Clinical Characteristics

The essential elements of delirium are summarized in Boxes 4.1 and 4.2. Among the proposed American Psychiatric Association’s criteria (DSM-V Proposed Revision, 2013) for this disorder is a disturbance that develops over a short period of time; tends to fluctuate; and impairs awareness, attention, and other areas of cognition. In general, awareness, attention, and cognition fluctuate over the course of a day. Furthermore, delirious patients have disorganized thinking and an altered level of consciousness, perceptual disturbances, disturbance of the sleep/wake cycle, increased or decreased psychomotor activity, disorientation, and memory impairment. Other cognitive, behavioral, and emotional disturbances may also occur as part of the spectrum of delirium. Delirium can be summarized into the 10 clinical characteristics that follow.

Box 4.2

Diagnostic and Statistical Manual of Mental Disorders, Fifth edition, Proposed Revision, Criteria for Delirium due to a General Medical Condition

A. Disturbance in level of awareness and reduced ability to direct, focus, sustain, and shift attention

B. A change in cognition (such as deficits in orientation, executive ability, language, visuoperception, learning, and memory):

Cannot be assessed in face of severely reduced level of awareness

Should not be better accounted for by a preexisting neurocognitive disorder

C. There is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by the direct physiological consequences of a general medical condition

D. The disturbance develops over a short period of time (usually hours to a few days) and tends to fluctuate in severity during the course of a day

Note: The following supportive features are commonly present in delirium but are not key diagnostic features: sleep/wake cycle disturbance, psychomotor disturbance, perceptual disturbances (e.g., hallucinations, illusions), emotional disturbances, delusions, labile affect, dysarthria, and EEG abnormalities (generalized slowing of background activity)

Modified from American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, fifth ed., proposed revision. American Psychiatric Association, Washington, DC.

Cognitive and Related Abnormalities

Attentional Deficits

A disturbance of attention and consequent altered awareness is the cardinal symptom of delirium. Patients are distractible, and stimuli may gain attention indiscriminately, trivial ones often getting more attention than important ones. All components of attention are disturbed, including selectivity, sustainability, processing capacity, ease of mobilization, monitoring of the environment, and the ability to shift attention when necessary. Although many of the same illnesses result in a spectrum of disturbances from mild inattention to coma, delirium is not the same as disturbance of arousal.

Confusion or Disorganized Thinking

Delirious patients are unable to maintain the stream of thought with accustomed clarity, coherence, and speed. There are multiple intrusions of competing thoughts and sensations, and patients are unable to order symbols, carry out sequenced activity, and organize goal-directed behavior.

The patient’s speech reflects this jumbled thinking. Speech shifts from subject to subject and is rambling, tangential, and circumlocutory, with hesitations, repetitions, and perseverations. Decreased relevance of the speech content and decreased reading comprehension are characteristic of delirium. Confused speech is further characterized by an abnormal rate, frequent dysarthria, and nonaphasic misnaming, particularly of words related to stress or illness, such as those referable to hospitalization.

Altered Level of Consciousness

Consciousness, or clarity of awareness, may be disturbed. Most patients have lethargy and decreased arousal. Others, such as those with delirium tremens, are hyperalert and easily aroused. In hyperalert patients, the extreme arousal does not preclude attentional deficits because patients are indiscriminate in their alertness, are easily distracted by irrelevant stimuli, and cannot sustain attention. The two extremes of consciousness may overlap or alternate in the same patient or may occur from the same causative factor.

Perceptual Disturbances

The most common perceptual disturbance is decreased perceptions per unit of time; patients miss things that are going on around them. Illusions and other misperceptions result from abnormal sensory discrimination. Perceptions may be multiple, changing, or abnormal in size or location. Hallucinations also occur, particularly in younger patients and in those in the hyperactive subtype. They are most common in the visual sphere and are often vivid, three-dimensional, and in full color. Patients may see lilliputian animals or people that appear to move about. Hallucinations are generally unpleasant, and some patients attempt to fight them or run away with fear. Some hallucinatory experiences may be release phenomena, with intrusions of dreams or visual imagery into wakefulness. Psychotic auditory hallucinations with voices commenting on the patient’s behavior are unusual.

Disturbed Sleep/Wake Cycle

Disruption of the day/night cycle causes excessive daytime drowsiness and reversal of the normal diurnal rhythm. “Sundowning”—with restlessness and confusion during the night—is common, and delirium may be manifest only at night. Nocturnal peregrinations can result in a serious problem when the delirious patient, partially clothed in a hospital gown, has to be retrieved from the hospital lobby or from the street in the middle of the night. This is one of the least specific symptoms and also occurs in dementia, depression, and other behavioral conditions. In delirium, however, disruption of circadian sleep cycles may result in rapid eye movement or dream-state overflow into waking.

Altered Psychomotor Activity

There are two subtypes of delirium, based on changes in psychomotor activity. The hypoactive-hypoalert subtype is characterized by psychomotor retardation. These are the patients with lethargy and decreased arousal. The hyperactive-hyperalert subtype is usually hyperalert and agitated and has prominent overactivity of the autonomic nervous system. Moreover, the hyperactive type is more likely to have delusions and perceptual disorders such as hallucinations. About half of patients with delirium manifest elements of both subtypes or fluctuate between the two. Only about 15% are strictly hyperactive. In addition to the patients being younger, the hyperactive subtype has more drug-related causes, a shorter hospital stay, and a better prognosis.

Disorientation and Memory Impairment

Disturbances in orientation and memory are related. Patients are disoriented first to time of day, followed by other aspects of time, and then to place. They may perceive abnormal juxtapositions of events or places. Disorientation to person—in the sense of loss of personal identity—is rare. Disorientation is one of the most common findings in delirium but is not specific for delirium; it occurs in dementia and amnesia as well. Among patients with delirium, recent memory is disrupted in large part by the decreased registration caused by attentional problems.

In delirium, reduplicative paramnesia, a specific memory-related disorder, results from decreased integration of recent observations with past memories. Persons or places are “replaced” in this condition. In general, delirious patients tend to mistake the unfamiliar for the familiar. For example, they tend to relocate the hospital closer to their homes. In a form of reduplicative paramnesia known as Capgras syndrome, however, a familiar person is mistakenly thought to be an unfamiliar impostor.

Other Cognitive Deficits

Disturbances occur in visuospatial abilities and in writing. Higher visual-processing deficits include difficulties in visual object recognition, environmental orientation, and organization of drawings and other constructions.

Writing disturbance may be the most sensitive language abnormality in delirium. The most salient characteristics are abnormalities in the mechanics of writing: The formation of letters and words is indistinct, and words and sentences sprawl in different directions (Fig. 4.1). There is a reluctance to write, and there are motor impairments (e.g., tremors, micrographia) and spatial disorders (e.g., misalignment, leaving insufficient space for the writing sample). Sometimes the writing shows perseverations of loops or aspects of the writing. Spelling and syntax are also disturbed, with spelling errors particularly involving consonants, small grammatical words (prepositions and conjunctions), and the last letters of words. Writing is easily disrupted in these disorders, possibly because it depends on multiple components and is the least used language function.

Fig. 4.1 Writing disturbances in delirium. Patients were asked to write indicated words to dictation.

(Reprinted with permission from Chédru, J., Geschwind, N., 1972. Writing disturbances in acute confusional states. Neuropsychologia 10, 343-353.)

Pathophysiology

The pathophysiology of delirium is not entirely understood, but it depends on widely distributed neurological dysfunction. Delirium is the final common pathway of many pathophysiological disturbances that reduce or alter cerebral oxidative metabolism. These metabolic changes result in diffuse impairment in multiple neuronal pathways and systems.

Several brain areas involved in attention are particularly disturbed in delirium. Dysfunction of the anterior cingulate cortex is involved in disturbances of the management of attention (Reischies et al., 2005). Other areas include the bilateral or right prefrontal cortex in attentional maintenance and executive control, the temporoparietal junction region in disengaging and shifting attention, the thalamus in engaging attention, and the upper brainstem structures in moving the focus of attention. The thalamic nuclei are uniquely positioned to screen incoming sensory information, and small lesions in the thalamus may cause delirium. In addition, there is evidence that the right hemisphere is dominant for attention. Cortical blood flow studies suggest that right hemisphere cortical areas and their limbic connections are the “attentional gate” for sensory input through feedback to the reticular nucleus of the thalamus.

Another explanation for delirium is alterations in neurotransmitters, particularly a cholinergic-dopaminergic imbalance. There is extensive evidence for a cholinergic deficit in delirium (Inouye, 2006). Anticholinergic agents can induce the clinical and EEG changes of delirium, which are reversible with the administration of cholinergic medications such as physostigmine. The beneficial effects of donepezil, rivastigmine, and galantamine—acetylcholinesterase-inhibitor medications used for Alzheimer disease—may be partly due to an activating or attention-enhancing role. Moreover, cholinergic neurons project from the pons and the basal forebrain to the cortex and make cortical neurons more responsive to other inputs. A decrease in acetylcholine results in decreased perfusion in the frontal cortex. Hypoglycemia, hypoxia, and other metabolic changes may differentially affect acetylcholine-mediated functions. Other neurotransmitters may be involved in delirium, including dopamine, serotonin, norepinephrine, γ-aminobutyric acid, glutamine, opiates, and histamine. Dopamine has an inhibitory effect on the release of acetylcholine, hence the delirium-producing effects of l-dopa and other antiparkinsonism medications (Trzepacz and van der Mast, 2002). Opiates may induce the effects by increasing dopamine and glutamate activity. Recently, polymorphisms in genes coding for a dopamine transporter and two dopamine receptors have been associated with the development of delirium (van Munster et al., 2010).

Inflammatory cytokines such as interleukins, interferon, and tumor necrosis factor alpha (TNF-α), may contribute to delirium by altering blood-brain barrier permeability and further affecting neurotransmission (Cole, 2004; Fong et al., 2009; Inouye, 2006). The combination of inflammatory mediators and dysregulation of the limbic-hypothalamic-pituitary axis may lead to exacerbation or prolongation of delirium (Maclullich et al., 2008). Finally, secretion of melatonin, a hormone integral to circadian rhythm and the sleep/wake cycle, may be abnormal in delirious patients compared to those without delirium (van Munster, de Rooij, and Korevaar, 2009).

Diagnosis

Diagnosis is a two-step process. The first step is the recognition of delirium, which requires a thorough history, a bedside mental status examination focusing on attention, and a review of established diagnostic scales or criteria for delirium. The second step is to identify the cause from a large number of potential diagnoses. Because the clinical manifestations offer few clues to the cause, crucial to the differential diagnosis are the general history, physical examination, and laboratory assessments.

The general history assesses several elements. An abrupt decline in mentation, particularly in the hospital, should be presumed to be delirium. Although patients may state that they cannot think straight or concentrate, family members or other good historians should be available to describe the patient’s behavior and medical history. The observer may have noted early symptoms of delirium such as inability to perform at a usual level, decreased awareness of complex details, insomnia, and frightening or vivid dreams. It is crucial to obtain accurate information about systemic illnesses, drug use, recent trauma, occupational and environmental exposures, malnutrition, allergies, and any preceding symptoms leading to delirium. Furthermore, the clinician should thoroughly review the patient’s medication list.