The brain donation was facilitated by his family and was in keeping with what they felt to be his wishes during life. His mother primarily provided the history, though we obtained additional information from his orthopedist and from an interview the participant gave to the New York Times.
His mother described him as a shy, quiet child who, in youth, was very close to his family. He played organized football for 16 years, beginning at age 10, including 2 years in the NFL as a safety and as kick coverage. His mother estimated that he suffered 20 lifetime concussions, 2 with brief loss of consciousness and 2 requiring emergency room visits. An MRI at age 21, after one concussion, showed no macro or microhemorrhages, no cavum septum pellucidum and no atrophy.
He suffered labial tears of both shoulders in college and underwent repair surgeries during his junior and senior years. After entering the NFL, he suffered two unspecified ankle injuries necessitating two surgeries. He required escalating doses of narcotics due to chronic pain from these orthopedic injuries.
During his football career, his mother thought that he distanced himself from his family. She speculated that he did not want his family to witness the extent of his chronic pain and narcotic use. Nevertheless, she found him more “aggressive” and “on edge” in his last years playing football. He also began to experience weekly, moderately severe headaches that would at times prevent him from participating fully in athletics. During his second NFL season, he was suspended after testing positive for Adderall. He swore that he took it on only one occasion to improve his performance at a public speaking engagement. During the pre-season of what would have been his third season, he suffered a final concussion with ongoing symptoms including headache and anxiety, prompting his team to release him. He worked out with other teams, but in the setting of ongoing concussive symptoms, he eventually returned to his hometown.
Upon his return, his mother noticed he would forget details from recent conversations and tell stories repeatedly, sometimes with confabulation of the details. He had difficulty composing emails and understanding written materials. He would leave the refrigerator door open and the milk on the counter. He repeatedly lost his wallet. He had difficulty managing his finances, accidentally transferring money into the wrong accounts while trying to pay bills. He briefly worked a part-time job, but a combination of pain and cognitive symptoms limited his ability to work.
Mood and behavior changes:
Changes in behavior and mood also were immediately apparent after his return home. He was intermittently aggressive and irritable, “exploding” with anger over minor issues on a monthly basis. On one occasion, he drove his car over the lawn to bypass a car parked at the end of his driveway. He would insult others and then later apologize for his behavior. Anxiety with racing thoughts, insomnia and panic attacks also developed. He became more apathetic, spending much of his time at home on the computer or on the phone. A year before his death, he discovered that his girlfriend (to whom he was about to propose) was unfaithful, triggering a major depressive episode with passive suicidal ideation. Finally, he developed paranoid delusions that intruders were trying to break into his house and that his pastor did not like him. His PCP described zolpidem for his insomnia and referred him to a therapist, but he never saw a psychiatrist nor was he prescribed psychiatric medications.
Pain management and substance use:
He saw a pain specialist until he broke his pain contract by obtaining outside narcotics, triggering the physician to discontinue treatment. His family noticed periods of intermittent confusion with sedation, which they attributed to narcotic use and encouraged him to cut back. In addition, he would binge drink weekly (8-10 drinks/evening). On one occasion while drunk, he fled from the police on a scooter before being arrested for public intoxication. During the days prior to his death, family described him as intermittently confused and agitated and suspected he was intoxicated. Two days later, he was discovered pulseless on his couch. There was no suicide note or other evidence of intentional overdose. Methadone, a drug he had never before been prescribed before, and hydrocodone were present on toxicology.
Selected comments from the clinical consensus panel:
Clinician 1: A substance use problem seems to dominate the clinical picture with a contribution from ongoing symptoms that likely reflect post-concussion syndrome (PCS).
Clinician 2: I agree that substance use seems to be the primary problem. I also feel that post-concussion syndrome is contributory in this case along with a mood disorder with psychotic features and chronic traumatic encephalopathy (CTE) that became clinically apparent at the end of his life
Clinician 3: Several factors seem to impair this individual’s frontal lobe function. Though he appears to have mood disorder symptoms, this diagnosis cannot be made in the context of substance use, and a psychotic disorder is less likely given the short duration of psychotic symptoms. We should also consider secondary gain from narcotic use.
Clinician 4: I agree that substance use was a major factor in this case, as was PCS. However, as the symptoms of PCS were subsiding, something else seemed to be getting worse. These symptoms kept him from making a life for himself. CTE could certainly be that something, and in retrospect CTE could have lowered his threshold for substance use. The case would be more classic if his impairments and substance use became a problem later in life, however.
Clinician 5: I’m not sure I agree that his symptoms were progressive when comparing his cognitive function toward the end of his life with that around his discharge from the NFL. I agree that CTE and PCS are contributory. I also think depression plays a significant role in his presentation.
Clinical consensus diagnosis:
Primary diagnoses: substance use
Contributory diagnoses: CTE, PCS
Neuropathologist: On gross inspection there are expected hypoxic-ischemic changes consistent with the patient’s manner of death, anoxic brain injury. This brain does not feature a cavum septum pellucidum. There is tau deposition consistent with CTE involving the superior frontal lobes (prominently perivascular here?), inferior temporal cortex, and entorhinal cortex to the beginnings of CA4 of the hippocampus. In the amygdala there is basal medial perivascular involvement, which may be of special significance with respect to his symptoms.
Chronic Traumatic Encephalopathy Stage II/IVDiscussion:
While conditions such as PCS, the effects of narcotic use and depression are possible explanations for many of this individual’s symptoms, CTE should be considered. CTE is a neurodegenerative condition that is associated with progressive changes in thinking, behavior and/or mood with pathological features that are distinct from other forms of dementia. All neuropathologically confirmed cases have had a history of exposure to repetitive head impacts (RHI), usually in the form of contact sports. Although these impacts may not cause an injury that results in immediate symptoms, they may trigger a neurobiological cascade that eventually results in protein deposition and symptoms years or even decades later.1 More and earlier exposure to RHI may increase CTE risk, though these relationships have not been well established.2
Mood and behavioral impairment in CTE includes depression, irritability, explosive anger, impulsivity and aggression. Cognitive deficits often include memory loss and executive dysfunction. At least two clinical subtypes of CTE have been described. The first subtype has an earlier onset (mean age ~35) and prominent mood and behavior symptoms while the other subtype features prominent cognitive impairment and onset at a later age (~60).1
CTE neuropathology is characterized by hyperphosphorylated tau in the form of neurofibrillary tangles (NFTs) surrounding blood vessels at the depths of brain sulci in an irregular distribution.3 A staging system (ranging from 1 to 4, 4 being most severe) has been proposed that reflects the extent and regional distribution of CTE NFT pathology.
Persisting symptoms of PCS may explain some of the problems observed in this individual. PCS occurs in a subset of people who experience concussion and refers to lingering symptoms such as headache, concentration difficulties, memory impairment, imbalance, fatigue, mood symptoms and trouble sleeping. Most often individuals recover from PCS within days to weeks after injury, although a small minority may experience persistent symptoms for more than a year.4 PCS does not have a clear neuropathological correlate. Following injury, this individual’s use of sedating opioid medications likely contributed to his symptoms, as the sedating properties of opioids may impair cognitive functioning and contribute to depressive symptoms. Conversely, substance use may be a feature of the behavioral subtype of CTE. Idiopathic depression features a constellation of symptoms including depressed mood, worsened concentration, decreased interest in previously enjoyed activities, changes in sleep, appetite and energy level, and in some cases suicidal ideation. Like PCS, idiopathic depression does not have a clear neuropathological correlate. Like substance use, depression may be an independent diagnosis contributing to symptoms or may be linked to another psychiatric or neurodegenerative disease.3 In this case, panel members thought that depression was secondary to substance use, PCS and CTE and therefore did not include it as an independent diagnosis.
Key points of this case:
CTE can occur early in life.
Those with CTE early in life tend to have a behavioral/mood presentation that is very difficult to distinguish from idiopathic psychiatric illness. The specific contribution of CTE pathology to the development of mood and behavior disorders, and interaction with other factors such as substance use, remains uncertain, especially at lower stages of CTE pathology and earlier in life.
Substance use is a common problem in former professional football players and may be a feature of CTE.
More and earlier exposure to RHI may increase CTE risk, though these relationships have not been well established.
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