Abstract
Background: Cerebrospinal fluid (CSF) analysis has great potential to advance understanding of delirium pathophysiology. Methods: A systematic literature review of CSF studies of DSM or ICD delirium was performed. Results: In 8 studies of 235 patients, delirium was associated with: elevated serotonin metabolites, interleukin-8, cortisol, lactate and protein, and reduced somatostatin, β-endorphin and neuron-specific enolase. Elevated acetylcholinesterase predicted poor outcome after delirium and higher dopamine metabolites were associated with psychotic features. Conclusions: No clear conclusions emerged, but the current literature suggests multiple areas for further investigation with more detailed studies.
References
1.
Siddiqi N, House A, Holmes J: Occurrence and outcome of delirium in medical in-patients: a systematic literature review. Age Ageing 2006;35:350–364.
2.
MacLullich A, Ferguson K, Miller T, de Rooij S, Cunningham C: Unravelling the pathophysiology of delirium: a focus on the role of aberrant stress responses. J Psychosom Res 2008;65:229–238.
3.
Young J, Inouye S: Delirium in older people. BMJ 2008;334:842–846.
4.
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, Text Revision. Washington, APA, 2000.
5.
Rockwood K, Cosway S, Carver D, Jarrett P, Stadnyk K, Fisk J: The risk of dementia and death after delirium. Age Ageing 1999;28:551–556.
6.
MacLullich A, Beaglehole A, Hall R, Meagher D: Delirium and long-term cognitive impairment. Int Rev Psychiatry 2009;21: 30–42.
7.
Flacker J, Lipsitz L: Neural mechanisms of delirium: current hypotheses and evolving concepts. J Gerontol 1999;54A:B239–B246.
8.
Olsson T: Activity in the hypothalamic-pituitary-adrenal axis and delirium. Dement Geriatr Cogn Dis 1999;10:345–349.
9.
Stroup D, Berlin J, Morton S, Olkin I, Williamson G, Rennie D, Moher D, Becker B, Sipe T, Thacker S: Meta-analysis of observational studies in epidemiology – a proposal for reporting. J Am Med Assoc 2000;283:2008–2012.
10.
The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva, World Health Organisation, 1992.
11.
Inouye S, Vandyck C, Alessi C, Balkin S, Siegal A, Horowitz R: Clarifying confusion – the confusion assessment method – a new method for detection of delirium. Ann Intern Med 1990;113:941–948.
12.
Sanderson S, Tatt I, Higgins J: Tools for assessing quality and susceptibility to bias in observational studies in epidemiology: a systematic review and annotated bibliography. Int J Epidemiol 2007;36:666–676.
13.
MacLullich A, Edelshain B, Hall R, de Vries A, Howie S, Pearson A, Middleton S, Gillies F, Armstrong I, White T, Cunningham C, de Rooij S, van Munster B: Cerebrospinal IL-8 levels are higher in hip fracture patients with delirium versus controls. J Am Geriatr Soc 2011;59:1151–1153.
14.
Tanaka K, Mitsushio H, Isse K: A clinical study of prostaglandin D2 in cerebrospinal fluid of elderly patients with delirium. Ann Rep Pharmacopsychiat Res Found 1993;24:14–21.
15.
Tanaka K: Increased levels of prostaglandin D2 in cerebrospinal fluid of elderly patients with delirium. Jpn J Psychiatry Neurol 1993;47:695–696.
16.
Koponen H, Lepola U, Leinonen E: A long-term follow-up study of cerebrospinal fluid 5-hydroxyindoleacetic acid in delirium. Eur Arch Psychiatry Clin Neurosci 1994;244:131–134.
17.
Koponen H, Sirvio J, Reinikainen K, Riekkinen P: A longitudinal study of cerebrospinal fluid acetylcholinesterase in delirium: changes at the acute stage and at one-year follow-up. Psychiatry Res 1991;38:135–142.
18.
Koponen H, Riekkinen P: A long-term follow-up study of cerebrospinal fluid beta-endorphin-like immunoreactivity in delirium: changes at the acute stage and at one-year follow-up. Acta Psychiatr Scand 1990;82:323–326.
19.
Koponen H, Stenback U, Mattila E, Reinikainen K, Soininen H, Riekkinen P: CSF beta-endorphin-like immunoreactivity in delirium. Biol Psychiatry 1989;25:938–944.
20.
Koponen H, Stenback U, Mattila E, Reinikainen K, Soininen H, Riekkinen P: Cerebrospinal fluid somatostatin in delirium. Psychol Med 1989;19:605–609.
21.
Koponen H, Reinikainen K, Riekkinen P: Cerebrospinal fluid somatostatin in delirium. II. Changes at the acute stage and at one year follow-up. Psychol Med 1990;20:501–505.
22.
Koponen H, Leinonen E, Lepola U, Riekkinen P: A long-term follow-up study of cerebrospinal fluid somatostatin in delirium. Acta Psychiatr Scand 1994;89:329–334.
23.
Koponen H, Sirvio J, Lepola U, Leinonen E: A long-term follow-up study of cerebrospinal fluid acetylcholinesterase in delirium. Eur Arch Psychiatry Clin Neurosci 1994;243:347–351.
24.
Ramirez-Bermudez J, Ruiz-Chow A, Perez-Neri I, Soto-Hernandez J, Flores-Hernandez R, Nente F, Montes S, Rios C: Cerebrospinal fluid homovanillic acid is correlated to psychotic features in neurological patients with delirium. Gen Hosp Psychiatry 2008;30:337–343.
25.
Pearson A, de Vries A, Middleton S, Gillies F, White T, Armstrong I, Andre R, Seckl J, MacLullich A: Cerebrospinal fluid cortisol levels are higher in patients with delirium versus controls. BMC Res Notes 2010;3:33.
26.
Caplan G, Kvelde T, Lai C, Yap S, Lin C, Hill M: Cerebrospinal fluid in long-lasting delirium compared with Alzheimer’s dementia. J Gerontol A Biol Med Sci 2010;65:1130–1136.
27.
Secin R, Esponda J, Rivera B: Validacion del Delirium Rating Scale (DRS) en espanol en una unidad de cuidados intensivos. Psiquis 1998;7:7–14.
28.
Trzepacz P, Baker R, Greenhouse J: A symptom rating scale for delirium. Psychiatry Res 1988;23:89–97.
29.
Ramirez-Bermudez J, Camilo R, Perez-Neri I, Sergio M, Francisco N, Chow A: Neurochemical markers of delirium in cerebrospinal fluid of neurological patients with delirium. 26th Collegium Internationale Neuro-Psychopharmacologicum Congress (CINP), Int J Neuropsychopharmacol 2008;11:296–296.
30.
Kudoh A, Takese H, Katagai H, Takazawi T: Postoperative interleukin-6 and cortisol concentrations in elderly patients with postoperative confusion. Neuroimmunomodulation 2005;12:60–66.
31.
McIntosh T, Bush H, Yeston N, Grasberger R, Palter M, Aun F, Egdahl R: Beta-endorphin. Cortisol and postoperative delirium: a preliminary report. Psychoneuroendocrinology 1985;10:303–313.
32.
Seehusen D, Reeves M, Fomin D: Cerebrospinal fluid analysis. Am Fam Physician 2003;68:1103–1108.
33.
von Elm I: Assessing the quality of observational studies – or a lesson from Mars. Int J Epidemiol 2007;36:677–678.
34.
Inouye S, Ferrucci L: Elucidating the pathophysiology of delirium and the interrelationship of delirium and dementia. J Gerontol Med Sci 2006;61A:1277–1280.
35.
Murakami K, Nakagawa T, Shozu M, Uchide K, Koike K, Inoue M: Changes with aging of steriodal levels in the cerebrospinal fluid of women. Maturitas 1999;33:71–80.
36.
Otte C, Hart S, Neylan T, Marmar C, Yaffe K, Mohr D: A meta-analysis of cortisol response to challenge in human aging: importance of gender. Psychoneuroendocrinology 2005;30:80–91.
37.
Ginaldi L, Mengoli L, De Martinis M: Review on immunosenescence. Rev Clin Gerontol 2008;17:161–169.
38.
Ballabh P, Braun A, Nedergaard M: The blood-brain barrier: an overview. Structure, regulation, and clinical implications. Neurobiol Dis 2004;16:1–13.
39.
Davies D: Blood-brain barrier breakdown in septic encephalopathy and brain tumours. J Anat 2002;200:639–646.
40.
Petzold A: CSF biomarkers for improved prognostic accuracy in acute CNS disease. Neurol Res 2007;29:691–708.
41.
Karkela J, Pasanen M, Kaukinen S, Morsky P, Harmoinen A: Evaluation of hypoxic brain injury with spinal fluid enzymes, lactate and pyruvate. Crit Care Med 1992;20:378–386.
42.
Parnetti L, Reboldi G, Gallai V: Cerebrospinal fluid pyruvate levels in Alzheimer’s disease and vascular dementia. Neurology 2000;54:735–737.
43.
Fillenz M: The role of lactate in brain metabolism. Neurochem Int 2005;47:413–417.
44.
White S: The neuropathogenesis of delirium. Rev Clin Gerontol 2002;12:62–67.
45.
van der Mast R, Fekkes D, Moleman P, Pepplinkhuizen L: Is postoperative delirium related to reduced plasma tryptophan? Lancet 1991;338:851–852.
46.
Pandharipande P, Morandi A, Adams J, Girard T, Thompson J, Shintani A, Ely E: Plasma tryptophan and tyrosine levels are independent risk factors for delirium in critically ill patients Intensive Care Med 2009;35:1886–1892.
47.
Trzepacz P: Is there a final common neural pathway in delirium? Focus on acetylcholine and dopamine. Semin Clin Neuropsychiatry 2000;5:132–148.
48.
Talesa V: Acetylcholinesterase in Alzheimer’s disease. Mech Ageing Dev 2001;122:1961–1969.
49.
Birks J: Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Systemat Rev 2006;CD005593.
50.
White S, Calver B, Newsway V, Wade R, Patel S, Bayer A, O’Mahoney M: Enzymes of drug metabolism during delirium. Age Ageing 2005;34:603–608.
51.
Vecsai L, Widerlov E: Preclinical and clinical studies with somatostatin related to the central nervous system. Prog Neuropsychopharmacol Biol Psychiat 1990;14:473–502.
52.
Murray R, Kim K, Ren S-G, Chelly M, Umehara Y, Melmed S: Central and peripheral actions of somatostatin on the growth hormone-IGF-1 axis. J Clin Investigat 2004;114:349–356.
53.
Broadhurst C, Wilson K: Immunology of delirium: new opportunities for treatment and research. Br J Psychiatry 2001;179.
54.
Adamis D, Lunn M, Martin FC, Treloar A, Gregson N, Hamilton G, MacDonald AJD: Cytokines and IGF-1 in delirious and non-delirious acutely ill older medical inpatients. Age Ageing 2009;38:326–332.
55.
Wilson K, Broadhurst C, Diver M, Jackson M, Mottram P: Plasma insulin-like growth factor-1 and incident delirium. Int J Geriatr Psychiatry 2005;20:154–159.
56.
Wollemann M, Benyhe S: Non-opioid actions of the opioid peptides. Life Sci 2004;75:257–270.
57.
O’Donahue T, Dorsa D: The opiomelanotropinergic neuronal and endocrine systems. Peptides 1982;3:353–395.
58.
Zager E, Black P: Neuropeptides in human memory and learning processes. Neurosurgery 1985;17:355–369.
59.
Jolkkonen J, Soininen H, Riekkinen P: Beta-endorphin-like immunoreactivity in cerebrospinal fluid of patients with Alzheimer’s dementia and Parkinson’s disease. J Neurol Sci 1987;77:153–159.
60.
Sulkava R, Erkinjuntti T, Laatikainen T: CSF beta-endorphin and beta-lipotropin in Alzheimer’s disease and multi-infarct dementia. Neurology 1985;35:1057–1058.
61.
Raskind M, Peskind E, Lampe T, Risse S, Taborsky G, Dorsa D: Cerebrospinal fluid vasopressin, oxytocin, somatostatin and beta-endorphin in Alzheimer’s disease. Arch Gen Psychiatry 1986;43:382–388.
62.
Munhoz C, Sorrells S, Caso J, Scavone C, Sapolsky R: Glucocorticoids exacerbate lipopolysaccharide-induced signaling in the frontal cortex and hippocampus in a dose-dependent manner. J Neurosci 2010;30:13690–13698.
63.
Perry V, Cunningham C, Holmes C: Systemic infections and inflammation affect chronic neurodegeneration. Nat Rev Immunol 2007;7:161–167.
64.
Puma C, Danik M, Quirion R, Ramon F, Williams S: The chemokine interleukin- 8 acutely reduces CA2+ currents in identified cholinergic septal neurons expressing CXCR1 and CXCR2 receptor mRNAs. J Neurochem 2001;78:960–971.
65.
Platasalaman C, Borkoski J: Interleukin-8 modulates feeding by direct action in the central nervous system. Am J Physiol 1993;265:R877–R882.
66.
Hussein M, Daoud G, Kakita H, Kato S, Goto T, Kamei M, Goto K, Nobata M, Ozaki Y, Ito T, Fukuda S, Kato I, Suzuki S, Sobajima HF, Hashimoto T, Togari H: High cerebrospinal fluid antioxidants and interleukin 8 are protective of hypoxic brain damage in newborns. Free Rad Res 2010;44:422–429.
67.
Hanson J, Bostick M, Campe C, Kodali P, Lee G, Yan J, Maher J: Transgenic overexpression of interleukin-8 in mouse liver protects against galactosamine/endotoxin toxicity. J Hepatol 2006;44:359–367.
68.
Holt R, Siddiqi N, Young J: The ethics of consent in delirium studies. J Psychosom Res 2008;65:283–287.
69.
Zetterberg H: Biomarkers reflecting different facets of Alzheimer’s dementia. Eur J Neurol 2008;15:1143–1144.
70.
Schwarz E, Bahn S: Cerebrospinal fluid: identification of diagnostic markers for schizophrenia. Expert Rev Mol Diagn 2008;8:209–216.
71.
Gudmundsson P, Skoog I, Waern M, Blennow K, Zetterberg H, Rosengren L, Gustafson D: Is there a CSF biomarker profile related to depression in elderly women? Psychiatry Res 2010;176:174–178.
72.
Regenold W, Phatak P, Marano C, Sassan A, Conley R, Kling M: Elevated cerebrospinal fluid lactate concentrations in patients with bipolar disorder and schizophrenia: implications for the mitochondrial dysfunction hypothesis. Biol Psychiatry 2009;65:489–494.
73.
Awad A, Hemmer B, Hartung H-P, Kieseier B, Bennett J, Stuve O: Analyses of cerebrospinal fluid in the diagnosis and monitoring of multiple sclerosis. J Neuroimmunol 2010;219:1–7.
74.
van Everbroeck B, Boons J, Cras P: Cerebrospinal fluid biomarkers in Creutzfeldt-Jakob disease. Clin Neurol Neurosurg 2005;107:355–360.
75.
Hyland K: Clinical utility of monoamine neurotransmitter metabolite analysis in cerebrospinal fluid. Clin Chem 2008;54:633–641.
76.
Frolich L, Dirr A, Gotz M, Gsell W, Reichmann H, Riederer P, Maurer K: Acetylcholine in human CSF: methodological considerations and levels in dementia of the Alzheimer type. J Neural Transm 1998;105:961–973.
77.
Bender M: Kinetics of cholinesterase in blood and spinal fluid. Am J Physiol 1939;126:180–187.
© 2011 S. Karger AG, Basel
2011
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.