Pathogenesis of Delirium

  • Pinar Soysal
  • Ahmet Turan Isik


Delirium is a complex syndrome defined as an acute, fluctuating syndrome of altered attention, awareness, and cognition. Delirium is common in the elderly, but unfortunately underdiagnosed. The consequences could be significant such as an increase in mortality, hospitalization, loss of autonomy, and increased risk to be institutionalized. The predisposing and precipitating factors are well known, but the pathogenesis is not yet identified clearly. However, evidence that delirium is a neurotoxic factor which develops due primarily to neurotransmitter (cholinergic insufficiency) and inflammatory (increase in stress response/neuroinflammation) mechanisms is increasing each passing day. In addition, changes in neuronal injury and permeability of blood-brain barrier, impairment in sleep pattern, genetic, and drugs may play a role in the development of delirium.


  1. Adamis D, Meagher D (2011) Insulin-like growth factor i and the pathogenesis of delirium: a review of current evidence. J Aging Res 951403:1–11CrossRefGoogle Scholar
  2. Adamis D, Lunn M, Martin FC et al (2009) Cytokines and IGF-I in delirious and non-delirious acutely ill older medical inpatients. Age Ageing 38(3):326–332CrossRefPubMedGoogle Scholar
  3. Alagiakrishnan K, Wiens CA (2004) An approach to drug induced delirium in the elderly. Postgrad Med J 80:388–393CrossRefPubMedPubMedCentralGoogle Scholar
  4. Ali MS, Harmer M, Vaughan R (2000) Serum S100 protein as a marker of cerebral damage during cardiac surgery. Br J Anaesth 85(2):287–298CrossRefPubMedGoogle Scholar
  5. Benbadis SR, Sila CA, Cristea RL (1994) Mental status changes and stroke. J Gen Intern Med 9:485CrossRefPubMedGoogle Scholar
  6. Brydon L, Harrison NA, Walker C, Steptoe A, Critchley HD (2008) Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans. Biol Psychiatry 63(11):1022–1029CrossRefPubMedPubMedCentralGoogle Scholar
  7. Cerejeir J, Firmino H, Vaz-Serra A et al (2010) The neuroinflammatory hypothesis of delirium. Acta Neuropathol 119:737–754CrossRefGoogle Scholar
  8. Cerejeira J, Mukaetova-Ladinska EB (2011) A clinical update on delirium: from early recognition to effective management. Nurs Res Pract 875196:1–12Google Scholar
  9. Cerejeira J, Batista P, Nogueira V et al (2011) Low preoperative plasma cholinesterase activity as a risk marker of postoperative delirium in elderly patients. Age Ageing 40:621–626CrossRefPubMedGoogle Scholar
  10. Cerejeira J, Batista P, Nogueira V et al (2013) The stress response to surgery and postoperative delirium: evidence of hypothalamic-pituitary-adrenal axis hyperresponsiveness and decreased suppression of the GH/IGF-1 axis. J Geriatr Psychiatry Neurol 26(3):185–194CrossRefPubMedGoogle Scholar
  11. Cole M, McCusker J, Dendukuri N, Han L (2003) The prognostic significance of subsyndromal delirium in elderly medical inpatients. J Am Geriatr Soc 51(6):754–760CrossRefPubMedGoogle Scholar
  12. Dimitrijevic OB, Stamatovic SM, Keep RF et al (2006) Effects of the chemokine CCL2 on blood-brain barrier permeability during ischemia-reperfusion injury. J Cereb Blood Flow Metab 26(6):797–810CrossRefPubMedGoogle Scholar
  13. Gao F, Harris DN, Sapsed-Byrne S (1999) Time course of neuron-specific enolase and S-100 protein release during and after coronary artery bypass grafting. Br J Anaesth 82(2):266–267CrossRefPubMedGoogle Scholar
  14. Hofer S, Bopp C, Hoerner C et al (2008) Injury of the blood brain barrier and up-regulation of ICAM-1 in polymicrobial sepsis. J Surg Res 146:276–281CrossRefPubMedGoogle Scholar
  15. Hovorka J, Mainerova B, Prasko J et al (2012) Delirium. Act Nerv Super Rediviva 54(4):180–191Google Scholar
  16. Hshieh TT, Fong TG, Marcantonio ER, Inouye SK (2008) Cholinergic deficiency hypothesis in delirium: a synthesis of current evidence. J Gerontol A Biol Sci Med Sci 63(7):764–772CrossRefPubMedPubMedCentralGoogle Scholar
  17. Hubbard RE, O’Mahony MS, Woodhouse KW (2013) Medication prescribing in frail older people. Eur J Clin Pharmacol 69:319–326CrossRefPubMedGoogle Scholar
  18. Inouye SK (1998) Delirium in hospitalized older patients: recognition and risk factors. J Geriatr Psychiatry Neurol 11(3):118–125CrossRefPubMedGoogle Scholar
  19. Inouye SK, Westendorp RGJ, Saczynski JS (2014) Delirium in elderly people. Lancet 383:911–922CrossRefPubMedGoogle Scholar
  20. Isik AT (2009) Approach to elderly patient with altered mental status. “Emergencies in Geriatrics and Geriatric Psychiatry”. SomKitap, Istanbul, TURKEY, pp 23–44. ISBN:978-605-60355-1-7Google Scholar
  21. Isik AT (2014) Delirium in the Elderly. İzmir Guven Kitap, Izmir, Turkey. ISBN:978-605-60355Google Scholar
  22. de Jonghe A, Korevaar JC, van Munster BC et al (2010) Effectiveness of melatonin treatment on circadian rhythm disturbances in dementia. Are there implications for delirium? A systematic review. Rooij. Int J Geriatr Psychiatry 25:1201–1208CrossRefPubMedGoogle Scholar
  23. Krabbe KS, Reichenberg A, Yirmiya R, Smed A, Pedersen BK, Bruunsgaard H (2005) Low-dose endotoxemia and human neuropsychological functions. Brain Behav Immun 19(5):453–460CrossRefPubMedGoogle Scholar
  24. Krzyszton CP, Sparkman NL, Grant RW et al (2008) Exacerbated fatigue and motor deficits in interleukin-10-deficient mice after peripheral immune stimulation. Am J Physiol Regul Integr Comp Physiol 295(4):R1109–R1114CrossRefPubMedPubMedCentralGoogle Scholar
  25. Lauretani F, Ceda GP, Maggio M et al (2010) Capturing side-effect of medication to identify persons at risk of delirium. Aging Clin Exp Res 22(5–6):456–458CrossRefPubMedGoogle Scholar
  26. Lee JW, Lee YK, Yuk DY et al (2008) Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflamm 5:37CrossRefGoogle Scholar
  27. Mac Lullich AMJ, Beaglehole A, Hall RJ, Meagher DJ (2009) Delirium and long-term cognitive impairment. Int Rev Psychiatry 21(1):30–42CrossRefGoogle Scholar
  28. Maldonado JR (2008) Pathoetiological model of delirium: comprehensive understanding of the neurobiology of delirium and an evidence-based approach to prevention and treatment. Crit Care Clin 24:789–856CrossRefPubMedGoogle Scholar
  29. Malek-Ahmadi P, Hilsabeck RC (2007) Neuropsychiatric complications of interferons: classification, neurochemical bases, and management. Ann Clin Psychiatry 19(2):113–123CrossRefPubMedGoogle Scholar
  30. Marchi N, Cavaglia M, Fazio V, Bhudia S, Hallene K, Janigro D (2004) Peripheral markers of blood-brain barrier damage. Clin Chim Acta 342(1–2):1CrossRefPubMedGoogle Scholar
  31. Martins S, Fernandes L (2012) Delirium in elderly people: a review. Front Neurol 3:101CrossRefPubMedPubMedCentralGoogle Scholar
  32. Matto SK, Grover S, Gupta N (2010) Delirium in general practice. Indian J Med Res 131:387–398Google Scholar
  33. McAfoose J, Baune BT (2009) Evidence for a cytokine model of cognitive function. Neurosci Biobehav Rev 33(3):355–366CrossRefPubMedGoogle Scholar
  34. McCaffrey G, Willis CL, Staatz WD et al (2009) Occludin oligomeric assemblies at tight junctions of the blood-brain barrier are altered by hypoxia and reoxygenation stress. J Neurochem 110(1):58–71CrossRefPubMedPubMedCentralGoogle Scholar
  35. Misra S, Ganzini L (2003) Delirium, depression, and anxiety. Crit Care Clin 19(4):771–787CrossRefPubMedGoogle Scholar
  36. Mittal V, Muralee S, Williamson et al (2011) Delirium in the elderly: a comprehensive review. Am J Alzheimers Dis Other Demen 26(2) 97–109Google Scholar
  37. Mullington J, Korth C, Hermann DM et al (2000) Dose-dependent effects of endotoxin on human sleep. Am J Physiol Regul Integr Comp Physiol 278(4):R947–R955PubMedGoogle Scholar
  38. van Munster BC, Korevaar JC, Korse CM, Bonfrer JM, Zwinderman AH, de Rooij SE (2010) Serum S100B in elderly patients with and without delirium. Int J Geriatr Psychiatry 25(3):234–239CrossRefPubMedGoogle Scholar
  39. National Institute for Clinical Excellence (NICE) (2010) Delirium: diagnosis, prevention and management, vol 3. NICE Clinical Guideline, London, pp 1–29Google Scholar
  40. Nguyen DN, Spapen H, Su F et al (2006) Elevated serum levels of S-100beta protein and neuron-specific enolase are associated with brain injury in patients with severe sepsis and septic shock. Crit Care Med 34(7):1967–1974CrossRefPubMedGoogle Scholar
  41. Nishioku T, Dohgu S, Takata F et al (2009) 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 29(3):309–316CrossRefPubMedGoogle Scholar
  42. Noble F, Rubira E, Boulanouar M et al (2007) Acute systemic inflammation induces central mitochondrial damage and Mnesic deficit in adult Swiss mice. Neurosci Lett 424(2):106–110CrossRefPubMedGoogle Scholar
  43. O’Keeffe ST, Nı´ Chonchubhair A (1994) Postoperative delirium in the elderly. Br J Anaesth 73(5):673–687Google Scholar
  44. Oztas B, Akgül S, Arslan FB (2004) Influence of surgical pain stress on the blood-brain barrier permeability in rats. Life Sci 74(16):1973–1979CrossRefPubMedGoogle Scholar
  45. Ozturk L, Pelin Z, Karadeniz D et al (1999) Effects of 48 hours sleep deprivation on human immune profile. Sleep Res Online 2(4):107–111PubMedGoogle Scholar
  46. Qin L, Wu X, Block ML et al (2007) Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia 55(5):453–462CrossRefPubMedPubMedCentralGoogle Scholar
  47. Rachal Pugh C, Fleshner M, Watkins LR, Maier SF, Rudy JW (2001) The immune system and memory consolidation: a role for the cytokine IL-1beta. Neurosci Biobehav Rev 25(1):29–41CrossRefPubMedGoogle Scholar
  48. Reichenberg A, Yirmiya R, Schuld A et al (2001) Cytokine associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry 58(5):445–452CrossRefPubMedGoogle Scholar
  49. Richwine AF, Sparkman NL, Dilger RN, Buchanan JB, Johnson RW (2009) Cognitive deficits in interleukin-10-deficient mice after peripheral injection of lipopolysaccharide. Brain Behav Immun 23(6):794–802CrossRefPubMedPubMedCentralGoogle Scholar
  50. Semmler A, Okulla T, Sastre M, Dumitrescu-Ozimek L, Heneka M (2005) Systemic inflammation induces apoptosis with variable vulnerability of different brain regions. J Chem Neuroanat 30:144–157CrossRefPubMedGoogle Scholar
  51. Sharshar T, Gray F, Lorin de la Grandmaison G et al (2003) Apoptosis of neurons in cardiovascular autonomic centres triggered by inducible nitric oxide synthase after death from septic shock. Lancet 362(9398):1799–1805CrossRefPubMedGoogle Scholar
  52. Sharshar T, Carlier R, Bernard F et al (2007) Brain lesions in septic shock: a magnetic resonance imaging study. Intensive Care Med 33(5):798–806CrossRefPubMedGoogle Scholar
  53. Siami S, Annane D, Sharshar T (2008) The encephalopathy in sepsis. Crit Care Clin 24(1):67–82CrossRefPubMedGoogle Scholar
  54. Sparkman NL, Buchanan JB, Heyen JR, Chen J, Beverly JL, Johnson RW (2006) Interleukin-6 facilitates lipopolysaccharide-induced disruption in working memory and expression of other proinflammatory cytokines in hippocampal neuronal cell layers. J Neurosci 26(42):10709–10716CrossRefPubMedGoogle Scholar
  55. Spiegel K, Leproult R, Van Cauter E (1999) Impact of sleep debt on metabolic and endocrine function. Lancet 354(9188):1435–1439CrossRefPubMedGoogle Scholar
  56. Tanaka S, Ide M, Shibutani T et al (2006) Lipopolysaccharide-induced microglial activation induces learning and memory deficits without neuronal cell death in rats. J Neurosci Res 83(4):557–566CrossRefPubMedGoogle Scholar
  57. Terry AV, Buccafusco JJ (2003) The cholinergic hypothesis of age and Alzheimer’s disease-related cognitive deficits: recent challenges and their implications for novel drug development. J Pharmacol Exp Ther 306:821–827CrossRefPubMedGoogle Scholar
  58. Tizard I (2008) Sickness behavior, its mechanisms, significance. Anim Health Res Rev 9(1):87–99CrossRefPubMedGoogle Scholar
  59. Tracey KJ (2009) Reflex control of immunity. Nat Rev Immunol 9(6):418–428CrossRefPubMedPubMedCentralGoogle Scholar
  60. Trzepacz PT (1994) The neuropathogenesis of delirium: a need to focus our research. Psychosomatics 35:374CrossRefPubMedGoogle Scholar
  61. Uchikado H, Akiyama H, Kondo H et al (2004) Activation of vascular endothelial cells and perivascular cells by systemic inflammation-an immunohistochemical study of postmortem human brain tissues. Acta Neuropathol 107(4):341–351CrossRefPubMedGoogle Scholar
  62. Van Der Mast RC (1998) Pathophysiology of delirium. J Geriat Psychiatr Neurol 11:138–145CrossRefGoogle Scholar
  63. Van Munster BC, de Rooij SE, Korevaar JC (2009) The role of genetics in delirium in the elderly patient. Dement Geriatr Cogn Disord 28(3):187–195CrossRefPubMedGoogle Scholar
  64. Watt DF, Koziol K, Budding D (2012) Delirium and confusional states. In: Noggleand CA, Dean RS (eds) Disorders in neuropsychiatry. Springer, New YorkGoogle Scholar
  65. Weinberger DR (1993) A connectionist approach to the prefrontal cortex. J Neuropsychiatry Clin Neurosci 5(3):241–253CrossRefPubMedGoogle Scholar
  66. White S (2002) The neuropathogenesis of delirium. Rev Clin Gerontol 12:62–67CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Geriatric CenterKayseri Education and Training HospitalKayseriTurkey
  2. 2.Unit for Aging Brain and Dementia, Department of Geriatric Medicine, Faculty of MedicineDokuz Eylul UniversityIzmirTurkey

Personalised recommendations