[en] Sepsis is a potentially fatal whole-body inflammatory state caused by severe infection, in which a maladaptive, system-wide inflammatory response follows initial attempts to eliminate pathogens, leading to a dangerous and often fatal increase in the permeability of the blood-brain barrier. These changes in the blood-brain barrier might lead to a major symptom of sepsis, sepsis-associated encephalopathy, which manifests as confusion with a rapid decline in cognitive functions, especially memory, or coma. Once presumed to be entirely reversible, research suggests that sepsis-associated encephalopathy could lead to permanent neurocognitive dysfunction and functional impairments, even after the patient has recovered. Sepsis might act as a major inflammatory hit and potentially increase the brain's susceptibility to neurodegenerative disease, further deterioration of cognitive ability, and risk of developing dementia in later life. Key opportunities for neuroprotective interventions and after-care for people who have survived sepsis might be lost because the long-term neurocognitive and functional consequences of sepsis are not fully characterised.
Disciplines :
Neurology
Author, co-author :
Widmann, Catherine N; Department of Neurology, Clinical Neuroscience Unit, University of Bonn, Bonn, Germany, German Centre for Neurodegenerative Diseases, Bonn, Germany
HENEKA, Michael ; Department of Neurology, Clinical Neuroscience Unit, University of Bonn, Bonn, Germany, German Centre for Neurodegenerative Diseases, Bonn, Germany. Electronic address: michael.heneka@ukb.uni-bonn.de
Iwashyna TJ, Cooke CR, Wunsch H, Kahn JM The population burden of long-term survivorship after severe sepsis among older Americans. J Am Geriatr Soc 2012, 60:1070-1077.
Stevenson EK, Rubenstein A, Radin GT, Wiener RS, Walkey AJ Two decades of mortality trends among patients with severe sepsis: a comparative meta-analysis. Crit Care Med 2014, 42:625-631.
Lamar CD, Hurley RA, Hayman LA, Taber KH Sepsis-associated encephalopathy: review of the neuropsychiatric manifestations and cognitive outcome. J Neuropsychiatry Clin Neurosci 2011, 23:237-241.
Gunther ML, Morandi A, Krauskopf E, et al. The association between brain volumes, delirium duration, and cognitive outcomes in intensive care unit survivors: the VISIONS cohort magnetic resonance imaging study. Crit Care Med 2012, 40:2022-2032. the VISIONS Investigation, VISualizing Icu SurvivOrs Neuroradiological SequelaeVISualizing Icu SurvivOrs Neuroradiological Sequelae.
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.
Iwashyna TJ, Ely EW, Smith DM, Langa KM Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 2010, 304:1787-1794.
Guenther U, Theuerkauf N, Frommann I, et al. Predisposing and precipitating factors of delirium after cardiac surgery: a prospective observational cohort study. Ann Surg 2013, 257:1160-1167.
Pandharipande PP, Girard TD, Jackson JC, et al. Long-term cognitive impairment after critical illness. N Engl J Med 2013, 369:1306-1316. the BRAIN-ICU Study Investigators.
Shah FA, Pike F, Alvarez K, et al. Bidirectional relationship between cognitive function and pneumonia. Am J Respir Crit Care Med 2013, 188:586-592.
Perry VH, Cunningham C, Holmes C Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 2007, 7:161-167.
Murray C, Sanderson DJ, Barkus C, et al. Systemic inflammation induces acute working memory deficits in the primed brain: relevance for delirium. Neurobiol Aging 2012, 33:603-616.e3.
Holmes C, Cunningham C, Zotova E, et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology 2009, 73:768-774.
Dlugaj M, Gerwig M, Wege N, et al. Elevated levels of high-sensitivity C-reactive protein are associated with mild cognitive impairment and its subtypes: results of a population-based case-control study. J Alzheimers Dis 2012, 28:503-514.
Davydow DS, Hough CL, Langa KM, Iwashyna TJ Presepsis depressive symptoms are associated with incident cognitive impairment in survivors of severe sepsis: a prospective cohort study of older Americans. J Am Geriatr Soc 2012, 60:2290-2296.
Karlsson S, Ruokonen E, Varpula T, Ala-Kokko TI, Pettilä V Long-term outcome and quality-adjusted life years after severe sepsis. Crit Care Med 2009, 37:1268-1274. the Finnsepsis Study Group.
Iwashyna TJ, Cooke CR, Wunsch H, Kahn JM Population burden of long-term survivorship after severe sepsis in older Americans. J Am Geriatr Soc 2012, 60:1070-1077.
Hossmann KA Viability thresholds and the penumbra of focal ischemia. Ann Neurol 1994, 36:557-565.
Nishioku T, Dohgu S, Takata F, et al. Detachment of brain pericytes from the basal lamina is involved in disruption of the blood-brain barrier caused by lipopolysaccharide-induced sepsis in mice. Cell Mol Neurobiol 2009, 29:309-316.
Chugh D, Nilsson P, Afjei S-A, Bakochi A, Ekdahl CT Brain inflammation induces post-synaptic changes during early synapse formation in adult-born hippocampal neurons. Exp Neurol 2013, 250:176-188.
Soult MC, Lonergan NE, Shah B, Kim WK, Britt LD, Sullivan CJ Outer membrane vesicles from pathogenic bacteria initiate an inflammatory response in human endothelial cells. J Surg Res 2013, 184:458-466.
Fox ED, Heffernan DS, Cioffi WG, Reichner JS Neutrophils from critically ill septic patients mediate profound loss of endothelial barrier integrity. Crit Care 2013, 17:R226.
Duchini A, Govindarajan S, Santucci M, Zampi G, Hofman FM Effects of tumor necrosis factor-alpha and interleukin-6 on fluid-phase permeability and ammonia diffusion in CNS-derived endothelial cells. J Investig Med 1996, 44:474-482.
Bozza FA, Garteiser P, Oliveira MF, et al. Sepsis-associated encephalopathy: a magnetic resonance imaging and spectroscopy study. J Cereb Blood Flow Metab 2010, 30:440-448.
Abramova AY, Pertsov SS, Kozlov AY, et al. Cytokine levels in rat blood and brain structures after administration of lipopolysaccharide. Bull Exp Biol Med 2013, 155:417-420.
Semmler A, Hermann S, Mormann F, et al. Sepsis causes neuroinflammation and concomitant decrease of cerebral metabolism. J Neuroinflammation 2008, 5:38.
Imamura Y, Wang H, Matsumoto N, et al. Interleukin-1β causes long-term potentiation deficiency in a mouse model of septic encephalopathy. Neuroscience 2011, 187:63-69.
Comim CM, Cassol OJ, Constantino LS, et al. Alterations in inflammatory mediators, oxidative stress parameters and energetic metabolism in the brain of sepsis survivor rats. Neurochem Res 2011, 36:304-311.
Field RH, Gossen A, Cunningham C Prior pathology in the basal forebrain cholinergic system predisposes to inflammation-induced working memory deficits: reconciling inflammatory and cholinergic hypotheses of delirium. J Neurosci 2012, 32:6288-6294.
Comim CM, Constantino LS, Petronilho F, Quevedo J, Dal-Pizzol F Aversive memory in sepsis survivor rats. J Neural Transm 2011, 118:213-217.
Reimann-Philipp U, Ovase R, Weigel PH, Grammas P Mechanisms of cell death in primary cortical neurons and PC12 cells. J Neurosci Res 2001, 64:654-660.
Liu B, Gao H-M, Wang JY, Jeohn GH, Cooper CL, Hong JS Role of nitric oxide in inflammation-mediated neurodegeneration. Ann N Y Acad Sci 2002, 962:318-331.
Lemstra AW, Groen in't Woud JC, Hoozemans JJ, et al. Microglia activation in sepsis: a case-control study. J Neuroinflammation 2007, 4:4.
Mawuenyega KG, Sigurdson W, Ovod V, et al. Decreased clearance of CNS β-amyloid in Alzheimer's disease. Science 2010, 330:1774. 1774.
Kettenmann H, Kirchhoff F, Verkhratsky A Microglia: new roles for the synaptic stripper. Neuron 2013, 77:10-18.
Xie Q, Nathan C The high-output nitric oxide pathway: role and regulation. J Leukoc Biol 1994, 56:576-582.
Kim PK, Zamora R, Petrosko P, Billiar TR The regulatory role of nitric oxide in apoptosis. Int Immunopharmacol 2001, 1:1421-1441.
Thiemermann C Nitric oxide and septic shock. Gen Pharmacol 1997, 29:159-166.
Satta MA, Jacobs RA, Kaltsas GA, Grossman AB Endotoxin induces interleukin-1beta and nitric oxide synthase mRNA in rat hypothalamus and pituitary. Neuroendocrinology 1998, 67:109-116.
Leist M, Volbracht C, Kühnle S, Fava E, Ferrando-May E, Nicotera P Caspase-mediated apoptosis in neuronal excitotoxicity triggered by nitric oxide. Mol Med 1997, 3:750-764.
Heneka MT, Löschmann PA, Gleichmann M, et al. Induction of nitric oxide synthase and nitric oxide-mediated apoptosis in neuronal PC12 cells after stimulation with tumor necrosis factor-alpha/lipopolysaccharide. J Neurochem 1998, 71:88-94.
Brown GC Mechanisms of inflammatory neurodegeneration: iNOS and NADPH oxidase. Biochem Soc Trans 2007, 35:1119-1121.
Calabrese V, Mancuso C, Calvani M, Rizzarelli E, Butterfield DA, Stella AMG Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci 2007, 8:766-775.
Fukunaga K, Miyamoto E A working model of CaM kinase II activity in hippocampal long-term potentiation and memory. Neurosci Res 2000, 38:3-17.
Stagi M, Dittrich PS, Frank N, Iliev AI, Schwille P, Neumann H Breakdown of axonal synaptic vesicle precursor transport by microglial nitric oxide. J Neurosci 2005, 25:352-362.
Eckel B, Ohl F, Bogdanski R, Kochs EF, Blobner M Cognitive deficits after systemic induction of inducible nitric oxide synthase: a randomised trial in rats. Eur J Anaesthesiol 2011, 28:655-663.
Weberpals M, Hermes M, Hermann S, et al. NOS2 gene deficiency protects from sepsis-induced long-term cognitive deficits. J Neurosci 2009, 29:14177-14184.
Semmler A, Okulla T, Sastre M, Dumitrescu-Ozimek L, Heneka MT Systemic inflammation induces apoptosis with variable vulnerability of different brain regions. J Chem Neuroanat 2005, 30:144-157.
Semmler A, Frisch C, Debeir T, et al. Long-term cognitive impairment, neuronal loss and reduced cortical cholinergic innervation after recovery from sepsis in a rodent model. Exp Neurol 2007, 204:733-740.
Cassol OJ, Comim CM, Constantino LS, et al. Acute low dose of MK-801 prevents memory deficits without altering hippocampal DARPP-32 expression and BDNF levels in sepsis survivor rats. J Neuroimmunol 2011, 230:48-51.
Petronilho F, Périco SR, Vuolo F, et al. Protective effects of guanosine against sepsis-induced damage in rat brain and cognitive impairment. Brain Behav Immun 2012, 26:904-910.
Zhou J, Chen Y, Huang G-Q, et al. Hydrogen-rich saline reverses oxidative stress, cognitive impairment, and mortality in rats submitted to sepsis by cecal ligation and puncture. J Surg Res 2012, 178:390-400.
Wang G, Wang W, Zhao J, Ni Y, Zhou X, Zhang W Ghrelin prevents neuronal apoptosis and cognitive impairments in sepsis-associated encephalopathy. Neuroreport 2011, 22:959-964.
Chavan SS, Huerta PT, Robbiati S, et al. HMGB1 mediates cognitive impairment in sepsis survivors. Mol Med 2012, 18:930-937.
Venet F, Filipe-Santos O, Lepape A, et al. Decreased T-cell repertoire diversity in sepsis: a preliminary study. Crit Care Med 2013, 41:111-119.
Hotchkiss RS, Monneret G, Payen D Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis 2013, 13:260-268.
Boomer JS, To K, Chang KC, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA 2011, 306:2594-2605.
Davis CG, Chang K, Osborne D, Walton AH, Dunne WM, Muenzer JT Increased susceptibility to Candida infection following cecal ligation and puncture. Biochem Biophys Res Commun 2011, 414:37-43.
Lazosky A, Young GB, Zirul S, Phillips R Quality of life after septic illness. J Crit Care 2010, 25:406-412.
Katan M, Moon YP, Paik MC, Sacco RL, Wright CB, Elkind MSV Infectious burden and cognitive function: the Northern Manhattan Study. Neurology 2013, 80:1209-1215.
Jak AJ, Bondi MW, Delano-Wood L, et al. Quantification of five neuropsychological approaches to defining mild cognitive impairment. Am J Geriatr Psychiatry 2009, 17:368-375.
Iwashyna TJ Trajectories of recovery and dysfunction after acute illness, with implications for clinical trial design. Am J Respir Crit Care Med 2012, 186:302-304.
Girard TD, Jackson JC, Pandharipande PP, et al. Delirium as a predictor of long-term cognitive impairment in survivors of critical illness. Crit Care Med 2010, 38:1513-1520.
Hayes JP, Vanelzakker MB, Shin LM Emotion and cognition interactions in PTSD: a review of neurocognitive and neuroimaging studies. Front Integr Neurosci 2012, 6:89.
Davydow DS, Hough CL, Langa KM, Iwashyna TJ Symptoms of depression in survivors of severe sepsis: a prospective cohort study of older Americans. Am J Geriatr Psychiatry 2013, 21:887-897.
Myhren H, Ekeberg O, Tøien K, Karlsson S, Stokland O Posttraumatic stress, anxiety and depression symptoms in patients during the first year post intensive care unit discharge. Crit Care 2010, 14:R14.
Kwaan HC Microvascular thrombosis: a serious and deadly pathologic process in multiple diseases. Semin Thromb Hemost 2011, 37:961-978.
Taccone FS, Scolletta S, Franchi F, Donadello K, Oddo M Brain perfusion in sepsis. Curr Vasc Pharmacol 2013, 11:170-186.
Piazza O, Cotena S, De Robertis E, Caranci F, Tufano R Sepsis associated encephalopathy studied by MRI and cerebral spinal fluid S100B measurement. Neurochem Res 2009, 34:1289-1292.
Polito A, Eischwald F, Maho A-LL, et al. Pattern of brain injury in the acute setting of human septic shock. Crit Care 2013, 17:R204.
Kaplan PW, Rossetti AO EEG patterns and imaging correlations in encephalopathy: encephalopathy part II. J Clin Neurophysiol 2011, 28:233-251.
Oddo M, Carrera E, Claassen J, Mayer SA, Hirsch LJ Continuous electroencephalography in the medical intensive care unit. Crit Care Med 2009, 37:2051-2056.
Fülesdi B, Szatmári S, Antek C, et al. Cerebral vasoreactivity to acetazolamide is not impaired in patients with severe sepsis. J Crit Care 2012, 27:337-343.
Venneti S, Wiley CA, Kofler J Imaging microglial activation during neuroinflammation and Alzheimer's disease. J Neuroimmune Pharmacol 2009, 4:227-243.
Guerra C, Linde-Zwirble WT, Wunsch H Risk factors for dementia after critical illness in elderly medicare beneficiaries. Crit Care 2012, 16:R233.
Kitazawa M, Oddo S, Yamasaki TR, Green KN, Laferla FM Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease. J Neurosci 2005, 25:8843-8853.
Sy M, Kitazawa M, Medeiros R, et al. Inflammation induced by infection potentiates tau pathological features in transgenic mice. Am J Pathol 2011, 178:2811-2822.
Hopkins RO The brain after critical illness: effect of illness and aging on cognitive function. Crit Care 2013, 17:116.
