Even though delirium has many different etiologies, its constellation of symptoms is largely stereotyped, with some considered core symptoms. Somehow, this diversity of physiological perturbations translates into a common clinical expression that may represent dysfunction ofcertain neural circuits (as well as neurotransmitters) — that is, a final common neural pathway.
The involvement of certain specific regions and pathways is largely based on limited structural and functional neuroimaging data. Dysfunction in both cortical and subcortical regions in delirium has been supported by studies of regional cerebral blood flow, single photon emission computed tomography, positron-emission tomography, EEG, and evoked potentials. Whereas some etiologies of delirium alter neurotransmission via generalmetabolism, others may antagonize or interfere with specific receptors and neurotransmitters.
The best-established neurotransmitter alteration accounting for many cases of delirium is reduced cholinergic activity. A wide variety of medications and their metabolites have anticholinergic activity and cause delirium. Some act postsynaptically; others act presynaptically; and still others, such as norfentanyl and normeperidine, have anticholinergic metabolites. Tune and colleagues measured the anticholinergic activity of many medications in “atropine equivalents.” They identifiedmedications usually not recognized as being anticholinergic (e.g., digoxin, nifedipine, cimetidine, and codeine).
Delirium induced by anticholinergic drugs is associated with generalized EEG slowing and is reversed by treatment with physostigmine or neuroleptics.
Several causes of delirium thought of as having diffuse, nonspecific effects on neuronal function may at least in part be acting through anticholinergic effects. Thia-mine deficiency, hypoxia, and hypoglycemia all may reduce acetylcholine by affecting the oxidative metabolism of glucose and the production of acetyl coenzyme A, the rate-limiting step for acetylcholine synthesis . Parietal cortex levels of choline are reduced inchronic hepatic encephalopathy. Serum levels of anticholinergic activity are elevated in patients with postoperative delirium and correlate with severity of cognitive impairment, improving with resolution of the delirium. Post-electro-convulsive therapy delirium is also associated with higher serum anticholinergic activity. Alzheimer’s and vascular dementias reduce cholinergic activity and are associated with increased risk for delirium. Dementia with Lewy bodies, with its fluctuating symptom severity, confusion, hallucinations (especially visual), delusions, and EEG slowing, mimics delirium and is associated with significant loss of cholinergic nucleus basalis neurons. Its delirium symptoms respond to donepezil. Age-associated changes in cholinergic function also increase delirium propensity. Stroke and traumatic brain injury are associated with decreased cholinergic activity and have enhanced vulnerability to antimuscarinic drugs. The low cholinergic state seems to correlate temporally with delirium following the acute event. Thus, there is broad support for an anticholinergic mechanism for many seemingly diverse mechanisms of delirium.
However, anticholinergic mechanisms cannot explain all deliria, because cholinergic toxicity from organophosphate insecticides, nerve poisons, and tacrine also can cause delirium. Increased dopamine also may play a role in some deliria. Delirium can occur from intoxication with dopaminergic drugs and cocaine binges. Excessive dopaminergic activity also might play a role in delirium, including during specific states such as alcohol withdrawal, opiate intoxication, hypoxia, and hepatic encephalopathy. The efficacy of anti-dopaminergic agents, particularly neuroleptics, in treating delirium, including that arising from anticholinergic causes, also suggests a neuropathogenetic role for dopamine.
Both increased and decreased gamma-aminobutyric acid (GABA) levels have been implicated in causing delirium. Increased GABAergic activity is one of several putative mechanisms implicated in hepatic encephalopathy. GABA activity is reduced during delirium following withdrawal from ethanol and sedative-hypnotic drugs. Decreased GABA activity is also implicated in the mechanism of antibiotic delirium caused by penicillins, cephalosporins, and quinolones. Both low and excessive levels of serotonin are also associated with delirium. Serotonin syndrome is the obvious example of the latter, but serotonergic activity may be increased in patients with hepatic encephalopathy and sepsis. Histamine may play a role in delirium through its effects on arousal and hypo-thalamic regulation of sleep-wake circadian rhythms. Both H1 and H2 antagonists can cause delirium, although both also have anticholinergic properties. Glutamate release is increased during hypoxia, and glutamatergic receptors may be activated by quinolone antibiotics.
Altered ratios of plasma amino acids during severe illness, surgery, and trauma may affect neurotransmitter synthesis in the brain. In addition to changes in major neurotransmitter systems, neurotoxic metabolites, such as quinolinic acid from tryptophan metabolism, and false transmitters, such as octopamine in patients with liver failure, have been implicated in the pathogenesis of delirium. Because glia help to regulate neurotransmitter amounts in the synapse, glial dysfunction also may be involved. Increased blood-brain barrier permeability, as occurs in uremia, is another possible mechanism contributing to delirium. Van der Mast and Fekkes proposed that surgery induces immune activation and a physical stress response, which is characterized by increased hypothalamic-pituitary-adrenocortical axis activity, low triiodothyronine (T3) syndrome, and alterations of blood-brain barrier permeability. Cytokines have been implicated as causes of inflammatory or infection-induced delirium, as well as when given as treatment (interferons, interleukins). Cytokines are increased during stress, rapid growth, inflammation, tumor, trauma, and infection. The mechanism by which they cause delirium may be as neurotoxins, through effects on a variety of neurotransmitters, by altering blood-brain barrier permeability, or through effects on glial function.
A final common neural pathway for delirium could have neuroanatomic and neurochemical components. The predominance of evidence supports a low cholinergic-excess dopaminergic state in this final common neural theory. Other neurotransmitter systems are known to be involved for certain etiologies (e.g., hepatic insufficiency or alcohol withdrawal), whereas cholinergic and dopaminergic pathways can be affected by these other neurotransmitters. The role of cholinergic and dopaminergic neurotransmission in delirium has been reviewed in detail elsewhere.