Delirium

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Delirium Dementia

• Michael A Hill, MD
• Professor Of Psychiatry

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DELIRIUM

• Acute brain dysfunction characterized by
• Global symptoms (affecting both cerebral
  hemispheres) including impairment of
  consciousness and attention
• Primary physiological changes with potential for
  reversibility
• waxing and waning symptoms usually worse in
  evening
• Life-threatening conditions underlying the
  syndrome

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Symptoms of Delirium

• Common symptoms of a delirium include
• Waxing and waning levels of consciousness
• Poor attention and disorientation
• Disturbed memory (long and short term)
• Psychosis
• Sleep dysregulation
• Fearfulness with agitation and aggression
• Seriously impaired insight and judgment

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Epidemiology of Delirium

• Very Common - 10-15 med/surg inpatients (30 if
  elderly)
• 30 of Adult Burn Patients
• 80of delirious patients have pre-existing
  dementia
• Predisposing Factors
• old age, postcardiotomy, s/p burns
• prexisting brain damage
• drug withdrawal states
• AIDS

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Causes of Delirium

• Often multifactorial
• Infections, trauma, brain diseases
• Cardiac diseases, lung disease, hypoxia,
  hypoglycemia
• Toxins, or intoxications
• Medication effects
• Substance withdrawals (e.g. DTs)
• Endocrinopathies
• In elderly dementia patients UTI, dehydration
  and pneumonia are the most common causes

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DELIRIUM - TREATMENT

• Must look for medical cause(s) and treat
• Symptoms can be helped by antipsychotic drugs
  such as haldoperidol or risperidone (especially
  psychosis, agitation)
• Consider anticholinesterases for anticholinergic
  delirium
• Comfort measures include reorientation
  strategies, reducing stimulation, frequent
  reassurance

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Delirium vs Dementia(summary)

• General rules of thumb
• Delirium Dementia
• acute chronic
• reversible
  irreversible
• physiological structural
• primary attention primary memory
• deficits
  deficits
• Delirium and dementia can coexist in fact
  delirium is very common in demented patients

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Dementia An acquired syndrome characterized by

• Short-term memory impairment (i.e. learning) AND
• At least one of the following
• Aphasia - language memory impairments
• Apraxia - motor memory impairments
• Agnosia - sensory memory impairments
• Abstract thinking / Exec. function impairments
• Impairment in social and/or occupational fn
• Sxs not explainable by another disorder

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Etiology Pathogenesis

• Dementia results from impaired functioning of
  multiple brain systems in both cortical and
  sub-cortical areas that are associated with
  short-term memory (i.e. learning) and other
  higher cognitive functions. Generally this is
  due to structural brain damage that is often
  progressive and relatively irreversible

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Clinical Presentation of Dementia

• Always associated with cognitive disturbances and
  functional impairments
• Visuospatial impairments and behavioral
  disturbances are usually seen as well
• Specific symptoms will vary by type of dementia
  (Frontal lobe dementias present with personality
  change and executive dysfunction to a much
  greater degree than memory impairment)

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Memory Impairments

• Difficulty learning or retaining new information
  (repeated conversations)
• Information retrieval deficits (cant recall
  names, list generation deficits)
• Personal episodic memory impairment (misplacing
  items)
• Declarative (semantic) memory (WHAT) gt procedural
  memory (HOW)

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Language Deficits

• List-generation deficits verbal fluency (esp.
  in AD)
• Word-finding difficulties (naming problems)
• Less complex sentence structure
• Relatively preserved auditory comprehension (can
  understand directions)

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Visuospatial impairments

• Visual recognition impairments (trouble
  recognizing familiar faces - CAPGRAS syndrome
  possible)
• Spatial deficits (getting lost in familiar
  surroundings, 3-D drawing deficits,
  constructional apraxia)

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Functional Impairments

• Deficits appear first in IADLs (managing
  finances, driving, shopping, working, taking
  medications, keeping appointments)
• Eventually problems with ADLs (feeding, grooming,
  dressing, eating, toileting)
• Rate and specific pattern of loss will vary by
  individual and somewhat by diagnosis
• NB Functional impairment and performance on
  cognitive testing may not correlate strongly
  early in the course of dementia

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Behavioral Symptoms

• Nearly universal and often the main focus of
  treatment. Inability to manage these symptoms is
  highly correlated with institutional placement.
• PERSONALITY CHANGE Occurs early
• passivity (apathy, social withdrawal)
• disinhibition (inappropriate sexual behavior or
  language, loss of social graces, aggression)
• self-centered behaviors (childishness, loss of
  generosity)

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Epidemiology Prevalence increases with age
Lower numbers represent moderate to severe
dementia
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Incidence Of Alzheimers Disease by Age
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Diagnostic ApproachEarly Detection Screening

• Careful history from patient and reliable
  informant
• PE with focus on neurological exam and cognitive
  testing
• Cognitive testing tools such as MMSE are helpful.
  Score below 24-27 often concerning depending on
  premorbid abilities
• Functional Assessment tools such as the
  Functional Activities Questionnaire

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Primary Care Screening Tools

• MMSE (normal varies somewhat by age and
  educational level an 80 y/o with only 4 years
  of education would be expected to only get a
  19/30)
• Clock Test easy to do, quick. Draw a clock,
  put numbers in correct locations, set hands to
  10 til 2.
• List generation number of animals that can be
  named in 60 seconds. lt12 is definitely abnormal,
  12-18 is marginal. Can also do words beginning
  with letter F. 10 in one minute is normal.
  Often very impaired in Alzheimers and some types
  of FTDs.
• Trails B testing is useful if frontal lobe
  deficits suspected (e.g. fronto-temporal
  dementias, AIDS dementia)
• Go No-Go Testing (inability to inhibit
  responses)

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MMSE norms by Age and Educational Level

• Educational level

0-4y 5-8y 9-12y gt12y
AGE 0-4y 5-8y 9-12y gt12y
18-24 23 28 29 30
35-39 23 27 29 30
50-54 22 27 29 30
70-74 21 26 28 29
80-84 19 25 26 28
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Diagnostic Work-Up

• This is done to
• (1) rule out disorders besides dementia (e.g.
  delirium)
• (2) to identify reversible/treatable dementias
  (13)
• (3) to clarify the specific dementia syndrome
• Routine Assessment CBC with diff, serum
  electrolytes, Ca, glucose, BUN/CR, LFTs, TFTs,
  B12 folate, U/A, RPR, head imaging
• When indicated Sed. rate, HIV, CXR, heavy
  metals, LP, EEG, functional imaging, Lyme titers,
  endocrine studies, rheumatologic studies,
  Neuropsychological Testing

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Guidelines For Use of Specialized Testing

• LP Suspicion of metastatic CA, CNS infections,
  neuropsyphilis, hydrocephalus, vasculitis. Also
  for dementia lt55 and rapidly progressive
  dementias
• Neuroimaging - consider in all new cases.
  However without focal symptoms or signs, seizures
  or gait disturbances in an individual over age 70
  - consider this optional
• Functional Imaging (SPECT, PET, MRS, fMRI) to
  clarify type of dementia when necessary (and in
  the future to track course of illness and
  response to tx)
• EEG - can help distinguish delirium from
  dementia, can help with seizure disorder and JCD

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Neuropsychological Testing

• Cognitive testing and functional testing are at
  odds or there is suspicion of early dementia in a
  high IQ individual with normal MMSE
• Mild impairment in a person with low IQ or
  limited education, trouble with English,
  impairments less than 6 months
• Determining capacity for legal purposes when
  deficits are mild

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Mild Cognitive Impairment

• Some cognitive deficits apparent on testing but
  not to dementia level (MMSE 24-29) range
• Minimal, if any, functional impairments
• 13-15 per year progress to dementia (A.D.) but
  not all progress and some improve
• Predictors of progression ApoE4 alleles, poor
  performance on cued recall and hippocampal
  atrophy by MRI

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Pseudodementia

• More appropriately called reversible dementia
• The classic case is depressive pseudodementia
  with overstated cognitive impairments due to
  decreased concentration and poor effort
• However, depression may be a risk factor for
  dementia
• 50 of elderly patients with depressive
  pseduodementia have Alzheimers at 5 year
  follow-up

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Late-Life Depression

• Defn First Major Depressive Episode occurs
  after age 65
• High correlation with dementia (50 go on to
  develop dementia within 3 years!)
• Many of these depression may be vascular or
  post-stroke depressions

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Most Common Dementias

• Alzheimers Disease (AD) (50-75)
• Lewy Body Dementias (DLB) (10-30)
• Vascular Dementias (VaD) (15-20)
• Alcohol-related dementias (including Korsakoffs
  (infrequent) and etoh-induced))
• HIV dementia - most common dementia in those
  under age 55

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Classification of Dementias

• Primary versus secondary based on the
  pathophysiology leading to damaged brain tissue
• Cortical versus sub-cortical depending on the
  cerebral location of the primary deficits
• Reversible versus irreversible depending on
  optimal treatment expectations
• Early (before age 65) versus late onset

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Economic Burden

• 80 to 100 billion per year in total treatment
  costs
• Alzheimers disease is the third most expensive
  disease to treat in the United States, following
  cancer and heart disease
• Currently 4 million people have Alzheimers
  disease in the U.S.
• More than 213,000 per family for the remainder
  of the patients life, including direct and
  indirect treatments costs (47,000 per patient
  per year)

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General Treatment Principles

• Treatment Of Underlying Disease Process (Primary
  Treatment)
• Management Of Behaviors and Symptoms (Secondary
  Treatment)
• Caregiver Support and Education

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Reversible Dementias

• May become irreversible if not treated soon
  enough
• Many dementias may be arrestible if not fully
  reversible
• Rule out depressive pseduodementia and delirium
  which can mimic dementia
• Some reversible dementias include hypoT4, B12
  def., some infections and tumors, drug-induced
  syndromes, etc.

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Primary Treatment Strategies(for progressive
dementias)

• 1. Prevention
• Identify risks and mitigate
• Develop neuroprotective strategies for those at
  risk
• 2. Slow or halt progression of illness
• Understanding pathophysiology leads to treatment
  ideas
• 5 year delay in onset ---gt 1/3 decrease in
  prevalence
• Delaying institutionalization by 1 month saves
  1.2 billion/yr
• 3. Reverse symptoms
• Compensate through augmentation of remaining
  neurons or other systems
• Reversal of destructive processes regeneration
  of tissue

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Delayed Onset Incidence
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ALZHEIMERS Pathophysiology

• Neuritic plaques -extracellular - abnormal
  insoluble amyloid protein fragments
• Neurofibrillary tangles - intracellular -
  disturbed tau-microtubule complexes
  (hyperphosphorylated tau)
• Cholinergic system degeneration with significant
  loss of neurons in certain areas (such as Nucleus
  Basalis of Meynert)
• Degeneration often begins in enterorhinal cortex
  and progresses to other limbic structures

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CHOLINERGIC SYSTEM STRATEGIES

• Reduce Serum anticholinergic load
• Precursor strategies (e.g. lecithin and choline)
• Receptor/synaptic strategies
• Metabolic strategies (anticholinesterases)

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Serum Anticholinergic Load Cognitive Impairment

• 90 of community elderly sample had detectable SA
  levels
• An SA level gt2.8 pmol/Ml was 13X more likely to
  be associated with an MMSE of 24 or less in the
  general elderly population than in those with
  undetectable SA levels
• Univ Of Pittsburgh, AAGP 5th Annual Meeting, 2002

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Commonly Prescribed Non-Psyciatric Drugs with
Significant Anticholinergic Activity

• cimetidine ranitidine
• prednisolone
• theophylline
• digoxin/Lanoxin
• furosemide
• nifedipine
• diphenhydramine (OTC)
• To a lesser extent codeine, warfarin,
  dipyradimole, isosorbide dinitrate

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Current AChE Inhibitors
promotes binding of acetylcholine
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Anticholinesterase Side Effects(i.e.
procholinergic)

• GI nausea, vomiting, diarrhea, increased
  gastric acid secretion
• Muscle cramps
• Fatigue
• Insomnia
• Syncope (2 vs 1 for placebo) (?bradycardia)

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STRATEGIES TO SLOW OR HALT PROGESSION

• Calcium channel modulation and excitatotoxic
  systems attenuation (such as memantine)
• Anti-inflammatory/immunosuppressive
  strategies(e.g. NSAIDs)
• Gene therapy for defective protein regulation
• Toxin removal (Desferroxamine, clioquinol) /
  Ventriculoperitoneal shunting (COGNIShunt)
• Amyloid Protein strategies
• Other Neuroprotective strategies

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Neuroprotective Strategies

• Nerve Growth Factor
• Acetyl-l(levo) carnitine (ALCAR)
• Estrogen
• Homocysteine reduction( folate, B6, B12)
• Antioxidants (Vit E, Gingko, deprenyl)
• Statins (Lipitor, Pravachol) (may lower
  abnormal amyloid levels)
• Rosiglitazone (Avandia) -anti-inflammatory,
  amyloid processing modulation activities
• Nutraceuticals

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Nutraceutical Strategies

• Vitamin E (antioxidant)
• Homocysteine Reduction (folate, B6, B12)
• Beta-carotene
• Physicians Health Study II found a cognitive
  protective effect of 50 mg every other day over
  two decades of use
• Gingko (antioxidant)
• Resveratrol

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Vitamin E

• Potent antioxidant properties
• Has been shown to slow progression at least as
  much as Deprenyl in one head-to-head study
• Recent study showed no difference from placebo in
  preventing progression from MCI to AD over 3 yrs
• Few side effects even in high doses, though
  recent studies in Europe suggest a higher death
  rate in those on hi-dose Vitamin E
• Doses used in recent studies up to 1000 IU bid
• Consider 400-800 IU per day for prevention
• May work better if combined with Vitamin C

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Days
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Estrogen

• At this point the summary of many studies
  suggests that Hormone replacement therapy (HRT)
  is questionably effective in slowing the onset of
  AD in some women
• The earlier started, the better. Limited
  exposure may be best.
• Progesterone may be detrimental
• Tacrine response can be enhanced by Estrogen
• WHY? neurotrophic effects, incr. ChAT, high
  serum E2 suppresses Apo E

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Statins

• Lovastatin(Mevacor), pravastatin(Pravachol),
  simvastatin(Zocor), atorvastatin(Lipitor)
• May prevent aggregation of B-amyloid in the brain
  by preventing cholesterol build up. May activate
  alpha-secretase.
• Conflicting evidence recent U of Wash study did
  not find a benefit, but looked at older
  individuals on statins only a short while.
• Earlier studies were more positive
• Not sure if all these drugs are equal

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Memantine

• Glutamate is the principal excitatory
  neurotransmitter in brain regions associated with
  cognition and memory (i.e. it stimulates
  cholinergic neurons)
• Glutamate hypothesis of dementia suggests that
  overactivation of these neurons leads to
  excitatoxic damage to these brain areas (by
  allowing calcium to continuously leak in to
  cells). It is post-synaptic receptor sensitivity
  rather than excess release of glutamate that is
  the problem.
• Memantine is a weak antagonist of glutamate-gated
  NMDA receptor channels which prevents
  overactivation during memory formation but
  allows normal function

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NSAID Use AD in Elderly Patients

• 2708 patients enrolled
• Examined NSAID use and prevalence of Alzheimers
  Disease
• NSAID users had 50 lower risk of being affected
  by AD
• Aspirin trended this way but was not significant
• Treatment studies have not shown any consistent
  benefits yet however.
• Landi, et al, Am J Geriatric Psychiatry,
  March-April, 2003

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Abnormal Amyloid Protein Strategies

• Most genetic mutations associated with AD affect
  amyloid processing
• Senile plaques contain abnormal amyloid B
  fragments (that precipitate out of solution
  easily)
• Attack enzymatic pathways that lead to production
  of abnormal type and amount of amyloid ( beta or
  gamma-secretase inhibitors)
• Enhance alpha-secretase system to promote normal
  amyloid
• Prevent aggregation (NSAIDS may do this!)
• Alter the abnormal gene expression
• GAG mimetics (glycosaminoglycans) Alzhemed
  interferes with formation of insoluble amyloid
  protein fragments

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Reversal Strategies

• Destroy the current plaques/amyloid
• Vaccination Strategy AN-1792 vaccine is in
  testing. This is an amyloid B protein fragment
  which can induce antibodies that bind to plaques
  and activate microglial destruction processes.
  Trial halted b/o menigoencephalopathies
• Plaque busters
• Alzhemed prevents Amyloid B fragments from
  forming fibrils
• Clioquinol - A metal-protein-attenuating compound
  (MPAC) that inhibits zinc and copper ions from
  binding to beta-amyloid, thereby helping to
  dissolve it and prevent it from accumulating.
• Transthyretin shows promise at interfering with
  toxic effects
• Generate new tissue -
• neuroregeneration strategies (STEM cells)
• neurotransplantation strategies

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Other Drugs in the Pipeline

• Tau protein modulators (to prevent abnormal
  phosphorylated tau protein
• Beta and gamma-secretase inhibitors
• Alpha secretase stimulators
• Bryostatin CA drug that stimulates brain
  protein production. Reduces B-amyloid levels in
  mice, enhances memory and learning.
• New generation NSAIDS (flubiprofen) testing in
  humans looks promising
• Immune enhancers (immunoglobulin)
• New vaccines and new anticholinesterases
  (huperzine)

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Caregiver Burden

• Alzheimers caregivers spend an average of 69 to
  100 hours per week providing care
• Caregivers of patients suffering from
  dementia(compared to control subjects) reported
• 46 more physician visits
• Over 70 more prescribed drugs
• More likely to be hospitalized
• More than 50 of caregivers are at risk for
  clinical depression

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Staging of Dementias

• MILD difficulties with checkbook maintenance,
  complex meal preparations, complicated medication
  schedules
• MODERATE difficulties with simple food
  preparation, household or yard work. May need
  some assistance with self-care
• SEVERE Need considerable assistance with
  feeding, grooming and toileting
• PROFOUND Largely oblivious to surroundings,
  totally dependent
• TERMINAL Bed bound require constant care

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Common Associated Problems

• depression (occurs in 20-40 - esp. AD and VaD)
• psychosis (occurs in 30- 50) - usually see
  paranoid delusions (theft, infidelity)
• wandering/purposeless activity
• agitation/threatening behavior
• sleep disturbances
• delirium - minor insults can lead to major
  decompensations

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Behavioral Problems in AD

• Almost universally a problem at some point
• 60 of AD at any one time exhibiting significant
  symptoms (usually delusions and/or agitation)
• Common problems by order of prevalence
• agitation
• depression
• delusions/psychosis
• Additional behavioral problems
• disinhibition, apathy, personality change,
  anxiety, wandering, insomnia

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Causes of Behavioral Problems

• Biological (due to the disease process itself
  e.g.)
• Psychological (loss of function and autonomy,
  attempts to maintain some control, denial of
  deficits, etc.)
• Social (family distress, economic issues, family
  conflicts over care)
• Environmental (increased sensitivity to changes,
  issues of safety, etc.)

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General Treatment Strategies

• Define symptoms clearly
• Rule out other psychiatric illness (e.g. MDD)
• Rule out medical causes for the symptoms (e.g.
  intercurrent illness, medication reactions, etc.)
• Identify non-pharmacologic strategies
• Pharmacotherapy

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Environmental Strategies

• Identify provocations and rectify if possible
• Appropriate re-orientation strategies
• Optimize sensory input i.e. correct visual and
  hearing impairments
• Behavior management strategies that respect the
  patients need for control and autonomy
  (announcing intentions, single-step instructions
  e.g.)
• Optimize physical activity, social stimulation,
  reminiscing

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Management Issues

• Alleviate patients distress
• Reduce care-giver burden
• Delay institutionalization
• Assure safety
• Patients often become more like themselves

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Caregiver information and support

• Caregivers should
• Encourage independence for the Alzheimers
  patient without sacrificing security
• Assist the patient, but only if necessary (i.e.
  allow the patient as much control as possible)
• Learn to compromise
• Develop ways to share activities
• Establish a support network get other family
  involved
• Educate themselves (alzheimers.org)

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Depression and Alzheimers

• Common early in the course of the illness
• Incidence 40-50
• Use SSRIs first avoid anticholinergic
  antidepressants
• ECT can be helpful but may temporarily worsen
  cognitive symptoms

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Treatment of Depression

• Recognize that irritability and/or apathy
  /withdrawal may be indicative of depression
• Allow patient choices and control
• Identify pleasurable activities (such as singing
  old songs, pet therapy, etc.)
• Cognitive enhancers (e.g. Aricept) may help
• Consider Ritalin for apathy, poor appetite

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Agitation

• Non-aggressive
• verbal complaining, constant requests for
  attention, repetition of words, constant talk,
  screaming
• physical pacing, disrobing, stereotypies, trying
  to get to a different place
• Aggressive
• Verbal threats, name calling, obscenities
• Non-verbal biting, scratching, spitting,
  kicking, pushing, swinging fists

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Treatment of Agitation/Violence

• Identify and reduce provocative stimuli if
  possible
• Optimize communication with patient
• Environmental modifications
• Pharmacotherapy - target underlying cause
  (neuroleptics, antidepressants, mood stabilizers,
  beta blockers, buspirone, trazodone)

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Medications for Agitation

• Buspirone Takes a while to work
• Antidepressants (SSRIs, Trazodone)
• Anticonvulsants (esp. valproate)
• Atypical Antipsychotics (stroke risk concerning)
• Low dose narcotics?
• Marinol?
• Estrogen?
• Benzos ataxia, worsening memory and
  disinhibition are problematic.

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Treatment of Psychosis

• Recognize common delusions as relating to
  impaired STM (improving memory may help - e.g.
  donepezil)
• Delusions often fade with time even without tx
• Traditional antipsychotics
• Low potency (chlorpromazine) orthostasis,
  sedation, anticholinergic
• High potency (haloperidol) EPS/TD but otherwise
  well tolerated
• New generations drugs (e.g. olanzapine,
  quetiapine, risperidone)- less EPS/TD but still
  see anticholinergic, BP and sedative effects

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Atypical Antipsychotics Risk of Serious Adverse
Events

• Retrospective review revealed a small (2-3) but
  2 fold increase in risk of stroke in demented
  patients receiving these agents compared to
  placebo.12
• FDA required Black Box warning due to 1.6 to
  1.7-fold increase in mortality in pooled sample
  of gt5000 persons with dementia exposed to these
  agents (in particular this was found in studies
  of olanzapine, risperidone and aripiprazole)

12Hermann N, et al. CNS Drugs 200519(2)91-103
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Atypical Antipsychotics Risk of Serious Adverse
Events

• The risk with traditional antipsychotics may be
  even higher.13
• Recent meta-analysis of 15 trials (some
  unpublished) by Schneider in JAMA14 confirmed a
  small increase in death with these agents
  compared with placebo. This was significant for
  the pooled data but not the individual drug data.
  The OR was 1.54

13Gill S, et al. BMJ 2005330(7489)445
14Schneider LS, et al. JAMA 2005294(15)1934-1943
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Recommendations on Use of Antipsychotic Agents in
Dementia

• Have a justifiable use -gt severe, distressing
  psychotic symptoms e.g. Do not use first-line
  for non-psychotic behavioral disturbances.
• Use lowest amounts for shortest possible times
• Caution patients and family about risk but
  remember that older agents may be worse, and
  there is little data on other psychotropics to
  suggest that they are safe.

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Treatment of Wandering

• Lock doors (but in a way that is confusing for AD
  patient but not others)
• Wander guards
• Decrease agitation (see above)
• Environmental changes (such as using visual
  patterns to redirect wandering, wander gardens)

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Treatment of Insomnia

• Sleep hygiene (avoid caffeine, etc.)
• Treat causative psychiatric or medical disorders
• Phsysiological remedies - melatonin, warm milk,
  lavendar oil
• Medications - Benadryl, benzos, sedating
  antidepressants or antipsychotics (all these
  drugs can make memory and confusion worse)
• Light Therapy - to reset natural circadian
  rhythms for sleep

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Sexually Disinhibited Behavior

• Includes sexual talk, sexual acts, implied sex
  acts, false reporting
• Treatment or sexual aggression and/or
  disinhibition
• Psychosocial reminders, move to private room,
  clothing modification, staff education
• Pharmacological SSRIs, antiandrogens
  (medroxyprogesterone acetate, cyproterone
  acetate), estrogen patches

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Wandering Behavior

• 4-26 of dementia patients in Nursing Homes
  wander
• If not located within 24 hours, 46 will die
  (usually of hypothermia or dehydration)
• TX Vigilance, wander guards, complicated exits,
  reduce agitation
• Safe Return nationwide identification program
  alert system for law enforcement officials, TV
  stations