Delirium 

Delirium or acute confusional state is a transient global disorder of cognition. The condition is a medical emergency associated with increased morbidity and mortality rates. Early diagnosis and resolution of symptoms are correlated with the most favorable outcomes. Therefore, it must be treated as a medical emergency.

Delirium is not a disease but a syndrome with multiple causes that result in a similar constellation of symptoms. Delirium is defined as a transient, usually reversible, cause of cerebral dysfunction and manifests clinically with a wide range of neuropsychiatric abnormalities. The clinical hallmarks are decreased attention span and a waxing and waning type of confusion.

Delirium often is unrecognized or misdiagnosed and commonly is mistaken for dementia, depression, mania, an acute schizophrenic reaction, or part of old age (patients who are elderly are expected to become confused in the hospital).

The word delirium is derived from the Latin term meaning "off the track." This syndrome was reported during Hippocrates' time, and, in 1813, Sutton described delirium tremens. Later, Wernicke described the encephalopathy that bears his name.

Case study

A 78-year-old female was brought to the Emergency Department by her daughter for vomiting, new onset urinary incontinence, confusion, and incoherent speech for the past 2 days. The patient was disoriented and could see people climbing trees outside the window. She had difficulty sustaining attention, and her level of consciousness waxed and waned. She had been talking about her deceased husband. Patient was also trying to pull out her intravenous access line. Past history included diabetes mellitus, hyperlipidemia, osteoarthritis, and stroke.

The patient's family physician had recently prescribed Tylenol with codeine for the patient's severe knee pain 5 days earlier. On examination, the patient was drowsy and falling asleep while practitioners were talking to her. Patient was not cooperative with the physical examination and with a formal mental status examination. Limited examination of the abdomen indicated that it was flat and soft with normal bowel sounds. The patient moves all 4 limbs and plantar is bilateral flexor. Laboratory test results revealed elevated BUN and creatinine levels, and the urine analysis was positive for urinary tract infection. CT scan of the head showed cortical atrophy.

Based on the state of arousal, 3 types of delirium are described. Hyperactive delirium is observed in patients in a state of alcohol withdrawal or intoxication with phencyclidine (PCP), amphetamine, and lysergic acid diethylamide (LSD). Hypoactive delirium is observed in patients in states of hepatic encephalopathy and hypercapnia. In mixed delirium, individuals display daytime sedation with nocturnal agitation and behavioral problems.

The mechanism of delirium still is not fully understood. Delirium results from a wide variety of structural or physiological insults. The neuropathogenesis of delirium has been studied in patients with hepatic encephalopathy and alcohol withdrawal. Research in these areas still is limited. The main hypothesis is reversible impairment of cerebral oxidative metabolism and multiple neurotransmitter abnormalities. The following observations support the hypothesis of multiple neurotransmitter abnormalities.

Acetylcholine

Data from animal and clinical studies support the hypothesis that acetylcholine is one of the critical neurotransmitters in the pathogenesis of delirium.^[1] A small prospective study among patients who have undergone elective hip replacement surgery showed reduced preoperative plasma cholinesterase activity in as many as one quarter of patients. In addition, reduced preoperative cholinesterase levels were significantly correlated with postoperative delirium.^[2]

Clinically, good reasons support this hypothesis. Anticholinergic medications are a well-known cause of acute confusional states, and patients with impaired cholinergic transmission, such those with Alzheimer disease, are particularly susceptible. In patients with postoperative delirium, serum anticholinergic activity is increased.

Dopamine

In the brain, a reciprocal relationship exists between cholinergic and dopaminergic activities. In delirium, an excess of dopaminergic activity occurs. Symptomatic relief occurs with antipsychotic medications such as haloperidol and other neuroleptic dopamine blockers.

Other neurotransmitters

Serotonin: Human and animal studies have found that serotonin is increased in patients with hepatic encephalopathy and septic delirium. Hallucinogens such as LSD act as agonists at the site of serotonin receptors. Serotoninergic agents also can cause delirium.

Gamma-aminobutyric acid (GABA): In patients with hepatic encephalopathy, increased inhibitory GABA levels also are observed. An increase in ammonia levels occurs in patients with hepatic encephalopathy, which causes an increase in the amino acids glutamate and glutamine, which are precursors to GABA. Decreases in CNS GABA levels are observed in patients with delirium resulting from benzodiazepine and alcohol withdrawal.

Cortisol and beta-endorphins: Delirium has been associated with the disruption of cortisol and beta-endorphin circadian rhythms. This mechanism has been suggested as a possible explanation for delirium caused by exogenous glucocorticoids.

Disturbed melatonin disturbance has been associated with sleep disturbances in delirium.^[3]

Inflammatory mechanism

Recent studies have suggested a role for cytokines, such as interleukin-1 and interleukin-6, in the pathogenesis of delirium. Following a wide range of infectious, inflammatory, and toxic insults, endogenous pyrogen, such as interleukin-1, is released from the cells. Head trauma and ischemia, which frequently are associated with delirium, are characterized by brain responses that are mediated by interleukin-1 and interleukin-6.^{[4, 5]}

Stress reaction mechanism

Studies indicate psychosocial stress and sleep deprivation facilitate the onset of delirium.

Structural mechanism

The specific neuronal pathways that cause delirium are unknown. Imaging studies of metabolic (eg, hepatic encephalopathy) and structural (eg, traumatic brain injury, stroke) factors support the hypothesis that certain anatomical pathways may play a more important role than others. The reticular formation and its connections are the main sites of arousal and attention. The dorsal tegmental pathway projecting from the mesencephalic reticular formation to the tectum and the thalamus is involved in delirium.

Disrupted blood-brain barrier can allow neurotoxic agents and inflammatory cytokines to enter the brain and may cause delirium. Contrast-enhanced MRI can be used to assess the blood-brain barrier.^{[6, 7]}

Visuoperceptual deficits in delirium such as hallucinations and delusions are not due to the underlying cognitive impairment.^[8] Visual hallucinations during alcohol-withdrawal delirium are seen in subjects with polymorphisms of genes coding for dopamine transporter and catechol-O-methyltransferase (COMT).^[9]

Frequency

United States

Delirium is common in the United States. It has been found in 14-56% of elderly patients who are hospitalized. Delirium is present in 10-22% of elderly patients at the time of admission, with an additional 10-30% of cases developing after admission. Delirium has been found in 40% of patients admitted to intensive care units. Prevalence of postoperative delirium following general surgery is 5-10% and as high as 42% following orthopedic surgery. As many as 80% of patients develop delirium near death. Delirium is extremely common among nursing home residents.

Mortality/Morbidity

• In patients who are admitted with delirium, mortality rates are 10-26%.^[10]
• Patients who develop delirium during hospitalization have a mortality rate of 22-76% and a high rate of death during the months following discharge.^[11]
• In patients who are elderly and patients in the postoperative period, delirium may result in a prolonged hospital stay, increased complications, increased cost, and long-term disability.^[12]

Age

Delirium can occur at any age, but it occurs more commonly in patients who are elderly and have compromised mental status. Delirium can occur on top of an underlying dementia. This diagnosis here requires not only a careful mental status but also a thorough history from the patient's family and the staff as well as a comprehensive chart review.