▶ The goal of the patient management problem is to understand the management of patients with Alzheimer's disease at various stages of disease progression and clinical disability.
▶ A 68-year-old woman is brought to your clinic by her husband because of memory problems. The patient has owned and managed her own retail shop for the past 30 years; however, her husband has noticed that she has had increasing difficulty remembering appointments, clients' orders, and even conversations with coworkers over the past year. She has recently asked her husband for help with some of the financial aspects of the business. He also describes a withdrawal from many long-standing social activities. For instance, the patient had previously been involved in fundraising for several major charities but declined participation this past year for unclear reasons. The patient's past health has been unremarkable.
A thorough history is necessary at this time. What questions are of particular relevance to your diagnosis and treatment plan?
|A1______||Family history of Alzheimer's disease (AD)|
|A2______||History of significant head injury|
|A3______||History of depression|
|A5______||Nonsteroidal anti-inflammatory drug and/or estrogen use|
|A6______||Detailed list of medications|
|A7______||Tempo of onset of difficulties|
|A8______||History of visual hallucinations|
|A9______||History of stroke|
The patient's general medical examination is normal.
To which of the following should you pay particular attention as you perform your neurologic examination?
|B1.______||Primary sensory examination|
|B2.______||Short-term verbal memory|
|B5.______||Presence of extrapyramidal signs|
|B9.______||Primary motor examination|
The patient's physical neurologic examination is normal; specifically, no lateralizing signs or extrapyramidal features are present. On mental status testing, the patient is not oriented to the exact date and demonstrates impaired short-term verbal memory. She has mild naming problems and difficulty with serial 7s and calculations. Visuospatial abilities are intact. There is no right-left confusion.
What laboratory testing is of particular relevance to your diagnosis and treatment plan?
|C1.______||CT scan or MRI of the brain|
|C2.______||Vitamin B12 level|
|C3.______||Thyroid function testing|
|C4.______||PET scan of the brain|
|C6.______||CSF Aβ and tau levels|
The patient's brain MRI is unremarkable except for some mild atrophy. Serum vitamin B12 levels and thyroid-function testing are normal. You feel that her clinical presentation is most consistent with AD.
What management interventions should you recommend once a diagnosis of AD has been made?
|D1.______||Immediately insist that the patient stop driving|
|D2.______||Initiate a cholinesterase inhibitor|
|D4.______||Suggest that the patient start vitamin E 2000 lU/d|
|D5.______||Start a neuroleptic medication|
|D6.______||Recommend financial counseling and an advanced directive|
The patient is seen at 3-month intervals and remains relatively stable over the next 12 to 18 months. Recently, she has begun to show significant disruption of her sleep-wake cycle. She is frequently awake during the night, dressing and undressing, pacing, talking to imaginary figures, and attempting to leave the house. The patient's spouse, her primary caregiver, appears exhausted.
Which management interventions should you now suggest?
|E1.______||Initiate trazodone at bedtime|
|E2.______||Consider an atypical neuroleptic such as quetiapine at bedtime|
|E3.______||Consider adult day care for the patient|
|E4.______||Recommend locks on doors|
|E5.______||Recommend a Safe Return® bracelet|
|E6.______||Recommend evaluation for depression in the caregiver|
|E7.______||Consider respite care and home health services|
|E8.______||Immediately discontinue the cholinesterase inhibitor and memantine|
A1. Family history of alzheimer's disease (AD) ?+1
Family history of AD is of great importance for a diagnosis of AD. With AD, a positive family history is the second major risk factor after age. Approximately 20% of patients with AD have one or more siblings or parents affected.
A2. History of significant head injury ?0
Head trauma has been suggested as a risk factor for AD, but studies are complicated by differences in reported series in the criteria applied to define significant previous head trauma. In addition, it has been suggested that individuals who carry the APOE ε4 allele do not recover as well from head trauma, so the head trauma may be a pseudomarker for APOE ε4 inheritance, itself an important risk factor for AD.
A3. History of depression ?+3
Depression frequently accompanies AD; however, it is also a very common disorder in older adults and an important treatable cause of cognitive dysfunction. This is useful information for management of this patient. If concerned that depression could be the cause of the patient's current difficulties, most clinicians would opt for early aggressive treatment with an antidepressant to see if there is a reversible component of this patient's cognitive dysfunction.
A4. Educational attainment ?+1
Increased education has been associated with reduced risk for AD or later onset of dementia. One hypothesis is that better-educated individuals have a cognitive reserve so that biological disease must progress further before the reserve is overcome and clinical symptoms develop. Educational attainment of the respondent can influence responses to mental status test items, and the clinician must make allowances for this in assessing patients with cognitive difficulties.
A5. Nonsteroidal anti-inflammatory drug (NSAID) and/or estrogen use ? 0
Several epidemiologic studies and very preliminary pilot trials had suggested that NSAID and estrogen use might prevent or delay progression in AD; however, the very large Women's Health Initiative Memory Study of estrogen in elderly women has shown that estrogen replacement may increase, rather than decrease, risk for AD. In addition, several large, double-blind, placebo-controlled trials have now reported no significant reduction in risk for AD with NSAIDs.
A6. Detailed list of medications ?+3
A number of drugs can have potential adverse effects on cognition with particular offenders, including anticholinergics, antihypertensives, antidepressants, anxiety drugs, antipsychotics, analgesics, and sedatives for sleep. Medications for bladder control are frequently responsible for cognitive changes and should not be overlooked.
A7. Tempo of onset of difficulties ?+5
AD characteristically has an insidious onset with slowly progressive worsening. Acute or subacute onset of disability, a more rapid course, or episodic changes along the course suggest possibilities of dementia etiology other than AD.
A8. History of visual hallucinations ?+1
Misidentifications (eg, child thought to be a spouse) and visual hallucinations are not uncommon in AD, especially as the disease progresses. However, visual hallucinations that are recurrent and well formed, are present early in the course of the illness, and do not diminish in later periods are suggestive of dementia with Lewy bodies.
A9. History of stroke ?+3
History of stroke suggests a vascular cause of, or at least a contributing factor to, the patient's dementia.
A10. Functional changes ?+5
Demonstration of functional impairment further supports a diagnosis of dementia in the setting of cognitive deficits. A skillfully taken history may reveal a change from a prior level of performance; for most patients, this information should be substantiated by an informant. In taking a history, changes in functional abilities such as preparing a balanced meal, playing games of skill (eg, bridge, other card games), pursuing previously enjoyed hobbies, filling out business forms (eg, insurance), handling financial records (eg, bills, checks, bank statements), and shopping alone are helpful in confirming the presence of new impairment.
B1. Primary sensory examination ? 0
The general physical neurologic examination, including primary sensory examination, is most often normal in AD.
B2. Short-term verbal memory ?+5
Memory loss is the cardinal and commonly presenting complaint in AD. Initially the patient has difficulty recalling new information, such as names or details of conversation, while remote memories are relatively preserved.
With progression, the memory loss in AD worsens to include remote memory.
B4. Cerebellar function ?+3
Presence of cerebellar findings such as abnormal eye movements, intention tremor, or ataxia should prompt the clinician to look for other etiologies for the patient's dementia.
B5. Presence of extrapyramidal signs ?+1
Extrapyramidal signs (masked facies, rigidity, bradykinesia) may be found in the moderate to severe stages of AD but, when present early, suggest the possibility of other dementing conditions, such as dementia with Lewy bodies. The clinician should also remember that a number of drugs (particularly neuroleptics) could cause extrapyramidal signs that may not resolve even after the offending agent has been removed.
Weakness or spasticity in an extremity suggests a vascular or space-occupying cause of the patient's dementia. Gait or balance impairment may also indicate Binswanger disease (a form of vascular dementia associated with multiple lacunar subcortical strokes), normal pressure hydrocephalus, or progressive supranuclear palsy. Extrapyramidal signs (masked facies, rigidity, bradykinesia) may be found in the moderate to severe stages of AD but, when present early, suggest the possibility of dementia with Lewy bodies.
Language is frequently normal early in AD, although reduced conversational output may be noted. As dementia progresses, many patients become more recognizably aphasic. Initially, this manifests as difficulty with naming and mild loss of fluency. Later, language becomes obviously nonfluent until, terminally, the patient may be reduced to a state of near mutism.
B8. Visuospatial abilities ?+1
Visuospatial impairment in AD results in symptoms such as misplacing objects or getting lost, difficulty with recognizing and drawing complex figures, and impaired driving. Significant visuospatial abilities, especially very early in the course of disease, suggest the possibility of dementia with Lewy bodies.
B9. Primary motor examination ?+3
Weakness or spasticity in an extremity suggests a vascular or space-occupying cause of the patient's dementia. Extrapyramidal signs (masked facies, rigidity, bradykinesia) may be found in the moderate to severe stages of AD but, when present early, suggest the possibility of dementia with Lewy bodies.
C1. CT scan or MRI of the brain ?+1
Although neuroimaging techniques such as CT and MRI are especially useful for excluding reversible and treatable causes of dementia (structural brain lesions such as tumors, subdural hematomas, and hydrocephalus), their use in making a positive diagnosis of AD is limited since the most prominent features—cortical atrophy and ventricular enlargement—are neither sensitive nor specific markers of AD and often accompany normal aging. Since most of the potentially reversible conditions requiring a neuroimaging procedure for diagnosis are large structural lesions, a noncontrast CT may suffice; small infarcts are clearly better visualized with MRI, however. Brain imaging may reveal changes that are not specific for AD, and the clinical significance of various findings, such as periventricular attenuation of the white matter and deep white matter changes, remains unclear.
C2. Vitamin B12 level ?+1
A serum vitamin B12 level is recommended as routine laboratory testing in the evaluation of a patient with dementia.
C3. Thyroid function testing ?+1
Thyroid function testing is recommended as a routine part of the laboratory evaluation in a patient with dementia.
C4. PET scan of the brain ? 0
A number of neuroimaging markers have been suggested for use in the diagnosis of AD, including the typical pattern of hypoperfusion or hypometabolism in temporoparietal cortex on PET imaging. Unfortunately, although many small series show highly effective discrimination of AD from control subjects, large pathologically validated clinical series are sparse, and significant overlap with normal aging continues to occur.
Recently, the importance of an individual's APOE gene status has received significant attention as an important genetic susceptibility risk factor for AD. The APOE ε4 allele is associated with both a high likelihood of developing AD and an earlier age of onset. The exact mechanism by which this occurs, and the utility of APOE genotyping for diagnostic purposes, remain unsettled. However, since up to 50% of patients with late-onset AD have no ε4 allele, genotyping is currently not recommended for predictive risk assessment except within specific research environments.
C6. CSF Aß and tau levels ?-1
Both Aβ1-42, the important constituent of the neuritic plaque, and tau protein, the principal component of the neurofibrillary tangle, can be measured in CSF and have been proposed as diagnostic markers for AD. There is general consensus that levels of Aβ1-42 are significantly decreased, and levels of tau and phospho-tau are significantly increased, in CSF of patients with AD compared with age-matched controls. It is unclear, however, whether CSF levels of Aβ1-42 are useful in patients with very mild AD. CSF tau, on the other hand, is significantly increased in patients with AD compared with normal controls; however, elevated CSF tau levels have also been detected in patients with other neurodegenerative diseases. As with Aβ, substantial overlaps exist between AD and normal aging. Combining these two measures does improve accuracy of diagnosis slightly, but it remains unclear whether CSF Aβ and tau measurements improve diagnostic accuracy over and above a competent clinical diagnosis. To date, the most conservative answer would probably be no.
C7. Neuropsychological testing ?+1
The outcome of the mental status examination should help guide requests for neuropsychological testing. Although not a routine part of the clinical evaluation, neuropsychological testing may show sufficient cognitive impairment to support a diagnosis of dementia in high-functioning individuals whose history and initial evaluation are borderline or suspicious. Neuropsychological testing may also aid in distinguishing depression from dementia or in determining competency for legal purposes and can assist in the evaluation of early dementia, particularly when major decisions need to be made with regard to a patient's job or other personal affairs.
D1. Immediately insist that the patient stop driving ?-1
Decisions regarding driving status for patients with dementia generally rest on the judgment of family members whose opinion is often at odds with the patient's perception of his or her driving skill (Wild and Cotrell, 2003). Physicians are encouraged to report patients who have conditions that may impair driving ability according to local laws. Patients with moderate and severe dementia should not drive (Dubinsky et al, 2000).
D2. Initiate a cholinesterase inhibitor ?+3
The most successful treatment strategy to date for AD has involved the use of the class of compounds known as cholinesterase inhibitors. These agents reduce the metabolism of acetylcholine, thereby prolonging its action at cholinergic synapses in the brain. Three cholinesterase inhibitors are currently marketed for the treatment of mild to moderate AD: donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon); donepezil (Aricept) has also recently been approved by the US Food and Drug Administration (USFDA) for the treatment of severe AD. As a class, these agents have demonstrated measurable, albeit modest, effects on cognition, behavior, activities of daily living, and global measures of functioning when compared with placebo in clinical trials (Doody et al, 2001). The primary side effects associated with treatment are gastrointestinal (eg, nausea, vomiting, diarrhea, anorexia, weight loss); insomnia, vivid dreams, and leg cramps have also been reported. In the absence of head-to-head comparisons of the cholinesterase inhibitors, the main differences appear to be their side effect profiles, titration schedules, and dosing regimens. The recent AAN practice parameter on the management of dementia concludes that cholinesterase inhibitors should be considered in patients with mild to moderate AD, although studies suggest only a small average degree of benefit (Doody et al, 2001).
Memantine belongs to a second class of drugs that work by antagonizing glutamate at the N-methyl-d-aspartate receptor, potentially improving signal transmission, and by preventing excess calcium influx into glutamate-stimulated neurons, thus providing neuroprotection. In patients with moderate- to severe-stage disease, memantine mildly improves cognitive deficits, functioning in activities of daily living, and behavior. Adverse effects with memantine are fewer than with the cholinesterase inhibitors, and one large, double-blind, placebo-controlled trial in patients on established donepezil suggested increased symptomatic benefits with the addition of memantine. Memantine is not currently recommended for use in milder-stage AD.
D4. Suggest that the patient start vitamin E 2000 IU/d ?-3
Vitamin E was previously found to delay functional deterioration, nursing home placement, and death by approximately 25% in moderate- to severe-stage patients with AD in a large, double-blind, placebo-controlled trial (Sano et al, 1997). A recent meta-analysis has suggested, however, at least theoretical risks concerning increased mortality with a 2000-IU vitamin E dose; thus, enthusiasm for use of vitamin E has considerably waned.
D5. Start a neuroleptic medication ?-5
Although many consider neuroleptic medications a mainstay in managing agitation in AD, others reserve their use for psychosis, since these agents may produce serious side effects, including parkinsonism, tardive dyskinesia, confusion, and falls. In fact, the USFDA recently issued a warning regarding higher mortality in association with the use of atypical antipsychotics in elderly patients with dementia. Thus, the need for these drugs for the treatment of behavioral disorders in patients with dementia should be clearly evident, which is not the case with this patient.
D6. Recommend financial counseling and an advanced directive ?+3
The patient and family should be instructed to begin discussions with regard to durable power of attorney, estate management, and advance directives, as well as appointment of surrogates for medical, financial, and legal decisions, soon after a diagnosis of AD in order to include the patient to the greatest possible extent.
E1. Initiate trazodone at bedtime ?+1
Insomnia and day-night sleep cycle disturbances are common in AD. Nonpharmacologic interventions should always be tried prior to pharmacologic ones to avoid problematic side effects. Interventions include sleep hygiene (regular sleep and waking times, limitation of daytime sleeping, avoidance of caffeine and evening fluid intake, and using a bed for sleep only), calming bedtime rituals, and daytime physical and mental activity. If ineffective, the insomnia and day-night sleep cycle disturbances may be responsive to trazodone (Desyrel), which should be used in as low a dose as possible (12.5 mg to 50.0 mg) and for the briefest period necessary to control symptoms.
E2. Consider an atypical neuroleptic such as quetiapine at bedtime ?+1
A sedating atypical neuroleptic such as quetiapine may be helpful for insomnia and day-night sleep cycle disturbances that are unresponsive to trazodone (Desyrel). Again, it should be used in as low a dose as possible and for the briefest period necessary to control symptoms. The USFDA recently issued a warning regarding higher mortality in association with the use of atypical antipsychotics in elderly patients with dementia. In analyses of 17 placebo-controlled studies of four drugs in this class, the rate of death for those elderly patients with dementia was about 1.6 to 1.7 times that of placebo. Thus, the need for these drugs for the treatment of behavioral disorders in patients with dementia should be continually reassessed.
E3. Consider adult day care for the patient ?+1
Evidence suggests that adult day care reduces levels of caregiver stress, improves the psychological well-being of caregivers, and provides a structured environment for patients that results in reduced behavioral symptoms. Many clinicians find that adult day care also decreases caregiver isolation by allowing caregivers to pursue their own interests while providing the patient with increased opportunities for social interaction.
E4. Recommend locks on doors ?+1
Many clinicians recommend a home visit by a physical or occupational therapist to evaluate home safety and offer suggestions for home modifications, including installing door locks, in-house alarms or bells, and safety gates.
E5. Recommend Safe Return bracelet ?+3
The hazard of wandering can be diminished with simple measures such as having the patient wear an identification bracelet at all times. The Alzheimer's Association Safe Return program is an identification, support, and enrollment service that provides assistance when a person with dementia becomes lost. Help is available 24 hours a day, 7 days a week (http://www.alz.org/Services/SafeReturn.asp).
E6. Recommend evaluation for depression in the caregiver ?+1
Patients with more than mild dementia usually have at least one caregiver who plays a vital role in disease management. Many clinicians routinely emphasize to family and caregivers that allowing themselves to become physically or mentally exhausted will render them unable to care for their loved one. Family caregivers of relatives with AD are at a high risk for clinical depression; therefore, many clinicians routinely direct caregivers to counseling, support groups, and medical care if necessary.
E7. Consider respite care and home health services ?+1
The treating physician should routinely direct caregivers to respite care and home health services, which are surprisingly underutilized by families caring for patients with dementia.
E8. Immediately discontinue the cholinesterase inhibitor and memantine ?-3
When to withdraw cholinesterase inhibitors and/or memantine is a topic of considerable interest to families and physicians. Withdrawing cholinesterase inhibitors abruptly may result in significant patient confusion and decline. A general principle is that withdrawal of these drugs should be considered when severely affected patients are no longer able to meaningfully interact with family or caregivers.