Delirium pathophysiology: Difference between revisions
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{{Delirium}} | {{Delirium}} | ||
{{CMG}}; {{AE}} {{PB}}; [[User:Vishal Khurana|Vishal Khurana, MBBS, MD]] [mailto:vishdoc24@gmail.com] | {{CMG}}; {{AE}} {{Sara.Zand}} {{PB}}; [[User:Vishal Khurana|Vishal Khurana, MBBS, MD]] [mailto:vishdoc24@gmail.com] | ||
==Overview== | ==Overview== | ||
The exact [[pathophysiology]] of [[delirium]] is still being investigated. The roles of [[neurotransmitters]] like [[acetylcholine]] and [[dopamine]] seem to be important. It involves disrupted connectivity between [[cortical]] and [[subcortical]] areas of the [[brain]], especially areas concerned with [[sleep]] and [[awakening]]. The role of increased inflammatory [[cytokines]] has been shown in [[delirious ]] [[patients]]. | |||
==Pathophysiology== | ==Pathophysiology== | ||
* [[Acetylcholine]] has a crucial role in [[sleep]], [[attention]], [[arousal]], and [[memory]]. | * [[Acetylcholine]] has a crucial role in [[sleep]], [[attention]], [[arousal]], and [[memory]]. | ||
* [[Dopamine]] is involved in the regulation of [[acetylcholine]]. | * [[Dopamine]] is involved in the regulation of [[acetylcholine]]. | ||
* Reduced [[acetylcholine]] and [[histamine]] activity and increased [[dopamine]] and [[glutamate]] activity are observed in [[delirium]]. | * Reduced [[acetylcholine]] and [[histamine]] activity and increased [[dopamine]] and [[glutamate]] activity are observed in [[delirium]].<ref name="AdamHaas2020">{{cite journal|last1=Adam|first1=Elisabeth Hannah|last2=Haas|first2=Victoria|last3=Lindau|first3=Simone|last4=Zacharowski|first4=Kai|last5=Scheller|first5=Bertram|title=Cholinesterase alterations in delirium after cardiosurgery: a German monocentric prospective study|journal=BMJ Open|volume=10|issue=1|year=2020|pages=e031212|issn=2044-6055|doi=10.1136/bmjopen-2019-031212}}</ref> | ||
* Roles of [[GABA]] and [[serotonin]] are uncertain.<ref name="Markowitz-2008">{{Cite journal | last1 = Markowitz | first1 = JD. | last2 = Narasimhan | first2 = M. | title = Delirium and antipsychotics: a systematic review of epidemiology and somatic treatment options. | journal = Psychiatry (Edgmont) | volume = 5 | issue = 10 | pages = 29-36 | month = Oct | year = 2008 | doi = | PMID = 19724721 }}</ref> | * Roles of [[GABA]] and [[serotonin]] are uncertain.<ref name="Markowitz-2008">{{Cite journal | last1 = Markowitz | first1 = JD. | last2 = Narasimhan | first2 = M. | title = Delirium and antipsychotics: a systematic review of epidemiology and somatic treatment options. | journal = Psychiatry (Edgmont) | volume = 5 | issue = 10 | pages = 29-36 | month = Oct | year = 2008 | doi = | PMID = 19724721 }}</ref> | ||
* [[Anticholinergics]] are known to predispose to [[delirium]] and at the same time, anti dopaminergics are known to curtail [[delirium]]. | * [[Anticholinergics]] are known to predispose to [[delirium]] and at the same time, anti dopaminergics are known to curtail [[delirium]]. | ||
* [[Cortical]] and [[subcortical]] dysfunctions are behind the development of [[delirium]]. | * [[Cortical]] and [[subcortical]] dysfunctions are behind the development of [[delirium]]. | ||
* Disrupted connectivity is a key feature in [[delirium]] and it is observed in the following [[neuronal]] connections: | * Disrupted connectivity is a key feature in [[delirium]] and it is observed in the following [[neuronal]] connections: | ||
:* The [[dorsal]] lateral [[prefrontal cortex]] and the posterior cingulate cortex | :* The [[dorsal]] lateral [[prefrontal cortex]] and the posterior cingulate [[cortex]] | ||
:* Intralaminar [[thalamus]] from [[brainstem]] and [[midbrain]] | :* Intralaminar [[thalamus]] from [[brainstem]] and [[midbrain]] [[nuclei]] | ||
* [[Midbrain]] nucleus basalis is a source of [[cholinergic]] activation, whereas the [[midbrain]] ventral tegmental area is a source of [[dopaminergic]] innervation. | * [[Midbrain]] nucleus basalis is a source of [[cholinergic]] activation, whereas the [[midbrain]] ventral tegmental area is a source of [[dopaminergic]] innervation. | ||
* [[Mesencephalic]] tegmentum and the [[thalamus]] are linked to the early [[restoration]] of [[alertness]]. | * [[Mesencephalic]] tegmentum and the [[thalamus]] are linked to the early [[restoration]] of [[alertness]]. | ||
* [[Subcortical]] connections tend to recover sooner than the [[cortical]] connection | * [[Subcortical]] connections tend to recover sooner than the [[cortical]] connection.<ref name="Gaudreau-2012">{{Cite journal | last1 = Gaudreau | first1 = JD. | title = Insights into the neural mechanisms underlying delirium. | journal = Am J Psychiatry | volume = 169 | issue = 5 | pages = 450-1 | month = May | year = 2012 | doi = 10.1176/appi.ajp.2012.12020256 | PMID = 22549202 }}</ref> | ||
* [[Individuals]] with [[brain]] abnormalities like [[cortical]] atrophy, [[ventricular]] enlargement, and increased [[white matter]] lesions are more likely to develop [[delirium]].<ref name="Choi-2012">{{Cite journal | last1 = Choi | first1 = SH. | last2 = Lee | first2 = H. | last3 = Chung | first3 = TS. | last4 = Park | first4 = KM. | last5 = Jung | first5 = YC. | last6 = Kim | first6 = SI. | last7 = Kim | first7 = JJ. | title = Neural network functional connectivity during and after an episode of delirium. | journal = Am J Psychiatry | volume = 169 | issue = 5 | pages = 498-507 | month = May | year = 2012 | doi = 10.1176/appi.ajp.2012.11060976 | PMID = 22549209 }}</ref> | |||
* [[Anticholinergic]] drugs such as [[biperiden]] and [[scopolamine]] may have [[hypocholinergic]] [[delirium]]-like effects.<ref>{{cite journal|last=Hshieh|first=TT|coauthors=Fong, TG; Marcantonio, ER; Inouye, SK|title=Cholinergic deficiency hypothesis in delirium: a synthesis of current evidence.|journal=The journals of gerontology. Series A, Biological sciences and medical sciences|date=July 2008|volume=63|issue=7|pages=764–72|pmid=18693233|pmc=2917793}}</ref> | * [[Anticholinergic]] drugs such as [[biperiden]] and [[scopolamine]] may have [[hypocholinergic]] [[delirium]]-like effects.<ref>{{cite journal|last=Hshieh|first=TT|coauthors=Fong, TG; Marcantonio, ER; Inouye, SK|title=Cholinergic deficiency hypothesis in delirium: a synthesis of current evidence.|journal=The journals of gerontology. Series A, Biological sciences and medical sciences|date=July 2008|volume=63|issue=7|pages=764–72|pmid=18693233|pmc=2917793}}</ref> | ||
* Profound systemic [[inflammation]] occurring during [[bacteremia]] or [[sepsis]] may cause [[delirium ]] (often termed [[septic encephalopathy]]). | * Profound systemic [[inflammation]] occurring during [[bacteremia]] or [[sepsis]] may cause [[delirium ]] (often termed [[septic encephalopathy]]). | ||
* Study showed even mild systemic [[inflammation]], a frequent [[trigger]] for [[clinical]] [[delirium]], induces acute and transient [[attentional]] or working [[memory]] deficits, but only in [[animals]] with prior [[pathology]].<ref name ="Cunningham 2012">{{cite journal|last=Cunningham|first=C|coauthors=Maclullich, AM|title=At the extreme end of the psychoneuroimmunological spectrum: Delirium as a maladaptive sickness behaviour response.|journal=Brain, behavior, and immunity|date=Aug 3, 2012|pmid=22884900|doi=10.1016/j.bbi.2012.07.012|volume=28|pages=1–13}}</ref> | * Study showed even mild systemic [[inflammation]], a frequent [[trigger]] for [[clinical]] [[delirium]], induces acute and transient [[attentional]] or working [[memory]] deficits, but only in [[animals]] with prior [[pathology]].<ref name ="Cunningham 2012">{{cite journal|last=Cunningham|first=C|coauthors=Maclullich, AM|title=At the extreme end of the psychoneuroimmunological spectrum: Delirium as a maladaptive sickness behaviour response.|journal=Brain, behavior, and immunity|date=Aug 3, 2012|pmid=22884900|doi=10.1016/j.bbi.2012.07.012|volume=28|pages=1–13}}</ref> | ||
* Prior [[dementia]] or age-associated [[cognitive]] impairment is the primary [[predisposing]] factor for clinical [[delirium]]. | * Prior [[dementia]] or age-associated [[cognitive]] impairment is the primary [[predisposing]] factor for clinical [[delirium]]. | ||
====[[Cerebrospinal fluid]] biomarkers==== | ====[[Cerebrospinal fluid]] biomarkers==== | ||
* A few studies have exploited the opportunity to sample [[CSF]] from persons undergoing [[spinal anesthesia]] for elective or emergency [[surgery]].<ref>{{cite journal|last=Hall|first=RJ|coauthors=Shenkin, SD; Maclullich, AM|title=A systematic literature review of cerebrospinal fluid biomarkers in delirium.|journal=Dementia and geriatric cognitive disorders|year=2011|volume=32|issue=2|pages=79–93|pmid=21876357|doi=10.1159/000330757}}</ref> | * A few studies have exploited the opportunity to sample [[CSF]] from persons undergoing [[spinal anesthesia]] for elective or emergency [[surgery]].<ref>{{cite journal|last=Hall|first=RJ|coauthors=Shenkin, SD; Maclullich, AM|title=A systematic literature review of cerebrospinal fluid biomarkers in delirium.|journal=Dementia and geriatric cognitive disorders|year=2011|volume=32|issue=2|pages=79–93|pmid=21876357|doi=10.1159/000330757}}</ref> | ||
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====Neuroimaging==== | ====Neuroimaging==== | ||
* [[Delirium]] duration was related to measures of [[white matter]] tract integrity and this, in turn, was related to poorer [[cognitive]] outcomes at 3 and 12 months.<ref>{{cite journal|last=Soiza|first=RL|coauthors=Sharma, V; Ferguson, K; Shenkin, SD; Seymour, DG; Maclullich, AM|title=Neuroimaging studies of delirium: a systematic review.|journal=Journal of psychosomatic research|date=September 2008|volume=65|issue=3|pages=239–48|pmid=18707946|doi=10.1016/j.jpsychores.2008.05.021}}</ref> <ref>{{cite journal|last=Morandi|first=A|coauthors=Rogers, BP; Gunther, ML; Merkle, K; Pandharipande, P; Girard, TD; Jackson, JC; Thompson, J; Shintani, AK; Geevarghese, S; Miller RR, 3rd; Canonico, A; Cannistraci, CJ; Gore, JC; Ely, EW; Hopkins, RO; VISIONS Investigation, VISualizing Icu SurvivOrs Neuroradiological, Sequelae|title=The relationship between delirium duration, white matter integrity, and cognitive impairment in intensive care unit survivors as determined by diffusion tensor imaging: the VISIONS prospective cohort magnetic resonance imaging study*.|journal=Critical Care Medicine|date=July 2012|volume=40|issue=7|pages=2182–9|pmid=22584766|doi=10.1097/CCM.0b013e318250acdc}}</ref> | |||
* [[Brain]] volumes were also assessed and related to cognitive outcomes in the same manner. | |||
* Longer duration of [[delirium]] was associated with smaller [[brain]] volume and more [[white matter]] disruption, and both these correlated with worse [[cognitive]] scores 12 months later. | |||
*Study showed that [[white matter]] damage predicted post-operative [[delirium]].<ref>{{cite journal|last=Hatano|first=Y|coauthors=Narumoto, J; Shibata, K; Matsuoka, T; Taniguchi, S; Hata, Y; Yamada, K; Yaku, H; Fukui, K|title=White-Matter Hyperintensities Predict Delirium After Cardiac Surgery.|journal=The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry|date=Sep 21, 2012|pmid=23000936|doi=10.1097/JGP.0b013e31826d6b10}}</ref><ref>{{cite journal|last=Shioiri|first=A|coauthors=Kurumaji, A; Takeuchi, T; Matsuda, H; Arai, H; Nishikawa, T|title=White matter abnormalities as a risk factor for postoperative delirium revealed by diffusion tensor imaging.|journal=The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry|date=August 2010|volume=18|issue=8|pages=743–53|pmid=20220599|doi=10.1097/JGP.0b013e3181d145c5}}</ref> | |||
* One [[functional MRI]] study reported a reversible reduction in activity in [[brain]] areas localizing with [[cognition]] and [[attention ]] function.<ref name="pmid31067980">{{cite journal |vauthors=Kalvas LB, Monroe TB |title=Structural Brain Changes in Delirium: An Integrative Review |journal=Biol Res Nurs |volume=21 |issue=4 |pages=355–365 |date=July 2019 |pmid=31067980 |pmc=6794667 |doi=10.1177/1099800419849489 |url=}}</ref><ref>{{cite journal|last=Choi|first=SH|coauthors=Lee, H; Chung, TS; Park, KM; Jung, YC; Kim, SI; Kim, JJ|title=Neural network functional connectivity during and after an episode of delirium.|journal=The American Journal of Psychiatry|date=May 2012|volume=169|issue=5|pages=498–507|pmid=22549209|doi=10.1176/appi.ajp.2012.11060976}}</ref> | |||
[[ | |||
====[[Neuropathology]]==== | |||
* Finding of Autopsy of [[ICU]] admitted patients in a study showed evidence of [[acute respiratory distress syndrome]], [[septic shock]], [[hypoperfusion]] and diffuse [[vascular]] injury, with consistent involvement of the [[hippocampus]].<ref>{{cite journal|last=Janz|first=DR|coauthors=Abel, TW; Jackson, JC; Gunther, ML; Heckers, S; Ely, EW|title=Brain autopsy findings in intensive care unit patients previously suffering from delirium: a pilot study.|journal=Journal of critical care|date=September 2010|volume=25|issue=3|pages=538.e7-12|pmid=20580199|doi=10.1016/j.jcrc.2010.05.004}}</ref> | |||
*The role of [[inflammatory]] [[cytokine]] has been shown in [[delerious]] [[patients]].<ref>{{cite journal|last=Munster|first=BC|coauthors=Aronica, E; Zwinderman, AH; Eikelenboom, P; Cunningham, C; Rooij, SE|title=Neuroinflammation in delirium: a postmortem case-control study.|journal=Rejuvenation research|date=December 2011|volume=14|issue=6|pages=615–22|pmid=21978081|doi=10.1089/rej.2011.1185}}</ref> | |||
* Persons with [[delirium]] had higher scores for [[HLA-DR]] and [[CD68]] (markers of [[microglial activation]]), [[IL-6]] (cytokines pro-[[inflammatory]] and anti-[[inflammatory]] activities) and GFAP (marker of [[astrocyte]] activity). | |||
==References== | ==References== | ||
Latest revision as of 11:30, 22 April 2021
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Zand, M.D.[2] Pratik Bahekar, MBBS [3]; Vishal Khurana, MBBS, MD [4]
Overview
The exact pathophysiology of delirium is still being investigated. The roles of neurotransmitters like acetylcholine and dopamine seem to be important. It involves disrupted connectivity between cortical and subcortical areas of the brain, especially areas concerned with sleep and awakening. The role of increased inflammatory cytokines has been shown in delirious patients.
Pathophysiology
- Acetylcholine has a crucial role in sleep, attention, arousal, and memory.
- Dopamine is involved in the regulation of acetylcholine.
- Reduced acetylcholine and histamine activity and increased dopamine and glutamate activity are observed in delirium.[1]
- Roles of GABA and serotonin are uncertain.[2]
- Anticholinergics are known to predispose to delirium and at the same time, anti dopaminergics are known to curtail delirium.
- Cortical and subcortical dysfunctions are behind the development of delirium.
- Disrupted connectivity is a key feature in delirium and it is observed in the following neuronal connections:
- Midbrain nucleus basalis is a source of cholinergic activation, whereas the midbrain ventral tegmental area is a source of dopaminergic innervation.
- Mesencephalic tegmentum and the thalamus are linked to the early restoration of alertness.
- Subcortical connections tend to recover sooner than the cortical connection.[3]
- Individuals with brain abnormalities like cortical atrophy, ventricular enlargement, and increased white matter lesions are more likely to develop delirium.[4]
- Anticholinergic drugs such as biperiden and scopolamine may have hypocholinergic delirium-like effects.[5]
- Profound systemic inflammation occurring during bacteremia or sepsis may cause delirium (often termed septic encephalopathy).
- Study showed even mild systemic inflammation, a frequent trigger for clinical delirium, induces acute and transient attentional or working memory deficits, but only in animals with prior pathology.[6]
- Prior dementia or age-associated cognitive impairment is the primary predisposing factor for clinical delirium.
Cerebrospinal fluid biomarkers
- A few studies have exploited the opportunity to sample CSF from persons undergoing spinal anesthesia for elective or emergency surgery.[7]
- Delirium may be associated with increased serotoninergic and dopamine signaling, decreased somatostatin, increased cortisol, increase in some inflammatory cytokines (IL-8), but not others (TNF-α, IL-1β).
- Postoperative delirium was strongly associated with pre-operative cognitive decline.[8]
- However, CSF Aβ1-42, tau, and phosphorylated tau levels were not associated with delirium status, nor did they correlate significantly with cognitive function
Neuroimaging
- Delirium duration was related to measures of white matter tract integrity and this, in turn, was related to poorer cognitive outcomes at 3 and 12 months.[9] [10]
- Brain volumes were also assessed and related to cognitive outcomes in the same manner.
- Longer duration of delirium was associated with smaller brain volume and more white matter disruption, and both these correlated with worse cognitive scores 12 months later.
- Study showed that white matter damage predicted post-operative delirium.[11][12]
- One functional MRI study reported a reversible reduction in activity in brain areas localizing with cognition and attention function.[13][14]
Neuropathology
- Finding of Autopsy of ICU admitted patients in a study showed evidence of acute respiratory distress syndrome, septic shock, hypoperfusion and diffuse vascular injury, with consistent involvement of the hippocampus.[15]
- The role of inflammatory cytokine has been shown in delerious patients.[16]
- Persons with delirium had higher scores for HLA-DR and CD68 (markers of microglial activation), IL-6 (cytokines pro-inflammatory and anti-inflammatory activities) and GFAP (marker of astrocyte activity).
References
- ↑ Adam, Elisabeth Hannah; Haas, Victoria; Lindau, Simone; Zacharowski, Kai; Scheller, Bertram (2020). "Cholinesterase alterations in delirium after cardiosurgery: a German monocentric prospective study". BMJ Open. 10 (1): e031212. doi:10.1136/bmjopen-2019-031212. ISSN 2044-6055.
- ↑ Markowitz, JD.; Narasimhan, M. (2008). "Delirium and antipsychotics: a systematic review of epidemiology and somatic treatment options". Psychiatry (Edgmont). 5 (10): 29–36. PMID 19724721. Unknown parameter
|month=ignored (help) - ↑ Gaudreau, JD. (2012). "Insights into the neural mechanisms underlying delirium". Am J Psychiatry. 169 (5): 450–1. doi:10.1176/appi.ajp.2012.12020256. PMID 22549202. Unknown parameter
|month=ignored (help) - ↑ Choi, SH.; Lee, H.; Chung, TS.; Park, KM.; Jung, YC.; Kim, SI.; Kim, JJ. (2012). "Neural network functional connectivity during and after an episode of delirium". Am J Psychiatry. 169 (5): 498–507. doi:10.1176/appi.ajp.2012.11060976. PMID 22549209. Unknown parameter
|month=ignored (help) - ↑ Hshieh, TT (July 2008). "Cholinergic deficiency hypothesis in delirium: a synthesis of current evidence". The journals of gerontology. Series A, Biological sciences and medical sciences. 63 (7): 764–72. PMC 2917793. PMID 18693233. Unknown parameter
|coauthors=ignored (help) - ↑ Cunningham, C (Aug 3, 2012). "At the extreme end of the psychoneuroimmunological spectrum: Delirium as a maladaptive sickness behaviour response". Brain, behavior, and immunity. 28: 1–13. doi:10.1016/j.bbi.2012.07.012. PMID 22884900. Unknown parameter
|coauthors=ignored (help) - ↑ Hall, RJ (2011). "A systematic literature review of cerebrospinal fluid biomarkers in delirium". Dementia and geriatric cognitive disorders. 32 (2): 79–93. doi:10.1159/000330757. PMID 21876357. Unknown parameter
|coauthors=ignored (help) - ↑ Witlox, J (July 2011). "Cerebrospinal fluid β-amyloid and tau are not associated with risk of delirium: a prospective cohort study in older adults with hip fracture". Journal of the American Geriatrics Society. 59 (7): 1260–7. doi:10.1111/j.1532-5415.2011.03482.x. PMID 21718268. Unknown parameter
|coauthors=ignored (help) - ↑ Soiza, RL (September 2008). "Neuroimaging studies of delirium: a systematic review". Journal of psychosomatic research. 65 (3): 239–48. doi:10.1016/j.jpsychores.2008.05.021. PMID 18707946. Unknown parameter
|coauthors=ignored (help) - ↑ Morandi, A (July 2012). "The relationship between delirium duration, white matter integrity, and cognitive impairment in intensive care unit survivors as determined by diffusion tensor imaging: the VISIONS prospective cohort magnetic resonance imaging study*". Critical Care Medicine. 40 (7): 2182–9. doi:10.1097/CCM.0b013e318250acdc. PMID 22584766. Unknown parameter
|coauthors=ignored (help) - ↑ Hatano, Y (Sep 21, 2012). "White-Matter Hyperintensities Predict Delirium After Cardiac Surgery". The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. doi:10.1097/JGP.0b013e31826d6b10. PMID 23000936. Unknown parameter
|coauthors=ignored (help) - ↑ Shioiri, A (August 2010). "White matter abnormalities as a risk factor for postoperative delirium revealed by diffusion tensor imaging". The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. 18 (8): 743–53. doi:10.1097/JGP.0b013e3181d145c5. PMID 20220599. Unknown parameter
|coauthors=ignored (help) - ↑ Kalvas LB, Monroe TB (July 2019). "Structural Brain Changes in Delirium: An Integrative Review". Biol Res Nurs. 21 (4): 355–365. doi:10.1177/1099800419849489. PMC 6794667 Check
|pmc=value (help). PMID 31067980. - ↑ Choi, SH (May 2012). "Neural network functional connectivity during and after an episode of delirium". The American Journal of Psychiatry. 169 (5): 498–507. doi:10.1176/appi.ajp.2012.11060976. PMID 22549209. Unknown parameter
|coauthors=ignored (help) - ↑ Janz, DR (September 2010). "Brain autopsy findings in intensive care unit patients previously suffering from delirium: a pilot study". Journal of critical care. 25 (3): 538.e7–12. doi:10.1016/j.jcrc.2010.05.004. PMID 20580199. Unknown parameter
|coauthors=ignored (help) - ↑ Munster, BC (December 2011). "Neuroinflammation in delirium: a postmortem case-control study". Rejuvenation research. 14 (6): 615–22. doi:10.1089/rej.2011.1185. PMID 21978081. Unknown parameter
|coauthors=ignored (help)