Dementia

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33e

Video Library of Gait Disorders

Gail Kang, Nicholas B. Galifianakis, Michael D. Geschwind


Problems with gait and balance are major causes of falls, accidents, and resulting disability, especially in later life, and are often harbingers of neurologic disease. Early diagnosis is essential, especially for treatable conditions, because it may permit the institution of prophylactic measures to prevent dangerous falls and also to reverse or ameliorate the underlying cause. In this video, examples of gait disorders due to Parkinson’s disease, other extrapyramidal disorders, and ataxias, as well as other common gait disorders, are presented.

 

34

Confusion and Delirium

S. Andrew Josephson, Bruce L. Miller


Confusion, a mental and behavioral state of reduced comprehension, 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 consultations. Delirium, a term used to describe an acute confusional state, remains a major cause of morbidity and mortality, costing over $150 billion dollars yearly in health care costs in the United States alone. Despite increased efforts targeting awareness of this condition, delirium often goes unrecognized in the face of evidence that it is usually the cognitive manifestation 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 confusional state, and postoperative or intensive care unit (ICU) psychosis. Delirium has many clinical manifestations, but 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 function, visuospatial tasks, and language—are variably involved. Associated 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 associated 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 life-threatening 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.

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, hallucinations, and autonomic instability. Patients who are quietly hypoactive are more often overlooked on the medical wards and in the ICU.

The reversibility of delirium is emphasized because many etiologies, such as systemic infection and medication effects, can be treated easily. The long-term cognitive effects of delirium remain largely unknown. 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. In other instances, delirium appears to cause permanent neuronal damage and cognitive decline. 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 re-experiencing 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 patients at high risk for this disorder, including those preparing for elective surgery or being admitted to the hospital. Although no single validated scoring system has been widely accepted as a screen for asymptomatic patients, there are multiple well-established risk factors for delirium.

The two most consistently identified risks are older age and baseline cognitive dysfunction. Individuals who are over age 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 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 bladder catheterization, physical restraints, sleep and sensory deprivation, and the addition of three or more new medications. Avoiding such risks remains a key component of delirium prevention as well as treatment. Surgical and anesthetic risk factors for the development of postoperative delirium include specific 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.

The relationship between delirium and dementia (Chap. 448) is complicated 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, termed dementia with Lewy bodies, is characterized by a fluctuating course, prominent visual hallucinations, parkinsonism, and an attentional deficit that clinically resembles hyperactive delirium; patients with this condition are particularly vulnerable to delirium. Delirium in the elderly often reflects an insult to the 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.

EPIDEMIOLOGY

Delirium is common, but its reported incidence has varied widely with the criteria used to define this disorder. Estimates of delirium in hospitalized patients range from 18 to 64%, 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 nursing homes and in 50 to 80% of those at the end of life. These estimates emphasize the remarkably high frequency of this cognitive syndrome in older patients, a population expected to grow in the upcoming decades.

Until recently, an episode of delirium was viewed as a transient condition that carried a benign prognosis. It is now recognized as a disorder with a substantial morbidity rate and increased mortality rate and often represents the first manifestation of a serious underlying illness. Recent estimates of in-hospital mortality rates among delirious patients have ranged from 25 to 33%, a rate similar to that of patients with 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 hospitalized patients. Delirious hospitalized patients have a longer length of stay, are more likely to be discharged to a nursing home, and are more likely to experience subsequent episodes of delirium and cognitive decline; as a result, this condition has enormous economic implications.

PATHOGENESIS

The pathogenesis and anatomy of delirium are incompletely understood. 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 to delirium pathogenesis. In most cases, delirium results from widespread disturbances in cortical and subcortical regions rather than a focal neuroanatomic cause. Electroencephalogram (EEG) data in persons with delirium usually show symmetric 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 also can precipitate delirium. Dementia patients are susceptible to episodes of delirium, and those with Alzheimer’s pathology and dementia with Lewy bodies or Parkinson’s disease dementia are known to have a chronic cholinergic deficiency state due to degeneration of acetylcholine-producing neurons in the basal forebrain. Additionally, other neurotransmitters are also likely to be involved in this diffuse cerebral disorder. For example, increases in dopamine can also lead to delirium. 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 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.


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) (Table 34-1); 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 consciousness. 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 of the patient usually will reveal an altered level of consciousness or a deficit of attention. Other features that are sometimes present include alteration of sleep-wake cycles, thought disturbances such as hallucinations or delusions, autonomic instability, and changes in affect.

TABLE 34-1

THE CONFUSION ASSESSMENT METHOD (CAM) DIAGNOSTIC ALGORITHMa


The diagnosis of delirium requires the presence of features 1 and 2 and of either feature 3 or 4.

Feature 1. Acute onset and fluctuating course


    This feature is satisfied by positive responses to the following questions: Is there evidence of an acute change in mental status from the patient’s baseline? Did the (abnormal) behavior fluctuate during the day, that is, tend to come and go, or did it increase and decrease in severity?

Feature 2. Inattention


    This feature is satisfied by a positive response to the following question: Did the patient have difficulty focusing attention, for example, being easily distractible, or have difficulty keeping track of what was being said?

Feature 3. Disorganized thinking


    This feature is satisfied by a positive response to the following question: Was the patient’s thinking disorganized or incoherent, such as rambling or irrelevant conversation, unclear or illogical flow of ideas, or unpredictable switching from subject to subject?

Feature 4. Altered level of consciousness


    This feature is satisfied by any answer other than “alert” to the following question: Overall, how would you rate the patient’s level of consciousness: alert (normal), vigilant (hyperalert), lethargic (drowsy, easily aroused), stupor (difficult to arouse), or coma (unarousable)?


aInformation is usually obtained from a reliable reporter, such as a family member, caregiver, or nurse.

Source: Modified from SK Inouye et al: Clarifying confusion: The Confusion Assessment Method. A new method for detection of delirium. Ann Intern Med 113:941, 1990.

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 collateral source or, if needed, via a review of outpatient records. Delirium by definition represents a change that is relatively acute, usually over hours to days, from a cognitive baseline. As a result, an acute confusional state is nearly impossible to diagnose without some knowledge of baseline cognitive function. Without this information, many patients with dementia or 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 validated instruments have been shown to diagnose cognitive dysfunction 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 unrecognized 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 symptoms of systemic infection.

Medications remain a common cause of delirium, especially compounds with anticholinergic or sedative properties. It is estimated 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.

Other important elements of the history include screening for symptoms of organ failure or systemic infection, which often contributes to delirium in the elderly. A history of illicit drug use, alcoholism, or toxin exposure is common in younger delirious patients. Finally, asking the patient and collateral source about other symptoms that may accompany delirium, such as depression, 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, tachypnea, pulmonary consolidation, heart murmur, and stiff neck. 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 intravenous drugs.

The neurologic examination requires a careful assessment of mental status. Patients with delirium often present with a fluctuating course; therefore, the diagnosis can be missed when one relies on a single time point of evaluation. Some but not all patients exhibit the characteristic pattern of sundowning, a worsening of their condition in the evening. In these cases, 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 hallmark 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 attention, 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 1-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 digit spans of three or fewer digits.

More formal neuropsychological testing can be helpful in assessing 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; however, performance of many tasks on the MMSE, including the spelling of “world” backward 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 neurodegenerative conditions such as parkinsonism, which is seen not only in idiopathic Parkinson’s disease but also in other dementing conditions such as Alzheimer’s disease, dementia with Lewy bodies, and progressive 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 often multifactorial. Common etiologies are listed in Table 34-2.

TABLE 34-2

COMMON ETIOLOGIES 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, 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 syndromes

Seizure-related disorders

    Nonconvulsive status epilepticus

    Intermittent seizures with prolonged postictal states

Neoplastic disorders

    Diffuse metastases to the brain

    Gliomatosis cerebri

    Carcinomatous meningitis

    CNS lymphoma

Hospitalization

Terminal end-of-life delirium


Abbreviations: CNS, central nervous system; GHB, γ-hydroxybutyrate; LSD, lysergic acid diethylamide; PCP, phencyclidine.

Prescribed, over-the-counter, and herbal medications all can precipitate 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 medication, less susceptible individuals may become delirious only with very high doses of the same medication. This observation emphasizes the importance of correlating the timing of recent medication changes, including dose and formulation, with the onset of cognitive dysfunction.

In younger patients, illicit drugs and toxins are common causes of delirium. In addition to more classic drugs of abuse, the recent rise in availability of methylenedioxymethamphetamine (MDMA, ecstasy), γ-hydroxybutyrate (GHB), “bath salts,” synthetic cannabis, and the phencyclidine (PCP)-like agent ketamine, has led to an increase in delirious young persons presenting to acute care settings (Chap. 469e). 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. Alcohol and benzodiazepine withdrawal should be considered in all cases of delirium 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 cognitive decline in the setting of a urinary tract infection in a patient with baseline dementia. Pneumonia, skin infections such as cellulitis, 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; however, in light of the high mortality rates associated with these conditions when they are not treated quickly, clinicians must always maintain a high index of suspicion.

In some susceptible individuals, exposure to the unfamiliar environment of a hospital itself can lead 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.

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, intermittent 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. Seizure activity spreading from an electrical focus in a mass or infarct can explain global cognitive dysfunction caused by relatively small lesions.

It is very common for patients to experience delirium at the end of life in palliative care settings. This condition, sometimes described as terminal restlessness, must be identified and treated aggressively because it is an important cause of patient and family discomfort at the end of life. It should be remembered 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 to the diagnostic evaluation of delirium allows the history and physical examination to guide further tests. No established algorithm for workup will fit all delirious patients due to the staggering number of potential etiologies, but one stepwise approach is detailed in Table 34-3. If a clear precipitant is identified, such as an offending medication, further testing may not be required. If, however, no likely etiology is uncovered with initial evaluation, an aggressive search for an underlying cause should be initiated.

TABLE 34-3

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

        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: 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 serologies

    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; CT, computed tomography; MRI, magnetic resonance imaging; p-ANCA, perinuclear antineutrophil cytoplasmic antibody.

Basic screening labs, 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, screening 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 early 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.

Multiple studies have demonstrated that brain imaging in patients with delirium is often unhelpful. If, however, the initial 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 etiology of delirium. The ability of magnetic resonance imaging (MRI) to identify most acute ischemic strokes as well as to provide neuroanatomic detail that gives clues to possible infectious, inflammatory, neurodegenerative, and neoplastic conditions makes it the test of choice. Because MRI techniques are limited by availability, speed of imaging, patient 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 appropriate neuroimaging in all patients in whom CNS infection is suspected. Spinal fluid examination can also be useful in identifying inflammatory and neoplastic conditions. As a result, LP should be considered in any delirious patient with a negative workup. EEG does not have a routine role in the workup of delirium, but it remains invaluable if seizure-related etiologies are considered.


PREVENTION

In light of the high morbidity associated with delirium and the tremendously increased health care costs that accompany it, development of an effective strategy to prevent delirium in hospitalized patients is extremely important. Successful identification of high-risk patients is the first step, followed by initiation of appropriate interventions. Simple standardized protocols used to manage risk factors for delirium, including sleep-wake cycle reversal, immobility, visual impairment, hearing impairment, sleep deprivation, and dehydration, have been shown to be effective. Recent trials in the ICU have focused both on identifying sedatives, such as dexmedetomidine, that are less likely to lead to delirium in critically ill patients and on developing protocols for daily awakenings in which infusions of sedative medications are interrupted and the patient is reorientated by the staff. All hospitals and health care systems should work toward decreasing the incidence of delirium.

 

35

Dementia

William W. Seeley, Bruce L. Miller


Dementia, a syndrome with many causes, affects >5 million people in the United States and results in a total annual health care cost between $157 and $215 billion. Dementia is defined as an acquired deterioration in cognitive abilities that impairs the successful performance of activities of daily living. Episodic memory, the ability to recall events specific in time and place, is the cognitive function most commonly lost; 10% of persons age >70 years and 20–40% of individuals age >85 years have clinically identifiable memory loss. In addition to memory, dementia may erode other mental faculties, including language, visuospatial, praxis, calculation, judgment, and problem-solving abilities. Neuropsychiatric and social deficits also arise in many dementia syndromes, manifesting as depression, apathy, anxiety, hallucinations, delusions, agitation, insomnia, sleep disturbances, compulsions, or disinhibition. The clinical course may be slowly progressive, as in Alzheimer’s disease (AD); static, as in anoxic encephalopathy; or may fluctuate from day to day or minute to minute, as in dementia with Lewy bodies. Most patients with AD, the most prevalent form of dementia, begin with episodic memory impairment, although in other dementias, such as frontotemporal dementia, memory loss is not typically a presenting feature. Focal cerebral disorders are discussed in Chap. 36 and illustrated in a video library in Chap. 37e; the pathogenesis of AD and related disorders is discussed in Chap. 448.

FUNCTIONAL ANATOMY OF THE DEMENTIAS


Dementia syndromes result from the disruption of specific large-scale neuronal networks; the location and severity of synaptic and neuronal loss combine to produce the clinical features (Chap. 36). Behavior, mood, and attention are modulated by ascending noradrenergic, serotonergic, and dopaminergic pathways, whereas cholinergic signaling is critical for attention and memory functions. The dementias differ in the relative neurotransmitter deficit profiles; accordingly, accurate diagnosis guides effective pharmacologic therapy.

AD begins in the entorhinal region of the medial temporal lobe, spreads to the hippocampus, and then moves to lateral and posterior temporal and parietal neocortex, eventually causing a more widespread degeneration. Vascular dementia is associated with focal damage in a variable patchwork of cortical and subcortical regions or white matter tracts that disconnect nodes within distributed networks. In keeping with its anatomy, AD typically presents with episodic memory loss accompanied later by aphasia or navigational problems. In contrast, dementias that begin in frontal or subcortical regions, such as frontotemporal dementia (FTD) or Huntington’s disease (HD), are less likely to begin with memory problems and more likely to present with difficulties with judgment, mood, executive control, movement, and behavior.

Lesions of frontal-striatal1 pathways produce specific and predictable effects on behavior. The dorsolateral prefrontal cortex has connections with a central band of the caudate nucleus. Lesions of either the caudate or dorsolateral prefrontal cortex, or their connecting white matter pathways, may result in executive dysfunction, manifesting as poor organization and planning, decreased cognitive flexibility, and impaired working memory. The lateral orbital frontal cortex connects with the ventromedial caudate, and lesions of this system cause impulsiveness, distractibility, and disinhibition. The anterior cingulate cortex and adjacent medial prefrontal cortex project to the nucleus accumbens, and interruption of this system produces apathy, poverty of speech, emotional blunting, or even akinetic mutism. All corticostriatal systems also include topographically organized projections through the globus pallidus and thalamus, and damage to these nodes can likewise reproduce the clinical syndrome of cortical or striatal injury.

THE CAUSES OF DEMENTIA

The single strongest risk factor for dementia is increasing age. The prevalence of disabling memory loss increases with each decade over age 50 and is usually associated with the microscopic changes of AD at autopsy. Yet some centenarians have intact memory function and no evidence of clinically significant dementia. Whether dementia is an inevitable consequence of normal human aging remains controversial.

The many causes of dementia are listed in Table 35-1. The frequency of each condition depends on the age group under study, access of the group to medical care, country of origin, and perhaps racial or ethnic background. AD is the most common cause of dementia in Western countries, accounting for more than half of all patients. Vascular disease is considered the second most frequent cause for dementia and is particularly common in elderly patients or populations with limited access to medical care, where vascular risk factors are undertreated. Often, vascular brain injury is mixed with neurodegenerative disorders, making it difficult, even for the neuropathologist, to estimate the contribution of cerebrovascular disease to the cognitive disorder in an individual patient. Dementias associated with Parkinson’s disease (PD) (Chap. 449) are common and may develop years after onset of a parkinsonian disorder, as seen with PD-related dementia (PDD), or can occur concurrently with or preceding the motor syndrome, as in dementia with Lewy bodies (DLB). In patients under the age of 65, FTD rivals AD as the most common cause of dementia. Chronic intoxications, including those resulting from alcohol and prescription drugs, are an important and often treatable cause of dementia. Other disorders listed in Table 35-1 are uncommon but important because many are reversible. The classification of dementing illnesses into reversible and irreversible disorders is a useful approach to differential diagnosis. When effective treatments for the neurodegenerative conditions emerge, this dichotomy will become obsolete.

TABLE 35-1

DIFFERENTIAL DIAGNOSIS OF DEMENTIA

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In a study of 1000 persons attending a memory disorders clinic, 19% had a potentially reversible cause of the cognitive impairment and 23% had a potentially reversible concomitant condition that may have contributed to the patient’s impairment. The three most common potentially reversible diagnoses were depression, normal pressure hydrocephalus (NPH), and alcohol dependence; medication side effects are also common and should be considered in every patient (Table 35-1).

Subtle cumulative decline in episodic memory is a common part of aging. This frustrating experience, often the source of jokes and humor, is referred to as benign forgetfulness of the elderly. Benign means that it is not so progressive or serious that it impairs reasonably successful and productive daily functioning, although the distinction between benign and more significant memory loss can be difficult to make. At age 85, the average person is able to learn and recall approximately one-half of the items (e.g., words on a list) that he or she could at age 18. A measurable cognitive problem that does not seriously disrupt daily activities is often referred to as mild cognitive impairment (MCI). Factors that predict progression from MCI to an AD dementia include a prominent memory deficit, family history of dementia, presence of an apolipoprotein ε4 (Apo ε4) allele, small hippocampal volumes, an AD-like signature of cortical atrophy, low cerebrospinal fluid Aβ, and elevated tau or evidence of brain amyloid deposition on positron emission tomography (PET) imaging.

The major degenerative dementias include AD, DLB, FTD and related disorders, HD, and prion diseases, including Creutzfeldt-Jakob disease (CJD). These disorders are all associated with the abnormal aggregation of a specific protein: Aβ42 and tau in AD; α-synuclein in DLB; tau, TAR DNA-binding protein of 43 kDa (TDP-43), or fused in sarcoma (FUS) in FTD; huntingtin in HD; and misfolded prion protein (PrPsc) in CJD (Table 35-2).

TABLE 35-2

THE MOLECULAR BASIS FOR DEGENERATIVE DEMENTIA

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APPROACH TO THE PATIENT:

Dementias


Three major issues should be kept at the forefront: (1) What is the best fit for a clinical diagnosis? (2) What component of the dementia syndrome is treatable or reversible? (3) Can the physician help to alleviate the burden on caregivers? A broad overview of the approach to dementia is shown in Table 35-3. The major degenerative dementias can usually be distinguished by the initial symptoms; neuropsychological, neuropsychiatric, and neurologic findings; and neuroimaging features (Table 35-4).

TABLE 35-3

EVALUATION OF THE PATIENT WITH DEMENTIA

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TABLE 35-4

CLINICAL DIFFERENTIATION OF THE MAJOR DEMENTIAS

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HISTORY

The history should concentrate on the onset, duration, and tempo of progression. An acute or subacute onset of confusion may be due to delirium (Chap. 34) and should trigger the search for intoxication, infection, or metabolic derangement. An elderly person with slowly progressive memory loss over several years is likely to suffer from AD. Nearly 75% of patients with AD begin with memory symptoms, but other early symptoms include difficulty with managing money, driving, shopping, following instructions, finding words, or navigating. Personality change, disinhibition, and weight gain or compulsive eating suggest FTD, not AD. FTD is also suggested by prominent apathy, compulsivity, loss of empathy for others, or progressive loss of speech fluency or single-word comprehension and by a relative sparing of memory and visuospatial abilities. The diagnosis of DLB is suggested by early visual hallucinations; parkinsonism; proneness to delirium or sensitivity to psychoactive medications; rapid eye movement (REM) behavior disorder (RBD; the loss of skeletal muscle paralysis during dreaming); or Capgras syndrome, the delusion that a familiar person has been replaced by an impostor.

A history of stroke with irregular stepwise progression suggests vascular dementia. Vascular dementia is also commonly seen in the setting of hypertension, atrial fibrillation, peripheral vascular disease, and diabetes. In patients suffering from cerebrovascular disease, it can be difficult to determine whether the dementia is due to AD, vascular disease, or a mixture of the two because many of the risk factors for vascular dementia, including diabetes, high cholesterol, elevated homocysteine, and low exercise, are also putative risk factors for AD. Moreover, many patients with a major vascular contribution to their dementia lack a history of stepwise decline. Rapid progression with motor rigidity and myoclonus suggests CJD (Chap. 453e). Seizures may indicate strokes or neoplasm but also occur in AD, particularly early-age-of-onset AD. Gait disturbance is common in vascular dementia, PD/DLB, or NPH. A history of high-risk sexual behaviors or intravenous drug use should trigger a search for central nervous system (CNS) infection, especially HIV or syphilis. A history of recurrent head trauma could indicate chronic subdural hematoma, chronic traumatic encephalopathy (a progressive dementia best characterized in contact sport athletes such as boxers and American football players), intracranial hypotension, or NPH. Subacute onset of severe amnesia and psychosis with mesial temporal T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities on magnetic resonance imaging (MRI) should raise concern for paraneoplastic limbic encephalitis, especially in a long-term smoker or other patients at risk for cancer. Related autoimmune conditions, such as voltage-gated potassium channel (VGKC)- or N-methyl-D-aspartate (NMDA)-receptor antibody-mediated encephalopathy, can present with a similar tempo and imaging signature with or without characteristic motor manifestations such as myokymia (anti-VGKC) and faciobrachial dystonic seizures (anti-NMDA). Alcohol abuse creates risk for malnutrition and thiamine deficiency. Veganism, bowel irradiation, an autoimmune diathesis, a remote history of gastric surgery, and chronic antihistamine therapy for dyspepsia or gastroesophageal reflux predispose to B12 deficiency. Certain occupations, such as working in a battery or chemical factory, might indicate heavy metal intoxication. Careful review of medication intake, especially for sedatives and analgesics, may raise the issue of chronic drug intoxication. An autosomal dominant family history is found in HD and in familial forms of AD, FTD, DLB, or prion disorders. A history of mood disorders, the recent death of a loved one, or depressive signs, such as insomnia or weight loss, raise the possibility of depression-related cognitive impairments.

PHYSICAL AND NEUROLOGIC EXAMINATION

A thorough general and neurologic examination is essential to document dementia, to look for other signs of nervous system involvement, and to search for clues suggesting a systemic disease that might be responsible for the cognitive disorder. Typical AD spares motor systems until later in the course. In contrast, FTD patients often develop axial rigidity, supranuclear gaze palsy, or a motor neuron disease reminiscent of amyotrophic lateral sclerosis (ALS). In DLB, the initial symptoms may include the new onset of a parkinsonian syndrome (resting tremor, cogwheel rigidity, bradykinesia, festinating gait), but DLB often starts with visual hallucinations or dementia. Symptoms referable to the lower brainstem (RBD, gastrointestinal or autonomic problems) may arise years or even decades before parkinsonism or dementia. Corticobasal syndrome (CBS) features asymmetric akinesia and rigidity, dystonia, myoclonus, alien limb phenomena, pyramidal signs, and prefrontal deficits such as nonfluent aphasia with or without motor speech impairment, executive dysfunction, apraxia, or a behavioral disorder. Progressive supranuclear palsy (PSP) is associated with unexplained falls, axial rigidity, dysphagia, and vertical gaze deficits. CJD is suggested by the presence of diffuse rigidity, an akinetic-mute state, and prominent, often startle-sensitive myoclonus.

Hemiparesis or other focal neurologic deficits suggest vascular dementia or brain tumor. Dementia with a myelopathy and peripheral neuropathy suggests vitamin B12 deficiency. Peripheral neuropathy could also indicate another vitamin deficiency, heavy metal intoxication, thyroid dysfunction, Lyme disease, or vasculitis. Dry, cool skin, hair loss, and bradycardia suggest hypothyroidism. Fluctuating confusion associated with repetitive stereotyped movements may indicate ongoing limbic, temporal, or frontal seizures. In the elderly, hearing impairment or visual loss may produce confusion and disorientation misinterpreted as dementia. Profound bilateral sensorineural hearing loss in a younger patient with short stature or myopathy, however, should raise concern for a mitochondrial disorder.

COGNITIVE AND NEUROPSYCHIATRIC EXAMINATION

Brief screening tools such as the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MOCA), and Cognistat can be used to capture dementia and follow progression. None of these tests is highly sensitive to early-stage dementia or discriminates between dementia syndromes. The MMSE is a 30 point test of cognitive function, with each correct answer being scored as 1 point. It includes tests in the areas of: orientation (e.g., identify season/date/month/year/floor/hospital/town/state/country); registration (e.g., name and restate 3 objects); recall (e.g., remember the same three objects 5 minutes later); and language (e.g., name pencil and watch; repeat “no if’s and’s or but’s”; follow a 3-step command; obey a written command; and write a sentence and copy a design). In most patients with MCI and some with clinically apparent AD, bedside screening tests may be normal, and a more challenging and comprehensive set of neuropsychological tests will be required. When the etiology for the dementia syndrome remains in doubt, a specially tailored evaluation should be performed that includes tasks of working and episodic memory, executive function, language, and visuospatial and perceptual abilities. In AD, the early deficits involve episodic memory, category generation (“name as many animals as you can in 1 minute”), and visuoconstructive ability. Usually deficits in verbal or visual episodic memory are the first neuropsychological abnormalities detected, and tasks that require the patient to recall a long list of words or a series of pictures after a predetermined delay will demonstrate deficits in most patients. In FTD, the earliest deficits on cognitive testing involve executive control or language (speech or naming) function, but some patients lack either finding despite profound social-emotional deficits. PDD or DLB patients have more severe deficits in visuospatial function but do better on episodic memory tasks than patients with AD. Patients with vascular dementia often demonstrate a mixture of executive control and visuospatial deficits, with prominent psychomotor slowing. In delirium, the most prominent deficits involve attention, working memory, and executive function, making the assessment of other cognitive domains challenging and often uninformative.

A functional assessment should also be performed to help the physician determine the day-to-day impact of the disorder on the patient’s memory, community affairs, hobbies, judgment, dressing, and eating. Knowledge of the patient’s functional abilities will help the clinician and the family to organize a therapeutic approach.

Neuropsychiatric assessment is important for diagnosis, prognosis, and treatment. In the early stages of AD, mild depressive features, social withdrawal, and irritability or anxiety are the most prominent psychiatric changes, but patients often maintain core social graces into the middle or late stages, when delusions, agitation, and sleep disturbance may emerge. In FTD, dramatic personality change with apathy, overeating, compulsions, disinhibition, euphoria, and loss of empathy are early and common. DLB is associated with visual hallucinations, delusions related to person or place identity, RBD, and excessive daytime sleepiness. Dramatic fluctuations occur not only in cognition but also in arousal. Vascular dementia can present with psychiatric symptoms such as depression, anxiety, delusions, disinhibition, or apathy.

LABORATORY TESTS

The choice of laboratory tests in the evaluation of dementia is complex and should be tailored to the individual patient. The physician must take measures to avoid missing a reversible or treatable cause, yet no single treatable etiology is common; thus, a screen must use multiple tests, each of which has a low yield. Cost/benefit ratios are difficult to assess, and many laboratory screening algorithms for dementia discourage multiple tests. Nevertheless, even a test with only a 1–2% positive rate is worth undertaking if the alternative is missing a treatable cause of dementia. Table 35-3 lists most screening tests for dementia. The American Academy of Neurology recommends the routine measurement of a complete blood count, electrolytes, renal and thyroid function, a vitamin B12 level, and a neuroimaging study (computed tomography [CT] or MRI).

Neuroimaging studies, especially MRI, help to rule out primary and metastatic neoplasms, locate areas of infarction or inflammation, detect subdural hematomas, and suggest NPH or diffuse white matter disease. They also help to establish a regional pattern of atrophy. Support for the diagnosis of AD includes hippocampal atrophy in addition to posterior-predominant cortical atrophy (Fig. 35-1). Focal frontal, insular, and/or anterior temporal atrophy (Fig. 35-1). Focal frontal, insular, and/or anterior temporal atrophy suggests FTD (Chap. 448). DLB often features less prominent atrophy, with greater involvement of amygdala than hippocampus. In CJD, magnetic resonance (MR) diffusion-weighted imaging reveals restricted diffusion within the cortical ribbon and basal ganglia in most patients. Extensive white matter abnormalities correlate with a vascular etiology (Fig. 35-2). Communicating hydrocephalus with vertex effacement (crowding of dorsal convexity gyri/sulci), gaping Sylvian fissures despite minimal cortical atrophy, and additional features shown in Fig. 35-3 suggest NPH. Single-photon emission computed tomography (SPECT) and PET scanning show temporal-parietal hypoperfusion or hypometabolism in AD and frontotemporal deficits in FTD, but these changes often reflect atrophy and can therefore be detected with MRI alone in many patients. Recently, amyloid imaging has shown promise for the diagnosis of AD, and Pittsburgh Compound-B (PiB) (not available outside of research settings) and 18F-AV-45 (florbetapir; approved by the U.S. Food and Drug Administration in 2013) are reliable radioligands for detecting brain amyloid associated with amyloid angiopathy or neuritic plaques of AD (Fig. 35-4). Because these abnormalities can be seen in cognitively normal older persons, however (~25% of individuals at age 65), amyloid imaging may also detect preclinical or incidental AD in patients lacking an AD-like dementia syndrome. Currently, the main clinical value of amyloid imaging is to exclude AD as the likely cause of dementia in patients who have negative scans. Once disease-modifying therapies become available, use of these biomarkers may help to identify treatment candidates before irreversible brain injury has occurred. In the meantime, the significance of detecting brain amyloid in an asymptomatic elder remains a topic of vigorous investigation. Similarly, MRI perfusion and structural/functional connectivity methods are being explored as potential treatment-monitoring strategies.

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FIGURE 35-1   Alzheimer’s disease (AD). Axial T1-weighted magnetic resonance images of a healthy 71-year-old (A) and a 64-year-old with AD (C). Note the reduction in medial temporal lobe volume in the patient with AD. Fluorodeoxyglucose positron emission tomography scans of the same individuals (B and D) demonstrate reduced glucose metabolism in the posterior temporoparietal regions bilaterally in AD, a typical finding in this condition. HC, healthy control. (Images courtesy of Gil Rabinovici, University of California, San Francisco and William Jagust, University of California, Berkeley.)

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FIGURE 35-2   Diffuse white matter disease. Axial fluid-attenuated inversion recovery (FLAIR) magnetic resonance image through the lateral ventricles reveals multiple areas of hyperintensity (arrows) involving the periventricular white matter as well as the corona radiata and striatum. Although seen in some individuals with normal cognition, this appearance is more pronounced in patients with dementia of a vascular etiology.

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FIGURE 35-3   Normal-pressure hydrocephalus. A. Sagittal T1-weighted magnetic resonance image (MRI) demonstrates dilation of the lateral ventricle and stretching of the corpus callosum (arrows), depression of the floor of the third ventricle (single arrowhead), and enlargement of the aqueduct (double arrowheads). Note the diffuse dilation of the lateral, third, and fourth ventricles with a patent aqueduct, typical of communicating hydrocephalus. B. Axial T2-weighted MRIs demonstrate dilation of the lateral ventricles. This patient underwent successful ventriculoperitoneal shunting.

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FIGURE 35-4   Positron emission tomography (PET) images obtained with the amyloid-imaging agent Pittsburgh Compound-B ([11C]PIB) in a normal control (left); three different patients with mild cognitive impairment (MCI; center); and a patient with mild Alzheimer’s disease (AD; right). Some MCI patients have control-like levels of amyloid, some have AD-like levels of amyloid, and some have intermediate levels. (Images courtesy of William Klunk and Chester Mathis, University of Pittsburgh.)

Lumbar puncture need not be done routinely in the evaluation of dementia, but it is indicated when CNS infection or inflammation are credible diagnostic possibilities. Cerebrospinal fluid (CSF) levels of Aβ42 and tau proteins show differing patterns with the various dementias, and the presence of low Aβ42 and mildly elevated CSF tau is highly suggestive of AD. The routine use of lumbar puncture in the diagnosis of dementia is debated, but the sensitivity and specificity of AD diagnostic measures are not yet high enough to warrant routine use. Formal psychometric testing helps to document the severity of cognitive disturbance, suggest psychogenic causes, and provide a more formal method for following the disease course. Electroencephalogram (EEG) is not routinely used but can help to suggest CJD (repetitive bursts of diffuse high-amplitude sharp waves, or “periodic complexes”) or an underlying nonconvulsive seizure disorder (epileptiform discharges). Brain biopsy (including meninges) is not advised except to diagnose vasculitis, potentially treatable neoplasms, or unusual infections when the diagnosis is uncertain. Systemic disorders with CNS manifestations, such as sarcoidosis, can usually be confirmed through biopsy of lymph node or solid organ rather than brain. MR angiography should be considered when cerebral vasculitis or cerebral venous thrombosis is a possible cause of the dementia.


1The striatum comprises the caudate/putamen.

 

36

Aphasia, Memory Loss, and Other Focal Cerebral Disorders

M.-Marsel Mesulam


The cerebral cortex of the human brain contains approximately 20 billion neurons spread over an area of 2.5 m2. The primary sensory and motor areas constitute 10% of the cerebral cortex. The rest is subsumed by modality-selective, heteromodal, paralimbic, and limbic areas collectively known as the association cortex (Fig. 36-1). The association cortex mediates the integrative processes that subserve cognition, emotion, and comportment. A systematic testing of these mental functions is necessary for the effective clinical assessment of the association cortex and its diseases. According to current thinking, there are no centers for “hearing words,” “perceiving space,” or “storing memories.” Cognitive and behavioral functions (domains) are coordinated by intersecting large-scale neural networks that contain interconnected cortical and subcortical components. Five anatomically defined large-scale networks are most relevant to clinical practice: (1) a perisylvian network for language, (2) a parietofrontal network for spatial orientation, (3) an occipitotemporal network for face and object recognition, (4) a limbic network for retentive memory, and (5) a prefrontal network for the executive control of cognition and comportment.

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FIGURE 36-1   Lateral (top) and medial (bottom) views of the cerebral hemispheres.

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