EPIDEMIOLOGY AND OUTCOME

Delirium is a common clinical syndrome. It is the clinical manifestation of disruption of the neuroendocrine homoeostasis. It presents in a wide variety of physical conditions and is associated with a poor prognosis. Prospective studies on elderly hospitalised medical patients demonstrate outcomes of increased mortality, increased length of hospital stay and increased likelihood of institutionalisation, with a significant minority having residual cognitive impairment (Reference O'Keefe and LavanO'Keefe & Lavan, 1997). No studies have examined the interface between the neuroendocrine and immune systems in delirium.

NEUROENDOCRINE/IMMUNE MEDIATION

Cytokines are released from brain cells in response to brain insult. They aid the immune response but also can contribute to neuronal death (Reference Tarowski, Rosengren and BlomstrandTarowski et al, 1995). Raised levels of cytokines occur in common causes of delirium such as infection. Their infusion promotes delirium in 30-50% of patients receiving the cytokine interleukin-2 as treatment for cancer (Reference Rosenberg, Loetz and YangRosenberg et al, 1989). Insulin-like growth factor I (IGF-I) and somatostatin are peptides that have important neurotrophic properties. In particular, somatostatin inhibits the release of cytokines (Reference ten Bokum, Hofland and van Hagenten Bokum et al, 2000).

In Reference Venters, Tang and Liu1999 Venters et al demonstrated that the cytokine tumour necrosis factor alpha (TNF-α) exerted its cytotoxicity by inhibiting IGF-I activity. Loddick & Rothwell (Reference Loddick and Rothwell1999) subsequently drew on this work in explaining some associated findings concerning the role of cytokines in neurodegeneration. Both TNF-α and interleukin-1 (IL-1) clearly enhance experimental neurodegeneration, yet even at high doses they fail to cause cell death in the healthy brain. These findings imply that these agents are not inherently neurotoxic but influence survival by inhibiting the protective effect of an endogenous growth factor that is produced in the injured brain. Tumour necrosis factor alpha, IL-1 and other pro-inflammatory cytokines are produced in the central nervous system (CNS) in response to systemic insults such as infection or inflammation and act as mediators of an array of host defence responses, including fever, appetite suppression and neuroendocrine changes. Even though cytokine production does not lead to overt neurodegeneration, there is evidence that systemic infections worsen clinical neurological conditions such as stroke and multiple sclerosis. Consequently, in otherwise healthy brains cytokine production may have no deleterious effect, but when neuronal damage is present they may enhance neurodegenerative processes.

The neurotrophic properties of IGF-I are wide ranging. Animal studies demonstrate that it regulates stem cell differentiation into neurons (Reference Brooker, Kalloniatis and RussoBrooker et al, 2000) and induces neurogenesis of the hippocampus (Reference Aberg, Aberg and HedbackerAberg et al, 2000). Further studies support the neuro-protective role of these peptides (Reference De Marinis, Mancini and ValleDe Marinis et al, 1999) in finding a reversible increase in IGF-I, mirrored by changes in somatostatin in post-head-injury comatose patients. The release of both hormones is closely linked to feedback mechanisms within the growth-hormone-releasing hormone/somatostatin—growth hormone—IGF-I axis.

There is evidence that both somatostatin and IGF-I may have a role in the pathogenesis of Alzheimer's disease. Both cerebrospinal fluid levels and brain somatostatin are reduced in Alzheimer's disease and other dementias (Reference Leake and FerrierLeake & Ferrier, 1993). There is also a selective reduction of somatostatin receptor type 2 (SSRT-2) in the frontal cortex and hippocampus of patients with Alzheimer's disease (Reference Krantic, Robitaille and QuironKrantic et al, 1992). Hong & Lee (Reference Hong and Lee1997) have demonstrated that IGF-I reduces τ-phosphorylation and has been shown to protect and even to rescue neurons from β-amyloid peptides (Reference Dore, Kar and QuironDore et al, 1997). The inhibitory effects of IGF-I on cell death (anti-apoptotic effects) are compromised by presenilin-1 mutations (Reference Tanii, Ankarcrona and FloodTanii et al, 2000), processes that have been implicated in the aetiology of Alzheimer's disease. Also, significant reductions in serum IGF-I have been found in some familial Alzheimer's disease yet normal levels are found in the carriers who do not develop this condition (Reference Mustafa, Lannfelt and LiliusMustafa et al, 1999).

IMPLICATIONS AND RESEARCH OPPORTUNITIES

Somatostatin and IGF-I would appear to be important peptides in relation to cognitive function. Infusion of a somatostatin analogue has been found to improve memory in patients with Alzheimer's disease (Reference Craft, Asthana and NewcomerCraft et al, 1999) and IGF-I administration attenuates the cognitive deficit in brain-injured rats (Reference Saatman, Contreras and SmithSaatman et al, 1997). Reversible somatostatin reduction has been found in delirious patients with no overt CNS disease, suggesting a temporary and reversible involvement of somatostatinergic neurons during and immediately after delirium (Reference Kaponen, Leinonen and LepolaKaponen et al, 1994). The relationship between delirium, exercise and these neurotrophic agents presents some intriguing associations. Exercise is known to increase plasma IGF-I and growth hormone levels. Carro et al (Reference Can o, Nunez and Busiguina2000) examined these issues further in rats, demonstrating that physical activity increased IGF-I uptake by the brain. A large clinical study subsequently demonstrated a potentially protective role of exercise in the management of delirium in medically ill in-patients (Reference InouyeInouye, 2000), implicating a neuroprotective role of IGF-I.

This is a rapidly developing field. We have attempted to draw together some of the evidence concerning the relationship between cytokines, the neuroprotective roles of IGF-I and somatostatin, cognitive function, Alzheimer's disease and delirium. Elevated levels of IGF-I and somatostatin may represent a general neuroprotective response to brain injury. If this is the case, then they have a potential role in the treatment or prevention of delirium (Reference Saatman, Contreras and SmithSaatman et al, 1997; Reference Craft, Asthana and NewcomerCraft et al, 1999). They may have a role also in the treatment of related conditions such as Alzheimer's disease (Reference Dore, Kar and QuironDore et al, 1997), stroke disease (Reference Gluckman, Guan and WilliamsGluckman et al, 1998) and head injury (Reference Hatton, Rapp and KudskHatton et al, 1997).