Pathogenesis

Delirium is not a single disease entity but rather a syndrome that represents pervasive cerebral dysfunction due to a variety of etiologies (Rummans et al. 1995). More than one pathophysiological mechanism is likely involved in the development of delirium. A wide variety of etiologies and mechanisms may alter brain functions, leading toward a final common pathway that results in the symptoms of delirium (Francis et al. 1990).

Delirium often occurs in conjunction with infection or inflammation from other causes. The inflammatory response is a highly complex, interrelated process during which any cytokine can modulate the response of many others, depending on clinical, physiological, and immune factors (Rudolph 2008). Macrophages secrete cytokines in response to infections, surgery, or other tissue injury, and circulating cytokines have been implicated in the pathogenesis of delirium (de Rooij et al. 2007).

Cytokines have major effects on cerebral function and cause changes in sleep patterns, mood, behavior, cognition, and memory (Dunlop and Campbell 2000). Treatment with cytokines such as interferon-a and interleukin-2 may cause dose-dependent cognitive, emotional, and behavioral disturbances, including delirium (Malek-Ahmadi and Hilsabeck 2007; van der Mast 1998). Interleukin-1, interleukin-2, interferon, and tumor necrosis factor can trigger excitatory central nervous system (CNS) effects of delirium, agitation, delusions, hallucinations, and seizures (Dunlop and Campbell 2000). Cytokines can also cause a reduction in acetylcholinergic pathways and impair cognition (de Rooij et al. 2007).

Delirium may be related to changes in the blood-brain barrier, which occur in response to systemic or local inflammation. Normally, the blood-brain barrier inhibits cytokines from crossing into the brain parenchyma, but in many situations related to the occurrence of delirium, the integrity of the blood-brain barrier may be compromised (Rudolph 2008). Chemokines, locally acting cytokines, compromise the blood-brain barrier and enhance migration of inflammatory cells into the brain (Rudolph 2008). Increased chemokine levels, but not cytokine levels, are found in patients with delirium (Rudolph 2008), and children with influenza and delirium have elevated levels of interleukin-6 (Fukumoto et al. 2007).

Delirium has been considered a "syndrome of cerebral insufficiency due to decreased oxidative metabolism in the brain" (Eikelenboom et al. 2002, p. 273). Patients identified with oxidative dysfunction develop delirium more often, independent of the severity of their underlying illness (Seaman et al. 2006). Interference with cerebral oxidative metabolism may be caused by many different factors, which include lack of oxygen, glucose, or amino acids; altered cerebral blood flow; increased permeability of the blood-brain barrier; toxins; hyperther-mia or hypothermia; damage to cell membranes; or vitamin deficiencies (van der Mast 1998). Impairment of oxidative metabolism results in reduced synthesis of neurotransmitters, especially acetylcho-line, which unbalances the cholinergic, dopaminer-gic, and noradrenergic systems (Eikelenboom et al. 2002). The following may underlie the symptoms and clinical presentation of delirium: decreased cholinergic function; excess release of dopamine, nore-pinephrine, and glutamate; decreased serotonin; and increased y-aminobutyric acid (GABA).

Dopamine, norepinephrine, and serotonin are implicated in control of the sleep-wake cycle and arousal, and serotonin is also involved in modulating behavior, mood, and motor activity. Increased dopamine release and neurotransmission are linked to psychosis. Antipsychotic medications that block dopamine receptors are typically used to treat delirium (van der Mast 1998).

Abnormal neurotransmitter release, alteration in complex neurotransmitter interactions, and abnormal signal conduction contribute to delirium (Maldonado 2008b). Drugs or toxins that act on these neurotransmitter systems may produce delirium, particularly abnormalities of cholinergic neurotransmission produced by anticholinergic drugs (Rum-mans et al. 1995). In clinical settings, such as in the ICU or after surgery, opioids and other anticholinergic agents are widely used. Anticholinergic drugs that can cross the blood-brain barrier and are able to induce delirium. Hypoxia, which is frequent in these clinical settings, also leads to decreased release of acetylcholine and increased extracellular dopamine levels. In turn, excessive dopamine release can be neurotoxic by producing oxyradicals and releasing glutamate (van der Mast 1998).

The most prevalent cerebral neurotransmitters are GABA, which is the major inhibitory neurotransmitter, and its amino acid precursor, glutamate, which is a major excitatory neurotransmitter. GABA and glutamate may stimulate almost any neuron and are highly vulnerable to metabolic disturbances. Glutamate has been associated with psychosis, and increased levels of glutamate induce excessive calcium flux into neurons, which activates enzymes producing free radicals. These free radicals destroy other chemical and cellular components, particularly membranes and mitochondria, and may play a role in the production of delirium (van der Mast 1998).

Alterations in the majority of neurotransmitters, including acetylcholine, dopamine, GABA, gluta-mine, serotonin, and histamine, are documented in delirium and lead to alterations in their complex interactions. Intraneuronal signal transduction and second messenger systems may be disturbed and further alter synthesis and release of neurotransmitters. Neurotransmitter perturbation causes neuronal membrane hyperpolarization, which ultimately leads to spreading neuronal depression (McGowan and Locala 2003) and the routine electroencephalo-graphic finding of nonspecific generalized slowing seen in most cases of delirium (Prugh 1980).

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