ARTICLE IN BRIEF
A case report finding chronic traumatic encephalopathy in a 25-year-old former college football player elicited discussion about the challenges of finding clinical correlates for the pathology in living patients.
A case report from one of two major ongoing studies seeking to discern clinical correlates of chronic traumatic encephalopathy (CTE) in living patients has highlighted the challenge facing neurologists who treat such patients.
The case, reported in the January 4 online issue of JAMA Neurology, involved a young man whose cognitive, mood, and behavioral symptoms progressively worsened following a history of 10 concussions incurred while playing football from age 6 till his junior year in college.
The patient completed a neurocognitive battery of tests prior to his death (due to an unrelated cardiac infection) at age 25. Although those tests revealed multiple deficits, and his symptoms steadily worsened for three years after he stopped playing, a consensus panel of clinicians blinded to his pathology report was unable to reach a primary diagnosis of CTE.
“Although CTE was considered,” the report stated, “the lack of delay in symptom onset, his young age, and his family history of depression reasoned against CTE as the primary diagnosis. Consensus members thought that neuropsychological performance, while impaired, did not discriminate postconcussive syndrome or major depression from CTE.”
That pathology report, however, was conclusive for a diagnosis of CTE, based on mild ventricular dilation, hippocampal atrophy, and pathological lesions of hyperphosphorylated tau consisting of neurofibrillary tangles, neurites, and astrocytes around small blood vessels found at the sulcal depths of the frontal and temporal lobes.
Preliminary consensus criteria from the National Institute of Neurological Disorders and Stroke released last year concluded that tau lesions are the defining pathological characteristic of CTE.
The case was among more than a hundred that have been studied so far as part of the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) study, said the study's principal investigator, Ann McKee, MD, a professor of neurology and pathology at Boston University.
“In retrospect, the fact that his symptoms continued to worsen after he stopped playing football is something the physicians reviewing the clinical and neuropsychological findings might have paid more attention to,” she told Neurology Today. “But the symptoms of CTE can be relatively nonspecific, and the physicians were very cautious.”
SEEKING CLINICAL CORRELATES
The UNITE study is designed to refine and illuminate the clinical correlates of pathologically confirmed CTE. The four-year study will eventually analyze the brains and spinal cords of 300 deceased subjects who had a history of repetitive head impacts sustained during participation in contact sports or military service. Blinded to the clinical data, a neuropathologist conducts a comprehensive assessment for neurodegenerative disease. Similarly blinded to the neuropathological data, a panel of physicians and neuropsychologists reaches a clinical consensus diagnosis.
“We're trying to get more precise clinical symptoms, so we can more accurately diagnose CTE in patients,” Dr. McKee said. “In the next six to 12 months, we're going to have more refined diagnostic criteria.”
An accompanying editorial suggested that if Dr. McKee's clinical colleagues are unable to diagnose CTE clinically in the described case, perhaps nobody can.
“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 at presentation,” wrote James M. Noble, MD, an assistant professor of neurology at Columbia University Medical College and director of its Concussion and Sports-Related Head Injury Program. “The case, in its findings, uncertainties and timing...underscores the many substantial, unresolved and essential questions left unanswered in the field.”
A $16 million grant from the National Institutes of Health was announced in December for another study aimed at developing methods to diagnosis CTE during life. The seven-year, multi-center longitudinal study is designed to recruit 240 people, including 120 former NFL players with and without likely CTE symptoms, 60 former college football players with and without symptoms, and 60 control subjects who never played contact sports or had any type of brain trauma.
Both studies have their strengths and weaknesses. Although the UNITE study is not prospective, its preliminary findings are expected to be available relatively soon. The other study, although prospectively designed, will take much longer to accrue pathology reports following autopsy.
CASE REPORT DETAILS
Although the identity of the patient was not disclosed in the case report, Dr. McKee confirmed media reports that Michael Keck was the young man described. His widow, friends, and other family members were quoted in print and broadcast interviews as saying that Keck had been a high-achieving student with a warm, friendly personality before experiencing his tenth concussion from a particularly violent hit to the side of his head as a freshman at the University of Missouri. He developed headaches, neck pain, blurred vision, tinnitus and difficulty sleeping.
He switched to Missouri State for his sophomore year but quit the football team there after playing in only one more. His grades declined so precipitously that he finally withdrew from school prior to graduation. He became withdrawn and dependent on his wife, smoked marijuana for relief of the headaches, experienced memory impairments, and finally became verbally and physically abusive.
Alerted to the case of San Diego Chargers linebacker Junior Seau, who committed suicide at the age of 43 in May of 2012 and was found to have CTE upon autopsy, Keck and his wife decided that he should undergo a thorough neuropsychological evaluation.
As described in the case report, Keck performed average on a number of tests, including for intelligence as measured by the WAIS-III/7 and WTAR. He scored within the impaired range, however, on some of the memory measures, including sections of the California Verbal Learning Test; on one of the language tests; and two of the attention/executive functioning measures.
Complicating his case history was his early upbringing by parents who were addicted to drugs. He was eventually raised by his grandmother, who took legal custody of him. When he died, his wife consented to have his brain examined for the UNITE study.
Neurologists agreed with both Dr. McKee and the editorial by Dr. Noble that the case report highlights the need for better diagnostic criteria.
“The dilemma we face as clinicians is that we don't know the pathology of the patients who see us,” said Christopher M. Filley, MD, FAAN, director of the behavioral neurology section and professor of neurology at the University of Colorado School of Medicine in Denver. “Even the consensus panel could not distinguish the clinical features of this young man from someone with depression or postconcussion syndrome. The message from this case is that we do not yet have the ability to diagnose CTE based only on clinical presentation.”
Chad Hales, MD, PhD, an assistant professor of neurology at Emory University, said that research has yet to correlate pathology burden with specific clinical symptoms. “That's what's really lacking in the field. Ongoing and future studies will be critical for establishing this relationship,” he said.
Dr. Hales and others also agreed with Dr. McKee that, in hindsight, the worsening of the patient's symptoms long after he had quit playing football might have increased the index of suspicion for a diagnosis of CTE.
“That's more consistent with CTE as opposed to postconcussive syndrome,” said Barry Jordan, MD, MPH, an assistant medical director at Burke Rehabilitation Hospital in White Plains, NY. He is also chief medical officer of the New York State Athletic Commission, a team physician for USA Boxing, and an associate professor of clinical neurology at Weill Medical College of Cornell University.
Dr. Jordan said he has seen similar cases in young men following a history of concussion, but that most get better once they stop engaging in potentially violent sports.
“Most of the time, there's a period after they stop playing where they're doing okay, and then they develop symptoms later on,” he said. “The indicator that this was more than just postconcussive syndrome is the fact that after he stopped playing, he still became progressively worse. That's not the natural history of postconcussive syndrome.”
Another factor that might have been taken into account was the very young age (6 years old) at which the patient had begun playing tackle football. A study published last March in Neurology found that former NFL football players who had started playing tackle football prior to age 12 showed significantly worse scores on measures of neuropsychological and cognitive abilities than those who had started later. (That study, however, generated questions from other researchers who pointed out that the lower scores might have been present in elementary school, before they started playing football.)
Whatever the diagnosis, Dr. Jordan said, the treatment for now would be the same: symptomatic, as necessary to ameliorate mood and cognitive challenges.
William P. Meehan III, MD, director of the Micheli Center for Sports Injury Prevention and director of research for the Brain Injury Center for Boston Children's Hospital, said he tells patients suffering from depression or mood swings: “Those are symptoms we have treatments for. Athletes will often ask me: ‘Do you think I have CTE?’ I always tell them, ‘I don't know, but regardless of whether you do or not, your symptoms are amenable to treatment.’ The message should never be that if you have it, you're doomed to a poor outcome.”
EXPERTS: ON THE DIFFICULTY OF DIAGNOSING CTE IN LIVING PATIENTS