Delirium pathophysiology

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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

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.

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.

 * Roles of GABA and serotonin are uncertain.  

• 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:

• The dorsal lateral prefrontal cortex and the posterior cingulate cortex.
• 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.
• Mesencephalic tegmentum and the thalamus are linked to the early restoration of alertness.
• Subcortical connections tend to recover sooner than the cortical connection.
• It may be due to the temporary pharmacological influence of the anticholinergic used in anesthesia and the antidopaminergic drugs administered to obtain behavioral control.
• Individuals with brain abnormalities like cortical atrophy, ventricular enlargement, and increased white matter lesions are more likely to develop delirium.
• Anticholinergic drugs such as biperiden and scopolamine may have hypocholinergic delirium-like effects.
• 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.
• 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.
• 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.
• 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.
• 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.
• One functional MRI study reported a reversible reduction in activity in brain areas localizing with cognition and attention function.

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.
• The role of inflammatory cytokine has been shown in delerious patients.
• 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