begin to identify clinical CTE incidence. Professional football has been associated with a significantly higher risk of subsequent neurodegenerative mortality (measured by standardized mortality ratios) related to Alzheimer disease and amyotrophic lateral sclerosis,14 with differences identified by position played. These disorders have clinically similar presentations to the CTE spectrum, and serve as close and suggestive surrogates for CTE, but inevitably cannot allow for definitive inference. The neurodegenerative risk of former players with less football experience remains even more uncertain, as no sufficiently powered standardized mortality ratio studies of former football players have yet been performed at the youth, high school, or collegiate levels. To date, the total number of pathologically diagnosed CTE cases number at most in the hundreds, with even fewer among former football players, among the millions of current and former athletes. However, even with the limitations of autopsy case series, a very rough, yet worrisome estimate of lifetime risk of pathologic CTE in professional football has emerged: between 3.7%15 to upwards of 90%.2

What stands out from this case is that 10 years after the first publication of CTE in football, and nearly 50 years of pathologic findings in boxing, a case report remains highly informative in framing important unmet needs in the field of concussion. Clearly, many people have played contact sports without developing clinical evidence of CTE or related neurodegenerative disease. Thus, this begs the final question: Why did CTE occur in this particular athlete?

Complementing the UNITE study, which aims to refine the clinicopathological correlations of CTE, several multi-institutional collegiate studies are under way to identify the epidemiology of concussion incidence and recovery. These include the NCAA-DOD Grand Alliance Concussion Assessment, Research and Education (CARE) Consortium (http://www.careconsortium.net/) and the Big 10/Committee on Institutional Cooperation–Ivy League Traumatic Brain Injury Research Collaboration (https://www.cic.net/projects/traumatic-brain-injury-research-collaboration).

The commitment to answering the questions posed here should not end with collegiate consortiums comprising relatively few schools, which may complement studies involving former professional athletes. The same institutions developing and supporting youth, high school, collegiate, and professional contact sports share a collective responsibility to assure the neurologic health of their players in the short- and long-term, much the same as is done supporting the academic, physical, and mental health of all students. Only when a comprehensive, collective commitment is made, including supporting collaborative research programs at all levels, can the field of concussion and CTE research begin to understand when risk periods begin for these outcomes and for whom we should be most concerned.

Several million young athletes play football and other high-risk contact sports every year. Some will have a concussion. Each time, many of the questions framed here will come from worried parents and players in the offices of neurologists and other physicians. Hopefully, in another 10 years some of these questions will be answered, refined, or inform others raised in context, and the chains will have been moved down the field a few more yards.

JAMA Neurol. 2016;73(3):263-265. doi:10.1001/jamaneurol.2015.4297.

 

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