Pathology and pathogenesis

It has been known since the nineteenth century that the brains of patients who have died from delirium show no obvious macroscopic or microscopic changes.38 The abnormalities associated with delirium are functional rather than anatomical. There have been studies of patients with delirium resulting from localised anatomical lesions of the brain. These have highlighted certain areas as having an important role in producing the symptoms of delirium. These include the right cerebral hemisphere (particularly the parietal cortex)39 and subcortical structures (particularly the thalamus).40 The frontal lobes are also suspected to be involved as they are known to subserve functions of major importance in delirium, such as attention.41 Much of the functional research of delirium has been obtained from EEG studies. An important conclusion from the early research by Engel and Romano was that delirium was probably due to a global reduction in brain metabolic rate. This was proposed from the finding that delirium produced slowing of EEG activity.42

In the delirious patient, the deviation of electrical activity on the EEG from that of the normal waking state correlates well with the clinical condition:43 in most cases, the greater the slowing of the EEG trace, the more clinically impaired the patient. Delirium associated with withdrawal states such as delirium tremens does not follow this general rule and tends to be associated with fast wave activity superimposed on generalised slowing of the trace, suggesting additional pathogenic mechanisms.42 The rate of change of frequency is important: single EEG recordings may occasionally give a false impression in delirious patients with unusually high or low premorbid baseline frequencies,44 implying the desirability of serial EEG recordings in the diagnosis of delirium. These changes are reversible and mirrored in the patient's recovery.42,45 Modern functional imaging studies, such as single photon emission computed tomography (SPECT), are small in number and inconclusive. They are often limited to small numbers of cases. A SPECT study of delirium tremens showed an association with widespread increased cerebral blood flow (CBF), suggesting increases in cerebral oxidative metabolism.46 A review of SPECT studies of subclinical hepatic encephalopathy47 has shown associations with decreased cortical CBF, with lateralising tendencies to the right side and frontal cortex. Some of the hepatic studies have shown a decrease in subcortical metabolism while others have shown an increase.

Many studies concerned with the neurochemical basis of delirium have indicated a major role for acetylcholine.

Acetylcholine is involved with the brain functions of memory, attention, and the sleep-wake cycle, all of which are affected in delirium.48 Anticholinergic drugs, taken medically or recreationally, have the capacity to induce delirious states.48 Hypoxia or hypoglycaemia, both known causes of delirium, lead to a marked decrease in cellular synthesis of acetylcholine.49 Deterioration in cholinergic function is associated with normal ageing and is even more marked in Alzheimer's disease.50 This fits with the known increased vulnerability of both of these groups to develop delirium. Also, Lewy body disease, a condition with symptoms which closely resemble delirium, is associated with an even greater neocortical cholinergic deficit than Alzheimer's disease.51

It is unlikely that acetylcholine is the only neurotransmitter associated with delirium. Other neurotransmitters implicated include dopamine, serotonin, GABA, and glutamate. Dopamine is implicated by the improvement in symptoms of delirium when treated with a dopamine blocker, such as haloperidol. It is also known that hypoxia leads to an increase in extracellular dopamine.52 An imbalance in acetylcholine and dopamine levels may be responsible for some of the symptoms of delirium. This is suggested by the effects of giving large doses of L-dopa to patients with Parkinson's disease who have low cortical cholinergic activity. When exposed to L-dopa, these patients develop complex visual hallucinations, often combined with sleep disturbance, similar to those in delirium and Lewy body disease.53 Delirium is a syndrome of global cerebral dysfunction. Most cases appear to be associated with widespread reductions in cerebral metabolism, apart from the known exception of delirium tremens. The various causes of delirium appear to work by affecting neurotransmitter function, particularly the cholinergic system. Neurotransmission may be affected directly by anticholinergic drugs or indirectly by interference with brain cell metabolism.54

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