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12 - Central Nervous System Disorders |
337
Alzheimer Disease
AD is the most common type of dementia, occur-
ring in 60% to 80% of dementia diagnoses.
Definite risk factors identified for AD are age,
family history, head trauma, identified apolipo-
protein e-4 mutations/polymorphisms, and Down
syndrome. Early-onset cases of AD are usually
attributed to inherited genetic mutations, or in
the case of Down syndrome, an additional copy
of chromosome 21. Late-onset AD is associated
with polymorphism of the apolipoprotein e-4.
Protective factors, such as increased educa-
tional attainment or dietary antioxidant consump-
tion, may exist but have yet to be proved.
Multiple pathophysiologic theories are
proposed and guide investigational drug devel-
opment in AD. The cholinergic hypothesis
involves the loss of cholinergic neuronal activity
in the hippocampus and cortex. Currently avail-
able drug therapy with cholinesterase inhibitors
(CIs) supports this hypothesis. Another hypoth-
esis is the beta-amyloid hypothesis, which has
developed because the location of beta-amyloid
plaques, one of the hallmark features of AD
at autopsy, corresponds to cognitive deficits.
Tau proteins become hyperphosphorylated,
producing neurofibrillary tangles. Cytokines and
inflammatory mediators are elevated in the brains
of individuals with AD, giving rise to the inflam-
mation hypothesis. It is based on evidence that
neuronal injury gives rise to interleukin-1 produc-
tion, which in turn triggers a host of immune-
mediated responses and beta-amyloid protein
deposition. Other current theories consider mito-
chondrial function, glucose metabolism, and
brain injury.
6
A definitive diagnosis of AD is only given with
autopsy, where beta-amyloid plaques and neuro-
fibrillary tangles are found in the brain. More useful
in practice are the National Institute of Neurologic
and Communicative Disorders–developed criteria
for clinical diagnosis of probable AD:
• Core features: presence of significant
episodic memory impairment that is gradual
and progressive, confirmed with objective
neuropsychological testing
•
Supportive features:
– Presence of medial temporal lobe atrophy
on magnetic resonance imaging (MRI)
– Abnormal cerebrospinal fluid biomarkers
(low amyloid beta 1-42, high tau or
phosphor-tau concentrations)
– Reduced glucose metabolism on func-
tional positron emission tomography
(PET) neuroimaging
– Proven autosomal dominant AD mutation
•
Exclusion of:
– Other medical disorders, which account
for these symptoms
– A history of sudden onset, early occur-
rence of gait disturbances, seizures, or
behavioral changes
– Focal neurological features or early
extrapyramidal signs
7
The newer objective measures listed as
supportive features are being evaluated primarily
for research. The hope is that these objec-
tive biomarkers will test positive early on in the
disease process, allowing for the use of effec-
tive interventions for prevention or cure while the
disease is in a preclinical stage.
8
Frequently, a patient may have symptoms
of AD for several years prior to diagnosis, but
family, co-workers, and friends begin to take on
duties and responsibilities that the patient can
no longer handle. For example, the spouse may
take over paying bills and balancing the check-
book if the patient starts to make mistakes or
forgets to pay bills on time. The timeline after
diagnosis varies, but survival can range from
3 to 20 years, with a median of 4.2 years for
men and 5.7 years for women.
9
Some patients
have a rapid decline, losing 5 points or more
on the Mini-Mental State Examination (MMSE)
each year, while others lose fewer than 2
points per year. Whatever the initial progres-
sion rate, patients tend to continue with that
rate throughout the course of the disease. AD
is the fifth leading cause of death in the United
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| Fundamentals of Geriatric Pharmacotherapy
States, and the disease is probably a significant
contributor to deaths attributed to pneumonia,
sepsis, and trauma.
Vascular Dementia or Vascular Cognitive
Impairment
Multiple names are applied to cognitive impair-
ment related to vascular disease in the brain,
including vascular dementia, multi-infarct
dementia, Binswanger disease, lacunar state,
or vascular cognitive impairment.
10,11
Vascular
dementia is diagnosed when new-onset
dementia occurs within 3 months of a cerebro-
vascular accident. In many cases, the course of
vascular dementia follows a stair-step decline,
with specific cognitive or functional deficits
occurring that place the patient on a lower
plateau. However, silent infarctions may occur
and build until cognitive impairment is the first
symptom of disease. Because the location and
amount of tissue damage influence the cognitive
deficits, patients with vascular dementia have
differing clinical presentations. Small cerebro-
vascular infarcts less than 15 mm, called lacunar
infarcts, may or may not precipitate cognitive
changes, depending on where they occur in the
brain. AD can coexist with vascular dementia
as 77% of brain autopsies meeting criteria for
vascular dementia also had AD in the Florida
Brain Bank study.
12
The pathology of vascular
dementia involves evidence of cerebrovas-
cular disease and infarction in the white matter
of the brain. Diagnosis is frequently supported
with MRI or computed tomography (CT) scan,
which shows infarction coupled with evaluation
of vascular risk factors. Risk factors for vascular
dementia mirror those for stroke, heart disease,
and atherosclerosis.
Dementia with Lewy Bodies
DLB was originally felt to be a rare disease, but
with newer staining techniques for recognition
of cortical Lewy bodies (at autopsy) it is now
known to be the second or third most common
type of dementia, depending on the study. It
usually occurs in patients aged 75–80 years and
has many overlapping features with AD. In addi-
tion to dementia, to be diagnosed with DLB the
patient must have at least two of three features:
1.
Fluctuating cognition with pronounced vari-
ations in attention and alertness
2.
Recurrent detailed visual hallucinations
3. Spontaneous features of parkinsonism
13
To differentiate DLB from dementia of
advanced PD, the timing of dementia and
parkinsonian symptoms must be considered.
In DLB, the onset of dementia should occur
concurrently with the onset of parkinsonism
(within 12 months), whereas in dementia of
advanced PD the dementia occurs late in the
course after PD has been well established in
the individual.
Neuroleptic sensitivity is a secondary
feature that is suggestive of DLB and particularly
important in considering drug therapy, because
antipsychotic therapy may be considered for
a patient with visual hallucinations. Excessive
sensitivity to D2 receptor blocking agents is seen
and causes an increased morbidity and mortality
in about half of patients with DLB treated with
these agents. Patients with DLB exposed to
neuroleptics had significantly more sedation,
confusion, rigidity, and immobility. Mortality in
one retrospective study was 2.7 times that of
control patients.
14
The atypical antipsychotics
have been tried as an alternative, with mixed
results. Case reports indicate enhanced sensi-
tivity to adverse effects with clozapine, risperi-
done, olanzapine, and quetiapine, although
some small studies indicate a modest thera-
peutic response to olanzapine and quetiapine.
14
Small doses and close monitoring are indicated
if an atypical antipsychotic is prescribed for a
patient with DLB. In many cases, clinicians can
educate caregivers and patients that hallucina-
tions can remain untreated as long as they do
not cause unnecessary fear or safety concerns,
thereby preventing exposure to antipsychotic
agents in a patient with DLB.
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KEY POINT:
Sensitivity to dopamine
antagonists in patients with DLB occurs
within 2 weeks of initiation or dose increase.
Frontotemporal Dementia
Frontotemporal dementia (FTD) is supported
by atrophy of the prefrontal or anterior temporal
areas of the brain on MRI. Patients will present
with a decline in interpersonal conduct, with
socially inappropriate behaviors such as rude,
caustic, or sexually explicit remarks; loss of
empathy and emotional blunting; and decline
in personal hygiene. FTD has several subsets,
including a behavioral variant (Pick disease)
where behavior is a primary component and
memory is initially well maintained, semantic
aphasia where the meaning of familiar words is
lost but other memory unaffected, and progres
-
sive aphasia, which is diagnosed when a patient
presents with nonfluent spontaneous speech.
Patients who are early in progressive or semantic
aphasia will preserve social skills, but these break
down similar to behavioral variant FTD at later
disease stages as they progress to mutism. The
incidence of FTD is highest in the youngest old,
with usual onset occurring before age 60, and the
prevalence does not increase in the higher age
groups, as FTD often has a rapid progression.
15
Other Types of Dementia
Normal pressure hydrocephalus is a reversible
dementia caused by increased pressure in the
ventricles of the brain, although on spinal tap the
opening pressure is normal. Diagnosis is based
on a classic triad of dementia, gait disturbance,
and urinary incontinence. This etiology is impor-
tant to identify because surgical placement
of a ventriculoperitoneal shunt can potentially
reverse the progression of the disorder.
Creutzfeldt-Jakob disease is a rare cause of
dementia that develops over weeks to months,
with rapid progression to death over 1–2 years.
Characteristic findings on the electroencepha-
lography (EEG) and in the cerebrospinal fluid
(CSF) support it as a diagnosis, whether inher-
ited or infectious in etiology. Neurosyphilis is
another infectious cause of dementia. It occurs
10–20 years after a primary syphilis infection,
manifesting as dementia, anxiety, paranoia, and
mania. A positive reactive plasma reagin (RPR)
or fluorescent treponemal antibody absorp-
tion (FTA-Abs) test indicate prior syphilis infec-
tion and raise the possibility of neurosyphilis in
a patient with dementia. Positive testing of the
CSF is required for definitive diagnosis. Because
of its rare occurrence, current guidelines for
dementia assessment do not recommend these
tests in every patient presenting with dementia.
However, if a patient presents with a new episode
of psychosis along with dementia, screening
with FTA-Abs followed with lumbar puncture is
indicated in order to identify a potentially revers-
ible cause of dementia.
Summary of Standard Treatment of
Dementias
When MCI or dementia is diagnosed, comorbid
conditions should be addressed early in the
course of disease to limit their contribution to
functional declines. Elimination of unnecessary
medications should occur first, especially those
with any anticholinergic or benzodiazepine
properties. Retrospective studies have shown
an increase in progression of dementia when
patients with AD receive anticholinergic medica-
tions. In addition, the patient should be assessed
for depression and treated if it is present. Depres-
sion causes apathy and difficulty with concentra-
tion, which can augment cognitive impairment.
KEY POINT:
Up to one-third of
patients with AD will have concurrent
depression, and patients with depression
may present with memory loss. ese
overlaps complicate the clinical picture.
Cardiovascular risk factors should be
addressed, particularly for patients with AD or
vascular dementia, as several observational
studies indicate a more rapid decline may occur
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| Fundamentals of Geriatric Pharmacotherapy
when hypertension, hyperlipidemia, or diabetes
are not controlled.
16
Vision and hearing should
be assessed to ensure that communication can
be optimized for as long as possible. Finally,
exercise programs for both physical and cogni-
tive activities are recommended.
9
Social issues should be tackled with family,
friends, and caregivers. Patients should be
encouraged to prepare advanced care direc-
tives and durable power of attorney documents.
Wishes for long-term care may be discussed, as
the disease course is expected to reduce the
patient’s functional abilities over time until he or
she will require 24-hour care, 7 days a week.
Currently, the mainstays of pharmaco-
therapy for dementia are the CIs and memantine,
an NMDA receptor antagonist. Tacrine was the
first CI on the market in the United States, but
because of the risk for hepatotoxicity, it is no
longer used. The pharmacokinetic comparisons
of other agents are shown in Table 12-2. These
agents have a Food and Drug Administration
(FDA)–labeled indication for treatment of AD but
are frequently used off-label for other types of
dementia, some with evidence and some without.
AD is the most studied of the demen-
tias, and current treatment algorithms from the
American College of Physicians and the Amer-
ican Academy of Family Physicians distinguish
a pathway for patients with mild-to-moderate
as compared to moderate-to-severe AD. For
mild-to-moderate AD, first-line therapy is a CI,
to be titrated to the maximally tolerated dose
in the therapeutic range (see Table 12-3). No
clinical data place one CI above the other as
an initial choice. If ineffective or not tolerated, a
switch to another CI is suggested. If poor clin-
ical response is noted, addition or substitution of
memantine in patients with moderate AD is the next
Table 12-2. Pharmacology of Medications for Alzheimer Disease
Generic
Drug (Trade
Name)
Mechanism of
Action
Serum
Half-life
Protein
Binding
Food
Delays
Absorption Metabolism
Renal
Elimination
Cholinesterase Inhibitors
Donepezil
(Aricept)
Reversible and
noncompetitive
inhibition of
acetylcholine
(ACH)
70–80
hours
96% No CYP2D6, 3A4 17% as
unchanged
drug
Galantamine
(Razadyne)
Reversible and
competitive
inhibition of
ACH; modulates
nicotinic
acetylcholine
receptors
5–7 hours 10% to
20%
Yes CYP2D6, 3A4 20% to 32% as
unchanged
drug
Rivastigmine
(Exelon)
Reversible
inhibition of
both acetyl-
and butyryl-
cholinesterases
2 hours
(oral)
3 hours
(patch)
40% Yes (oral) Hydrolysis
in brain,
D-methylation
or sulfation in
liver
Insignificant
NMDA Receptor Antagonist
Memantine
(Namenda)
Prevents
overstimulation
of glutamate
receptors
to prevent
excitotoxicity of
neurons
60–80
hours
45% No Glucuronidation,
reduction,
hydrolysis
52% to 80% as
unchanged
drug
See reference 128 for additional information.
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341
step. In moderate-to-severe AD, the pathway allows
for a CI or memantine first-line, followed by combi-
nation therapy. Intolerance or loss of clinical benefit
is addressed by switching from one CI to another,
just as in the mild-to-moderate pathway. If there
is a treatment failure, loss of benefit or intolerance
after all three CIs and memantine have been tried,
withdrawal of either or both medications is recom-
mended for both algorithms. In essence, the current
pathways are equivalent except that memantine can
be tried first-line as monotherapy or as dual therapy
with a CI in moderate-to-severe disease.
17
Also marketed is caprylidene, a medium-
chain triglyceride that the body metabolizes to
ketone bodies. It is classified as a medical food for
AD. The potential mechanism of action is based on
the fact that the brain may have impaired glucose
metabolism and is better able to utilize ketone
bodies for energy. While short-term results support
its use, measures became nonsignificant at 12
weeks. Adverse effects include diarrhea, flatu-
lence, dyspepsia, dizziness, and headache.
18
It is
rarely used in practice.
Monitoring of erapy
Monitoring for effectiveness of both CIs and
memantine involves assessment from the
patient, caregiver, and physician. Generally,
effectiveness can be assessed after treatment
for 3 months using standard instruments such as
the MMSE, Clinician’s Interview-Based Impres-
sion of Change-Plus Caregiver Input, Activities of
Daily Living, and/or the Neuropsychiatric Inven-
tory Questionnaire, as described in Chapter 4.
17
Most commonly, CIs cause GI adverse
effects including nausea, vomiting, diarrhea,
and anorexia in 5% to 20% of patients due to
Table 12-3. Initiation and Titration of Drugs Used in Dementia
Drug Initial Dose
Titration
Schedule
Every
Recommended
Dose
Minimum
Therapeu-
tic Dose
Renal
Adjust-
ment Formulations
Donepezil 5 mg/day 4 weeks 10 mg/day 5 mg/day No 5- and 10-mg
tablets;
5- and 10-mg orally
disintegrating
tablets;
23-mg film-coated
tablet
Galantamine IR 4 mg 2×/day 4 weeks 8–12 mg 2×/day 8 mg 2×/day Yes 4-, 8-, and 12-mg
tablets;
4 mg/mL solution
Galantamine ER 8 mg/day 4 weeks 24 mg/day 16 mg/day Yes 8-, 12-, and 24-mg
capsules
Rivastigmine 1.5 mg 2×/day 4 weeks 6 mg 2×/day 3 mg 2×/day No 1.5-, 3-, 4.5-, and
6-mg capsules;
2 mg/mL solution
Rivastigmine
transdermal
4.6 mg/day 4 weeks 9.5–13.3 mg/day 9.5 mg/day No 4.6-, 9.5-, and
13.3-mg patches
Memantine IR 5 mg/day 1 week 10 mg 2×/day 10 mg/day Ye s 5- and 10-mg
tablets;
2-mg/mL solution
Memantine XR 7 mg/day 1 week 28 mg/day 28 mg/day Ye s 7-, 14-, 21-, and
28-mg capsules
See reference 128 for additional information.
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| Fundamentals of Geriatric Pharmacotherapy
the increased peripheral cholinergic stimula-
tion. This pharmacologic effect can also cause
incontinence and bradycardia. Dizziness and
insomnia have been reported frequently. Once-
daily CIs are generally started at bedtime, to
reduce patient complaints of GI side effects;
however, if insomnia occurs, doses can be given
in the morning. If more than 2–3 days therapy
of a CI is missed, the drug should be retitrated
from the initial dose, to avoid increased adverse
effects. The Beers criteria list CIs as contraindi-
cated in patients with syncope. In one observa-
tional study, patients on CIs were hospitalized for
syncope almost twice as often as patients with
dementia not receiving a CI. Additionally, there
was an increase in bradycardia, pacemaker
placement, and risk for hip fracture.
18
Memantine is generally well tolerated with
dizziness, headache, constipation, and somno-
lence reported more frequently than in placebo-
treated subjects.
19
Other reported adverse
effects, such as agitation, falls, and accidental
injuries, did not occur more often in the meman-
tine-treated patients, although they were impor-
tant issues in this patient group.
Pharmacotherapy of Other Dementias
Less is known about optimal pharmacotherapy
of other dementias. Generally, the medications
used to treat AD may be tried, and patients are
assessed for clinical response within a similar
timeframe as with AD. One exception is FTD,
which rarely responds to CIs. In fact, one study
indicates these agents may aggravate behav-
ioral problems in FTD patients.
15
Review of Evidence Base
Supporting Treatment
Recommendations for Elderly
Patients
As dementia is a syndrome found primarily in
older adults, all studies have included geri-
atric patients. Several reviews and meta-anal-
yses have been published to summarize the
evidence for effectiveness and safety of the
CIs and memantine in treatment of dementia
and MCI.
20-22
For AD, effectiveness data agree
across most studies and all meta-analyses that
cognition, function, and behavior are improved
with CIs, although debate continues as to
whether the statistical significance translates to
clinically important differences. At least 26 well-
by one author, and 59 studies including over
16,000 subjects in CIs and/or memantine for
dementia or MCI by another.
20,22
The beneficial
effect is modest at best, and a subgroup of indi-
viduals appears to have clinical benefit. Similar
conclusions were drawn in the evidence review
that included AD along with other dementias,
although the numbers of subjects were much
smaller in the non-AD studies. Although some
pharmacologic differences are seen in the
CIs, no clinical differences are seen with thera-
peutic or adverse effects when the agents are
compared; therefore, no currently available CI is
preferred for initial treatment over another.
A higher dose of donepezil was approved for
individuals with AD who do not receive adequate
response from lower doses of the CIs after at
least 3 months of treatment. The 23-mg tablet is
film-coated with a time to peak at 8 hours instead
of 3–4 hours. However, controversy exists as to
the risk-benefit ratio of the higher dose. Subjects
receiving donepezil 23 mg experienced nearly
a two- to threefold higher frequency of adverse
events, with 30% of patients discontinuing treat-
ment early. Small statistical improvement was
shown in cognition, but global benefit was not
shown except in subgroup analysis of U.S.
subjects. A U.S. consumer advocacy group has
called for removal of the 23-mg tablet from the
market.
18,23
Similarly, evidence for the effectiveness of
memantine in dementia shows statistically signif-
icant improvement in cognition, function, and
reduction in caregiver burden, although clinical
significance is not as clear. Withdrawal rates are
similar for both treatment and placebo groups, at
7% to 13%. Evidence supports use in moderate-
to-severe AD; however, no benefit has been
shown in patients with mild disease. Information
published on use of memantine in DLB report
mixed results. In one report, delusions, halluci-
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nations, agitation, and parkinsonism worsened in
some patients.
14
However, in another report DLB
hallucinations emerged with memantine dechal-
lenge and resolved with memantine rechal-
lenge.
24
Randomized, controlled trials have been
small and tended to include both patients with
DLB and patients with dementia of advanced
PD, making it difficult to draw conclusions.
The combination of a CI and memantine is
recommended in clinical practice guidelines for
moderate-to-severe AD and is frequently tried for
patients who continue to deteriorate. Few studies
have been done with the combination; donepezil
in combination with memantine has shown statis-
tically significant improvements in measures
designed for severe dementia assessment.
25,26
A
trial that allowed any CI for maintenance did not
show significant change when memantine was
added.
27
Three randomized, controlled trials evalu-
ated over 3,500 subjects with MCI for the effect
of CIs on progression to dementia.
21
Dropout
rates were high, 40% in treatment groups and
29% in placebo groups, but the risk for progres-
sion to dementia or AD was reduced 25% in
treated subjects compared to control subjects.
One study noted this positive effect to occur
predominantly in subjects who were carriers of
the apolipoprotein ε-4 genotype.
Only one controlled study with a CI in DLB
has been performed and indicates benefit with
reduction of apathy, anxiety, delusions, and hallu-
cinations.
28
Open-label studies of the use of CIs
and memantine in FTD show no benefit or wors-
ening of disease. Small controlled trials of certain
selective serotonin reuptake inhibitors (SSRIs) to
reduce certain behaviors are promising.
15
Common Problems Encountered
When Treating Elderly Patients
Neuropsychiatric Symptoms
Although cognitive decline is the hallmark feature
of dementia, neuropsychiatric (NP) symptoms
typically cause the most anxiety and stress for
patients and caregivers. They include delusions,
hallucinations, repetitive activities, sleep distur-
bances, and mood changes. These symptoms
are frequently called behavior problems in that
they precipitate agitation, physical aggression,
psychosis, and wandering—behaviors that
cause problems with caregiving. However, the
better term refers to them as symptoms rather
than problems because they frequently result
from an undiagnosed underlying issue, which
the patient with dementia cannot communicate
effectively to caregivers in order to achieve a
resolution.
29
NP symptoms generally manifest as the
disease progresses into a moderate-to-severe
stage when the patient is partially functional but
has begun to lose the ability to perceive and
communicate effectively. Nursing home admis-
sion becomes likely as caregivers are unable
to provide the amount of care needed. When
the dementia progresses to the end stage, the
patient’s functional status will have diminished
such that he or she is unable to interact with others
or the environment and becomes bedbound. NP
symptoms are no longer discernible.
When new NP symptoms develop, the first
step is to assess the patient for a medical or envi-
ronmental precipitant that can be corrected. For
example, a patient with moderate-stage AD who
starts wandering at night should be evaluated
for changes in caffeine intake, new medications,
excess heat in the bedroom, or strange noises at
night. Any of these items could cause the patient
to have sleep problems that he or she could not
communicate effectively to caregivers. Pain is a
common medical precipitant to NP symptoms
and should always be considered.
Evidence supports the use of nonpharmaco-
logic treatments for NP symptoms, although the
treatments are widely varied. Person-centered
bathing, where the patient was kept covered
at all times during the bath, showed significant
reduction in agitation compared to standard
bathing procedures. Use of lavender oil, lemon
balm, and pet and music therapy has likewise
shown reduction in agitation. Exercise training
coupled with caregiver education reduced
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| Fundamentals of Geriatric Pharmacotherapy
depression and improved functional status in a
randomized controlled trial.
9,29
Medications are frequently used when
nonpharmacologic interventions fail or are
impractical. Generally, a patient should be evalu-
ated to determine whether only acute, as-needed
medication is required or chronic/maintenance
treatments are necessary. Benzodiazepines
and antipsychotics are most commonly used
when acute rescue medication is needed, and
CIs, memantine, SSRIs, or atypical antipsychotic
agents are more often prescribed for mainte-
nance medications, as described below.
CIs and/or memantine may be tried if the
patient is not already being treated with these
agents. However, evidence to support their
effectiveness is meager. In DLB, it is especially
useful to try CIs first, as increased sensitivity to
adverse effects of other agents is likely. Certain
SSRIs may be effective if anxiety is present,
although it may be difficult to objectively assess
the presence of anxiety, making assessment of
their benefit challenging. However, withdrawal
of any psychoactive may be attempted after 3–6
months, as these symptoms do not consistently
persist as the disease progresses. Valproic acid
at a dose of 125–500 mg daily may be tried for
symptoms of agitation and aggression, sleep-
wake disruption, and disinhibition (manic-like
behaviors), although evidence of effectiveness
is also sparse.
Antipsychotics are frequently the drugs of
choice for psychosis, psychomotor agitation, and
aggression in patients with dementia. Evidence
of effectiveness is not strong, and concerns
over an increased risk for mortality in elderly
patients with dementia when these medications
are used have forced manufacturers to include a
boxed warning on both typical and atypical anti-
psychotics. A multicenter randomized controlled
clinical trial compared risperidone, olanzapine,
and quetiapine to placebo in treatment of
psychosis, aggression, and agitation in nursing
home residents with AD. The primary outcome
of interest was time until discontinuation of treat-
ment for either lack of effectiveness or adverse
effects. No difference was seen with discontinu-
ation occurring from 5–8 weeks after initiation
of the antipsychotic or placebo, although the
reason for discontinuation was lack of effective-
ness for the placebo group compared to pres-
ence of significant adverse events in the anti-
psychotic groups. Improvement was seen in
21% of placebo-treated subjects and 26% to
32% of antipsychotic-treated subjects.
30
The Agency for Healthcare Research and
Quality has published a summary on the use
of atypical antipsychotic agents for off-label
indications. It states that although atypical anti-
psychotics improve behavioral symptoms of
dementia, effect sizes are small and adverse
effects are significant. It lists the risk of death at 1
for every 100 patients treated. In addition, risper-
idone and olanzapine are noted to increase the
risk of stroke.
31
Quality improvement initiatives
aimed at reducing the use of antipsychotics
in nursing home patients have been imple-
mented by the Centers for Medicare & Medicaid
Services, resulting in the national prevalence
rate dropping from 23.8% to 10.2%.
32
Continued
efforts are needed to ensure antipsychotic use
is limited to patients in whom the benefits clearly
outweigh the risks, appropriate monitoring with a
validated tool occurs, and periodic dose reduc-
tions are attempted.
D
Etiology, Epidemiology, and
Clinical Presentation Specic to
Geriatrics
Denition
Delirium can be confused with dementia because
both disorders are characterized by altered
cognition and memory impairment. The patient
with delirium may develop confusion, distract-
ibility, disorientation, disordered thinking, hallu-
cinations, and agitation all within hours or days.
The hyperactive, agitated subtype of delirium is
most recognized and concerning to the clinician,
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as frequently the patient is pulling out catheters,
intravenous lines, or other tubes and may be a
danger to him- or herself or others. However,
patients experiencing a hypoactive delirium are
subdued and quiet, unable to interact with their
surroundings. A third type of delirium is mixed,
with the patient switching between hyperactive
and hypoactive states.
33
The DSM-5 states that delirium is a distur-
bance in attention and awareness, developing
over hours to days, with fluctuation over the
course of the day. In delirium, the patient has
a reduced ability to focus or shift attention and
is unaware of the environment. Memory impair-
ment and disorientation are identified when the
patient is questioned. Sensory impairment is also
seen, as the patient may confuse loud noises
with gunshots, misinterpret television programs
as a party occurring in the room, or have the
inability to interact appropriately with objects at
the bedside.
1
Delirium has a highly variable course.
Studies indicate from 20% to 69% of patients
recover from delirium within 1 day; however,
as many as 15% may have symptoms lasting
10 days or more.
34
Individuals with advanced
age or pre-existing dementia are likely to have
a more prolonged course, as will those with
multiple contributing causes. Therefore, delirium
is considered a syndrome of the elderly.
Epidemiology and Pathophysiology
Delirium has been reported in 29% to 64% of
hospitalized older adults, with an incidence as
high as 82% of patients in intensive care.
35
One
study of postoperative patients identified delirium
occurring within 7 days after surgery in 44% of
subjects.
36
Within the geriatric nursing home
population, the overall occurrence of delirium is
as high as 36%.
33
Recognizing delirium is impor-
tant, because it is associated with an increase
in mortality at 30 days and 6 months, reportedly
as high as 76% in one study. Morbidity is also
higher in patients with delirium, evidenced by
longer hospital stays, increased time in the inten-
sive care unit, pneumonias, and pressure sores.
Finally, costs increase when delirium is present.
Several pathophysiologic theories have
been proposed; however, neurotransmitter
disruption particularly of acetylcholine and
dopamine are most supported. Inflammation,
metabolic disorders, or electrolyte disturbances
may also play major roles.
35
Numerous risk factors for delirium have been
identified. Many medical and surgical conditions
can precipitate delirium, but increased age and
the presence of dementia are clearly associated
with an increase in the risk for delirium. Postoper-
ative delirium increased from 22% for age 50–59
years to 92% in patients over 80.
36
Individuals
with pre-existing brain pathology lack sufficient
cognitive reserve to balance a sudden alteration
in neurotransmitters.
Medications have been implicated as a
cause in 30% of delirium cases. Any medication
that has central nervous system (CNS) effects
can cause delirium and confusion, especially
anticholinergic agents, analgesics, sedative/
hypnotics, antimicrobial agents, muscle relax-
ants, corticosteroids, anticonvulsants, antidia-
betic drugs, and GI agents. In addition, abrupt
discontinuation of alcohol or depressant medi-
cations may cause delirium as part of the with-
drawal syndrome.
Clinical Presentation
Delirium is frequently overlooked by clinicians,
especially if the patient exhibits hypoactive
symptoms. The criteria for diagnosis from the
DSM-5 have been adapted into several screening
tools. The Confusion Assessment Method is one
simple tool that has been validated in multiple
populations and can be applied by any health-
care provider to identify the patient likely to have
delirium (see Table 12-4).
37
Generally, features
are assessed by asking a series of questions to
a family member, friend, or nurse who has spent
time with the patient and knows the patient’s
baseline cognitive status. For delirium to be
present, the patient must have features 1 and 2
and either feature 3 or 4.
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Delirium should be distinguished from
dementia, as both of these may cause a patient
to be unable to correctly answer questions
about orientation; however, delirium has the
contrasting features of inattention, acute onset,
and fluctuation in alertness or consciousness.
Patients with dementia will have a slow onset
of symptoms and are alert. Because of the high
mortality and morbidity attributed to delirium,
any complaint from a family member or nurse
that “the patient is not himself/herself” should be
investigated in spite of the nonspecific nature of
the observation.
Summary of Standard Treatment of
Delirium
Preventive Strategies
Interventions have been proven to reduce the
incidence of delirium in elderly hospitalized
patients. In a multicomponent model for hospital-
ized elderly patients, delirium episodes occurred
in 9.9% of the intervention group, compared
to 15% of the control group.
38
Interventions
included an orientation protocol, cognitive stimu-
lation, environment control, nonpharmacologic
sleep aids, early mobilization, minimization of
physical restraints, visual and hearing aids for
those with impairment, dentures for those without
teeth, other personal effects, and early volume
repletion for patients with dehydration. This
intervention has been successfully replicated in
other institutions.
39,40
Similar interventions can be
adapted for use in nursing home and home care
patients to reduce the risk of delirium. Volunteers
may be recruited to provide added nonpharma-
cologic support when friends, family, or nursing
staff are not available.
Recommended pharmacologic consider-
ations to prevent delirium include continuation
of medications that may cause withdrawal symp-
toms if abruptly stopped and avoiding medica-
tions with a high potential for causing delirium,
if possible. Also, adequate pain management,
Table 12-4. Confusion Assessment Method
Feature
Description (Ask Family Member or Nurse
the Following Questions) Requirement
1. Acute onset and
fluctuating course
Is there evidence of an acute change in mental status
from the patient’s baseline?
Did the abnormal behavior fluctuate during the
day, that is tend to come and go, or increase and
decrease in severity?
Must be present
2. Inattention Did the patient have difficulty focusing attention? (For
example, was the patient easily distractible?)
Did the patient have difficulty keeping track of what
was being said?
Must be present
3. Disorganized thinking Was the patient’s thinking disorganized or incoherent,
such as rambling or irrelevant conversation, unclear
or illogical flow of ideas, or unpredictable switching
from subject to subject?
If absent, Feature 4
must be present
4. Altered level of
consciousness
How would you rate this patient’s level of
consciousness?
Alert (normal)
Vigilant (hyperalert)
Lethargic (drowsy, easily aroused)
Stupor (difficult to arouse)
Coma (unarousable)
If absent,
Feature 3
must be present
Source: Information compiled from reference 37.
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