Delirium pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Pratik Bahekar, MBBS [2]; Vishal Khurana, MBBS, MD [3]

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.

• 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 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.

Animal models

• The pathophysiology of delirium is not well understood and a lack of animal models that are relevant to the syndrome has left many keys 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 may have delirium-like effects.
• These models, along with clinical studies of drugs with anticholinergic activity have contributed to a hypocholinergic theory of delirium.
• Profound systemic inflammation occurring during bacteremia or sepsis may cause delirium (often termed septic encephalopathy).
• Animal models 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.

Clinical studies

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

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.

Most of the literature has been summarised by a systematic review. 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.

Since publication of the systematic review, five further studies have been published. The largest-scale report was VISIONS. 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.

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. One functional MRI study reported a reversible reduction in activity in brain areas localizing with cognition and attention function.

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.

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). 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. 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. 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.

References