Chapter 4: The neurophysiology of delirium

Emerging themes

EEG

In the first direct exploration of cerebral function in delirium since Engel & Romano’s EEG studies (1959), Yokota et al (2003) have studied regional cerebral blood flow using xenon-enhanced computed tomography in 9 men and one woman in intensive care- all had clinically diagnosed hypoactive delirium and were seriously ill- none had head injury. They had apparently been psychiatrically well prior to their delirium and all subsequently recovered from it when they were re-investigated. The changes suggested hypo-perfusion throughout the cortex and subcortical areas during delirium. There seemed to be no lateralisation. The significance of this is unknown.

Neuroinflammatory markers

As discussed in the update for Chapter 1, Eikelenboom and colleagues have constructed a cogent neuroinflammatory hypothesis to explain both the genesis of delirium and depression in dementia (2002). They argue that the effect of acute phase reactants on pre-existing neurotransmitter deficits are responsible for a wide spectrum of behavioural disorders in dementia, and they include delirium in this category.

Uchikado and colleagues report on a method of assessing post-mortem brain tissue inflammation and applied this to 47 patients with a variety of pre-existing psychiatric illnesses including Alzheimer's disease and other forms of dementia and schizophrenias (2004). They found a good correlation between immunohistochemistry scores and pre-mortal C- reactive protein levels, and identified a correlation between systemic inflammation and activation of endothelial and perivascular cells; however, this did not apply well in patients without specific brain degenerative lesions. Their findings are highly relevant to delirium research, and in particular the permanent decrements found after delirium in patients with Alzheimer's disease, and the mechanisms of neuronal "devastation" that may be responsible.

There have been no prospective studies of the relationship between the inflammatory marker C-reactive protein and incident or prevalent delirium. However Belooesky has shown that complications of operative correction of hip fracture are independently associated with disturbed C-reactive protein kinetics. These complications include delirium and other adverse outcomes (Beloosesky, Grinblat, Pirotsky et al (2004)

In their discussion about the apparent benefits of haloperidol in nearly 1000 patients who were mechanically ventilated Milbrandt, Kersten, Kong et al (2005) postulate that haloperidol might work simply because it is less harmful than other sorts of sedation or that it may inhibit the release of pro-inflammatory cytokines and slow down what they described as the "cytokine storm" associated with critical illness. This is an important although uncontrolled cohort study, because it opens up the idea that treatment of delirium itself may improve mortality, even when there are few behavioural problems.

Given its importance in neuroinflammatory processes it is disappointing that perioperative plasma nitric oxide concentration changes do seem to reflect cognitive deficits, at least after coronary artery bypass surgery (Harmon, Eustace, Ghori et al (2005). However, it is intriguing that in a small study which showed a surprising effect size Wilson, Broadhurst, Diver et al (2005) have shown that low IGF-1 levels predicted incident delirium in 100 older medical inpatients.

Melatonin

In what appears to be only the second study of the role of melatonin in the genesis of delirium Balan and colleagues tested the hypothesis that high levels would be associated with hypoactive delirium and vice versa (2003). They measured urinary 6-sulphatoxymelatonin in 31 medical inpatients with delirium as assessed by DRS (Trzepacz, Baker, & Greenhouse (1988) cut point. 7 were classified as hyperactive, 10 hypoactive and the remainder mixed. Using level after recovery as a comparator, they confirmed their hypothesis and raise some interesting questions about the mechanism. Following observations on the emergence of delirium after sleep deprivation by Shiihara, Nogami, Chigira et al (2001), a study of eight patients requiring ventilator therapy in intensive care, four of whom were over 65, is reported of melatonin levels in relation to sleep-wake pattern disturbances such as are found in delirium (Olofsson, Alling, Lundberg et al (2004). They found a disturbed melatonin secretion rhythm in these patients, and suggested that bright light and medication may be responsible. Their findings supported a trial of melatonin in this situation in order to prevent delirium. It is interesting that Hobson (2004) has drawn a parallel between delirium and dreaming, and suggests that some of the neurobiology of sleep might be studied with benefits in delirium research.

Footnotes

Flacker et al (2001) have reported a small but intriguing study of serum anticholinergic activity in medical inpatients who have not apparently taken any known anticholinergic medication. The issue of the assessment of anticholinergic activity has been critically reviewed by Carnahan, Lund, Perry et al (2002) but the finding that serum anticholinergic activity in community based older people was strongly and inversely correlated with MMSE scores is of some importance in delirium research (Mulsant, Pollock, Kirshner et al (2003).

Abnormal sodium levels and normal white counts in hip fracture patients appear to predict delirium (Zakriya, Christmas, Wenz, Sr. et al (2002)- the latter supposed to represent failure to mount an effective stress response.

Nakamura and colleagues have extended their work on the utility of mianserin by showing that plasma free-3-methoxy-4-hydroxyphenyl (ethylene) glycol levels preoperatively may predict post-operative delirium while natural killer cell activity does not (2001).

Rudolph, Babikian, Birjiniuk et al (2005)have found a high correlation between atherosclerosis in the aorta and other arteries and post-operative delirium in 36 patients aged between 49 and 98 years undergoing coronary artery bypass surgery. The incidence of delirium was 41.7%. They speculate that the frontal lobes, which are particularly associated with inattention and thought disturbances are more susceptible to atherosclerosis. The anterior cingulate cortex was the focus of a study by Reischies, Neuhaus, Hansen et al (2005) et al of delirium after ECT. Twelve patients with major depressive disorder with a mean age of 56.7 years were included. All patients received an anticholinergic drug as premedication; cognitive tests and EEGs were recorded at the beginning of the ECT course, shortly after the 6th session and 24 hours later. There was a significant improvement in cognitive tests between the last two assessments, which the authors took to indicate transient delirium. Impairment of orientation for time, episode memory and awareness of the environment were observed in all patients in the study. The study confirmed a significant increase of slow brain electrical activity during this period of impairment, and in a complex EEG source analysis they found that the most pronounced increase of Theta activity during this episode was in the anterior cingulate cortex

Gaudreau and Gagnon (2005) have presented a hypothesis of delirium genesis in which the thalamus plays a central role., particularly in that caused by psychotropic drugs

Criticising Uchida, Aoki, & Ishizuka (1999) hypothesis of delirium genesis involving serotonin and melatonin, Lewis and Barnett (2004) suggest that this only explains hypoactive delirium. They have extended the construct to include a central role for tryptophan homeostasis which they suggest explains more of the delirium phenomenology

Miyamoto, Nakao, Tomimoto et al (2004) have postulated that the basal ganglia are particularly effective by hypocapnia in a rat model of cerebrovascular disease and suggested that this may be related to long-term delirium. They found that the NMDA receptor their suggestion that ketamine might be used as a treatment for delirium flies in the face of its known propensity to cause delirium.

Given its importance in neuroinflammatory processes it is disappointing that perioperative plasma nitric oxide concentration changes do seem to reflect cognitive deficits, at least after coronary artery bypass surgery (Harmon, Eustace, Ghori, Butler, O'Callaghan, O'Donnell, Moore-Groarke, and Shorten (2005).

Reference List Chapter 4

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