Delirium is a syndrome characterized by confusion with inattention, alteration of arousal, disorientation, and global cognitive impairment. All patients with delirium should be promptly evaluated because of the progressive and potentially lethal nature of many of the etiologic factors as well as the danger these patients may pose to themselves. Management of the underlying cause leads to resolution in most circumstances. In this chapter, the terms deliriumand confusion are used interchangeably.
All physicians encounter delirious patients during their careers, and knowing the patients at risk for delirium improves early recognition of the syndrome. The point prevalence of adults in the general population older than 55 years is 1.1%. About 10% to 40% of the hospitalized elderly and 60% of nursing home patients older than 75 years are delirious. Patients with cancer, AIDS, or a terminal illness and those who have undergone bone marrow transplantation and other surgical procedures are at increased risk of delirium.
I. ETIOLOGY
The common pathophysiologic mechanism of all causes of delirium is widespread dysfunction of both the cortical and the subcortical neurons.
A. The causes can affect a focal population or disrupt neuronal functioning diffusely.
B. The neurotransmitters acetylcholine and dopamine are known to play a central role in the regulation and communication of large numbers of neurons.
1. Cholinergic neuronal pathways serve almost all areas of the brain and participate in most executive brain functions, including those of a delirious patient.
a. Anticholinergic medications induce hyperactivity and decrease the ability to selectively attend.
2. Dopaminergic neurons are primarily found in the nigrostriatal, hypothalamic-pituitary, and ventral tegmental areas but diffusely project to the frontal and temporal areas responsible for delirious symptoms.
3. Intoxication with dopamine agonists commonly causes delirium.
4. Antidopaminergic (neuroleptics) actions are commonly used to manage delirium.
The causes of delirium (Table 1.1) include commonly encountered and rare conditions. Many are reversible and carry an excellent prognosis if the patient is treated in a timely manner. The following are the basic etiologic categories of delirium.
A. Infection is one of the most common causes of delirium.
1. Systemic infections always should be considered, especially with elderly patients and those with previous brain damage.
2. CNS infections should be a primary consideration in the postoperative neurosurgical and immunosuppressed patients.
B. Metabolic abnormalities are a common cause of delirium and often coexist with other precipitants of delirium.
C. End-organ failure manifests as striking abnormalities at general physical examination and usually is readily recognized.
1. Failure to promptly control hypotension and hypoxia can allow patients to suffer severe brain damage.
2. Liver and kidney failure can cause delirium alone or decrease the metabolism and excretion of certain medications and their metabolites.
TABLE 1.1 Causes of Delirium
Infection
Outside CNS
Sepsis
Localized
CNS
Meningitis
Bacterial
Tuberculous
Cryptococcal
Lyme disease
Syphilitic
Toxoplasmosis
Tertiary syphilis
Encephalitis
Herpes simplex
PML
HIV virus
Abscess
Brain
Epidural
Subdural empyema
Subacute spongiform encephalopathy
Whipple’s disease
Autoimmune
ADEM
Systemic lupus erythematosus
Metabolic abnormalities
Electrolyte disorders
Hyperosmolality, hypoosmolality
CPM
Hypernatremia, hyponatremia
Hypokalemia
Hypercalcemia
Hypophosphatemia
Hypermagnesemia, hypomagnesemia
Acid–base disorders
Acidosis
Alkalosis
End-organ failure
Hyperglycemia
Diabetic ketoacidosis
Hyperosmolar nonketotic hyperglycemia
Hypoglycemia
Hypercapnia
Hypoxia
Hypotension
Uremia
Hepatic encephalopathy
Reye’s syndrome
Pancreatic encephalopathy
Acute intermittent porphyria
Endocrinopathy
Hyperthyroidism, hypothyroidism
Cushing’s syndrome
Adrenal cortical insufficiency
Pituitary failure
Nutritional deficiency
Wernicke’s encephalopathy
Pellagra
Vitamin B12 deficiency
Intoxication
Acute alcohol intoxication
Alcohol withdrawal
Opioid intoxication
Cocaine intoxication
Amphetamine intoxication
Phencyclidine intoxication
Sedative-hypnotic intoxication
Sedative-hypnotic withdrawal
Barbiturate intoxication
Barbiturate withdrawal
Benzodiazepine intoxication
Benzodiazepine withdrawal
Lithium intoxication
Carbon monoxide poisoning
Medications
Hemorrhage
Intracranial hemorrhage
SAH
Aneurysm
Arteriovenous malformation
Disseminated intravascular coagulation
CNS trauma
Acute subdural hematoma
Subacute subdural hematoma
Epidural hematoma
SAH
Concussion
Contusion
Vascular
Transient ischemic attack
Cerebral infarction
Vasculitis
Venous occlusion
Tumors
CNS
Primary
Metastatic
Meningeal carcinomatosis
Paraneoplastic
Limbic encephalitis
Seizures
Generalized
Partial
Postconvulsive
Miscellaneous
Hypertensive encephalopathy
Beclouded dementia
Postoperative delirium
Cardiac bypass
Temperature dysregulation
Sensory deprivation
Sleep deprivation
Hydrocephalus
D. Endocrinopathy manifests as abnormalities of multiple organ systems and usually has a subacute onset.
E. Nutritional deficiencies most often (in the United States) affect patients with alcoholism, systemic cancer, and malabsorption syndromes.
F. Intoxication with and withdrawal from illicit drugs and alcohol can be life threatening and necessitate prompt recognition and timely intervention.
G. Medications cause delirium among patients who have impaired renal and liver function or interference with metabolism from other drugs especially those with anticholinergic and dopaminergic properties.
H. Hemorrhage and infarction in the CNS that cause delirium usually are associated with focal neurologic signs and are an emergency, frequently necessitating neurosurgical intervention.
I. CNS trauma can cause concussion, brain contusion, and epidural and subdural hematoma, each potentially manifesting as a confused state with associated focal neurologic features.
J. Vascular causes usually manifest as focal neurologic signs.
1. Lesions localizing to particular areas of the posterior circulation and right hemisphere may manifest as confusional states.
K. CNS tumors, malignant and benign, primary and metastatic, can cause prominent changes in mental status, including confusion, focal neurologic findings, headaches, and signs of increased intracranial pressure (ICP).
L. Seizures and postconvulsive states are common causes of intermittent confusion.
M. Hypertensive encephalopathy should be considered in patients with extreme hypertension and mental status changes.
N. Beclouded dementia and postoperative delirium are encountered frequently by physicians practicing in a general medical setting.
1. Patients with dementia are particularly sensitive to infections, metabolic abnormalities, and medications that may cause delirium.
II. CLINICAL MANIFESTATIONS
A. Mental status. Examination of a delirious patient is challenging.
1. Histories must be interpreted with skepticism. Seek information from families and friends.
2. Prodromal symptoms can develop abruptly or over hours to days, with resolution occurring in days to weeks. Hour-to-hour fluctuations of mental status are common.
3. Understanding the premorbid functioning of patients may assist in the diagnosis and prognosis, especially if the patient has an underlying structural pathologic condition.
4. The history and physical examination should be performed in a quiet room.
5. Avoid distractions or interruptions.
6. Restraints should be avoided if it can be done safely.
7. Engage the patient in a friendly and polite manner. Note whether the patient follows a logical progression of thoughts.
8. Frequent topic changes can signify confusion and avoid frustrating questions.
a. Attention. The hallmark of delirium is the inability to maintain selective attention to the environment and mental processes.
b. Orientation. Delirious patients often are disoriented to time and place but oriented to person.
c. Arousal. Changes in level of arousal are common, ranging from agitation with increased alertness to somnolence.
d. Memory. Because registration depends on the ability to focus attention, delirious patients frequently are unable to form new memories and do so only during lucid periods.
e. Perception. Impairment of both qualitative and quantitative perception is common for delirious patients. Hallucinations usually are either visual or auditory. Illusions and delusions are prominent.
f. Disordered thinking. Abnormalities of cognitive processing and problem solving are common.
g. Emotional disturbances. Marked emotional lability and inappropriate emotional responses occur frequently.
h. Language abnormalities. The inattention and distractibility of delirium challenges meaningful interaction and communication with others. The verbal output of delirious patients tends to be rambling and incoherent. Aphasia often is mistaken for confusion.
i. Disturbances of the sleep–wake cycle are common. Patients may remain awake for most of the day and night with only brief naps or may reverse their normal sleep pattern. The nocturnal exacerbation of confusion (“sundowning”) is common.
B. Other neurologic findings.
1. Papilledema is a sign of increased ICP or hypertensive encephalopathy. However, its absence does not rule out an increase in ICP.
2. Pupillary changes.
a. Fixed and dilated pupils occur with anticholinergic (e.g., atropine and scopolamine) intoxication.
b. Enlarged but reactive pupils are present with increased sympathetic activity, intoxication with amphetamines or cocaine, and therapeutic use of epinephrine and norepinephrine as pressor agents.
c. Midposition unreactive pupils can be caused by glutethimide overdose or focal midbrain dysfunction, often from distortion by an expanding supratentorial mass.
d. Use of opioids is associated with constriction of the pupils (<2 mm).
e. The presence of a unilaterally dilated pupil with or without the other components of third cranial nerve palsy is a sign of brainstem distortion. This is a neurologic emergency until proved otherwise and necessitates immediate diagnosis and treatment.
3. Abnormalities of ocular motility associated with confusion usually signal the presence of either increased ICP or brainstem distortion.
a. Upgaze palsy suggests a lesion of the dorsal upper midbrain or distortion due to hydrocephalus.
b. Unilaterally impaired eye adduction (with pupillary dilation) and diminished consciousness represent a third nerve palsy, which is a neurologic emergency.
c. Delirium with quadriparesis can occur as a result of central pontine myelinolysis (CPM), progressive multifocal leukoencephalopathy (PML), and acute disseminated encephalomyelitis (ADEM).
d. Delirium with paraparesis can occur with cryptococcosis, vitamin B12 deficiency, and ADEM.
e. Cushing’s disease and hypokalemia can manifest as proximal muscular weakness.
4. The presence of abnormal limb movement often is helpful in determining the cause of delirium.
a. Myoclonus is asynchronous irregular twitching of a single muscle, groups of muscles, or entire limbs, usually with proximal predominance. It can be associated with metabolic abnormalities, hypoxic-ischemic injury, lithium intoxication, and CNS infections.
b. Asterixis is recurrent brief lapses of posture observed with arms raised and elbows and wrists extended. It is a common manifestation of hepatic encephalopathy and uremia.
c. The tremor most frequently observed with delirium is coarse and irregular, most prominent in the fingers of the extended arms and absent at rest, and most commonly associated with hyperthyroidism, intoxication with sympathomimetics (amphetamine, cocaine, and phencyclidine), alcohol intoxication and withdrawal, and barbiturate and benzodiazepine withdrawal.
d. Gait ataxia is prominent with intoxication, vitamin B12 deficiency, syphilis, and Wernicke’s encephalopathy.
e. Seizures can cause confusion and often signify a structural brain abnormality, metabolic abnormality, or intoxication or withdrawal state.
(1) Partial complex seizures are the most common type of focal seizures that can cause confusion. Although rarely encountered, epilepsia partialis continua is a focal motor epilepsy whereby clonic movements of the face, arm, and leg recur intermittently for long periods of time.
(2) Generalized seizures can cause confusion or postconvulsive encephalopathy.
(3) Absence seizures are generalized seizures that induce brief lapses of consciousness with prominent automatisms.
III. EVALUATION
The neurologic findings of delirium are discussed in II.B.
A. The history is the most important part of the evaluation. Often family members and other observers must be the primary historian for delirious patients.
1. Headache. Acute headache reported by a confused patient can signify a severe intracranial pathologic condition such as subarachnoid hemorrhage (SAH) or intraparenchymal hemorrhage, whereas progressive headaches are more suggestive of a CNS neoplasm, infection, or hydrocephalus.
2. Previous brain damage. Patients with cerebral infarction, progressive neurologic disease, psychiatric illness, head trauma, or previous neurosurgical procedures are predisposed to delirium, often in association with other neurologic signs.
3. Preexisting medical conditions such as cardiac and lung disease are risk factors for life-threatening conditions that cause delirium.
4. Drug history. When evaluating a delirious patient, the clinician should always obtain a detailed substance abuse history.
5. Exposure history. Inquiries should be made about exposure to meningitis, HIV, carbon monoxide, and other potential CNS toxins.
6. Medications. Addition of new medications or changes of dosage frequently are associated with confusion.
B. General physical examination.
1. Abnormalities of vital signs often herald a medical emergency.
a. Hypotension from dehydration, sepsis, cardiac arrhythmia, or congestive heart failure must be recognized and controlled.
b. Tachycardia can be a manifestation of infection, cardiac abnormality, hyperthyroidism, dehydration, withdrawal states, intoxication with sympathomimetic drugs, or sympathetic overactivity from delirium.
c. Hypoventilation related to pneumonia or drug overdose can result in hypoxia or hypercapnia.
d. Increases in body temperature are associated with infection, withdrawal states, and hyperthyroidism. Hypothermia is associated with sepsis and barbiturate overdose.
2. Nuchal rigidity is a sign of meningeal irritation as frequently occurs with CNS infection and SAH. Meningitis, encephalitis, and SAH should be pursued diagnostically in the presence of nuchal rigidity or if clinical suspicion is high even in its absence.
3. In all cases of confusion, there should be a search for evidence of head trauma such as scalp laceration, depressed skull fracture, or hemotympanum.
4. Purulent drainage from the nares or a gray and immobile tympanic membrane can represent sinusitis or otitis media, respectively. The nasal septum should be examined for erosions due to cocaine use.
5. The skin should be examined for cyanosis, hirsutism, hyperpigmentation, and scaly dermatitis. The clinician should inspect the skin of all patients for the presence of track or “pop” marks, which imply intravenous drug use.
6. Examination of the heart can reveal murmurs and irregular rhythms that predispose patients to cerebral circulatory compromise.
7. Decreased or absent breath sounds can be caused by congestive heart failure or pneumonia, the resulting hypoxia potentially contributing to delirium.
8. Patients with abdominal tenderness should be evaluated for intraabdominal infection. Neurosurgical patients with a ventriculoperitoneal shunt can have shunt infection that manifests as abdominal peritonitis.
9. Patients with delirium from hepatic failure can have ascites, splenomegaly, spider telangiectasia, caput medusae, icteric sclera, and jaundice.
C. Ancillary tests.
1. Measurement of serum levels of electrolytes, glucose, blood urea nitrogen, and creatinine, complete blood cell count (with differential), liver enzymes, prothrombin and partial thromboplastin times,and arterial blood gases with arterial ammonia level cover all of the metabolic abnormalities that must be urgently identified.
2. A drug screen and a blood alcohol level should be included.
3. If the results of the foregoing laboratory tests are negative, HIV, fluorescent treponemal antibody-absorption, thyroid function, and cortisol stimulation tests are needed.
4. An ECG to rule out arrhythmia and cardiac ischemia and a chest radiograph to rule out infections (e.g., pneumonia) that contribute to delirium or pulmonary processes that can compromise ventilation and oxygenation should be obtained.
D. Lumbar puncture. If meningitis or encephalitis is suspected, CSF analysis is mandatory. CSF examination is also indicated if findings at CT of the brain are negative in cases of suspected SAH. Routine CSF analysis consists of WBC count with differential and RBC count, glucose and total protein, and Gram stain and culture. Often, patients with delirium need more than the basic CSF studies.
1. Contraindications to lumbar puncture.
a. Coagulopathy or platelet count <50,000 mm3.
b. Loss of cisternal spaces, evidence of brainstem distortion, absent or distorted fourth ventricle, and any posterior fossa mass on a CT scan.
c. Abscess over the lumbar puncture site.
d. Clinical suspicion of an intracranial mass lesion or increased ICP.
2. TheCSF WBC count is considered abnormal when more than four WBCs of any type or one neutrophil are found. An increased WBC count suggests CNS infection.
a. Neutrophils predominate in bacterial infection of the CNS and in early viral encephalitis, particularly that caused by enteroviruses.
b. Lymphocytes predominate in tuberculous and cryptococcal meningitis, syphilitic infection, herpes simplex encephalitis, toxoplasmosis, and HIV infection.
3. The presence of any RBCs in the CSF is abnormal and requires explanation. Traumatic tap is the most common cause.
a. Two important pathologic processes that increase the RBC count include SAH and herpes simplex encephalitis. Cerebral infarction, brain tumor (primary and metastatic), traumatic hematoma, and nontraumatic intracerebral hemorrhage inconsistently increase the RBC in the CSF.
b. Xanthochromia is yellow color caused by the presence of oxyhemoglobin and bilirubin from lysed RBCs in the supernatant of centrifuged CSF.
4. A normal CSF glucose level is >50% of the serum glucose level. A low CSF glucose occurs with CNS infection, SAH, hepatic failure, and hypoglycemia.
5. Increases in CSF protein level occur with CNS infection, hemorrhage, and obstruction of CSF flow.
a. Assuming a normal concentration of serum proteins, CSF protein level increases 1 mg per 1,000 RBCs. If a higher ratio is present, the presence of a pathologic process should be suspected.
6. CSF Gram stain and cultures should be performed on all CSF specimens. In cases of suspected bacterial meningitis, latex agglutination testing provides rapid identification of some common bacterial antigens.
7. PCR analysis can assist with the identification of CNS infection due to organisms not readily grown on culture media (e.g., viruses).
8. CSF cryptoccocal antigen staining can be used to rapidly determine the presence of cryptococci. Fungal cultures are more sensitive.
9. CSF cytologic evaluation is used to screen for carcinomatous meningitis, CNS lymphoma, and intracellular toxoplasmosis.
E. Neuroimaging.
1. CT can help identify most causes of delirium that involve structural damage to the brain, including intraparenchymal, epidural, subdural, and SAH, tumors, infarction, hydrocephalus, and edema.
a. The CT scan may be normal in cases of early cerebral infarction, meningitis, or hemorrhage of low volume or if the patient has severe anemia.
b. Intravenous contrast material should be administered for cases of suspected brain abscess or tumor. If the patient’s condition is stable, MRI should be performed instead of CT with contrast material.
2. MRI of the brain is useful in the evaluation of delirious patients with suspected herpes simplex encephalitis, white matter processes (e.g., ADEM), a posterior fossa mass, multiple lesions (e.g., metastasis and septic emboli), or immunosuppression.
3. Magnetic resonance angiography (MRA) and venography (MRV) of the brain are noninvasive diagnostic studies used to diagnose many conditions that affect the vasculature of the brain. Aneurysms, arteriovenous malformations, dissection of large vessels, cerebral venous sinus occlusion, and stenosis and occlusion of both intracranial and extracranial vessels often can be detected with MRA/MRV. Conventional angiography is more sensitive than is MRA/MRV for the diagnosis of CNS vascular disease.
4. Angiography should be considered when aneurysm, arteriovenous malformation, venous occlusive disease, or CNS vasculitis is suspected.
F. EEG has a role in the evaluation of delirious patients.
1. Almost all patients with delirium have an abnormal EEG with either a posterior dominant rhythm frequency of > 8 Hz or a relative decrease from an alpha wave of 12 to 10 Hz with mild encephalopathy. As the encephalopathy worsens, the background becomes disorganized, and high-voltage theta and delta activity (slowing) appears with loss of EEG reactivity at frequencies > 5 to 6 Hz.
2. EEG helps in the diagnosis of complex partial status epilepticus and absence seizures.
3. Specific EEG patterns such as triphasic waves or high-voltage slowing with sharp waves on a flat background can be seen.
G. Brain biopsy is rarely indicated for the evaluation of delirium. It is necessary when histologic typing of CNS tumors will affect management and outcome and in cases of suspected CNS vasculitis or abscess if the risks of empiric therapy outweigh the risks of the procedure.
IV. DIFFERENTIAL DIAGNOSIS
Certain conditions can masquerade as delirium (Table 1.2), often requiring an experienced clinician to differentiate the actual process from delirium. Accurate diagnosis is imperative for proper prescription of therapy.
A. Aphasia. Language formulation disturbance (aphasia) can be initially misdiagnosed as confusion. Because other focal abnormalities (e.g., visual field defects, hemiparesis, and hemisensory loss) frequently accompany aphasia more than they do delirium, focal examination findings should drive a thorough “ruling-out” of aphasia.
TABLE 1.2 Differential Diagnosis of Delirium
Aphasia
Mania
Psychosis
Depression
Dementia
Transient global amnesia
B. Psychiatric disorders usually are characterized by prominent changes in several aspects of the mental status examination. Examples include mania, depression, and schizophrenia. A manic patient has a consistently elevated mood, increased goal-directed activity, and grandiosity. In contrast, a delirious patient has emotional lability and is unable to complete tasks.
C. Dementia. Patients with dementia have memory impairment out of proportion to other aspects of the mental status examination.
D. Transient global amnesia usually occurs among middle-aged or elderly persons and is an acute, self-limited episode of amnesia that lasts for several hours. The memory deficit is for the present and recent past. The key features of delirium are notably absent.
V. DIAGNOSTIC APPROACH
In the evaluation of a patient with delirium, a logical, stepwise approach enables the clinician to rapidly and accurately diagnose the underlying cause.
A. On presentation, consider causes such as hypotension and hypoxia that are an immediate threat to life.
B. If oxygenation and circulation are adequate, a neurologic examination for signs of increased ICP, intracranial hemorrhage, cerebral infarction, tumor, or CNS infection should be performed. If the findings at examination are abnormal, emergency CT of the brain should be performed. If available, MRI or the brain should be considered if the patient has no contraindications and is medically stable.
C. On arrival, admission tests should be performed to rule out a metabolic, cardiac, or toxic cause.
D. EEG should be performed to rule out ictal activity, if seizures are suspected.
E. CT and EEG should be performed if all laboratory results are negative.
F. A lumbar puncture should be performed, if there are no contraindications, if CT and EEG have not led to a diagnosis.
G. MRI should be performed if the clinician suspects that a structural lesion exists despite normal CT findings or if encephalitis, a white matter process, multiple lesions, or a posterior fossa mass is suspected or the patient is immunosuppressed.
VI. CRITERIA FOR DIAGNOSIS
The diagnosis of delirium or acute confusion is given to any patient for whom the predominate abnormalities at mental status examination are inattention and a decline in general cognitive functioning. The Diagnostic and Statistical Manual of Mental Disorders-IV 1 lists the following criteria for the diagnosis of delirium due to a general medical condition:
A. Disturbance of consciousness (e.g., reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention.
B. A change in cognition (e.g., memory deficit, disorientation, and language disturbance) or the development of a perceptual disturbance that is not better accounted for by preexisting, established, or evolving dementia.
C. A disturbance that develops over a short time, usually hours to days, and tends to fluctuate during the course of the day.
D. Evidence from the history, physical examination, or laboratory findings that the disturbance is caused by the direct physiologic consequences of a general medical condition.
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1From the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, revised. Washington, DC: American Psychiatric Association, 2000. Reprinted with permission.