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QJM: An International Journal of Medicine, 2015, 1–5
doi: 10.1093/qjmed/hcv070
Original Article
ORIGINAL ARTICLE
Chronic traumatic encephalopathy: a potential late and
under recognized consequence of rugby union?
W. Stewart1, P.H. McNamara2, B. Lawlor3, S. Hutchinson2 and M. Farrell4
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From the 1Department of Neuropathology, Laboratory Medicine Building, Southern General Hospital, 1345
Govan Road, Glasgow G51 4TF, UK, 2Department of Neurology and 3Mercer’s Institute for Research on Ageing, St.
James’s Hospital, Dublin 8, Ireland and 4Department of Neuropathology, Beaumont Hospital, Dublin 9, Ireland
Address correspondence to Dr M. Farrell, Department of Neuropathology, Beaumont Hospital, Dublin 9, Ireland. email: [email protected]
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Summary
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The association between exposure to head injury and increased risk of neurodegenerative disease, specifically chronic
traumatic encephalopathy (CTE), is widely recognized. Historically, this was largely considered a phenomenon restricted to
boxers, with more recent case series identifying further ‘high risk’ individuals, such as former American footballers, or
military personnel. However, in all cases thus far reported, it is clear that it is the exposure to head injury which is associated with increased dementia risk, and not the circumstances or environment of exposure. As such, there is considerable
potential for under-recognition of CTE in patients presenting with neurodegenerative disease, particularly where head
injury exposure might have been historical and through sport. This article reviews current understanding of CTE and, via an
illustrative case in rugby union, highlights the value of a detailed history on head injury and also draws attention to imaging
studies in assessing patients with neurodegenerative disease.
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Introduction
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Concussions are a frequent occurrence in contact sports, with
an estimated 1.6–3.8 million sports-related mild traumatic brain
injury (mTBI)/concussions annually in USA.1 In recent years,
there has been an explosion in interest in the long-term outcomes of sports-associated brain injury. Specifically, there is
growing awareness of the association between exposure to
repetitive mTBI and increased risk of neurodegenerative
disease, in particular chronic traumatic encephalopathy (CTE),
through reports of CTE in former athletes from a range of contact sports and in exmilitary personnel (for review).2
In current understanding, CTE is associated with gradual
onset of neuropsychological, psychiatric and behavioural
disturbance followed by progressive cognitive decline.3,4 To
date, no clinical diagnostic criteria have been established and,
as such, autopsy examination with detailed neuropathological
review remains the only means to establish the diagnosis. At
autopsy, a degree of cortical atrophy may be present, with
abnormalities of the septum pellucidum also described, specifically cavum septum pellucidum (CSP) or septal fenestration.2,4
Microscopy reveals a mixed pathology, typically featuring
deposition of abnormal, hyperphosphorylated forms of the
microtubule associated protein tau in a distinctive pattern and
distribution which assists differentiation of CTE from other
tau-associated pathologies.2,5,6,7
Nevertheless, despite increasing recognition of the association between mTBI/concussion and CTE, confirmed cases
remain few, perhaps as confirmation still rests with autopsy
examination and there remains limited awareness in clinics
that the condition occurs in sports outside of boxing. However,
common to all cases described, thus far, is a history of exposure
to repetitive head impacts with mTBI / concussion.
Received: 20 February 2015; Revised (in revised form): 18 March 2015
C The Author 2015. Published by Oxford University Press on behalf of the Association of Physicians.
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All rights reserved. For Permissions, please email: [email protected]
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Herein, by way of illustration, we present the first comprehensive case report of CTE in a former amateur rugby union
player in whom the diagnosis in life was unclear, but confirmed
as CTE at autopsy. The implications of this case and our current
understanding of CTE are then reviewed.
Case report
Ethical approval
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The Dublin Brain Bank programme is approved by the Ethics
Committee of The Royal College of Surgeons in Ireland, with
specific consent for research tissue usage and for publication
obtained from the patient’s next of kin.
Clinical history
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A 56-year-old businessman first presented in 2011 following an
apparent acute confusion episode where he was unable to find
his way home. On closer enquiry, a 5-year history of gradually
progressive attention, memory and organizational difficulties
was elicited, leading to difficulty managing his previously
successful business which, as a consequence, had run into
financial difficulties.
His mother had developed a psychotic depressive disorder in
her 70 s and died 10 years later with mild cognitive difficulties.
A maternal uncle had late onset Alzheimer disease. The patient
was a non-smoker, had consumed 20–30 units of alcohol
weekly. Past medical history was notable for asthma, hypertension, hypertrophic cardiomyopathy, gout and left myringotomy.
Medications were ramipril, aspirin and atorvastatin.
Of note, the patient was a former rugby union prop forward,
with a notably long playing career which extended from early
teens to his last game at age 50; participating prior to professionalization to senior provincial level, and just below international standard. On retrospective enquiry from first-degree
relatives, it was reported that, throughout his rugby career, he
experienced countless head injuries with features in keeping
with mild TBI/concussion, though none required hospitalization. In addition to this sports-associated exposure to TBI, there
was a single work-related head injury, without loss of
consciousness, as a consequence of being struck by falling
scaffolding; again formal medical attention was not required.
There was no history of boxing, martial arts or other notable
contact sports participation.
fenestrated septum pellucidum, together with bilateral
increased signal intensity in the hippocampi in keeping with
gliosis (Figure 1a, b). A dopamine transporter scan at diagnosis
revealed reduced accumulation of isotope in the caudate and
putamen nuclei bilaterally, with 18F-FDG-PET demonstrating
evidence of frontal and posterior cingulate hypometabolism.
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Initial diagnosis and clinical course
He was initially diagnosed as dysexecutive mild cognitive
impairment. However, over the subsequent year, there was
progression of cognitive symptoms and the emergence of
Parkinsonism, with axial rigidity and abnormal vertical
saccades. Because a clinical diagnosis of progressive supranuclear palsy (PSP) was made. A trial of levodopa and carbidopa
was unsuccessful.
Over the following months, he experienced continued symptom progression, requiring admission to hospital because of
further acute confusion episodes and increasing falls. He
continued to deteriorate to his death from respiratory failure
secondary to aspiration pneumonia at age 57, a year after first
neurologic presentation and an estimated 6 years after first
symptoms.
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Neuropathological findings
Gross neuropathology
External examination of the brain was unremarkable, with the
weight of the intact, whole brain 1350 g. There was no evidence
of focal pathology related to previous TBI, the meninges were
thin and transparent and there was no evidence of sulcal
widening, gyral abnormalities or external abnormalities of the
cerebellum or brainstem. The vessels comprising the Circle of
Willis were in the normal anatomic position and unremarkable.
Dividing the cerebral hemispheres in the midline sagittal
plane confirmed a fenestrated septum pellucidum. Coronal
sections of the cerebral hemispheres revealed an apparently
unremarkable cortical mantle, centrum semiovale and corpus
callosum. The hippocampi appeared somewhat atrophic. In the
basal ganglia, there was pallor of the substantia nigra.
Otherwise the caudate nuclei, putamen and globus pallidus
were unremarkable. The cerebellum appeared unremarkable.
Again, there was no evidence of TBI-related focal pathology.
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Microscopic neuropathology
Neurologic examination
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Positive examination findings at presentation included axial
rigidity, hypomimia, positive glabellar tap and the ‘around the
houses’ sign of hypometric vertical saccades, asymmetrical
upper limb rigidity, bradykinesia and ideomotor apraxia.
Cognitive examination performed using the Montreal Cognitive
Assessment (MoCA) yielded a score of 17/30. There was a
dysexecutive–amnestic pattern with sparing of the orientation,
naming, repetition and digit-span components of the MoCA but
marked difficulty with the trail-making, cube copy, serial 7 s,
verbal fluency and recall components.
Imaging studies
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Initial reports of magnetic resonance imaging at presentation
described age-related white matter changes, with no other significant observations. However, retrospective review of imaging
prior to autopsy identified anteriorly cavum, posteriorly
Tissue blocks were sampled using standard protocols for the
assessment of neurodegenerative disease and assessed
independently by two experienced neuropathologists (MF, WS)
using established diagnostic criteria for neurodegenerative 100
disorders.
The most striking observation was the presence of widespread p-tau pathologies throughout the neocortex, hippocampus and striatum in the form of p-tau-immunoreactive
neurofibrillary tangles (NFT) and dystrophic neurites, with 105
notable perivascular, subpial and sulcal depth accentuation
(Figure 2a–c), and p-tau-immunoreactive neurites dispersed
throughout white matter. Further, p-tau-immunoreactive
profiles in keeping with immunopositive astroglia (Figure 2d)
were noted, largely in perivascular and subpial locations. 110
Coinciding with this, pathology was extensive cortical superficial linear spongiosis and profoundly atrophic hippocampi, with
near total loss of neurons from the CA4, CA3 and CA2 regions,
with relative sparing of CA1.
W. Stewart et al.
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Figure 1. Flare MR studies at first neurologic presentation illustrating abnormalities in the septum pellucidum and medial temporal lobe. (a) Axial section showing anteroposterior extent of septum pellucidum, (b) Bilateral increased signal intensity is also present in the structures of the medial temporal lobe in keeping with gliosis.
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Widespread p-tau pathologies were also present in sections
from the hindbrain as immunopositive NFTs in residual
neurons of the substantia nigra, which otherwise showed profound depletion of pigmented neurons, together with astrocytic
gliosis and pigmentary incontinence. Further p-tau positive
neurites were noted throughout the white matter, in particular
of the cerebral peduncles and in the cerebellar subcortical white
matter, and showing periaqueductal accentuation. No PSP-like
globose tangles were identified. Very rare tufted astrocytes
(Figure 2e) were noted in superficial subpial cortex of the sulcal
depths but not elsewhere.
In sections stained for abnormally phosphorylated-TDP
(p-TDP), cytoplasmic inclusions were present in neurons of the
dentate fascia, hippocampus and entorhinal cortex (Figure 3).
However, no classical or cortical Lewy bodies were present in
sections stained for a-synuclein and no amyloid-associated
pathologies were observed in sections stained for amyloid-b.
Clinicopathological diagnosis
Chronic traumatic encephalopathy.
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Discussion
This case illustrates CTE arising in a patient whose exposure to
repetitive mTBI/concussion was through participation in
amateur rugby union. In life, the clinical impression was of a
PSP-like syndrome; the diagnosis of CTE not considered prior to
death. However, after death the history of rugby participation,
together with imaging review identifying CSP raised the possibility of CTE, which was subsequently confirmed on detailed
neuropathology examination.
The association between exposure to TBI in sport and longterm neurological sequelae first came to note in 1928 thorough
observations on the ‘Punch Drunk Syndrome’ by the New York
City Medical Examiner, Harrison S Martland, in which he
described a constellation of stereotypical neuropsychiatric and
motor symptoms in former boxers.8 In the decades that
followed, further cases were reported9,10 and detailed examinations of former boxers’ brains described a distinctive neurodegenerative pathology termed ‘dementia pugilistica’ (DP),
reflecting its almost exclusivity to boxers in these early case
descriptons.11,12 However, not until the recognition of this same
pathology in non-boxer and military personnel did the association between exposure to repetitive mTBI and increased risk of
this form of neurodegenerative disease, now more inclusively
termed CTE, gain attention.
In 2005 Omalu described the first case of CTE in a former
National Football League player.13 Subsequently, CTE has been
described in several selected postmortem cohorts of professional and non-professional athletes including examples from
American football, ice hockey and wrestling,14–17 in addition to
military veterans.18,19 Despite increasing descriptions of CTE in
former athletes, understanding of the incidence of this condition remains remarkably limited, with the only insight coming
from studies estimating up to 17% of former boxers at risk in
some series. Prior to this report, to the best of our knowledge,
just a single confirmed case of CTE in rugby union has been
described in a patient dying at age 71 years,14 although in that
report very little information on the patient’s history, participation in rugby or investigations is provided. The current low CTE
case ascertainment in rugby union may well be due to a lower
frequency of CTE in rugby union. Additionally, as demonstrated
in this patient, low clinical recognition of CTE might be contributing to under-reporting, with cases perhaps given alternate
neurodegenerative diagnoses, including PSP.
Notably, in all cases thus far described, the only common
identified risk factor is exposure to repetitive mTBI. In this
regard, the incidence of concussion in elite level rugby union is
reported as among the highest in contact sport,20 with so called
‘sub-concussive’ head impacts occurring as frequently in rugby
union as in American Football.21 As a consequence of this perceived risk, World Rugby (formerly International Rugby Board)
has introduced programmes to better manage concussion injuries and to consider introduction of measures to reduce
incidence.22
The clinical features of CTE typically presents years to
decades after injury exposure and span neuropsychiatric,
behavioural, cognitive and motor symptoms.3,4 In particular,
emotional lability, aggression, poor judgement and depression
are described as perhaps distinctive and early clinical features
of CTE. In this regard, it is notable that, although our case
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QJM: An International Journal of Medicine, 2015, Vol. 0, No. 0
Figure 2. Representative immunohistochemical sections of the brain illustrating the pathology of CTE. In sections stained for hyperphosphorylated tau (monoclonal
antibody to PHF-1; courtesy Dr P Davies), immunopositive glial and neuronal profiles were identified in a typical pattern and distribution showing (a) perivascular
concentration (b) subpial accumulation with abundant NFTs and (c) at the depths of sulci, (d) Rare phospho-tau positive astrocytic plaques, (e) infrequent tufted subpial
astrocytes.
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presented with cognitive impairment, prior to admission he
displayed symptoms of mood and behavioural disturbance,
including impaired judgment, precipitating difficulties in his
normally successful business affairs.
A particular feature in this case was the presence of
Parkinsonian symptoms, with gaze palsy, falls and axial rigidity;
hence the clinical impression of PSP was raised. However, at
autopsy, PSP pathologies were not confirmed, and there was
widespread neuronal loss, gliosis and p-tau pathology in the
striatum and midbrain typical of CTE. Though less commonly
reported in current case series of non-boxer athletes with CTE, a
variety of motor symptoms, in particular Parkinsonian symptoms, are commonly described in case series of CTE in former
boxers.4,8–10
Notably, on retrospective review of imaging studies after
death, CSP and septal fenestration were identified, together
with imaging evidence in keeping with gliosis in the medial
temporal lobe. CSP represents one of the most frequent macroscopic findings in CTE, particularly in boxing-associated cases.2
However, given its presence as an incidental observation in
imaging studies in ‘normal’, non-head injured populations23,24
its significance in assessing CTE is often questioned. However,
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W. Stewart et al.
Figure 3. Scattered abnormally phosphorylated TDP (polyclonal antibody to TDP
phosphorylated at residues 409/410; courtesy Dr J Trojanowski) cytoplasmic inclusions were present in neurons of the dentate gyrus.
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from both historical accounts and more recent literature, there
is evidence to support increased incidence and severity of CSP
and associated septal abnormalities in patients with CTE and,
whilst CSP may simply represent exposure to repetitive TBI, rather than being directly consistent with CTE, in the context of a
supportive clinical history, its presence might warrant consideration of a diagnosis of CTE in a patient under investigation for a
neurodegenerative disorder.
We believe this is the first comprehensive report of pathologically confirmed CTE in a former rugby union player which
adds to current understanding of CTE in contact sports. In
particular, the possibility of under-recognition and, with that,
under-diagnosis is raised. With increased awareness of CTE, we
would suggest the diagnosis might be considered in any patient
presenting to dementia services with a prior history of exposure
to TBI, in particular where structural imaging studies demonstrate abnormalities in the septum pellucidum.
Conflict of interest: None declared.
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