Cognitive Change and Dementia

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[edit] Cognitive Change and Dementia

Claire A. Levesque

Dementing illnesses occur often, particularly in elderly persons, and are major causes of devastating losses of function, leading to institutionalization. Dementia, a syndrome resulting from many etiologies, is a slow loss of previously acquired intellectual or behavioral function without alteration in level of awareness. At least two areas of cognitive function, such as memory, language, personality, visuospatial abilities, or judgment, are impaired in dementia, and the disabilities affect independent daily living.^[1]

Dementia differs from delirium. Delirium, or an acute confusional state, is an acute or subacute onset of disorientation with alterations in levels of awareness, including hyperalert and drowsy states. It often disrupts day/night cycles and can be accompanied by delusions (see Chapter 157 ). Delirium may coexist with dementia. Dementia also differs from normal aging. In elderly persons, short-term memory may be impaired in tasks requiring the manipulation of material such as digit spans backward or in memory tasks requiring divided attention. Response time can increase, and memory for proper names may be affected. This “benign senescent forgetfulness” is a gradual process that does not impair daily living or disrupt social skills.

Dementia is a common disorder in elderly persons, occurring in all ethnic groups. There may be some variabilities in etiologies based on ethnic background and other precipitant factors. People in all ethnic groups show an increasing prevalence of dementia with increasing age. Alzheimer's disease (AD) is the most common cause of dementia, and the estimated prevalence of probable AD in those over 84 years old in one study was 47.2%.^[2] These statistics are sobering in the context of a predicted population of 4.6 million over age 85 in the United States in the year 2000.

Dementia is truly a devastating disease that robs patients of their personalities and their ability to interact. It is also the fourth or fifth most common cause of death, although it rarely appears on death certificates. The economic impact of this problem is staggering. The annual cost of the formal and informal care for one patient with AD is estimated at $47,000 in 1990 dollars, with the annual cost for all forms of dementia at $58 billion.^[3] The cost of a full diagnostic evaluation (usually less than $2000) is clearly cost-effective even if a treatable form of dementia is found only occasionally. Also, the difference in the quality of life is vast. Unfortunately, many patients have progressive irreversible forms of dementia. Families often keep their loved ones in the home in the face of staggering caregiver burden. Behaviors most likely to lead to institutionalization include wandering, aggressive outbursts, sleep disturbances, and incontinence. Home care can be practical and cost-effective in the early stages of dementia, but levels of service vary depending on the latest insurance regulations, and the burden on family is immense. In later stages, nursing home care provides relief to the overburdened caregiver and can also be less costly than formal and informal home care costs.

Multiple studies have been done on the risk factors for the development of dementia. Many have focused on AD, the most common progressive neurodegenerative cause. Some studies have implicated factors such as history of head trauma or lower educational level, but no definitive risk factors have been identified. Hypertension and diabetes are major risk factors for vascular forms of dementia, such as multiinfarct dementia and Binswanger's disease. Since the differential diagnosis of dementia is so broad, other risk factors can be found specific to particular etiologies, such as alcohol abuse and subdural hematomas or exposure to the transmissible agents and the development of Creutzfeldt-Jakob disease. Genetic factors also play a role in some dementing illnesses, such as Huntington's disease, the familial form of AD, and perhaps even in “sporadic” cases of AD.

Most causes of dementia lead to the death or metabolic dysfunction of neurons, producing losses in cognitive function. The location of the cell loss is a critical factor. In AD the cell loss is most prominent in the cortex, hippocampus, and amygdala, disrupting connections critical for memory and other cognitive function. In multiinfarct dementia, small strokes placed in strategic locations can lead to the loss of memory, visuospatial abilities, language, and personality. Dementia can also occur because of a change in the overall chemical milieu of the brain; common examples include endocrine disturbances such as hypothyroidism and toxic encephalopathies resulting from medications. These and other “reversible” dementias are less common but are critically important to diagnose. Patients with a definitive neurodegenerative cause of dementia often have a coexisting treatable factor at initial presentation or later in the course of the disease. For instance, a patient with AD may have a rapid functional deterioration caused by problems such as depression or endocrine disturbances.

[edit] HISTORY

In a dementing illness, it is critically important to obtain history from the caregiver as well as the patient. In addition to questions about the changes in the patient's behavior, specific questions should be asked about difficulties with activities of daily living such as eating, dressing, and toileting. Some standardized questions have been developed to assist in this history taking, such as the Blessed dementia scale (Box 158-1). All medications, including over-the-counter (OTC) medications, folk remedies, alcohol, and street drugs, should be carefully reviewed. A change in drinking pattern may go unnoticed by family members, especially if the patient lives alone, and may represent self-treatment of depression. Currently, a history of street drug use occurs infrequently in elderly persons but may be expected to increase in prevalence in the ensuing years and is a risk factor for dementia related to acquired immunodeficiency syndrome (AIDS). A medical review of systems should focus on a history of hypertension, diabetes, thyroid disease, vitamin B₁₂ deficiency (including history of gastric surgery), and syphilis and on an evaluation of the risk factors for disease related to the human immunodeficiency virus (HIV). The family history of dementia is vital for certain diagnoses such as Huntington's disease and familial AD. Prior psychiatric illnesses in the patient or other family members should be recorded. The patient's educational and occupational history allows an estimation of premorbid cognitive functioning.

[edit] PHYSICAL AND NEUROLOGIC EXAMINATION

In addition to a general medical examination, including cardiac and thyroid examinations plus evaluation for carotid bruits, orthostatic blood pressures are determined for any patient with vascular risk factors. Because of incorrect answers, “covering” of memory lapses, and overreliance on empty social comments, open-ended discussion with the patient often suggests a diagnosis of dementia. The mental status examination should include a range of questions to assess multiple cognitive spheres. The Folstein minimental status examination (see Chapter 8 ) and the Blessed dementia scale (see Box 158-1) include scales of information, memory, concentration, language, and visuospatial abilities. Testing for apraxia can include imitation of gestures and demonstrations of complex movements, such as saluting or brushing hair. Vision can be tested with a hand-held card with patients wearing eyeglasses, if applicable. Hearing can be tested by whispering numbers in each ear. The remainder of the neurologic examination should focus on finding focal abnormalities. Hemiparesis, reflex asymmetries, and sensory changes may be signs of previous strokes or mass lesions. Patterns of sensory loss may represent peripheral neuropathy suggestive of vitamin B₁₂ deficiency, alcohol-related causes of dementia, neurosyphilis, and multiple other reversible causes. These focal signs suggest the need for further neurologic consultation.

[edit] DIFFERENTIAL DIAGNOSIS

Evaluation of the patient with dementing illness, particularly in the mild to moderate stages, must emphasize a search for potentially reversible causes. Patients may also have multiple causes for dementia, and even when the clinical impression strongly suggests a neurodegenerative process, coexisting reversible causes should be investigated. The primary care physician should consider neurologic consultation when the dementing process is accompanied by elementary neurologic findings, when atypical features emerge, or when therapeutic questions arise. The differential diagnoses listed here emphasize the most common and the most treatable causes.^[4][5]

[edit] Alzheimer's Disease and Familial Alzheimer's Disease

AD is the most common cause of devastating progressive dementia.^[2][6] The characteristic neuropathologic change consists of senile plaques (Fig. 158-1), neurofibrillary tangles (Fig. 158-2), and atrophy. Although some of these changes can be seen with normal aging, both the distribution and the extent of the senile plaques and tangles are different.^[7]

Figure 158-1 Senile plaque appears to be made up of degenerating neural processes with a central accumulation of amyloid. (From Spielmeyer W: Histopathologie des Nervensystems, Berlin, 1922, Springer.)

Figure 158-2 Neurofibrillary tangles consist of intraneuronal bundles of filamentous material that progressively amass in swirls within the perikaryon and neurites. (From Spielmeyer W: Histopathologie des Nervensystems, Berlin, 1922, Springer.)

Many neurotransmitters are decreased in brains of AD patients. The cholinergic system shows consistent involvement and has been a target of various therapeutic approaches, including tacrine and donepezil. Multiple lines of research implicate β-amyloid or its processing as a key event in causation. The β-amyloid protein is a major constituent of the plaque seen in brains of AD patients (see Fig. 158-1), and mutations have been found in some pedigrees of familial AD on chromosome 21 near the gene encoding amyloid precursor protein. However, other pedigrees have mutations in other loci on chromosomes 14 and 19. These genetic data, plus the variability in age at presentation and extrapyramidal features, point to heterogeneity even in familial cases.^[8] A potential genetic link for sporadic cases has been identified with an association with the E4 allele for apolipoprotein E (the basis for APOE testing), which is involved in lipoprotein metabolism and binds to the β-amyloid protein.^[8][9][10] Environmental toxins have also been considered in AD, and studies have demonstrated aluminum in the neurofibrillary tangles.

In patients with both sporadic and familial AD, mental changes are gradual and progressive. Sometimes, the changes are first noted by family members or health care providers after a major event in the patient's life, such as the death of a family member, surgery, or another medical illness. The mental change usually begins with impaired recall of recent events, word-finding difficulty, and inability to perceive spatial relationships. A series of words may be correctly done with immediate repetition if the patient is attentive, but the patient is unable to perform accurately if an interval of 3 to 4 minutes is interposed. Complaints by family members that the patient is “living in the past” reflect the relative preservation of remote memory. The attentive examiner often is able to detect difficulty in word finding as the patient makes word substitutions and circumlocutions. Asking the patient to name a series of common objects and their parts confirms this finding. Difficulty in drawing a simple map of a familiar intersection, an outline map of the United States, or a geometric shape reveals the associated difficulty with spatial relationships. A patient with this problem often becomes lost when driving alone or walking even in a familiar area.

These three features—retentive memory, spatial difficulties, and word-finding problems—are usually well established before frontal lobe dysfunction occurs. With progression, inappropriate behavior with neglected personal hygiene develops. The episodic outburst, sometimes called a catastrophic reaction, can involve aggressive behavior toward family members. These outbursts by a patient with dementia are very frightening to caregivers and consist of an outpouring of negative emotions unresponsive to reassurance or redirection. Wandering is another behavior that is very difficult for family members. Patients may leave the home inappropriately attired and lose their way. Wandering patients with dementia unfortunately may be found dead because of exposure to the environment or traumatic injury. Sleep disturbances also occur, and patients wake in the middle of the night and wander in the home. This can be particularly dangerous, since the patient can drop burning cigarettes, turn on the gas stove, or engage in other potentially dangerous activities while the caregiver sleeps. Disrobing and inappropriate sexual advances occur in some individuals as the disinhibition progresses. These behaviors are poorly tolerated in both the family home and nursing home and do respond to a combination of behavioral techniques and medications.

Even the most severe abnormalities in these higher functions are not ordinarily accompanied by elementary neurologic findings. The motor abnormalities occur only in advanced cases and include hyperreflexia, spasticity, or upgoing toes. Most patients have paratonic rigidity with a tendency toward flexed immobility in the upper and lower extremities. Frontal release signs, such as grasp, suck, and snout reflexes, develop in later stages. This state is preceded by a deterioration in gait, which has been attributed to grasp reflexes in the feet. Initiating gait becomes difficult, and the patient takes many small steps before moving forward. Seizures may occur very late in the course of AD. A patient with focal neurologic signs or early onset of seizures should be evaluated by a neurologist because other causes of dementia may be present.

Patients with AD usually die 2 to 10 years after diagnosis, although some live longer. Pneumonia is a common cause of death. There is no “gold standard” test for AD. The only definitive test is neuropathologic evaluation of the brain at biopsy or at postmortem examination. Since no curative treatment currently exists for AD, brain biopsy is not recommended. Computed tomography (CT) scans or magnetic resonance imaging (MRI) of the head shows widespread atrophy with a predilection for the temporal lobes and helps exclude other causes. Biparietal hypoperfusion is seen on single-positron emission computed tomography (SPECT) scanning, although this finding is not specific and has not been well documented pathologically. Genotypes for the E4 allele of apolipoprotein E (APOE) are commercially available and may be used as supportive data if the clinical syndrome is present. APOE testing is not indicated in presymptomatic individuals at this time. Other peripheral markers in blood, skin, and cerebrospinal fluid (CSF) have been investigated, but none is definitive currently. The use of potential diagnostic tests for AD, especially those felt to predict future risk, is fraught with potential problems, particularly in the absence of preventive or curative treatments. Test results may have a negative impact on employment and insurance status and cause emotional trauma.^[9][10]

Although no gold standard test exists for AD, clinicopathologic correlations have shown that experienced clinicians correctly diagnose AD in most cases. This accuracy is improved by an initial evaluation by a clinician specializing in dementia and a clinical reevaluation about 6 to 12 months after the diagnostic evaluation. Although previously underdiagnosed, AD may now be overdiagnosed, and reversible causes may be missed. In addition, AD sometimes does not occur in isolation. Overlap of AD and vascular dementia is relatively common, and treatable causes such as depression, drug effects, vitamin B₁₂ deficiency, and coexisting chronic infections can occur. AD is slowly progressive, and rapid deteriorations in function or additional focal neurologic signs should always prompt evaluation for other causes, such as intercurrent pneumonia, urinary tract infection, or chronic subdural hematoma.

[edit] Alzheimer's Disease and Down Syndrome

The pathologic changes seen in AD have been found in the brains of adults with Down syndrome.^[11] However, many of these individuals do not develop the clinical syndrome. In some, no cognitive deterioration is apparent. In others the presentation is atypical. Diagnosis is also hindered by the lack of an appropriate neuropsychologic instrument to delineate cognitive deficits across the intelligence quotient (IQ) spectrum found in Down syndrome.^[12] APOE testing is unlikely to be helpful, since the distribution of alleles in a population with Down syndrome appears to be similar to that in the general population. However, the presence of the E4 allele may correlate with earlier onset of the disease.^[13] Other potentially treatable causes of dementia, particularly hypothyroidism and depression, are also common and must always be considered.

[edit] Other Neurodegenerative Diseases

Frontal lobe dementias are syndromes characterized by frontal atrophy with prominent behavioral features. The most common is Pick's disease, a neurodegenerative disorder that is sometimes difficult to differentiate from AD. The temporal and frontal lobes are selectively involved in this disease. Features that support a diagnosis of Pick's disease include early onset of personality change, disinhibition, increased oral behaviors (e.g., eating, smoking, drinking), and onset before age 65. A very severe and unusual form of aphasia may be an early manifestation and is often combined with behavioral disturbances. This disorder may occur more often than previously thought. The course of Pick's disease appears to be more rapid than that of AD. Imaging studies may show preferential enlargement of the temporal horns with focal frontal and temporal atrophy. SPECT scanning also shows a preferential hypoperfusion of the frontal lobes with relative sparing of parietal lobes. Definite diagnosis requires examination of the brain, which reveals “knife-edge” atrophy of the superior temporal gyrus, absence of the characteristic plaques and tangles of AD, and the presence of Pick's cells and Pick's bodies. No known treatment exists for Pick's disease, and patients with this condition often require earlier nursing home placement because of the behavioral disturbances.^[14]

Dementia with Lewy bodies is now felt to be more common than previously thought.^[15] Although a positive diagnosis is possible only by biopsy or at autopsy, certain clinical features support the diagnosis. The presence of visual hallucinations and Parkinson's disease must prompt consideration of this form of dementia. The course is progressive, although cognitive performance can vary. This disorder is also marked by an acute sensitivity to neuroleptic agents, and these medications must be used with great caution and careful monitoring, if at all.^[15]

Other primary neurologic causes of dementia have associated elementary neurologic findings accompanying the changes in mental status. Huntington's disease is an autosomal dominant disorder with dementia, chorea, and psychiatric changes. The average age of onset is the fourth decade, although dementia may appear more than a year before any movement disorder is present. During this time, diagnosis may be difficult if a positive family history has not been determined. CT or MRI shows marked atrophy of the caudate nucleus. Wilson's disease is an autosomal recessive disorder of copper metabolism characterized by behavioral disturbances, tremors, other abnormal movements, Kayser-Fleischer rings, and liver disease. The onset is usually in adolescence or young adulthood but may be as late as the fifth decade of life.

Multiple sclerosis may present as a dementing disease because of the development of bilateral periventricular demyelination. In such a case the evaluation should include a detailed search of the medical history for evidence of a previous demyelinating episode in an atypical cause of dementia, especially with early, severe frontal lobe features. Examination of the spinal fluid for oligoclonal banding and for immunoelectrophoresis and MRI of the brain showing the characteristic white-matter changes are diagnostic in the appropriate clinical setting.

The tremor, rigidity, and bradykinesias present in Parkinson's disease eliminate diagnostic difficulties in this cause of dementia. The treatment of Parkinson's disease and any associated depression often temporarily improves these patients' cognitive function. Olivopontocerebellar degeneration is a progressive disorder and is often associated with very slow, progressive dementia. Characteristic shrinkage of the pons and cerebellum can be best seen on MRI and is always present at the time mental changes supervene. No effective treatment is available for this disorder. A mild dementia, compounded by extreme slowness in expression, language, and movement, accompanies progressive supranuclear palsy. Loss of vertical eye movements and development of truncal rigidity are characteristic features of this rare disease. These patients do not respond to dopaminergic drugs.

[edit] Cerebrovascular Disease

In the past, dementia was commonly thought to result from “hardening of the arteries.” This misconception resulted in the widespread use of cerebrovasodilators for dementia, a treatment of dubious value. Cerebrovascular disease, however, does produce dementia if lesions are strategically placed. One series demonstrated a 38.7% prevalence of vascular dementia in a white Northern European cohort of 85-year-old people,^[6] which is even higher than previously reported. Also, vascular causes of dementia can also coexist with AD. A patient who has several strokes in areas important for cognitive function (e.g., deep temporal lobe, frontal lobes) can be easy to diagnose. However, in other patients, multiple small lacunar infarcts can occur, often in “silent” areas of the brain. Hypertension or diabetes significantly increases the risk for lacunar infarctions. A careful history may elicit several episodes of clear-cut deterioration in function. Since multiinfarct dementia can be difficult to distinguish from AD, a scoring system called the Hachinski ischemic score (Table 158-1) can be a useful reminder of features that suggest vascular disease.^[16] MRI can also be helpful in this diagnosis because very small infarctions can be seen using this modality. This diagnosis is important to make, since careful control of hypertension while maintaining adequate perfusion and avoiding episodic hypotension may be the key to preventing further deterioration. Another dementing cerebrovascular disorder is Binswanger's encephalopathy. The dementia in this case is accompanied by bilateral pyramidal signs (weakness, increased reflexes) and intense frontal lobe signs. The patient may appear abulic and have diffusely increased muscle tone. Prominent palmar and plantar grasp reflexes are often present, and urinary incontinence and a slow, unsteady gait are common. MRI shows multiple white-matter infarcts in a periventricular distribution becoming confluent. Unfortunately, MRI also shows this pattern in patients who do not exhibit a clinical syndrome. The diagnosis of Binswanger's disease and other forms of dementia are in evolution, and several criteria have recently been proposed.^[17][18][19]

Table 158-1 Hachinski Ischemic Score to Distinguish Cerebrovascular Dementia from Alzheimer's Disease

✢A total score less than 4 means that vascular dementia is unlikely, whereas scores greater than 7 indicate that vascular dementia is probable.

[edit] Vasculitis

Systemic vasculitides, such as systemic lupus erythematosus, can involve the brain and cause a confusional state. These patients can be diagnosed by the systemic signs and symptoms. Vasculitis involving the brain occurs infrequently in other systemic illnesses, such as sarcoidosis and AIDS. Less often, isolated central nervous system (CNS) vasculitis occurs without involvement of other organs and without increases in sedimentation rate or antibody titers. Cerebral angiography may show beading of blood vessels and other changes in vessel caliber, but often the results are normal. Biopsy of meningeal vessels can show vasculitic changes in some cases. Although CNS vasculitis is a challenging diagnosis, patients do respond, at least transiently, to immunosuppressive agents.

[edit] Depression and Psychiatric Disorders

Depression can cause a syndrome termed pseudodementia, which can be difficult to distinguish from other causes of dementia.^[20] Depression can also coexist in AD, usually in the early stages in patients with enough retained insight. A depressed affect may be present in some of these patients but is not universal. As with other forms of depression in elderly patients, agitation or psychotic features can occur. During cognitive testing, these patients frequently answer, “I don't know,” and often give up easily. The examination reveals inconsistencies in performance. The failures tend to occur in all areas of testing, unlike the more selective deficits seen in other dementias. A previous history of depression in the patient or a positive family history can be helpful. Patients with mild or moderate dementia can still answer questions about their mood, and statements can be corroborated by caregivers. Formal testing by a qualified neuropsychologist may be helpful, but even then, the patient's condition may be indistinguishable from that of true dementia. Extensive and repeated interdisciplinary assessments may be necessary.

If depression is a serious consideration, a trial of antidepressant treatment should be given. However, this treatment should have clear end points with reevaluations because long-term use of antidepressants, particularly those with anticholinergic side effects, can cause confusion. The pharmacologic options for the treatment of depression include the serotonin reuptake inhibitors and tricyclic antidepressants and related compounds. The medication chosen should have the least potential for serious side effect and the most potential for improvement. Close follow-up is essential. Methylphenidate, a stimulant drug, may be helpful in depressed elderly patients with psychomotor retardation but should be started at low doses, gradually increased, and continued only if improvement is noted. Electroconvulsive therapy is sometimes beneficial and safe even in the fragile elderly patient, especially when medication side effects prohibit drug use (see Chapter 48 ). Referral to a psychiatrist or behavioral neurologist should be considered to confirm the diagnosis in atypical cases if symptoms persist after first line treatment or if side effects limit therapy.

Patients with chronic schizophrenia can also appear cognitively slowed in their older years. It is important to remember the potential effects of long-term use of neuroleptic agents on motor function and response time. Episodic periods of institutionalization can also produce limits on knowledge of current and historical information, making some memory testing more complicated. Patients with schizophrenia are also naturally at risk for all causes of dementia, and a careful diagnostic evaluation is warranted if a cognitive deterioration is suspected. Reduction of medication doses and changes to the newer atypical antipsychotic medications should also be considered.

[edit] Normal-Pressure Hydrocephalus

In normal-pressure hydrocephalus (NPH), the clinical triad of dementia, incontinence, and gait disorder is associated with enlarged cerebral ventricles out of proportion to any atrophy present. This is a disorder of CSF circulation or absorption, with normal or high-normal opening pressure on lumbar puncture. The syndrome may develop after inflammatory states within the subarachnoid space, such as meningitis, encephalitis, or subarachnoid bleeding, but most are idiopathic. The dementia associated with NPH does not appear to have any characteristic features. CT or MRI of the head shows enlargement of ventricles out of proportion to the amount of atrophy, transependymal fluid, and rounding of the ventricular horns. On MRI, a signal void caused by moving CSF has been described in the third ventricle. Radioisotope cisternography demonstrates the absence of isotope flow in the subarachnoid space over the hemispheric convexities. Another test that may be helpful is removing a large amount (20 to 30 ml) of CSF, followed by a careful observation for transient improvements in cognitive status and gait. Cognitive and timed-gait testing is then repeated after the lumbar puncture at intervals over several days. An improvement in clinical status after a high-volume lumbar puncture has been felt to be predictive of a positive response to lumboperitoneal shunting, although this has been challenged.^[21] Unfortunately, none of the diagnostic tests has been effective in demonstrating a high probability of favorable response to shunting. Therefore the risk-benefit ratio of shunting must be carefully considered in consultation with the patient, the family, and the neurosurgeon.^[22][23]

[edit] Nonconvulsive Status

Most seizures are dramatic events with sudden alteration in consciousness, stereotyped behaviors, and jerking movements. However, in some instances, subclinical seizures can occur and may be almost continuous, resulting in a state called nonconvulsive status or complex partial status. This state of continuous nonclinical seizures can continue for prolonged periods. It is readily diagnosed by electroencephalography (EEG), with a characteristic ictal pattern. This syndrome occurs infrequently but is treatable with anticonvulsants. It may occur with metabolic or toxic disruptions or with no apparent precipitant. A prior seizure history is not necessary.

[edit] Infections

At the turn of the twentieth century, neurosyphilis would have been one of the most common reasons for chronic progressive dementia. Although the widespread use of penicillin has made CNS syphilis a rare disorder, it has been more prevalent since the onset of AIDS. The CSF in active cases always contains increased numbers of white blood cells and produces positive results from the Venereal Disease Research Laboratories (VDRL) test. Patients tend to have a progressive frontal-type dementia associated with bilateral pyramidal signs and distal and perioral tremors, along with delusions of grandeur and Argyll Robertson pupils. Treatment with intravenous (IV) penicillin is indicated.^[24][25]

Several diseases traditionally classified as degenerative are now known to be caused by prions; the prime example is Creutzfeldt-Jakob disease. This disorder affects middle-aged individuals, who develop severe dementia, widespread myoclonic jerking, and rigidity, with a fatal outcome usually in weeks to months. Some patients have survived for several years and have had a more chronic course. This disease has been transmitted to nonhuman primates, and human-to-human transmission has been documented via corneal transplants, injection with growth hormone extracted from human pituitary glands, human cadaveric dura mater implants, and indwelling brain electrodes. Usual methods of sterilization are not adequate to destroy the agents responsible for this disease; common household bleach is most effective. Tissue may remain infectious for years, and the transmissible agent appears to be a prion. Brain biopsy is required to prove the diagnosis. The clinical syndrome and an EEG showing characteristic periodic complexes support the diagnosis of Creutzfeldt-Jakob disease. Rare familial forms of prion diseases (e.g., Gerstmann-Sträussler disease) appear to represent a situation in which the genome can manufacture an infectious polypeptide. The recent outbreak of “mad cow disease” in the United Kingdom has raised concerns of possible transmission to humans by the ingestion of affected meat products. There have been a limited number of atypical cases of Creutzfeldt-Jakob disease with prominent psychiatric and sensory symptoms in younger individuals in the United Kingdom, but to date none has been conclusively linked to the ingestion of meat products.^[26]

Other infectious causes of dementia include frontal or temporal lobe brain abscesses and chronic meningitides, such as cryptococcal meningitis, which is spread by ubiquitous spores. Although most common in immunosuppressed patients, cryptococcal meningitis is one of the only fungal meningitides that occurs in an otherwise healthy adult.

HIV encephalopathy must also be considered in the initial evaluation of dementia. Inquiries about risk factors for HIV disease are often neglected in elderly persons. Consent for HIV testing can be difficult to obtain in patients with dementia. Low T-cell counts are surrogate markers of HIV disease but can raise ethical questions if performed without consent. Neuroimaging such as MRI or CT with contrast delineates many of the mass lesions associated with deterioration in cognitive function in this population or the atrophy and white-matter changes seen in HIV encephalopathy. Fortunately the advent of new medications has decreased the prevalence of HIV encephalopathy. However, some patients, particularly the elderly, are not diagnosed in early asymptomatic stages or are not taking antiretroviral treatment and present with dementia (see Chapter 32 ).

[edit] Metabolic Disorders

Metabolic disorders may cause gradual changes in mental status, and the aged brain is extremely vulnerable to a host of changes in the metabolic state. Mild degrees of pulmonary, renal, hepatic, or cardiac failure that would not cause mental changes in younger individuals seem capable of causing mental disease in older persons. Small imbalances in endocrine function, particularly hypothyroidism and the apathetic form of hyperthyroidism, are frequently associated with change in mental status as the dominant clinical feature. Disturbances in electrolyte or acid-base balance and mild anemia or anoxia may also present with mental changes. Laboratory examinations are available to confirm or deny clinical suspicion of most of these metabolic, endocrine, or deficiency states. Even chronic constipation causes decreased mental acuity and confusion in elderly persons. Hepatic encephalopathy, common in alcoholic patients but found in patients with other forms of liver disease or with various medications such as valproic acid, produces a drowsy confusional state that sometimes may be misinterpreted as dementia.

Nutritional deficiencies are a prominent problem in elderly persons, who may lead isolated lives on inadequate incomes. This, combined with depression, may result in severe neglect of dietary intake of vitamins. The most common vitamin disorder that can produce dementia is vitamin B₁₂ deficiency. Most traditional American diets are rich in vitamin B₁₂, but occasionally, strict vegetarians can become deficient. Gastric surgery or pernicious anemia may be the cause. Signs of a peripheral neuropathy and myelopathy are often present. Neuropsychiatric manifestations of B₁₂ deficiency can occur in the absence of anemia or macrocytosis. A vitamin B₁₂ level should be performed routinely in evaluation of dementia. In patients with other signs of B₁₂ deficiency, it is important to remember that tissue stores can be depleted before the serum level falls. If B₁₂ deficiency is strongly suspected, a normal B₁₂ level should prompt a request for methylmalonic acid assay, a metabolite of vitamin B₁₂ that is increased in B₁₂ deficiency.

Thiamine deficiency can produce an acute Wernicke's encephalopathy, sometimes followed by Korsakoff's psychosis, also known as alcoholic amnestic syndrome (see Chapter 51 ). Although most often seen in alcoholic patients, patients with thiamine malabsorption caused by surgery (e.g., gastric plication) or severe malnutrition have occasionally been reported to develop thiamine deficiency with neurologic effects. The classic patient is apathetic and has marked impairment of immediate and short-term memory and relative preservation of more distant memory. These patients repeat a list of three objects and then cannot recall them after a 10-second distraction. Confabulation may occur but is not necessary for the diagnosis, and it can be induced in some patients who want to please the examiner. Recovery of memory function is variable and slow. Peripheral neuropathy, cerebellar degeneration, and other signs of neurologic damage from alcoholism are often present.

[edit] Tumors

Dementia can be a presenting feature of certain tumors that develop in the frontal or temporal lobes, especially when they are situated medially and impinge on the limbic system without causing elementary neurologic signs. Some are benign and easily resected, even in elderly people. A subfrontal meningioma that distorts and compresses the frontal lobes in the olfactory tracts causes loss of sense of smell and lends itself to surgical treatment. Certain tumors in the midline fail to cause lateralizing signs but often result in deterioration of behavior, which may be caused by direct effects on the limbic, hypothalamic, or endocrine system or by hydrocephalus. The mental status of patients with hydrocephalus improves dramatically with CSF shunting, even if the tumor cannot be removed. Neoplasms can also cause dementia through more distant effects. Meningeal carcinomatosis with spread of neoplastic cells to CSF can present as dementia. Neoplasms also produce multiple metabolic disturbances that can affect mental status. Limbic encephalitis can occur as a result of antibody to neuronal cells produced as part of a paraneoplastic syndrome. In tumors involving the brain, imaging studies may provide a diagnosis. In some cases, stereotactic biopsy of the mass may be necessary for a definitive answer. Indirect effects of tumors can be more challenging. CSF studies with cytology, serum samples for neuronal antibodies, and metabolic studies should be considered in the evaluation and may need to be repeated to establish a diagnosis.

[edit] Trauma

Trauma to the nervous system occurs frequently, particularly in patients with a history of alcohol or drug abuse. Traumatic injuries to the brain are easy to diagnose near the time of the event if the patient remembers it. However, minor head injuries can produce chronic subdural hematomas, particularly in elderly and alcoholic patients. The normal loss of brain volume in aging causes a slight stretching of the veins that bridge the subdural space, allowing relatively trivial trauma to tear a vein with accumulation of blood in the subdural space. When the accumulation is unilateral, early herniation may cause somnolence, sometimes without other focal neurologic deficits. Bilateral subdural hematomas (about 20% of cases) may not present with focal signs, and mental changes often occur without drowsiness. These patients may show an extreme degree of apathy and immobility, which is sometimes mistaken for advanced depression. These chronic subdural hematomas can be missed because they are isodense with brain tissue on a CT scan of the head. This is a particular problem when the hematomas are bilateral and do not produce a shift of the brain. MRI of the head can be extremely helpful in these cases (Fig. 158-3).

Figure 158-3 Subacute subdural hematoma. A, Head computed tomography scan shows a nearly isodense subdural hematoma. B and C, With magnetic resonance imaging the hematoma is much more apparent. C, Sagittal image demonstrates the mass effect of the lesion.

In addition to subdural hematomas, repetitive traumatic head injury can cause widespread damage and present like dementia. Imaging studies may show traces of the past trauma, but the deficits can be expected to remain stable or perhaps to improve with rehabilitation. The elderly brain is more sensitive, and responses are often less robust.

[edit] Alcohol-Related Dementia

In addition to Wernicke-Korsakoff syndrome, which is specific to thiamine deficiency, another less clearly delineated disorder is called alcohol-related dementia. This disorder is likely a result of the combined effect of alcohol on the brain, poor nutrition, and multiple traumatic insults. The cognitive disabilities are more varied than in Wernicke-Korsakoff syndrome and include loss of memory function, visuospatial abilities, and naming. Precise clinical criteria are lacking.^[27] Head CT or MRI shows diffuse cerebral atrophy. Abstinence from alcohol and good nutrition may result in essentially complete recovery of cognitive function in some of these patients. The cognitive losses in the active alcoholic patient can pose considerable challenges for the clinician. The patient may be essentially incompetent while drinking and highly functional when abstinent. Alcohol rehabilitation services are critical to the treatment of these patients. In the acute phases, the retention of material related to alcohol avoidance is minimal because of cognitive impairment, and patient education sessions need to be repeated later.

[edit] Toxic Causes

The most important toxic cause of dementia is prescription or OTC medications. A good dementia workup must include complete cataloging of the patient's medications and careful consideration of their possible adverse effects on the brain. Any drug used to treat behavioral or psychiatric disorders, such as benzodiazepines, antipsychotic medications, and antidepressants, can depress cognitive abilities. When possible a trial off of these medications is warranted in the evaluation of cognitive decline, using slow tapers in those that can cause withdrawal symptoms.

Various drugs often used for general medical illnesses are capable of causing mental changes. Some examples are antihypertensives, analgesics, and H₂ blockers. In addition, drugs that may be well tolerated as monotherapy have prolonged half-lives, and their side effects are potentiated when used in combination with other medications. The average elderly patient takes multiple medications and has a higher likelihood of experiencing significant side effects. After careful review of medications, all potentially unnecessary drugs should be discontinued. In the medications deemed necessary, the lowest possible dose should be given. It is important to remember that low doses in elderly patients may produce the intended result and dramatically reduce side effects.

OTC medicines, home remedies, and folk remedies must also be considered during the evaluation of patients. Patients and their families often neglect to mention the use of OTC antihistamines, sleeping preparations, and analgesics that may alter sensorium. A home visit by health care providers can be helpful if the patient allows a review of the medicine cabinet. This may also reveal a stash of expired medications that the patient may use intermittently. Patients with dementia may also use overdoses or underdoses of their medications. Calendar-type drug boxes may be helpful, but often the caretaker must dispense medications.

[edit] Sensory Deprivation

Losses in hearing ability and visual acuity are common in elderly persons and when undetected or minimized by the patient can present as confusion. With treatment, improvements are noted, even in those with neurodegenerative disease.

[edit] LABORATORY INVESTIGATIONS

The evaluation of any patient with dementia should be tailored to the patient's clinical history, risk factors, and examination. The evaluation must stress the search for the most probable disorder but must also contain an evaluation for less common but highly treatable etiologies.^[4] It is also important to remember that dementia can be multifactorial.

[edit] Laboratory Studies

In mild to moderate dementia, all patients should have a complete blood count with differential, thyroid-stimulating hormone level, vitamin B₁₂ level, syphilis testing (VDRL), liver function tests, and urinalysis. These laboratory tests should be supplemented by the analysis of other endocrine functions, if necessary, or arterial blood gas concentrations, ceruloplasmin levels, erythrocyte sedimentation rate, or antinuclear antibody testing. The physician should consider HIV testing, remembering that this disease occurs in elderly as well as young persons. Testing for the apoprotein E E4 allele in a patient with clinical features suggesting AD can be considered.^[8][9][10] If familial AD is considered, the physician can look for the common mutations found in this disorder, but it may be best to refer the patient to a consultant with expertise in the genetics of neurologic disorders.^[9]

[edit] Lumbar Puncture

A lumbar puncture is an appropriate examination for patients with early or moderate dementia. Although positive studies occur infrequently, they often reveal the presence of a treatable etiology. The spinal tap should be deferred until imaging is performed to avoid possible brain herniation and to guide any special CSF studies. CSF should be collected with careful note of the opening pressure and the fluid's appearance. Cell count, protein, and glucose levels, a VDRL test, cryptococcal antigen, and cultures should be performed. If multiple sclerosis is suspected, oligoclonal bands should also be sent. High-volume lumbar puncture is indicated in NPH. If AIDS is possible, testing for viral load and other atypical infections is warranted.

[edit] Imaging Studies

All patients should have an imaging study at the time of the initial diagnosis of dementia. A repeat of the imaging study should be considered in patients with acute deterioration in function, particularly with development of new focal neurologic signs or any history of head trauma. A CT scan of the head or an MRI should be performed. The determination of the most appropriate test depends on the likely diagnosis, the level of patient cooperation, and any contraindications. CT scan of the head, particularly with contrast, demonstrates most mass lesions, cerebrovascular accidents, subdural hematomas, and atrophy. However, isodense subdural hematomas may be missed or underestimated (see Fig. 158-3), and small lesions of all types may also be inapparent. Temporal lobe lesions and atrophy may be difficult to diagnose with CT. Head CT with contrast carries the risk associated with the contrast agent and cannot be performed in patients who have renal insufficiency.

For the evaluation of dementia, MRI can usually be performed without contrast. However, the MRI procedure is very difficult for claustrophobic patients and requires a higher level of cooperation than CT scanning. MRI cannot be performed in patients who have any metal in their body, including many surgical clips and metal fragments from occupational injuries (e.g., welding-related eye injuries). Pacemakers are also an absolute contraindication for MRI. The anxiety associated with MRI can be ameliorated by reassurance by the technologists, but this may sometimes need to be supplemented by a low dose of a sedating agent (e.g., a benzodiazepine) with a short half-life.

SPECT scanning may also have a role in the evaluation of patients with dementia. Characteristic patterns have been described in AD and Pick's disease but have not been fully substantiated with clinicopathologic correlations. The test involves the infusion of a radionucleotide followed by a relatively brief period of imaging. It again requires some patient cooperation, but most patients can tolerate the procedure. At this stage, results should be considered supportive but not diagnostic. SPECT scans are not part of a routine evaluation at this stage.

[edit] Electroencephalography

An EEG should be considered in some patients with dementia. This test is diagnostic in nonconvulsive status, showing a pattern of continuous ictal discharges. Also, a characteristic pattern is usually present in Creutzfeldt-Jakob disease. In other cases the EEG may suggest a mass lesion by showing high-voltage slow-wave activity in the area involved. However, imaging studies make this indication rarely useful. The low-voltage fast activity present with the use of sedatives may indicate a toxic encephalopathy. The EEG in certain metabolic derangements shows slowing and highly suggestive triphasic waves. However, in both these instances, other hints from the history or laboratory studies are more definitive in making the diagnosis.

[edit] Neuropsychologic Testing

Formal neuropsychologic testing consists of a battery of standardized tests of cognitive functions such as memory, visuospatial abilities, and language function. IQ testing is a well-known example. Neuropsychologists can be particularly helpful in establishing a diagnosis of dementia in early cases and in patients with high premorbid IQs. They can sometimes be helpful in supporting a diagnosis of depression by demonstrating variability in performance and patterns of losses inconsistent with a neurodegenerative process. Neuropsychologic evaluations are sometimes also performed before and after a course of treatment to help determine response or before and after high-volume lumbar puncture to diagnose NPH and potential response to shunting.

[edit] Summary

Dementia is the result of many common and uncommon disorders. The clinician's skills and judgment are important in delineating the most likely cause and in evaluating for all potentially present, treatable causes.

[edit] MANAGEMENT

A full account of treatments for disorders that may cause dementia would be inappropriate. These treatments may range from penicillin for neurosyphilis to shunting for NPH to discontinuation of medications. Some of these therapies are described in the section on differential diagnosis. This section presents common treatable features and an approach to the neurodegenerative disorders.

Therapy for all treatable causes must be maximized. However, treatable causes rarely reverse totally, but they can be arrested. In all patients, medications known to cause confusion should be discontinued if possible. The essential medications should be used in the lowest possible dosage. Alcohol use should be discouraged in patients who have a long history of frequent alcohol use; even small amounts may require detoxification. Hearing and vision correction should be prescribed when necessary, even for patients with neurodegenerative causes such as AD, which may be worsened by visual or auditory misperceptions.

Multiple nonpharmacologic interventions are helpful for patients and their caregivers. One of the first measures is to ensure safety at home by making sure outside doors cannot be opened by the patient and stoves can be disconnected intermittently when necessary. Home visits by clinicians who have trained as dementia specialists can provide valuable assistance to the family by providing safety hints and activity suggestions. Patients with wandering habits should be enrolled in the National Alzheimer Wanderers Alert Registry sponsored by the Alzheimer's Association, which enters patients into a national database, provides labels for them and their clothing, and ensures access to recent, high-quality photographs of patients. Driving by the patient can be a concern. Families may hide the keys or disable vehicles if the patient has moderate dementia. In early dementia the patient and caregiver can avoid adversarial roles by finding an objective third party to arbitrate. Some state motor vehicle departments or rehabilitation hospitals retest patients at the request of a physician or family member. In other cases the patient can be referred to a driving school for a safety evaluation.

Some general measures are also helpful in improving the level of functioning of patients with dementia. Patients do better if their environment and daily routines are stable. In nursing homes, color coding of the room, stripes leading along the hallway to various shared areas, and large-print calendars with a single day on each page are all simple measures that help the patient retain orientation. Sundowning is a term often used to describe the agitated, confused state that may be brought on in demented patients when the level of light is reduced in the evening. This problem is sometimes resolved by leaving the light on. Even during the day, many patients do better if present in a room where some activities are occurring. Frequent recreational activities keep the patient occupied, decrease the number of catastrophic reactions, and increase the number of positive interactions between the patient and caregiver. Activities may include reminiscence sessions, singing of old favorites, art activities, and continued involvement in household duties. It is important to tailor the task to the level of the patient's cognitive abilities. When frustration occurs over inability to perform the task, a simpler activity should be substituted.

The ability to perform activities of daily living eventually deteriorates, and the patient gradually requires more and more assistance. The ability to eat with silverware deteriorates, and substituting finger foods is helpful. Bath time may be stressful, with the patient becoming fearful of the running water. Preparing the bath in advance may help, and sponge baths can be substituted. Dressing can be facilitated by providing each item in a stepwise fashion and eliminating choices. Incontinence is a significant stress for caregivers and often prompts nursing home referrals. Frequent trips to the bathroom can minimize accidents in early stages, and adult diapers can be used later in the course. A workup for urinary tract infections, benign prostatic hypertrophy, and prostate cancer is indicated for new-onset incontinence.

Support groups are important for the patient in the early stages and for the caregiver throughout the disease and are available through local chapters of the Alzheimer's Association. If the family understands the symptoms to be expected, the patient can often be maintained in the home setting for much longer. This is particularly true when an interdisciplinary approach is available, including access to nurses, social workers, and physicians. Literature available from the Alzheimer's Association and books written specifically for families of patients (e.g., The 36-Hour Day by Mace and Rabins^[28]) can be of enormous value. A book called Living in the Labyrinth,^[29] written by a person with dementia, also provides insight. Adult day-care programs can allow family members to continue working or provide them with free time for other errands and respite. Overnight respite programs are unfortunately rare, and the financial burden for these usually falls on the family. As the disease progresses, the focus becomes the caregiver, who needs additional assistance with care and emotional support, especially when the often heart-rending decision about nursing home placement approaches.

Health care proxy forms and durable power of attorney decisions should preferably be made in the early stages of the disease when the patient can participate. Decisions regarding resuscitation attempts and other aggressive measures can be difficult for family but are best discussed before a crisis. In late stages, decisions about nutritional support are emotionally difficult for family members.

[edit] PHARMACOLOGIC INTERVENTIONS

In treatable causes of dementia, treatment for the target disease is naturally the first approach. However, it is important to remember that cognitive abilities may not return to baseline and there may be permanent deficits. It is particularly important to advise patients and family that recovery of function may not be complete.

Only two medications (tacrine and donepezil) have been approved by the Food and Drug Administration for use in AD, and both are cholinesterase inhibitors developed to increase the availability of acetylcholine. Both drugs slow progression of cognitive deficits, but their effects are modest. Positive effects on behavior are also reported but have been more difficult to prove objectively.^[30][31] Both agents require a gradual titration of dose, and neither has immediate effects. Side effects include nausea, vomiting, and diarrhea, which are usually self-limited. Tacrine was the first drug released, and widespread use has been hindered by the need for dosing four times a day and the possibility of hepatotoxicity, necessitating close monitoring of liver function. Although elevations of alanine aminotransferase occur in about 25% of patients, they seem to be reversible if the administration of tacrine is stopped.^[32] The starting dose of tacrine is 10 mg four times a day; it is increased in 6 weeks to 20 mg, then 30 mg 6 weeks later, and finally 40 mg, four times a day. Donepezil is given once a day with a starting dose of 5 mg at bedtime, increasing to 10 mg. Liver function tests do not seem to be affected, and no monitoring of blood work is needed. Therefore it is currently the preferred agent. It is reasonable to consider a trial of donepezil in all patients in the early or moderate stages of AD, since it can delay the later stages and the need for nursing home placement. Both tacrine and donepezil have been tried in other progressive dementias, but the published literature is currently too limited to develop guidelines for other uses.

Multiple other medications are being promoted to either slow or prevent the development of AD. It is important for the physician to note that the data on most of these treatments are limited, the studies are often flawed, and the improvements are often small. Vitamin E is frequently recommended, but a review of the literature indicates small studies and no available meta-analysis. The major complication appears to be rare instances of bleeding complications. Since so many patients now take vitamin E without a physician's recommendation, it may be difficult to perform the necessary studies to gauge its effect. A meta-analysis of studies of Gingko biloba revealed a modest improvement at doses of 120 to 240 mg, but most of the reviewed studies were excluded because of flaws in design or incomplete information.^[33] Nonsteroidal antiinflammatory drugs appear to have a protective effect for AD.^[34][35] Estrogen therapy in women may also have a protective effect, but there are conflicting results and flawed studies.^[36] Since estrogen therapy can have considerable risk, it is prudent to wait for more convincing data before recommending estrogen for the treatment or prevention of dementia.

Treatment also focuses on the behavioral symptoms of dementia. In all patients a trial of an antidepressant should be considered in the early stages. It is important to remember that the presentation of depression can be atypical in this population. Sleep disruptions are common and can sometimes be treated with attention to sleep routines. Short-acting benzodiazepines and trazodone can also be used. Agitation is a major problem, and the initial assessment must first exclude medical causes, particularly pain and infection. Next, it is important to look at the patterns of agitation, and the other signs and symptoms to guide medication use. Agitation can come from many causes, including depression, mania, and psychosis. Treatment targeted to the most likely etiology used in the lowest effective dose has the highest chance for success.^[37]

The treatment of a patient with dementia can be disheartening to a physician. However, the support of a knowledgeable and caring physician can make tremendous improvements in quality of life for both the patient and the caregiver.

[edit] EVIDENCE-BASED MEDICINE

Primary sources for this chapter were found using MEDLINE with searches dating back to 1966. Review articles, meta-analyses, and consensus statements were stressed, and the last search was done in January 1999.

[edit] SUPPORT GROUPS

Alzheimer's Association National Office, 919 North Michigan Avenue, Suite 1000, Chicago, IL 60611-1676, (800) 272-3900, www.alz.org

[edit] REFERENCES