Erfan Bashar
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Delirium — Pathophysiology

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Educational scope notice: This is a study note for medical students, not medical advice, diagnosis, or treatment guidance. Clinical management should follow local protocols and current guidelines.

The pathophysiology of delirium is not fully settled. The current framework holds that many different insults converge on a shared pathway: a diffuse failure of cerebral metabolism and signalling that disrupts several neuronal systems at once. No single mechanism explains every case, and the mechanisms below likely interact rather than compete.

The broadest proposal is cerebral metabolic insufficiency, a generalised fall in the brain’s metabolic state that weakens the coupling between neurons and astrocytes. Astrocytes carry out active glycolysis and hold the brain’s glucose reserve, while neurons depend on that supply; when the coupling fails, structures with the highest metabolic demand suffer first. This generality is both the strength and the weakness of the theory: it explains why such different causes produce one syndrome, but it predicts little on its own.

The attention networks that fail

Delirium strikes attention first because the attentional circuitry is widely distributed and therefore widely exposed. The structures most involved are:

Brain areaRole in attention
Anterior cingulate cortexManaging and directing attention
Prefrontal cortex (both sides, or right-sided)Sustaining attention and executive control
Temporoparietal junctionDisengaging and shifting attention
ThalamusEngaging attention; even small lesions can cause delirium
Upper brainstemMoving the focus of attention
Right hemisphere overallDominant for attention as a whole

Cortical blood flow studies point to right-hemisphere and limbic regions acting as an attentional gate, feeding back through the reticular nucleus of the thalamus. This right-sided dominance is why right-hemisphere lesions so often produce neglect, a focal preview of the global attentional failure seen in delirium.

Cholinergic deficit with dopaminergic excess

The best pharmacologically supported model pairs too little acetylcholine with too much dopamine. Anticholinergic drugs can induce the clinical and EEG picture of delirium, and the picture reverses with physostigmine, which boosts cholinergic transmission. Drugs developed for the cholinergic deficit of Alzheimer disease, such as donepezil, rivastigmine, and galantamine, have shown some attention-enhancing effect in delirium, though without definitive evidence. This is also why anticholinergic burden, from drugs such as diphenhydramine or tricyclic antidepressants, precipitates delirium so readily in elderly patients with little cholinergic reserve.

On the dopaminergic side, L-DOPA can induce delirium, and abrupt L-DOPA withdrawal can trigger it as well. Variants in dopamine transporter and receptor genes have been associated with delirium risk. The rationale for dopamine-blocking drugs follows from this limb of the model, though trials of haloperidol against placebo in intensive care have not shown the benefit the theory would predict, so the dopaminergic account remains debated. Serotonin, norepinephrine, GABA, glutamate, and histamine are all implicated as well, but their roles are less defined.

Inflammation, the barrier, and susceptibility

Inflammatory cytokines, including interleukins, interferon, and tumour necrosis factor-alpha, may act by loosening the blood-brain barrier and disturbing neurotransmission further, with dysregulation of the limbic-hypothalamic-pituitary axis prolonging the episode. These mechanisms lack specificity: they accompany many critical illnesses without delirium, so inflammation reads better as an amplifier than as a cause. Disrupted melatonin secretion may explain the characteristic sleep-wake reversal, while hypoxemia, shock, and metabolic derangement add their own diffuse insults.

Genetic susceptibility exists but has no defining marker. Carriers of the APOE ε4 allele, already at higher Alzheimer risk, tend to endure longer delirious episodes, plausibly because their cholinergic reserve is thinner. Roughly 200 gene variants have been statistically linked to delirium without any single causative gene emerging.

In short: a metabolically fragile brain, thinned cholinergic reserve, dopaminergic overactivity, and an inflammatory hit combine in different proportions in each patient. That multifactorial picture is exactly why delirium has so many precipitants and only one real treatment strategy, which is to remove them.

Evidence anchors

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