Transcript 幻灯片 1 - shsmu.edu.cn

CASE PRESENTATION
Dr. LU, QINCHI

DEPARTMENT OF NEUROLOGY
REN JI HOSPITAL
SHANGHAI JIAO TONG UNIVERSITY
SCHOOL OF MEDICINE

Tel: 58752345-3094
Email: [email protected]
History
A 68-year-old woman has been noted by her
daughter to have memory loss and confusion.
The daughter states that her mother has been
going “downhill” for the past several months.
The mother has lived on her own for many
years ,but recently she has begun to become
unable to take care of herself.
History
The daughter states that her mother has
become withdrawn and has lost interest in her
usual activities, such as gardening and reading.
Her mother’s memory is poor, and she is often
fatigued. The patient states that she sleeps well
at night and that her appetite is good, although
she has lost 10 lb over the past 6 months. She
denies bowel and urinary incontinence.
History
The patient’s past medical history is significant
for hypertension for which she has been taking
hydrochlorethiazide. The patient was last
hospitalized 35 years ago when she underwent
a total abdominal hysterectomy with bilateral
salpingo-oophorectomy. The patient has
enjoyed overall good health. She does not
smoke or drink.
Physical Exam
On examination, her blood pressure is 116/56
mmHg, her heart rate is 78 bpm, her
temperature is 37.5。C, and her respiratory rate
is 18 breaths per minute. She weighs 88 kg and
her height is 1.62m. The patient is a welldeveloped white women with a flat affect. She
is oriented to person, but she is not oriented to
time and place.
Pyhsical & Neuro Exam
Mini Mental Status Examination gives a score of
18 out of 30. The head and neck and cardiovascular
examination are unremarkable. Abdomen is benign
without hepatosplenomegaly. The extremities are
without edema, cyanosis, or clubbing. The neurologic
examination reveals that the cranial nerves are intact,
and the motor and sensory exams are within normal
limits. Cerebellum examination is unremarkable and
the gait is normal.
Questions



What is the most likely diagnosis?
What are the next diagnostic steps?
What is the best treatment for this condition?
Summary:
A 68-year-old woman has memory loss,
confusion, and fatigue, and is withdrawn. She
had a flat affect. She is oriented to person, but
she is not oriented to time and place. The
remainder of the examination, including
neurological examination, is normal except for
a low score on the MMSE.
Most likely diagnosis:
Alzheimer dementia.
Next diagnostic step:
Assess for depression
and reversible causes
of dementia.
Probable treatment:
Acetylcholinesterase
inhibitor
Analysis
Objectives



Know some of the common causes of
dementia
Understand the presentation and diagnosis of
Alzheimer dementia
Know the treatment for Alzheimer dementia
is acetylcholinesterase inhibitor
Considerations
This is an elderly woman without any
significant past medical history except for
hypertension who was brought to your office
with a history of progressive functional decline
and memory loss. The first step should be to
rule out depression. Depression in the elderly
may have a presentation very similar to that of
dementia with withdrawal, apathy, irritability,
memory impairment, and confusion.
Considerations
The next step should be to rule out all the
possible causes of reversible or arrestable
dementia, such as multi-infarct dementia,
hypothyroidism, drugs, B12 deficiency, normal
pressure hydrocephalus, alcoholism, HIV, and
syphilis.
Considerations
Laboratory tests will help you to eliminate
some of these common causes of reversible
dementia: complete blood count (CBC),
comprehensive metabolic panel, thyroidstimulating hormone (TSH), urinalysis,
serologic test for syphilis, and a head CT (see
table 49-1).
Table 49-1
ABBREVIATED WORKUP FOR DEMENTIA
Complete blood count and consider erythrocyte
sedimentation rate (ESR)
Chemistry panel
Thyroid-stimulating hormone level
Venereal Disease Research Laboratory (VDRL)
HIV assay
Urinalysis
Serum vitamin B12 and folate levels
Chest radiograph
Electrocardiogram
CT or MRI imaging of the head
Considerations
The possibility of HIV-induced dementia is not
high on the differential in this case given the
patient’s age, but it would certainly be a
consideration in younger people. Possible
infectious causes of reversible dementia
include not only HIV but also neurosyphilis.
Therefore, a serologic test for syphilis is
indicated.
Considerations
Because our patient does not have a history of
chronic alcoholism, we can rule out this
condition. The CBC and mean cell volume
(MCV) are normal, as is the TSH, eliminating
the possibilities of vitamin B12 deficiency and
of hypothyroidism. The patient is only taking
hydrochlorothiazide, which is not associated
with the described mental status changes. A CT
head scan can assess for brain lesions, multiple
infarcts, and hydrocephalus.
Considerations
Therefore, in this case we are left with the
possibility of multi-infarct dementia and
Alzheimer disease. Multi-infarct dementia
develops later in life and is caused by diffuse
cerebrovascular disease. Most of the patients
will have a history of transient ischemic
attacks and strokes, and stepwise progression
of dementia which our patient does not report.
In this particular case, Alzheimer dementia
becomes the most likely diagnosis.
APPROACH
TO
DEMENTIA
Definitions


Alzheimer disease: The leading cause of
dementia, accounting for half of the cases
involving elderly individuals, correlating to
brain atrophy with ventricular enlargement.
Dementia: Progressive and generalized decline
of intellectual ability from a previously
attained level, usually without alteration of
consciousness.
Definitions


Multiinfarct dementia: Numerous small cerebral
vascular accidents, most commonly caused by
atherosclerotic disease, leading to dementia.
Normal pressure hydrocephalus: Reversible form of
dementia where the cerebral ventricles slowly enlarge
as a result of disturbances to cerebral spinal fluid
resorption. The classic triad is dementia, gait
disturbance, and urinary or bowel incontinence.
Clinical Approach
A patient who presents with memory and
functional impairment should be approached
from the perspective that many etiologies can
be causative. A thorough description of the
patient’s cognitive, adaptive, memory, and
behavioral ability over time is critical.
Multiple family members are often needed to
construct a complete and accurate picture. The
time frame (months to years versus days to
weeks) is important.
Clinical Approach
A history of head trauma, neurological
symptoms, a stepwise decline (multi-infarct
dementia) versus a insidious gradual decline
may be helpful. A record of all medications,
habits, alcohol use (even remote), can
potentially cause mental status changes in the
elderly. A resting tremor of Parkinson disease,
cold intolerance suggestive of hypothyroidism,
or vitamin deficiencies may be helpful.
Clinical Approach
The other intracranial diseases that could cause
a dementia-like picture include subdural
hematoma and normal pressure hydrocephalus.
Usually, a CAT (computed axial tomography)
scan will allow you to rule out these disease
processes. Also, remember, that normal
pressure hydrocephalus is usually
accompanied by gait disturbances and urinary
incontinence which our patient does not have.
Clinical Approach
Parkinson disease is also associated with the
development of dementia but patients with
Parkinson disease have symptoms and physical
findings that will alert you to the diagnosis.
Table 49-2 lists the neurological diseases that
impair cognitive ability.
Table 49-2
NEUROLOGICAL DISEASES IMPAIRING COGNITIVE ABILITY
DISEASE
CLINICAL FEATURES
TREATMENT
Alzheimer disease
Slow decline in cognitive and
behavioral ability; pathology:
neurofibrillary tangles, enlarged
cerebral ventricles, and atrophy
Cholinesterase inhibitors such
as donepezil or rivastigmine
Normal-pressure
hydrocephalus
Gate disturbance, dementia,
Ventricular shunting process
incontinence; enlarged ventricles
without atrophy
Multi-infarct
dementia
Focal deficits, stepwise loss of
function; multiple areas of
infarct usually subcortical
Address atherosclerotic risk
factors, identify and treat
thrombus
Parkinson disease
Extrapyramidal signs (tremor,
rigidity), slow onset
Dopaminergic agents
Table 49-2 (cont)
NEUROLOGICAL DISEASES IMPAIRING COGNITIVE ABILITY
DISEASE
CLINICAL FEATURES
TREATMENT
HIV defintion
Systemic involvement; risk factors Treat specific infection
for acquisition; positive HIV
serology
Neurosyphilis
Optic atrophy, Argyll-Robertson
pupils, gait disturbance; positive
cerebro-spinal fluid serology
High dose intravenous
penicillin
Multiple sclerosis
Brainstem signs, optic atrophy,
long-standing disease with
exacerbations and remissions;
MRI showing white matter
abnormalities
Recombinant interferon,
corticosteroids
Intracranial tumor
Focal signs, papilledema, seizures
Corticosteroids to reduce
intracranial pressure, treat
the lesion
Clinical Approach
The etiology of Alzheimer dementia is an unknown
but Alzheimer disease has a genetic component. The
risk of developing the disease for an individual in a
family with Alzheimer disease increases by a factor
of 3 or 4. The gene that codes for apoprotein E seems
to be associated with some prediction. The pathologic
changes in the brains of Alzheimer disease patients
include neurofibrillary tangles with a deposition of
abnormal amyloid in the brain.
Amyloid Precursor Protein
A-ß
Neurofibrillary
Tangles
A-ß Aggregation
Neuron Death
Neuritic
Plaques
Basal Forebrain
and Brainstem
Nuclei
Neurotransmitter
Deficits
Demantia Syndrome
Neuron
Death
Cortex
Mutations and vulnerability genes associated
with Alzheimer’s disease
Genotype
Mutations
Down syndrome
(trisomy 21)
Cellular effect
Increased APP production
with enhanced generation
of Aβ
APP mutations
Altered APP processing
(varions)
resultiong in increased
21q21.1-21.3
production of Aβ
Chromosome 14 (PS1 Increased Aβ production
mutation)
14q24.2-24.3
Chromosome 1 (PS2 Increased Aβ production
mutation)
1q31-32
Mutations and vulnerability genes associated with
Alzheimer’s disease
Genetic risk factors
Chromosome 19 (ApoE-4)
Increase Aβ aggregation
19q13.2
Chromosome 12 (low-density Lipoprotein receptor
lipoprotein receptor-related
mediating the molecular
protein)
effects of ApoE-4
Chromosome 6 (HLA-A2)
HLA histocompatibility
allele regulating the
inflammatory response
Chromosome 17
Bleomycin hydrolase;
implicated in APP
processing
Classical neuritic plaque
(Bielschowsky silver stain)
Neurofibrillary Tangles
Neurofibrillary tangles
(H&E stain)
Cerebral amyloid angiopathy
(H&E stain)
Clinical Approach
The disease onset can be very insidious and the
average life expectancy after diagnosis is 7-10
years. The clinical course is characterized by
the progressive decline of cognitive functions
(memory, orientation, attention and
concentration) and the development of
psychological and behavioral symptoms
(wandering, aggression, anxiety, depression
and psychosis) (see Table 49-3)
Table 49-3
ALZHEIMER DISEASE CLINICAL COURSE
CLINICAL STAGE
MANIFESTATIONS
Early
Mild forgetfulness, poor concentration, fairly good
function, denial, occasional disorientation
Intermediate
Drastic deficits for recent memory, can travel to
familiar locations, suspicious, anxious, aware of
confusion
Late
Cannot remember names of family members or close
friends; may have delusions or hallucinations, agitation,
aggression, wandering, disoriented to time and place,
need for substantial care
Advanced
Totally incapacitated and disoriented, incontinent,
personality and emotional changes; eventually all
verbal and motor skills deteriorate, leading to need for
total care
Treatment
The goals of treatment in Alzheimer disease
are to
(a) improve cognitive function
(b) reduce behavioral and psychological
symptoms, and
(c) improve the quality of life.
Treatment

Donepezil (Aricept) and revastigmine (Exelon) are
cholinesterase inhibitors that are effective in
improving cognitive function and global clinical state.

Memantine ( Namenda) is the only NMDA receptor
antagonist for moderate to severe Alzheimer
dementia

Risperidone reduces psychotic symptoms and
aggression in patients with dementia.
Treatment
Other issues include wakefulness,
nightwalking and wandering, aggression,
incontinence, and depression. A structured
environment, with predictability, and judicious
use of pharmacotherapy, such as selective
serotonin reuptake inhibitor (SSRI) for
depression or short-acting benzodiazepine for
insomnia, are helpful.
Opportunities for treatment of AD

Enhancement of cholinergic function

Cholinesterase inhibitors






Tacrine
Donepezil (Aricept)
Rivastigmine ( Exelon)
Huperzine A
Cholinesterase receptor agonists
NMDA receptor antagonist

Memantine( Namenda)
Treatment
The primary caregiver is a often overwhelmed
and needs support. The Alzheimer Association
is a national organization developed to give
support to family members, and can be
contacted through www.alz.org.
Comprehension
Questions
[1] A 78-year-old female is diagnosed with
Alzheimer disease. Which of the following
agents is most likely to help with the cognitive
function?
 A. Haloperidol
 B. Estrogen replacement therapy
 C. Donepezil
 D. High dose Vitamin B12 injections
ANSWER
[1] C. Cholinesterase inhibitors help with the
cognitive function in Alzheimer disease and
may slow the progression somewhat.




[2] A 74-year-old male was noted to have excellent
cognitive and motor skill 12 months ago. His wife
noted that 6 months ago, his function deteriorated in a
noticeable way, and, again, 2 months ago, another
level of deterioration was noted. Which of the
following is most likely to reveal the etiology of his
functional decline?
A. HIV Antibody test
B. Magnetic resonance imaging of the brain
C. Cerebrospinal fluid VDRL test
D. Serum thyroid-stimulating hormone (TSH)
ANSWER
[2] B. The stepwise decline in function is
typical for multi-infarct dementia, diagnosed
by viewing multiple areas of the brain infarct.
[3] A 55-year-old man is noted by his family members
to be forgetful and become disoriented. He also has
difficulty making it to the bathroom in time, and
complains of feeling as though “he is walking like he
was drunk”. Which therapy is most likely to improve
his condition?
 A. Intravenous penicillin for 21 days
 B. Rivastigmine
 C. Treatment with fluoxetine for 9 to 12 months\
 D. Ventriculoperitoneal shunt
 E. Enrollment into Alcoholic Anonymous
ANSWER
[3] D. The classic triad for normal pressure
hydrocephalus is dementia, incontinence, and
gait disturbance; one treatment is shunting the
cerebrospinal fluid.
[4] Which of the following commonly seen in brain
imaging of patients with Alzheimer disease?
 A. Normal cerebral ventricles and atrophic brain
tissue
 B. Enlarged cerebral ventricles and atrophic brain
tissue
 C. Enlarged cerebral ventricles and no atrophy of
brain tissue
 D. Normal cerebral ventricles and normal brain tissue,
acetylcholine deficiency
ANSWER
[4] B. Alzheimer disease typically has enlarged
cerebral ventricles and brain atrophy, whereas
normal pressure hydrocephalus has enlarged
brain ventricles without brain atrophy.
CLINICAL PEARLS


Alzheimer disease is the most common type of
dementia, followed by multi-infarct
(arteriosclerotic) dememtia.
Approximately 5% of people older than age of
65 years and 20% older than age 80 years have
some form of dementia.
CLINICAL PEARLS


Depression and reversible causes of dementia
should be considered in the evaluation of a
patient with memory loss and functional
decline.
A cholinesterase inhibitor such as donepezil is
effective in improving cognitive function and
global clinical state in patients with Alzheimer
disease.
THANKS!