Neuropathological Criteria for Chronic Traumatic Encephalopathy: Comparison
Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Ioannis Mavroudis.

Chronic traumatic encephalopathy (CTE) is a complex pathological condition characterized by neurodegeneration, as a result of repeated head traumas. Currently, the diagnosis of CTE can only be assumed postmortem. Thus, the clinical manifestations associated with CTE are referred to as traumatic encephalopathy syndrome (TES), for which diagnostic multiple sets of criteria can be used.

  • chronic traumatic encephalopathy
  • traumatic encephalopathy syndrome
  • traumatic brain injury
  • diagnosis algorithm

1. Introduction

Chronic traumatic encephalopathy (CTE) was first described in 1928 as the neuropsychiatric sequelae of repetitive head impacts in boxing athletes, for which the term “punch drunk” syndrome was used [1]. Several decades later, in 1954, Brandenburg and Hallervorden [2] published the first neuropathological reports of this condition, while 19 years later, Corsellis and colleagues described pathological findings associated with the condition known as dementia pugilistica, following a systematic neuropathological study on former professional and amateur boxers [3].
Although CTE was described almost 100 years ago, it was only less than 20 years ago when Dr. Bennet Omalu began a powerful program to raise awareness of its importance, public burden, and increased impact on affected people’s wellbeing, as well as increased mortality rates, all of which culminated with the premiere of the American biographical sports drama film, “Concussion”, in 2015. It is now understood that this condition is not as uncommon as wresearchers thought before and that it can occur in athletes involved in contact sports, such as boxing, martial arts, American football, and rugby, as well as soccer, water polo, and ice hockey [4,5,6,7,8,9,10,11][4][5][6][7][8][9][10][11]. Furthermore, it was described in military personnel with a yet unsolved correlation with post-traumatic stress disorder (PTSD) [11,12][11][12].
CTE is considered a rare, progressive, and fatal brain disorder that is most often associated with repeated traumatic brain injury (TBI). Despite that, other causes of CTE are not yet described, and the pathophysiology of CTE is yet not very well understood and described. The physiology of the CTE-affected brain is often specific for neurodegeneration and includes brain matter atrophy, white matter perivascular spaces, and, rarely, cerebellar abnormalities [13]. While the pathological profiles of younger TES patients are often characterized by behavioural and mood impairments, it was shown that older patients often exhibit symptoms similar to the hallmarks of neurodegeneration as seen in Alzheimer’s disease [14,15][14][15].
The neurodegenerative processes in CTE were described as the accumulation of neurofibrillary tangles (NFT) as a result of tau protein hyperphosphorylation, amyloid beta depositions, and immunoreactive inclusion bodies [13,14][13][14]. The mechanisms through which repetitive TBIs are leading to neurodegenerative changes in the brain are currently proposed to include chronic inflammation, amyloid cascade activation, axonal protein degeneration, and neuronal homeostasis disbalance [15]. However, these mechanisms are not completely described and understood within the pathophysiological changes in TES/CTE.
The clinical implications of CTE were found to include neuropsychiatric symptoms, such as behavioural changes, suicidality, cognitive dysfunction, motor disturbance, and emotional dysregulation [16]. However, currently, the diagnosis of CTE can only be assumed postmortem. Thus, the clinical manifestations associated with CTE are referred to as traumatic encephalopathy syndrome (TES), according to multiple sets of diagnostic criteria.

2. Clinical Diagnostic Criteria and Diagnostic Algorithm

According to the recent guidelines (Table 1), TES can be classified based on different diagnostic criteria, proposed by different groups [16,17,18[16][17][18][19],19], the most common of which discriminate between possible, probable, and improbable TES [20]. Despite the slight differences in terms, all the previously proposed diagnostic criteria include exposure to significant and repetitive head impacts, the progressive character of the symptoms, and their persistence for at least one year. However, a valid diagnostic requires the presence of behavioural/cognitive impairment, motor symptoms, and neuropathological confirmation [21,22][21][22].
Table 1. Current validated TES/CTE diagnostic criteria.
Study Mandatory Condition Symptoms Symptom Duration/

Progression
Comments
Jordan [20] Exposure to repetitive head impact events Two or more symptoms:
  • cognitive and/or behavioural impairments;
  • cerebellar dysfunction;
  • pyramidal or extrapyramidal tract symptoms
At least one year, in the absence of new head trauma Diagnosis can be supported by neuroimaging
Montenigro et al. [19] Exposure to head trauma events At least one core symptom:
  • cognitive decline;
  • behavioural impairment;
  • mood disturbance
At least one year; Progressive course, or delayed onset. Diagnostic criteria should be applied after the exclusion of other conditions that could account for the symptoms.
Two supportive features:
  • motor signs, impulsivity, anxiety, apathy, paranoia, suicidality
Reams et al. [16] Exposure to repetitive head impact events Cognitive decline, confirmed by neuropsychological testing Longer than two years;

Progressive course, late symptom onset.
Provides classification for TES/CTE according to the predominant symptomatology and based on symptoms progression.
NINDS Consensus [21] Exposure to repetitive head impact events originating from contact sports, military service, or other causes
  • Cognitive impairments, episodic memory, and/or
  • executive functioning, and/or
  • neurobehavioural dysregulation.
Progressive course Progressive course of the symptoms not fully accounted for by any other neurologic, psychiatric, or medical conditions.
Montenigro et al. suggested that TES/CTE diagnosis procedure requires exposure to repetitive head trauma events, one core clinical feature (such as cognitive, behavioural, or mood disturbance) alongside two supportive features (including headaches, motor signs, impulsivity, anxiety, apathy, paranoia, suicidality, and progressive course, or delayed onset), and symptom persistence for longer than one year in the absence of another condition that could account for the symptoms [20]. On the other hand, Reams et al. proposed that the diagnosis should be confirmed if the patient has symptoms that persisted for longer than two years (and no other neurologic disorder can explain those symptoms), history of exposure to traumatic events with concussive and/or sub-concussive head traumas, confirmed progressive course, late symptom onset, and cognitive decline confirmed by neuropsychological testing [19]. These diagnostic criteria also provide a classification for TES/CTE according to the predominant symptomatology (behavioural or mood variant, cognitive variant, mixed variant, and dementia variant) and based on symptom progression (progressive, stable, and unknown or inconsistent type) [19]. A panel of 20 experts in the fields of neurology, neuropsychology, psychiatry, neurosurgery, rehabilitation, and physical medicine affiliated with different academic institutions reviewed the evidence from all the reported cases of definite TES/CTE and published the diagnostic criteria known as The National Institute of Neurological Disorders and Stroke Consensus Diagnostic Criteria for TES [21]. These criteria require (1) substantial exposure to repetitive head trauma events from contact sports, military service, or other causes; (2) core clinical features of cognitive impairment in episodic memory and/or executive functioning, and/or neurobehavioural dysregulation; and (3) progressive course of the condition, (4) in the absence of any other neurologic, psychiatric, or medical condition. However, biomarkers were not included, as the technological and scientific developments in the field are not sufficiently mature, according to NINDS Consensus [21]. Furthermore, Jordan et al. suggested that probable TES/CTE should be diagnosed if two or more of the following are present: cognitive and/or behavioural impairment, cerebellar dysfunction, and pyramidal or extrapyramidal tract symptoms. Meanwhile, Katz et al. suggested that the diagnosis should be supported by abnormal findings from positron emission tomography, single-emission tomography, structural magnetic resonance imaging, or diffusion-tensor imaging [20,21][20][21]. Thus, it seems that cognitive impairment is one of the most common clinical symptoms in patients diagnosed with TES/CTE, being reported in more than 60% of the cases, while the behavioural features, such as violent, impulsive, or explosive behaviour, socially inappropriate behaviour, aggression, rage, short fuse, and lack of behavioural control, are identified in more than 40% of the cases. Mood changes, anxiety, and paranoid delusions are also frequently reported, and more than 30% of TES/CTE patients are diagnosed with depression, anxiety, hopelessness, and apathy. A progressive cognitive decline is seen in more than 95% of cases, whereas more than 50% of TES/CTE patients may develop problems with balance or gait, 23% develop dysarthria, and 28% develop parkinsonism [21]. Furthermore, despite the general understanding that CTE could be mainly an issue of repetitive head impacts over time, it was recently suggested that the behavioural response to TBI could be a major predisposing factor in CTE development. For instance, Ganau et al. [22] proposed that agitation and delirium seen in TBI patients could be significant risk factors that predict long-term changes within the patients’ neurophysiology and thus possibly promote CTE onset.

References

  1. Martland, H. Punch drunk. J. Am. Med. Assoc. 1928, 91, 1103–1107.
  2. Brandenburg, W.; Hallervorden, J. Dementia pugilistica mit anatomischem Befund. Virchows Archiv. Pathol. Anat. 1954, 325, 680–709.
  3. Corsellis, J.A.; Bruton, C.J.; Freeman-Browne, D. The aftermath of boxing. Psychol. Med. 1973, 3, 270–303.
  4. Omalu, B.I.; DeKosky, S.T.; Minster, R.; Kamboh, M.I.; Hamilton, R.L.; Wecht, C.H. Chronic traumatic encephalopathy in a National Football League player. Neurosurgery 2005, 57, 128–134.
  5. McKee, A.C.; Daneshvar, D.H.; Alvarez, V.E.; Stein, T.D. The neuropathology of sport. Acta Neuropathol. 2014, 127, 29–51.
  6. Ling, H.; Morris, H.R.; Neal, J.W.; Neal, J.W.; Lees, A.J.; Hardy, J.; Holton, J.L.; Revesz, T.; Williams, D.D. Mixed pathologies including chronic traumatic encephalopathy account for dementia in retired association football (soccer) players. Acta Neuropathol. 2017, 133, 337–352.
  7. Lee, E.B.; Kinch, K.; Johnson, V.E.; Trojanowski, J.Q.; Smith, D.H.; Stewart, W. Chronic traumatic encephalopathy is a common co-morbidity, but less frequent primary dementia in former soccer and rugby players. Acta Neuropathol. 2019, 138, 389–399.
  8. Omalu, B.I.; Fitzsimmons, R.P.; Hammers, J.; Bailes, J. Chronic traumatic encephalopathy in a professional American wrestler. J. Forensic Nurs. 2010, 6, 130–136.
  9. Stewart, W.; McNamara, P.H.; Lawlor, B.; Hutchinson, S.; Farrell, M. Chronic traumatic encephalopathy: A potential late and under recognized consequence of rugby union. QJM 2016, 109, 11–15.
  10. Buckland, M.E.; Sy, J.; Szentmariay, I.; Kullen, A.; Lee, M.; Harding, A.; Halliday, G.; Suter, C.M. Correction to: Chronic traumatic encephalopathy in two former Australian National Rugby League players. Acta Neuropathol. Commun. 2019, 7, 122.
  11. Omalu, B.; Hammers, J.L.; Bailes, J.; Hamilton, R.L.; Kamboh, M.I.; Webster, G.; Fitzsimmons, R.P. Chronic traumatic encephalopathy in an Iraqi war veteran with posttraumatic stress disorder who committed suicide. Neurosurg. Focus 2011, 31, E3.
  12. Priemer, D.S.; Iacono, D.; Rhodes, C.H.; Olsen, C.H.; Perl, D.P. Chronic Traumatic Encephalopathy in the Brains of Military Personnel. N. Engl. J. Med. 2022, 386, 2169–2177.
  13. McKee, A.C.; Stein, T.D.; Kiernan, P.T.; Alvarez, V.E. The neuropathology of chronic traumatic encephalopathy. Brain Pathol. 2015, 25, 350–364.
  14. Bieniek, K.F.; Ross, O.A.; Cormier, K.A.; Walton, R.L.; Soto-Ortolaza, A.; Johnston, A.E.; DeSaro, P.; Boylan, K.B.; Graff-Radford, N.R.; Wszolek, Z.K.; et al. Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank. Acta Neuropathol. 2015, 130, 877–889.
  15. Ruchika, F.; Shah, S.; Neupane, D.; Vijay, R.; Mehkri, Y.; Lucke-Wold, B. Understanding the Molecular Progression of Chronic Traumatic Encephalopathy in Traumatic Brain Injury, Aging and Neurodegenerative Disease. Int. J. Mol. Sci. 2023, 24, 1847.
  16. Reams, N.; Eckner, J.T.; Almeida, A.A.; Aagesen, A.L.; Giordani, B.; Paulson, H.; Lorincz, M.T.; Kutcher, J.S. A Clinical Approach to the Diagnosis of Traumatic Encephalopathy Syndrome: A Review. JAMA Neurol. 2016, 73, 743–749.
  17. Mavroudis, I.; Kazis, D.; Chowdhury, R.; Petridis, F.; Costa, V.; Balmus, I.M.; Ciobica, A.; Luca, A.C.; Radu, I.; Dobrin, R.P.; et al. Post-Concussion Syndrome and Chronic Traumatic Encephalopathy: Narrative Review on the Neuropathology, Neuroimaging and Fluid Biomarkers. Diagnostics 2022, 12, 740.
  18. Victoroff, J. Traumatic encephalopathy: Review and provisional research diagnostic criteria. Neuro Rehabil. 2013, 32, 211–224.
  19. Montenigro, P.H.; Bernick, C.; Cantu, R.C. Clinical features of repetitive traumatic brain injury and chronic traumatic encephalopathy. Brain Pathol. 2015, 25, 304–317.
  20. Jordan, B.D. The clinical spectrum of sport-related traumatic brain injury. Nat. Rev. Neurol. 2013, 9, 222–230.
  21. Katz, D.I.; Bernick, C.; Dodick, D.W.; Mez, J.; Mariani, M.L.; Adler, C.H.; Alosco, M.L.; Balcer, L.J.; Banks, S.J.; Barr, W.B.; et al. National Institute of Neurological Disorders and Stroke Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome. Neurology 2021, 96, 848–863.
  22. Ganau, M.; Lavinio, A.; Prisco, L. Delirium and agitation in traumatic brain injury patients: An update on pathological hypotheses and treatment options. Minerva Anestesiol. 2018, 84, 632–640.
More