Dementia

Introduction

Perhaps the most important challenge in treating dementia is identifying cases (albeit uncommon) of reversible dementia such as chronic drug intoxication, vitamin deficiencies (B-12 and folate), subdural hematoma(s), major depression (causing forgetfulness), normal pressure hydrocephalus (NPH), and hypothyroidism. The management of such causes is aimed at treating the underlying disease process.

However, most causes of dementia, including degenerative brain diseases (ie, Alzheimer disease) and multi-infarct states, are incurable. This does not mean that symptoms cannot be treated. The pharmacotherapy of dementia is tailored to the specific problems confronted, although these are influenced by the underlying diagnosis.

Six clinical categories associated with dementia are amenable to pharmacotherapeutic intervention, as follows:

• Prevention of neurodegeneration
• Intellectual decline
• Behavioral disorders
• Sleep disorders
• Common medical complications
• Abrupt worsening of dementia

These categories are applicable to almost all cases of irreversible dementia, although some are more frequently problematic depending on the specific disease involved. Nonetheless, this basic framework can be applied, with some fine-tuning, to most patients with dementia.

Prevention of Neurodegeneration

There are ongoing efforts to study drugs that may have an effect on the progression of neurodegeneration. These data are available primarily for Alzheimer disease (AD), although such effects, if ultimately proven to be significant, might be applicable to the broader family of neurodegenerative diseases. Some of the more popular agents are estrogen replacement therapy (in women only), vitamins (E and C), and nonsteroidal anti-inflammatory drugs (NSAIDs).

A few clinical studies seem to suggest that estrogen replacement therapy (ERT) is associated with a lower incidence of AD in women.

• However, based on results from the Women's Health Initiative Memory Study (WHIMS), daily conjugated equine estrogens (CEE) with or without medroxyprogesterone acetate (MPA) should not be used to either prevent dementia or improve cognitive function in women older than 65 years.
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• The WHIMS trial revealed that there was actually an increased risk of dementia with CEE and MPA compared with placebo. While, this conclusion can be drawn from WHIMS, it does not mean that estrogen treatment has no effect on dementia. The WHIMS is an ancillary study portion of the Women's Health Initiative (WHI). This large study was discontinued early because of increased risks of coronary disease, stroke, thromboembolism, and breast cancer.

Vitamin E has been available as a nutritional supplement for many years without prescription in doses ranging from 30 international units (IU) to 1000 IU.

• A recent study suggested that 2000 IU daily delayed the need for institutionalization of patients with AD.
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• Minor bleeding (subcutaneous) was a potential adverse effect.
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• The same study showed a similar benefit for selegiline. However, no additional benefit for combination therapy (ie, vitamin E and selegiline) was found.
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• Concerns have been raised regarding the statistical methods used in this study, as well as its true biological validity. Thus, it cannot yet be recommended that high doses of vitamin E (1000-2000 mg) be taken solely to prevent dementia.
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• A recent study seemed to indicate that the incidence and prevalence of AD may be lower in those that use vitamin E and C in combination. However, again, there awaits larger controlled trials to be able to make clear recommendations in favor of vitamins for dementia.

NSAIDs are thought to retard neurodegenerative progression because of biochemical inflammatory markers found in the microscopic lesions of the brain (particularly neuritic plaques) in AD.

• Small clinical and large epidemiological studies support the hypothesis that patients who take NSAIDs have reduced risks of dementia onset and rate of progression.
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• However, dose and specific agent remain unclear.
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• Given the risk of serious upper gastrointestinal bleeding associated with NSAIDs, caution must be exercised.
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• Data are conflicting regarding the potential prophylactic efficacy of low-dose aspirin (81-325 mg daily) in dementia. Aspirin already is used for stroke and myocardial infarction prophylaxis.
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• A recent meta-analysis of NSAID use and risk of dementia studies was undertaken. The studies found that bias in the studies (recall, prescription, and publication bias) could account for the conclusion that NSAIDs are beneficial. Hence, it cannot be recommended that NSAIDs be used solely in an effort to prophylaxis against dementia.

Limited data suggest that Ginkgo biloba, a plant extract, may have a modest neuroprotective effect.

• Whether it has an additive effect with any other neuroprotective agent is unknown.
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• Limited case reports have been published of hemorrhagic conditions such as intracranial and intraocular bleeding in patients taking ginkgo, but these reports are rare and not unique to ginkgo.
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• Additionally, a recent randomized, double-blind, placebo-controlled trial of two doses of ginkgo biloba extract in dementia of the Alzheimer type did not find a difference in efficacy. However, the authors noted a study limitation due to similar result with placebo.
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• Given the concern of ginkgo's interaction with some medications used in the elderly and lack of clear benefit, recommending ginkgo solely for dementia cannot be given at this point.

Intellectual Decline

Intellectual decline is intrinsic to the definition of dementia. One of the prominent pathophysiological changes is a loss of cholinergic neurons (especially in the basal forebrain). In an attempt to ameliorate this cerebral cholinergic deficiency state, centrally acting acetylcholinesterase inhibitors have been developed that are modestly effective in enhancing intellectual skills such as memory in patients with AD.

The first such medication, tacrine (Cognex), has a high incidence of adverse effects, especially gastrointestinal (nausea, diarrhea, hepatotoxicity). These occurred at higher dosages (40 mg qid), which tend to be the therapeutically effective doses. Thus, many patients are not able to tolerate potentially effective doses.

The second drug, donepezil (Aricept), released in the United States in January 1997, is similar to tacrine in efficacy but has a low incidence of dose-limiting adverse effects.

Two more cholinesterase inhibitors have become available since donepezil. They are rivastigmine (Exelon) and galantamine (Razadyne). In addition to oral administration, rivastigmine is also available as transdermal patch. All 3 drugs represent different classes of cholinesterase inhibitors and are all approved by the FDA for use in Alzheimer disease. Additionally, rivatigmine is indicated for dementia associated with Parkinson disease. They differ primarily in their pharmacologic properties rather than in efficacy. As such, when the initial drug fails in efficacy or tolerability, then a different cholinesterase inhibitor can be tried. Combining two cholinesterase inhibitors is not recommended.

Generally, it is recommended to start treatment early in the course of illness to maximize longer-term benefits. Limited data exist on use of cholinesterase inhibitors in other dementias (multi-infarct, Pick disease, dementia with Lewy bodies). However, it may be considered given some of the pathological similarities to Alzheimer disease and lack of FDA approved medicines for other dementias. However, third party payers may or may not provide coverage when use is outside of product labeling.

Side effects of cholinesterase inhibitors, in a minority of patients, can include nausea, vomiting, diarrhea, and anorexia. These side effects are more common in the initiation phase of the drug rather than during maintenance.

Some studies have suggested that the cholinesterase inhibitors may also improve secondary symptoms of dementia such as behavior/psychiatric. Therefore, it is prudent to avoid starting another medication to address additional dementia symptoms till the effect of the cholinesterase inhibitor is determined.

Recently, an analysis of clinical trials published in the British Medical Journal online concluded that, due to methodological concerns and modest benefit, the scientific basis of the true efficacy of donepezil, rivastigmine, and galantamine is questionable. However, in the US, the FDA requires rigorous controlled trials to approve medications.

More recently, another medication memantine, an uncompetitive N -methyl-D-aspartate (NMDA) antagonist, has received FDA approval for Alzheimer disease. Additionally, some studies suggest that improvement in primary and secondary symptoms in Alzheimer disease may be greater when memantine is used in combination with a cholinesterase inhibitor.

Side effects of memantine include somnolence, dizziness, headache, and constipation.

Behavioral Disorders

Three categories of behavioral or psychiatric disturbances are common in patients with dementia: psychosis, anxiety, and depression. Although dementia is defined by intellectual decline, its course is complicated by behavioral changes. Behavioral problems correlate more strongly with the need for nursing home placement than intellectual decline alone.

Psychosis

Psychosis in dementia, while variable in its features, typically involves paranoid delusions and formed visual hallucinations.

• Typical paranoid themes involve infidelity and money/theft.
• These sentiments can interfere with a well-intentioned caregiver and may make it impractical for the patient to remain at home.
• Fortunately, psychotic symptoms respond to neuroleptic management in most patients.

A seemingly endless number of neuroleptic medications are available, but a working familiarity with the following 4 can be useful. Two are "typical" neuroleptic agents and 2 are "atypical" neuroleptic agents. The main difference between the 2 types is that the typical agents produce extrapyramidal adverse effects (ie, parkinsonism) at a higher frequency, although in general they are quite effective in ameliorating psychosis. The atypical agents are less likely to cause extrapyramidal side effects, but efficacy is less predictable, especially in cases of acute severe agitation.

• Two commonly used typical neuroleptics are haloperidol (Haldol) and risperidone (Risperdal). They share a similar dosing schedule.
  • The 2 most frequent errors in their use are overdosing and delaying treatment until a mild problem escalates into a crisis.
  • Most patients can be treated with a low maintenance dose without undue parkinsonism.
  • Typical maintenance doses for haloperidol and risperidone are between 0.5 and 2 mg daily.
  • Extrapyramidal adverse effects can develop gradually despite a stable low dose, and the patient must be monitored carefully for these effects.
  • Risperidone is more selective neurochemically than haloperidol, and extrapyramidal effects are milder at low doses. This is variable, however, and risperidone can cause severe parkinsonism despite its greater selectivity. At the doses described, the adverse effects do not differ greatly, and haloperidol is much less expensive.
• Two relatively new atypical neuroleptic agents are quetiapine (Seroquel) and olanzapine (Zyprexa). Both can be quite effective, although they are better used in less acute settings.
  • Starting doses for quetiapine are 25 mg once or twice daily, and for olanzapine 2.5 mg once or twice daily.
  • These agents are more expensive than haloperidol, and cost can be a limiting factor.
  • They are most useful in patients in whom dementia is associated with parkinsonism (particularly Parkinson-dementia complex, diffuse Lewy body disease, and related disorders).

Acute psychotic crises require more aggressive (and sometimes inpatient) management. These crises often occur in the hospitalized patient with dementia.

• Initial doses of 5-10 mg of haloperidol parenterally are often necessary, with rapid tapering of the dose as the agitated psychosis abates.
• In a hospitalized patient, regularly scheduled doses are more effective than "as needed" doses.
• For example, rather than giving 5 mg of haloperidol intramuscularly for acute agitation, a maintenance dose of 1 mg twice a day orally may prevent such episodes.
• The course of acute agitation/psychosis is much more variable than that of chronic (and generally milder) psychosis, and psychiatric consultation is advisable if the initial measures are inadequate.

In patients with dementia who are undergoing scheduled surgery, initiation of a neuroleptic several days before the surgery may be helpful in reducing the incidence and severity of postoperative confusion and agitation. An example might be to begin haloperidol 1 mg bid 3 days before scheduled hip replacement in a patient with mild to moderately severe AD. If the patient does well postoperatively, the dose can be tapered.

Once a patient's behavior has improved in any of these circumstances, tapering and discontinuation of the neuroleptic should be considered.

Anxiety

Many patients with dementia are anxious, often clinging to their caregiver.

• Benzodiazepines, while often effective, have 2 potential drawbacks: They run the risk of causing paradoxical agitation and, even when effective, they are often sedating. They generally should not be considered first-line agents in this setting.
• Buspirone (BuSpar) generally is tolerated better than benzodiazepines and rarely causes paradoxical agitation, so it is a first-line agent in this setting. A typical starting dose in mild cases is 5 mg twice daily, with gradual titration of the dose according to symptoms and adverse effects (which are typically few).
• When anxiety is more severe, trazodone 50 mg at bedtime can be helpful, and in more severe cases, neuroleptic therapy may be necessary.

Depression

A comprehensive discussion of the pharmacotherapy of depression in the elderly and demented patient is beyond the scope of this article, but a few practical principles are worth mentioning.

• Tricyclic antidepressants should be avoided in the population of patients with dementia.
  • These agents are associated with a high incidence of increased confusion and daytime sedation related to the anticholinergic adverse effects. They should not be used as sleeping pills.
  • Much preferred in elderly patients with dementia are the selective serotonin reuptake inhibitors (SSRIs).
• Sertraline (Zoloft) is a good example of the SSRIs but is only one of several that can be considered in this context.
  • It has a neurochemically selective profile, is generally well tolerated and, in addition to its antidepressant effects, may have a mild antipsychotic effect as well.
  • Typical doses of sertraline range from 25-50 mg each morning.
• Paroxetine (Paxil) is another good choice (among others), generally in doses of 10-20 mg daily.

These medications are sometimes helpful even in nondepressed patients with dementia who have significant fatigue or abulia, 2 other common problems in this context (especially in the frontotemporal dementia syndromes).

Patients with severe depression should be referred for psychiatric consultation for more definitive and aggressive management.

Sleep Disturbances

The disturbed and reversed sleep-wake cycle is a notorious problem not only for the patient with dementia, but also for the caregiver. Restoration of the sleep-wake cycle is therefore of major importance. Short-acting sedative-hypnotic medications are preferred over long-acting agents to facilitate sleep onset and to avoid daytime somnolence. These agents include diphenhydramine (Benadryl), chloral hydrate, and zolpidem, and the newer drugs eszopiclone, zaleplon, and ramelteon.

• Diphenhydramine (25-50 mg at bedtime) is inexpensive, available without prescription, and has few adverse effects. Unfortunately, it is often ineffective, and thus many patients with significant sleep disorders require a stronger agent such as chloral hydrate or zolpidem.
• Chloral hydrate (500-1000 mg at bedtime) is an old medication, has few adverse effects, and is used by electroencephalography (EEG) laboratories to obtain sleep EEGs.
  • It has no effect on EEG patterns and is well tolerated, in addition to being relatively inexpensive.
  • Unfortunately, it is becoming more difficult to obtain as it is replaced by newer generation drugs like zolpidem.
• Zolpidem (5-10 mg at bedtime) has positive qualities similar to those of chloral hydrate, but it is more expensive than chloral hydrate. Zolpidem now is available in extended-release formulations (CR) to minimize nighttime awakenings. Zolpidem is FDA approved for short-term use.
• Like zolpidem, zaleplon is approved for short-term use to help with sleep onset.
• Eszopiclone has indication to help sleep onset and maintenance and longer-term use.
• Ramelteon works at the MT1 and MT2 receptors in the suprachiasmatic nucleus, which are involved in the sleep wake cycle. Additionally, it does not act on the GABA-benzodiazepine receptor complex. It has an FDA approval for longer-term use.
• Trazodone 50 mg at bedtime may help patients sleep through the night and may be given in conjunction with the shorter-acting sedative-hypnotic agents.

As in the treatment of any associated symptoms in elderly persons, drug interactions need to be considered because of the multiple medications that elderly persons may already be taking.

Associated Symptoms

Several problems are encountered frequently in the patient with dementia, either as a direct result of the dementing illness or as an unrelated problem.

• Incontinence
  • Pharmacotherapy consists of oxybutynin (Ditropan) or tolterodine (Detrol).
    • These are predominantly peripherally acting anticholinergic drugs, but they carry some risk of exacerbating confusion.
    • Small doses (eg, 2.5-5 mg oxybutynin bid, or 2 mg tolterodine bid) should be used if necessary, with careful monitoring and forewarning of caregivers.
  • Despite the small risk of increased confusion, both are generally well tolerated.
• Parkinsonism
  • Whether due to the underlying disease or a complication of neuroleptic therapy, parkinsonism is a common problem in the population of patients with dementia.
  • An important question to be considered is whether the parkinsonism is disabling to the patient.
  • The principle of therapy for parkinsonism is to increase dopamine levels in the brain. This is accomplished either by stopping dopaminergic antagonists (neuroleptics) or by administering a dopamine agonist (typically levodopa/carbidopa).
  • Increasing dopamine levels in the brain of a patient with dementia can cause or aggravate confusion and/or worsen hallucinations.
  • Hence, the only reason to treat parkinsonism is that it is disabling to the patient (particularly if associated with increased risk of falls, which can cause hip fracture).
  • If a medication change is made, it should be gradual, and the possibility of behavioral deterioration should be monitored.
  • In patients with parkinsonism due to their underlying disease, initial levodopa doses should be low (50 mg in the morning) and be titrated carefully upward according to symptoms and side effects.
  • Some diseases, including corticobasal ganglionic degeneration, small-vessel multi-infarct dementia, and progressive supranuclear palsy, are not responsive to levodopa (though an empirical therapeutic trial still may be reasonable in some patients).
  • Other Parkinson-dementia complex diseases such as Parkinson disease with dementia and diffuse Lewy body disease often are responsive to levodopa, but higher doses may increase confusion and hallucinations.
• Pain
  • Causes of pain in an elderly patient with or without dementia are innumerable and include vertebral compression fracture, low back pain, neck pain, and arthritis.
  • In the patient with dementia, pain can cause behavioral deterioration and should be considered in this context. The offending problem may not be clinically obvious, but treatment is warranted.
  • Acetaminophen, NSAIDs, and if necessary, propoxyphene are the most commonly used agents.
  • Severe pain from a serious problem, such as a hip fracture, must be treated more aggressively and may require narcotic analgesia.
  • Concomitant prophylactic neuroleptic use should be considered in this setting.
• Dysphagia
  • This is a common problem in the later stages of most neurodegenerative diseases, and generally it occurs earlier in those that impair motor function, such as those associated with parkinsonism or motor neuron disease.
  • A formal swallowing study is useful to determine if the patient is actually aspirating (ie, food and/or liquid getting into the windpipe and lungs).
  • Aspirating is a potentially serious situation that can be handled initially by altering the consistency of the food (ie, smaller pieces, mechanically soft food), changing the position of the patient when swallowing, and other swallowing strategies. Consultation with speech pathology and/or occupational therapy can be helpful in this situation.
  • If aspiration is severe, an invasive procedure may be required.
    • Feeding tubes (such as a nasogastric tube) are uncomfortable and temporary.
    • A percutaneous gastrostomy in a patient with an advanced degenerative brain disease is a more definitive step, but one that may not always be appropriate. Quality-of-life issues are of paramount importance in this context.
  • A different type of "swallowing disorder" occurs in some patients with frontotemporal dementia, who can swallow but hold the food in their mouth for long periods of time and may eventually swallow or spit it out.
    • This is not a true swallowing problem and does not jeopardize the airway, though it may interfere with nutrition.
    • It generally is handled best through behavioral measures rather than a feeding tube.
• Driving
  • Patients with clinically obvious visuospatial impairment occurring within the context of a degenerative brain disease should not drive. This may be particularly apparent in patients with progressive visual syndromes (also termed "the visual variant of Alzheimer disease" and "posterior cortical atrophy") or corticobasal ganglionic degeneration.
  • Driving within the context of clinically typical AD, in which visual cortices and visual function typically are preserved, is a more challenging, but very important, issue confronting the patient, family, and physician.
    • Caregiver surveys reveal that a significant proportion of patients with AD continue to drive despite driving difficulties.
    • Although one survey of moving violation and police accident reports from a state motor vehicle authority failed to disclose an increased number of reports for a sample of 143 licensed drivers with AD, this was thought to reflect the far fewer number of miles driven by the study patients than by the average driver due to the active intervention of family and physicians to reduce patient road exposure.
    • In contrast, multiple road test–based studies of driving skills in patients with AD uniformly report poorer driving safety records compared to age-matched controls, even in mild stages of AD.
    • These and more recent studies employing driving simulators have shown that neuropsychological measures of attention and spatial skills in particular correlate well with driving performance.
  • Roughly 50% of patients with AD do not stop driving for at least 3 years after initial diagnosis, yet 41-63% of patients with mild AD fail a road test.
  • Clearly, the spatially challenging task of driving represents a clinically important concern, even in the absence of obvious, severe visuospatial impairment in patients with AD.

Abrupt Decline

In a patient with a known slowly progressive degenerative dementia, sudden changes in cognitive, behavioral, or health status sometimes occur. Mental status is often a barometer of health in the patient with dementia, and abrupt changes necessitate searching for a superimposed problem. Treatment then is directed at the superimposed problem. Four categories of common superimposed problems are the following:

• Intercurrent illness
  • The most common intercurrent illnesses in all patients with dementia are infections, especially urinary tract infections and pneumonia.
  • Many other serious illnesses need to be considered, including subdural hematoma and stroke and nonneurological problems such as pulmonary embolism and myocardial infarction.
  • Essentially, any serious illness should be considered.
• Catastrophic reaction
  • Behavioral outbursts can be precipitated by sudden psychosocial stressors such as an unfamiliar environment (especially when traveling), crowds, and confrontation with others.
  • Disturbed sleep-wake cycles can lead to further deterioration in behavior.
  • Confusion is typically worse in the evening ("sundowning"), and if a patient is up much of the night, he or she may be even more confused the following day.
• Pain
  • As previously noted, patients with severe dementia who are unable to articulate their discomfort may exhibit a decline in their behavior, with agitation and combativeness, as the consequence of a painful condition.
  • Osteoporotic vertebral compression, pelvic, and even hip fractures are common in such a setting.
• Medications
  • Medication errors, side effects, and interactions are important causes of rapid behavioral decline. Patients with dementia should have their medication administration supervised because both missed doses and overdosage can occur.
  • Thyroid and diabetes medications, as well as psychotropic medications, commonly cause problems.
  • Sedative-hypnotics and benzodiazepines may cause paradoxical agitation rather than sedation owing to behavioral disinhibition, even when properly administered.
  • Neuroleptics cause parkinsonism in a dose-related fashion, which can be mild (eg, lethargy, drooling).
  • Patients with psychiatric disorders on long-term psychotropic medications (eg, lithium) can develop signs of toxicity at previously therapeutic doses and blood levels.

Summary

The syndrome of dementia is a multifaceted symptom complex, and no single medication adequately addresses all possible complications. A systematic analysis of each patient's clinical situation leads to an appropriately tailored treatment plan. This plan is influenced by the primary dementing illness as well as coexistent problems. The outline provided in this article is a framework to be adapted to the specific needs of the individual patient. It is not a comprehensive listing of all possible medications, but rather a deliberately abbreviated, practically oriented list of examples.

Finally, clinicians must remember that not all patients respond equally well to any one drug, and alternate strategies must be considered in patients in whom a recommended agent fails to help or has adverse side effects. Psychiatric consultation may be helpful in patients who are not responding to first-line pharmacotherapeutic efforts, but the neurologist must have a working plan to address the problems presented by this common neurological syndrome.