Address for correspondence:
Bruce G Charlton MD
Reader in Evolutionary Psychiatry
Department of Psychology
University of Newcastle upon Tyne
NE2 4HH
England

Editor-in-Chief, Medical Hypotheses

bruce.charlton@ncl.ac.uk
Tel: 0191 222 6247
Fax: 0191 222 5622

J Lee Kavanau
Department of Organismic Biology, Ecology and Evolution
UCLA
University of California
Los Angeles
CA 90095-1606
USA



Summary

Delirium may be a common cause of psychotic symptoms such as hallucinations, bizarre delusions and thought-disorder, even in conditions such as schizophrenia, mania and depression where delirium has traditionally been excluded by definition. This situation is a consequence of the insensitivity of current clinical criteria for the diagnosis of delirium, which recognize only the most severe forms of functional brain impairment (including disorientation and clouding of consciousness). Serial electroencephalograms (EEGs) are the most sensitive method for detecting delirium and until such studies are performed, the true incidence of delirium in psychotic patients will not be known. The suggested causal mechanism of delirium in psychosis is sleep disruption. Sleep is essential for maintenance of memory circuits which otherwise suffer progressive synaptic weakening due to molecular turnover. When sleep is disrupted, memory circuits deteriorate, and subsequent activation of incompetent circuits can generate psychotic symptoms. Induction of physiologically-normal sleep would therefore be expected to produce significant clinical improvement in patients with psychotic symptoms. Furthermore, the ‘anti-delirium’ action of electroconvulsive therapy may account for its effectiveness in alleviating a wide range of psychiatric and neurological pathologies.



Delirium and Psychotic Symptoms - an integrative model

Delirium is functional cognitive impairment - brain dysfunction without permanent changes in brain structure. Other terms for delirium include acute organic syndrome, and acute or toxic confusional state [1]. The causes of delirium are many-fold and include any severe insult to the brain, such as pharmacological intoxication or withdrawal, fever, trauma, or any generalized physiological or biochemical derangement. It is recognized that psychotic phenomena, such as irrational thinking and speech, and abnormal psychological experiences, such as hallucinations and bizarre delusions, are a common feature of delirium [2]. When a brain is globally dysfunctional, it cannot perform cognitive processing in the normal fashion. For instance, delusional beliefs are unsurprising when the cognitive processes by which beliefs are generated are themselves impaired.

We suggest that delirium may be a much commoner cause of psychotic symptoms in psychiatry than is generally acknowledged; even in the ‘functional psychoses’ such as schizophrenia, mania and depression, where delirium was traditionally considered to be excluded by definition.

Clinical diagnosis of delirium

An electroencephalogram (EEG) constitutes the most sensitive method for detecting delirium [3] - however EEGs are very seldom performed in psychiatric practice. Furthermore, because of the wide range of normal variation, serial EEGs are necessary, with measurements taken during and after recovery from the acute delirious episode, each patient serving as his or her own control. Until such studies are performed, the true incidence of delirium in psychiatric patients will not be known.

Lacking objective measurements of delirium, the clinical diagnosis of delirium in psychiatric practice has typically been reserved for the most severe forms of functional brain impairment - when disorientation and clouding of consciousness are present [4]. This definition of delirium is parsimonious, and prevents false positives in diagnosis; but this clinical practice carries the implication that significant but mild delirium is probably routinely under-diagnosed.

It is hard to exclude delirium in any individual patient because the condition demonstrates a continuum of severity, with milder symptoms being difficult to discriminate from normal behavior [1]. For example, a mood of fearful perplexity is often typical of early stages of brain dysfunction; and distractible attention is an early cognitive change, such that a mildly delirious patient cannot concentrate for very long on any single line of reasoning and is readily diverted from any particular line of thought or attempted task [5]. However, both perplexity and distractibility are non-specific symptoms, difficult to identify objectively, and typically recognized as being a part of the clinical syndrome of delirium only retrospectively, when the condition has progressed to include qualitatively abnormal behaviors such as hallucinations.

The routine under-diagnosis of delirium in psychiatric practice is potentially important since delirium can potentially lead to a wide range of severe psychiatric symptoms. Indeed, the 'Kraepelinian' diagnostic categories of the ‘functional’ psychoses (schizophrenia, mania and major depressive disorder) are defined in terms of the exclusion of organic disease such as delirium [6]. This distinction is crucial since the symptoms of delirium may be strikingly similar to those typical of the functional psychoses. For example, both delirium and acute mania may include perplexed, fearful and labile emotions, distractible attention, jumbled speech, disinhibited behavior, and hallucinations and delusions [1, 5]. Indeed, the presence or absence of disorientation and 'clouding' of consciousness may be the only symptoms that distinguish between the diagnostic categories. Yet even that criterion is not considered to be decisive: for example some psychiatrists have long recognized that clouding and disorientation can occur in patients who are otherwise typically ‘manic’ [5].

The whole of modern neo-Kraepelinian diagnostic practice in schizophrenia, mania and 'psychotic depression' therefore hangs upon the validity of the clinical exclusion of delirium [6]. Yet there is a strong theoretical case that many patients who demonstrate 'classic' psychotic symptoms such as hallucinations, bizarre delusions and thought disorder are suffering from delirium - even in the ‘functional psychoses’ where disorientation and clouding of consciousness are not evident. In other words, we predict that patients with hallucinations, bizarre delusions or thought disorder should exhibit delirium. Available evidence, much of it from the research literature of the mid-twentieth century, is ambiguous; but acutely psychotic patients may demonstrate EEG abnormalities [5, 6, 7].

But the question of the prevalence of EEG abnormalities in patients with psychotic symptoms needs to be studied afresh, since (as explained above) serial EEGs are necessary to exclude delirium. Furthermore, modern EEG technology has improved considerably compared with that available during the 1950s and 1960s when most of the relevant studies were carried out.

Delirium and illusory dreams

Chronic severe sleep loss and other forms of sleep disruption are significant clinical features in many psychotic patients, although they are seldom considered as potential aetiological factors for psychotic symptoms. Yet chronic, severe sleep loss can certainly cause delirium [8], and the probable mechanisms of this link have recently been elucidated [9], [10].

It was the 18th Century Scottish physician, William Cullen, who first drew the analogy between delirium and illusory dreams (ie. dreams containing incongruent, bizarre, or impossible contents). It is now believed that many memory circuits of the brain are reinforced during sleep, a process in which synaptic strengths are maintained at dedicated levels [11, 12, 13]. Synaptic strength maintenance occurs largely through the action of self-generated, spontaneously occurring, slow brain waves (waves at frequencies less than about 14 cycles per second). This occurs both during rapid-eye-movement (REM) and nonREM sleep, though there are significant differences in function between the two phases [14, 15]. Maintenance is necessary since all synaptic strengths weaken with time due to "turnover" of essential molecules. Without remedial action during sleep, all memory circuits that were not being regularly ‘exercised’ by frequent use while awake, would gradually deteriorate and their encoded memories be lost.

Incidentally, some of the memories being reinforced during sleep rise to the level of "unconscious" awareness, and these are the memories that provide the substance of our dreams [14, 16, 17]. If our stored memories were valid in every respect, then our dreams would consist solely of "replays" of past or plausible events in our lives. And indeed, roughly 85-95% of dream contents derive from authentic contents [17, 18]. On the other hand, when memory circuits are faulty, the events and perceptions in the resulting dreams may be distorted or largely illusory.

The sources of illusory dream contents are at least three-fold: first, there are disordered synaptic strengths that owe to normal imperfections in the processes that store and maintain memories; second, there are the abnormal influences of pathologically altered brain waves; and third, there are the influences of sleep loss leading to incomplete refreshment of synaptic strengths.

The earliest manifestations of sleep deprivation, even after a single night, include significant impairment of cognitive performance and changes in mood. After only 48 hours most subjects report illusions and/or visual and tactile hallucinations, and these become more intense as deprivation progresses [19]. The pathology underlying organic delirium additionally involves abnormalities in slow waves observable by EEG and characterized by deviations from normal frequency, form, magnitude or distribution [3, 20, 21]. Such pathological waves are presumably incapable of reinforcing memory circuits in the usual fashion. With a cumulative weakening of synaptic strengths in affected circuits, subsequent recall of such distorted memories produces hallucinations, delusions, and other hallmarks of delirium [10].

These alterations of mental state apparently reflect the use of incompetent circuitry that accumulates during the extended periods of sleep loss and/ or the effects of pathological brain waves. Just as illusory dreams in normal individuals often are the result of activation of incompetent circuits, the symptoms of organic delirium probably owe their origin primarily to the activation of incompetent circuitry of functionally pathological origin.

Treatment of delirium

The first-line management of delirium is, of course, directed at the identification and treatment of the underlying cause [22]. However, symptomatic treatment may also be vital, and in patients with a history of severe sleep loss and either EEG or clinical evidence of delirium, management directed primarily at securing deep and restorative sleep would be expected to produce significant clinical improvement [6].

Assuming that delirium is indeed responsible for psychotic symptoms in many patients with acute pscyhosis, it is interesting to speculate what proportion of the clinical benefit of neuroleptic and other tranquilizing drugs (such as lorazepam) currently used in the management of acute psychosis might be attributable simply to their sleep-promoting effects. Choice of pharmacological agents may turn out to be important, since different sedative drugs have different effects on EEG. For example, it has been suggested that the ‘atypical’ neuroleptics may provide a particularly close simulation of ‘natural’ sleep [23].

Adopting this view of the genesis of organic delirium, it seems likely that the useful, but often only temporary, clinical benefit of electroconvulsive therapy (ECT) for organic delirium [24, 25], may be due to the inducing electrical shock temporarily suppressing abnormal slow-wave regimes, allowing spontaneous resumption of synaptic maintenance by remedial slow waves [9]. A relevant analogy might be the way in which a cardiac defibrillating shock halts fibrillation and allows the intrinsically-generated normal sinus rhythm to resume spontaneously. Following ECT the remedial regimes of slow waves operating during natural sleep then act to restore dedicated functional strengths in synapses of previously incompetent circuitry. On ECT maintenance therapy, the abnormal slow waves remain suppressed, and normal reinforcement regimes, with their alleviating influences, prevail. But when maintenance therapy ceases, the abnormal slow waves may regain dominance, because of prevalence of the underlying functional pathology, and delirium returns.

This ‘anti-delirium’ mechanism proposed for ECT [9, 26] may account for the effectiveness of ECT in alleviating a wide range of psychiatric and neurological pathologies; probably including not only severe depressive disorder but also acute schizophrenia, mania, Parkinson’s disease, delirium tremens, CNS syphilis, typhoid catatonia, and phencyclidine psychosis [24]. All these conditions plausibly have a delirious element which may be contributing significantly to their symptomatology.

The time appears to be ripe to reconsider the nature, status, classification and prevalence of delirium in psychiatric patients. We suggest that delirium is routinely under-detected in practice due to the insensitivity of clinical diagnostic criteria. Hence we predict that serial EEGs would confirm that delirium is responsible for severe psychotic symptoms in many patients, particularly those with severe sleep loss or disruption. To confirm or refute these hypotheses would require that delirium should again become the focus of systematic research effort in psychiatry.



References
1. Lipowski, Z.J. Delirium: acute confusional states, New York: Oxford University Press, 1990.

2. Sims, A. Symptoms in the mind, London: WB Saunders, 1995.

3. Niedermeyer, E., da Silva, L. Electroencephalography: basic principles, clinical applications , and related fields, Baltimore: Williams and Williams, 1993.

4. Hamilton, M.. Fish’s outline of psychiatry. Bristol: John Wright and sons, 1984.

5. Slater, E. & Roth, M. Clinical psychiatry 3rd edition, London: Balliere Tindall, 1977

6. Charlton, B.G. Psychiatry and the human condition, Oxford: Radcliffe Medical Press, 2000.

7. Fink M. Neglected disciplines in human psychopharmacology: pharmaco-EEG and electroshock. (ed. Healy D). The Psychopharmacologists III. London: Arnold, 2000.

8. Wehr, T.A. Effects of wakefulness and sleep on depression and mania. In Sleep and biological rhythms: basic mechanisms and applications. (ed. Montplaisir J, Godbout R) New York: Oxford University Press, 1990.

9. Kavanau, J.L. Adaptations and pathologies linked to dynamic stabilization of neural circuitry. Neuroscience and Biobehavioural Reviews, 1999; 23: 635-648.

10. Kavanau, J.L. Sleep, memory maintenance, and mental disorders. Journal of Neuropsychiatry and Clinical Neurosciences, 2000; 12: 199-208.

11. Kreuger, J.M. & Obal, F. A neuronal group theory of synaptic function. Journal of Sleep Research, 1993; 2: 63-69.

12. Kavanau, J.L. Sleep and dynamic stabilization of neural circuitry: a review and synthesis. Behavioural Brain Research, 1994; 63: 111-126.

13. Siegel, J.M. Phylogeny and the function of REM sleep. Behavioural Brain Research, 1995; 69: 29-34.

14. Stickgold, R. Sleep: off-line memory re-processing. Trends in Cognitive Science, 1998; 2: 484-492.

15. Hobson, J.A., Stickgold, R., Pace-Schott, E.F. The neuropsychology or REM sleep dreaming. NeuroReport 1998; 9: R1-R14.

16. Kavanau, J.L. Memory, sleep and dynamic stabilization of neural circuitry: evolutionary perspectives. Neuroscience and Biobehavioral Reviews, 1996; 20: 289-311.

17. Foulkes, D. Children’s dreaming and the development of consciousness. Cambridge, MA., Harvard University Press, 1999.

18. Antrobus, J.S. & Bertini, M. Introduction. (ed. Antrobus JS., Bertini M). The neurobiology of sleep and dreaming. Hillsdale, NJ, USA, Erlbaum, 1992.

19. Everson, C.A. Clinical manifestations of sleep deprivation. (ed Schwartz WJ.). Sleep science: integrating basic research and clinical practice. New York, Karge, 1997.

20. Schear, H. The EEG pattern in delirium tremens. Clinical Encephalography, 1985; 16: 30-32.

21. Slaby, A.E. & Cullen, L.O. Dementia and delirium. (ed. Stoudemire A, Fogel BS) Principles of medical psychiatry, New York, Grune and Stratton, 1987.

22. Charlton, B.G. Psychiatric implications of surgery and critical care. (ed. Glasby MA & Huang CL-H) Applied physiology for surgery and critical care, London, Butterworth Heinemann, 1995.

23. Janssen, P. From haloperidol to risperidone. (ed. Healy D). The psychopharmacologists II. London, Altman, 1998.

24. Abrams, R. Electroconvulsive therapy 3rd edition. New York, Oxford University Press, 1997.

25. Stromgren, L.S. ECT in acute delirium and related clinical states. Convulsive Therapy, 1997;13: 10-17.

26. Charlton, B.G. The ‘anti-delirium’ theory of electro-convulsive therapy action. Medical Hypotheses, 1999; 52: 609-11.

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