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Dementia: Clinical Challenges
Caroline Harada, MDUABJune 2, 2013
Disclosures/Funding
Donald W. Reynolds Foundation
LEARNING OBJECTIVES
Describe the benefits and burdens of cholinesterase inhibitors and NMDA antagonists
Name five essential items to consider when evaluating home safety in dementia patients
Articulate the risks of antipsychotics in older adults with dementia and list three non-pharmacologic alternatives
Describe the reasons why feeding tubes are not recommended in end-stage dementia
Roadmap
Dementia epidemiology, definitions, and workup
Early stage: dementia medications
Moderate stage: agitation, home safety
Advanced stage: feeding tubes
Ms. H.
69 yo woman with chronic low back pain, hyperlipidemiaComplains of 2 years of memory impairment, now worsening
Epidemiology
Dementia in the US population
Over 65: 5-10% Over 85: 30-50%
Gauthier S et al. Lancet 2006. 376: 1262-1270. Kennedy, GJ. Geriatric Medicine, 4th Ed. Cassel et al, Eds. 2003. p.1079
Daughter confirms patient forgets things she has been told, is no longer able to manage her personal finances or drive
Physical examination unremarkable
Workup reveals normal labs, head CT shows mild atrophy
Cognitive Screening
Mini Cog:
- apple
- penny
- table
✓✗✓
Diagnostic criteriaDecline in 2 of the following 5 domains:
1. Memory2. Language3. Visuospatial skills4. Executive function
Handling complex tasks Judgment/reasoning
Rule out delirium, psychiatric disordersDecline from baselineResults in a decline in function
Knopman DS. Mayo Clin Proc. Feb 2006; 81(2):223-230.
Ms. H’s daughter says, “well, I’m just so relieved this is dementia and not Alzheimer’s!”
Dementia types
Alzheimer Disease
Mixed
Vascular
DLB
Other
60%
15-20%
5-10%5-10%
5%
Mild Cognitive Impairment (MCI)
Subjective complaint Objective findings of memory impairment Minimal interference with function
MCI types: Amnestic, multiple domains
In the US population over 65: : 3-19%
Gauthier S et al. Lancet 2006. 376: 1262-1270.
Alzheimer Disease
New diagnostic criteria published in 2011 Clinical criteria
Insidious onset of months to years Progression of cognitive decline Amnestic or nonamnestic symptoms Differential diagnosis of Alzheimer dementia
Biomarkers Accumulation of amyloid beta Neuronal injury
McKhann GM et al. Alzheimer Dement 2011
Dementia with Lewy Bodies
Characteristics Prominent visual hallucinations Parkinsonism Fluctuations in cognition Sensitivity to antipsychotics (EPS) REM sleep behavior disorder
Knopman DS. Mayo Clin Proc, 2006; Blass DM, Rabins PV. Annals Int Med, 2008
Ms. H: Early stage
“Is there a medicine that can help me?”
Dementia Drugs
Acetylcholinesterase Inhibitors
Donepezil (Aricept)
Galantamine (Razadyne)
Rivastigmine (Exelon)
Efficacy
Rogers: Neurology, 1998.136-145
Trinh NH et al. JAMA. 2003 Jan 8;289(2):210-6.
Statistically significant? Yes.
Clinically significant? Maybe?
Adverse effects: nausea, vomiting, diarrhea, dizziness, tremor, and bradycardia
Efficacy: Cholinesterase Inhibitors
Raina, P et al. Ann Intern Med. 2008
Dementia Drugs Match
NMDA antagonist: Memantine (Namenda)
Mechanism of action: inhibition of glutamate
Randomized, placebo-controlled trials show similarly small (but statistically significant) benefits
Reisberg B et al. NEJM 2003; Raina, P et al. Ann Intern Med. 2008
NMDA antagonist
Memantine (Namenda)
Reisberg B et al. NEJM 2003
FDA-approved only for moderate to severe dementia
Adverse effects: minimal
Benefit to combination therapy with cholinesterase inhibitors: unclear
Howard R et al, N Engl J Med. 2012 Mar 8; 366(10):893-903
Ketone BodiesCaprylic Triglyceride (Axona)
Axona
Drug candidates that to date have no proven efficacy
Anti-inflammatories
Statins
Estrogen
Antioxidants
Gingko biloba
Fish oil, omega-3 fatty acids
Vitamin E
Lowering homocysteine
Alcohol, especially wine
Huperzine
Curcumin
Nicotine
Insulin & insulin sensitizers, ketones
What’s on the horizon?
Cummings JL, NEJM, 2004
APP Amyloid beta
Aggregation into plaques
Neurofibrillary tangles
Excitotoxicity
Oxidation
Inflammation
Neurons die or
malfunction Neurotransmitter
deficit
Dementia
AD recent developments
A mutation in the gene encoding amyloid precursor protein that prevents cleavage into amyloid‐β (Aβ) protects against late‐onset AD
Monoclonal antibodies to Aβ failed in Phase III trials
Disease process seems to start >20 years before onset of symptoms
Misfolded tau protein and amyloid beta may be transferred from neuron to neuron, like prions?
Wiener MW, Nature Reviews Neurology 2013
If you want to know more about ongoing research…
Clinical trials at UAB: Mild Cognitive Impairment: ADNI Alzheimer’s Disease: Ceregene, IVIg, ADNI Call Denise Ledlow at (205)996- 3679 (99M-EMRY)
or (205)934-6223
www.alz.org to access the clinical trials index
Ms. H: Moderate stage
Clock draw test
Ms. H is now losing weight (5 lbs in last 6 months)
Has moved in with her daughter because she requires assistance with all IADLs and also bathing
Daughter works as a nurse and has to be at work before patient wakes up in the morning
Home Safety
A classic story… Ms. H has chronic nocturia and low back pain. She visits
her primary care provider complaining of worsening of her back pain. The pain is so bad that she has stopped going out and prefers to spend the day in her recliner chair. The PCP notes some paravertebral muscle spasm and prescribes methocarbamol.
Pt gets up to go to bathroom at night, falls, and is unable to get up.
She lies on the floor until her daughter returns from work the next evening. Her daughter finds her lying in feces, somnolent and more confused than her baseline.
She is brought to ER, where she is found to be delirious, dehydrated, and in acute renal failure.
Concept Map
A concept map is a diagram showing the relationships among concepts. It is a graphical tool for organizing and representing knowledge.
Wikepedia, “Concept map” Accessed Sept 4, 2009
Example Concept MapTired person Skips
exercise
Eats muffins
Drinks lots of coffee
Gains weight
Doesn’t sleep well at night
Concept mapping exercise Ms. H has chronic nocturia and low back pain. She
visits her primary care provider complaining of worsening of her back pain. The pain is so bad that she has stopped going out and prefers to spend the day in her recliner chair. The PCP notes some paravertebral muscle spasm and prescribes methocarbamol.
Pt gets up to go to bathroom at night, falls, and is unable to get up.
She lies on the floor until her daughter returns from work the next evening. Her daughter finds her lying in feces, somnolent and more confused than her baseline.
She is brought to ER, where she is found to be dehydrated and in acute renal failure
Concept MapMetho-
carbamol
Hospital ization
FallDelirium
Back Pain
Concept MapMetho-
carbamol
Hospital izationDaughter
at work all day
Fall
Dementia
Poor po intake
Delirium
Back Pain
Concept MapNocturia
Immobility
Metho-carbamol
Hospital izationDaughter
at work all day
Fall
Deconditioning
Dementia
Poor po intake
Delirium
Back Pain
Concept MapNocturia
Immobility
Metho-carbamol
Hospital izationDaughter
at work all day
Fall
Deconditioning
On floor 18 hours
Dementia
Poor po intake
Delirium
Back Pain
Concept MapNocturia
Immobility
Metho-carbamol
Hospital izationDaughter
at work all day
Fall
Deconditioning
On floor 18 hours
Dementia
Poor po intake
Dehydra-tion, muscle
injury
Acute kidneyinjury
Delirium
Back Pain
Concept MapNocturia
Immobility
Metho-carbamol
Hospital izationDaughter
at work all day
Fall
Deconditioning
On floor 18 hours
Dementia
Poor po intake
Dehydra-tion, muscle
injury
Acute kidneyinjury
Delirium
Back Pain
Concept MapNocturia
Immobility
Metho-carbamol
Hospital izationDaughter
at work all day
Fall
Deconditioning
On floor 18 hours
Dementia
Poor po intake
Dehydra-tion, muscle
injury
Acute kidneyinjury
Delirium
Back Pain
Home Safety Issues to Consider
Driving
Cooking
Pets
Children
Finances
Vulnerability to criminals
Wandering
Medication administration
Hygiene
Falls
Weight loss
Agitation
Defining agitation
Aggression Physical Verbal
Resistance to care
Delusions
Hallucinations
Repetitive vocalizations
Wandering
Behavioral and Psychiatric Symptoms
60-98% of dementia patients
Consequences: increased caregiver stress and unemployment Increased risk of NH placement increased health care costs more rapid cognitive decline
30% of cost of caring for patients with dementia is due to BPSD
Pharmacologic Management
AntipsychoticsAcetyl cholinesterase inhibitorsNMDA antagonistsAntidepressantsAnticonvulsants/mood stabilizers
Sink et al, JAMA, 2005; Trinh N 2003
Efficacy of Antipsychotics
Moderate to low efficacy
CATIE-AD trial RCT of olanzapine, risperidone, quetiapine 63% discontinued by 12 weeks Olanzapine and risperidone were slightly better
than placebo at controlling agitation Did not improve patient quality of life scores Patients on placebo often improved
Sultzer Dl et al, Am J Psychiatry 2008, Schneider LS et al, NEJM 2006
Adverse Effects of Antipsychotics
Sedation Tardive dyskinesia Extrapyramidal symptoms (EPS)Weight gainMetabolic syndromeProlonged QTCVA Infection
Schneider LS et al, JAMA 2005; 294: 1934-1943 Wang PS et al, NEJM 2005; 353:2335-41
Black Box Warning
Increased risk of mortality 2.3% vs 3.6% Mortality 1.6 times as high as placebo
Therefore: Antipsychotics should be used ONLY for severe
symptoms Doses should be low Discontinuation should be attempted early and
often
Discontinuing Antipsychotics
Federal regulations recommend discontinuation after 3-6 months
110 patients with BPSD responsive to risperidone Risk of relapse was high for patients who continued
risperidone (33%) Risk of relapse was almost double in patients who
stopped risperidone after 4-8 months of treatment (60%)
Devanand DP et al, NEJM 2012
Atypical Antipsychotics
Risperidone (Risperdal)
Quetiapine (Seroquel)
Olanzapine (Zyprexa)
Ziprasidone (Geodon)
Aripiprazole (Abilify)
Clozapine (Clozaril)
Cholinesterase Inhibitors and Memantine
Some evidence of MILD benefit for agitation
Studies limited by methodologic issues
Rodda J, International Psychogeriatrics 2009
Antiseizure medications
Valproic acid
Carbamazepine
Gabapentin
Benzodiazepines
Limited evidence
Likely unhelpful due to potential for: paradoxical agitation increased risk of falls and hip fracture risk of oversedation
Non Pharmacologic Management
Try to analyze the behavior using A-B-C
A- antecedentB- behaviorC- consequence
http://www.youtube.com/watch?v=5RxX72u3WCc
Wandering outside the home
Safe Return bracelet
Bells on doors
Notify police and neighbors
Trying to “go home”
Distraction
Identify/address trigger
Create a daily routine
Keep environment familiar
Ensure adequate sleep
Provide respite to caregiver
Resisting Bathing
Consider alternative settings for bathing
Check water and room temperature
Minimize time naked and exposed
Change the caregiver who does bathing
Frequent reassurance and explanation
Fix what you can
Also: Correct sensory deficits Create daily routine with activities Create a structured environment Ensure adequate sleep and eating Provide respite and support to caregivers Redirection and distraction
Gitlin LN et al, JAMA 2012
Ms. H: Advanced stage
Ms. H: Advanced Stage
Bedbound
Dependent for all IADLs and ADLs
Minimal speech
Now does not swallow when food is put in her mouth
Feeding tubes
Improved Survival?
Observational studies: Study of 99 hospitalized patients with advanced
dementia survival without PEG 189 days, with PEG 195 days
(P=0.9) Mortality is high after G-tube placement
6-28% in first 30 days 60% mortality at 6 months, perhaps 90% at one
year
Murphy LM. Arch Int Med, 2003; Gillick MR. N Engl J Med. 2000; Meier DE et al, Arch Int Med 2001
Patient Comfort?
Studies of dying cancer or ALS patients with anorexia: Little hunger or thirst
Any thirst can be treated with mouth swabs and ice chips
Sense of euphoria (endorphins) Goes away if fed
Patients were left alone more
Gillick MR. NEJM, 2000
Comfort?
Eating is pleasant! depriving a person (who wants to eat) of the
pleasure of eating does not increase comfortPulling out the tube Return trips to GI or IR Restraints
More stool and urine Caregiver burdens high
Finucane T et al. JAMA 1999
Aspiration
Aspiration of oral secretions is not reduced by feeding tubes
Aspiration of refluxed stomach contents is still also possible… and perhaps more likely given tendency towards gastric distension, low LES tone in tube-fed patients
Mitchell SL. JAMA 2007
Slow hand feeding Survival can be substantial despite emaciation
and poor po intake
Human, nurturing, time for closeness with loved ones
Finucane TE, JAMA, 1999
Ms. H.
Feeding tube is not placed, enrolled in hospice
She eats 3-5 mouthfuls of pureed food or ice cream each day
7 weeks later, she develops symptoms consistent with aspiration pneumonia
Dies without discomfort, with her children at her bedside, 9 years from the time of diagnosis
Dementia prognosis
Life expectancy from the time of diagnosis:
Alzheimer Disease 5-10 years
Vascular Dementia 4 years
Dementia with Lewy Bodies 4 years
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