Correspondence
of pro-inflammatory compounds released in response to infection. Consequently, multiple-organ systems might be affected, leading to their failure. Sepsis-associated encephalopathy, a life-threatening yet reversible deterioration of mental status that occasionally accompanies sepsis, is the most common type of encephalopathy encountered in patients in the intensive care unit; sepsis-associated encephalopathy contributes to increased mortality in these patients, and those who survive often have long-term, disabling, cognitive dysfunction or other devastating outcomes, including impaired memory, attention, mentalprocessing speed, and visual-spatial abilities. This long-term disabling state can affect all aspects of a patient’s life, including the ability to return to normal daily activity or work, imposing a further burden to their families and healthcare providers.2 Clinically, sepsis-associated encephalopathy manifests as acute altered mental status, inattention, disorientation, agitation, stupor, and coma. It is characterised by leukoencephalopathy, abnormalities in somatosensory-evoked potentials and electroencephalogram activity, and an increase in brain-injury biomarkers, such as neuron-specific enolase and S100B protein. 3 The magnitude of brain dysfunction and deterioration in cognitive performance is difficult to measure through bedside assessments. The pathophysiology of encephalopathy in patients with sepsis is multifaceted, encompassing both inflammatory and noninflammatory insults that lead to direct brain-cell damage, impaired neurotransmission, and mitochondrial or endothelial dysfunction. 4 Furthermore, the complex balance between proinflammatory and anti-inflammatory responses induced by sepsis, known as the mixed antagonistic response 968
syndrome, will shift towards either the inflammatory or the antiinflammatory response during the course of sepsis. Sepsis can also lead to impairment of the function of individual organs; this impairment might be sepsisassociated or sepsis-induced. The pathophysiology underlying sepsisinduced multi organ failure is a severely compromised, rather than an overactive, immune system.5 It is this subsequent impaired balance in immune response that leads to multiorgan failure. Critically ill patients might also develop iatrogenic organ dysfunction. Renal dysfunction is a common scenario noted in patients, due to the use of nephrotoxic drugs such as aminoglycosides, and is therefore termed as sepsis-associated, rather than sepsis-induced, renal dysfunction. Despite the organ impairment noted throughout sepsis, any brain damage originates directly from the systemic infection. Sepsis-associated encephalopathy is associated with diffuse or multifocal cerebral dysfunction prompted by the systemic response to the infection without any evident direct infection of the brain. The brain has a central role in sepsis, both mediating the immune responses and being a target endorgan for the pathological process. Hence, cerebral involvement is a result of progression to severe sepsis, rather than being an adjuvant occurrence. Therefore, the term sepsis-associated encephalopathy used by most authors1 should be substituted with the more appropriate term sepsis-induced encephalopathy. We declare no competing interests.
Samad EJ Golzari, *Ata Mahmoodpoor [email protected] Liver and Gastrointestinal Disease Research Center (SEJG) and Cardiovascular Research Center (AM), Tabriz University of Medical Sciences, Tabriz, 5157698616, Iran 1
Widmann CN, Heneka M. Long-term cerebral consequences of sepsis. Lancet Neurol 2014; 13: 630–36.
2
3
4
5
Hurley RA, Hayman LA, Taber KH. Sepsis-associated encephalopathy: review of the neuropsychiatric manifestations and cognitive outcome. J Neuropsychiatry Clin Neurosci 2011; 23: 236–41 Iacobone E, Bailly-Salin J, Polito A, Friedman D, Stevens RD, Sharshar T. Sepsis-associated encephalopathy and its differential diagnosis. Crit Care Med 2009; 37 (10 suppl): S331–36. Zampieri FG, Park M, Machado FS, Azevedo LCP. Sepsis associated encephalopathy. Clinics 2011; 66: 1825–31. Hotchkiss RS, Opal S. Immunotherapy for sepsis: a new approach against an ancient foe. N Engl J Med 2010; 363: 87–89.
Authors’ reply Cognitive and cerebral damage after sepsis could have many causes, and whether sepsis-associated encephalopathy is the only cause is unclear. Furthermore, whether encephalopathy during sepsis is a result of sepsis itself or due to myriad other factors during acute illness is also unclear. Potentially contributing factors during acute disease include immunological weakness; neurological or psychiatric diseases (especially post-traumatic stress disorder, depression, and anxiety); other comorbidities; the presence and type of infection, and severity and duration; the type of treatment given at the intensive-care unit (especially analgesia and sedation); delirium; which, if any, diagnostic and rehabilitative measures were taken; and pre-existing physical disabilities. These factors vary between patients, and are likely to interact. In our Personal View,1 we sought to outline the best-known mechanisms that directly or indirectly affect the brain— systemic and cerebral blood flow, permeability of the blood–brain barrier, oxidative stress, neuronal dysfunction and neuronal death, and immunosuppression. Golzari and Mahmoodpoor are correct that, in addition to the mechanisms we outlined, dysfunction in and failure of organs other than the brain will have an indirect effect on brain function. In view of the fact that sepsis and the inflammatory response are highly dynamic processes, and despite the
www.thelancet.com/neurology Vol 13 October 2014
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
of pro-inflammatory compounds released in response to infection. Consequently, multiple-organ systems might be affected, leading to their failure. Sepsis-associated encephalopathy, a life-threatening yet reversible deterioration of mental status that occasionally accompanies sepsis, is the most common type of encephalopathy encountered in patients in the intensive care unit; sepsis-associated encephalopathy contributes to increased mortality in these patients, and those who survive often have long-term, disabling, cognitive dysfunction or other devastating outcomes, including impaired memory, attention, mentalprocessing speed, and visual-spatial abilities. This long-term disabling state can affect all aspects of a patient’s life, including the ability to return to normal daily activity or work, imposing a further burden to their families and healthcare providers.2 Clinically, sepsis-associated encephalopathy manifests as acute altered mental status, inattention, disorientation, agitation, stupor, and coma. It is characterised by leukoencephalopathy, abnormalities in somatosensory-evoked potentials and electroencephalogram activity, and an increase in brain-injury biomarkers, such as neuron-specific enolase and S100B protein. 3 The magnitude of brain dysfunction and deterioration in cognitive performance is difficult to measure through bedside assessments. The pathophysiology of encephalopathy in patients with sepsis is multifaceted, encompassing both inflammatory and noninflammatory insults that lead to direct brain-cell damage, impaired neurotransmission, and mitochondrial or endothelial dysfunction. 4 Furthermore, the complex balance between proinflammatory and anti-inflammatory responses induced by sepsis, known as the mixed antagonistic response 968
syndrome, will shift towards either the inflammatory or the antiinflammatory response during the course of sepsis. Sepsis can also lead to impairment of the function of individual organs; this impairment might be sepsisassociated or sepsis-induced. The pathophysiology underlying sepsisinduced multi organ failure is a severely compromised, rather than an overactive, immune system.5 It is this subsequent impaired balance in immune response that leads to multiorgan failure. Critically ill patients might also develop iatrogenic organ dysfunction. Renal dysfunction is a common scenario noted in patients, due to the use of nephrotoxic drugs such as aminoglycosides, and is therefore termed as sepsis-associated, rather than sepsis-induced, renal dysfunction. Despite the organ impairment noted throughout sepsis, any brain damage originates directly from the systemic infection. Sepsis-associated encephalopathy is associated with diffuse or multifocal cerebral dysfunction prompted by the systemic response to the infection without any evident direct infection of the brain. The brain has a central role in sepsis, both mediating the immune responses and being a target endorgan for the pathological process. Hence, cerebral involvement is a result of progression to severe sepsis, rather than being an adjuvant occurrence. Therefore, the term sepsis-associated encephalopathy used by most authors1 should be substituted with the more appropriate term sepsis-induced encephalopathy. We declare no competing interests.
Samad EJ Golzari, *Ata Mahmoodpoor [email protected] Liver and Gastrointestinal Disease Research Center (SEJG) and Cardiovascular Research Center (AM), Tabriz University of Medical Sciences, Tabriz, 5157698616, Iran 1
Widmann CN, Heneka M. Long-term cerebral consequences of sepsis. Lancet Neurol 2014; 13: 630–36.
2
3
4
5
Hurley RA, Hayman LA, Taber KH. Sepsis-associated encephalopathy: review of the neuropsychiatric manifestations and cognitive outcome. J Neuropsychiatry Clin Neurosci 2011; 23: 236–41 Iacobone E, Bailly-Salin J, Polito A, Friedman D, Stevens RD, Sharshar T. Sepsis-associated encephalopathy and its differential diagnosis. Crit Care Med 2009; 37 (10 suppl): S331–36. Zampieri FG, Park M, Machado FS, Azevedo LCP. Sepsis associated encephalopathy. Clinics 2011; 66: 1825–31. Hotchkiss RS, Opal S. Immunotherapy for sepsis: a new approach against an ancient foe. N Engl J Med 2010; 363: 87–89.
Authors’ reply Cognitive and cerebral damage after sepsis could have many causes, and whether sepsis-associated encephalopathy is the only cause is unclear. Furthermore, whether encephalopathy during sepsis is a result of sepsis itself or due to myriad other factors during acute illness is also unclear. Potentially contributing factors during acute disease include immunological weakness; neurological or psychiatric diseases (especially post-traumatic stress disorder, depression, and anxiety); other comorbidities; the presence and type of infection, and severity and duration; the type of treatment given at the intensive-care unit (especially analgesia and sedation); delirium; which, if any, diagnostic and rehabilitative measures were taken; and pre-existing physical disabilities. These factors vary between patients, and are likely to interact. In our Personal View,1 we sought to outline the best-known mechanisms that directly or indirectly affect the brain— systemic and cerebral blood flow, permeability of the blood–brain barrier, oxidative stress, neuronal dysfunction and neuronal death, and immunosuppression. Golzari and Mahmoodpoor are correct that, in addition to the mechanisms we outlined, dysfunction in and failure of organs other than the brain will have an indirect effect on brain function. In view of the fact that sepsis and the inflammatory response are highly dynamic processes, and despite the
www.thelancet.com/neurology Vol 13 October 2014
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
