11: Delirium and Dementia

Delirium and dementia are both syndromes of neurologic dysfunction that present as a “change in mental status.” Since the term “altered mental status” can be broad, categorizing the change as chronic or acute and then further classifying acute changes as fluctuating or nonfluctuating may be helpful (Figure 11-1). A patient whose mental status change is acute may have either fluctuating or nonfluctuating symptoms. A patient with acute, fluctuating mental status change is probably delirious. A patient with an acute but stable mental status change may have delirium but may also have a long list of other CNS insults (head trauma, CNS infection, hypoglycemia, CVA among others). Chronic mental change is caused by an irreversible change to the CNS, such as dementia, chronic psychiatric disease, or long-standing CNS injury.

Delirium and dementia are thus very different syndromes. Whereas delirium is acute, usually reversible and nearly always has an underlying, non-neurologic etiology, dementia is chronic and seldom reversible. The definition of delirium from the DSM-V is:

1. A disturbance in attention (ie, reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment).

2. The disturbance develops over a short period of time, represents a change from baseline attention and awareness, and tends to fluctuate in severity during the course of a day.

3. An additional disturbance in cognition (eg, memory deficit, disorientation, language, visuospatial ability, or perception).

4. The disturbances in Criteria A and C are not better explained by another preexisting, established, or evolving neurocognitive disorder and do not occur in the context of a severely reduced level of arousal, such as coma.

5. There is evidence from the history, physical exam, or laboratory findings that the disturbance is a direct physiologic consequence of another medical condition, substance intoxication or withdrawal, or exposure to a toxin, or is due to multiple etiologies.

The DSM V now defines dementia as a major neurocognitive disorder and then defines the many underlying diseases. The definition of a major cognitive disorder is:

1. Evidence of significant cognitive decline from a previous level of performance in 1 or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual-motor, or social cognition) based on:

   1. Concern of the individual, a knowledgeable informant, or the clinician that there has been a significant decline in cognitive function; and

   2. A substantial impairment in cognitive performance, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment.

2. The cognitive deficits interfere with independence in everyday activities (ie, at a minimum, requiring assistance with complex instrumental activities of daily living [ADLs] such as paying bills or managing medications).

3. The cognitive deficits do not occur exclusively in the context of a delirium.

4. The cognitive deficits are not better explained by another mental disorder (eg, major depressive disorder, schizophrenia).

Because any illness can cause delirium in a susceptible patient, the differential diagnosis of delirium is long and needs to consider a broad range of illnesses, comorbidities, and medication effects. The differential diagnosis of dementia is more finite; disorders have been listed in order of their approximate prevalence as etiologic factors.

1. Delirium

   1. Metabolic

      1. Dehydration

      2. Electrolyte abnormalities

      3. Hyperglycemia or hypoglycemia

      4. Acidosis or alkalosis

      5. Liver disease

      6. Hypoxia or hypercarbia

      7. Uncontrolled thyroid disease

      8. Uremia

      9. Thiamine deficiency (Wernicke encephalopathy)

   2. Infectious disease

      1. CNS infection

      2. Systemic infection of any kind

   3. Cerebrovascular event

      1. Ischemic stroke

      2. Hemorrhagic stroke

      3. Vasculitis

   4. CNS mass

      1. Tumor

      2. Subdural hematoma

   5. Cardiovascular

      1. Myocardial infarction

      2. Heart failure

      3. Arrhythmia

   6. Drugs

      1. Alcohol withdrawal

      2. Diuretics

      3. Anticholinergics

      4. Corticosteroids

      5. Digoxin

      6. Opioids

      7. Antidepressants

      8. Anxiolytics

   7. Miscellaneous

      1. Fecal impaction

      2. Urinary retention

      3. Sensory deprivation

      4. Severe illness

2. Dementia

   1. Alzheimer dementia

   2. Dementia with Lewy bodies

   3. Vascular dementia

   4. Frontotemporal dementia

   5. Alcohol-related

   6. Uncommon dementias

      1. Subdural hematoma

      2. Hypothyroidism

      3. Vitamin B₁₂ deficiency

      4. Infectious

         • (1) Syphilis

         • (2) Prion disease

      5. Normal-pressure hydrocephalus

         Almost any illness can cause delirium in a susceptible patient.

Based on his history, Mr. B’s subacute mental status change appears to fulfill the definition of delirium. The pivotal points in this case are the waxing and waning symptoms and his disorientation and inattentiveness. His postoperative state, recent exposure to sedatives and pain medications (anesthesia), and fluid shifts are all potential causes of delirium. Although Mr. B does not have a history of alcohol abuse, alcohol withdrawal is always a possible diagnosis for acute mental status change in the hospital and is a “must not miss” hypothesis. Stroke and seizure, although commonly considered in the differential diagnosis of mental status change, actually are exceedingly rare causes of delirium. Table 11-1 lists the differential diagnosis.

Leading Hypothesis: Delirium

Textbook Presentation

Delirium commonly manifests as inattention and confusion. It is usually seen in older patients with severe illness. Clouding of consciousness has classically been used to describe a patient’s symptoms.

Disease Highlights

1. Almost any illness can present as delirium in a susceptible patient.

2. Delirium often complicates medical or surgical hospitalizations.

3. The most important clue to delirium is the acuity of onset and fluctuation in course.

4. Delirium most commonly occurs in older persons and in patients with underlying neurologic disease.

   There is always a cause of delirium. Clinicians must recognize delirium and identify the cause.

5. Several diseases are more likely to cause delirium than others.

   1. Severe illness

   2. Drug toxicity

   3. Fluid and electrolyte disturbances (hyponatremia and azotemia)

   4. Infections

   5. Hypothermia or hyperthermia

6. Delirium is very common in sick, hospitalized patients over the age of 65.

   1. 10% of emergency department patients

   2. 12–25% of medical patients

   3. 20–50% of surgical patients (highest in patients after hip replacement)

      Most acutely ill, older patients, who have an acute deterioration in mental status are suffering from delirium.

7. The prognosis of delirium is poor.

   1. Although reliable data is difficult to obtain, delirium is a predictor of poor outcomes.

   2. A recent meta-analysis showed that, after controlling for age, sex, comorbid illness or illness severity, and baseline dementia, patients who experienced delirium had a higher risk of death, institutionalization, and dementia during follow-up.

      1. The mortality rate, over about 2 years, for patients in whom delirium developed was 38%.

      2. The rate of institutionalization, over about a year, was 33.4%.

      3. The rate of developing dementia over the next 4 years was 62.5%.

   3. In this same study, patients with dementia and delirium had the highest risk of death.

8. Delirium in often persistent. Many studies show that most patients in whom delirium develops have at least some persistent symptoms at discharge. These symptoms may be present for months.

   Only a small percentage of patients with delirium have complete resolution of symptoms with treatment of the underlying disease and return home.

9. Delirium can occasionally “unmask” an underlying dementia. This occurs when a patient with a mild, undiagnosed dementia becomes delirious in the hospital and is then evaluated more fully for cognitive impairment.

Evidence-Based Diagnosis

1. Pretest probability

   1. Predictors of delirium have been identified. These help provide pretest probabilities.

   2. One study developed a model to determine a patient’s risk of delirium developing while in the hospital. Predictors included:

      1. Vision impairment

      2. Severe illness

      3. Cognitive impairment

      4. High BUN/creatinine ratio

   3. In a patient population with a mean age of 78, the number of risk factors present correlated with the risk of developing delirium.

      1. No risk factors: 3% chance of delirium developing.

      2. 1 or 2 risk factors: 14% chance of delirium developing.

      3. 3 or 4 risk factors: 26% chance of delirium developing.

   4. Several predictors from another study, with ORs for association with delirium, are listed below:

      1. Abnormal sodium level (OR 6.2)

      2. Severe illness (OR 5.9)

      3. Chronic cognitive impairment (OR 5.3)

      4. Hypothermia or hyperthermia (OR 5.0)

      5. Moderate illness (OR 4.0)

      6. Psychoactive drug use (OR 3.9)

      7. Azotemia (OR 2.9)

         Consider a patient’s risk of delirium upon hospital admission; an accurate identification of risk can prompt intervention to lessen the likelihood of delirium and allow more rapid intervention if delirium does occur.

2. Diagnosis

   1. Doctors are generally not very good at recognizing delirium.

   2. A routine exam is specific but insensitive for the diagnosis of delirium.

   3. Multiple tools (such as the Confusion Assessment Method [CAM]) have been developed to diagnose delirium.

   4. The CAM is the best-validated and most widely used tools for diagnosing delirium.

   5. The CAM is considered positive when a patient fulfills both criteria a and b as well as either c or d:

      1. The mental status change is of acute onset and fluctuating course.

      2. There is inattention. The patient has difficulty focusing his attention (being easily distracted or having trouble following a conversation).

      3. There is disorganized thinking. The patient’s thinking is disorganized or incoherent (such as rambling or irrelevant conversation, unclear or illogical flow of ideas, or unpredictable switching from subject to subject).

      4. There is an altered level of consciousness. This can be anything other than alert (vigilant, lethargic, stuporous).

   6. The test characteristics for the CAM are good and surpass those of an unaided physician assessment.

      1. CAM: sensitivity, 86%; specificity, 93%; LR+, 12.3; LR–, 0.15.

      2. Physician evaluation (in the emergency department): sensitivity, 17–35%; specificity, 98–100; LR+, 8.5– ∞; LR–, 0.65–0.85.

3. Etiology

   1. Because delirium is a symptom and not a disease, once a diagnosis of delirium is made, it is necessary to identify the cause.

   2. The initial evaluation of the patient involves a review of the most common causes of delirium.

      1. Repeat a full physical exam, focusing on sources of infection.

      2. Review medications in detail, including reconciling home and hospital medications.

         Medication toxicity, even at therapeutic doses, is a common cause of delirium and is particularly common in older patients. Review all medications, especially psychoactive ones.

      3. Always order basic laboratory tests, such as a CBC, basic metabolic panel, LFTs, and urinalysis.

      4. Consider other tests (based on the clinical situation) such as ECG, chest radiograph, pulse oximetry (with ABG if the patient is at risk for CO₂ retention), and blood and urine cultures.

   3. Uncommon causes

      1. A common question when evaluating a patient with delirium is: If the initial work-up is negative, is it reasonable to assume the delirium is related to the acute illness or should the patient be assessed for diseases that directly affect the CNS (eg, stroke, seizure, and meningitis or encephalitis)?

         • (1) Stroke

           • (a) Very rare cause of delirium

           • (b) A very good study reported that only about 7% of cases of delirium are caused by stroke.

           • (c) 97% of these patients had focal abnormalities on a careful neurologic exam.

         • (2) Seizure

           • (a) Nonconvulsive seizures, such as temporal lobe epilepsy, are usually recognized by their intermittent nature.

           • (b) Nonconvulsive status epilepticus is very rare but is a potential cause of mental status change that could be confused with delirium. Patients with nonconvulsive status epilepticus almost always have risk factors for seizures or abnormal eye movements (eye jerking, hippus, repeated blinking, persistent eye deviation).

         • (3) Meningitis: Fever and mental status change may be the only presenting symptoms.

      2. When evaluating a delirious patient, consider neuroimaging, EEG, and lumbar puncture only in certain conditions.

         • (1) Neuroimaging is only necessary if delirium is associated with a focal neurologic exam or if there is a very high suspicion of a cerebrovascular event.

         • (2) EEG is only necessary if there is no other explanation for delirium and the patient has risk factors for, or signs of, seizures.

         • (3) Lumbar puncture is only necessary if there is fever with no other source or a suspicion for a CNS infection.

Treatment

1. Prevention

   1. Because of its poor prognosis, delirium should be prevented when possible.

   2. Multidisciplinary interventions have been shown to prevent delirium. One study demonstrated a decrease in the rate of delirium from 15% to 9.9% (number needed to treat ≅ 20).

   3. Recently, the National Institute for Health and Clinical Excellence published a guideline for the prevention of delirium. Among the 13 recommendations were:

      1. Addressing cognitive impairment (such as stimuli to reorient patients)

      2. Paying attention to hydration status, constipation, and hypoxia

      3. Focusing on preventing, identifying, and treating infection

      4. Encouraging early mobility

      5. Addressing sensory impairments (use of glasses and hearing aids, cerumen disimpaction)

      6. Promoting good sleep patterns/sleep hygiene

2. Treatment

   1. Once delirium occurs, the causes must be addressed and then supportive measures must be instituted.

      1. Administer fluids to treat and prevent dehydration.

      2. Avoid sleep deprivation.

      3. Provide a quiet environment.

      4. Keep nighttime awakenings to a minimum.

      5. Protect from falls or self-inflicted injury.

         • (1) “Sitters” are preferable to restraints as the latter can increase the risk of physical injury.

         • (2) Sitters can also provide constant reorientation and reassurance.

         • (3) Occasionally, medications such as low doses of neuroleptics can be used for sedation. Long-term use should be avoided whenever possible.

By CAM criteria, Mr. B is delirious. He has recently undergone a major surgery, and he is taking medications known to cause delirium. Despite his intraoperative blood loss and hypotension, there are no signs of a stroke, cardiac ischemia, heart failure, or anemia.

Alternative Diagnosis: Alcohol Withdrawal

Textbook Presentation

A typical presentation of alcohol withdrawal in the inpatient setting is agitation, hypertension, and tachycardia occurring during the first 2 days after hospital admission. Seizures may soon follow with delusions and delirium occurring during the first 3–5 days.

Disease Highlights

1. Symptoms of alcohol withdrawal are stereotypical, occurring on a predictable time line as outlined in Figure 11-2.

2. The predominant symptoms of minor withdrawal are irritability, hypertension, and tachycardia.

3. Alcoholic hallucinosis

   1. Syndrome of hallucinations (usually visual)

   2. Patients with alcoholic hallucinosis usually have a clear sensorium (ie, they would perform well on CAM). This fact usually makes alcoholic hallucinosis easily distinguishable from delirium.

4. Major withdrawal is synonymous with delirium tremens.

   1. Occurs in patients with history of severe alcohol abuse.

   2. Confusion, disorientation, and autonomic hyperactivity are hallmarks.

   3. Delirium tremens can be fatal if not appropriately treated.

5. Wernicke encephalopathy

   1. Wernicke encephalopathy is not an alcohol withdrawal syndrome but is caused by thiamine deficiency.

   2. Alcohol abuse is the most common cause of thiamine deficiency.

   3. Wernicke encephalopathy may occur when a patient, who is thiamine deficient, receives intravenous glucose.

   4. Symptoms include the triad of confusion, disorders of ocular movement, and ataxia. The confusion commonly manifests as disorientation and indifference.

   5. Korsakoff syndrome is the chronic form of Wernicke encephalopathy. Korsakoff syndrome presents with memory problems and resulting confabulation.

Evidence-Based Diagnosis

1. Delirium tremens and Wernicke encephalopathy are the alcohol-related syndromes most likely to be confused with nonalcohol-related delirium. Various features clearly differentiate these syndromes.

2. Wernicke encephalopathy

   1. Generally requires long-term alcohol abuse. (Rare cases of Wernicke encephalopathy with hyperemesis gravidarum or after bariatric surgery do occur).

   2. It is important to recognize that Wernicke encephalopathy usually presents with only 1 or 2 of the features of the classic triad.

   3. Fluctuation that characterizes nonalcohol-related delirium is absent.

   4. The diagnosis of Wernicke encephalopathy can be made if 2 of the following 4 signs are present:

      1. Dietary deficiencies (as evidenced by underweight, thiamine deficiency, or abnormal dietary history)

      2. Disorders of ocular movement (such as ophthalmoplegia, nystagmus or gaze palsy)

      3. Cerebellar signs

      4. Altered mental state or memory impairment

   5. Wernicke encephalopathy is a difficult diagnosis to make in the setting of hepatic encephalopathy.

   6. There are specific MRI findings that are seen in Wernicke encephalopathy.

3. Delirium tremens

   1. Always preceded by minor withdrawal.

   2. Minor withdrawal can be overlooked in the hospital if a patient is critically ill, sedated, or anesthetized.

   3. History of heavy alcohol use required.

   4. Adrenergic overactivity (hypertension, tachycardia, fever) is always present unless masked by medications.

      Every patient should have an alcohol history taken on admission. If a clinical syndrome suggestive of alcohol withdrawal occurs in a patient who denied alcohol use, information about alcohol use should be sought from other sources.

Treatment

1. Both Wernicke encephalopathy and delirium tremens are preventable.

2. Wernicke encephalopathy

   1. Any patient in whom thiamine deficiency is suspected should receive 100 mg of IV thiamine prior to receiving glucose-containing fluids.

   2. Patients in whom Wernicke encephalopathy is suspected should receive thiamine until symptoms resolve.

3. Alcohol withdrawal and delirium tremens

   1. Supportive care

   2. Benzodiazepines

      1. Benzodiazepines decrease the symptoms of withdrawal and can prevent delirium tremens, seizures, and death.

      2. Some patients can be treated for alcohol withdrawal with benzodiazepines as outpatients.

      3. Indications for inpatient therapy

         • (1) Moderate to severe withdrawal

         • (2) Prior history of seizures or delirium tremens

         • (3) Patient unable to cooperate with outpatient therapy

         • (4) Comorbid psychiatric or medical conditions

         • (5) Unsuccessful outpatient detoxification

      4. Inpatient management

         • (1) The optimal dose of benzodiazepines cannot be determined in advance and must be titrated to the particular needs of the patient.

         • (2) Benzodiazepines may either be given on a fixed-scheduled or be given to treat symptoms. Both strategies require careful patient monitoring and medication adjustment.

         • (3) The Addiction Research Foundation Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) developed a tool to predict the level of alcohol withdrawal.

           • (a) The tool scores the severity of symptoms in various categories such as tremor, anxiety, and sensory disturbances.

           • (b) A higher score (> 8–12) generally calls for active pharmacologic management, whether using a fixed-dose or symptom-triggered protocol.

           • (c) Printable versions of the tool are available online.

         • (4) Fixed-schedule therapy

           • (a) Delivers regular fixed doses of benzodiazepines.

           • (b) Careful monitoring is still required to avoid undertreatment or oversedation.

           • (c) Fixed-schedule therapy may provide a slight margin of safety if careful monitoring cannot be performed adequately.

         • (5) Symptom-triggered therapy

           • (a) Avoids unnecessary medications in the group of patients who will not need them.

           • (b) Careful monitoring is required to avoid withdrawal and delirium tremens.

             Careful monitoring and prompt patient-specific adjustment of benzodiazepine dose is the key to successful management of the alcoholic patient.

   3. Beta-blockers

      1. Can decrease sympathetic overactivity in patients during withdrawal

      2. Are useful adjuncts but, because they can mask sympathetic signs that alert the clinician to increasingly severe withdrawal, they increase the risk of inadequate use of benzodiazepines.

The patient’s delirium was severe for 3–4 days and persisted for at least 1 week. The delirium was assumed to be a symptom of the postsurgical state, and medication complication. No specific therapy was given. The patient’s safety was ensured with a “sitter” and the reversible factors were addressed.

Mr. R has had a decline in cognitive status. He has lost to the ability to do a higher-level task. Given the patient’s advanced age, dementia—most commonly Alzheimer disease (AD)—has to be included in the differential diagnosis of his cognitive decline. The subacute onset of this patient’s symptoms makes AD the leading hypothesis. Another common cause of dementia in older persons is vascular dementia (VaD). It will be important to determine whether this patient has risk factors for cerebrovascular disease. In an older person, clinicians also have to consider the normal cognitive decline that comes with aging. This, however, never causes functional compromise. An alternative diagnosis is mild cognitive impairment (MCI), a syndrome of memory loss more severe than normal, age-related cognitive decline. MCI also does not cause functional impairment. Delirium and depression should always be considered in an older patient with cognitive decline because they are highly treatable. Table 11-2 lists the differential diagnosis.

A patient who is unable to successfully live independently because of cognitive issues always has an abnormality.

Leading Hypothesis: AD

Textbook Presentation

Typically, a family member brings in an older patient because of confusion, memory loss, or personality change. The patient may deny that a problem exists. Detection of dementia during casual conversation may be difficult early in its course; more formal assessment is frequently necessary.

Disease Highlights

1. AD most commonly occurs after the age of 65, although earlier presentations are possible.

2. Language disturbances

   1. In addition to memory loss, behavioral or personality change, functional impairments, or social withdrawal, language disturbances are often present early in the course of disease and often become severe with time.

   2. These may include fluent aphasia, paraphasias, and word substitutions.

3. Later in the course of the disease, global cognitive impairment develops and patients become unable to independently accomplish the most basic ADLs.

   Although present, memory loss may not be the presenting symptom in patients with AD; rather, behavioral or personality changes, functional impairments, social withdrawal, or language disturbances may be the initial symptoms.

4. AD accounts for about 67% of cases of dementia.

5. Strictly speaking, the diagnosis of AD can only be made pathologically. That said, the diagnosis of AD is always made clinically.

6. All definitions of AD include the deterioration in a person’s ability to function independently. A patient’s level of functioning can be evaluated by assessing his ability to do the instrumental ADLs.

   1. Instrumental ADLs include

      1. Cooking

      2. House cleaning

      3. Laundry

      4. Management of medications

      5. Management of the telephone

      6. Management of personal accounts

      7. Shopping

      8. Use of transportation

   2. Late in the disease, a patient’s ability to perform the ADLs often becomes compromised. These ADLs are

      1. Bathing

      2. Eating

      3. Walking

      4. Toileting and continence

      5. Dressing

      6. Grooming

7. The prognosis of AD is poor.

   1. Estimates of median survival have traditionally ranged from 5 to 9 years with more recent data suggesting median survival close to 3 years with a range of 2.7 to 4 years.

   2. Patients with advanced dementia do especially poorly. In 1 cohort of patients with advanced dementia who were monitored for 18 months, 54.8% died, 41.1% developed pneumonia and 85.8% developed an eating problem.

   3. Patients with AD also have a much worse prognosis after an acute illness. In the same cohort, the 6-month mortality rate for patients who had pneumonia was 46.7%.

Evidence-Based Diagnosis

1. Diagnosing AD can be challenging because patients often have subtle symptoms early in the disease course.

   1. AD presents with self-reported memory loss in only a minority of patients.

      1. Memory loss reported by a spouse, relative, or close friend is more predictive of dementia.

      2. Memory loss reported by a patient is more predictive of depression.

   2. Behavioral changes and mood changes are commonly recognized by family members.

   3. Clinicians may recognize behavioral changes, such as increased anxiety, increased somatic complaints, or delusional thinking regarding illness, as early symptoms of the disease.

      Be aware that AD should be on the differential diagnosis of subtle behavioral changes in older patients.

2. The most efficient way to diagnose AD is to follow these 3 steps:

   1. Consider the probability that a patient has dementia.

   2. Diagnose dementia.

   3. Diagnose AD by ruling out other causes of dementia and ensuring that the patient’s symptoms are consistent with AD.

3. Diagnosing dementia

   1. The prevalence of dementia in the older population is very high. The prevalence at different ages is given in Table 11-3.

   2. Screening tests

      1. Multiple tests are used to screen patients for dementia. Those most commonly used are the Mini-Mental Status Exam (MMSE), the Modified Mini-Mental Status Exam (3MSE), the Mini-Cog, and the Memory Impairment Screen (MIS).

         • (1) 3MSE

           • (a) An expanded version of the MMSE

           • (b) It is scored out of 100 and takes 15–20 minutes to administer.

         • (2) Mini-Cog

           • (a) 3-item recall and clock drawing (which serves as the interference task)

           • (b) It is scored out of 5 (1 point for each item and 2 points for a normal clock) and takes about 3 minutes to administer.

         • (3) MIS

           • (a) 4-word recall after an interference task (counting by 3s).

           • (b) It is scored out of 8 (2 points for words spontaneously recalled and 1 point for words recalled with a clue) and takes about 4 minutes to administer.

      2. A study showed these 3 tests have similar performance, with the Mini-Cog being almost as accurate as the more time-consuming 3MSE. The MIS was the most specific. Test characteristics are shown in Table 11-4.

   3. Neuropsychiatric testing

      1. Considered the clinical gold standard for diagnosing dementia

      2. Neuropsychiatric testing can be very helpful when the diagnosis of dementia is especially difficult. Situations in which neuropsychiatric testing is commonly used are

         • (1) When there is disagreement between the clinical suspicion and in-office tests.

         • (2) To specifically gauge deficits in order to recommend ways of compensating.

         • (3) When present or suspected psychiatric disease (usually depression) complicates the diagnosis.

         • (4) When a more definitive diagnosis would be helpful for the patient or family members.

           Neuropsychiatric testing is especially useful when in office testing is negative despite a high clinical suspicion of dementia.

4. The diagnosis of AD is clinical, based on the diagnosis of dementia and the presence of features consistent with AD.

   1. Various office-based tests are useful in making this diagnosis. The National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD are currently the most commonly used by specialists.

   2. Criteria for the clinical diagnosis of probable AD include all of the following:

      1. Dementia

      2. Deficits in 2 or more areas of cognition

         • (1) Orientation

         • (2) Registration

         • (3) Visuospatial and executive functioning

         • (4) Language

         • (5) Attention and working memory

         • (6) Memory

      3. Progressive worsening of memory and other cognitive functions

      4. No disturbance of consciousness

      5. Onset between ages 40 and 90, most often after age 65

      6. Absence of other disorders that could account for the symptoms

   3. The test characteristics for these criteria are:

      1. Sensitivity, 83%; specificity, 84%

      2. LR+, 5.19; LR–, 0.2

   4. The NINCDS-ADRDA also gives factors that support the diagnosis. These are very helpful clinically, although none are necessary to make the diagnosis. Some of these are included below:

      1. Progressive deterioration of specific cognitive functions

         • (1) Aphasia

         • (2) Apraxia

         • (3) Agnosia

      2. Impaired ADLs and altered patterns of behavior

      3. Family history of dementia

      4. Normal lumbar puncture, normal or nonspecific EEG findings, and cerebral atrophy on neuroimaging

   5. Because these criteria are not perfect in the diagnosis of AD, patients in whom dementia or AD is suspected but who do not meet the criteria should be monitored closely or referred for more detailed neuropsychiatric testing.

5. Reversible dementias

   1. An important issue when diagnosing AD is how much more of a work-up should be done? The concern is that when making a clinical diagnosis, potentially reversible dementias might be missed. These reversible dementias include:

      1. CNS infections

      2. Hypothyroidism

      3. B₁₂ deficiency

      4. CNS masses

         • (1) Neoplasms

         • (2) Subdural hematomas

      5. Normal-pressure hydrocephalus

      6. Medications

   2. Current practice is to order the following tests:

      1. CBC

      2. TSH

      3. Basic metabolic panel and LFTs

      4. Vitamin B₁₂ level

      5. Rapid plasma reagin

      6. Consider neuroimaging (MRI or CT)

         • (1) Imaging is not required in most patients with dementia.

         • (2) In practice, most patients will undergo imaging both to assess for diagnoses other than AD and to detect brain atrophy that may support the diagnosis of AD.

Treatment

1. Counseling

   1. When the diagnosis of AD is made, patients and families should be educated on course, complications, and prognosis of the disease.

   2. Decisions need to be made regarding health care proxies, financial and estate planning, and end-of-life care.

   3. It is crucial to make these decisions while the patient is still a competent decision maker. Referral to support services, such as the Alzheimer’s Association, may be helpful.

2. Safety

   1. As the disease progresses, patient safety often becomes an issue.

   2. Driving, wandering, and cooking are often early concerns.

      1. Driving is usually the most difficult to address because patients lack insight into the dangers they pose and resist the loss of independence that not driving brings.

      2. Physicians should raise this issue since it is often difficult for caregivers to bring up.

      3. Patients with even mild dementia should either be told to not drive or be required to undergo frequent performance evaluations.

      4. Home safety checklists are available online that can help family members protect patients with dementia.

3. Behavioral

   1. Caregivers should be told to expect behavioral and personality changes, and be instructed on how to respond.

   2. Maintenance of routines is important.

   3. Situations likely to be stressful to patients, such as those in which a patient’s deficits interfere with his functioning, should be avoided.

4. Pharmacotherapy

   1. Cholinesterase inhibitors

      1. 4 cholinesterase inhibitors are approved for treatment

         • (1) Donepezil

         • (2) Tacrine

         • (3) Rivastigmine

         • (4) Galantamine

      2. These medications have been shown to have modest effects on objective measures of dementia and functional status.

   2. Memantine is an NMDA receptor antagonist also approved for the treatment of AD. It has similar efficacy to the drugs above and may be used in combination with cholinesterase inhibitors.

   3. Associated neuropsychiatric symptoms

      1. May include agitation (60–70%) or either delusions or hallucinations (30–60%)

      2. Atypical neuroleptics, such as olanzapine and risperidone, are frequently used but the evidence base for their efficacy is poor and they have been associated with higher mortality. Neither of these drugs is approved for this indication.

   4. Depression

      1. Very common in patients with AD

      2. Present in up to 50% of patients

      3. All patients with AD should be screened for depression and treated if it is found.

   5. Caregiver care

      1. Taking care of a friend or relative with AD can be extremely challenging.

      2. Caregivers should be counseled on the importance of taking time off and the availability of respite care.

      3. They should be counseled that behavioral difficulties are a result of the disease and not the patient’s anger or heartlessness.

      4. Caregiver support groups can be extremely helpful.

Mr. R’s exam thus far reveals some difficulty with recalling recent events. Given his age, his baseline risk of dementia is at least 10%. The first step in his work-up would be to perform 1 of the screening tests for dementia. If this is positive, consider whether he fulfills the NINCDS-ADRDA criteria for probable AD.

Alternative Diagnosis: Multi-infarct Dementia (Vascular Dementia, VaD)

Textbook Presentation

A patient with VaD may have dementia that has an abrupt onset or is slowly worsening. The patient usually has risk factors for vascular disease or has previously diagnosed vascular disease. The patient often has difficulty walking during the neurologic exam.

Disease Highlights

1. Generally considered to be the most common cause of dementia after AD.

2. Most common in patients with risk factors for vascular disease or embolic stroke.

3. Patients have dementia and evidence that cerebrovascular disease has caused the dementia.

   1. A classic, but insensitive, clue is a “step-like deterioration” related to intermittent cerebrovascular accidents.

   2. Other clues are a focal neurologic exam or evidence of strokes, white matter changes, or atrophy on neuroimaging.

4. Symptoms of VaD include gait disturbance, urinary symptoms, and personality changes.

Evidence-Based Diagnosis

1. The DSM-V criteria for the clinical diagnosis of VaD are:

   1. The criteria are met for major or mild neurocognitive disorder.

   2. The clinical features are consistent with a vascular etiology, as suggested by either of the following:

      1. Onset of the cognitive deficits is temporally related to 1 or more cerebrovascular events.

      2. Evidence for decline is prominent in complex attention (including processing speed) and frontal-executive function.

   3. There is evidence of the presence of cerebrovascular disease from history, physical exam, and/or neuroimaging considered sufficient to account for the neurocognitive deficits.

   4. The symptoms are not better explained by another brain disease or systemic disorder.

2. Features consistent with the diagnosis of VaD are

   1. Exaggeration of deep tendon reflexes

   2. Extensor plantar response

   3. Gait abnormalities (consider history of unsteadiness and frequent, unprovoked falls)

   4. Pseudobulbar palsy (pathologic laughing, crying, grimacing; and weakness of the muscles associated with cranial nerves V, VII, IX, X, XI, and XII)

   5. Focal neurologic signs

3. The actual diagnosis of VaD is complicated by the presence of multiple different criteria.

4. The Hachinski Ischemic Score seems to be a clinically useful test for determining whether ischemic disease is playing a role in a patient’s dementia.

   1. In the score, 2 points are given for each of the following features:

      1. Abrupt onset

      2. Fluctuating course

      3. History of stroke

      4. Focal neurologic signs and symptoms

   2. 1 point is given for each of the following features:

      1. Stepwise deterioration

      2. Nocturnal confusion

      3. Preservation of personality

      4. Depression

      5. Somatic complaints

      6. Emotional lability

      7. Hypertension

      8. Atherosclerosis

   3. A score of greater than 7 carries a LR+ of 8.3 for differentiating VaD from AD. The score performs less well for differentiating AD or VaD from a mixed dementia.

Treatment

1. Behavioral, pharmacologic, and surgical means of modifying risk factors for cerebrovascular disease and preventing recurrent vascular events should be used.

2. Behavioral interventions include smoking cessation and dietary intervention to decrease vascular risk.

3. Pharmacologic interventions include treatment of hypertension and diabetes mellitus, treatment of hypercholesterolemia (to an LDL < 100 mg/dL), aspirin therapy, and anticoagulation when indicated.

4. Surgical therapy includes carotid endarterectomy when indicated.

AD can be confidently diagnosed in this patient. He has no risk factors for VaD. His ischemia score is 1. Dementia was diagnosed at his previous visit; since his symptoms have progressed, he now fulfills the criteria for AD. Reversible causes of dementia are unlikely given the normal evaluation. The patient’s functional limitations exclude MCI as a cause. The patient has no symptoms of delirium or depression.

Mild Cognitive Impairment (MCI)

Textbook Presentation

Usually presents in an older patient complaining of memory loss. Common complaints are difficulty remembering names and appointments or solving complex problems. Detailed testing shows abnormal memory, but patients have no functional impairment.

Disease Highlights

1. MCI is a diagnosis that stands between the normal, age-related decline in cognition and dementia.

2. The diagnosis can be difficult to make as memory complaints, and concern about dementia, are very common in older people.

3. 4 types of MCI are:

   1. Single domain amnestic MCI in which people have memory loss and no other deficits.

   2. Multiple domain amnestic MCI in which people have memory loss as well as other deficits.

   3. Single domain non-amnestic MCI in which people have impairment in a single, non–memory-related, cognitive domain.

   4. Multiple domain non-amnestic MCI in which people have impairment in multiple, non–memory-related, cognitive domain.

4. Patients with this disorder are not neurologically normal.

   1. For patients with amnestic types of MCI, their memory is worse than age-matched controls.

   2. Patients with MCI have a higher rate of progression to dementia than age- matched controls.

Evidence-Based Diagnosis

The diagnosis of this disease is generally made by neuropsychiatric testing. Evaluation for reversible causes, as in patients with dementia, is appropriate.

Treatment

Presently, there is no proven treatment for MCI. Patients should be monitored closely for development of more severe cognitive or functional decline.

Dementia with Lewy Bodies (DLB)

Textbook Presentation

DLB is typically seen in a patient with Parkinson disease who has dementia. The predominant symptoms of the dementia are a fluctuating course and the presence of hallucinations. In patients without a previous diagnosis of Parkinson disease, motor symptoms similar to those seen in Parkinson disease are often present.

Disease Highlights

1. DLB is among the most common types of dementia after AD.

   1. Lewy bodies are seen in the cortex of about 20% of patients with dementia.

   2. Lewy bodies may be present in some patients with a clinical diagnosis of AD thus DLB may coexist with AD.

2. The most important features of DLB are included in the Evidence-Based Diagnosis section below.

3. Patients with DLB may have a fluctuating course.

   1. Early in the disease patients may seem nearly normal at times and demented at other times.

   2. Because of the fluctuation in symptoms, delirium needs to be included in the differential diagnosis.

4. Visual hallucinations are common in DLB, unlike in most other types of dementia.

5. Mild extrapyramidal motor symptoms (rigidity and bradykinesis) are often seen. These may occur late in the course of other dementias but occur early with DLB and worsen over time.

Evidence-Based Diagnosis

The diagnostic criteria for DLB are presented below.

1. There is dementia that might be mild at the onset of disease.

2. 2 of the following are essential for a diagnosis of probable DLB:

   1. Fluctuating cognition with pronounced variations in attention and alertness

   2. Recurrent visual hallucinations that are typically well formed and detailed

   3. Spontaneous motor features of parkinsonism

3. The following features are supportive of the diagnosis of DLB:

   1. Repeated falls

   2. Syncope

   3. Transient loss of consciousness

   4. Neuroleptic sensitivity

   5. Systematized delusions and hallucinations

Treatment

1. Supportive treatment of patients with DLB is the same as for patients with AD.

2. Cholinesterase inhibitors have also been shown to be effective.

3. Neuroleptics can be dangerous, potentially worsening symptoms.

   Patients with dementia with parkinsonian features, a fluctuating course, and visual hallucinations should be evaluated for DLB before they are treated with neuroleptics.