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444 final > Cognitive Impairment Pt 2 > Flashcards

Cognitive Impairment Pt 2 Flashcards

1
Q

Diagnosis – Process, Rule out

A
  • Interview of family/caregivers
  • Neurological and physical exam
  • CT/MRI Head
  • Neuropsychological testing
  • CXR
  • ECG
  • EEG
  • Blood work - CBC, electrolytes, Ca, Mg, etc.
  • Review of medications
  • Assessment of substance use
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2
Q

Revised Research Criteria

A
  • Focus on biomarkers
  • PET
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3
Q

NINCDS-ARDVA Diagnosis - AD

A
  • Definite
  • All criteria for Probable AD
  • Histopathologic evidence
  • Probable
  • Progressively impaired memory, cognitive function
  • Multiple domains affected
  • Onset > age 40 years
  • Possible
  • Atypical
  • Gradually progressive decline
  • One domain affected
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4
Q

DSM V vs IV

A
  • DSM V changes terminology
  • Neurocognitive disorder (NCD)
  • Dementia derived from ‘without mind’
  • Same cognitive domains assessed
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5
Q

major neurocog disorder diagnostic criteria
major or mild meurocog disorder due to alzheimer’s disease

A

sig cognitive declinefrom prev lvl of performance
cog deficits interfere w/ indepence in everyday activities

Alzheimer’s: insidious onset and progression of impairment

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6
Q

Goals of Treatment

A
  • Minimize cognitive decline
  • Maintain function
  • Maintain socialization
  • Prevent harm of patient
  • Delay institutionalization?
  • Prevent malnutrition
  • Support caregiver
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7
Q

Non-pharmacological Treatment

A
  • Family support
  • Cueing, scheduling
  • Orientation
  • Environmental modifications
  • Exercise
  • Therapy sessions
  • e.g. music therapy, pet therapy
  • Cognitive training
  • Evidence is variable
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8
Q

Pharmacologic Therapy

A
  • Cure
  • Not available
  • Symptomatic treatment
  • Cholinesterase inhibitors
  • Memantine
  • Disease Modifying treatment
  • Aducanumab
  • Future biologics
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9
Q

Donepezil Rivastigmine Galantamine

A

Precautions/ Contraindications bradycardia (pulse <50 bpm)
reactive airway disease
active peptic ulcer disease
seizures
New warnings – risk of NMS, rhabdomyolysis
(Note: In US rivastigmine has a black box warning for GI complications; N/V, anorexia)
Side effects N/V, insomnia, vivid dreams,
muscle cramps, fatigue, urgency

SJS for galantamine

cholinesterase inhibitors

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10
Q

A Systematic Review and Meta-Analysis of the
Effectiveness of Acetylcholinesterase Inhibitors and
Memantine in Treating the Cognitive Symptoms of
Dementia –6 months

A Systematic Review and Meta-Analysis of the Effectiveness of Acetylcholinesterase Inhibitors
and Memantine in Treating the Cognitive Symptoms of Dementia – 12 months

A
  • Effect of CI in AD interpreted as
    benefit of 0.91 MMSE points at
    6 months
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11
Q

Cholinesterase Inhibitors

A

Expectations
* Maintain cognitive function for a period of time
* Stabilization vs improvement
* NNT = 12
* Stabilize decline in:
* Cognitive tests
* Functional assessments
* Behaviours
* Improve:
* Caregiver burden

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12
Q

Duration and Choice

A
  • Trial: 3-6 months
  • Discontinuation may lead to abrupt decline
  • Approaching severe stage
  • consider behaviour versus cognitive goals
  • One not superior to another
  • Often choice is for once daily formulation
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13
Q

Cholinesterase Inhibitors
Side effects
Contraindications

A

Side effects
* Increased effect of ACh
* bradycardia
* bronchospasm
* GI complaints (black box warning on rivastigmine)
* Neurological – seizures, syncope, dizziness
* Generalized complaints – fatigue
Contraindications
* Active PUD
* Bradycardia
* Asthma
* QT prolongation
* donepezil

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14
Q

Cholinesterase Inhibitors - Dosing

A
  • When should they be taken?
  • AM vs PM
  • All taken with food
  • Initial dose – subtherapeutic
  • Titration schedule to reach goal/max dose
  • Response is dose related
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15
Q

Switching

A
  • Washout necessary if side effects
  • Washout for no more than 7 days
  • If no toxicity demonstrated, switch immediately to equivalent dose
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16
Q

Cholinesterase Inhibitors - Cost

A
  • Economic impact
  • Shifts time spent in non-severe AD
  • Evidence of decreasing overall health care costs
  • Controversies
  • Is cost shifted to the family/caregivers?
  • Should medications be covered by provincial plan?
17
Q

Cholinesterase Inhibitors - Summary

A
  • Benefit is modest
  • Early initiation is most beneficial
  • Side effects are often poorly tolerated by older adults
18
Q

Memantine (Ebixa)

A
  • NMDA receptor antagonist
    Rationale
  • Levels of the excitatory neurotransmitter glutamate are elevated
  • Glutamate leads to cell excitation, calcium dysregulation, and cell death
  • Memantine prevents calcium influx
19
Q

Memantine (Ebixa)
other info

A

Indication Moderate to severe AD
Monotherapy or as adjunct with CI
Pharmacology Blocks the effect of glutamate by blocking the NMDA receptors
Plasma T1/2 60-80 hours
Elimination Unchanged in the urine; pH dependent
Interactions Bicarbonate
Carbonic anhydrase inhibitors
NMDA receptor antagonists: ketamine, amantadine, dextromethorphan
Effect of interactions Decrease elimination of memantine
Titration Week 1: 5 mg every morning
Week 2: 5 mg bid
Week 3: 10 mg every morning, 5 mg every evening
Week 4: 10 mg bid
Goal/Maximum dose 20 mg/day
Precautions Seizure disorder
Urinary tract infection (altering urine pH)
Severe renal impairment
Side effects Increased confusion (early in therapy)
Increased blood pressure
Corneal opacities
GI complaints
Monitoring Blood pressure
Annual eye examination

20
Q

Memantine - Evidence

A

Memantine
20 mg vs
placebo for
mod/severe
AD –
Cognitive
function

Memantine
20 mg vs
placebo for
mod/severe
AD –
ADL
(Function)

Memantine
20 mg vs
placebo for
mod/severe
AD –
Behaviour/
Mood

21
Q

Memantine
Studies
use

A

Studies
* Compared to placebo
* In combination with a CI
* Outcomes studied for mod/severe AD:
* Function, Behaviour, Caregiver outcomes
* Note that cognition not as prioritized
Use:
* Moderate to severe AD
* Can be added on to a CI

22
Q

Other Therapies

A
  • NSAIDs
  • Anti-inflammatory hypothesis; toxicity
  • Vitamin E
  • Evidence but not replicated
  • HT
  • Not indicated for men’s or women’s health
  • Supplementation may worsen
  • NHP
  • E.g. fish oil, ginkgo, ginseng, lecithin
  • Inconsistent findings
  • Evidence for the original food vs the supplement
  • Evidence if there is a deficiency
23
Q

Aducanumab

A
  • Classification
  • Human monoclonal Ig G1 antibody
  • Targets amyloid-beta aggregates (soluble oligomers, insoluble fibrils)
  • Clears amyloid plaques from the brain
  • Availability
  • Approval by FDA 2021
  • Submitted to Health Canada for review
  • Controversies
  • FDA approval went against independent Peripheral and Central Nervous System Drugs advisory committee
  • Approved without published studies
  • Biogen withdrew a manuscript from JAMA
  • Approved through Accelerated Approval Pathway
  • Phase 3 trials terminated for futility after interim analysis
  • Reduction in amyloid plaques is a surrogate endpoint
  • Amyloid not proven to be the sole cause of AD
  • Reduction in amyloid not necessarily lead to improved cognitive outcomes
  • Primary and secondary outcomes did not meet minimum clinically important difference
  • MMSE should be 1-3 points for MCID; EMERGE trial was only 0.6 points
  • IV infusion q4weeks
  • Cost (56K USD/y/patient)
  • MRI monitoring to monitor for ARIA
24
Q

Aducanumab

A
  • Classification
  • Human monoclonal Ig G1 antibody
  • Targets amyloid-beta aggregates (soluble oligomers, insoluble fibrils)
  • Clears amyloid plaques from the brain
  • Availability
  • Approval by FDA 2021
  • Submitted to Health Canada for review
  • Controversies
  • FDA approval went against independent Peripheral and Central Nervous System Drugs advisory committee
  • Approved without published studies
  • Biogen withdrew a manuscript from JAMA
  • Approved through Accelerated Approval Pathway
  • Phase 3 trials terminated for futility after interim analysis
  • Reduction in amyloid plaques is a surrogate endpoint
  • Amyloid not proven to be the sole cause of AD
  • Reduction in amyloid not necessarily lead to improved cognitive outcomes
  • Primary and secondary outcomes did not meet minimum clinically important difference
  • MMSE should be 1-3 points for MCID; EMERGE trial was only 0.6 points
  • IV infusion q4weeks
  • Cost (56K USD/y/patient)
  • MRI monitoring to monitor for ARIA
25
Q

Aducanumab - Evidence

A
  • 2 clinical trials (ENGAGE, EMERGE)
  • Enrolled patients with MCI or early AD
  • Confirmed diagnosis with PET scan showing amyloid pathology
  • Randomized to high dose aducanumab x 18 months or placebo
  • Patients stratified by ApoE epsilon-4 status
  • Dose was modified after phase 1b
  • Study termination
  • Pre-specified interim analysis March 2019 showed futility
  • Biogen conducted post-hoc analysis showing
  • Safety
  • Most common:
  • headache (20 vs 15%)
  • Falls (15 vs 12%)
  • Diarrhea
  • Confusion/delirium/altered mental status
  • ARIA (amyloid related imaging abnormalities)
  • Swelling, sometimes associated with headache, confusion, dizziness, vision changes, nausea
  • Edema or effusion 35% vs 2.7%
  • Microhemorrhages 20.5% vs 6.5%
  • Angioedema, urticaria

444 final (16 decks)

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