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Delirium & Dementia

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  1. Delirium & Dementia Michael A Hill, MD Professor Of Psychiatry

  2. 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

  3. 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

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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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)

  11. 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)

  12. 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)

  13. 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)

  14. 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

  15. 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)

  16. Epidemiology: Prevalence increases with age *Lower numbers represent moderate to severe dementia

  17. Incidence Of Alzheimer’s Disease by Age

  18. 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

  19. 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)

  20. MMSE ‘norms’ by Age and Educational Level Educational level

  21. 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

  22. 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

  23. 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

  24. 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

  25. 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

  26. 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

  27. 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

  28. 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

  29. 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)

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

  31. 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.

  32. 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 ---> 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

  33. Delayed Onset Incidence

  34. 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

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

  36. 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

  37. 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

  38. Current AChE Inhibitors *promotes binding of acetylcholine

  39. 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)

  40. 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

  41. 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

  42. 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

  43. 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

  44. Days

  45. 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

  46. 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…

  47. 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

  48. 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