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I am professor Yasser Metwally, porofessor of neurology, Ain Shams university, Cairo, Egypt, Visit my web site at: www.yassermetwally.com

This post contains simple medical information to neurological patients (vist my site at http://patients.yassermetwally.com)

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INTRODUCTION

Delirium (sometimes called acute confusional state) and dementia are the most common causes of cognitive impairment, although affective disorders (eg, depression) also can disrupt cognition. Delirium and dementia are separate disorders but are sometimes difficult to distinguish. In both, cognition is disordered, but dementia affects mainly memory and delirium affects mainly attention.

Other specific characteristics help distinguish between the 2 disorders. Delirium is typically caused by acute illness or drug toxicity (sometimes life threatening) and is often reversible, whereas dementia is typically caused by anatomic changes in the brain, has slower onset, and is generally irreversible. Delirium often develops in patients with dementia. Mistaking delirium for dementia in an elderly patient—a common clinical error—must be avoided, particularly when delirium is superimposed on chronic dementia. No laboratory test can definitively establish the cause of cognitive impairment; a thorough history and physical examination as well as knowledge of baseline function are essential.

BEHAVIOURAL DISORDERS IN DEMENTIA

Disruptive actions are common in patients with dementia and are the primary reason for up to 50% of nursing home admissions. Actions include wandering, restlessness, yelling, throwing, hitting, refusing treatment, interrupting staff members, insomnia, and crying. Behavior disorders in dementia have not been well characterized, and their treatment is poorly understood.

Deciding what actions constitute a behavior disorder is highly subjective. Tolerability (what actions care -givers can tolerate) depends partly on the patient’s living arrangements, particularly safety. For example, wandering may be tolerable if a patient lives in a safe environment (with locks and alarms on all doors and gates); however, if the patient lives in a nursing home or hospital, wandering may be intolerable because it disturbs other patients or interferes with the operation of the institution. Many behaviors (eg, wandering, repeatedly questioning, being uncooperative) are better tolerated during the day. Whether sundowning (exacerbation of disruptive behaviors at sundown or early evening) is a matter of tolerability or true diurnal variation is unknown. In nursing homes, 12 to 14% of patients with dementia have more behavior disturbances during the evening than during the day.

• Etiology

Behavior disorders may result from functional changes related to dementia: Reduced ability to control behavior, misinterpretation of visual and auditory cues, impaired short-term memory (eg, patients repeatedly ask for things already received), and reduced ability or inability to express needs (eg, they wander because they are lonely, frightened, or looking for something or someone).

Patients with dementia often adapt poorly to the regimentation of institutional living. For many elderly patients with dementia, behavior disorders develop or worsen after they are moved to a more restrictive environment.

Physical problems (eg, pain, shortness of breath, urinary retention, constipation, physical abuse) can exacerbate behavior disorders partly because patients may be unable to adequately communicate. Physical problems can lead to delirium, and delirium superimposed on chronic dementia may worsen the behavior disorder.

• Evaluation

The best approach is to characterize and classify the behavior, rather than to label all such behaviors agitation, a term with too many meanings to be useful. Specific behaviors, precipitating events (eg, feeding, toileting, drug administration, visits), and time the behavior started and resolved should be recorded, which helps identify changes in pattern or intensity of a behavior and makes planning a management strategy easier. If behavior changes, a physical examination should be done to exclude physical disorders and physical abuse, but environmental changes (eg, a different caregiver) should also be noted, because they, rather than a patient-related factor, may be the reason.

Psychotic behavior must be identified because management differs. Presence of delusions or hallucinations indicates psychosis. Delusions and hallucinations must be distinguished from disorientation, fearfulness, and misunderstanding, which are common among patients with dementia. Delusions without paranoia may be confused with disorientation, but delusions are usually fixed (eg, a nursing home is repeatedly called a prison), and disorientation varies (eg, a nursing home is called a prison, a restaurant, and a home).

• Treatment

Management of behavior disorders in dementia is controversial and has been inadequately studied. Supportive measures are preferred; however, drugs are commonly used.

Environmental measures: The environment should be safe and flexible enough to accommodate behaviors that are not dangerous. Signs to help patients find their way and doors equipped with locks or alarms can help ensure the safety of patients who wander. Flexible sleeping hours and organization of beds can help patients with sleeping problems. Measures used to treat dementia generally also help minimize behavior disorders: providing cues about time and place, explaining care before giving it, and encouraging physical activity. If an institution cannot provide an appropriate environment for a particular patient, transferring the patient to one that can may be preferable to drug treatment.

Caregiver support: Learning how dementia leads to behavior disorders and how to respond to disruptive behavior can help family members and other caregivers provide care for and cope with the patient better. Learning how to manage stress, which may be considerable, is essential.

Drugs: Drugs are used only when other approaches are ineffective and when drugs are essential for safety. The need for continued treatment should be reassessed at least every month. Drugs should be selected to target the most intolerable behaviors. Antidepressants, preferably SSRIs, should be prescribed only for patients with signs of depression.

Antipsychotics are often used even though their efficacy has been shown only in psychotic patients. Other patients are unlikely to benefit and likely to experience adverse effects, particularly extrapyramidal symptoms. Tardive dyskinesia or tardive dystonia may develop; they often do not resolve when the dose is reduced or the drug withdrawn.

Choice of antipsychotic depends on relative toxicity. Of conventional antipsychotics, haloperidol is relatively nonsedating and has less potent anticholinergic effects but is most likely to cause extrapyramidal symptoms; thioridazine and thiothixene are less likely to cause extrapyramidal symptoms but are more sedating and have more anticholinergic effects than haloperidol. Second-generation (atypical) antipsychotics (eg, olanzapine, risperidone) are minimally anticholinergic and produce fewer extrapyramidal symptoms than conventional antipsychotics; however, these drugs, used for an extended period, may be associated with an increased risk of hyperglycemia and all-cause mortality. Also, risk of cerebrovascular events may be increased in elderly patients with dementia-related psychosis using these drugs.

If antipsychotics are used, they should be given in a low dose (eg, olanzapine2.5 to 15 mg po once/day; risperidone 0.5 to 3 mg po q 12 h; haloperidol 0.5 to 1.0 mg po, IV, or IM) and for a short period.

The anticonvulsants carbamazepine, valproate, gabapentin, and lamotrigine may be useful in controlling violent outbursts. Evidence suggests that ß-blockers (eg, propranolol 10 mg bid initially, slowly increased, if needed, to 40 mg bid) can be useful in some patients with violent physical outbursts. Patients should be monitored for hypotension, bradycardia, and depression.

Sedatives (eg, short-acting benzodiazepines) are sometimes used in the short term to alleviate anxiety but are not recommended in the long term.

DELIRIUM

Delirium is an acute, transient, usually reversible, fluctuating disturbance in attention, cognition, and consciousness level. Causes include almost any disorder, intoxication, or drug. Diagnosis is clinical, with laboratory and imaging tests to identify the cause. Treatment is correction of the cause and supportive measures.

Delirium may occur at any age but is more common among the elderly. At least 10% of elderly patients who are admitted to the hospital have delirium; 15 to 50% experience delirium at some time during hospitalization. Delirium is also common among nursing home residents. When delirium occurs in younger people, it is usually due to drug use or a life-threatening systemic disorder.

• Etiology and Pathophysiology

Many conditions and drugs (particularly anticholinergics, psychoactive drugs, and opioids) can cause delirium (see Table 1). In about 10 to 20% of patients, no cause is identified.

Table 1. Causes of Delirium

Mechanisms are not fully understood but may involve reversible impairment of cerebral oxidative metabolism, multiple neurotransmitter abnormalities, and generation of cytokines. Stress of any kind upregulates sympathetic tone and downregulates parasympathetic tone, impairing cholinergic function and thus contributing to delirium. The elderly are particularly vulnerable to reduced cholinergic transmission, increasing their risk of delirium. Regardless of cause, the cerebral hemispheres or arousal mechanisms of the thalamus and brain stem reticular-activating system become impaired.

Predisposing factors include brain disorders (eg, dementia, stroke, Parkinson’s disease), advanced age, sensory impairment, and multiple coexisting disorders. Precipitating factors include use of = 3 new drugs, infection, dehydration, immobility, undernutrition, and use of bladder catheters. Recent exposure to anesthesia also increases risk, especially if exposure is prolonged and if anticholinergics are given during surgery. Decreased sensory stimuli at night may trigger delirium in at-risk patients. For elderly patients in an ICU, risk of delirium (ICU psychosis) is particularly high.

• Symptoms and Signs

Delirium is characterized primarily by difficulty focusing, maintaining, or shifting attention (inattention). Consciousness level fluctuates; patients are disoriented to time, place, and sometimes person. They may have hallucinations. Confusion regarding day-to-day events and daily routines is common, as are changes in personality and affect. Thinking becomes disorganized, and speech is often disordered, with prominent slurring, rapidity, neologisms, aphasic errors, or chaotic patterns. Symptoms fluctuate over minutes to hours; they may lessen during the day and worsen at night.

Symptoms may include inappropriate behavior, fearfulness, and paranoia. Patients may become irritable, agitated, hyperactive, and hyperalert, or they may become quiet, withdrawn, and lethargic. Some patients alternate between the two. Usually, patterns of sleeping and eating are grossly distorted. Because of the many cognitive disturbances, insight is poor, and judgment impaired. Other symptoms and signs depend on the cause.

• Diagnosis

Diagnosis is clinical. All patients with any sign of cognitive impairment require a formal mental status examination. Attention is assessed first. Simple tests include immediate repetition of the names of 3 objects, digit span (ability to repeat 7 digits forward and 5 backward), and naming the days of the week forward and backward. Inattention (patient does not register directions or other information) must be distinguished from poor short-term memory (patient registers information but rapidly forgets it). Further cognitive testing is futile for patients who cannot register information.

After initial assessment, standard diagnostic criteria, such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) or Confusion Assessment Method (CAM) may be used. Features required for diagnosis are an acute change in cognition that fluctuates during the day, inattention (eg, difficulty focusing or following what is said), plus another feature: with DSM, disturbance of consciousness (ie, less clarity); with CAM, either an altered level of consciousness (eg, hyperalert, lethargic, stuporous, comatose) or disorganized thinking (eg, rambling, irrelevant conversation, illogical flow of ideas).

Interviewing family members, caregivers, and friends can determine whether the change in mental status is recent and is distinct from any baseline dementia. The history helps distinguish a psychiatric disorder from delirium. Psychiatric disorders, unlike delirium, almost never cause inattention or fluctuating consciousness, and onset of psychiatric disorders is nearly always subacute. History should also include use of alcohol and illicit, OTC, and prescription drugs, focusing particularly on drugs with CNS effects and on new additions, discontinuations, or changes in dose, including overdosing.

The physical examination can detect signs of CNS trauma or infection (eg, fever, meningismus, Kernig and Brudzinski signs). Tremor and myoclonus suggest uremia, hepatic failure, or drug intoxication. Ophthalmoplegia and ataxia suggest Wernicke-Korsakoff syndrome. Focal neurologic findings (eg, cranial nerve palsies, motor or sensory deficits) or papilledema suggests a structural CNS disorder.

Tests should include serum glucose, thyroid function tests, toxicology screening, CBC with differential, serum electrolytes, urinalysis, appropriate cultures (especially urine), and cardiac and pulmonary evaluation (eg, ECG, pulse oximetry, chest x-ray).

CT or MRI should be done if clinical findings suggest a CNS lesion or if initial testing has not identified the cause of delirium, especially in patients = 65 yr, because a primary CNS disorder is more likely. Lumbar puncture may be indicated to rule out meningitis, encephalitis, or subarachnoid hemorrhage. If nonconvulsive status epilepticus, a rare cause, is suspected (based on history, subtle motor twitches, automatisms, or presence of a steadier but less intense pattern of bewilderment and drowsiness), EEG should be done.

• Prognosis

Morbidity and mortality rates are higher in patients who have delirium when they are hospitalized and in those who develop delirium during hospitalization.

Certain causes of delirium (eg, hypoglycemia, intoxication, infection, iatrogenic factors, drug toxicity, electrolyte imbalance) typically resolve rapidly with treatment. However, recovery may be slow (days to even weeks or months), especially in the elderly, resulting in longer hospital stays, increased complications, increased costs, and long-term disability. Some patients never fully recover from delirium. For up to 2 yr after delirium occurs, risk of cognitive and functional decline, institutionalization, and death is increased.

• Treatment

Treatment consists of correcting the cause and removing aggravating factors (eg, stopping drugs, treating infection), providing support for the patient and family members, and managing agitation to ensure patient safety. Adequate fluid and nutrition should be provided, and nutritional deficiencies (eg, of thiamin or vitamin B12) should be corrected.

The environment should be stable, quiet, and well-lit and include visual cues to orient the patient (eg, calendar, clocks, family photographs). Frequent reorientation and reassurance by hospital staff or family members may also help. Patients’ sensory deficits should be minimized (eg, by replacing hearing-aid batteries, by encouraging patients who need eyeglasses or hearing aids to use them).

Approach to treatment should be multidisciplinary (with a physician, physical and occupational therapists, nurses, and social workers); it should involve strategies to enhance mobility and range of motion, treat pain and discomfort, prevent skin breakdown, ameliorate incontinence, and minimize risk of aspiration.

Agitation may threaten the well-being of the patient, a caregiver, or a staff member. Simplifying drug regimens and avoiding use of IV lines, Foley catheters, and physical restraints (particularly in the long-term care setting) as much as possible can help prevent exacerbation of agitation and reduce risk of injury. However, in certain circumstances, physical restraints may be needed to prevent patients from harming themselves or others. Restraints should be applied by a staff member trained in their use; they should be released at least every 2 h to prevent injury and discontinued as soon as possible. Use of hospital-employed assistants (sitters) as constant observers may help avoid the need for restraints.

Drugs, typically low-dose haloperidol (0.5 to 1.0 mg po, IV, or IM), may lessen agitation or psychotic symptoms but do not correct the underlying cause and may prolong or exacerbate delirium. Second-generation (atypical) antipsychotics (eg, risperidone 0.5 to 3 mg po q 12 h, olanzapine 2.5 to 15 mg po once/day) may be used instead because they have fewer extrapyramidal adverse effects; however, long-term use in the elderly may increase risk of stroke. These drugs are not typically given IV or IM. Benzodiazepines (eg, lorazepam 0.5 to 1.0 mg) have a more rapid onset of action (5 min after parenteral administration) than antipsychotics but commonly worsen confusion and sedation in patients with delirium. Overall, antipsychotics and benzodiazepines are equally effective for managing agitation in delirium, but antipsychotics have fewer adverse effects. Benzodiazepines are preferred for delirium attributed to sedative withdrawal and for patients intolerant of antipsychotics (eg, those with Parkinson’s disease or Lewy body dementia). Dose of these drugs should be reduced as quickly as possible.

DEMENTIA

Dementia is chronic, global, usually irreversible deterioration of cognition. Diagnosis is clinical; laboratory and imaging tests are used to identify treatable causes. Treatment is supportive. Cholinesterase inhibitors can sometimes temporarily improve cognitive function.

Dementia may occur at any age but affects primarily the elderly (about 5% of those aged 65 to 74 and 40% of those > 85). It accounts for more than 1/2 of nursing home admissions. At least 4 to 5 million people in the US have dementia.

• Etiology and Classification

Dementias can be classified in several ways: Alzheimer’s or non-Alzheimer’s type, cortical or subcortical, irreversible or potentially reversible, or common or rare. Dementias may be primary neurodegenerative disorders or due to another condition (see Table 2).

Table 2. Classification of Some Dementias

The main types are Alzheimer’s disease, vascular dementia, Lewy body dementia, frontal-temporal dementias, and HIV-associated dementia. Other disorders associated with dementia include Parkinson’s disease, Huntington’s disease, progressive supranuclear palsy, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, other prion disorders, and neurosyphilis. Distinguishing type or cause of dementia is difficult; definitive diagnosis often requires postmortem pathologic examination of brain tissue. Patients can have > 1 type (mixed dementia).

Some structural brain disorders (eg, normal-pressure hydrocephalus, subdural hematoma), metabolic disorders (eg, hypothyroidism, vitamin B12 deficiency), and toxins (eg, lead) cause a slow deterioration of cognition that may resolve with treatment. This impairment is sometimes called reversible dementia, but some experts restrict the term dementia to irreversible cognitive deterioration. Depression may mimic dementia (and was formerly called pseudodementia); the 2 disorders often coexist. Changes in cognition occur with aging, but they are not dementia.

Any disorder may exacerbate cognitive deficits in patients with dementia. Delirium often occurs in patients with dementia. Drugs, particularly benzodiazepines and anticholinergics (eg, some tricyclic antidepressants, antihistamines, antipsychotics, benztropine), may temporarily cause or worsen symptoms of dementia, as may alcohol, even in moderate amounts. New or progressive renal or hepatic failure may reduce drug clearance and cause drug toxicity after years of taking a stable drug dose (eg, of propranolol).

• Symptoms and Signs

Dementia impairs cognition globally. Often, loss of short-term memory is the 1st sign. Although symptoms exist in a continuum, they can be divided into early, intermediate, and late. Personality changes and behavioral disturbances may develop early or late. Motor and other focal neurologic deficits occur at different stages, depending on the type of dementia; they occur early in vascular dementia and late in Alzheimer’s disease. Incidence of seizures is somewhat increased during all stages. Psychosis—hallucinations, delusions, or paranoia—occurs in about 10% of patients with dementia, although a higher percentage may experience these symptoms temporarily.

Early: Recent memory is impaired; learning and retaining new information become difficult. Language problems (especially with word finding), mood swings, and personality changes develop. Patients may have progressive difficulty with independent activities of daily living (eg, balancing their checkbook, finding their way around, remembering where they put things). Abstract thinking, insight, or judgment may be impaired. Patients may respond to loss of independence and memory with irritability, hostility, and agitation.

Agnosia (impaired ability to identify objects despite intact sensory function), apraxia (impaired ability to perform previously learned motor activities despite intact motor function), or aphasia (impaired ability to comprehend or use language) may further limit functional ability.

Although early dementia may not compromise sociability, family members may report strange behavior accompanied by emotional lability.

Intermediate: Patients become unable to learn and recall new information. Memory of remote events is reduced but not totally lost. Patients may require help with basic activities of daily living (eg, bathing, eating, dressing, toileting). Personality changes may progress. Patients may become irritable, anxious, self-centered, inflexible, or angry more easily, or they may become more passive, with a flat affect, depression, indecisiveness, lack of spontaneity, or general withdrawal from social situations. Behavior disorders may develop: Patients may wander or become suddenly and inappropriately agitated, hostile, uncooperative, or physically aggressive.

By this stage, patients have lost all sense of time and place, because they cannot effectively use normal environmental and social cues. Patients often get lost; they may be unable to find their own bedroom or bathroom. They remain ambulatory but are at risk of falls or accidents secondary to confusion. Altered sensation or perception may culminate in psychosis with hallucinations and paranoid and persecutory delusions. Sleep patterns are often disorganized.

Late (severe): Patients cannot walk, feed themselves, or perform any other activities of daily living; they may become incontinent. Recent and remote memory is completely lost. Patients may be unable to swallow. They are at risk of undernutrition, pneumonia (especially due to aspiration), and pressure ulcers. Because they depend completely on others for care, placement in a long-term care facility often becomes necessary. Eventually, patients become mute.

Because such patients cannot relate any symptoms to a physician and because elderly patients often have no febrile or leukocytic response to infection, a physician must rely on experience and acumen whenever a patient appears ill. End-stage dementia results in coma and death, usually due to infection.

• Diagnosis

Diagnosis focuses on distinguishing dementia from delirium and identifying the cerebral areas affected and potentially reversible causes. Distinguishing between dementia and delirium is crucial (because delirium is usually reversible with prompt treatment) but can be difficult. Attention is assessed first. If a patient is inattentive, the diagnosis is likely to be delirium, although advanced dementia also severely impairs attention. Other features that suggest delirium rather than dementia (eg, duration of cognitive impairment) are determined by the history, physical examination, and tests for specific causes.

Dementia must also be distinguished from age-associated memory impairment; the elderly have a relative deficiency in recall, particularly compared with recall during their youth. This change is not progressive and does not affect daily function. If such people are given enough time to learn new information, their intellectual performance is good. Mild cognitive impairment involves a subjective memory complaint; memory is impaired compared with that of age-matched controls, but other cognitive domains and daily function are not affected. Up to 50% of patients with mild cognitive impairment develop dementia within 3 yr.

Dementia should also be distinguished from the dementia of depression; this cognitive disturbance resolves with treatment of depression. Depressed older patients may experience cognitive decline, but unlike patients with dementia, they tend to exaggerate their memory loss and rarely forget important current events or personal matters. Neurologic examinations are normal except for signs of psychomotor slowing. When tested, patients with depression make little effort to respond, but those with dementia often try hard but respond incorrectly. When depression and dementia coexist, treating depression does not fully restore cognition.

The best screening test for dementia is a short-term memory test (eg, registering 3 objects and recalling them after 5 min); patients with dementia forget simple information within 3 to 5 min. Another test assesses the ability to name objects within categories (eg, lists of animals, plants, or pieces of furniture). Patients with dementia struggle to name a few; those without dementia easily name many.

In addition to loss of short-term memory, diagnosis of dementia requires at least one of the following cognitive deficits: aphasia, apraxia, agnosia, or impaired ability to plan, organize, sequence, or think abstractly (executive dysfunction). Each cognitive deficit must substantially impair function and represent a significant decline from a previous level of functioning. Also, the deficits must not occur only during delirium.

History and physical examination should focus on signs of systemic disorders that may indicate delirium or on treatable disorders that cause cognitive impairment (vitamin B12 deficiency, advanced syphilis, hypothyroidism, depression—see Table 1).

A formal mental status examination should be done. When delirium is absent, a score of < 24 points suggests dementia; adjustments for education improve diagnostic accuracy. If the diagnosis remains in doubt, patients should be referred for full neuropsychologic testing, which may help characterize specific deficits due to dementia.

Tests should include CBC, liver function tests, and thyroid-stimulating hormone and vitamin B12 levels. If clinical findings suggest a specific disorder, other tests (eg, HIV tests, syphilis serology) are indicated. Lumbar puncture is rarely needed but should be considered if a chronic infection or neurosyphilis is suspected. Other tests may be used to exclude causes of delirium.

CT or MRI should be done in the initial evaluation of dementia or after any sudden change in cognition or mental status. Brain imaging can identify potentially reversible structural disorders (eg, normal-pressure hydrocephalus, brain tumors, subdural hematoma) and metabolic disorders (eg, Hallervorden-Spatz disease, Wilson’s disease). Occasionally, EEG is useful (eg, to evaluate episodic lapses in attention or bizarre behavior). Functional MRI or single-photon emission CT can provide information about cerebral perfusion patterns and help with differential diagnosis.

• Prognosis and Treatment

Dementia is usually progressive. However, progression rate varies widely and depends on the cause. Dementia shortens life expectancy, but survival estimates vary.

Measures to ensure patient safety and to provide an appropriate environment are essential to treatment, as is caregiver assistance. Several drugs are available.

Patient safety: Occupational and physical therapists can evaluate the home for safety; the goals are to prevent accidents (particularly falls), to manage behavior disorders, and to plan for change as dementia progresses

How well patients function in various settings (ie, kitchen, automobile) should be evaluated using simulations. If patients have deficits and remain in the same environment, protective measures (eg, unplugging the stove, removing the car, confiscating car keys) may be required. Some states require physicians to notify the Department of Motor Vehicles of patients with dementia because at some point, such patients can no longer drive safely. If patients wander, signal monitoring systems can be installed. Ultimately, assistance (eg, housekeepers, home health aides) or a change of environment (living facilities without stairs, assisted-living facility, skilled nursing facility) may be indicated.

Environmental measures: An appropriate environment can help preserve feelings of self-control and personal dignity. Measures include frequent reinforcement of orientation; a bright, cheerful, familiar environment; minimal new stimulation; and regular, low-stress activities.

Large calendars and clocks and a routine for daily activities can help with orientation; medical staff members can wear large name tags and repeatedly introduce themselves. Changes in surroundings, routines, or people should be explained to patients precisely and simply, omitting nonessential procedures. Patients require time to adjust and become familiar with the changes. Telling patients about what is going to happen (eg, about a bath or feeding) may avert resistance or violent reactions. Frequent visits by staff members and familiar people encourage patients to remain social.

The room should be reasonably bright and contain sensory stimuli (eg, radio, television, night-light) to help patients remain oriented and focus their attention. Quiet, dark, private rooms should be avoided.

Activities can help patients function better; those related to interests before dementia began are good choices. Activities should be enjoyable, provide some stimulation, but not involve too many choices or challenges. Exercise to reduce restlessness, improve balance, and maintain cardiovascular tone should be done daily. Exercise can also help improve sleep and reduce behavior disorders. Occupational and music therapy helps maintain fine motor control and provides nonverbal stimulation. Group therapy (eg, reminiscence therapy, socialization activities) may help maintain conversational and interpersonal skills.

Drugs: Eliminating or limiting drugs with CNS activity often improves function. Sedating and anticholinergic drugs, which tend to worsen dementia, should be avoided.

The cholinesterase inhibitors donepezil, rivastigmine, and galantamine are somewhat effective in improving cognitive function in patients with Alzheimer’s disease or Lewy body dementia and may be useful in other forms of dementia. These drugs inhibit acetylcholinesterase, increasing the acetylcholine level in the brain. A new drug, memantine, may help to slow progression of moderate to severe dementia and can be used with a cholinesterase inhibitor.

Other drugs (eg, antipsychotics) have been used to control behavior disorders. Patients with dementia and signs of depression should be treated with nonanticholinergic antidepressants, preferably SSRIs.

Caregiver assistance: Immediate family members are largely responsible for care of a patient with dementia. Nurses and social workers can teach them and other caregivers how to best meet the patient’s needs (eg, how to deal with daily care and handle financial issues); teaching should be ongoing. Other resources (eg, support groups, educational materials, Internet web sites) are available. Caregivers may experience substantial stress. Stress may be caused by worry about protecting the patient and frustration, exhaustion, anger, and resentment from having to do so much to care for someone. Health care practitioners should watch for early symptoms of caregiver stress and burnout and, when needed, suggest support services (eg, social worker, nutritionist, nurse, home health aide). If a patient with dementia has an unusual injury, the possibility of elder abuse should be investigated.

End-of-life issues: Because insight and judgment deteriorate in patients with dementia, appointment of a family member, guardian, or lawyer to oversee finances may be necessary. Early in dementia, before the patient is incapacitated, the patient’s wishes about care should be clarified, and financial and legal arrangements (eg, durable power of attorney, durable power of attorney for health care) should be made. When these documents are signed, the patient’s capacity should be evaluated, and evaluation results recorded.

• Alzheimer’s Disease

Alzheimer’s disease causes progressive cognitive deterioration and is characterized by senile plaques, ß-amyloid deposits, and neurofibrillary tangles in the cerebral cortex and subcortical gray matter.

Alzheimer’s disease is the most common cause of dementia; it accounts for > 65% of dementias in the elderly. The disease is twice as common among women as among men, partly because women have a longer life expectancy. Alzheimer’s disease affects about 4% of people aged 65 to 74 and 30% of those > 85. Prevalence in industrialized countries is expected to increase as the proportion of the elderly increases.

• Etiology and Pathophysiology

Most cases are sporadic, with late onset (> 60 yr) and unclear etiology. However, about 5 to 15% are familial; 1/2 of these cases have an early onset (< 60 yr) and are typically related to specific genetic mutations.

Typically, extracellular ß-amyloid deposits, intracellular neurofibrillary tangles (paired helical filaments), and senile plaques develop, and neurons are lost. Cerebrocortical atrophy is common, and use of cerebral glucose is reduced, as is perfusion in the parietal lobe, temporal cortices, and prefrontal cortex.

At least 5 distinct genetic loci, located on chromosomes 1, 12, 14, 19, and 21, influence initiation and progression of Alzheimer’s disease. Genes for the amyloid precursor proteins presenilin I and presenilin II are involved. Mutations in these genes may alter the processing of amyloid precursor protein, leading to deposition and fibrillar aggregation of ß-amyloid. ß-Amyloid may lead to neuronal death and formation of the neurofibrillary tangles and senile plaques, which consist of degenerated axonal or dendritic processes, astrocytes, and glial cells around an amyloid core.

Other genetic determinants include the apolipoprotein (apo) E alleles (e). Apo E proteins influence ß-amyloid deposition, cytoskeletal integrity, and efficiency of neuronal repair. Risk of Alzheimer’s disease is substantially increased in people with 2 e4 alleles and may be decreased in those who have the e2 allele.

Other common abnormalities include increased brain and CSF concentrations of the tau protein (a component of neurofibrillary tangles and ß-amyloid) and reduced levels of choline acetyltransferase and various neurotransmitters (eg, somatostatin).

The relationship of environmental factors (eg, low hormone levels, metal exposure) and Alzheimer’s disease is under study, but no link has been established.

• Symptoms, Signs, and Diagnosis

Symptoms and signs of Alzheimer’s disease are similar to those of other dementias, with early, intermediate, and late stages. Loss of short-term memory is often the first sign. The disease progresses gradually but may plateau for periods of time. Behavior disorders (eg, wandering, agitation, yelling) are common.

Generally, diagnosis is similar to that of other dementias. Traditional diagnostic criteria for Alzheimer’s disease include dementia established by physical examination and documented by a formal mental status examination; deficits in = 2 areas of cognition; gradual onset and progressive worsening of memory and other cognitive functions; no disturbance of consciousness; onset after age 40, most often after age 65; and no systemic or brain disorders that could account for the progressive deficits in memory and cognition. However, deviations from these criteria do not exclude a diagnosis of Alzheimer’s disease.

Distinguishing Alzheimer’s disease from other dementias is difficult. Assessment tools (eg, Hachinski Ischemic Score—see Table 3) can help distinguish vascular dementia from Alzheimer’s disease. Fluctuations in cognition, parkinsonian symptoms, well-formed visual hallucinations, and relative preservation of short-term memory suggest Lewy body dementia rather than Alzheimer’s disease (see Table 5: Delirium and Dementia: Differences Between Alzheimer’s Disease and Lewy Body Dementia). Patients with Alzheimer’s disease are often better-groomed and neater than patients with other dementias. For about 85% of patients with Alzheimer’s disease, a thorough history and standard neurologic examination provide a correct diagnosis.

Table 3. Modified Hachinski Ischemic Score

PAD = peripheral arterial disease.

*Total score is determined: < 4 suggests primary dementia (eg, Alzheimer’s disease); 4–7 = indeterminate; and > 7 suggests vascular dementia.

Cholinesterase inhibitors modestly improve cognitive function and memory in some patients. Four are approved for use; generally, donepezil , rivastigmine, and galantamine are equally effective, but tacrine is rarely used because of its hepatotoxicity. Donepezil is a 1st-line drug because it has once/day dosing and is well-tolerated. The recommended dose is 5 mg once/day for 4 to 6 wk, then increased to 10 mg once/day. Treatment should be continued if functional improvement is apparent after several months, but otherwise it should be stopped. The most common adverse effects are GI (eg, nausea, diarrhea). Rarely, dizziness and cardiac arrhythmias occur. Adverse effects can be minimized by increasing the dose gradually.

• Vascular Dementia

Vascular dementia is acute or chronic cognitive deterioration due to diffuse or focal cerebral infarction that is most often related to cerebrovascular disease.

Vascular dementia is the 2nd most common cause of dementia among the elderly. It is more common among men and usually begins after age 70. It occurs more often in people who have vascular risk factors (eg, hypertension, diabetes mellitus, hyperlipidemia, smoking) and in those who have had several strokes. Many patients have both vascular dementia and Alzheimer’s disease.

Vascular dementia occurs when multiple small cerebral infarcts (or sometimes hemorrhages) cause enough neuronal or axonal loss to impair brain function. Vascular dementia results from disease of small vessels (lacunar disease) or of medium-sized vessels (multi-infarct dementia).

Binswanger’s dementia (subcortical arteriosclerotic encephalopathy) is an uncommon variant of small-vessel dementia associated with severe, poorly controlled hypertension and systemic vascular disease. It involves multiple lacunar infarcts in deep hemispheric white and gray matter.

• Symptoms and Signs

Symptoms and signs are similar to those of other dementias. However, because infarction is the cause, vascular dementia tends to progress in discrete steps; each episode is accompanied by intellectual decline, sometimes followed by modest recovery. As the disease progresses, focal neurologic deficits often develop; they include exaggeration of deep tendon reflexes, extensor plantar response, gait abnormalities, weakness of an extremity, hemiplegias, pseudobulbar palsy with pathologic laughing and crying, and other signs of extrapyramidal dysfunction. However, with small-vessel ischemic damage, the decline is gradual. Cognitive loss may be focal. Patients with partial aphasia may be more aware of their deficits; thus, depression may be more common than in other dementias.

• Diagnosis

Diagnosis is similar to that of other dementias. If focal signs or evidence of cerebrovascular disease is present, a thorough evaluation for stroke should be done..

CT and MRI may show bilateral multiple infarcts in the dominant hemisphere and limbic structures, multiple lacunar strokes, or periventricular white-matter lesions extending into the deep white matter. In Binswanger’s dementia, imaging shows leukoencephalopathy in the cerebrum semiovale adjacent to the cortex, often with multiple lacunae affecting structures deep in the gray matter (eg, basal ganglia, thalamic nuclei).

Low-Density Periventricular Changes in Deep White Matter

The Hachinski Ischemic Score is sometimes used to help differentiate vascular dementia from Alzheimer’s disease.

• Prognosis and Treatment

The 5-yr mortality rate is 61%, which is higher than that for most forms of dementia, presumably because other atherosclerotic disorders coexist.

Generally, treatment is the same as that of other dementias. However, vascular dementia may be preventable, and its progression may be slowed by BP control, cholesterol-lowering therapy, regulation of blood sugar (90 to 150 mg/dL), and smoking cessation.

The efficacy of cognition-enhancing drugs, including cholinesterase inhibitors, is uncertain. However, because many patients also have Alzheimer’s disease, these drugs may have some benefit. Adjunctive drugs for depression, psychosis, and sleep disorders are useful.

• Lewy Body Dementia

Lewy body dementia is chronic cognitive deterioration characterized by cellular inclusions called Lewy bodies in the cytoplasm of cortical neurons.

Lewy body dementia is the 3rd most common dementia. Age of onset is typically > 60.

Lewy bodies are spherical, eosinophilic, neuronal cytoplasmic inclusions composed of aggregates of a-synuclein, a synaptic protein. They occur in the cortex of some patients with primary Lewy body dementia and in the substantia nigra of patients with Parkinson’s disease. In Lewy body dementia, neurotransmitter levels and neuronal pathways between the striatum and the neocortex are abnormal. But whether the Lewy bodies cause or result from disease is unclear.

• Symptoms and Signs

Initial cognitive deterioration resembles that of other dementias. But extrapyramidal symptoms differ from those of Parkinson’s disease: In Lewy body dementia, tremor does not occur early, axial rigidity with gait instability occurs early, and deficits tend to be symmetric.

Fluctuating cognitive function is a relatively specific feature of Lewy body dementia. Periods of being alert, coherent, and oriented may alternate with periods of being confused and unresponsive to questions, usually over a period of days to weeks but sometimes during the same interview. Memory is impaired, but the impairment appears to result more from deficits in alertness and attention than in memory acquisition; thus, short-term recall is affected less than digit span memory (ability to repeat 7 digits forward and 5 backward). Excessive daytime drowsiness is common. Visuospatial and visuoconstructional abilities (tested by block design, clock drawing, or figure copying) are affected more than other cognitive deficits. Thus, Lewy body dementia may be difficult to distinguish from delirium, and all patients presenting with these symptoms and signs should be evaluated for delirium.

Visual hallucinations are common and often threatening, unlike the benign hallucinations of Parkinson’s disease. Auditory, olfactory, and tactile hallucinations are less common. Delusions occur in 50 to 65% of patients and are often complex and bizarre, compared with the simple persecutory ideation common in Alzheimer’s disease. Autonomic dysfunction is common, and unexplained syncope may result. Autonomic dysfunction may occur simultaneously with or after onset of cognitive deficits. Extreme sensitivity to antipsychotics is typical.

• Diagnosis, Prognosis, and Treatment

Diagnosis is clinical, but sensitivity and specificity are generally poor. Diagnosis is considered probable if 2 of 3 features—fluctuations in cognition, visual hallucinations, and parkinsonism—are present and possible if only one is present. Supportive evidence consists of repeated falls, syncope, and antipsychotic sensitivity. Overlap in symptoms between Lewy body dementia and Parkinson’s disease may complicate diagnosis. When motor deficits of Parkinson’s disease precede and are more severe than cognitive impairment, Parkinson’s disease is usually diagnosed. When early cognitive impairment and behavioral disturbances predominate, Lewy body dementia is usually diagnosed.

CT and MRI show no characteristic changes but are helpful initially in ruling out other causes of dementia. Positron emission tomography with fluorine-18-labeled deoxyglucose and single-photon emission CT (SPECT) with 123I-FP-CIT (N-w-fluoropropyl-2b-carbomethoxy-3b-[4-iodophenyl]-tropane), a fluoroalkyl analog of cocaine, may help identify Lewy body dementia but are not routinely done. Definitive diagnosis requires autopsy samples of brain tissue.

Lewy body dementia progresses; prognosis is poor. Treatment is generally supportive. Rivastigmine 1.5 mg po bid, titrated upward as needed to 6 mg bid, may improve cognition. Other cholinesterase inhibitors may also be useful. In about 1/2 of patients, extrapyramidal symptoms respond to antiparkinsonian drugs, but psychiatric symptoms may worsen. If such drugs are needed, levodopa is preferred.

Traditional antipsychotics, even at very low doses, tend to acutely worsen extrapyramidal symptoms and are best avoided.

• HIV-Associated Dementia

HIV-associated dementia is chronic cognitive deterioration due to brain infection by HIV or opportunistic organisms.

HIV-associated dementia (AIDS dementia complex) may occur in the late stages of HIV infection. Unlike almost all other forms of dementia, it tends to occur in younger people. The dementia may result from HIV infection or from secondary infection with JC virus causing progressive multifocal leukoencephalopathy. Other opportunistic infections (eg, fungal, bacterial, viral, protozoan) may also contribute.

In purely HIV-associated dementia, subcortical pathologic changes result when infected macrophages or microglial cells infiltrate into the deep gray matter (ie, basal ganglia, thalamus) and white matter.

Prevalence of HIV dementia in late-stage HIV infection ranges from 7 to 27%, but 30 to 40% may have milder forms. Incidence is inversely proportional to CD4+ count.

• Symptoms and Signs

Symptoms and signs may be similar to those of other dementias. Early manifestations include slowed thinking and expression, difficulty concentrating, and apathy; insight is preserved, and manifestations of depression are few. Motor movements are slowed; ataxia and weakness may be evident. Abnormal neurologic signs may include paraparesis, lower-extremity spasticity, ataxia, and extensor-plantar responses. Mania or psychosis is sometimes present.

• Diagnosis, Prognosis, and Treatment

Generally, diagnosis is similar to that of other dementias except for the search for a cause.

HIV patients with untreated dementia have a worse prognosis (average life expectancy of 6 mo) than HIV patients without dementia. With treatment, cognitive impairment stabilizes, and some improvement may occur.

When a patient with HIV infection presents or when cognitive function changes acutely, lumbar puncture and CT or MRI should be done to check for CNS infection. MRI is more useful than CT because it can exclude other CNS causes of dementia (eg, toxoplasmosis, progressive multifocal leukoencephalopathy, cerebral lymphoma). Late-stage findings may include diffuse nonenhancing white matter hyperintensities, cerebral atrophy, and ventricular enlargement.

The primary treatment is highly active antiretroviral therapy, which increases CD4+ counts and improves cognitive function. Supportive measures are similar to those for other dementias.

• Frontotemporal Dementia

Frontotemporal dementia refers to sporadic hereditary disorders that affect the frontal and temporal lobes, including Pick’s disease.

Frontotemporal dementia (FTD) accounts for up to 10% of dementias. Age at onset is typically younger (age 55 to 65) than in Alzheimer’s disease. FTDs affect men and women about equally. Pick’s disease is a variant of FTD, which may be pathologically characterized by severe atrophy, neuronal loss, gliosis, and presence of abnormal neurons (Pick cells) containing inclusions (Pick bodies).

About 1/2 of FTDs are inherited; most gene mutations involve tau on chromosome 17q21-22 and result in abnormalities of the microtubule-binding tau protein; thus, FTDs are considered tauopathies. Some experts classify supranuclear palsy and corticobasal degeneration with FTDs because they share similar pathology and gene mutations affecting the tau protein. Symptoms do not always correspond to the gene mutation or to pathology and vice versa. For example, the same mutation causes FTD symptoms in one family member but symptoms of corticobasal degeneration in another, and Pick’s cells may be absent in patients with typical symptoms of Pick’s disease.

• Symptoms and Signs

Generally, FTD affects personality, behavior, and usually language function (syntax and fluency) more and memory less than does Alzheimer’s disease. Abstract thinking and attention (maintaining and shifting) are impaired; responses are disorganized. Orientation is preserved, but retrieval of information may be impaired. Motor skills are generally preserved. Patients have difficulty sequencing tasks, although visual-spatial and constructional tasks are less affected.

Frontal release signs (grasp, root, suck, snout, and palmomental reflexes and glabellar sign) appear late in the disease but also occur in other dementias. Some patients develop motor neuron disease with generalized muscle atrophy, weakness, fasciculations, bulbar symptoms (eg, dysphagia, dysphonia, difficulty chewing), and increased risk of aspiration pneumonia and early death.

Frontal variant FTD: Social behavior and personality change because the orbitobasal frontal lobe is affected. Patients become impulsive and lose their social inhibitions (eg, they may shoplift); they neglect personal hygiene. Some have Klüver-Bucy syndrome, which involves emotional blunting, hypersexual activity, hyperorality (eg, bulimia, sucking and smacking of lips), and visual agnosias. Impersistence (impaired concentration), inertia, and mental rigidity appear. Behavior becomes repetitive and stereotyped (eg, patients may walk to the same location every day). Patients may pick up and manipulate random objects for no reason (called utilization behavior). Verbal output is reduced; echolalia, perseveration (inappropriate repetition of a response), and eventually mutism occur.

Primary progressive aphasia: Language function deteriorates because of asymmetric (worse on left) anterolateral temporal lobe atrophy; hippocampus and memory are relatively spared. Most patients present with difficulty finding words. Attention (eg, digit span) may be severely impaired. Many patients have aphasia, with decreased fluency and difficulty comprehending language; hesitancy in speech production and dysarthria are also common. In some patients, aphasia is the only symptom for = 10 yr; in others, global deficits develop within a few years.

Semantic dementia is a type of primary progressive aphasia. When the left side of the brain is affected most, the ability to comprehend words is progressively lost. Speech is fluent but lacks meaning (eg, a generic or related term is used instead of the specific name of an object). When the right side is affected most, patients have progressive anomia (inability to name objects and prosopagnosia (inability to recognize familiar faces). They cannot remember topographic relationships. Some patients with semantic dementia also have Alzheimer’s disease.

• Diagnosis, Prognosis, and Treatment

Diagnosis is suggested by typical clinical findings. As for other dementias, cognitive deficits are evaluated. CT and MRI are done to determine location and extent of brain atrophy and to exclude other possible causes (eg, brain tumors, abscesses, stroke). FTDs are characterized by severely atrophic, sometimes paper-thin gyri in the temporal and frontal lobes. Because MRI or CT may not show the regionally prominent cortical atrophy until late in FTD, neuroimaging may be less useful for excluding Alzheimer’s disease (which affects the hippocampus and parietal lobes early), but clinical differences may help distinguish them. For example, primary progressive aphasia differs from Alzheimer’s disease in that memory and visuospatial function are preserved and syntax and fluency are impaired.

FTDs usually progress gradually, but progression rate varies; if symptoms are limited to speech and language, progression to general dementia may be slower. There is no specific treatment for Pick’s disease. Treatment is generally supportive.

The author,

Professor Yasser Metwally