- Email: [email protected]
Sports-related head trauma and neurodegenerative disease
Correspondence
many biomarkers used to diagnose sepsis, so far it is difficult to distinguish between the different stages of sepsis or to accurately determine the phase of response clinically in terms of compensatory anti-inflammatory response syndrome or mixed antagonist response syndrome. The long-term effect of the magnitude of brain dysfunction warrants further exploration at the intensive care unit, because most studies up to now report mortality as the only outcome. In our Review 1 we state that increasing evidence shows that survivors of sepsis do not fully recover from the acute effects of the disease in the long term, hence, we do not support the idea that sepsis-associated encephalopathy is reversible.1 Although patients do recover from this disorder, about 17% of the severe sepsis cohort in the Health and Retirement study 2 had long-term cognitive and functional impairment for many years afterwards. In our preliminary study of survivors of sepsis, about 60% had global cognitive impairment of at least 1 SD below the expected normal level, about 30% had 1·5 SD below the expected normal level, and about 18% had more than 2 SD below the expected normal level in the 6 to 24 months after initial recovery (data not shown).3 This was a greater level of impairment than that shown in the Health and Retirement study. Because the level of cognitive impairment was similar in the non-sepsis comparison group, which also had high levels of inflammation, we think that this systemic inflammation might be a key factor in cognitive impairment. In a separate analysis, we found that high concentrations of procalcitonin and interleukin-6 were associated with hippocampal atrophy in a small group of general patients who had survived a stay in an intensivecare unit, including survivors of sepsis, but that other clinical scales that measure of severity, such www.thelancet.com/neurology Vol 13 October 2014
as APACHE II, TISS-10 and SAPS II, and systemic inflammatory response syndrome were not. 4 Further examination of serum and CSF cytokine concentrations over the long-term could offer better predictive assessments. We need, therefore, to better characterise long-term outcomes, to identify who and why some sepsis patients do not return to their baseline level of cognitive and functional ability, and to discover what key factors can determine this trajectory. The main goals should be neuroprotective interventions during the acute phase of sepsis, and early and appropriate rehabilitation measures afterwards. These include early identification of patients at risk; diagnosis of sepsis-associated encephalopathy up to now has probably been underestimated in patients with sepsis. Rehabilitation measures should include not only physical, cognitive, and functional training, but also help survivors to build a skill set to cope with their traumatic near-death experience with its many life-changing complications. We declare no competing interests.
Catherine N Widmann, Jens-Christian Schewe, *Michael T Heneka [email protected] Department of Neurology, Clinical Neuroscience Unit, University of Bonn, Bonn, and German Center for Neurodegenerative Diseases, 53127 Bonn, Germany (CTW, MTH); Department of Anaesthesiology and Operative Intensive Care Medicine, University of Bonn, Bonn, Germany (J-C S) 1
2
3
4
Widmann CN, Heneka MT. Long-term cerebral consequences of sepsis. Lancet Neurol 2014; 13: 630–36. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 2010; 304: 1787–94. Semmler A, Widmann CN, Okulla T, et al. Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors. J Neurol Neurosurg Psychiatry 2013; 84: 62–69. Lindlau A, Widmann CN, Putensen C, Jessen F, Semmler A, Heneka MT. Predictors of hippocampal atrophy in critically ill patients. Eur J Neurol 2014; published online April 12. http.10.1111/ene.12443.
Sports-related head trauma and neurodegenerative disease In the past decade, several small studies and anecdotal reports have suggested that sports in which athletes are exposed to repeated head trauma might be associated with long-term risks of neurodegenerative disease. These concerns have gained more prominence with the recent announcement that the US Department of Defense and National Collegiate Athletic Association will undertake a $30 million research programme into the effects of repeated concussions in sport, and with comments from US President Obama that he himself might have sustained concussions as a young athlete. In the UK, the Industrial Injuries Advisory Council has also recently called for new evidence on neurodegenerative disease in professional sportspeople. The short-term and long-term effects of head trauma from boxing have been known since the 1920s, and have been progressively labelled as punch-drunk syndrome, dementia pugilistica, and more recently as chronic traumatic encephalopathy.1 A change in recent years has been the increasing recognition that these problems do not just occur in former boxers, but might occur in a variety of sports associated with repeated concussions, such as American football, ice hockey, and rugby. Although a great deal of evidence exists about the short-term effects of head injury in terms of both symptoms and pathology, relatively little evidence is available about the long-term effects of either single or repeated trauma. Only recently, chronic traumatic encephalopathy— defined by the occurrence of repetitive mild traumatic brain injuries—has been described and staged as a neuropathological entity featuring
For more on sports-related concussions see Editorial Lancet Neurol 2014; 13: 747
For more on President Obama’s sports summit see http://www. whitehouse.gov/ blog/2014/05/29/presidentobama-hosts-healthy-kids-andsafe-sports-concussion-summit For the report by the Industrial Injuries Advisory Council see http://iiac.independent.gov.uk/ calls-addtional-research/index. shtml
969
Correspondence
progressive accumulation of hyperphosphorylated tau protein in specific areas of the brain.1 Results from several studies have suggested increased risks of various neurological disorders in professional sportspeople with head traumas, including amyotrophic lateral sclerosis2,3 and subclinical effects such as impaired cognitive function,4 and associations between head trauma and Parkinson’s disease5 and other neurological symptoms, such as headache and sleep disturbances. Even more disturbing is evidence that longterm consequences of head trauma might also occur in sports such as football (soccer for North American readers), in which concussion is rare, but in which low-level head trauma (eg, from heading the ball) is common.2 A UK study of 138 former professional football players aged 55 years or older from four clubs (two in England and two in Scotland) found that the prevalence of mild cognitive impairment and dementia was similar to what one would expect in the general population.6 However, little information was available about whether the participants had
970
had concussion, and whether this was associated with mild cognitive impairment. So where does this leave us? We certainly cannot afford to be complacent about the long-term effects of head injury in contact sports such as American football, ice hockey, and rugby. Clearly, more research is needed to establish whether the present evidence, which is based mainly on anecdotes and small clinical studies, is valid, and whether sports-related head injuries really do have major, long-term neurodegenerative effects. Furthermore, whether research from these sports can be applied to football (soccer) is not clear, because this sport involves few concussions, but many low-level head traumas. Thus, sound, evidence-based, high-quality studies are needed to investigate the longterm consequences of repeated, lowintensity head trauma in professional sportspeople, including football players, and the associated long-term risks of developing devastating and life-threatening neurodegenerative disorders. Scientists, players, professional bodies, and funders should closely collaborate to reach this goal.
We declare no competing interests.
*Neil Pearce, Valentina Gallo, Damien McElvenny [email protected] Centre for Global NCDs, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK (NP); Centre for Public Health Research, Massey University Wellington Campus, Wellington, New Zealand (NP); Queen Mary University of London, London, UK (VG); Institute of Occupational Medicine, Edinburgh, UK (DM). 1
2
3
4
5
6
McKee AC, Stern RA, Nowinski CJ, et al. The spectrum of disease in chronic traumatic encephalopathy. Brain 2013; 136: 43–64. Chiò A, Benzi G, Dossena M, et al. Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain 2005; 128: 472–76. Lehman EJ, Hein MJ, Baron SL, et al. Neurodegenerative causes of death among retired National Football League players. Neurology 2012; 79: 1970–74. Mielke MM, Savica R, Wiste HJ, et al. Head trauma and in vivo measures of amyloid and neurodegeneration in a population-based study. Neurology 2014; 82: 70–76. Harris MA, Shen H, Marion SA, et al. Head injuries and Parkinson’s disease in a case-control study. Occup Environ Med 2013; 70: 839–44. Vann Jones SA, Breakey RW, Evans PJ. Heading in football, long-term cognitive decline and dementia: evidence from screening retired professional footballers. Br J Sports Med 2014; 48: 159–61.
www.thelancet.com/neurology Vol 13 October 2014
many biomarkers used to diagnose sepsis, so far it is difficult to distinguish between the different stages of sepsis or to accurately determine the phase of response clinically in terms of compensatory anti-inflammatory response syndrome or mixed antagonist response syndrome. The long-term effect of the magnitude of brain dysfunction warrants further exploration at the intensive care unit, because most studies up to now report mortality as the only outcome. In our Review 1 we state that increasing evidence shows that survivors of sepsis do not fully recover from the acute effects of the disease in the long term, hence, we do not support the idea that sepsis-associated encephalopathy is reversible.1 Although patients do recover from this disorder, about 17% of the severe sepsis cohort in the Health and Retirement study 2 had long-term cognitive and functional impairment for many years afterwards. In our preliminary study of survivors of sepsis, about 60% had global cognitive impairment of at least 1 SD below the expected normal level, about 30% had 1·5 SD below the expected normal level, and about 18% had more than 2 SD below the expected normal level in the 6 to 24 months after initial recovery (data not shown).3 This was a greater level of impairment than that shown in the Health and Retirement study. Because the level of cognitive impairment was similar in the non-sepsis comparison group, which also had high levels of inflammation, we think that this systemic inflammation might be a key factor in cognitive impairment. In a separate analysis, we found that high concentrations of procalcitonin and interleukin-6 were associated with hippocampal atrophy in a small group of general patients who had survived a stay in an intensivecare unit, including survivors of sepsis, but that other clinical scales that measure of severity, such www.thelancet.com/neurology Vol 13 October 2014
as APACHE II, TISS-10 and SAPS II, and systemic inflammatory response syndrome were not. 4 Further examination of serum and CSF cytokine concentrations over the long-term could offer better predictive assessments. We need, therefore, to better characterise long-term outcomes, to identify who and why some sepsis patients do not return to their baseline level of cognitive and functional ability, and to discover what key factors can determine this trajectory. The main goals should be neuroprotective interventions during the acute phase of sepsis, and early and appropriate rehabilitation measures afterwards. These include early identification of patients at risk; diagnosis of sepsis-associated encephalopathy up to now has probably been underestimated in patients with sepsis. Rehabilitation measures should include not only physical, cognitive, and functional training, but also help survivors to build a skill set to cope with their traumatic near-death experience with its many life-changing complications. We declare no competing interests.
Catherine N Widmann, Jens-Christian Schewe, *Michael T Heneka [email protected] Department of Neurology, Clinical Neuroscience Unit, University of Bonn, Bonn, and German Center for Neurodegenerative Diseases, 53127 Bonn, Germany (CTW, MTH); Department of Anaesthesiology and Operative Intensive Care Medicine, University of Bonn, Bonn, Germany (J-C S) 1
2
3
4
Widmann CN, Heneka MT. Long-term cerebral consequences of sepsis. Lancet Neurol 2014; 13: 630–36. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 2010; 304: 1787–94. Semmler A, Widmann CN, Okulla T, et al. Persistent cognitive impairment, hippocampal atrophy and EEG changes in sepsis survivors. J Neurol Neurosurg Psychiatry 2013; 84: 62–69. Lindlau A, Widmann CN, Putensen C, Jessen F, Semmler A, Heneka MT. Predictors of hippocampal atrophy in critically ill patients. Eur J Neurol 2014; published online April 12. http.10.1111/ene.12443.
Sports-related head trauma and neurodegenerative disease In the past decade, several small studies and anecdotal reports have suggested that sports in which athletes are exposed to repeated head trauma might be associated with long-term risks of neurodegenerative disease. These concerns have gained more prominence with the recent announcement that the US Department of Defense and National Collegiate Athletic Association will undertake a $30 million research programme into the effects of repeated concussions in sport, and with comments from US President Obama that he himself might have sustained concussions as a young athlete. In the UK, the Industrial Injuries Advisory Council has also recently called for new evidence on neurodegenerative disease in professional sportspeople. The short-term and long-term effects of head trauma from boxing have been known since the 1920s, and have been progressively labelled as punch-drunk syndrome, dementia pugilistica, and more recently as chronic traumatic encephalopathy.1 A change in recent years has been the increasing recognition that these problems do not just occur in former boxers, but might occur in a variety of sports associated with repeated concussions, such as American football, ice hockey, and rugby. Although a great deal of evidence exists about the short-term effects of head injury in terms of both symptoms and pathology, relatively little evidence is available about the long-term effects of either single or repeated trauma. Only recently, chronic traumatic encephalopathy— defined by the occurrence of repetitive mild traumatic brain injuries—has been described and staged as a neuropathological entity featuring
For more on sports-related concussions see Editorial Lancet Neurol 2014; 13: 747
For more on President Obama’s sports summit see http://www. whitehouse.gov/ blog/2014/05/29/presidentobama-hosts-healthy-kids-andsafe-sports-concussion-summit For the report by the Industrial Injuries Advisory Council see http://iiac.independent.gov.uk/ calls-addtional-research/index. shtml
969
Correspondence
progressive accumulation of hyperphosphorylated tau protein in specific areas of the brain.1 Results from several studies have suggested increased risks of various neurological disorders in professional sportspeople with head traumas, including amyotrophic lateral sclerosis2,3 and subclinical effects such as impaired cognitive function,4 and associations between head trauma and Parkinson’s disease5 and other neurological symptoms, such as headache and sleep disturbances. Even more disturbing is evidence that longterm consequences of head trauma might also occur in sports such as football (soccer for North American readers), in which concussion is rare, but in which low-level head trauma (eg, from heading the ball) is common.2 A UK study of 138 former professional football players aged 55 years or older from four clubs (two in England and two in Scotland) found that the prevalence of mild cognitive impairment and dementia was similar to what one would expect in the general population.6 However, little information was available about whether the participants had
970
had concussion, and whether this was associated with mild cognitive impairment. So where does this leave us? We certainly cannot afford to be complacent about the long-term effects of head injury in contact sports such as American football, ice hockey, and rugby. Clearly, more research is needed to establish whether the present evidence, which is based mainly on anecdotes and small clinical studies, is valid, and whether sports-related head injuries really do have major, long-term neurodegenerative effects. Furthermore, whether research from these sports can be applied to football (soccer) is not clear, because this sport involves few concussions, but many low-level head traumas. Thus, sound, evidence-based, high-quality studies are needed to investigate the longterm consequences of repeated, lowintensity head trauma in professional sportspeople, including football players, and the associated long-term risks of developing devastating and life-threatening neurodegenerative disorders. Scientists, players, professional bodies, and funders should closely collaborate to reach this goal.
We declare no competing interests.
*Neil Pearce, Valentina Gallo, Damien McElvenny [email protected] Centre for Global NCDs, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK (NP); Centre for Public Health Research, Massey University Wellington Campus, Wellington, New Zealand (NP); Queen Mary University of London, London, UK (VG); Institute of Occupational Medicine, Edinburgh, UK (DM). 1
2
3
4
5
6
McKee AC, Stern RA, Nowinski CJ, et al. The spectrum of disease in chronic traumatic encephalopathy. Brain 2013; 136: 43–64. Chiò A, Benzi G, Dossena M, et al. Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain 2005; 128: 472–76. Lehman EJ, Hein MJ, Baron SL, et al. Neurodegenerative causes of death among retired National Football League players. Neurology 2012; 79: 1970–74. Mielke MM, Savica R, Wiste HJ, et al. Head trauma and in vivo measures of amyloid and neurodegeneration in a population-based study. Neurology 2014; 82: 70–76. Harris MA, Shen H, Marion SA, et al. Head injuries and Parkinson’s disease in a case-control study. Occup Environ Med 2013; 70: 839–44. Vann Jones SA, Breakey RW, Evans PJ. Heading in football, long-term cognitive decline and dementia: evidence from screening retired professional footballers. Br J Sports Med 2014; 48: 159–61.
www.thelancet.com/neurology Vol 13 October 2014