Table of Contents
I. Diagnostic
Approach to Dementia
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A. To make the diagnosis, the
clinician must document evidence of intellectual and practical
functional decline in:
1. cognitive function
a. demonstrable decline in short and long
term memory and in at least one other area of cognitive function
(attention, abstraction, language, praxis, visual-spatial relationships,
judgment, and calculations) or personality changes. This article
explores these in greater details later.
b. I suggest the use of a standard assessment
tool such as the mini-mental state exam (MMSE). Table 1 -- Mini-mental
state exam (MMSE)
c. The MMSE must be correlated with the
patient's educational level Table 2 -- Accuracy of the MMSE for detecting
dementia
2. work, social, and interpersonal function
a. demonstrable decline and/or interference
with work, social and interpersonal activities, or with the ability
to function within society.
b. I suggest the use of a standard assessment
tool, to document decline in activities of daily living (ADL's)
such as dressing, feeding, and toileting. Table 3 -- Activities of
daily living (ADL's)
c. I suggest the use of a standard assessment
tool, to document decline in instrumental activities of daily
living (IADL's) such as handling money or using the telephone.
Table
4 -- Instrumental activities of daily living (IADL's)
3. demonstration that the decline in these
spheres is not part of a delirium, acute confusional state, and
cannot be accounted for by psychiatric illness.
B. Comprehensive patient evaluation includes:
1. a complete medical history and physical
examination
2. neurological and mental status assessments
3. ancillary tests: blood and urine, electrocardiogram,
electroencephalogram (EEG), lumbar puncture, imaging exam (CT
or MRI), and brain biopsy.
C. Indications for Testing
1. In all cases, I believe it is incumbent
upon clinicians to support their clinical evaluation with some
testing that both supports the diagnosis and attempts to uncover
treatable or co-morbid conditions affecting the patient's dementia.
The following sections discuss several relevant testing possibilities
and a proposed suggestion for their indications:
2. EEG
a. clinical history suggesting a seizure
disorder (including fluctuating levels of consciousness or transient
brief episodes of behavior change)
b. suspicion of Cruetzfeldt-Jakob disease
(CJD) based upon a history of rapid decline in cognitive function
over 3 months or less, or ataxia, chorea, myoclonus early in
the course of dementia and any extrapyramidal or cerebellar features
that are not attributable to some other diagnosis.
c. pseudodementia of depression
3. Imaging Study
a. duration of cognitive complaints less
than 6 months
b. symptom onset before the age of 60
c. focal signs, focal symptoms, or papilledema
d. diagnosis of a seizure by history, or
usual gait abnormalities (e.g.. ataxia or apraxic gait)
4. Lab Work
a. CBC, electrolytes and calcium, renal
function, VDRL (if positive, order FTA-ABS), Thyroid function
studies, B12 level, level of oxygenation.
b. Consider HIV testing, drug screening,
toxin screen, collagen-vascular studies, general biochemical
screens
5. Lumbar Puncture
a. cognitive symptoms less than 1 month
b. history of connective tissue disease
c. immunosuppression
d. CNS infection suspected
e. FTA-ABS positive
f. diagnosis of meningeal spread of neoplasm
g. dementia onset in person less than 55
years old.
h. diagnosis of normal pressure hydrocephalus
6. Brain biopsy
a. I suggest that the clinician respectively
remember that any clinical diagnosis of dementia should be considered
as possible or probable, rather than definite.
b. definite diagnosis of a specific cause
requires confirmation by tissue diagnosis either by biopsy or
examination of brain tissue at autopsy.
II. Clinical
Features of Dementia
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A. Dementia is characterized primarily
by a gradual onset of progressive symptoms, including:
1. memory loss and changes in personality
2. noticeable decline in cognitive abilities
(including speech and understanding)
3. loss of decision-making function
4. impairment of activities of daily living
(dressing, eating, toileting, etc.)
B. DSM-IV (Diagnostic and Statistical
Manual of Mental Disorder) diagnosis of dementia requires:
1. memory impairment
2. at least one of the following: aphasia,
apraxia, agnosia, or disturbance in decision-making functioning
3. impairment of social or occupational
function
4. diagnosis should not be made during
the course of a delirium.
a. delirium diagnosis requires the acute
onset of decline in level of consciousness
b. cognitive impairment is generally proportional
to degree of disorientation and the disturbance in attention.
c. perceptual disturbances are frequent
and include hallucinations
d. diagnosis is usually attributed to an
identifiable toxic/metabolic insult, hence it's name, "acute
toxic/metabolic encephalopathy."
C. Early Signs of Possible Dementia
Memory loss that affects home or job
skills
All of us occasionally forget an assignment,
deadline, colleague's name, or how to do something at home. More
frequent forgetfulness or unexplainable confusion at home or
in the workplace may signal that something's wrong.
Difficulty performing familiar tasks
All of us occasionally get distracted and
leave something on the stove too long or don't remember to serve
part of a meal. People with dementia might prepare a meal and
not only forget to serve it but also forget they made it.
Problems with language
Everyone can have occasional trouble finding
the right word. People with dementia may forget simple words
or substitute inappropriate words, making their sentences difficult
to understand.
Disorientation to time and place
Occasional momentary forgetting of the
day of the week or what you need from the store is normal. People
with dementia can become lost on their own street, not knowing
where they are, how they got there, or how to get back home.
Poor or decreased judgment
Choosing not to bring a sweater or coat
along on a chilly night is common. People with dementia, however,
may dress inappropriately in more noticeable ways, wearing a
bathrobe to the store or several blouses on a hot day.
Problems with complex and abstract tasks
Balancing a checkbook can be challenging
for many people. People with dementia may find recognizing numbers
or performing basic calculation to be impossible.
Misplacing things
Everyone temporarily misplaces a wallet
or keys from time to time. People with dementia may put these
and other items in inappropriate places — such as an iron
in the freezer or a wristwatch in the sugar bowl — and then
not recall how they got there.
Changes in mood or behavior
All of us experience a broad range of emotions.
People with dementia tend to exhibit more rapid mood swings for
no apparent reason.
Changes in personality
Personality may change as people age. People
with dementia often exhibit dramatic, either sudden or over a
period of time, personality changes. For example, someone who
is generally easygoing may become angry, suspicious, or fearful.
Loss of initiative
All of us normally tire of housework, business
activities, or social obligations and most people retain or eventually
regain their interest over time. People with dementia may remain
uninterested and uninvolved in many or all of their usual pursuits.
III. Differential
Diagnosis of Dementia
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A. Introduction
1. The first responsibility of the clinician
is to identify potentially reversible causes of dementia.
a. Studies in the US indicate that 13%
of all dementias are potentially reversible. This percent is
higher in inpatient and tertiary referral centers.
b. Clearly age of onset is a very important
consideration. Treatable causes of dementia occur in 21% of
those under 65 and 5% of those over 65%.
c. Unfortunately, even in the potentially
treatable group of illnesses, response rate is not 100%. In the
largest composite study, where the incidence was 13% (see
above), 3% demonstrated complete recovery and 8%
show partial recovery, leaving 2% with no response.
d. Greatest chance for complete recovery
occurs in patients suffering from depression, metabolic abnormalities
such as hypothyroidism, and drug toxicity.
e. Table 5 --Frequency of dementia causes from
32 studies
f. Table 6 -- Potentially reversible causes
of dementia
2. The second responsibility of the clinician
is to identify coexisting medical conditions which may worsen
the dementia. We call this "co-morbidity."
a. Undetected or untreated comorbid conditions
may exacerbate an already existing cognitive impairment.
b. The most common comorbid conditions
affecting demented patients are: Parkinson's disease, depression,
infections (particularly urinary tract, congestive heart failure,
and chronic obstructive pulmonary disease.
3. For more on this, see Image 1 -- Algorithm
for the differential diagnosis in the evaluation of dementia
B. Alzheimer's disease
1. Alzheimer's is the most common cause
of dementia in the US (50-60%). 4 million Americans have Alzheimer's.
One in 10 persons over 65, and nearly half of those over 85 have
Alzheimer's disease.
2. A person with Alzheimer's lives an average
of 8 years and as many as 20 years or more from the onset of
symptoms.
3. Alzheimer's disease (AD) is progressive,
resulting in impairment in cognitive function. The clinical symptoms
associated with this disease include memory loss, language disorders,
visual-spatial impairment, and behavioral disturbances. AD may
present with a variety of symptoms, but difficulties with memory
are common to all.4.
4. For a diagnosis of probable AD, the
criteria are:
a. dementia established by examination
and objective testing
b. deficits in two or more cognitive areas
c. progressive worsening of memory and
other cognitive functions
d. no disturbance in consciousness
e. onset between ages 40 and 90.
f. absence of systemic disorders or other
brain diseases, which could account for the deficits in memory
and cognition
5. Neuropathology
a. The classic findings are neurofibrillary
tangles and neuritic plaques.
b. However, there
are no universally accepted set of quantitative criteria for
pathological diagnosis.
6. Genetic testing
a. Early-onset familial Alzheimer's disease:
three genes associated with this form of the disease: presenilin
1 (PS1) on chromosome 14, presenilin 2 (PS2) on chromosome 1,
and amyloid precursor protein (APP) on chromosome 21. These mutations
are relatively rare. Only 120 families worldwide are currently
known to carry these mutations.
b. Late-onset and sporadic Alzheimer's
disease: detecting an e4 allele of the APOE gene on chromosome
19 can add confidence to the clinical diagnosis. APOE testing
is only appropriate after clinical evaluation yields a likely
diagnosis of Alzheimer's. APOE testing cannot be used as a sole
diagnostic test and is not appropriate for asymptomatic individuals.
c. Tests of cerebrospinal fluid for abnormal
levels of indicator proteins — Ab42 and tau — come
closest to fulfilling the criteria for a useful biomarker.
C. Vascular dementia
1. Vascular dementia (VaD) may arise as
a sequel to any form of cerebrovascular disease. VaD is responsible
for approximately 20 percent of dementia cases.
2. As a co-morbid condition, VaD may worsen
the dementia of Alzheimer's disease.
3. Diagnosis of probable vascular dementia
is supported from the following criteria:
a. sudden onset of dysfunction in one or
more cognitive domains
b. stepwise deteriorating course
c. presence of focal signs on neurologic
examination such as: hemiparesis, facial weakness, Babinski sign,
sensory deficit, or hemianopia.
d. history of previous strokes
e. evidence of stroke risk factors and
of systemic vascular disease.
f. evidence of relevant CVD by brain imaging,
including multiple large-vessel infarcts or a single strategically
placed infarct (angular gyrus, thalamus, basal forebrain), as
well as multiple basal ganglia and white matter lacunes or extensive
periventricular white matter lesions, or combinations of these.
g. Other criteria include any combination
of onset of dementia within three months following a recognized
stroke; abrupt deterioration in cognitive functions; or fluctuating,
stepwise progression of cognitive deficits
4. Table 7 -- Hachinski ischemic index is probably the most widely used set of criteria
for vascular dementia. The scale is easy to apply in clinical
practice and has reliably distinguished between possible atherosclerotic
causes of dementia and Alzheimer's disease.
D. Medication-induced dementia
1. Medication-induced dementia is the most
frequent cause of "reversible" dementia.
2. Incidence of adverse drug reactions
increases with age.
3. Alterations in pharmacokinetics and
pharmacodynamics, together with the presence of concomitant illnesses
(especially renal, hepatic, and cardiac) and the number of prescribed
and over-the-counter medications taken, all make older people
more vulnerable to this.
4. Take a thorough drug history by reviewing
of all current medication (both prescription and over-the-counter).
Have the patient bring into the office all their medication for
inspection.
E. Metabolic/endocrine/nutritional/systemic
disorders
1. Metabolic/endocrine/nutritional/systemic
disorders (e.g., hypothyroidism, B12 deficiency (most with dementia
also have hematological impairment or myelopathy. 12-14% of all
elderly have low B12 but only a small number have dementia related
to it), and systemic infections) are additional causes of "reversible"
dementias.
2. Diagnose with routine laboratory tests.
I recommend blood count, sedimentation rate (if indicated), electrolytes
(including calcium), liver and renal function tests, urinalysis,
syphilis serology, B12 levels, thyroid function tests, and a
toxin and drug screen.
F. HIV
1. It is well known that HIV-1 DNA is present
in the brains of both asymptomatic and symptomatic individuals.
The virus has been shown to pass the blood-brain barrier early
in the course of infection. Immune activation is associated with
neuronal damage. We classify direct HIV-1 involvement as follows:
a. subclinical impairment
b. minor cognitive-motor disorder (MCMD)
i. Diagnostic criteria for MCMD include
at least two of the following symptoms for at least 1 month by
self-report, confirmed by either clinical neurologic examination
or by neuropsychologic testing
ii. cognitive: impaired attention or concentration,
mental slowing, impaired memory
iii. motor: slowed movements, incoordination
iv. emotional: personality change or irritability
or emotional lability
v. exclusion of other causes of cognitive-motor
impairment.
c. HIV-1–associated dementia (HAD)
i. HAD is thought to generally be a sub-cortical
dementia. Diagnostic criteria include: cognitive dysfunction
in at least two cognitive functions for at least 1 month by self-report
with objective verification by neuropsychologic testing or by
clinical neurologic examination;
ii. moderate to severe functional status
decrements
iii. exclusion of other causes of cognitive-motor
impairment.
G. HIV Associated Conditions -- Viral
Infection
1. Progressive Multifocal Leukoencephalopathy
a. PML occurs in up to 5% of all AIDS patients.
PML is a demyelinating disease caused by papovavirus (JC virus
-- JCV)
b. lesions are white matter demyelination
without mass effect.
c. Most common presentations is: focal
weakness, sensory disturbances, visual deficits (homonymous hemianopsia,
quadrantanopsia, or cortical blindness in 50% of PML cases),
and cognitive abnormalities. Cerebellar involvement with limb
and trunk ataxia (10% ).
d. dementia is rapidly advancing unlike
HAD.
e. death within 4 months is common and
80% die within one year.
2. Other common viral infections include:
CMV and Herpes simplex and zoster
H. HIV Associated Conditions -- Neoplasms
1. Lymphoma
a. This is the most common primary brain
neoplasm is occurring in 1-4% on AIDS. This frequency in AIDS
is 1,000 times greater than that expected in the general population.
b. The incidence may increase as treatment
for reduced CD4 counts improve.
c. present with memory loss, seizures,
cranial nerve deficits (10% )
d. tumors are B cell in origin (95% ) and
have an aggressive histologic type (large cell or large cell
immunoblastic) as opposed to the intermediate- to high-grade
subtypes seen in non-AIDS cases.
e. almost always associated with EBV infection
f. neuroimaging show homogeneously enhancing
lesions found most frequently in the periventricular deep gray
matter area or corpus callosum. Two thirds of will have multiple
lesions on scanning, but virtually all have it at autopsy.
g. CSF shows pleocytosis, elevated protein.
Diagnosis is by brain biopsy
h. treatment
is with radiation therapy and steroids.
2. Metastatic tumors
I. HIV Associated Conditions -- Opportunistic
infections (OIs)
1. develop frequently in association with
HIV-1 infection. These opportunistic complications usually develop
once the CD4 cell count is <200/mm.
2. Since the introduction of anti-retrovirals
(protease inhibitors) have enabled suppression of viral replication
to very low levels, CD4 cell count levels have persisted for
longer periods of time leading to partial and temporary restoration
of the immune system. Therefore treatment has reduced the incidence
of OIs.
3. Parasitic
a. Toxoplasmosis:
i. most common OI of the CNS in AIDS (5%
and 15%).
ii. acquired by ingestion in undercooked
meat. Primary infection is usually asymptomatic, or may manifest
itself with regional lymphadenopathy or a mononucleosis-like
illness.
iii. cerebral toxoplasmosis results from
reactivation of a previously acquired T gondii infection during
a period of immuno-compromise. Typically with CD4 cell count's
<100/mm.
iv. subacute presentation over days to
weeks with lethargy, fever, headache, confusion, and focal signs
(up to 75%). Seizures in up to 30%.
v. Typical signs are hemiparesis, hemianesthesia,
apraxia, aphasia, and movement disorders (hemichorea and hemiballismus).
Cerebellar and brain stem abnormalities are less common.
vi. Histopathologic changes vary from a
localized granulomatous process to a diffuse necrotizing encephalitis.
Can also have perivascular cuffing and frank vasculitis.
vii. Measurement of serum antitoxoplasma
immunoglobulin G (IgG) antibodies occurs in less than 50%. CSF
has mild elevation of protein and a mild to moderate mononucleated
pleocytosis. However, not infrequently CSF findings can be normal.
viii. neuroimaging, especially MR is extremely
useful. Lesions (multiple in 66%) demonstrate ring or nodular
enhancement in 90% of cases, and usually some surrounding mass
effect is observed. Typical location is corticomedullary junction
or in the basal ganglia.
ix. Treatment is with an antitoxoplasmosis
regimen for 10 to 14 days (combination of pyrimethamine and sulfadiazine).
Lifetime suppressive therapy with the same regimen at lower doses
is highly recommended, since relapses are otherwise common. Primary
prophylaxis is recommended for T gondii-seropositive patients
with CD4 cell counts <100/mm.
4. Fungal Infections
a. Cryptococcus
i. encapsulated yeast infection acquired
through the respiratory tract. It is the most common CNS fungal
infection in AIDS (5% to 10%) associated with CD4 cell counts
of <100/mm.
ii. meningitis is the chief clinical CNS
event presenting with headache and fever (85%); nausea, vomiting,
photophobia, blurred vision, stiff neck; and confusion and lethargy
(about 30%).
iii. focal neurologic deficits and seizures
in about 10%.
iv. CSF with elevated opening pressure,
increased protein, decreased glucose level, monocytic pleocytosis.
Indian ink staining positive in more than 70%, positive cryptococcal
antigen in 90%.
v. neuroimaging is frequently negative
vi. treatment with high-dose amphotericin
B plus flucytosine for a minimum of 2 weeks, followed by oral
fluconazole for 8 to 10 weeks or until CSF sterilization is achieved.
vii. acute or subacute hydrocephalus should
be treated aggressively.
b. Other Fungal Infections
i. These include: Candida (microabscesses,
meningitis, and meningoencephalitis -- treatment with amphotericin
B); Aspergillosis (subacute fever, altered mental status, and
focal neurologic signs. Abcess and vasculitic occlusive strokes
occur. -- treatment with amphotericin B); Mucormycosis (extensive
cerebral lesions); Histoplasmosis, Coccidiomycosis, and Blastomycosis
(encephalopathy, meningitis, and focal abscesses -- treatment
with amphotericin B.
5. Bacterial Infections
a. Syphilis
i. Syphilitic meningitis during the course
of secondary syphilis, late manifestations of meningovascular
syphilis (meningitis, cranial nerve abnormalities, and hydrocephalus),
tabes dorsalis (sensory loss, ataxia, lancinating pains to the
lower extremities, sphincter abnormalities), strokes, general
paresis (forgetfulness, dementia, psychiatric symptoms, changes
in personality, pupillary abnormalities), meningomyelitis, syphilitic
polyradiculopathy, and cerebral gummata.
ii. CSF shows mononuclear pleocytosis,
increased protein and IgG. Positive CSF FTA-ABS and VDRL
iii. treatment with penicillin
b. Tuberculosis
i. Tuberculous meningitis is the most frequent
neurologic manifestation (preceded by a period of 2 to 8 weeks
of nonspecific symptoms, including malaise, anorexia, fatigue,
fever, chills, and headache).
ii. Later signs are: worsening headache,
altered mentation, seizures, and focal deficits when associated
with intracerebral mass lesions ( tuberculomas or abscesses
iii. Cranial nerve abnormalities can occur.
Fewer than 10% of cases may develop radiculomyelitis, transverse
myelitis, or anterior spinal artery syndromes.
iv. CSF of mononuclear pleocytosis, low
glucose, increased protein (generally between 100 mg/dL and 200
mg/dL). CSF cultures positive (about 33%) and positive acid-fast
staining to about 80% by the fourth spinal tap.
v. treatment for 9 to 12 months with four-drug
regimen (isoniazid, rifampin, pyrazinamide, and ethambutol) for
first 2 months, followed by a two-drug regimen (isoniazid, rifampin)
until completion of the treatment period.
J. Other Conditions
1. Normal pressure hydrocephalus (dementia,
gait disturbance, and incontinence), brain tumors, and subdural
hematoma, are the most common of the structural brain lesions,
presenting with dementia.
2. Confirmation or exclusion of their presence
usually requires a CT or MRI scan.
IV. Depression
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A. Depression is perhaps the most common
cause of "reversible" dementia in the geriatric population.
B. Unlike younger individuals, elderly
depressed patients may present with cognitive impairment, i.e.,
confusion, memory disturbance, attention deficits, all of which
can be mistaken for dementia.
C. Depression may also coexist with dementia
and worsen the problem.
D. DSM-IV criteria for a diagnosis of depression:
1. five (or more) of the following symptoms
during the same two-week period (every day for most of the day,
or nearly every day).
2. at least one of the symptoms is either:
a) depressed mood [indicated by either subjective report (e.g.,
feels sad) or observation by others (e.g., appears tearful)]
or b) loss of interest or pleasure in nearly all activities.
3. Significant weight loss or weight gain
(e.g., more than 5 percent of body weight in a month) or decrease
or increase in appetite.
4. Insomnia or hypersomnia.
5. Psychomotor agitation or retardation.
6. Fatigue or loss of energy.
7. Feelings of worthlessness or guilt.
8. Diminished ability to think or concentrate,
or indecisiveness.
9. Recurrent thoughts of death (not just
fear of dying), recurrent suicidal ideation without a specific
plan, or a suicide attempt or a specific plan for committing
suicide.
10. The symptoms: must cause clinically
significant distress or impairment in social and occupational
functioning; are not due to the direct physiological effects
of a substance or a general medical condition; are not better
accounted for by bereavement; and persist for longer than two
months or are characterized by marked functional impairment,
morbid preoccupation with worthlessness, suicidal ideation, psychotic
symptoms, or psychomotor retardation.
E. Recommendations
1. Screen all patient for depression initially
and then every sixth months using either:
2. I suggest you use a validated screening
questionnaire such as: Table 8 -- Cornell scale for depression
in dementia or the Table 9 -- Geriatric
depression scale--short form
V. Behavioral
Symptoms Associated with Dementia
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A. demented patients may behave unpredictably.
Typical modes are: anxious, aggressive, repetitive questions
or gestures. Often these behaviors occur in combination, making
it difficult to distinguish one from another.
B. Behavioral problems may appear slowly
and change as dementia progresses. The most common problematic
behaviors are:agitation; aggression and combativeness; suspiciousness/paranoia;
delusions; hallucinations; insomnia; and wandering
C. Approach
1. first evaluate your patient for potential
underlying medical causes.
2. behavioral symptoms may result from
the following. But often the patient is unable to communicate
their problems:
3. physical discomfort; medication side
effects; chronic pain; infection; nutritional deficiencies; dehydration;
impaired vision or hearing.
4. these may respond to non-drug treatment.
4. Non-Drug Treatment
1. We recommend non-drug treatments as
a first-line approach such as modifying the environment (lighting,
color, and noise). Dim lighting, for example, makes some individuals
uneasy, while loud or erratic noise often causes confusion and
frustration. Also it may help to keep familiar personal possessions
visible.
2. Planning activities. Planned activities
help patients feel independent and needed by focusing their attention
on pleasurable or useful tasks. Daily routines such as bathing,
dressing, cooking, cleaning, and laundry can be turned into productive
activities. Other more creative leisure activities can include
singing, playing a musical instrument, painting, walking, playing
with a pet, or reading. Planned activities may relieve depression,
agitation, and wandering.
5. Drug Treatment
1. Antipsychotics (neuroleptics) such as
Haloperidol (Haldol®), Olanzapine (Zyprexa®). Quetiapine
(Seroquel®), Risperidone (Risperdal®), or the Phenothiazines.
2. Anxiolytics such as Alprazolam (Xanax®),
Buspirone (Buspar®), Diazepam (Valium®), Lorazepam (Ativan®).
3. Antidepressants such as Amitriptyline
(Elavil® or Endep®), Bupropion (Wellbutrin®), Desipramine
(Norpramin® or Pertofrane®) , Fluoxetine (Prozac®),
Fluvoxamine (Luvox®), Nefazodone (Serzone®), Nortriptyline
(Pamelor or Aventyl®), Paroxetine (Paxil®), Sertraline
(Zoloft®),Trazodone (Desyrel®).
VI. Treating
Cognitive Symptoms
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A. Alzheimer's disease now has two available
treatments, both of which are acetylcholinesterase inhibitors
1. Tacrine (Cognex)
i. administered four times a day
ii. most common side effect is an increase
in the liver enzyme alanine aminotransferase (ALT), potentially
leading to liver damage.
iii. regular monitoring required for increased
levels of ALT. If abnormal levels of ALT are present, physicians
must adjust the dosage accordingly or discontinue administration
of this drug.
iv. frequent side effects are nausea, vomiting,
diarrhea, abdominal pain, indigestion, and skin rash.
v. Tacrine has provided relief to some
individuals yet is not tolerated by others.
2. Donepezil (Aricept)
i. available in 5 mg or 10 mg tablets,
administered once daily, at bedtime.
ii. taken with or without food.
iii. improves cognition, general function,
and behavior.
iv. most frequent side effects are diarrhea,
nausea, vomiting, insomnia, fatigue, and anorexia. These are
mild in most cases and usually last from one to three weeks,
declining with continued use of the drug.
B. A third drug, rivastigmine (Exelon®),
received an approval letter from the FDA and is expected to be
available sometime this year. A fourth drug, galantamine (Reminyl®),
is under FDA review.
C. None of these drugs will cure Alzheimer's,
nor do they alter the progression of the disease. They are indicated
for the treatment of individuals with mild to moderate Alzheimer's
and may not be as effective for those in the advanced stages
of the disease.
VII. Current
Drug Trials and Medications Available
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A. AIT-082 (Neotrophin™)
1. AIT-082 is being developed as a promoter
of nerve cell repair and regeneration in patients with Alzheimer's
disease.
2. Preclinical studies have demonstrated
that AIT-082 stimulates the production of multiple natural nerve
growth factors and restores function in animal models of memory
decline, aging, brain injury, and spinal cord injury. Human clinical
trials have demonstrated positive effects of AIT-082 on memory
and behavioral function in Alzheimer patients. AIT-082 is in
Phase II clinical trials.
B. AN-1792
1. Prevents the formation of plaque (7/8/99
issue of Nature) in young mice genetically altered to
develop Alzheimer's disease. AN-1792 also significantly reduced
and inhibited further formation of amyloid plaques in older mice
that had already exhibited signs of the disease.
2. AN-1792 is a synthetic form of naturally
occurring beta amyloid protein, which has long been identified
as the primary component of amyloid plaques — one of the
pathological characteristics of Alzheimer's disease. Amyloid
plaques impede nerve cell function and cause nerve cell death
in the brains of people with Alzheimer's disease. Although amyloid
plaques are found in the brains of most individuals with Alzheimer's
disease, it is not yet known whether plaques are a cause or a
result of the disease process.
C. Astaxanthin
1. Astaxanthin is a nutraceutical with
strong antioxidant properties that is being studied in human
safety trials. Astaxanthin has been tested in test tubes and
animal models of human disease for macular degeneration, cancer,
ulcers, cholesterol, and Alzheimer's disease.
D. Celecoxib
1. Celecoxib (Celebrex®) is a cyclooxygenase-2
inhibitor, which is a new class of nonsteroidal anti-inflammatory
drugs. Celecoxib was recently approved for the treatment of arthritis
and, because of its anti-inflammatory properties, is now being
investigated as a potential treatment for Alzheimer's disease.
E. Galantamine
1. Galantamine (Reminyl®) increases
levels of acetylcholine in the brain in two ways: by inhibiting
acetylcholinesterase and by stimulating other receptors in the
brain to release more acetylcholine.
F. Ginkgo biloba
1. Ginkgo is a plant extract containing
several compounds that may have positive effects on cells within
the brain and the body. Ginkgo biloba is thought to have both
antioxidant and anti-inflammatory properties, to protect cell
membranes, and to regulate neurotransmitter function. Ginkgo
has been used for centuries in traditional Chinese medicine and
currently is being used in Europe to alleviate cognitive symptoms
associated with a number of neurological conditions. In a study
researchers found modest improvements in cognition, activities
of daily living (such as eating and dressing), and social behavior
— but no measurable difference was noticed in overall impairment.
G. Melatonin
1. Melatonin is a naturally occurring hormone
secreted by the pineal gland. It has sleep-inducing effects and
is well tolerated by most individuals. In Alzheimer's disease,
sleep disruption is one of the most common behavioral problems,
occurring in approximately 45 percent of affected individuals.
These nocturnal awakenings and agitation create a considerable
burden for caregivers and frequently lead families to place the
individual with Alzheimer's in a nursing home. Melatonin is currently
being studied in individuals with Alzheimer's disease in a study
conducted by the Alzheimer's Disease Cooperative Study Unit.
H. Memantine
1. Memantine is a unique compound, differing
from drugs currently marketed or soon to be available for the
symptomatic treatment of Alzheimer's disease. It is an "NMDA
antagonist" that works by blocking a major mechanism responsible
for the death of brain cells. Memantine is currently marketed
in Germany for other indications. Memantine may prevent further
neuronal loss in Alzheimer's disease, in addition to improving
symptoms. A previous clinical trial suggested that memantine
may slow the progression of functional loss in moderately severe
to severe Alzheimer's disease.
I. Selegiline and Vitamin E
1. Selegiline (Deprenyl® or Elderyl®)
is currently used for the treatment of Parkinson's disease. Both
caused slowing of progression in patients with moderate disease,
who them for two years when compared to place.
VIII. Tables
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Table 1 -- Mini-mental
state exam (MMSE) 30 points possible
| Area |
Question |
Point Score |
| ORIENTATION |
|
|
| |
What is the day? |
1 point |
| |
What is the date? |
1 point |
| |
What is the month? |
1 point |
| |
What is the year? |
1 point |
| |
What is the season? |
1 point |
| |
What is the city? |
1 point |
| |
What is the state? |
1 point |
| |
What is the county? |
1 point |
| |
What is the building? |
1 point |
| |
What is the floor? |
1 point |
| IMMEDIATE MEMORY |
|
|
| |
Name three objects
and 1 second to say each. Then ask patient to repeat the names
of all three objects. |
Give 1 point for
each correct answer. 3 points possible. |
| ATTENTION AND
CALCULATION |
|
|
| |
Use either of these but not both:
Serial 7's: Ask patient to count backwards
from 100 by 7's.
Spell W-O-R-L-D backwards.
|
1 point for each
correct answer. 5 points possible. |
| RECALL |
|
|
| |
After 2 minutes,
ask for the name of the three objects in immediate memory question. |
1 point for each
correct answer. 3 points possible. |
| LANGUAGE |
|
|
| |
Point to a pencil
and a watch. Ask patient to name them. |
1 point for each
correct answer. 2 points possible. |
| |
Ask patient to
repeat: "NO IFS, ANDS, OR BUTS." |
1 point for the
correct answer. |
| |
Ask patient to
perform a 3-step command, "take this piece of paper, fold
it in half, give it back to me." |
1 point for each
correct step. 3 points possible. |
| |
Read & Do,
"CLOSE YOUR EYES." |
1 point for the
correct answer. |
| |
Write a sentence.
Must contain a noun and verb and make sense. |
1 point for the
correct answer. |
| Other |
|
|
| |
Draw an interlocking
pentagon. |
1 point for the
correct answer. |
| |
|
|
| |
|
|
| |
|
|
| |
|
|
Table 2 -- Accuracy
of the MMSE for detecting dementia
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- THIS STUDY LISTS THE PROPORTION
OF PATIENTS CORRECTLY CLASSIFIED AS DEMENTED OR NOT DEMENTED.
- DATA ASSUME THE PREVALENCE OF
DEMENTIA IS 20%.
- Example: IF YOU SET 21 AS THE
MINIMUM NORMAL SCORE FOR PATIENTS WITH SUSPECTED DEMENTIA WHO
HAVE ATTAINED A MIDDLE SCHOOL EDUCATION (GRADE 9), YOUR ACCURACY
OF DIAGNOSIS WILL BE 92%.
|
EDUCATIONAL ATTAINMENT |
| MMSE THRESHOLD
SCORE (Minimum normal MMSE score) |
MIDDLE
SCHOOL |
HIGH
SCHOOL |
COLLEGE
AND/ OR GRADUATE SCHOOL |
|
19 |
0.88 |
0.9 |
0.89 |
|
20 |
0.88 |
0.89 |
0.91 |
|
21 |
0.92 |
0.89 |
0.94 |
|
22 |
0.87 |
0.92 |
0.95 |
|
23 |
0.76 |
0.93 |
0.96 |
|
24 |
0.67 |
0.81 |
0.97 |
|
25 |
0.48 |
0.75 |
0.81 |
|
26 |
0.39 |
0.67 |
0.75 |
|
27 |
0.34 |
0.53 |
0.67 |
|
28 |
0.25 |
0.42 |
0.4 |
Table
3 -- Activities of daily living (ADL's)
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Instructions: Indicate the level of assistance
needed with the following six ADLs by circling the score that
most closely describes the patient.
1. Bathing (either sponge bath, tub bath,
or shower)
Receives no assistance (gets in and out
of tub by self if tub is usual means of bathing (3)
Receives assistance in bathing only one
part of body, such as the back or a leg (2)
Receives assistance in bathing more than
one part of body or is not bathed (1)
2. Continence
Controls urination and bowel movement completely
by self (3)
Has occasional "accidents" (2)
Needs supervision to keep urine or bowel
control, uses catheter, or is incontinent (1)
3. Dressing
(gets clothes from closets and
drawers, including underwear / outer garments; uses fasteners,
including braces, if worn)
Gets clothes and gets completely dressed
without assistance (3)
Gets clothes and gets dressed without assistance
except in tying shoes (2)
Receives assistance in getting clothes
or getting dressed or stays partly or completely undressed. (1)
4. Feeding
Feeds self without assistance (3)
Feeds self except for assistance in cutting
meat or buttering bread (2)
Receives assistance in feeding or is fed
partly or completely by nasogastric or gastric tubes or intravenous
fluids (1)
5. Toileting
(going to the "toilet room"
for bowel or urine elimination, cleaning self after elimination
and arranging clothes)
Goes to "toilet room," cleans
self, and arranges clothes without assistance (may use object
for support, such as cane, walker, or wheelchair, and may manage
night bedpan or commode and empty same in morning) (3)
Receives assistance in going to "toilet
room," cleaning self, or arranging clothes after elimination
or receives assistance in using night bedpan or commode (2)
Does not go to room termed "toilet"
for the elimination process (1)
6. Transferring
Moves in and out of bed or chair without
assistance (may use object for support such as cane or walker)
(3)
Moves in and out of bed or chair with assistance
(2)
Does not get out of bed 1
Total score__________
Table 4 --
Instrumental activities of daily living (IADL's)
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(Instructions: For the following seven
categories, indicate the patient's level of function, ranging
from independent = I, needs assistance = A, or dependent = D;
then sum the number of activities in each function level)
1. Telephone
(I) Able to look up numbers, dial, receive,
and make calls without help
(A) Able to answer phone or dial operator
in an emergency but needs special phone or help in getting number
or dialing
(D) Unable to use telephone
2. Traveling
(I) Able to drive own car or travel alone
on bus or taxi
(A) Able to travel but not alone
(D) Unable to travel
3. Shopping
(I) Able to take care of all shopping with
transportation provided
(A) Able to shop but not alone
(D) Unable to shop
4. Preparing meals
(I) Able to plan and cook full meals
(A) Able to prepare light foods but unable
to cook full meals alone
(D) Unable to prepare any meals
5. Housework
(I) Able to do heavy housework (e.g., scrub
floors)
(A) Able to do light housework, but needs
help with heavy tasks
(D) Unable to do any housework
6. Medication
(I) Able to take meds in the right dose
at the right time
(A) Able to take meds but needs reminding
or someone to prepare it
(D) Unable to take medications
7. Money
(I) Able to manage buying needs; writes
checks, pays bills
(A) Able to manage daily buying needs,
but needs help managing checkbook, paying bills
(D) Unable to manage money
Total number of IAD's rated as
____ Independent
____ Assistance needed
____ Dependent
Table 5 --Frequency
of dementia causes from 32 studies
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| CAUSE |
OCCURRENCE |
Total |
| Alzheimer's Disease (AD) |
57.0% |
|
| Vascular dementia (VD) |
13.0% |
70.00% |
| Depression |
4.5% |
|
| Alcohol |
4.0.0% |
|
| Normal Pressure Hydrocephalus |
1.6% |
|
| Metabolic |
1.5% |
|
| Medications |
1.5% |
|
| Neoplasm |
1.5% |
|
| Parkinson's Disease |
1.2% |
|
| Huntington's Disease |
0.9% |
|
| Mixed AD and VD |
0.8% |
|
| Infection |
0.6% |
|
| Subdural Hematoma |
0.4% |
|
| Post-trauma |
0.4% |
|
| Anoxia |
0.2% |
|
| Miscellaneous |
6.9% |
|
| Not demented |
3.7% |
|
Table 6 --
Potentially reversible causes of dementia
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1. Depression ("pseudodementia")
2. Intoxication: Therapeutic drugs; Alcohol;
Other substances (for example, heavy metals, CO)
3. Metabolic-endocrine derangements: Renal
failure; Hyponatremia; Volume depletion; Hypoglycemia; Hepatic
failure; Hypothyroidism; Hyperthyroidism; Hypercalcemia; Cushing's
syndrome; Hypopituitarism
4. Brain disorders: Stroke; Subdural
hematoma; Infection (for example, meningitis, neurosyphilis,
abscess); Tumors (primary or metastatic); Normal pressure hydrocephalus.
5. Cardiopulmonary disorders: Congestive
heart failure, arrhythmias, chronic obstructive pulmonary disease
6. Generalized infections: Tuberculosis,
endocarditis
7. Deficiency states: Vitamin B12, folate,
niacin
8. Miscellaneous causes: Sensory deprivation
(for example, blindness, deafness); Hospitalization (for example,
from isolation or anesthesia); Fecal impaction;
9. Anemia
10. Remote effects of cancer
Table 7 --
Hachinski ischemic index
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- IF TOTAL SCORE IS LESS THAN OR EQUAL
TO 4, ALZHEIMER'S DISEASE IS LIKELY.
- IF TOTAL SCORE IS 5 TO 7, DIAGNOSIS
IS UNCERTAIN.
- IF TOTAL SCORE IS GREATER THAN 7, VASCULAR
DEMENTIA IS LIKELY.
| FEATURE |
SCORE |
| Abrupt Onset |
2 |
| Stepwise deterioration |
1 |
| Fluctuating course |
2 |
| Nocturnal confusion |
1 |
| Relative preservation of personality |
1 |
| Depression |
1 |
| Somatic complaints |
1 |
| Emotional incontinence |
1 |
| History of hypertension |
1 |
| History of strokes |
2 |
| Evidence of associated atherosclerosis |
1 |
| Focal neurological symptoms |
2 |
| Focal neurological signs |
2 |
|
|
| TOTAL SCORE |
|
Table 8 --
Cornell scale for depression in dementia
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(Use this measurement scale to document
depressive signs and symptoms in patients with dementia that
are reported by the care giver or family member. Ratings should
be based on symptoms and signs occurring during the week prior
to interview. No score should be given if symptoms result from
physical disability or illness. )
Scoring System: a = unable to evaluate
0 = absent 1 = mild or intermittent 2 = severe
Mood-Related Signs
|
|
| 1. Anxiety
(anxious expression, ruminations,
worrying) |
a 0 1 2 |
| 2. Sadness
(sad expression, sad voice, tearfulness) |
a 0 1 2 |
| 3. Lack of
reactivity to pleasant events |
a 0 1 2 |
| 4. Irritability
(easily annoyed, short tempered) |
a 0 1 2 |
| |
|
Behavioral Disturbance
|
|
| 5. Agitation
(restless, hand wringing, hair
pulling) |
a 0 1 2 |
| 6. Retardation
(slow movements, slow speech, slow
reactions) |
a 0 1 2 |
| 7. Multiple
physical complaints (score 0 if
GI symptoms only) |
a 0 1 2 |
| 8. Loss of
interest (less involved in usual
activities -- score only if change occurred acutely, i.e., in
less than 1 month) |
a 0 1 2 |
| |
|
Physical Signs
|
|
| 9. Appetite
loss (eating less than usual) |
a 0 1 2 |
| 10. Weight
loss (score 2 if greater then 5
lbs. in 1 month) |
a 0 1 2 |
| 11. Lack of
energy (fatigues easily, unable
to sustain activities -- score only if acute change in less than
1 month) |
a 0 1 2 |
| |
|
Cyclic Functions
|
|
| 12. Diurnal
variation of mood (symptoms worse
in the morning) |
a 0 1 2 |
| 13. Difficulty
falling asleep (later than usual
for this individual) |
a 0 1 2 |
| 14. Multiple
awakens during sleep |
a 0 1 2 |
| 15. Early morning
awakenings (earlier than usual
for person) |
a 0 1 2 |
| |
|
Ideational Disturbance
|
|
| 16. Suicide
(feels life is not worth living,
has suicidal wishes, or makes suicide attempt) |
a 0 1 2 |
| 17. Self-deprecation
(self-blame, poor self esteem,
or feelings of failure) |
a 0 1 2 |
| 18. Pessimism
(anticipation of the worst) |
a 0 1 2 |
| 19. Mood congruent
delusions (delusions of poverty,
illness, or loss) |
a 0 1 2 |
Total Score _____________
Score > 7 probable
depression
Table 9 --
Geriatric depression scale--short form
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1. Are you basically satisfied with
your life? Yes No
2. Have you dropped many of your activities
and interests? Yes No
3. Do you feel that your life is empty?
Yes No
4. Do you often get bored? Yes No
5. Are you in good spirits most of the
time? Yes No
6. Are you afraid that something bad is
going to happen to you? Yes No
7. Do you feel happy most of the time?
Yes No
8. Do you often feel helpless? Yes
No
9. Do you prefer to stay at home, rather
than going out and
doing new things? Yes No
10. Do you feel you have more problems
with memory than most? Yes No
11. Do you think it is wonderful to be
alive now? Yes No
12. Do you feel pretty worthless the way
you are now? Yes No
13. Do you feel full of energy? Yes No
14. Do you feel that your situation is
hopeless? Yes No
15. Do you think that most people are better
off than you are? Yes No
(Total up the number of underlined answers)
Score__________
Normal = 3 +/- 2
Mildly depressed = 7 +/- 3
Very depressed = 12 +/- 2
Image 1 -- Algorithm
for the differential diagnosis in the evaluation of dementia
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