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29 Confusion and Delirium

pressure applied to a small nylon filament is used to assess sensation over the plantar aspect of the foot, can be used to screen for neuropathy in patients with diabetes. Sensory testing should also include proprio­ ceptive awareness at the great toe and ankle. A heel-to-shin test can assess cerebellar input on the lower extremity. The remainder of the neurologic examination should assess gait and balance as described earlier in this chapter. Fall Patterns  The description of a fall event may provide further clues to the underlying etiology. While there is no standard nosology of falls, some common clinical patterns may emerge and provide a clue. DROP ATTACKS AND COLLAPSING FALLS  Drop attacks and collapsing falls are associated with a sudden loss of postural tone. Patients may report that their legs just “gave out” underneath them or that they “col­ lapsed in a heap.” Syncope or orthostatic hypotension may be a factor in some such falls. Neurologic causes are relatively rare but include atonic seizures, myoclonus, and intermittent obstruction of the fora­ men of Monro by a colloid cyst of the third ventricle causing acute obstructive hydrocephalus. An emotional trigger suggests cataplexy. While collapsing falls are more common among older patients with vascular risk factors, drop attacks should not be confused with verte­ brobasilar ischemic attacks. TOPPLING FALLS  Some patients maintain tone in antigravity muscles but fall over like a tree trunk, as if postural defenses had disengaged. Causes include cerebellar pathology and lesions of the vestibular sys­ tem. There may be a consistent direction to such falls. Toppling falls are an early feature of PSP, and a late feature of Parkinson’s disease, once postural instability has developed. Thalamic lesions causing truncal instability (thalamic astasia) may also contribute to this type of fall. FALLS DUE TO GAIT FREEZING  Freezing of gait is seen in Parkinson’s disease and related disorders. The feet stick to the floor and the center of mass keeps moving, resulting in a disequilibrium from which the patient has difficulty recovering, resulting in a forward fall. Similarly, patients with Parkinson’s disease and festinating gait may find their feet unable to keep up and may thus fall forward. FALLS RELATED TO SENSORY LOSS  Patients with somatosensory, visual, or vestibular deficits are prone to falls. These patients have particular difficulty dealing with poor illumination or walking on uneven ground. They often report subjective imbalance, apprehension, and fear of falling. These patients may be especially responsive to a rehabilitation-based intervention. FALLS RELATED TO WEAKNESS  Patients who lack strength in antigrav­ ity muscles have difficulty rising from a chair or maintaining their bal­ ance after a perturbation. These patients are often unable to get up after a fall and may have to remain on the floor for a prolonged period until help arrives. If due to deconditioning, this is often treatable. Resistance strength training can increase muscle mass and leg strength, even for people in their eighties and nineties. TREATMENT Interventions to Reduce the Risk of Falls and Injury Efforts should be made to define the mechanism underlying falls in a given patient, as specific treatment may be possible once a diag­ nosis is established. Exercise should be recommended for everyone. Home- and group-based exercise programs focusing on leg strength and balance, physical therapy, and use of assistive devices reduce fall risk in individuals with a history of falls or disorders of gait and bal­ ance. Rehabilitative interventions aim to improve muscle strength and balance stability and to make the patient more resistant to injury and fracture. Resistance training with weights and machines is useful to improve muscle mass, even in frail older patients. Improvements realized in posture and gait should translate to reduced risk of falls and injury. Sensory balance training is another approach to improving balance stability. Measurable gains can be made in a few weeks of training, and benefits can be maintained over 6 months by a 10- to 20-min home exercise program. This

strategy is particularly successful in patients with vestibular and somatosensory balance disorders. The Centers for Disease Control and Prevention’s STEADI program (Stopping Elderly Accidents, Deaths and Injuries) is freely available online and contains tools for use by clinicians, patients, and their families to screen, assess, and offer interventions to minimize the risk of falls in older adults.

Orthostatic changes in blood pressure and pulse should be recorded. Contributory medications should be scrutinized and behavioral modifications initiated. Medications (including overthe-counter) should be reviewed, reevaluating benefits and burdens of medications that might increase fall risk. Treatment of cataracts and avoidance of multifocal lenses could be considered for patients whose falls may result from vision impairment. A home visit (often by an occupational therapist) to look for environmental hazards can be helpful. A variety of modifications may be recom­ mended to improve safety, including improved lighting, installation of grab bars and nonslip surfaces, and use of adaptive equip­ ment like walkers. Cognitive training, including dual-task training, may improve mobility in older adults with cognitive impairment. Adequate supervision appears to be most essential in this high-risk population. Confusion and Delirium CHAPTER 29 ■ ■FURTHER READING American Geriatrics Society, British Geriatrics Society, American Academy of Orthopedic Surgeons Panel on Falls Prevention: Guideline for the prevention of falls in older persons. J Am Geriatr Soc 49:664, 2001. Centers for Disease Control and Prevention: STEADI: Older Adult Fall Prevention. Available from https://www.cdc.gov/steadi/ index.html.  Accessed January 2, 2024. Colón-Emeric CS et al: Risk assessment and prevention of falls in older community-dwelling adults: A review. JAMA 331:1397, 2024. Nutt JG: Classification of gait and balance disorders. Adv Neurol 87:135, 2001. Pirker W, Katzenschlager R: Gait disorders in adults and the elderly. Wien Klin Wochenschr 129:81, 2017. S. Andrew Josephson, Bruce L. Miller

Confusion and Delirium Confusion, a mental and behavioral state of reduced comprehen­ sion, coherence, and capacity to reason, is one of the most common problems encountered in medicine, accounting for a large number of emergency department visits, hospital admissions, and inpatient con­ sultations. Delirium, a term used to describe an acute confusional state, remains a major cause of morbidity and mortality, costing billions of dollars yearly in health care costs in the United States alone. Despite increased efforts targeting awareness of this condition, delirium often goes unrecognized despite evidence that it is often the cognitive mani­ festation of serious underlying medical or neurologic illness. ■ ■CLINICAL FEATURES OF DELIRIUM A multitude of terms are used to describe patients with delirium, including encephalopathy, acute brain failure, acute altered mental status, acute confusional state, and postoperative or intensive care unit (ICU) psychosis. Delirium has many clinical manifestations, but it is defined as a relatively acute decline in cognition that fluctuates over hours or days. The hallmark of delirium is a deficit of attention, although all cognitive domains—including memory, executive func­ tion, visuospatial tasks, and language—are variably involved. Associ­ ated symptoms that may be present in some cases include altered

sleep-wake cycles, perceptual disturbances such as hallucinations or delusions, affect changes, and autonomic findings that include heart rate and blood pressure instability.

Delirium is a clinical diagnosis that is made only at the bedside. Two subtypes have been described—hyperactive and hypoactive—based on differential psychomotor features. The cognitive syndrome associ­ ated with severe alcohol withdrawal (i.e., “delirium tremens”) remains the classic example of the hyperactive subtype, featuring prominent hallucinations, agitation, and hyperarousal, often accompanied by lifethreatening autonomic instability. In striking contrast is the hypoactive subtype, exemplified by benzodiazepine intoxication, in which patients are withdrawn and quiet, with prominent apathy and psychomotor slowing. PART 2 Cardinal Manifestations and Presentation of Diseases This dichotomy between subtypes of delirium is a useful construct, but patients often fall somewhere along a spectrum between the hyperactive and hypoactive extremes, sometimes fluctuating from one to the other. Therefore, clinicians must recognize this broad range of presentations of delirium to identify all patients with this potentially reversible cognitive disturbance. Hyperactive patients are often easily recognized by their characteristic severe agitation, tremor, hallucina­ tions, and autonomic instability. Patients who are quietly hypoactive are more often overlooked and underdiagnosed on the medical wards and in the ICU. The reversibility of delirium is emphasized because many etiologies, such as infection and medication effects, can be treated easily. The long-term cognitive consequences of delirium remain an area of active research. Some episodes of delirium continue for weeks, months, or even years. The persistence of delirium in some patients and its high recurrence rate may be due to inadequate initial treatment of the underlying etiology, including neurodegenerative diseases. In other instances, delirium appears to cause permanent neuronal damage and long-term cognitive decline. Therefore, prevention strategies are important to implement. Even if an episode of delirium completely resolves, there may be lingering effects of the disorder; a patient’s recall of events after delirium varies widely, ranging from complete amnesia to repeated reexperiencing of the frightening period of confusion, similar to what is seen in patients with posttraumatic stress disorder. ■ ■RISK FACTORS An effective primary prevention strategy for delirium begins with identification of high-risk patients. Some hospital systems have initi­ ated comprehensive delirium programs that screen most or all patients upon admission or before elective surgery; positive screens trigger a host of focused prevention measures. Multiple validated scoring sys­ tems have been developed as a screen for asymptomatic patients, many of which emphasize well-established risk factors for delirium. The two most consistently identified risk factors are older age and baseline cognitive dysfunction. Individuals who are aged >65 or exhibit low scores on standardized tests of cognition develop delirium upon hospitalization at a rate approaching 50%. Whether age and baseline cognitive dysfunction are truly independent risk factors or are related is uncertain. Other predisposing factors include sensory deprivation, such as preexisting hearing and visual impairment, as well as indices for poor overall health, including baseline immobility, malnutrition, and underlying medical or neurologic illness. In-hospital risks for delirium include the use of physical restraints, bladder catheterization, sleep and sensory deprivation, and the addi­ tion of three or more new medications. Avoiding such risks remains a key component of delirium prevention as well as treatment. Surgi­ cal and anesthetic risk factors for the development of postoperative delirium include procedures such as those involving cardiopulmonary bypass, inadequate or excessive treatment of pain in the immediate postoperative period, and perhaps specific agents such as inhalational anesthetics or benzodiazepines. The relationship between delirium and dementia (Chap. 31) is com­ plicated by significant overlap between the two conditions, and it is not always simple to distinguish between them. Dementia and preexisting cognitive dysfunction serve as major risk factors for delirium, and at least two-thirds of cases of delirium occur in patients with coexisting

underlying dementia. A form of dementia with parkinsonism, demen­ tia with Lewy bodies (Chap. 445), is characterized by a fluctuating course, prominent visual hallucinations, parkinsonism, and an atten­ tional deficit that clinically resembles hyperactive delirium; patients with this condition are particularly vulnerable to delirium. Delirium in the elderly often reflects an insult to a brain that is vulnerable due to an underlying neurodegenerative condition. Therefore, the development of delirium sometimes heralds the onset of a previously unrecognized brain disorder, and after the acute delirious episode has cleared, careful screening for an underlying condition should occur in the outpatient setting. ■ ■EPIDEMIOLOGY Delirium is common, but its reported incidence has varied widely with the criteria used to define this disorder. Estimates of delirium in hospi­ talized patients range from 10% to >50%, with higher rates reported for elderly patients and patients undergoing hip surgery. Older patients in the ICU have especially high rates of delirium that approach 75%. The condition is not recognized in up to one-third of delirious inpatients, and the diagnosis is especially problematic in the ICU environment, where cognitive dysfunction is often difficult to appreciate in the setting of serious systemic illness and sedation. Delirium in the ICU should be viewed as an important manifestation of organ dysfunction not unlike liver, kidney, or heart failure. Outside the acute hospital setting, delirium occurs in nearly one-quarter of patients in nurs­ ing homes and in 50–80% of those at the end of life. These estimates emphasize the remarkably high frequency of this cognitive syndrome in older patients, a population that continues to grow. An episode of delirium was previously viewed as a transient condi­ tion that carried a benign prognosis. It is now recognized as a disorder with substantial morbidity and mortality that often represents the first manifestation of a serious underlying illness. Estimates of in-hospital mortality rates among delirious patients range from 25% to 33%, similar to mortality rates due to sepsis. Patients with an in-hospital episode of delirium have a fivefold higher mortality rate in the months after their illness compared with age-matched nondelirious hospital­ ized patients. Delirious hospitalized patients also have a longer length of stay, are more likely to be discharged to a nursing home, have a higher frequency of readmission, and are more likely to experience subsequent episodes of delirium and cognitive decline; as a result, this condition has an enormous economic cost. ■ ■PATHOGENESIS The pathogenesis and anatomy of delirium are incompletely under­ stood. The attentional deficit that serves as the neuropsychological hallmark of delirium has a diffuse localization within the brainstem, thalamus, prefrontal cortex, and parietal lobes. Rarely, focal lesions such as ischemic strokes have led to delirium in otherwise healthy persons; right parietal and medial dorsal thalamic lesions have been reported most commonly, pointing to the importance of these areas in delirium pathogenesis. In most cases, however, delirium results from widespread disturbances in cortical and subcortical regions of the brain. Electroencephalogram (EEG) often reveals symmet­ ric slowing, a nonspecific finding that supports diffuse cerebral dysfunction. Multiple neurotransmitter abnormalities, proinflammatory factors, and specific genes likely play a role in the pathogenesis of delirium. Deficiency of acetylcholine may play a key role, and medications with anticholinergic properties can commonly precipitate delirium. As noted earlier, patients with preexisting dementia are particularly susceptible to episodes of delirium. Alzheimer’s disease (Chap. 442), dementia with Lewy bodies (Chap. 445), and Parkinson’s disease dementia (Chap. 446) are all associated with cholinergic deficiency due to degeneration of acetylcholine-producing neurons in the basal forebrain. In addition, other neurotransmitters are also likely to be involved in this diffuse cerebral disorder. For example, increases in dopamine can lead to delirium, and patients with Parkinson’s disease treated with dopaminergic medications can develop a delirium-like state that features visual hallucinations, fluctuations, and confusion.

Not all individuals exposed to the same insult will develop signs of delirium. A low dose of an anticholinergic medication may have no cognitive effects on a healthy young adult but produce a florid delirium in an elderly person with known underlying dementia, although even healthy young persons develop delirium with very high doses of anticholinergic medications. This concept of delirium developing as the result of an insult in predisposed individuals is currently the most widely accepted pathogenic construct. Therefore, if a previously healthy individual with no known history of cognitive illness develops delirium in the setting of a relatively minor insult such as elective surgery, a urinary tract infection, or hospitalization, an unrecognized underlying neurologic illness such as a neurodegenerative disease, multiple previous strokes, or another diffuse cerebral cause should be considered. In this context, delirium can be viewed as a “stress test for the brain” whereby exposure to known inciting factors such as systemic infection and offending drugs can unmask a decreased cerebral reserve and herald a serious underlying and potentially treatable illness. New blood-based biomarkers for specific dementias may soon be available to help predict people at risk for delirium prior to surgical procedures or hospitalization. APPROACH TO THE PATIENT Delirium Because the diagnosis of delirium is clinical and is made at the bedside, a careful history and physical examination are necessary in evaluating patients with possible confusional states. Screening tools can aid physicians and nurses in identifying patients with delirium, including the Confusion Assessment Method (CAM); the Nursing Delirium Screening Scale (NuDESC); the Organic Brain Syndrome Scale; the Delirium Rating Scale; and, in the ICU, the ICU version of the CAM and the Delirium Detection Score. Using the well-

validated CAM, a diagnosis of delirium is made if there is (1) an acute onset and fluctuating course and (2) inattention accompanied by either (3) disorganized thinking or (4) an altered level of conscious­ ness. These scales may not identify the full spectrum of patients with delirium, and all patients who are acutely confused should be presumed delirious regardless of their presentation due to the wide variety of possible clinical features. A course that fluctuates over hours or days and may worsen at night (termed sundowning) is typical but not essential for the diagnosis. Observation will usu­ ally reveal an altered level of consciousness or a deficit of attention. Other features that are only sometimes present include alteration of sleep-wake cycles, thought disturbances such as hallucinations or delusions, autonomic instability, and changes in affect. HISTORY It may be difficult to elicit an accurate history in delirious patients who have altered levels of consciousness or impaired attention. Information from a collateral source such as a spouse or another family member is therefore invaluable. The three most important pieces of history are the patient’s baseline cognitive function, the time course of the present illness, and current medications. Premorbid cognitive function can be assessed through the col­ lateral source or, if needed, via a review of outpatient records. Delir­ ium by definition represents a change from a cognitive baseline that is relatively acute and usually develops over hours to days. An acute confusional state is nearly impossible to diagnose without some knowledge of baseline cognitive function. Without this informa­ tion, many patients with dementia or longstanding depression may be mistaken as delirious during a single initial evaluation. Patients with a more hypoactive, apathetic presentation with psychomotor slowing may be identified as being different from baseline only through conversations with family members. A number of vali­ dated instruments have been shown to diagnose cognitive dysfunc­ tion accurately using a collateral source, including the modified Blessed Dementia Rating Scale and the Clinical Dementia Rating (CDR). Baseline cognitive impairment is common in patients with

delirium. Even when no such history of cognitive impairment is elicited, there should still be a high suspicion for a previously unrec­ ognized underlying neurologic disorder. Establishing the time course of cognitive change is important not only to make a diagnosis of delirium but also to correlate the onset of the illness with potentially treatable etiologies such as recent medication changes or systemic infection. Medications remain a common cause of delirium, especially compounds with anticholinergic or sedative properties. It is esti­ mated that nearly one-third of all cases of delirium are secondary to medications, especially in the elderly. Medication histories should include all prescription as well as over-the-counter and herbal substances taken by the patient and any recent changes in dosing or formulation, including substitution of generics for brand-name medications. Confusion and Delirium CHAPTER 29 Other important elements of the history include screening for symptoms of organ failure or systemic infection, which often con­ tributes to delirium in the elderly. A history of illicit drug use, alcoholism, or toxin exposure is important, particularly in younger delirious patients. Finally, asking the patient and collateral source about other symptoms that may accompany delirium, such as depression or anxiety, may help identify potential therapeutic targets. PHYSICAL EXAMINATION The general physical examination in a delirious patient should include careful screening for signs of infection such as fever, tachy­ pnea, pulmonary consolidation, heart murmur, and meningismus. The patient’s fluid status should be assessed; both dehydration and fluid overload with resultant hypoxemia have been associated with delirium, and each is usually easily rectified. The appearance of the skin can be helpful, showing jaundice in hepatic encephalopathy, cyanosis in hypoxemia, or needle tracks in patients using intrave­ nous drugs. The neurologic examination requires a careful assessment of mental status. Patients with delirium often present with a fluctuat­ ing course; therefore, the diagnosis can be missed when one relies on a single time point of evaluation. For patients who worsen in the evening (sundowning), assessment only during morning rounds may be falsely reassuring. An altered level of consciousness ranging from hyperarousal to lethargy to coma is present in most patients with delirium and can be assessed easily at the bedside. In a patient with a relatively normal level of consciousness, a screen for an attentional deficit is in order, because this deficit is the classic neuropsychological hall­ mark of delirium. Attention can be assessed while taking a history from the patient. Tangential speech, a fragmentary flow of ideas, or inability to follow complex commands often signifies an attentional problem. There are formal neuropsychological tests to assess atten­ tion, but a simple bedside test of digit span forward is quick and fairly sensitive. In this task, patients are asked to repeat successively longer random strings of digits beginning with two digits in a row, said to the patient at one per second intervals. Healthy adults can repeat a string of five to seven digits before faltering; a digit span of four or less usually indicates an attentional deficit unless hearing or language barriers are present, and many patients with delirium have forward digit spans of three or fewer digits. More formal neuropsychological testing can be helpful in assess­ ing a delirious patient, but it is usually too cumbersome and time-consuming in the inpatient setting. A Mini-Mental State Examination (MMSE) provides information regarding orientation, language, and visuospatial skills (Chap. 31); however, performance of many tasks on the MMSE, including the spelling of “world” back­ ward and serial subtraction of digits, will be impaired by delirious patients’ attentional deficits, rendering the test unreliable. The remainder of the screening neurologic examination should focus on identifying new focal neurologic deficits. Focal strokes or mass lesions in isolation are rarely the cause of delirium, but patients with underlying extensive cerebrovascular disease or neurodegenerative

conditions may not be able to cognitively tolerate even relatively small new insults. Patients should be screened for other signs of neurode­ generative conditions such as parkinsonism, which is seen not only in idiopathic Parkinson’s disease but also in other dementing conditions including Alzheimer’s disease, dementia with Lewy bodies, and pro­ gressive supranuclear palsy. The presence of multifocal myoclonus or asterixis on the motor examination is nonspecific but usually indicates a metabolic or toxic etiology of the delirium. ETIOLOGY Some etiologies can be easily discerned through a careful history and physical examination, whereas others require confirmation with laboratory studies, imaging, or other ancillary tests. A large, diverse group of insults can lead to delirium, and the cause in many patients is multifactorial. Common etiologies are listed in Table 29-1. PART 2 Cardinal Manifestations and Presentation of Diseases Prescribed, over-the-counter, and herbal medications all can pre­ cipitate delirium. Drugs with anticholinergic properties, narcotics, and benzodiazepines are particularly common offenders, but nearly any compound can lead to cognitive dysfunction in a predisposed patient. Whereas an elderly patient with baseline dementia may become delirious upon exposure to a relatively low dose of a medi­ cation, in less susceptible individuals, delirium occurs only with very high doses of the same medication. This observation empha­ sizes the importance of correlating the timing of recent medication changes, including dose and formulation, with the onset of cogni­ tive dysfunction. In younger patients, illicit drugs and toxins are common causes of delirium. In addition to more classic drugs of abuse, the avail­ ability of fentanyl (Chap. 467), synthetic cannabis (Chap. 466), “bath salts,” methylenedioxymethamphetamine (MDMA, ecstasy), γ-hydroxybutyrate (GHB), and the phencyclidine (PCP)-like agent ketamine has led to an increase in delirious young persons present­ ing to acute care settings (Chap. 468). Many common prescription drugs such as oral narcotics and benzodiazepines are often abused and readily available on the street. Alcohol abuse leading to high serum levels causes confusion, but more commonly, it is withdrawal from alcohol that leads to a hyperactive delirium (Chap. 464). Alcohol and benzodiazepine withdrawal should be considered in all cases of delirium, including in the elderly, because even patients who drink only a few servings of alcohol every day can experience relatively severe withdrawal symptoms upon hospitalization. Metabolic abnormalities such as electrolyte disturbances of sodium, calcium, magnesium, or glucose can cause delirium, and mild derangements can lead to substantial cognitive disturbances in susceptible individuals. Other common metabolic etiologies include liver and renal failure, hypercarbia and hypoxemia, vitamin deficiencies of thiamine and B12, autoimmune disorders including central nervous system (CNS) vasculitis, and endocrinopathies such as thyroid and adrenal disorders. Systemic infections often cause delirium, especially in the elderly. A common scenario involves the development of an acute cogni­ tive decline in the setting of a urinary tract infection in a patient with baseline dementia. Pneumonia, skin infections such as cel­ lulitis, and frank sepsis also lead to delirium. This so-called septic encephalopathy, often seen in the ICU, is probably due to the release of proinflammatory cytokines and their diffuse cerebral effects. CNS infections such as meningitis, encephalitis, and abscess are less common etiologies of delirium, as are cases of autoimmune or para­ neoplastic encephalitis; however, in light of the high morbidity and mortality rates associated with these conditions when they are not treated, clinicians must always maintain a high index of suspicion. In some susceptible individuals, exposure to the unfamiliar envi­ ronment of a hospital itself can contribute to delirium. This etiology usually occurs as part of a multifactorial delirium and should be considered a diagnosis of exclusion after all other causes have been thoroughly investigated. Many primary prevention and treatment strategies for delirium involve relatively simple methods to address the aspects of the inpatient setting that are most confusing.

TABLE 29-1  Differential Diagnosis of Delirium Toxins Prescription medications: especially those with anticholinergic properties, narcotics, and benzodiazepines Drugs of abuse: alcohol intoxication and alcohol withdrawal, opiates, ecstasy, LSD, GHB, PCP, ketamine, cocaine, “bath salts,” marijuana and its synthetic forms Poisons: inhalants, carbon monoxide, ethylene glycol, pesticides Metabolic Conditions Electrolyte disturbances: hypoglycemia, hyperglycemia, hyponatremia, hypernatremia, hypercalcemia, hypocalcemia, hypomagnesemia Hypothermia and hyperthermia Pulmonary failure: hypoxemia and hypercarbia Liver failure/hepatic encephalopathy Renal failure/uremia Cardiac failure Vitamin deficiencies: B12, thiamine, folate, niacin Dehydration and malnutrition Anemia Infections Systemic infections: urinary tract infections, pneumonia and other respiratory infections, skin and soft tissue infections, sepsis CNS infections: meningitis, encephalitis, brain abscess Endocrine Conditions Hyperthyroidism, hypothyroidism Hyperparathyroidism Adrenal insufficiency Cerebrovascular Disorders Global hypoperfusion states Hypertensive encephalopathy Focal ischemic strokes and hemorrhages (rare): especially nondominant parietal and thalamic lesions Autoimmune Disorders CNS vasculitis Cerebral lupus Neurologic paraneoplastic and autoimmune encephalitis Seizure-Related Disorders Nonconvulsive status epilepticus Intermittent seizures with prolonged postictal states Neoplastic Disorders Diffuse metastases to the brain Diffuse glioma Carcinomatous meningitis CNS lymphoma Hospitalization Terminal end-of-life delirium Abbreviations: CNS, central nervous system; GHB, γ-hydroxybutyrate; LSD, lysergic acid diethylamide; PCP, phencyclidine. Cerebrovascular etiologies of delirium are usually due to global hypoperfusion in the setting of systemic hypotension from heart failure, septic shock, dehydration, or anemia. Focal strokes in the right parietal lobe and medial dorsal thalamus rarely can lead to a delirious state. A more common scenario involves a new focal stroke or hemorrhage causing confusion in a patient who has decreased cerebral reserve. In these individuals, it is sometimes difficult to distinguish between cognitive dysfunction resulting from the new neurovascular insult itself and delirium due to the infectious, metabolic, and pharmacologic complications that can accompany hospitalization after stroke.

Because a fluctuating course often is seen in delirium, intermit­ tent seizures may be overlooked when one is considering potential etiologies. Both nonconvulsive status epilepticus and recurrent focal or generalized seizures followed by postictal confusion can cause delirium; EEG remains essential for this diagnosis and should be considered whenever the etiology of delirium remains unclear following initial workup. Seizure activity spreading from an electri­ cal focus in a mass or infarct can explain global cognitive dysfunc­ tion caused by relatively small lesions. It is extremely common for patients to experience delirium at the end of life in palliative care settings. This condition must be identi­ fied and treated aggressively because it is an important cause of patient and family discomfort at the end of life. It should be remem­ bered that these patients also may be suffering from more common etiologies of delirium such as systemic infection. LABORATORY AND DIAGNOSTIC EVALUATION A cost-effective approach allows the history and physical examina­ tion to guide further tests after initial screening laboratory studies are obtained. No single algorithm will fit all delirious patients due to the staggering number of potential etiologies, but one stepwise approach is detailed in Table 29-2. If a clear precipitant such as an offending medication is identified, further testing may not be required. If, how­ ever, no likely etiology is uncovered with initial evaluation, an aggres­ sive search for an underlying cause should be initiated. TABLE 29-2  Stepwise Evaluation of a Patient with Delirium Initial Evaluation History with special attention to medications (including over-the-counter and herbals) General physical examination and neurologic examination Complete blood count Electrolyte panel including calcium, magnesium, phosphorus Liver function tests, including albumin Renal function tests First-Tier Further Evaluation Guided by Initial Evaluation Systemic infection screen   Urinalysis and culture   Chest radiograph and tests for respiratory pathogens   Blood cultures Electrocardiogram Arterial blood gas Serum and/or urine toxicology screen (perform earlier in young persons) Brain imaging with MRI with diffusion and gadolinium (preferred) or CT Suspected CNS infection or other inflammatory disorder: lumbar puncture after brain imaging Suspected seizure-related etiology: electroencephalogram (EEG) (if high suspicion, should be performed immediately) Second-Tier Further Evaluation Vitamin levels: B12, folate, thiamine Endocrinologic laboratories: thyroid-stimulating hormone (TSH) and free T4; cortisol Serum ammonia Sedimentation rate Autoimmune serologies: antinuclear antibodies (ANA), complement levels; p-ANCA, c-ANCA, consider paraneoplastic/autoimmune encephalitis testing in the serum and CSF Infectious serologies: rapid plasmin reagin (RPR); fungal and viral serologies if high suspicion; HIV antibody Lumbar puncture (if not already performed) Brain MRI with and without gadolinium (if not already performed) Abbreviations: c-ANCA, cytoplasmic antineutrophil cytoplasmic antibody; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; MRI, magnetic resonance imaging; p-ANCA, perinuclear antineutrophil cytoplasmic antibody.

Basic screening lab tests, including a complete blood count, electrolyte panel, and tests of liver and renal function, should be obtained in all patients with delirium. In elderly patients, screen­ ing for systemic infection, including chest radiography, urinalysis and culture, and possibly blood cultures, is important. In younger individuals, serum and urine drug and toxicology screening may be appropriate earlier in the workup. Additional laboratory tests addressing other autoimmune, endocrinologic, metabolic, and infectious etiologies should be reserved for patients in whom the diagnosis remains unclear after initial testing. Confusion and Delirium CHAPTER 29 Multiple studies have demonstrated that brain imaging in patients with delirium is often unhelpful. If, however, the ini­ tial workup is unrevealing, most clinicians quickly move toward imaging of the brain to exclude structural causes. A noncontrast computed tomography (CT) scan can identify large masses and hemorrhages but is otherwise unlikely to help determine an etiol­ ogy of delirium. The ability of magnetic resonance imaging (MRI) to identify nearly all acute ischemic strokes as well as to provide neuroanatomic detail that gives clues to possible infectious, inflam­ matory, neurodegenerative, and neoplastic conditions makes it the test of choice. Because MRI techniques are limited by availability, speed of imaging, patient’s cooperation, and contraindications, many clinicians begin with CT scanning and proceed to MRI if the etiology of delirium remains elusive. Lumbar puncture (LP) must be obtained immediately after neuroimaging for all patients in whom CNS infection is suspected. Spinal fluid examination can also be useful in identifying autoim­ mune, other inflammatory, and neoplastic conditions. As a result, LP should be considered in any delirious patient with a negative workup. EEG remains invaluable if seizures are considered or if there is no cause readily identified. TREATMENT Delirium Management of delirium begins with treatment of the underlying inciting factor (e.g., patients with systemic infections should be given appropriate antibiotics, and underlying electrolyte distur­ bances should be judiciously corrected). These treatments often lead to prompt resolution of delirium. Blindly targeting the symp­ toms of delirium pharmacologically only serves to prolong the time patients remain in the confused state and may mask important diagnostic information. Relatively simple methods of supportive care can be highly effective (Fig. 29-1). Reorientation by the nursing staff and fam­ ily combined with visible clocks, calendars, and outside-facing windows can reduce confusion. Sensory isolation should be pre­ vented by providing glasses and hearing aids to patients who need them. Sundowning can be addressed to a large extent through vigilance to appropriate sleep-wake cycles. During the day, a well-lit room should be accompanied by activities or exercises to prevent napping. At night, a quiet, dark environment with limited interruptions by staff can assure proper rest; melatonin can be considered before bed to promote sleep. These sleep-wake cycle interventions are especially important in the ICU setting as the usual constant 24-h activity commonly provokes delirium. Attempting to mimic the home environment as much as possible also has been shown to help treat and even prevent delirium. Visits from friends and family throughout the day minimize the anxiety associated with the constant flow of new faces of staff and physicians. Allowing hospitalized patients to have access to home bedding, clothing, and nightstand objects makes the hospital environment less foreign and therefore less confusing. Simple standard nursing practices such as maintaining proper nutri­ tion and volume status as well as managing pain, incontinence, and skin breakdown also help alleviate discomfort and resulting confusion.