Dementia
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Dementia. Michael A Hill, MD Professor Of Psychiatry. 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

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Dementia

Dementia

Michael A Hill, MD

Professor Of Psychiatry


Dementia an acquired syndrome characterized by

DementiaAn 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


Etiology pathogenesis

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


Clinical presentation of dementia

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)


Memory impairments

Memory Impairments

  • Difficulty learning or retaining new information (repeated conversations)

  • Information retrieval deficits (can’t recall names, list generation deficits)

  • Personal episodic memory impairment (misplacing items)

  • Declarative (semantic) memory (WHAT) > procedural memory (HOW)


Language deficits

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)


Visuospatial impairments

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)


Functional impairments

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


Behavioral symptoms

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)


Epidemiology prevalence increases with age

Epidemiology: Prevalence increases with age

*Lower numbers represent moderate to severe dementia


Incidence of alzheimer s disease by age

Incidence Of Alzheimer’s Disease by Age


Diagnostic approach early detection screening

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


Primary care screening tools

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. <12 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 Alzheimer’s 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)


Cognitive testing

Cognitive Testing

  • Serial 7’s (5 answers) - If you can do it, that’s good, but as many as 50% of normal elderly can’t(WORLD backwards is not much better as only 62% of elderly can do it with no errors)

  • Orientation:If you are disoriented that’s bad, especially to month or year, however many early dementia patients are fully oriented (40%)

  • 3-item recall: Not being able to recall 2/3 is bad as only 19% of dementia patients can do this, but 74% or normal elderly can

  • MMSE: Sensitivity: 87%, Specificity: 82%


Mmse norms by age and educational level

MMSE ‘norms’ by Age and Educational Level

Educational level


Diagnostic work up

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


Guidelines for use of specialized testing

Guidelines For Use of Specialized Testing

  • LP: Suspicion of metastatic CA, CNS infections, neuropsyphilis, hydrocephalus, vasculitis. Also for dementia <55 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

  • Neuropsychological testing – language barriers, MR, legal proceedings


Mild cognitive impairment

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 (especially amnestic type – aMCI)

  • Predictors of progression: ApoE4 alleles, poor performance on cued recall (amnestic type) and hippocampal atrophy by MRI


Pseudodementia

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 Alzheimer’s at 5 year follow-up


Late life depression

Late-Life Depression

  • Def’n: 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


Most common dementias

Most Common Dementias

  • Alzheimer’s Disease (AD) (50-75%)

  • Lewy Body Dementias (DLB) (10-30%)

  • Vascular Dementias (VaD) (15-20%)

  • Alcohol-related dementias (including Korsakoff’s (infrequent) and etoh-induced))

  • HIV dementia - most common dementia in those under age 55


Classification of dementias

Classification of Dementias

  • Primary versus secondarybased on the pathophysiology leading to damaged brain tissue

  • Cortical versus sub-corticaldepending on the cerebral location of the primary deficits

  • Reversible versus irreversibledepending on optimal treatment expectations

  • Early (before age 65) versus late onset


Alzheimer s pathophysiology

ALZHEIMER’S Pathophysiology

  • Neuritic plaques -extracellular - abnormal insoluble amyloid (beta) 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


Lewy body pathology

Lewy Body Pathology

  • Concentric spheres found within vacuoles (eosinophilic cytoplasmic inclusions)

  • Seen in cortex, midbrain and brainstem neurons in patients with idiopathic parkinsonism, Alzheimer's disease and especially Lewy Body dementias

  • The main structural component is alpha-synuclein. Ubiquitin is sometimes seen also.


Risk factors for ad

Risk Factors for AD

  • Age

  • Family history / genetics

  • Down’s syndrome (trisomy 21)

  • Head Trauma (esp. late in life) [TBI may double risk]

  • Female gender (mixed results: age bias and possible higher ‘clinical’ expression in women)

  • Ethnicity (Caucasians have the lowest risk)

  • Late-onset depression (after age 65)

  • Mild Cognitive Impairment (MCI)


Additional risk factors for dementia

Additional Risk Factors for Dementia

  • Cerebrovascular disease (and the risk factors for CV disease – including smoking, diabetes, hyperlipidemia, hypertension) is associated with vascular dementia risk

  • Recurrent MDD may be associated with risk of dementia in general.(Kessing and Anderson found risk of dementia to be 6 times higher in patients with 5 or more prior episodes.)1

  • Subclinical Hyperthyroidism (especially when antithyroid antibodies are present.2

1Kessing LF, Anderson PK. J Neurol Neurosurg Psychiatry. 2004;75:1662-1666

2Kalmijn S, Mehta KM, Pols HA, et al. Clin Endocrinology (Oxf) 2000;53:733-737


Genetic risk factors

Genetic risk factors

  • Chromosome 19 - autosomal recessive - Apolipoprotein E-4 allele - associated with late-onset disease (not relevant for non-caucasians)

  • TOMM40 – newly identified – affects age of onset

  • Chromosome 1, 14, 21 - autosomal dominant mutations - associated with early-onset/familial cases (5%). Amyloid processing genes.

  • CLU – clusterin and PICALM (phosphatidylinositol-binding clathin assembly protein)

  • Chromosome 9 – ‘ubiquilin 1’ polymorphisms – needs replication

  • BDNF – val/val variant might be protective


Protective factors in ad

Protective Factors in AD

  • Education

  • Anti-inflammatory agents (those that decrease amyloid production)

  • Estrogen replacement therapy (+/-)

  • Smoking (+)[?nicotine/past use](-) [CVD/current use]

  • APO E-3, CETP VV (longevity gene)

  • Vitamin E & other antioxidants?

  • Homocysteine reduction

  • Statin use (protects against PD, AD?)


Vascular dementia

Vascular dementia

  • Includes Binswanger’s disease, MID, anoxic damage, post-CABG, inflammatory diseases

  • RISK FACTORS: age, hypertension, diabetes and hyperlipidemia

  • 2nd most common dementia but incidence drops after the age of 75 (unlike Alzheimer’s disease)

  • In one study, 87% of ‘vascular dementias’ at autopsy had AD pathology1

1Nolan KA, Lino MM, et al. J Am Geriatr Soc, 1998;46:597-604


Other less common dementias

Other less common dementias

  • Primary degenerative dementias

    • Diffuse Lewy Body dementias (7-26% of dementias)

    • Frontotemporal dementias (Pick’s, ALS, Huntington’s)

  • Neurological disordersassociated with dementia

    • PSP, Parkinson’s dementia, NPH, neoplasms, head trauma, subdurals, demyelinating diseases


Less common dementias cont

Less common dementias (cont.)

  • Infectious causes

    • neurosyphilis, Lyme disease

    • post-encephalitic dementias (esp. herpes)

    • viral, parasitic, bacterial and fungal meningitidies

    • opportunistic infections or brain abscess

    • Human prion disease (transmissible spongiform encephalopathies) - sCJD, ‘Mad-cow disease’(vCJD), Kuru, fatal familial insomnia


General medical causes of dementia

General medical causes of dementia

  • Thyroid and adrenal diseases

  • Vitamin deficiency states (thiamin, niacin, B12)

  • Metabolic derangements (hepatic encephalopathy, dialysis dementia, etc.)

  • Medications(sedatives, antihypertensives, narcotics, anticholinergics)

  • Whipple’s Disease, sarcoidosis, Wilson’s disease

  • Toxins (heavy metals, organic poisons)


Rapidly progressive dementias

Rapidly Progressive Dementias

  • Hashimoto’s Encephalitis (treatable with steroids)

  • Cerebellar degeneration syndromes

  • Transmissible spongiform encephalopathies (prion diseases)

  • Paraneoplastic syndromes

  • Postviral encephalitis

  • Rare cases of AD, DLB, FTD


Economic burden

Economic Burden

  • $80 to $100 billion per year in total treatment costs

  • Alzheimer’s disease is the third most expensive disease to treat in the United States, following cancer and heart disease

  • Currently 4 million people have Alzheimer’s disease in the U.S.

  • More than $213,000 per family for the remainder of the patient’s life, including direct and indirect treatments costs ($47,000 per patient per year)


General treatment principles

General Treatment Principles

  • Treatment Of Underlying Disease Process (Primary Treatment)

  • Management Of Behaviors and Symptoms (Secondary Treatment)

  • Caregiver Support and Education


Reversible dementias

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.


Primary treatment strategies

Primary Treatment Strategies

  • 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 ---> 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


Delayed onset incidence

Delayed Onset Incidence


Alzheimer s pathophysiology1

ALZHEIMER’S 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


Cholinergic system strategies

CHOLINERGIC SYSTEM STRATEGIES

  • Reduce Serum anticholinergic load

  • Precursor strategies (e.g. lecithin and choline)

  • Receptor/synaptic strategies

  • Metabolic strategies (anticholinesterases)


Serum anticholinergic load cognitive impairment

Serum Anticholinergic Load & Cognitive Impairment

  • 90% of community elderly sample had detectable SA levels

  • An SA level >2.8 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


Commonly prescribed non psychiatric drugs with significant anticholinergic activity

Commonly Prescribed Non-Psychiatric Drugs with Significant Anticholinergic Activity

  • cimetidine & ranitidine

  • prednisolone

  • theophylline

  • digoxin/Lanoxin

  • furosemide

  • nifedipine

  • diphenhydramine (OTC)

  • To a lesser extent: codeine, warfarin, dipyradimole, isosorbide dinitrate


Current ache inhibitors

Current AChE Inhibitors

*promotes binding of acetylcholine and stimulates pre-synaptic release of ACh


Anticholinesterase side effects i e procholinergic

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)

*most common with rivastigmine


Strategies to slow or halt progession

STRATEGIES TO SLOW OR HALT PROGESSION

  • Calcium channel modulation and excitatotoxic systems attenuation (such as memantine)

  • Anti-inflammatory/immunosuppressive strategies(e.g. NSAIDs)

  • Gene therapyfor defective protein regulation

  • Toxin removal (Desferroxamine, clioquinol) / Ventriculoperitoneal shunting (COGNIShunt)

  • Amyloid Protein strategies

  • Other Neuroprotective strategies


Neuroprotective strategies

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)

  • B-blockers in AD

  • Rosiglitazone (Avandia) -anti-inflammatory, amyloid processing modulation activities

  • Levetiracetam(Keppra) for aMCI – reduces hippocampal hyperactivity


Nutraceutical strategies

Nutraceutical Strategies

  • Vitamin E (antioxidant)

  • Homocysteine Reduction (folate, B6, B12)

  • Beta-carotene –

    • Physician’s Health Study II found a cognitive protective effect of 50 mg every other day over two decades of use

  • Gingko (antioxidant)

  • Resveratrol (a type of polyphenol found in red grape skins – and thus red wine) ?anti-inflammatory, anti-aging, anti-cancer


Vitamin e

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 but higher dietary intake over 10 years in non-demented patients resulted in 26% lower incidence of AD (Rotterdam Study)

  • 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


Dementia 1316242

Days


Estrogen

Estrogen

  • At this point the summary of many studies suggests that Hormone replacement therapy (HRT) is questionably effective in slowing the onset of AD insome 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


Statins

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… Ability to enhance tissue plaminogen activator (tPA) and thus production of plasmin may be important. Plasmin may activate alpha-secretase and can also increase production of BDNF.

    *AKA amyloid-beta peptide or ABeta


Memantine

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


Memantine1

Memantine

Trade name: Namenda

Dose range: 5 to 20 mg (bid dosing)

Side effects: Constipation, somnolence, confusion/psychosis

Agitation was significantly less likely in memantine groups than placebo


Nsaid use ad in elderly patients

NSAID Use & AD in Elderly Patients

  • 2708 patients enrolled

  • Examined NSAID use and prevalence of Alzheimer’s 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


Abnormal amyloid protein strategies

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 orgamma-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


Anti amyloid treatments

Anti-amyloid Treatments

  • Gamma and beta secreatase inhibitors

    • Poor response to gamma inhibitors in Phase III trials so far

    • Aggregation inhibitors (e.g. tamiprosate) – negative in Phase III trials

    • Immunotherapy

      • AN-1792 – worked in mice but high rate of encephalitis in humans – less powerful antigen form being developed

      • Passive immunization – bapineuzumab – monocloncal AB against amyloid-B protein

  • Autophagy enhancers


Reversal strategies

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


Other drugs in the pipeline

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)


Caregiver burden

Caregiver Burden

  • Alzheimer’s 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


Staging of dementias

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


Common associated problems

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


Delirium

DELIRIUM

  • Definition - transient, usually reversible, dysfunction of global cerebral metabolism or physiology that has an acute or subacute onset manifested by a wide array of neuropsychiatric abnormalities, and often associated with life-threatening medical disorders

  • AKA acute organic brain syndrome, acute encephalopathy


Delirium signs and sx

Delirium (signs and sx)

  • Symptoms: Impairments of alertness (arousal) and attention are the core deficits. Symptoms will wax and wane as alertness and attention decreases and increases. Functions that depend on attention and alertness including orientation, perception, working memory and awareness will be impaired leading to a host of potential secondary sx such as psychosis, sleep-wake cycle disturbances, agitation, anxiety, and neurological abnormalities (dysgraphia, constructional apraxia, tremor, etc.)

  • Signs: EEG slowing, asterixis, sleep/wake cycle changes, S100B* elevations in CSF?

    *(S100B is a 21-kDa calcium-binding protein produced and released primarily by astrocytes in the CNS, where it exerts neurotropic and gliotropic actions. Several studies have investigated the potential role of S100B as a peripheral biochemical marker of neural injury.


Delirium vs dementia summary

Delirium vs Dementia(summary)

  • General rules of thumb:

    DeliriumDementia

    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


Dsm iv diagnosis

DSM-IV DIAGNOSIS

  • Criteria

    A. Disturbance of consciousness with decreased attention/focus

    B. Change in cognition or development of perceptual disturbances

    C. Develops rapidly and fluctuates over time

  • Code as ‘Delirium due to...’

    1. General Medical Condition (specify)

    2. Substance Intoxication/Withdrawal

    3. Multiple Etiologies

    4. NOS


Epidemiology of delirium

Epidemiology of Delirium

  • Very Common - 10-15% med/surg inpatients (30%+ if elderly); 2/3 of patients admitted from NH have delirium

  • 30% of Adult Burn Patients

  • 80% of delirious patients have pre-existing dementia

  • Mortality rates for elderly hospitalized patients with delirium is as high as 65% in some studies (double the non-delirious rate)

  • As many as two thirds of deliria go undetected

  • Annual costs exceed $8 billion

  • All sudden mental status changes in dementia patients should be considered a delirium until proven otherwise


Etiology of delirium

Etiology of delirium

  • many potential causes

  • often multifactorial (only 56% have a single probable etiology)

  • infections, metabolic derangements, anoxia, drug intoxications, withdrawals, CNS disease, toxins, fevers, etc.

  • susceptibility increased by aging, brain injury (esp. dementia and CV disease), polypharmacy (esp. anticholinergic load), malnutrition and fever

  • suspect UTI, dehydration and/or pneumonia in dementia patients with delirium


Delirium general treatment

DELIRIUM - General Treatment

  • Treatment:

    • Must look for medical cause(s) and treat as the primary intervention

    • Secondary symptoms can be helped by drugs such as haloperidol or risperidone (unless the cause of the delirium is NMS) and by reorientation strategies. Quetiapine has also become popular due to minimal dopamine blocking properties

    • Avoid anticholinergic, antihistaminic, and sedating drugs


Specific treatments

Specific Treatments

  • Anticholinesterases may be useful if cholinergic systems are impaired (which may be the case in most deliria)

  • Thiamine for W-K, benzodiazepines for etoh/sedative withdrawal delirium

  • Benzodiazepine antagonists have been useful in some cases of hepatic encephalopathy

  • What about stimulants?


Behavioral problems in ad

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


Causes of behavioral problems

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.)


General treatment strategies

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


Environmental strategies

Environmental Strategies

  • Identify provocations and rectify if possible

  • Appropriate re-orientation strategies – task simplification

  • Optimize sensory input [i.e. correct visual and hearing impairments]

  • Behavior management strategies that respect the patient’s need for control and autonomy (announcing intentions, single-step instructions e.g.)

  • Optimize physical activity, social stimulation, reminiscing


Management issues

Management Issues

  • Alleviate patient’s distress

  • Reduce care-giver burden

  • Delay institutionalization

  • Assure safety

  • Patient’s often become ‘more like themselves’


Caregiver information and support

Caregiver information and support

Caregivers should:

  • Encourage independence for the Alzheimer’s 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)


Depression and alzheimer s

Depression and Alzheimer’s

  • 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


Treatment of depression

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


Agitation

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


Treatment of agitation violence

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)


Medications for agitation

Medications for Agitation

  • Buspirone – Takes a while to work

  • Antidepressants (SSRIs, Trazodone)

  • Anticonvulsants (esp. valproate)

  • Atypical Antipsychotics (stroke/mortality risk concerning)

  • Low dose narcotics? Marinol?

  • Anticholinesterases and/or memantine

  • Estrogen?

  • Benzos – ataxia, worsening memory and disinhibition are problematic.


Treatment of psychosis

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


Atypical antipsychotics risk of serious adverse events

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 >5000 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 2005;19(2):91-103


Atypical antipsychotics risk of serious adverse events1

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 2005;330(7489):445 14Schneider LS, et al. JAMA 2005;294(15):1934-1943


Recommendations on use of antipsychotic agents in dementia

Recommendations on Use of Antipsychotic Agents in Dementia

  • Have a justifiable use -> 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.


Treatment of wandering

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)


Apathy

Apathy

*Int J Psychiatry. 2011; 26(2)

Common symptom of frontal lobe damage which can occur in most dementias

Can be part of depression but usually a stand-alone symptom

Bothers family more than patient, so hard to treat

Donepezil has been shown in one study* to delay onset of this sx

Stimulants – may or may not help


Treatment of insomnia

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


Sexually disinhibited behavior

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


Wandering behavior

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


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