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==
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 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]]. Dopamine is involved in the regulation of acetylcholine.  Reduced [[acetylcholine]] and [[histamine]] activity, increased [[dopamine]] and [[glutamate]] activity are observed in delirium.  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.  Cortical and subcortical dysfunctions are behind the development of the delirium.  Disrupted connectivity is a key feature in delirium and it is observed in the following neuronal connections.
* [[Acetylcholine]] has a crucial role in [[sleep]], [[attention]], [[arousal]], and [[memory]].
 
* [[Dopamine]] is involved in the regulation of [[acetylcholine]].   
* The dorsal lateral prefrontal cortex and the posterior cingulate cortex.
* 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>
* Intralaminar thalamus from brainstem and midbrain nuclei.
* 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>  
* Mesencephalic  tegmentum, relaying brainstem reticular activation, the midbrain nucleus basalis, and the midbrain ventral tegmental area.  Midbrain nucleus basalis is a source of cholinergic activation, whereas midbrain ventral tegmental area is a source of dopaminergic innervation. Mesencephalic tegmentum and the [[thalamus]] is linked to the early restoration of alertness.
* [[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]].  
Subcortical connections tend to recover sooner than the cortical connections.  This may be due to the temporary pharmacological influence of the [[anticholinergic]] used in anesthesia and the antidopaminergic drugs administered to obtain behavioral control.<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>
* 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]]
===Animal models===
:* Intralaminar [[thalamus]] from [[brainstem]] and [[midbrain]] [[nuclei]]
The pathophysiology of delirium is not well understood and a lack of animal models that are relevant to the syndrome has left many key questions in delirium pathophysiology unanswered.  Earliest rodent models of delirium used an antagonist of the muscarinic acetylcholine receptors, [[atropine]], to induce cognitive and [[EEG]] changes similar to delirium.  Similar [[anticholinergic]] drugs such as biperiden and scopolamine have also produced delirium-like effects. These models, along with clinical studies of drugs with [[anticholinergic]] activity have contributed to a hypocholinergic theory of delirium.<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>
* [[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]].
Profound systemic inflammation occurring during bacteraemia or sepsis is also known to cause delirium (often termed septic encephalopathy). Modeling this in mice also causes robust brain dysfunction and probably a delirium-like state, although these animals are typically too sick to assess cognitively and measures such as [[EEG]] and magnetic resonance imaging or spectroscopy are necessary to demonstrate dysfunction.
* [[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>
Animal models that interrogate interactions between prior degenerative pathology and superimposed systemic inflammation have been developed more recently and these demonstrate that 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 and prior pathology as defined by these new animal models may consist of synaptic loss, network disconnectivity, and primed [[microglia]] (brain macrophages that are primed by the primary pathology to produce exaggerated responses to subsequent inflammatory insults).
* [[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]]).
While it is difficult to state with confidence whether delirium is occurring in a non-verbal animal, comparisons with human DSM-IV criteria remain useful.  According to DSM-IV, demonstration of acute onset impairments in attention and some other cognitive domain, that cannot be better explained by existing dementia and that are triggered by physiological disturbances resulting from some general medical condition should be present in order to reach a diagnosis of delirium.  Recent animal models fulfill these criteria reasonably well.<ref name ="Cunningham 2012"/> Whether the deficit is one of attention or short-term memory is difficult to dissect, but it is undeniably distinct from long-term memory, consistent with observations in patients with delirium. There is an urgent need to understand more about the mechanisms of dysfunction underpinning delirium and data arising from these and other animal models must form part of the discussion on delirium pathophysiology.
* 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]].
===Clinical studies===
====[[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>  
Studies of cerebrospinal fluid ([[CSF]]) in delirium are difficult to perform.  Apart from the general difficulty of recruiting participants who are often unable to give consent, the inherently invasive nature of CSF sampling makes such research particularly challenging.  However, a few studies have exploited the opportunity to sample [[CSF]] from persons undergoing spinal anesthesia for elective or emergency surgery.  Indeed, spinal anesthesia may in fact be the anaesthetic modality of choice for frail older patients, so these studies are often undertaken in highly relevant populations.
*[[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.<ref>{{cite journal|last=Witlox|first=J|coauthors=Kalisvaart, KJ; de Jonghe, JF; Verwey, NA; van Stijn, MF; Houdijk, AP; Traast, HS; MacLullich, AM; van Gool, WA; Eikelenboom, P|title=Cerebrospinal fluid β-amyloid and tau are not associated with risk of delirium: a prospective cohort study in older adults with hip fracture.|journal=Journal of the American Geriatrics Society|date=July 2011|volume=59|issue=7|pages=1260–7|pmid=21718268|doi=10.1111/j.1532-5415.2011.03482.x}}</ref>  
A systematic review identified 8 studies involving 235 patients (142 with delirium).<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> Overall, 17 different biomarkers were considered and each article identified in the review focused on a narrow range of biomarkers with no overlap between studies.  Studies were generally small, studying heterogeneous populations with different times of [[CSF]] sampling in relation to delirium, and no clear conclusions could be drawn.  Broadly, delirium may be associated with increased serotoninergic and dopamine signalling; reversible fall in [[somatostatin]]; increased [[cortisol]]; and increase in some inflammatory cytokines ([[IL-8]]), but not others ([[TNF-α]], IL-1β).
*However, [[CSF]] Aβ1-42, tau, and [[phosphorylated tau]] levels were not associated with [[delirium]] status, nor did they correlate significantly with [[cognitive]] function
 
One additional study has since been published.<ref>{{cite journal|last=Witlox|first=J|coauthors=Kalisvaart, KJ; de Jonghe, JF; Verwey, NA; van Stijn, MF; Houdijk, AP; Traast, HS; MacLullich, AM; van Gool, WA; Eikelenboom, P|title=Cerebrospinal fluid β-amyloid and tau are not associated with risk of delirium: a prospective cohort study in older adults with hip fracture.|journal=Journal of the American Geriatrics Society|date=July 2011|volume=59|issue=7|pages=1260–7|pmid=21718268|doi=10.1111/j.1532-5415.2011.03482.x}}</ref> Postoperative delirium was strongly associated with pre-operative cognitive decline.  However, [[CSF]] Aβ1-42, tau, and phosphorylated-tau levels were not associated with delirium status, nor did they correlate significantly with cognitive function before the onset of delirium.  The two main explanations for these findings are either that the study was underpowered to detect mediating pathways between premorbid cognitive impairment, [[Alzheimer’s]] pathology biomarkers and subsequent delirium, or that the postoperative delirium arises through pathophysiological pathways that are distinct from [[Alzheimer's disease]].


====Neuroimaging====
====Neuroimaging====
The neuroimaging correlates of delirium are very difficult to establish.  Many attempts to image people with concurrent delirium will be unsuccessful.  In addition, there is a more general bias selecting younger and fitter participants amenable to scanning, especially if using intensive protocols such as [[MRI]].
* [[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.
Most of the literature has been summarised by a systematic review.<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> This found 12 articles for inclusion, most with small sample sizes (total number of cases 127).  There was substantial heterogeneity in populations, study design, and imaging modalities such that no firm conclusions were made.  Generally, structural imaging suggested that diffuse brain abnormalities such as atrophy and leukoaraiosis might be associated with delirium, though few studies could account for differences in key variables such as age, sex, education or underlying cognitive function and education.
* 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>  
Since publication of the systematic review, five further studies have been published.  The largest-scale report was VISIONS.<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>  This prospectively examined the neuroimaging correlates of delirium in 47 participants after critical illness.  Delirium duration was related to measures of white matter tract integrety and this in turn was related to poorer cognitive outcomes at 3 and 12 months.  In addition, brain volumes were also assessed and related to cognitive outcomes in the same manner. Overall, the study found that 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.
* 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>
 
Two studies examined delirium risk as a post-operative complication after elective cardiac surgery.  These both 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>{{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>
 
====Neurophysiology====
[[Electroencephalography]] ([[EEG]]) is an attractive mode of study in delirium as it has the ability to capture measures of global brain function.  There are also opportunities to summarise temporal fluctuations as continuous recordings, compressed into power spectra (quantitative [[EEG]], qEEG).  Since the work of Engel and Romano in the 1950s, delirium has been known to be associated with a generalised slowing of background activity.<ref>{{cite journal|last=Engel|first=GL|coauthors=Romano, J|title=Delirium, a syndrome of cerebral insufficiency. 1959.|journal=The Journal of neuropsychiatry and clinical neurosciences|date=2004 Fall|volume=16|issue=4|pages=526–38|pmid=15616182|doi=10.1176/appi.neuropsych.16.4.526}}</ref>
 
A systematic review identified 14 studies for inclusion, representing a range of different populations: 6 in older populations, 3 in ICU, sample sizes between 10 and 50).<ref>{{cite journal|last=van der Kooi|first=AW|coauthors=Leijten, FS; van der Wekken, RJ; Slooter, AJ|title=What are the opportunities for EEG-based monitoring of delirium in the ICU?|journal=The Journal of neuropsychiatry and clinical neurosciences|date=2012 Fall|volume=24|issue=4|pages=472–7|pmid=23224454|doi=10.1176/appi.neuropsych.11110347}}</ref> For most studies, the outcome of interest was the relative power measures, in order: alpha, theta, delta frequencies.  The relative power of the theta frequency was consistently different between delirium and non-delirium patients.  Similar findings were reported for alpha frequencies.  In two studies, the relative power of all these bands was different within patients before and after delirium.
 
====Neuropathology====
Only a handful of studies exist where there has been an attempt to correlate delirium with pathological findings at autopsy.  A case series has been reported on 7 patients who died during ICU admission.<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> Each case was admitted with a range of primary pathologies, but all had [[acute respiratory distress syndrome]] and/or [[septic shock]] contributing to the delirium.  6/7 had evidence of hypoperfusion and diffuse vascular injury, with consistent involvement of the [[hippocampus]] in 5/7.


A case-control study examined 9 delirium cases with 6 age-matched controls, investigating inflammatory cytokines and their role in delirium.<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 delirum 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).  These results might suggest a neuroinflammatory substrate to delirium, but the conclusions are limited by biases from selection of controls.
====[[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==

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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

Cerebrospinal fluid biomarkers

Neuroimaging

Neuropathology

References

  1. ↑ 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.
  2. ↑ 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)
  3. ↑ 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)
  4. ↑ 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)
  5. ↑ 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)
  6. ↑ 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)
  7. ↑ 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)
  8. ↑ 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)
  9. ↑ 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)
  10. ↑ 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)
  11. ↑ 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)
  12. ↑ 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)
  13. ↑ 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.
  14. ↑ 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)
  15. ↑ 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)
  16. ↑ 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)

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