Dementia : Causes And Treatment–6% had dementia and while anxiety disorders, alcoholism and...
Transcript of Dementia : Causes And Treatment–6% had dementia and while anxiety disorders, alcoholism and...
Dementia : Causes And Treatment
Associate Professor (Clinical) Dr Rosdinom Razali
Dept of Psychiatry
UKMMC
24 Feb 2014
H-Care Seminar on:
Caring For Persons With Dementia: The Way Forward
1
Dementia: Causes And Treatment
Topics: 1. Demography and epidemiology
2. Normal ageing, MCI & dementia
3. Types of dementia
4. Clinical features of AD
5. The Cholinergic Hypothesis of AD
6. Diagnosing dementia
7. Pharmacological treatment of dementia
2
Malaysia • “Population is ageing due to a steady decline in its
birth rate”- 3rd stage of demographic transition.
• The number of older persons in Malaysia has doubled in the past two decades to almost 1.4 million in 2000.
• By 2020, this number is expected to grow to more than 3.4 million.
3
Prevalence of psychiatric illness
• Study by Fadillah on elderly above the age of 60 in the community in Cheras, showed that out of the 226 elderly, 31% had been physically ill in the last one month and 16% had psychiatric illnesses.
• Out of this 16%, – 7% had depressive illness,
– 6% had dementia and while anxiety disorders, alcoholism and schizophrenia were much rarer,
– 50% of those with dementia had physical illnesses including hypertension, diabetes mellitus and one patient had carcinoma with secondary.
(MMA, 2002)
Relationship between normal ageing, mild cognitive impairment & dementia
5
Clinical Characterization of Mild Cognitive Impairment (MCI)
Petersen Criteria:
• 1. Subjective memory complaint
• 2. Normal activities of daily living (ADLs)
• 3. Normal general cognitive function
• 4. Abnormal memory for age
• 5. Not demented Petersen RC et al; Arch Neurol 1999;56:303-308
Memory declines with age
Age
Memory
and
Cognition
Education Cognitive
demand
I.Q.
Normal
Dementia
MCI
8
Memory : Normal Aging vs. Dementia
Slow
Accurate recall
Remedied by cues e.g.
appointment calendars and lists
Stable
Does not interfere with function
Slow
Inaccurate recall
Reminders fail eventually,
recall poor despite cueing
Progressive decline
Interferes with function
9
Normal Aging Dementia
Misplaces items infrequently
Independent retrieval possible
Can follow directions; oral or
verbal
Capable of self-care
Misplaces items frequently
Needs help from others to find
items
Can hardly follow directions even
with guide
Gradually unable to care for self
Memory: Normal Aging vs. Dementia
10
Normal Aging Dementia
Normal Aging Vs. Dementia
AGE AGE
• Minimal forgetfulness
• no change in other cognitive domains
• intact ADL’s
• normal n/p test result
•Poor memory
•Decline in other cognitive domains
• impaired ADL’s
• abnormal n/p test result
Cognitiv
e S
tatu
s
Cognitiv
e S
tatu
s
11
Dementia is a syndrome that refers to a global impairment of the higher cortical function that causes behavioural, cognitive and emotional impairments.
Sustained acquired decline in intellectual functions which interferes with an individual’s daily activities.
12
…………
TYPES OF DEMENTIA
1) Alzheimer’s Disease (AD) – the most common type
2) Vascular cognitive impairment (VaD)
3) Dementia with Lewy Body (DLB)
4) Fronto-temporal lobar degeneration (FTLD)
5) Jakob-Creutzfeldt Dementia (CJD)
6) Parkinson’s Disease Dementia
7) Huntington’s Disease Dementia
13
Major Dementia Subtypes
Fratiglioni L et al. Neurology. 2000;54 S10-5
Alzheimer's disease
60-70%
Vascular dementia
15-20%
Other dementias, eg,Lewy body disease
Parkinson’s disease
10-25%
14
Alzheimer’s disease
• Most common cause of dementia in the elderly • Average duration is of illness 8- 11 years • Prevalence doubles every 5 years from 6-8% at 65 years • Risk factors: age*, genetic influence*, ApoE status*, Down syndrome (chromosome 21- develop AD if they live past the age of 50 years old.), female gender, lack of education, head trauma, infection, inorganic compounds (aluminum and silicon) , myocardial infarction
15
Cortical Atrophy1
Normal
1. Halliday GM, et al. Neurobiol Aging. 2003;24:797-806.
2. Ng'walali PM, et al. Leg Med. 2002;4:223-231.
Alzheimer’s Disease (AD) Is a Progressive, Irreversible Brain Disorder
Alzheimer’s Disease
Amyloid Plaques Extracellular deposits
of -amyloid protein
Neurofibrillary Tangles Abnormal intraneuronal
fibrillar material —
tau protein
Neuropathologic Hallmarks2
16
17
Anatomical hallmarks of Alzheimer’s disease
Extraneuronal
plaques Intraneuronal
neurofibrillary tangles
17
18
AD pathology: brain atrophy and distribution of plaques and neurofibrillary tangles
Alzheimer Pathology
18
Shadow of
‘healthy’ brain
Neurofibrillary tangles (pink)
Plaques (yellow)
18
Other dementias: Cerebrovascular pathology (VaD)
19
Vascular Pathology
Multi-infarct dementia
(dark blue)
Leukoaraiosis
(yellow)
19
Other dementias: Frontotemporal lobar degeneration (FTLD)
20
Frontotemporal Degeneration
Semantic dementia
(orange)
Slowly progressive,
non-fluent aphasia
(green)
Frontotemporal
dementia
(yellow)
20
Other dementias: Dementia with Lewy bodies (DLB)
21
Dementia with Lewy Bodies
Substantia nigra
21
22
What these symptoms mean to a person with Alzheimer’s disease
– Forgetting more and more things … and people
– Loss of initiative and decreased judgement
– Disorientation to time and place
– Difficulty in finding the right words or understanding what people are saying
– Difficulty in performing previously routine everyday tasks
– Personality and mood changes – Isolation, depression – Loss of independence
22
23
Alzheimer’s disease doesn’t only affect the patient
• Alzheimer’s disease affects the entire family
• The greatest impact is on the primary caregiver as caregiver burden
• Practical care for the patient 24 hours a day
• Personal and emotional stress
• Time off from paid employment and loss of income
• Spouses likely to be older themselves: difficulty coping with the situation
• If children or young relatives: interference with professional, family and social roles
23
The Cholinergic Hypothesis
24
Deficient Cholinergic Transmission Is a Core Deficit in AD
ACh = acetylcholine; AChE = acetylcholinesterase; CoA = coenzyme A.
Wilkinson DG, et al. Drugs Aging. 2004;21:453-478.
Postsynaptic
Pre synaptic
ACh
ACh
ACh
AChE
ACh
Acetyl CoA
Choline
ACh
acetyltransferase Choline
AChE inhibitor
Choline
+ acetate
ACh release
+
+ –
ACh
25
26
Cholinergic changes in Alzheimer’s disease
• In the cerebral cortex and hippocampus of patients with AD
• Decline in choline acetyltransferase (ChAT) activity1
• Decreased levels of acetylcholinesterase (AChE) 1
• Increased levels of butyrylcholinesterase (BuChE) 1
• Depletion of ACh-positive neurons in the basal forebrain: especially in moderate to severe disease stages2
1. Perry EK, et al. Neuropathol Appl Neurobiol 1978;4:273–7
2. Whitehouse PJ, et al. Science 1982;215:1237–9 26
27
Evolution of the cholinergic hypothesis
• 1970s Cholinergic hypothesis of Alzheimer's disease first proposed1
• 1980s ACh deficit cause of cognitive impairment • Destruction of cholinergic neurons in basal forebrain • Cholinergic system damage correlated with severity • Cholinergic system involved in arousal and attention2
• 1990s Introduction of ChEIs3
• 2000s Recognition of the role of butyrylcholinesterase (BuChE) as well as AChE4
• A potential role in disease progression • An additional therapeutic target • Clinical relevance of dual inhibition remains a hot topic of debate
1. Davies P, Maloney AJ. Lancet 1976;2:1403
2. Rossor M. Brain 1982;105:313–30
3. Davis KL, et al. N Engl J Med 1992;327:1253–9
4. Mesulam M, et al. Neurobiol Dis 2002;9:88–93
27
28
The cholinergic hypothesis updated: AChE and BuChE co-regulate ACh
AChE without
BuChE with
AChE with
BuChE without
ACh
28
Diagnosing Dementia
29
Dementia is a clinical diagnosis
• Assessment of presenting problems
• Taking an informant-based history
• Physical and neurological examination
• Evaluation of cognitive, behavioral & functional status
30
SIGNS NORMAL NOT NORMAL
1. Memory Loss
affects home or job
skills
a. Occasionally forgets
names, appointments, phone
numbers, deadlines
(remembers later)
a. Frequently forgets
things ( unable to
remember later)
b. Unexplained confusion
2. Difficulty
performing familiar
tasks
a. Washing clothes, forgets
to hang ( remembers later)
b. Brings home important
assignment for presentation;
wakes up middle of night and
prepares.
a. Forgets she washed
clothes at all.
b. Wakes up in the
morning and cannot
explain why he
brought home
something.
3. Problems with
language
a. Difficulty finding the right
word, substitutes related
word.
a. Forgets simple word,
substitutes inappropriate
word.
- Adapted from AAN, 2002
History: 10 Common Presenting
Symptoms of Dementia
31
SIGNS NORMAL NOT NORMAL
4. Disorientation in
time and place
a. Momentarily forgets the
day or time.
b. Sometimes forgets
purpose why he gets to a
place (store).
a. Frequently forgets time
and place.
b. Getting lost in a
familiar place; or why he
is in a certain place at all.
5. Poor or decreased
Judgement
a. Choosing not to bring
umbrella or sweater ( which
maybe important).
a. Appearing in public
inappropriately dressed,
and not minding it.
6. Problems with
complex tasks and
abstract thinking.
a. Difficulty sending text
messages.
b. Depositing/withdrawing
money from banks maybe
confusing.
c. Sometimes forgets
birthdays.
a. Do not know what cell
phone is.
b. Cannot recognize
checkbook.
c. Do not know what
birthday means.
History: 10 Common Presenting
Symptoms of Dementia
32
SIGNS NORMAL NOT NORMAL
7. Misplacing things a. At times people misplace
watches, keys, wallets, etc.
(remembers later).
a. Misplace things in
inappropriate places;
clothes in refrigerator,
food in closet.
8. Changes in mood
and behavior
a. Common to have bad day;
moody, sad.
a. Having rapid mood
swings – for no apparent
reason.
9. Changes in
Personality
a. People change with age
(mellowing).
a. Drastic change
( suspicious, confused,
withdrawn).
10. Loss of initiative a. Losing interest at times
(daily routines) regain later.
a. Remaining uninvolved,
passive and respond
only with repeated
prodding.
History: 10 Common Presenting
Symptoms of Dementia
33
Physical Examination
• Hypertension and signs of vascular disease
• Signs of cardiac disease, particularly features that increase risk
for cerebral embolism.
• Signs suggestive of endocrine disturbance.
• Neurologic abnormalities, such as focal weakness, gait and
balance disturbance, tremors or other movement disorders.
34
ADL
Cognition
Behavior
Dementia
The ABC’s of Dementia
35
DIAGNOSTIC CRITERIA
The widely used diagnostic criteria for dementia of the Alzheimer’s
type are those of the :
1. Diagnostic and Statistical Manual of Mental Disorders (DSM 5 ),
published by the American Psychiatric Association.
2. The National Institute of Neurological and Communicative
Disorders and Stroke and the Alzheimer’s Disease and Related
Disorders Association (NINCDS/ADRDA).
Using these criteria, the ability to make an accurate diagnosis of
AD has improved to about 90% of patients.
36
DSM-IV-TR: Diagnostic Criteria for Dementia of the Alzheimer’s Type
1. Memory impairment
2. At least one of the following:
3. Disturbance in 1 and 2 interferes with daily function
4. Course is gradual in onset with continuing cognitive decline
5. Does not occur exclusively during delirium
6. Other etiologies ruled out prior to diagnosis
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Text Revision. Washington, DC: American Psychiatric Press; 2000:157.
Aphasia Disturbances in language—misuse of words or inability to
remember and use words correctly
Apraxia Disturbances in skilled movements—impaired ability to carry
out motor activities despite intact motor function
Agnosia Disturbances in recognition—unable to recognize objects even
though sensory function remains intact
Disturbances in
executive functioning
Ability to think abstractly and to plan, initiate, sequence,
monitor, and stop complex behavior
37
Differences between DSM 5 and DSM 4R
38
• Introduction • DSM 5 has replaced the term “dementia” with “major
neurocognitive disorder” and “mild neurocognitive disorder”.
• Reason for change: To reduce stigma as “dementia” means “mad” or “insane”
• However, APA still uses “dementia” as it has been widely used and understood by many people.
39
Dementia vs. Neurocognitive Disorder
1. Focusing on Abilities—Not Disabilities
• DSM 5 focuses on a decline rather than a deficit in function.
2. Memory and Early Detection
• DSM 5 is less focussed on memory impairment
• a) Major neurocognitive disorder (Major NCD) exhibits cognitive deficits which interfere with independence
• b) Mild neurocognitive disorder (Mild NCD) may retain ability to be independent.
40
Types of Neurocognitive Disorder (NCD):
• Delirium
• Major ND
• Mild ND
41
Major Neurocognitive Disorder
A. Evidence of significant cognitive decline in one or more cognitive domains from:
• Patient, informants or clinicians
• Substantial impairment in cognitive perforamance (using neuropsychological tests or other clinical assessments)
B. Cognitive deficits interfere with independent ADL
C. Not due to delirium
D. Not due to other psychiatric conditions (eg. depression or schizophrenia)
42
Specify whether due to: • Alzheimer disease
• Frontotemporal lobar degeneration
• Lewy body disease
• Vascular dementia
• Traumatic brain injury
• Substance/medication use
• HIV infection
• Prion disease
• Parkinson disease
• Huntington disease
• Another medical condition
• Multiple aetiologies
• Unspecified
43
• Specify presence of:
• Without behavioural disturbance
• With behavioural disturbance (identify disturbance)
• Specify severity
• Mild
• Moderate
• Severe
44
Mild Neurocognitive Disorder A. Evidence of modest cognitive decline in one or more cognitive
domains from:
• Patient, informants or clinicians
• Modest impairment in cognitive perforamnce (using neuropsychological tests or other clinical assessments)
B. Cognitive deficits do not interfere with independent ADL
C. Not due to delirium
D. Not due to other psychiatric conditions (eg. depression or schizophrenia)
45
Specify whether due to: • Alzheimer disease
• Frontotemporal lobar degeneration
• Lewy body disease
• Vascular dementia
• Traumatic brain injury
• Substance/medication use
• HIV infection
• Prion disease
• Parkinson disease
• Huntington disease
• Another medical condition
• Multiple aetiologies
• Unspecified
46
Mild/ Major NCD Due To Alzheimer Disease 1. Insidious onset and gradual progression of impairment in 1 or
more cognitive domains
2. Probable AD if either is present:
• i. Family history or positive genetic testing OR
• ii. All 3 are present:
• Decline in memory & learning or at least another cognitive functions (history or neuropsychological tests)
• Gradual but steady decline in cognitive functioning
• No other aetiologies
47
NINDS-AIREN criteria for VaD
A. Impairment of memory and of two or more cognitive domains.
Must interfere with patient functioning (ADL) independently of physical defects
A. Evidence for cerebrovascular disease (CVD) from Neuroimaging (multi-infarcts & white matter lesions) & Physical examination (focal signs on neurological examination)
C. Possible or probable relationship between dementia and CVD:
a) onset of dementia within 3 months following a recognized stroke;
b) abrupt deterioration in cognitive functions; or fluctuating, stepwise progression of cognitive deficits.
NINDS-AIREN - National Institute of Neurological Diseases and Stroke & Association
Internationale pour la recherche et L’Enseignement en Neuroscience
48
49
What is MMSE (Mini-Mental State
Examination)?
It is the most widely recognized clinical instrument used to
evaluate cognition in patients with Alzheimer’s Disease. Most
clinicians consider the MMSE to be a routine part of the
diagnosis of the disease.
The MMSE is a brief ( 5-10 minutes) mental status exam that
is used to evaluate cognitive aspects of mental function in
terms of orientation, memory, attention, language and praxis.
50
Mini Mental State Examination
Items tested are :
•Orientation to time (5)
• Orientation to place (5)
• Registration (3)
• Attention (5)
• Recall (3)
• Language (9): naming (2), repetition (1), comprehension
(3), reading (1), writing (1), copying (1)
51
• The subtests most useful in detecting relatively early Alzheimer’s disease are the recall of 3 items, followed by orientation and drawing.
• Language tests are the least sensitive.
• MMSE is susceptible to ‘floor effects’ in patients with severe dementia as they tend to score very low, beyond which, progression cannot be further assessed.
52
Mini-Mental State Examination
(MMSE)
The highest total possible score is 30.
• 27 to 30 - no AD
• 26 to 20 - mild AD
•10 to 19 - moderate AD
• < 10 - severe AD
53
CLOCK DRAWING TASK (CDT)
The Clock Drawing Task is particularly useful as a screening tool
to differentiate normal elderly individuals from individuals with
cognitive impairment.
Takes about 3 to 5 minutes and can be administered by
paramedical staff.
The patient is asked to draw the face of the clock, placing the
numbers in the correct positions. After this task is completed, the
patient is asked to draw in the hands indicating 10 minutes after
11 or 20 minutes after 8.
54
CLOCK DRAWING TASK
One point is earned by the patient for each of the following tasks
involved in the CDT:
•DRAWING A CLOSE CIRCLE (1 mark)
•PLACING NUMBERS IN CORRECT POSITION (1 mark)
•INCLUDING ALL 12 CORRECT NUMBERS (1 mark)
•PLACING HANDS IN CORRECT POSITION (1 mark)
55
ADAS-cog (Alzheimer’s Disease
Assessment Scale - cognition)
• It measures the severity of cognitive and non-cognitive
impairments; cognitive portion (ADAS-cog) has 11 items that
test memory, orientation, language, and praxis functions that
have been extensively validated in patients with AD.
• Scored from 0 to 70, with higher score indicating greater
magnitude of cognitive impairment.
• Score increases by 6 to 10 points per year in patients with
mild to moderately severe AD.
56
CDR- CLINICAL DEMENTIA RATING
It employs a semi-structured clinical interview, with both the patient
and an informant, to rate performance in six domains: Memory ,
Orientation, Judgement, and Problem Solving, Community Affairs,
Home and Hobbies, and Personal Care.
The scale is scored from 0 ( no impairment) to 3 ( severe
impairment). A questionable category is scored as 0.5 or Mild
Cognitive Impairment (MCI).
57
NPI – Neuropsychiatric Inventory
The Neuropsychiatric Inventory (NPI) was developed to assess 10
behavioral disturbances occurring in dementia patients: delusions,
hallucinations, dysphoria, anxiety, agitation/aggression, euphoria,
disinhibition, irritability, apathy, aberrant motor activity (appetite and
sleep).
The NPI uses a screening strategy to minimize administration time,
examining and scoring only those behavioral domains with positive
responses to screening questions. Both the frequency and severity of
each behavior are determined.
Information for the NPI is obtained from a caregiver familiar with
patient’s behavior.
144 = total score (12 domains X 12 – severity and frequency)
Severity ( mild, moderate, marked)/ frequency ( frequently, occasional)
58
GDS – Geriatric Deterioration Scale
The Geriatric Deterioration Scale (GDS) provides caregivers an
overview of the stages of cognitive function for those suffering from a
primary degenerative dementia such as Alzheimer's disease.
It is broken down into 7 different stages:
•Stages 1-3 are the pre-dementia stages.
•Stages 4-7 are the dementia stages. Beginning in stage 5, an
individual can no longer survive without assistance.
Caregivers can get a rough idea of where an individual is at in the
disease process by observing that individual's behavioral
characteristics and comparing them to the GDS.
59
Advantages of early and accurate
diagnosis:
• Provides diagnostic answer and education for patient and family.
• Relieve anxiety of a progressive disease.
• Allows treatment for underlying disease if reversible, prevention
and rehabilitation.
• Early treatment of cognitive and behavioral symptoms, delay
dependency in degenerative dementias.
• No cure but treatment is available
60
No laboratory test can confirm
diagnosis of dementia
• Laboratory tests and neuroimaging only assist in diagnosing the
cause of dementia and excluding other differentials.
• Diagnosis is based exclusively on clinical assessment .
61
Clinical Practice Guideline for Dementia
A basic dementia screen should be performed at the first assessment include:
• Routine hematology e. g. full blood count (FBC) and erythrocyte
sedimentation rate (ESR)
• Biochemistry tests (including renal profile, calcium, glucose, and renal and
liver function)
• Thyroid function tests
• Serum vitamin B12 and folate levels
• ECG and CXR for comorbidities
• Routine screening for syphilis is not indicated for all cases, only for suspected cases or those with features of neurosyphilis.
62
Clinical Practice Guideline for Dementia
Neuroimaging: • Structural neuroimaging: brain CTScan & MRI should be done if available
to look for intracranial abnormalities (cortical thinning, subcortical white matter changes & subcortical vascular changes)
Functional neuroimaging: functional MRI, magnetic resonance spectroscopy (MRS), positron emission tomography (PET) & single emission computed tomography (SPECT). Functional neuroimaging is useful for early detection of dementia, subtyping of dementia & predicting changes of MCI to AD.
Neuroimaging biomarkers eg. radioligands Pittsburgh Compound-B (PIB) for PET binds directly to ß amyloid bodies in AD.
Not recommended routinely in diagnosis of dementia
63
Clinical Practice Guideline for Dementia
Genetic biomarkers and plasma lipoproteins
• Useful as prognostic markers for those at risk or to monitor drug therapy
• Impt CNS biomarkers :β amyloid, ApoE, total tau and hyperphosphorylated tau (p-tau).
• In AD, β amyloid is reduced and CSF tau is raised.
• ApoE epsilon (ε) 4 allele is a genetic risk factor for dementia with stroke, including vascular dementia (VaD) and AD with cardiovascular diseases (CVD).
• Not recommended routinely in diagnosis of dementia
64
Treatment of Dementia
3 basic approach to management
• Psychosocial measures
• Behavioural therapy
• Pharmacotherapy
65
Current Treatment Approaches
Behavioural and psychological symptoms of dementia (BPSD)
• Agitiation
• Inappropriate verbal, vocal or motor activity. Symptoms: physical aggression; verbal aggression, wandering
• Depression • Self-pity, rejection sensitivity, anhedonia and psychomotor disturbance
• Psychosis • Visual or auditory hallucinations, delusions
• Sleep-wake pattern disturbance • Disturbances of sleep and day-night reversals
• Anxiety • Pacing, wringing of hands, fidgeting, Godot syndrome (anxiety regarding upcoming events),
fear of being left alone
• Disinhibition • Inappropriate behaviour, emotionally unstable,poor insight
and judgement
• Apathy • Appetite problems • Incontinence
67
Reversible causes of BPSD
• Visiual and auditory disturbances
• Medical illnesses (e.g. urinary infections)
• Drugs
• Pain
• Fatigue
• Constipation
• Environmental changes (illumination, temperature,
change of location, over- or under-stimulation)
68
Treatment of the BPSD
• Evaluation of type, intensity and frequency of symptoms
• Identification and treatment of reversible causes
• Caregiver education
• Non-pharmacological treatment (1st line treatment)
• Pharmacological treatment if symptoms impact severely on patients’ and caregivers’ lives
69
Non-pharmacological treatment of the behavioural symptoms of AD
• Environmental modifications (e.g. music, noise, plants, animals)
• Speak slowly, gentle touch
• Simple commands using gestures
• Behavioural management techniques
• Structured activities and use of schedules
• Massage, aromatherapy
• Physical exercise • Pet therapy
70
Pharmacological treatment of the behavioural symptoms of AD
Classes of drugs • Antipsychotics
• Conventional (es. haloperidol, phenothiazines) • Atypical (risperidone, olanzapine, quetiapine, clozapine,
aripiprazole) • Caution: Black box warning!
• Antidepressants • Benzodiazepines • Anticonvulsants • ChEIs • Memantine
71
Pharmacotherapy for AD
• Cholinesterase Inhibitors (ChEI)
– Mild to Moderate AD: Rivastigminine, Galantamine
– Mild, Moderate and Severe AD: Aricept® (Donepezil)
• N-Methyl-D-aspartate (NMDA) Receptor Antagonist
– Moderate to Severe AD: Memantine
72
Cholinesterase Inhibitors
Generic Brand name
Exelon Rivastigmine
Donepezil Aricept
Galantamine Reminyl
73
EFNS recommendations for the treatment of dementia
Alzheimer’s disease
• Start ChEIs early at diagnosis
• Memantine alone, or in combination with a ChEI, in patients with moderate to severe Alzheimer’s disease
• Insufficient evidence for the use of ginkgo biloba, anti-inflammatory drugs, nootropics, selegiline, oestrogens, vitamin E or statins
Parkinson’s disease dementia
• ChEIs (rivastigmine is the only ChEI approved for PDD)
• Insufficient evidence for the use of memantine
74
75
Starting ChEI therapy
Rivastigmine Donepezil Galantamine
Patch Capsule Capsule Capsule
Starting dose 4.6 mg/24 h 4 mg b.i.d. 5 mg q.d. 4 mg b.i.d.
Titration
(tolerability
permitting)
One-step dose
increase after
4 weeks
Increase dose by
4 mg b.i.d. every
4 weeks
Increase dose after
4–6 weeks
Increase dose by
4 mg b.i.d. every
4 weeks
Target dose 9.5 mg/24 h 12 mg b.i.d. 10 mg q.d. 12 mg b.i.d.
75
Challenges with ChEI therapy
• Not a cure
• Underdosing and poor treatment compliance are key issues
• The answer is to improve therapeutic
benefit by:
• Optimizing dosing
• Monitoring treatment compliance
• Simplifying administration
• Minimizing side effects with smooth drug delivery
76
Most common side effects of ChEIs
77
1. Prescribing information for oral donepezil (2007), galantamine (2007) and
rivastigmine (2006)
2. Winblad B, et al. Int J Geriatr Psychiatry 2007;22:456–67
Prescribing information (older oral meds)1 Patch study2
Placebo Donepezil
10 mg/day
Galantamine
16–24 mg/day
Rivastigmine
6–12 mg/day
Placebo Rivastigmine
9.5 mg/24 h
Nausea 6–12% 11% 24% 47% 5% 7%
Vomiting 3–6% 5% 13%
31% 3% 6%
Diarrhoea 5–11%
10%
9% 19%
3% 6%
Transdermal therapy appears to be an effective
method of reducing reports of nausea and
vomiting
Starting transdermal ChEI therapy
78
Rivastigmine
4.6 mg/24 h
patch
Rivastigmine
9.5 mg/24 h
patch
Starting dose Target dose
4 weeks
One-step dose increase
79
Algorithm for starting or switching to rivastigmine transdermal patch
Start on
4.6 mg/24 h patch
4 w
ee
ks
Switch directly to target
dose 9.5 mg/24 h patch
What oral dose is the patient receiving?
Increase to
9.5 mg/24 h patch
Is the patient already receiving oral rivastigmine?
NO YES
< 6 mg/day 6–12 mg/day
Rationale for a transdermal patch in Alzheimer’s disease
80
Providing continuous drug delivery over 24 h for longer duration of action
Allowing easier and faster access to higher doses
Reducing side effects by providing smooth drug delivery
Simplifying treatment for elderly patients often taking many other medicines
Making administration independent of food intake
Avoiding the first-pass effect
Helping family members to monitor treatment compliance
Providing visual reassurance of treatment
Smooth, continuous delivery by transdermal patches keeps drug levels in optimal “therapeutic window”
81
Increased
side effects
Poor activity
Optimal
therapeutic
window
Dru
g le
ve
l in
th
e b
loo
d
Peak
Oral Dose Trough
Patch Time
82
Rivastigmine patch: Easy to apply
• Visually reassures that medication is being taken
• Can be dosed at any time of day, with or without food
• Try to apply the patch at about the same time every day
• Apply to: • Upper and lower back • Upper arm • Chest
• The skin must be dry and hairless before the patch is applied
• Normal daily activities, such as bathing, are permitted
Clinical benefits of rivastigmine patch
83
Introducing the “next generation of ChEIs”
Smooth, continuous drug delivery over 24 h
Easier and faster access to high dose efficacy
Avoids the gastrointestinal tract
Target dose provides similar efficacy to highest dose capsules, with three
times fewer reports of nausea and vomiting
Physicians can be more aggressive with dosing without side effect trade-off
Caregiver preference, ease of use, improved tolerability and easier access
to high dose efficacy all have potential to improve compliance potentially
leading to a better clinical outcome
1st cholinesterase inhibitor launched for Alzheimer’s disease treatment
Easy dosing: ONCE-daily
Treatment benefits: Improves COGNITION, BEHAVIOUR, ADL FUNCTION & GLOBAL FUNCTION.
Reduce caregivers burden
Well tolerated, less incidence of adverse events
Extensive clinical publication including MCI, Mild to Severe AD, VAD, Neuroprotection, etc.
1st & ONLY Cholinesterase inhibitor indicated for
Full Spectrum AD Therapy
(Mild, Moderate and Severe AD) 84
Aricept Evess® 5 mg General tablet (Plain)
(Don’t contain active ingredient)
Shortly after
dropping in 30
cc of water
(after 3
seconds)
85
Ebixa (Memantine)® Prescribing practicalities
Ebixa Formulations
• Film-coated tablet (10 mg, 20mg) and oral-drop solution (10 mg/g of solution)
• The two formulations are bioequivalent and are therefore clinically equivalent
• Both formulations should be taken orally, and can be taken either with or without food
Dosing and administration
• The maximum daily dose is 20 mg once daily in adults
• To reduce the risk of side effects, treatment should be initiated with 5 mg once daily, and titrated upwards by 5 mg/week over a period of 3 weeks
• Both formulations should be taken orally either with or without food
• Recommended dose for elderly patients (>65 years of age) is 20 mg once daily
• Cautions in renal and liver failure
H. Lundbeck A/S, Ebixa® SmPC
Undesirable Effects
Undesirable Effects
Summary: • Treatment of BPSD is mainly behavioural therapy.
Pharmacotherapy is indicated when behavioural treatment fails.
• ChEIs are efficacious for mild to moderate AD for at least 6 months, with significant benefits seen in:
oActivities of daily living oBehavioural disturbances oCognitive function
• Higher doses generally associated with greater efficacy. • Memantine is an option for the treatment of moderate to
severe AD • Adverse events associated with oral ChEIs are typically
cholinergic in nature (nausea, diarrhoea, vomiting).
91
Terima Kasih
92