Handbook of Consultation-Liaison Psychiatry

7. Delirium, Dementia, Alcohol Intoxication, and Withdrawal Syndromes

Hoyle Leigh

CONTENTS

7.1 Vignette

7.2 Delirium

7.2.1 Diagnosis

7.2.2 Management

7.3 Dementia

7.3.1 Diagnosis

7.3.2 Secondary Dementias

7.3.3 Primary Degenerative Demential

7.3.4 Management

7.1 Vignette

A 72-year-old man with a long-standing diagnosis of schizophrenia living in a board and care home was brought to the hospital by the police because of altered mental state and agitation. The patient was combative both in the ambulance and in the emergency department (ED). He was prescribed lorazepam 1 mg IM in the ED, but the agitation did not subside. The patient was noted to be disoriented to time and place. He attempted to hit the nursing staff, and thus was placed in leather restraints. The patient continued screaming obscenities. He then received 2 mg of haloperidol IM and an additional 2 mg of lorazepam, which made him somnolent. Laboratory findings indicated the presence of a urinary tract infection.

On the inpatient service, the patient was still agitated but was a little more cooperative with the psychiatric consultant, who was able to ascertain that the patient felt he was in jail, unjustifiably because he did not commit any crime. The psychiatric consultant reassured the patient that he was in the hospital, not jail, and that he was being treated for a urinary tract infection. Though somewhat reassured, the patient continued to feel paranoid about his surroundings and showed fluctuating levels of awareness, with agitation and somnolence. The psychiatric consultant also noted that the patient showed some rigidity and mild resting tremor that she attributed to the IM haloperidol the patient had received in the ED. She contacted the patient's outpatient psychiatrist, who confirmed that the patient had a diagnosis of chronic schizophrenia that had been under control with olanzapine 20 mg hs. The psychiatric consultant diagnosed (1) delirium, probably secondary to the urinary tract infection and the hospital environment; and (2) chronic undifferentiated schizophrenia based on the history and the psychotic symptoms exacerbated by delirium and the hospital environment. She recommended (1) restarting olanzapine 20 mg hs, (2) haloperidol 1 to 2 mg IV q 2 to 4 hours prn for agitation (repeated haloperidol IM should not be given as there is an increased risk of extrapyramidal side effects); (3) avoiding using lorazepam since it is a central nervous system (CNS) depressant that might attenuate the frontal lobe function and thus cause paradoxical agitation; (4) discharge planning should include appointment with outpatient psychiatrist soon after discharge; and (5) follow-up by psychiatry while the patient is in the hospital.

This vignette illustrates several important points: (1) Delirium is often superimposed on other psychiatric illnesses, including schizophrenia. But the clinician should not assume that all symptoms in such patients are due to schizophrenia. (2) In addition to a urinary tract infection, which is the most common cause of delirium in elderly patients, the lorazepam may also have contributed to the delirium. The patient's belief that he was in jail may have been exacerbated by the fact that he had been put in restraints for agitation, though he may have had baseline paranoia associated with schizophrenia.

7.2 Delirium

Delirium was formulated as a syndrome of cerebral insufficiency by Engel and Romano (1953). Depending on the degree and extent of the insufficiency, various aspects of cortical function are impaired in delirium. The underlying cause of delirium is usually a metabolic encephalopathy. As the encephalopathy waxes and wanes, there is often fluctuation of function, especially in levels of awareness. Higher cerebral functions such as abstraction, planning, and judgment are affected as well as attention, concentration, arousal, and memory. In delirium, unlike in dementia or other amnestic syndromes, memory registration itself may be impaired (i.e., immediate memory). A frequent component of delirium is psychotic symptoms, such as hallucinations (particularly visual and tactile), delusions, paranoia, illusions, and bizarre behavior. Psychotic symptoms are the results of impairment in the brain's ability to integrate perceptions correctly, coupled with memory deficits and confusion.

7.2.1 Diagnosis

7.2.1.1 Symptoms

Both delirium and dementia are characterized by cognitive deficits that may include, to varying degrees, confusion, disorientation, memory deficits, inability to concentrate, decline in executive function (e.g., planning), delusions, and perceptual changes (illusions, hallucinations). Psychomotor agitation and retardation may occur, as well as lability in affect. In delirium, fluctuation of levels of awareness as well as in cognitive function is often pronounced, indicating fluctuations in the encephalopathy. Florid psychotic symptoms, especially visual and tactile hallucinations, and incoherent speech are more likely to be delirium than dementia. There may be alternating agitation and stupor or placid drowsiness. Delirium is often superimposed on preexisting dementia; determination of the baseline level of functioning, therefore, is critical.

7.2.1.2 Laboratory Findings

Laboratory studies are critical in diagnosing the underlying cause of delirium. The study of body fluids (blood, urine, and cerebrospinal fluid) and brain imaging [computed tomography (CT), magnetic resonance imaging (MRI)] will determine the potential metabolic changes underlying the encephalopathy in a vast majority of delirium. Vital signs (blood pressure, heart rate, respiratory rate, temperature) will also provide important clues.

7.2.1.2.1 Blood Studies: The following blood studies should be done:

CBC and differential: for anemia (both microcytic and macrocytic), leukocytosis (infection), leukopenia (agranulocytosis, HIV)

Serum electrolyte imbalance (Na, K, Ca, Cl, Ph), osmolality

Renal failure (BUN, creatinine), hepatic failure (Bilirubin, ammonia, liver enzymes)

Oxygen saturation

Endocrinopathies [e.g., thyroid-stimulating hormone (TSH), thyroxine (T4)], glucose level, cortisol/adrenocorticotropic hormone (ACTH) if indicated

Vitamin B6, BL2, folate

Serology for syphilis

HIV testing

Alcohol level, acetaminophen level in suspected overdose

7.2.1.2.2 Urine: The following urine studies should be done:

Screen for toxic substances including illicit drugs, e.g., cocaine, methamphetamine, barbiturates, PCP

Evidence of urinary tract infection

7.2.1.2.3 Cerebrospinal Fluid: The following cerebrospinal fluid (CSF) studies should be done: pressure, infectious agents, serology for syphilis, protein, evidence of hemorrhage.

7.2.1.3 Vital Signs

Fever is a common cause of delirium, especially in children. In the elderly, fever may not be prominent in the presence of infection.

7.2.1.3.1 Heart Rate: Increased heart rate (HR) may be an indicator of infection in a relatively afebrile elderly patient. Tachycardia may be associated with hyperthyroidism that may underlie delirium. Cardiac arrhythmias may underlie delirium.

7.2.1.3.2 Respiratory Rate: Hyperventilation may be a cause of delirium or light-headedness. Hypoventilation and hypoxia may underlie delirium.

7.2.1.4 Imaging Studies

Imaging studies should be done for trauma, intracranial mass, stroke, infection, and degenerative changes.

7.2.2 Management

7.2.2.1 Immediate Management of Agitation

Acute agitation is often a medical-psychiatric emergency requiring immediate management to reduce the potential for harm to both the patient and the staff. An acutely agitated patient may first need to be physically restrained. If an intravenous (IV) line is not already in place, an intramuscular (IM) injection of haloperidol 1 to 2 mg may be given stat, and an additional dose of lorazepam 1 to 2 mg IM may be needed. Once an IV line is in place, haloperidol 1 to 5 mg IV (depending on the degree of agitation and the size of the patient) every 1 to 4 hours may be needed until the patient is reasonably calm. Then the patient may be given the effective dose of haloperidol every 4 to 6 hours. In severe agitation associated with delirium, large doses of haloperidol may be used without significant extrapyramidal side effects as long as it is given intravenously (at our center we have used up to 130 mg of haloperidol IV in a 24-hour period). Haloperidol IV, however, may lower the seizure threshold and may also cause QT prolongation in some patients (electrocardiogram should be monitored on IV haloperidol patients). In contrast to IV doses, oral and IM doses of haloperidol exceeding 1 to 2 mg may be associated with extrapyramidal side effects, requiring the use of benztropine or diphenhydramine. If the patient is willing to take oral medication, immediately dissolving forms of second-generation antipsychotics may gradually be substituted for IV haloperidol, for example, Zyprexa Zydis 5 or 10 mg PO hs, plus IV haloperidol 1 to 2 mg q 4 hours prn for agitation. Lorazepam 1 to 2 mg IV may be added to the haloperidol if the patient is so agitated that inducing sleep might be desirable, but in patients with delirium and dementia, benzodiazepines may cause paradoxical agitation due to suppression of the frontal lobe function. Oral haloperidol or chlorpromazine was shown to be more effective than lorazepam with fewer side effects in a prospective study of HIV/AIDS delirium (Breitbart et al., 1996).

If the presumptive reason for the agitation is alcohol withdrawal, lorazepam rather than haloperidol may be used, followed by an institution of an alcohol withdrawal schedule using an oral benzodiazepine (e.g., oxazepam, temazepam). If the presumptive underlying cause is phencyclidine (PCP) intoxication, haloperidol and phenothiazines should be avoided and the agitation should be controlled with lorazepam.

Psychologically, the staff should approach a delirious patient calmly, and avoid any behaviors that might be interpreted as being threatening, including standing or sitting too close to the patient. The patient should be oriented each time the staff approaches, e.g., "I am your nurse, Susan, and you are in University Hospital. I am here to take your temperature and give you an injection for your infection. "

Agitated patients should be in a quiet room if possible, and there should be someone to observe the patient at all times. When the delirium has cleared, the patient should be reassured that the frightening experiences of confusion and hallucinations are a part of the transient brain abnormality caused by the medical disease or substance and not signs of being "crazy".

7.2.2.2 Alcoholic Intoxication

The blood alcohol level should be obtained in all patients who present with agitation. Alcohol is a potent CNS depressant, a y-aminobutyric acid (GABA) agonist, and an inhibitor of glutamate excitation of the N-methyl-D-aspartate (NMDA) receptor. Thus, alcohol causes initial suppression of higher cortical functions including the frontal lobe function (inhibition of socially unacceptable behavior and impulse control), and then general CNS depression, including respiratory depression. In chronic use, abrupt withdrawal results in uncontrolled CNS excitation and autonomic hyperactivity, as well as the effects of thiamine and other vitamin B complex deficiency that often accompany chronic alcoholism.

Pathological alcohol intoxication, which may represent a dissociative state triggered by alcohol (Hollender, 1979), is characterized by agitation, delirium, and psychotic symptoms, and may occur in susceptible individuals even with low blood alcohol levels. Such patients may become violent, and may be amnestic for such periods, which are usually followed by prolonged sleep. Treatment for the acute phase involves protection of the patient from impulsive acts, and sedation with lorazepam 1 to 2 mg po or IM, haloperidol 2 to 5 mg IV, or olanzapine 5 to 10 mg po.

7.2.2.3 Alcohol Withdrawal Syndromes

Alcohol withdrawal seizures, usually grand mal seizures, occur within 24 hours of cessation of drinking, and rarely continue longer than 48 to 72 hours. Up to 10% to 25% of patients with alcohol withdrawal seizures may develop status epilepticus. Alcohol withdrawal seizures are best controlled with parenteral lorazepam, whereas phenytoin may be ineffective. Carbamazepine may be effective in early stages of withdrawal seizures. Alcohol withdrawal seizures may be prevented in seizure-prone patients through the use of antiseizure medications.

7.2.2.4 Delirium Tremens or Acute Alcohol Withdrawal Delirium

Delirium tremens (DTs) is a potentially lethal (5% to 15% mortality if untreated) medical-psychiatric emergency. About 5% to 10% of all patients admitted to general hospitals suffer from the DTs (DeBellis et al., 2005).

Delirium tremens combines symptoms of delirium, tremulousness, and autonomic hyperactivity. Prominent symptoms include tremulousness of extremities, agitation, confusion, perceptual disturbance, especially visual hallucinations of a frightening nature, and increases in heart rate, blood pressure, and respiratory rate. The DTs usually occur between 3 and 5 days after cessation or reduction in alcohol intake, and the symptoms usually taper off in 5 to 10 days.

7.2.2.4.1 Treatment: The immediate goal in treating the DTs is sufficient sedation to allow the patient to be lightly somnolent (Mayo-Smith et al., 2004). Lorazepam is preferable for this purpose (if given frequently or continuously), as it has no active metabolites and can be given parenterally, but other benzodiazepines may be used as well, including diazepam, chlordiazepoxide, temazepam, or oxazepam. An example is lorazepam 2 to 4 mg IV every 5 to 15 minutes until the patient is adequately sedated. Blood should be drawn for a complete blood count (CBC) with differential, hemoglobin and hematocrit, electrolytes, routine chemistry, alcohol level, and B 12 and folate level, as well as thyroid, renal, and hepatic function tests. To prevent vitamin deficiency syndromes such as Wernicke-Korsakoff syndrome (see below), the patient should be given an intravenous thiamine and vitamin B complex combination (called "banana bag" in some medical centers). It should include at least 100 mg of thiamine, and 1 mg of folic acid, as well as vitamin B complex.

Once the sedating dose of lorazepam has been determined, for example, after 16 mg of lorazepam (4 mg x 4) in an hour, the patient is resting comfortably. Then, the patient may be given lorazepam 16 mg every hour for the next 24 hours. Once the patient is stabilized for at least a day, the daily dose may be decreased by 10% to 20% a day with additional prn doses if the patient experiences withdrawal symptoms. (See also Chapter 12 for a discussion on using diazepam in delirium tremens.)

Haloperidol IV/IM may be used as an adjunct to benzodiazepines if necessary for the control of florid psychotic symptoms that are not sufficiently controlled with benzodiazepines.

Gabapentin and propofol have also been used effectively in DT patients (DeBellis et al., 2005; Myrick et al., 1998).

7.2.2.5 Acute Alcoholic Hallucinosis

Classically, the term acute alcoholic hallucinosis refers to vivid, usually auditory, hallucinations occurring in a clear sensorium, usually within 1 to 2 days after cessation or reduction in drinking. The hallucinations are often accusatory or derogatory in nature, and patients often develop paranoid ideation and delusions that may be indistinguishable from paranoid schizophrenia. As the hallucinations occur in a clear sensorium, patients may impulsively act on the hallucinations, including acts of violence against self or others. The treatment consists of protecting the patient, and use of benzodiazepines or antipsychotic drugs, for example, risperidone 2 mg b.i.d. or olanzapine 10 mg hs. The term alcoholic hallucinosis is also often used to denote the various visual, auditory, and tactile hallucinations that accompany delirium tremens.

7.2.2.6 Wernicke-Korsakoff Syndrome

Wernicke's encephalopathy is an acute life-threatening condition caused by thiamine (vitamin B) deficiency, usually seen in alcoholics in developed countries, but may also be seen in patients with other causes of malnutrition, such as HIV infection or esophageal stricture. Wernicke syndrome consists of delirium (confusion, disorientation, fluctuating levels of consciousness, illusions, hallucinations), oculomotor symptoms (ophthalmoplegia or palsy, disturbance in conjugate gaze, nystagmus), and incoordination, especially of the lower extremities (e.g., ataxia).

Three enzymes essential in carbohydrate metabolism [transketolase, pyruvate dehydrogenase (PDH), and a-ketoglutarate dehydrogenase ((X -KGDH)] are dependent on the presence of thiamine. At the cellular level, thiamine deficiency, depending on the cell type, especially in magnesium deficient conditions (which alcoholics often have) may result in mitochondrial damage, cell necrosis, and apoptosis. Alcoholics may develop thiamine deficiency through poor intake, poor gastrointestinal (GI) absorption, and poor cellular utilization. When a thiamine-deficient patient is to be given an IV glucose solution, thiamine 100 mg should always be added, as the glucose may deplete existing body storage of thiamine, causing or exacerbating Wernicke's encephalopathy.

In fact, it is prudent to recommend to any malnourished or alcoholic patient to take thiamine 100 mg po per day (or a therapeutic multivitamin tablet) to prevent thiamine deficiency.

Wernicke-Korsakoff patients' brains may show degeneration in the mamillary bodies, thalamus, hypothalamus, brainstem, and cerebellum. Only about 20% of brains shown to have such lesions at autopsy, however, have been diagnosed with Wernicke-Korsakoff during life (Harper, 1998).

About 80% to 90% of Wernicke patients eventually develop Korsakoff's psychosis, a chronic amnestic syndrome particularly characterized by confabulations. Confabulation refers to unintentionally "made up" memories, that is, false recollections in place of actual memory. For example, when a stranger asks the patient, "Have we met before?" the patient may answer, "Yes, we had dinner together last night; wasn't it a great restaurant?"

The memory deficit may be both anterograde and retrograde, the anterograde element often being more striking. For example, a patient may have a prolonged conversation about a past event, and not recall that the conversation ever took place.

7.2.2.6.1 Treatment: Wernicke's encephalopathy is a medical emergency requiring hospitalization and acute intravenous treatment with thiamine 100 mg/day, folate 1 mg/day, and vitamin B complex, and treatment for delirium as indicated. When the patient is able to tolerate oral intake, thiamine 100 to 300 mg and a therapeutic multivitamin plus mineral tablet should be given per day orally.

For Korsakoff's psychosis, thiamine 100 to 300 mg and multivitamin plus mineral tab per day po are prescribed for at least 3 to 6 months. The patient may be managed in a convalescent home or as an outpatient if the patient can be protected, as the memory deficit may be severe enough for the patient not to be able to find his or her way home. Many patients with Korsakoff's psychosis eventually improve, especially with vigorous treatment.

7.2.2.7 Other Sedative-Hypnotic Withdrawal

Any sedative-hypnotic drug withdrawal, including barbiturates and benzodiazepines, may cause delirium and seizures. The diagnosis is made on the basis of a history of substance use and urine toxicology. Treatment should be geared to treating the withdrawal state with a cross-tolerant sedative-hypnotic (e.g., lorazepam), and then a gradual detoxification schedule (10% reduction per day may be safe).

7.3 Dementia

As compared to delirium, which is an acute condition reflecting an encephalopathy and cerebral insufficiency, dementia is a more chronic condition of loss of higher cerebral functioning, often representing the loss of cortical and subcortical neurons. Dementia does not show the degree of fluctuation in awareness common in delirium, and tends to show a more stable or progressive cognitive deficit over time, particularly associated with recent memory and higher cognitive functions. Delirium, however, may be superimposed on dementia, for example, when a dementia patient develops a urinary tract infection.

In mental retardation, there is inadequate development of higher cognitive function. Both dementia and mental retardation are often associated with agitation, as patients may lack the capacity to integrate sensory input and thus may perceive their surroundings in a threatening way. They may also lack the cognitive and reflective abilities to assess the situation correctly, and, especially in case of frontal lobe damage, be unable to plan their actions or understand the potential consequences of their action, resulting in poor impulse control.

7.3.1 Diagnosis

The syndrome of dementia consists of subacute to chronic development of cognitive deficits, eventually causing decline in function. The cognitive deficits generally reflect an underlying neuronal loss in the brain.

Dementias have been classified in several different ways: secondary vs. primary (idiopathic); reversible vs. irreversible; cortical vs. subcortical; and, on the basis of severity as mild, moderate, or severe.

Alzheimer's disease is the most common type of dementia, comprising about 60% of dementias. Vascular dementia comprises about 10% to 20% of dementias, followed by dementia associated with Parkinson's disease.

Of utmost importance in consultation-liaison psychiatry is the fact that dementias secondary to medical diseases (see below) are largely reversible or arrestable if the underlying disease is adequately diagnosed and treated. Though these dementias represent less than 10% of all dementias, the recognition and treatment of reversible dementias is a great service for the families and caregivers of these patients as well as a way of achieving significant cost-savings.

7.3.1.1 Symptoms and Signs

Short-term memory deficits are prominent in dementia, though long-term memory eventually is affected in later stages. There are varying degrees of deterioration in abstraction, calculation, and judgment as well as lability in affect sometimes interspersed with vacuous expressions. Patients are often stimulus-bound, that is, they respond to immediate stimuli without a sense of perspective or understanding of the situation. They often show impulsivity and inability to plan, especially with frontal lobe involvement. There may be associated neurologic deficits, such as dysnomia and focal neurologic signs.

Orientation may be impaired, particularly as to date, followed by place and situation. Patients usually know their name until a very advanced stage.

"Sun-downing" refers to an increase in confusion and disorientation in the evenings and nights, often accompanied by agitation or lethargy commonly seen in dementia patients, due to the reduction in orienting stimuli. The Mini-Mental Status Examination (MMSE) is a useful tool in documenting the degree of cognitive deficit in patients suspected of dementia (see Appendix at end of chapter). Generally, a score above 26 is considered normal; 20 to 26 indicates mild impairment; 10 to 19 indicates moderate impairment; and below 10 indicates severe impairment. Age, educational level, and premorbid functioning should be considered in determining to what extent the MMSE score represents a decline of cognitive function (median 29 for ages 18 to 25, and 25 for ages 80 and older; 29 for educational level greater than 9 years, 26 for 5 to 8 years, 22 for 0 to 4 years (Crum et al., 1993).

7.3.1.2 Laboratory Tests

Once the syndromic diagnosis of dementia is made or strongly suspected, laboratory tests should be performed to identify possible secondary dementias that may be treatable etiologically. They should include basic blood and urine analyses, screening for endocrine disorders, serology, brain imaging studies, EEG, and other studies as indicated. Neuropsychological testing may be indicated if there is suspicion of specific cerebral dysfunction associated with trauma or injury.

Blood: CBC with differential, Hgb, Hct, glucose, electrolytes, calcium, magnesium, phosphate, vitamin B6, BL2, folate, TSH and T4, lipids (cholesterol, low- and high-density lipoproteins, triglycerides), BUN and creatinine, serology for syphilis, HIV

Urine: urinalysis, toxicology screen

Imaging studies: head CT, MRI

EEG if seizure suspected, or to rule out delirium where slowing would be prominent

Others as indicated, for example, blood levels of drugs, ceruloplasmin level if Wilson's disease suspected, etc.

7.3.2 Secondary Dementias

The term secondary dementia is generally used to denote those dementias that are not caused by primary degeneration of cerebral tissue. Dementia may be secondary to any medical system disease, and the diagnosis and treatment of such an underlying disease can be lifesaving for the patient. Vascular dementia is the most common secondary dementia, though it is sometimes classified with primary dementia because of its presumed irreversibility. Nevertheless, vascular dementia may be arrested if proper treatment is instituted for the underlying cardiovascular disease.

A careful history, physical examination, vital signs, and laboratory are essential in recognizing secondary dementias.

Vascular dementia is diagnosable when there is a history of hypertension, strokes, or transient ischemic episodes. Brain imaging studies may reveal evidence of past strokes or diffuse white matter lesions. Vascular dementia may be associated with such underlying diseases as systemic lupus erythematosus. Vascular dementia may be subdivided into multiinfarct dementia and diffuse white matter disease (Binswanger disease). In multiinfarct dementia, there is evidence of multiple strokes on brain imaging, and the history is typically a discrete stepwise progression of neurologic deficits and dementia. Left-sided strokes are associated with worse symptoms. In Binswanger disease, the diffuse white matter pathology is due to the occlusion of small penetrating cerebral arteries and arterioles. The course tends to be more insidious, with mild confusion, apathy, personality change, and psychotic symptoms in the early stages. Gait disturbance is common, and pseudobulbar palsy may occur. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a form of progressive vascular dementia developing in patients in their 50s to 70s in multiple family members who may also have a history of migraine and recurrent stroke without hypertension. Skin biopsy may show characteristic dense bodies in the media of arterioles.

The consultant may suspect hypothyroidism in a patient who shows cognitive deficits and whose hands are cold and clammy, or normal pressure hydrocephalus in an elderly ataxic patient who developed cognitive deficits.

The presence of associated symptoms and signs as well as laboratory tests will help confirm the diagnosis of the underlying medical condition. Routine CBC, hemoglobin, hematocrit, and red blood cell (RBC) morphology will reveal anemias, infections, and some heavy metal poisonings. Vitamin B6, BL7, folic acid, thiamine, and niacin levels may indicate dementias secondary to nutritional deficiency. Endocrine and metabolic workups may reveal underlying medical disease. Tertiary syphilis and HIV, as well as other infections, can be diagnosed with appropriate specific tests. Occupational and travel history may call for tests for heavy metals and infections/parasites that might underlie the cognitive deficit.

Primary psychiatric illnesses may be associated with cognitive disturbance that may mimic or be associated with dementia. Cognition is often disturbed in acute anxiety states. Depression is often associated with lack of concentration and focus, indecisiveness, and lack of motivation presenting a dementiform mental status (pseudodementia of depression). Cognitive dysfunction is now considered to underlie schizophrenia independently of other symptoms. As with general medical conditions, coexisting primary psychiatric illnesses can be diagnosed through a careful history, collateral information, and mental status examination documenting the presence of a primary psychiatric illness (Table 7.1).

7.3.3 Primary Degenerative Dementias

The diagnosis of a primary degenerative dementia can only be entertained after secondary dementias have been ruled out. Primary degenerative dementias include Alzheimer's disease, Lewy body dementia, frontotemporal dementia/Pick's disease, Parkinson's disease, Huntington's disease, and the prion diseases Creutzfeldt-Jakob disease and bovine spongiform encephalopathy.

7.3.3.1 Alzheimer's Disease

Alzheimer's disease is a diffuse degenerative disease of the brain. Microscopically, characteristic findings are neuritic "senile" plaques containing A(3 amyloid, and silver-staining neurofibrillary tangles. A(3 amyloid is also found to accumulate in the cerebral vascular walls. Neurofibrillary tangles are made up of filaments in the neural cytoplasm that are abnormally phosphorylated tau proteins. Tau proteins are important in assembling and stabilizing the microtubules in the neurons.

Alzheimer's disease is associated with a decrease in cholinergic transmission in the cortex and a reduction of choline acetyltransferase, and nicotinic acetylcholine receptors. Brain imaging studies show diffuse cortical atrophy with prominent sulci and ventricles. The prevalence of Alzheimer's disease increases with advancing age such that up to 20% to 40% are affected over the age of 85.

Four susceptibility genes to Alzheimer's disease (AD) have been recently identified. First is the amyloid precursor protein (APP) gene on chromosome 21, the mutation of which results in early-onset, autosomal-dominant AD. APP is cleaved by secretases to smaller molecules, such as toxic AN42. All Down syndrome patients eventually develop Alzheimer's disease.

Two additional genes, presenilin-1 on chromosome 14 and presenilin-2 on chromosome 1, have been identified as causes of early-onset familial AD. Affected individuals have been found to have increased levels of plasma A1342.

Late-onset AD, both familial and sporadic, may be associated with the apolipoprotein E (APOE) gene on chromosome 19. The APOE gene, involved in cholesterol transport, has three alleles, Epsilon2, 3, and 4. APOE Epsilon4 gene, especially in the homozygous state, may be a strong risk factor for AD; 40% to 65% of AD patients have at least one APOE Epsilon4 gene (compared to 24-30% of the nondemented Caucasian population). People who have one APOE Epsilon4 allele are considered to be at three times the risk for developing AD compared to those who do not, and those who have two APOE Epsilon4 alleles have three times the risk (Hsiung et al., 2004). APOE is found in neuritic plaques and may be involved with clearance of amyloid protein as well as in neurofibrillary tangle formation by binding tau. APOE Epsilon4 is associated with diminished amyloid clearance.

7.3.3.1.1 Clinical Features: Memory disturbance is typically found in early stages of AD, though in about 20%, the presenting problems may be nonmemory related, such as difficulty with organization or navigation. Memory disturbance is followed by language difficulties, such as word finding, comprehension, and finally fluency. Apraxia and anosognosia may occur. Visuospatial disturbance results in inability to dress self. Capgras syndrome, in which the patient may believe that the caregiver is an impostor, may occur in about 10%. Personality change and disinhibition symptoms occur, such as socially inappropriate behavior, impulsive acts, and violence. With progression of disease, daily function becomes impaired, with an inability to work, to manage financial affairs, and eventually to find one's way home. In late stages, the patient is usually incontinent, rigid, mute, and unable to feed oneself. Myoclonic jerks may occur. Death usually occurs as a consequence of malnutrition, aspiration, and secondary infection.

7.3.3.2 Frontotemporal Dementia /Pick's Disease

Frontotemporal dementia (FTD) typically develops between the ages of 50 and 70. It usually has a more insidious onset and slower progression than Alzheimer's with prominent early behavioral symptoms. There is early neglect of personal hygiene and grooming; apathy; loss of social awareness; disinhibition symptoms such as impulsive sexuality, violent behavior, mental rigidity, and inflexibility; hyperorality; stereotypy and perseverative behavior; distractibility; and impulsivity (Brun et al., 1994). Cognitive symptoms typically spare the memory in the early stages. There are often parkinsonian and motor neuron symptoms, reflecting degeneration of anterior frontal, temporal, basal ganglia, and motor neurons. Aphasias are often associated, either nonfluent (frontal lobe involvement) or semantic aphasia, associated with left anterior temporal degeneration. In semantic aphasia, concepts associated with language are lost. It is often associated with visual agnosia (not recognizing faces, objects, etc.). Recently, chromosome 17-linked frontotemporal dementia (FTDP- 17) has been found to be associated with the gene for the microtubule-associated protein tau (MAPtau) (Hutton et al., 1998). There are, however, FTDs that are not associated with tau. Pick's disease is now considered to be a subset of FTD that shows the typical Pick's inclusion bodies at autopsy.

7.3.3.3 Lewy Body Demential Dementia Secondary to Parkinson's Disease Both of these conditions are characterized by Lewy bodies throughout the cortex, amygdala, cingulate gyrus, and substantia nigra. Lewy bodies are intra- neuronal cytoplasmic inclusion bodies often displacing the nucleus, containing ubiquitin and a-synuclein.

Psychiatric symptom are prominent, particularly well-formed visual hallucinations. Fluctuations in cognition and extrapyramidal symptoms and falls are frequent. If the extrapyramidal symptoms and signs precede the cognitive/psychiatric symptoms by a year or more, parkinsonism is diagnosed. About 20`Y% of parkinsonism patients develop dementia. If cognitive deficit and hallucinations precede or occur within a year of the onset of extrapyramidal symptoms, Lewy body disease (LBD) is diagnosed. In LBD, memory is often better preserved than in AD, but visuospatial defects may be more pronounced. The fluctuations of cognition are often deliriform, but tend to persist over time without detectable underlying metabolic derangement. An important precaution concerning LBD and Parkinson's disease (PD) is that these patients are exquisitely sensitive to the extrapyramidal side effects of antipsychotic medications. They also develop delirium with L-dopa administration. Cholinergic transmission is impaired in these patients and cholinesterase inhibitors seem to have a salutary effect.

7.3.3.4 Progressive Supranuclear Palsy

This degenerative disease is characterized by falls, vertical downward gaze palsy, symmetrical rigidity, and dementia. Patients often exhibit unstable rigid posture with hyperextended neck and slow gait. The dementia is similar to FTD with prominent apathy and frontal lobe symptoms.

7.3.3.5 Cortical Basal Degeneration

Cortical basal degeneration usually begins unilaterally with rigidity, dystonia, and apraxia of one arm and hand ("alien hand") that eventually becomes bilateral with dysarthria, ataxia, intention tremor, and dementia.

7.3.3.6 Huntington's Disease

An autosomal dominant disease associated with CAG repeat expansion in the gene coding for huntingtin in chromosome 4, it causes degeneration of the caudate nucleus. The onset is usually in the 40s to 50s with wide variation, and it is characterized by chorea and frontal executive function and behavioral disturbances. Delusions and other psychotic symptoms may occur. Phenothiazines and haloperidol have been used for both movement and behavioral symptoms with some success.

7.3.3.7 Creutzfeldt-Jakob Disease and Bovine Spongioform Encephalopathy

These prion diseases are associated with typical progressive movement disorders and dementia.

7.3.4 Management

Management of dementia involves three important aspects: protection, compensation, and pharmacologic treatment. Providing support for caregivers is an important aspect of management of dementia, such as support groups and periods of respite.

Protection is geared to slowing further progression of dementia and avoiding possible harm or injury when the patient wanders off (perhaps into traffic), being exposed to the elements, or being taken advantage of or attacked by others. Both physical and mental exercise may play a role in retarding the progression of dementia ("use it or lose it"). Night lights are necessary for impaired vision as well as for orientation at night. The patient's residence may need to be modified, or the patient may require assisted living or eventual nursing home placement.

Assistance may be needed by family, caregivers, or guardians concerning finances and activities of daily living. Compensation for the patient's loss of memory and living skills may involve calendars, clocks, PDAs, large notes, etc. Frequent orientation, especially in the hospital setting when a procedure such as a blood draw is to be performed, may prevent an impulsive outburst by the patient who may perceive such a procedure as an attack. Compensation for loss of autonomy and social support in later stages of dementia should include communal support, frequent visits of relatives and friends, entertainment and music activities, pets, etc. Adequate nutrition may be an issue with reduction in gustatory sensation in late stages. Increasing sugar content of meals may stimulate food intake.

7.3.4.1 Pharmacologic Treatment

Pharmacologic treatment may be divided into treatment of associated symptoms and treatment of cognitive deficit.

7.3.4.1.1 Treatment of Associated Symptoms: Psychosis (delusions, hallucinations), depression, and impulsivity are commonly associated with primary dementia and may require pharmacologic treatment for each. Second-generation antipsychotics such as olanzapine, risperidone, quetiapine, and aripiprazole have been used successfully, though they, especially risperidone, have been associated with the risk of stroke in demented elderly patients, and all have been associated with an increased risk of death in elderly population. Nevertheless, the quality of life without tormenting psychotic symptoms may outweigh any risks involved. In elderly patients, the medications should be used in the smallest effective dose in view of impaired metabolism and clearance of the drugs as well as probable comorbidity.

Antipsychotics with prominent extrapyramidal side effects such as haloperidol, risperidone, and ziprasidone should be used very cautiously in patients with LBD and dementia associated with parkinsonism.

For depression, selective serotonin reuptake inhibitors (SSRIs), serotoninnorepinephrine reuptake inhibitors (SNRIs), mirtazapine, and bupropion may be effective. The SSRIs include fluoxetine, sertraline, citalopram, escitalopram, and paroxetine, among others. The SNRIs include venlafaxine and duloxetine. Stimulants such as dextroamphetamine (5-10 mg in the a.m.) or methylphenidate (10 to 20 mg in the a.m.) may be useful for depressed mood, anergy, and demoralization in some patients.

Mood stabilizers, such as valproic acid and carbamazepine may be tried for impulsivity and aggressiveness, as well as second-generation antipsychotics such as quetiapine or olanzapine.

Benzodiazepines may be used for anxiety, but caution should be exercised as disinhibition is likely to be exacerbated in patients with dementia, and cognitive dysfunction will likely increase. For the consultant-liaison psychiatrist, stopping benzodiazepines is often the most helpful intervention. Small doses of antipsychotic medications (e.g., 0.5 mg of haloperidol or 2.5 mg of olanzapine at night or b.i.d.-t.i.d. po) may be a better choice for anxiety and irritability in patients with dementia.

7.3.4.1.2 Pharmacologic Treatment of Cognitive Deficit: There is currently no drug that reverses the cognitive deficit of primary dementia. Drugs that may retard the progression of dementia to varying degrees include cholinesterase inhibitors (tacrine, donepezil, rivastigmine, and galanthamine) and the NMDA receptor antagonist memantine. Cholinesterase inhibitors are moderately useful in the early stages of dementia. Due to hepatotoxicity, tacrine is seldom used, and donepezil is most often used in doses of 5 to 10 mg per day.

Memantine can be used in conjunction with donepezil and may be moderately effective in moderately advanced dementia in doses of 20 mg per day (Table 7.2).

Appendix: Mini-Mental Status Examination (MMSE)

(Score to be added up)

Orientation

Registration

Attention, concentration, calculation

Recall

Language

Visuomotor function

Adapted from Folstein MF, Folstein SE, McHugh PR. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12(3):189-198.

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