Neuroinflammatory and Aberrant Stress Hypothesis

Accumulating evidence shows that acute peripheral inflammatory stimulation [e.g., with IL-1 or lipopolysaccharide (LPS)-induced inflammatory response] induces a cascade of functional and structural changes in the CNS with consequent neurochemical and functional disturbances in different brain structures [57]. In animal models, these changes underlie acute and transient disturbances in cognition and behavior (the so-called ‘sickness behavior syndrome’) supporting that an acute

Table 7.5 Clinical investigations to aid diagnosis of delirium [50]

Clinical investigations

Examples of common indications

Blood tests

Full blood count

Infection, anemia, blood dyscrasias

Erythrocyte sedimentation rate/C-reactive protein (CRP)

Nonspecific markers of inflammation, including infections, cancers, and autoimmune diseases


Hyponatremia, hypokalemia, hypercalcemia, etc.


Hypoglycemia, diabetic ketoacidosis, hyperosmolar nonketotic states

Renal and liver function tests

Renal and liver failure/impairment (e.g., cholestasis, hepatitis, etc.)

Thyroid function


Thiamine and vitamin B12 levels

Malnutrition, malabsorption, renal dialysis

Blood cultures, HIV tests, serology, bacteriological and viral etiologies

To diagnose infection

These tests are not performed routinely, though 30-40 % of hospitalized patients with HIV infection develop delirium while inpatients [50]

Urine tests

Microscopy, culture, and sensitivity

Infection, renal casts


Biochemical abnormalities in support of working diagnosis, e.g., elevated urine sodium seen in syndrome of inappropriate ADH secretion (SIADH), hypothyroidism, diuretic use, etc. Decreased urinary sodium seen in hyponatremia, hepatorenal syndrome, nephrotic syndrome, renal failure

Urine dipstick

Simple bedside test for the presence of red blood cells, white blood cells, ketones, glucose, nitrites in urine, etc.

Urine and blood toxicology screen

Detection of substance abuse (e.g., alcohol, amphetamines, barbiturates, opiates, tetrahydrocannabinol (THC), etc.)

Other investigations

Electrocardiogram (ECG)

Assess for dysrhythmias (e.g., atrial fibrillation, atrioventricular block, sinus pauses, etc.), acute coronary syndrome, etc.

Chest X-ray

Assess for cardiac, pulmonary, and other mediastinal abnormalities


Helpful to investigate stroke, hemorrhage, structural lesions, and Dementia with Lewy bodies

1. Structural imaging (CT, MRI)

2. Functional neuroimaging (SPECT, 123I-FP-CIT SPECT, PET)

Electroencephalogram (EEG)

Slowing of the posterior dominant rhythm and increased slow-wave activity can be present on EEG in some subjects with delirium, whereas in alcohol/benzodiazepine withdrawal, there is an increase in fast-wave activity

neuroinflammatory response is likely to be implicated in the pathophysiology of delirium (Table 7.6). Elevated levels of plasma C-reactive protein (CRP) have been reported in some [58,64,65], but not all [61-63], studies that involved medical and surgical patients with delirium. Although one study reported that subjects who developed delirium following elective hip arthroplasty had a higher ratio of proinflammatory to anti-inflammatory cytokines [9], higher plasma levels of IL-6, IL-8, and IL-10 in patients with delirium have not been consistently replicated. In a case- control study, only IL-8 (but not IL-1b, IL-6, IL-10, IL-12p70, and TNF-a) was found to be increased in cerebrospinal fluid (CSF) of patients with preoperative or postoperative delirium [77]. Preoperative CSF levels of interleukin-1 receptor antagonist and interleukin-6 were significantly lower in elderly hip fracture patients who developed delirium postoperatively [73] . Brains of patients who developed delirium near death also had higher microglial and astrocytic activation coupled with increased levels of IL-6 compared with age-matched controls without delirium postmortem [54].

The pathophysiology of delirium can also involve a dysfunctional centralized response to acute infection or injury through exaggerated activation of efferent networks including the hypothalamic-pituitary-adrenal (HPA) axis. In fact, cortisol levels have been found to be elevated in plasma and cerebrospinal fluid of patients with delirium in various medical and surgical conditions which is consistent with the hypothesis of an “aberrant stress response” associated with delirium [96, 97]. However, it remains unclear if cortisol elevation is the result of a primary dysfunction of the HPA axis or represents a secondary change to a more intense inflammatory reaction.

So far, two proteomic studies have been published in delirium subjects. One study utilized urine from subjects following cardiac surgery but found no distinct protein fingerprint specific to delirium [98]. The other study reported a dysregulated protein expression in the CSF of 17 delirious patients compared to controls with mild Alzheimer’s disease. These proteins included apolipoproteins, chromogranin/ secretogranins (downregulated in most delirium subjects), and inflammation-related proteins (mostly upregulated in delirium) [99].

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