ABSTRACT: Delirium is highly prevalent in cancer patients with advanced disease. Frequently a preterminal event, the condition is a sign of significant physiologic disturbance, typically involving multiple medical etiologies including infection, organ failure, adverse medication effects, and in rare situations, paraneoplastic syndromes. Unfortunately, delirium is frequently underrecognized or misdiagnosed and, therefore, inappropriately treated or untreated in terminally ill patients. The clinical features of delirium are numerous and encompass a variety of neuropsychiatric symptoms common to other psychiatric disorders. Three clinical subtypes of delirium, based on arousal disturbance and psychomotor behavior, have been described: hyperactive, hypoactive, and mixed. The differential diagnosis for delirium includes depression, mania, psychosis, and dementia. Numerous instruments have been developed to aid the clinician in rapidly screening for the disorder. Standard management requires an investigation of the etiologies, correction of the contributing factors, and management of symptoms. Symptomatic and supportive therapies, including numerous pharmacologic approaches, are important, but several aspects of the use of neuroleptics and other agents in the management of delirium in the dying patient remain controversial.
Delirium is the most common and serious neuropsychiatric complication in cancer patients with advanced illness and has enormous relevance to symptom control and palliative care. The condition is highly prevalent in cancer patients with advanced disease, particularly in the last weeks of life, with prevalence rates ranging from 25% to 85%.[1-8] Indeed, delirium is one of the most common mental disorders encountered in general hospital practice. An estimated 33% of hospitalized medically ill patients have serious cognitive impairments.
In a study of 334 hospitalized cancer patients evaluated by psychiatric consultation, 25% were diagnosed with delirium. In a smaller sampling of 13 terminal cancer patients, 85% were diagnosed with delirium. Pereira and coworkers identified the prevalence of cognitive impairment in cancer inpatients to be 44%, with the prevalence rising to 62.1% prior to death. Delirium has been described in up to 51% of postoperative patients.[11,12]
With increased numbers of elderly patients who are particularly susceptible, the incidence of delirium is rising. Studies of elderly patients admitted to medical wards estimate that 30% to 50% of patients age 70 years or older demonstrate symptoms of delirium at some point during their hospitalization.[13-17] Elderly patients who develop delirium during a hospitalization have an estimated 22% to 76% chance of dying during that admission.
Delirium in the Terminally Ill
In the terminally ill, delirium is associated with increased morbidity, which causes distress in patients, family members, and staff.[2,19,20] In a recent study of terminally ill cancer patients, Breitbart and colleagues discovered that 54% of patients recalled their delirium experience after resolution of their delirium. Factors predicting diminished recollection of the delirium experience included severe short-term memory impairment, severe delirium, and the presence of intense perceptual disturbances.
In the same study, distress related to the episode of delirium was rated by patients, spouses or caregivers, and nurses. Distress was rated as severe by all three groups, with the spouse or caregiver group experiencing the most distress. A significant predictor of heightened spouse distress was a low Karnofsky performance status for the patient, indicating debilitation. The most significant factor predicting distress for patients was the presence of delusions. Patients with hypoactive delirium were as distressed as patients with hyperactive delirium (see Subtypes of Delirium, below). Delirium severity and intensity of perceptual disturbances also enhanced nurses' distress. In the later stages of illness, delirium interferes dramatically with the recognition and control of other physical and psychological symptoms such as pain.[21-23]
A recent retrospective study of 284 hospice patients sought to identify factors that contribute to the impairment of communication capacity in terminally ill cancer patients. The study demonstrated that communication capacity was frequently impaired in terminally ill cancer patients, and the degree of impairment significantly associated with higher doses of opioids. Patients who did not require high doses of opioids were able to retain complex and simple communication capacity longer than those who required high doses of opioids prior to death. Delirium was found in 20% of patients in this study, which emphasized the importance of further investigations to explore new strategies for maintaining communication capacity in this population.
Frequently a preterminal event, delirium is a sign of significant physiologic disturbance, typically involving multiple medical etiologies including infection, organ failure, adverse medication effects, and in rare situations, paraneoplastic syndromes.[8,25-28] Lawlor and colleagues recently reported on their experience in the management of delirium in advanced cancer patients admitted to a palliative care unit. While only 42% of patients had delirium upon admission, "terminal" delirium was seen in 88% of patients at the time of death.
Unfortunately, delirium is frequently underrecognized or misdiagnosed, and therefore inappropriately treated or untreated in terminally ill patients. Impediments to progress in the recognition and treatment of delirium include confusion regarding terminology as well as lack of consistency in utilizing diagnostic classification systems. In addition, the signs and symptoms of delirium are diverse and frequently mistaken for other psychiatric disorders. Practitioners need to diagnose delirium accurately, undertake appropriate assessment of etiologies, and familiarize themselves with the benefits and risks of pharmacologic and nonpharmacologic interventions currently available to manage delirium in the terminally ill.
The clinical features of delirium are numerous and encompass a variety of neuropsychiatric symptoms common to other psychiatric disorders, including depression, dementia, and psychosis. Clinical features of delirium include prodromal symptoms (restlessness, anxiety, sleep disturbance, and irritability); rapidly fluctuating course; reduced attention (easily distractible); altered arousal; increased or decreased psychomotor activity; disturbance of the sleep-wake cycle; affective symptoms (emotional lability, sadness, anger, or euphoria); altered perceptions (misperceptions, illusions, poorly formed delusions, and hallucinations); disorganized thinking and incoherent speech; disorientation as to time, place, or person; and memory impairment (difficulty registering new material).
Neurologic abnormalities may be present during delirium, including cortical abnormalities (dysgraphia, constructional apraxia, dysnomic aphasia); motor abnormalities (tremor, asterixis, myoclonus, and reflex or tone changes); and electroencephalogram (EEG) abnormalities (typically global slowing). The protean nature of delirium, with its profound variability and fluctuation in clinical course, makes the condition more difficult to diagnose accurately and treat effectively.
Table 1 lists the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), criteria for delirium. The essential defining features of delirium, based on DSM-IV criteria, have shifted from an extensive list of typical symptoms and abnormalities to a focus on the two essential concepts of disordered attention (arousal) and cognitive disturbance. The definition continues to recognize the importance of acute onset, fluctuating course, and organic etiology. Associated phenomena including altered psychomotor activity and behavior, perceptual disturbances, and delusions are not essential for the diagnosis of delirium.
Delirium is now conceptualized primarily as "a disorder of arousal and cognition," in contrast to dementia, which is a disorder of cognition without an arousal disturbance. Disorder of the arousal system resulting in altered levels of consciousness and impaired attention is pathognomonic of delirium. This arousal disturbance is, in part, the basis for classifying delirium into several subtypes.
Subtypes of Delirium
Three clinical subtypes of delirium, based on arousal disturbance and psychomotor behavior, have been described. These include the hyperactive subtype (hyperaroused, hyperalert, or agitated), the hypoactive subtype (hypoaroused, hypoalert, or lethargic), and a mixed subtype with alternating features of hyperactive and hypoactive delirium.[33,34] Research suggests that the hyperactive subtype is more frequently characterized by hallucinations, delusions, agitation, and disorientation, whereas the hypoactive subtype is characterized by confusion and sedation, and less frequently accompanied by hallucinations or delusions.
In addition, there is evidence suggesting that the subtypes of delirium may result from specific etiologies, demonstrate unique pathophysiologies, and display differential responses to treatment.[36,37] An estimated 67% of cases of delirium are either the hypoactive or mixed subtype. The prototypical agitated delirium most familiar to clinicians actually occurs in a minority of cases.[33-35]
Many of the clinical features and symptoms of delirium may be associated with other psychiatric disorders including depression, mania, psychosis, or dementia. A patient with delirium may exhibit mood disturbances such as anxiety, fear, depression, irritability, anger, euphoria, apathy, or mood lability.
• Depression and Mania—Delirium, particularly the hypoactive subtype, is often initially misdiagnosed as depression. Symptoms of major depression, including altered level of activity (hypoactivity), insomnia, impaired concentration, depressed mood, and suicidal ideation, may overlap with symptoms of delirium, making an accurate diagnosis more difficult. To differentiate delirium from depression, particularly in the context of advanced disease, an evaluation of the onset and temporal sequencing of depressive and cognitive symptoms is particularly helpful. Importantly, the degree of cognitive impairment in delirium is more severe, pervasive, and abrupt in onset than that associated with depression. Most notably, in delirium, a disturbance in arousal or consciousness is present. Arousal disturbance is not characteristic of depression.
Similarly, a manic episode may share some features of delirium, particularly the hyperactive or mixed subtype. Again, the temporal onset and course of symptoms, as well as the presence of an arousal disturbance associated with cognitive impairment, assist in differentiating these disorders.
•Psychosis—Delirium characterized by vivid hallucinations and delusions must be distinguished from a variety of psychotic disorders. In delirium, psychotic symptoms occur in the context of a disturbance in consciousness or arousal associated with memory impairment and disorientation. These features are not present in other psychotic disorders. The delusions associated with delirium tend to be poorly organized and abrupt in onset. Visual and tactile hallucinations predominate in delirium, in contrast to the auditory hallucinations more characteristic of schizophrenia. Finally, the development of these psychotic symptoms in the context of advanced medical illness makes delirium a more likely diagnosis.
• Dementia—A common diagnostic task is to differentiate delirium from dementia or delirium superimposed upon a preexisting dementia. Both delirium and dementia are cognitive impairment disorders, sharing clinical features such as impaired memory, disordered thinking, limited judgment, and disorientation. However, the patient with dementia is alert without the disturbance of consciousness or arousal characteristic of delirium. The temporal onset of symptoms in dementia is subacute and chronically progressive, and the patient's sleepwake cycle is less disrupted. The most prominent disturbances in dementia include short- and long-term memory deficits, impaired judgment, reduced capacity for abstract thinking, and alterations in higher cortical functions (aphasia and apraxia).
In contrast to dementia, delirium is typically conceptualized as a reversible process. Delirium is frequently reversible even in patients with advanced illness. However, delirium may not be reversible in the last 24 to 48 hours of life. This is most likely due to irreversible processes including multiple organ failure. Delirium occurring in these last days of life is sometimes referred to as "terminal" delirium in the palliative care literature.
Delirium Screening/Diagnostic Scales
Numerous scales or instruments have been developed to aid the clinician in rapidly screening for cognitive impairment disorders (dementia or delirium), or in establishing a diagnosis of delirium (see Table 2).[38- 46] Such scales have been described, and their relative strengths and weaknesses reviewed elsewhere.[43,47] Perhaps most helpful to clinicians are the Mini-Mental State Examination (a cognitive impairment screening tool) and several delirium diagnostic and severity rating scales, including the Delirium Rating Scale, the Delirium Rating Scale-Revised-98, the Confusion Assessment Method, the Abbreviated Cognitive Test for Delirium, and the Memorial Delirium Assessment Scale. These tools are briefly described in the subsections below.
• Mini-Mental State Examination— The Mini-Mental State Examination (MMSE) is useful in screening for cognitive failure but does not distinguish between delirium and dementia. The MMSE provides a quantitative assessment of the patient's cognitive performance and capacity, measuring the severity of cognitive impairment. It is most sensitive to cortical dementias such as Alzheimer's disease and less sensitive in detecting subcortical deficits such as those found in AIDS dementia.
The MMSE assesses five general cognitive areas: orientation, registration, attention/calculation, delayed recall, and language. Traditionally, a score of 23 or less is considered indicative of cognitive impairment. However, a multitiered system is frequently utilized, with a score of 24- 30 indicating no impairment, a score of 18-23 indicating mild impairment, and a score of 0-17 indicating severe impairment.
• Delirium Rating Scale—The Delirium Rating Scale (DRS), developed by Trzepacz and colleagues is a 10-item clinician-rated symptom rating scale for diagnosing delirium. Based on DSM-III-R (third edition, revised) diagnostic criteria for delirium, the scale is designed to be used by the clinician to identify delirium and distinguish it reliably from dementia and other neuropsychiatric disorders. Each item is scored by choosing the best rating, which has a numerical weight designed to distinguish the phenomenologic characteristics of delirium. A score of 12 or greater is diagnostic of delirium.
• Delirium Rating Scale-Revised 98—A revision of the Delirium Rating Scale (DRS), the Delirium Rating Scale-Revised 98 (DRS-R-98) has 13 severity and 3 diagnostic items with descriptive anchors for each rating level. Although it was designed for phenomenologic and treatment research, the scale may be used clinically. Indeed, the DRS-R-98 is a valid, sensitive, and reliable instrument for the rating of delirium severity. It has advantages over the original DRS for repeated measures and phenomenologic studies due to its enhanced breadth of symptoms and separation into severity and diagnostic subscales.
• Confusion Assessment Method— The Confusion Assessment Method (CAM) is a nine-item delirium diagnostic scale utilizing the DSMIII- R criteria for delirium, which can be administered rapidly by a trained clinician. The CAM may be administered using a simplified diagnostic algorithm that includes only four items designed for rapid identification of delirium by nonpsychiatrists. The fouritem algorithm requires an acute onset and a fluctuating course with inattention and either disorganized thinking or altered level of consciousness.
• Abreviated Cognitive Test for Delirium—Abreviated Cognitive Test for Delirium (CTD) was recently developed as a tool to identify delirium in patients in the intensive care unit setting who have limited ability to communicate verbally. This brief tool utilizes visualization span and recognition memory of pictures. It reliably identifies delirium and discriminates delirium from dementia, depression, and schizophrenia.
• Memorial Delirium Assessment Scale—Memorial Delirium Assessment Scale (MDAS) is a 10-item delirium assessment tool (see Table 3), validated among hospitalized inpatients with advanced cancer and AIDS. The MDAS is both a good delirium diagnostic screening tool as well as a reliable tool for assessing delirium severity among patients with advanced disease. A cutoff score of 13 is diagnostic of delirium. The MDAS has advantages over other delirium tools in that it is both a diagnostic and a severity measure ideal for repeated assessments and for treatment intervention trials. Recently, Lawlor and colleagues further examined the clinical utility and validation of the MDAS in a population of advanced cancer patients in a palliative care unit. The investigators demonstrated the usefulness of the MDAS in this select population. A cutoff score of 7 out of 30 yielded the highest sensitivity (98%) and specificity (76%) for a delirium diagnosis in this palliative care population.