Evaluating and treating neurobehavioral symptoms in professional American football players: Lessons from a case series

Abstract

In the aftermath of multiple high-profile cases of chronic traumatic encephalopathy (CTE) in professional American football players, physicians in clinical practice are likely to face an increasing number of retired football players seeking evaluation for chronic neurobehavioral symptoms. Guidelines for the evaluation and treatment of these patients are sparse. Clinical criteria for a diagnosis of CTE are under development. The contribution of CTE vs other neuropathologies to neurobehavioral symptoms in these players remains unclear. Here we describe the experience of our academic memory clinic in evaluating and treating a series of 14 self-referred symptomatic players. Our aim is to raise awareness in the neurology community regarding the different clinical phenotypes, idiosyncratic but potentially treatable symptoms, and the spectrum of underlying neuropathologies in these players.

Figure 1. FDG PET, amyloid PET, and structural neuroimaging in symptomatic retired professional football players suggest a spectrum of underlying neuropathologies

Fluorodeoxyglucose (FDG) and amyloid PET imaging were obtained on 5/14 patients (cases 7, 9, 11, 12, and 13 corresponding sequentially to rows A-E). Amyloid PET was obtained using either 11C-Pittsburgh Compound-B (PIB) (A, C, and E) or 18F-florbetapir (AV45) (B and D) amyloid tracer. While all 5 had a cavum septum pellucidum (CSP) and abnormal FDG scans, only 2 were diffusely amyloid positive (A and B). One was focally amyloid positive (C, see red arrow), suggesting a traumatic mechanism, and highlighting the complexity of interpreting amyloid positivity after brain trauma. The other 2 were amyloid negative (D and E), suggesting non-AD neuropathologies. Indeed, one has since undergone autopsy consistent with chronic traumatic encephalopathy (CTE) (figure 2). Aside from CSP, additional structural abnormalities were identified including white matter lesions, cortical atrophy, and mammillary body flattening, the latter of which has been described in advanced cases of CTE. Images are displayed in neurologic orientation. DVR = distribution volume ratio; SUVR = standard uptake value ratio.

Figure 2. Brain autopsy of patient 13 revealed tauopathy consistent with chronic traumatic encephalopathy

Coronal sections of the cerebrum revealed moderate atrophy (hippocampi, entorhinal cortex, posterior frontal cortex) with ex vacuo ventricular enlargement, reduced pigmentation of substantia nigra and locus coeruleus, and absence of the septum pellucidum (A–B). There were tau-positive neurofibrillary tangles (tau is stained brown in C–H) identified in numerous neurons in hippocamal CA3 (C), entorhinal cortex (D), amygdala, subpial temporal cortex (E), and several brainstem nuclei, including the substantia nigra (F), locus coeruleus, dorsal raphe nucleus, superior colliculus, periaqueductal gray, cranial nerve III complex (G), nucleus ambiguus, and dorsal motor nucleus of the vagus. The morphologic features of the tau aggregates ranged from flame-shaped neurofibrillary tangles in cortical and hippocampal neurons to globus neurofibrillary tangles in brainstem neurons. Outside of the above-referenced areas, there were rare clusters of tau protein aggregates in cortical neurons and astrocytes at the depth of the sulcus (H, depicts sulcus in frontal cortex). In addition to the tau pathology, there was prominent TAR DNA-binding protein 43 (TDP-43) proteinopathy (TDP-43 is stained brown in I–J) in the hippocampus CA1 (I), and entorhinal cortex (J), characterized by loss of normal TDP-43 nuclear staining in neurons and scattered TDP-43–positive dystrophic neurites in neuropils. Other contributing neuropathologic features included abundant neurons containing prominent α-synuclein protein aggregates (α-synuclein is stained brown in K–L) in cytoplasm and in dystrophic neurites in substantia nigra (K), ventral tegmental area, locus coeruleus, ventral pontine nuclei, nucleus ambiguus, raphe nucleus, nucleus tractus solitarius, and dorsal motor nucleus of the vagus (L).