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