Treatment Options for Dementia

Treatment Options for Dementia
By:Deb Bynum, MD
Division of Geriatric Medicine
University of North Carolina

Objectives
* 1. Understand the use of cholinesterase inhibitors in the treatment of alzheimer type, vascular and mixed dementias
* 2. Review the current literature regarding the use of Memantine for severe dementia
* 3.Understand the appropriate use of nonpharmacologic strategies for behavioral problems with dementia
* 4. Review the appropriate use of antipsychotics for psychosis and behavioral symptoms in dementia
* 5. Discuss possible means of preventing dementia

Overview
* 1. Cholinesterase inhibitors in the treatment of AD, vascular and overlap dementias
* 2. Memantine
* 3. Treatment of behavioral symptoms
* 4. ?Prevention
* 5. Future Directions


The Cholinergic Hypothesis
* Depletion of acetylcholine and nicotinic receptors thought to occur early and relate to memory impairment with AD
* Focus on AD treatment with Acetylcholinesterase inhibitors: Recommended as first line treatment for patients with mild to moderate AD


Cholinesterase Inhibitors
* Trials in patients with mild to moderate disease (10-24 on MMSE)
* On average these drugs seem to stabilize cognitive function and activities of daily living and may have benefits with QOL and behavioral disturbances for at least one year
* Side Effects: GI

Tacrine
* Trials demonstrating delay of cognitive decline by 6 months
* Delayed time to nursing home placement: At 800 days, 45% in low dose or no tacrine underwent placement vs 21% in high dose tacrine group
* Evidence for long term cost effectiveness
* Reversible hepatotoxicity in 50%

Donepezil (Aricept)
Three large RCT demonstrate modest effectiveness in stabilizing cognitive function
Well tolerated (no difference in adverse events compared to placebo)
Not hepatoxic, no significant drug-drug interactions
Single bedtime dose: start 5 mg, increase to 10 mg after 4-6 weeks
Most common side effects: sleep disturbance, GI

Rivastigmine
* May have increased selectivity for hippocampus and neocortex (areas affected by AD)
* Modestly effective in treatment of mild to moderate AD (but only at high doses of 6-12 mg/day)
* Recommended starting dose: 1.5 mg BID with breakfast and dinner
* Minimize GI side effects with 4-6 week titration, increasing to 3 mg BID, 4.5 mg BID, 6 mg BID
* More GI side effects, weight loss (dose dependent)

Galantamine
* Potential second mechanism: modulator at nicotinic cholinergic receptor
* Three large RCTs indicate effectiveness in mild to moderate AD (same degree as other agents) at doses of 16, 24, 32 mg/day
* Open label 6 month extension of US trial: Possible disease modifying effect
* Starting dose: 4mg BID with meals, increase by 4mg BID every 4-6 weeks

Cholinesterase inhibitors in moderate to severe AD
* RCT of donepezil vs placebo: 24 week international trial of 290 patients (MMSE 5-18)
* 63 % of donepezil treated patients were stable/better vs 42% in placebo group

Comparison of Cholinesterase Inhibitors…
* Cochrane Dementia Group: 3 systematic reviews on efficacy of donepezil, rivastigmine, and galantamine
* Each drug seems to have similar treatment effect at 6 months on global and cognitive rating scales
* No double blind head to head trial

Cholinesterase Inhibitors and AD: Summary
* Approved for treatment of mild to moderate AD
* Probably effective in treatment of more severe AD
* Goal: stabilization (not miracle drugs)
* Delay in nursing home placement, decline in ADLS
* Probably benefits behavioral and functional status as well
* Data suggest no big difference in efficacy among the 3 agents, although donepezil is easier to titrate and better tolerated

Cholinesterase Inhibitors and Other Dementias…
* Vascular dementia and Dementia with Lewy Bodies each account for 10-15% cases
* Prominence of mixed pathology (especially vascular and AD in older population)

Galantamine: Vascular and AD/Vascular Dementia
* Placebo controlled trial, 6 months, 592 patients
* 50% in study had AD plus radiological evidence of CVD, 41% had probable vascular dementia, 9% indeterminant
* Results for the whole group were similar to previous trials in typical AD : 74% galantamine groupwere improved/stable vs 59% in placebo group
* AD-CVD subgroup similar effects to prior trials with AD patients


Summary of Galantamine and Vascular dementia
* Patients with typical features of AD mixed with features of CVD or evidence of CVD on radiological tests seem to respond similarly to patients with AD alone
* Subgroup with CVD alone does better over long term (even with placebo)
* Surprise: patients with what appears to be only CVD also seem to have some benefit (these patients not traditionally felt to have specific degeneration of cortical cholinergic pathways)

Cholinesterase Inhibitors and Other dementias
* Lewy Body Dementia: may respond even more than AD patients
* Frontal Lobe Dementia: often respond adversely to cholinesterase inhibitors with increased agitation and insomnia

Memantine
* NMDA (glutamate) receptor activation thought to be involved in neurodegeneration
* Memantine: NMDA antagonist aimed at protecting neurons from glutamate mediated excitotoxicity
* Approved in Europe in 2002 for treatment of severe AD (MMSE 3-14)
* Randomized, double blind, placebo controlled study: 166 patients with severe dementia (AD and vascular, MMSE <10)
* Cognitive and Behavioral Rating Scale significantly better with treatment, regardless of dementia type
* Other European studies have looked at treatment for moderate-severe Vascular Dementia, demonstrating similar efficacy
* 28 week RCT of 252 patients with severe AD (MMSE 3-14) in NEJM: memantine associated with less deterioration in cognitive and functional measures than placebo
* Problem: small numbers, high drop out rate
* Preliminary study: 400 patients with severe AD, 6 months RCT of memantine plus donepezil vs placebo plus donepezil: memantine group had significant benefit in comparison

Memantine: Summary
* Approved for treatment of moderate-severe AD
* Likely of benefit also in severe vascular and mixed dementias as well
* Likely will be used in combination with donepezil or other cholinesterase inhibitors
* Cochrane Dementia Group: “memantine is a safe drug and may be useful for treating AD, vascular and mixed dementia, although most of the trials so far reported have been small and not long enough to detect clinically important benefit”

Behavioral Symptoms: Nonpharmacologic Treatment
* Depression, agitation, aggression, wandering, sleep disturbance, paranoia, anxiety
* Assess for/treat depression
* Assess cause for increased symptoms (caregiver, environmental changes, medications, infection)
* Assess for caregiver depression
* ID and avoid triggers of negative behavior
* Redirection
* Environmental modification for wandering
* Sleep hygiene

Use of Atypical Antipsychotics
* Older, “typical” agents such as haloperidol and thioridazine (mellaril) associated with significant extrapyramidal symptoms
* Theoretically combination of dopamine and serotonin effects of atypical agents allow treatment of positive and negative psychotic symptoms with less EPS

Risperidone
* Evidence demonstrates efficacy in treatment of psychotic and behavior symptoms in patients with dementia
* Exacerbates movement disorder in patients with Parkinson’s
* Start .25/day, average daily dose 1-1.5mg/day
* EPS in dose dependent manner (6mg/day)
* Insomnia, hypotension, weight gain
* Elevation of prolactin levels

Olanzapine
* Evidence that it is effective in AD patients
* Increases motor symptoms in PD patients
* Recommended not to use with PD
* Start: 1.25-2.5/day, increase to 5/day (dosages of 10-15/day are not more effective!)
* More sedating than others (more anticholinergic effects)
* Sedation, weight gain, orthostatic hypotension, seizures, glucose intolerance
* Showing promise in patients with AD and PD
* Does not exacerbate movement disorder of PD
* May be first line for PD patients with psychosis
* 12.5 QHS, titrate every 3-5 days
* Sedation, HA, orthostatic hypotension
* ?Cataract formation

Ziprasidone (Geodon)
* New, clinical data lacking
* Non dose-dependent QT prolongation

Clozapine
* Very effective in treating psychosis in PD patients
* The most effective agent in treatment of drug induced psychosis in PD
* Some efficacy with AD patients
* Start: 6.5mg/day
* Agranulocytosis, frequent monitoring limits use

Antipsychotics in Dementia: Summary
* Start very low, monitor for hypotension, P450 effects, sedation, EPS
* Monitor and avoid use as “chemical restraint”
* Avoid if at all possible in Dementia with Lewy Bodies

Prevention of Dementia
* HTN and Hyperlipidemia
o Observational studies show less risk of AD in patients on statin agents (RCTs do not show effect)
o Original HTN in Elderly studies: patients initially on placebo with systolic HTN had persistent elevation in risk of dementia
* Vascular risk factors seem to play role even for AD!
* Evidence lacking for Vit E, Estrogen, NSAIDS

Future Directions
* Amyloid B peptide (plaque component) vaccination
* Amyloid modulators
* ?Anti-inflammatory drugs
* Treatment with statins
* ?Low flow VP shunting

Take Home Points
* Cholinesterase Inhibitors are MODESTLY effective in treatment of mild to moderate AD
* Cholinesterase Inhibitors are probably effective in more severe AD
* No large difference in efficacy between agents, but Donepezil more easily titrated and tolerated
* Evidence to support use of cholinesterase inhibitors for vascular and vascular/AD dementia
* Memantine looks to be effective for more severe AD and vascular dementia, will likely be used in combination with cholinesterase inhibitors
* Behavioral symptoms common, first line of treatment is nonpharmacologic
* Atypical antipsychotics can be effective, but use in low doses and watch carefully for problems (especially EPS, hypotension)
* For PD, quetiapine (seroquel) may be first line for psychotic symptoms
* Avoid antipsychotics with Lewy Body Disease!

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Palliative care of advanced dementia

Palliative care of advanced dementia A patient centered approach
By:VJ Periyakoil, MD
Director, Palliative Care Fellowship Program
Stanford University General Internal Medicine &
VA Palo Alto Health Care System


Main Message
* Currently, patients with dementia do not get access to quality palliative care
* Access to quality palliative care can be facilitated only if we take an inter-disciplinary approach to care


Talk Agenda
* Current state of palliative care for dementia
* Key challenges in providing palliative care for dementia patients
+ Prognostication
+ Decision making
+ Advance care plan
+ Symptom management
+ Caregiver stress

Prognostication questions in dementia
* Patient’s question: “How long do I have before my mind is shot?”
* Health professional’s question: “ Is s/he eligible for palliative care?”
* Family’s question: “How long does s/he have to live ?”
* Caregiver’s question: “ I am exhausted. How much longer can I do this?”

Is dementia a terminal illness? If so, when do they start dying?

Dementia hospice eligibility
* Stage 7 or beyond according to the FAST scale
* Unable to ambulate without assistance
* Unable to dress without assistance
* Unable to bathe without assistance
* Urinary or fecal incontinence, intermittent or constant
* No meaningful verbal communication, stereotypical phrases only, or ability to speak limited to six or fewer intelligible words
* Plus one of the following within the past 12 months:
o Aspiration pneumonia
o Pyelonephritis or other upper UTI
o Septicemia
o Multiple stage 3 or 4 decubitus ulcers
o Fever that recurs after antibiotic therapy
o Inability to maintain sufficient fluid and calorie intake, with 10 percent weight loss during the previous six months or serum albumin level less than 2.5 g per dL (25 g per L)

Schonwetter RS, Han B, Small BJ, Martin B, Tope K, Haley WE. Predictors of six-month survival among patients with dementia: an evaluation of hospice Medicare guidelines. Am J Hosp Palliat Care 2003;20:105-13.

Decision making in dementia
* Hierarchy of decision making
* Competence v. capacity
* Special circumstances

Special circumstances
Case 1: Incapacitated pt with no proxy and unknown preferences
Case 2: Chronically mentally ill pts with no capacity
Case 3: Chronically mentally ill pts with fluctuating capacity

Intact decision making prior to death in the elderly
Alzheimer’s Disease
Diseases other than Alzheimer’s
Lentzer HR et al “ The quality of life in the year before death”. Am J Public Health 82: 1093-1098, 1992
Interface between palliative care and dementia

* Clarity of decision making
o Soft balls ( relatively speaking):
o Hard balls

The decisions themselves are never easy.
Advance care planning
Shades of Gray
Possible levels of care:
Heroic life prolonging measures
* CPR
* “Whopper no veggie*”
* Artificial nutrition
* Artificial hydration
* Antibiotics

What are the goals of care?

Tube feed or not tube feed?
That’s the question
* The facts:
Palliative care symptoms and cognitive impairment
Symptoms
Presentation of these symptoms is skewed
What does dying look like?

* Decline in functional status
* Lack of desire to eat or drink
* Withdrawn
* Sleep- wake state
* Mottling of limbs
* Jaw movement
* Death rattle
* Co-morbid symptoms
* Unpaid
* Overworked
* On-call 24/7
* Sleep deprived
* No social life
* Poor support system

Palliative care of advanced dementia A patient centered approach.ppt

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Geropsychiatry: Delirium and Dementia

Geropsychiatry: Delirium and Dementia
By:Robert Averbuch, MD
Assistant Professor
Department of Psychiatry

Disorders of Cognition
* DSM-IV devotes an entire section to a subset of “organic” disorders that primarily affect cognition: “Delirium, Dementia, and Amnestic and other Cognitive Disorders”

What is “organic”?
* Previous differentiation between mental disorders with a clear “physical or biological” etiology (Organic) and those without (“Functional” or “Primary”)
* Falsely implied that Functional (or primary) disorders have no underlying pathophysiological basis
* Primary mental disorder- not due to a GMC or substance

Disorders of Cognition
* Delirium-disturbance in consciousness and cognition that develops rapidly
* Dementia- multiple cognitive deficits that include memory disturbance
* Amnestic Disorder- primarily memory impairment

Delirium
Delirium: defined
* Disturbance of consciousness (awareness of the environment) and attention,
* PLUS…
o Changes in cognition (ie, “thinking”-memory, orientation, language, etc) OR
o Perceptual disturbances

The Course of Delirium
* Evolves rapidly (hrs to days)
* Usually resolves rapidly as well:
o May be self-limited, persist for weeks, or progress to death
* Degree of impairment fluctuates

Delirium: Associated Features
* Disturbance in sleep-wake cycle
* Easily distracted by irrelevant stimuli
* Changes in activity level
o Restlessness, hyperactivity
o Picking at clothes, getting out of bed
o OR hypoactivity (lethargy)
* Emotional disturbances- mood lability, anger, irritability, euphoria, apathy

Delirium: Associated Features
* Speech or language disturbances
* Perceptual abnormalities- common:
o Illusions, hallucinations, delusions
* Neurological deficits/dysfunction

What Are the Causes?
* DIRECT: Brain pathology: head injury, seizures (during and after), strokes, infections
* INDIRECT: Systemic Illness: electrolyte abnormalities, dehydration, uremia, hepatic encephalopathy, cardiovascular compromise

More Causes of Delirium
* Sensory deprivation
* After surgery (post-operative state)- ie. “ICU Psychosis”
* Side effects of medications or toxins or with abused recreational drugs:
“Substance-Induced Delirium”
o Ex. NMS (Neuroleptic Malignant Syndrome)
o Ex. Serotonin Syndrome

Treating Delirium
* Considered a Medical Emergency
* Supportive care in an ICU setting
* Safety- close monitoring
* Remove offending agent, treat underlying cause

Dementia
Hallmark is Memory Impairment
* Memory problems usually evident early
* Memory impairment alone is not enough to make the diagnosis…

Dementia- defined
* Memory problems AND at least one additional cognitive deficit:
o Aphasia
o Apraxia
o Agnosia
o Problems with “executive functioning”

Details, Details: Aphasia
* Aphasia is a drop off in language function that shows up in a variety of ways

Apraxia
* “impaired ability to pantomime the use of known objects or to execute known motor acts”

Agnosia
* Trouble recognizing or identifying things despite intact sensations (ex. You can see fine, but you can’t recognize a stop sign)
* May include difficulty recognizing family members or even themselves in the mirror

Disturbances in Executive Functioning
* Abstract thinking
* Planning, initiating, sequencing, and stopping behaviors
* May manifest as trouble with novel tasks or new situations

Associated Features
* Spatial disorientation
* Poor insight and judgment means…they get themselves in trouble by overestimating their abilities and underestimating risks
* Perceptual Abnormalities:
o Delusions- especially persecution
o Hallucinations- especially visual

More associated features
* Personality Changes:
o Disinhibition
o Neglect of personal hygiene
o Apathy and withdrawal

Course of Dementia
* Course may be progressive, static, or remitting
* Small percentage of cases are reversible

What causes Dementia?
* Alzheimer’s is by far the most common type
* Cerebrovascular Disease
* Degenerative Diseases: Parkinson’s, Huntington’s, CJD (Mad Cow Disease)

More causes:
* Autoimmune Illness
o Lupus
o Multiple Sclerosis
* B12, Folate Deficiencies
* Head Trauma, Brain Tumors
* Infections- like HIV and Syphilis

Alzheimer’s
Dementia of the Alzheimer’s Type (DAT)
* Diagnosis of exclusion
* Hallmark: gradual onset of recent memory problems
* Onset may be early (65 y/o or younger) or Late (over 65)

DAT
* Slowly progressive (8-10 years from diagnosis to death)
* Many show personality changes
* Often with associated behavioral disturbances (wandering, agitation, etc.)

Vascular Dementia
Aka Multi-Infarct Dementia
Vascular Dementia
* Evidence of cerebrovascular disease on physical exam and head scans
* Usually caused by several strokes over time
* Onset abrupt, followed by stepwise, fluctuating course with “patchy” deficits

Treatment of Dementia
* Search for a reversible cause and treat (ex. B12 deficiency, Normal Pressure Hydrocephalus, Syphilis, etc)
* Rule out Pseudodementia (change in cognition associated with depression)
* Environmental/behavioral interventions- ex. no fail environment
* Medications

Medications
* Cholinesterase Inhibitors:
o Aricept (donepezil)
o Reminyl (galantamine)
o Exelon (rivastigmine)

Medications
* NMDA-receptor antagonists
o Namenda (memantine)
o Neuroprotective by blocking excessive glutamate stimulation of the NMDA (N-methyl-D-aspartate) receptor

Geropsychiatry: Delirium and Dementia.ppt

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