Delerium, Dementia and Insomnia

1. Delerium, Dementia and Insomnia 14th Feb 2006

2. Delerium Delirium - “to go out of the furrow”

3. Acute Confusional State • 30% of elderly medical inpatients • High Mortality • High Morbidity • Longer hospital stays • Predicts institutionalisation • Often missed • Poorly managed

4. Diagnosis of Delirium • Disturbance of consciousness with reduced ability to focus, sustain or shift attention • Change in cognition or perceptual disturbance • Short period of time (hours to days) and fluctuates • Caused by the direct physiological consequences of a general medical condition, substance intoxication or substance withdrawal

5. Differential Diagnosis • Dementia - AMT / MMSE cannot distinguish - often delerium superimposed on dementia • Psychotic illness

6. Delirium vs Dementia • Collateral history • Acute onset, short duration • Reduced consciousness • Diurnal fluctuation • Hallucinations common • Physical precipitant

7. Risk factors • Age • Dementia • Severe illness • Physical frailty • Infection/dehydration • Sensory impairment • Polypharmacy • Excess alcohol • Psychosocial stresses

8. Common Causes • Infection • Drugs • Neurological • Cardiac • Respiratory • Pain • Electrolytes • Endocrine/metabolic • Nutritional • Often multiple aetiologies

9. Drug classes commonly implicated in Delirium • Opiates • Anticholinergics • Sedative/hypnotics including withdrawal • Dopamine agonists • Antidepressants • Alcohol withdrawal • Corticosteroids • Lithium

10. Investigations - for all • FBC • Calcium • Urea and electrolytes • LFTs • Glucose • TFTs • CXR • ECG • Blood cultures • Urinalysis

11. Investigations - when indicated • ABG • B12 & Folate • Specific cultures • Lumbar puncture • CT head • EEG

12. CT Brain Scanning • Not helpful if performed routinely • Focal neurological signs • Confusion following head injury • Confusion following a fall • Raised intracranial pressure

13. EEG • Limited use • Delirium versus dementia • Non-convulsive status epilepticus • Focal intracranial lesions

14. Management • Identify and treat the underlying cause • Evaluate response (monitor AMT) • Optimum environment • Multidisciplinary team • Avoid physical restraints • Avoid major tranquilizers where possible • Control dangerous and disruptive behavior

15. Psychotropic medication • To prevent harm or allow evaluation and treatment • Low-dosehaloperidol (0.5 to 1.0 mg orally or intramuscularly) to control agitation or psychotic symptoms • MOA: D2 dopamine receptor antagonist • Low frequency of sedation and hypotension • Onset of action is 30 to 60 minutes after parenteral administration or longer with the oral route • s/e extrapyramidal; neuroleptic malignant syndrome • Atypical antipsychotics - ↑ risk cerebrovascular disease

16. Benzodiazepines • Benzodiazepines (eg, lorazepam 0.5 to 1.0 mg po/IM) have a more rapid onset of action (five minutes after parenteral administration) • Commonly worsen confusion and sedation • Drugs of choice in cases of sedative drug and alcohol withdrawal • May be useful adjuncts to neuroleptics to promote light sedation and reduce extrapyramidal side effects

18. Alois Alzheimer 1864-1915

19. Dementia • A general decrease in the level of cognition, especially memory • Behavioral disturbance • Interference with daily function and independence

20. Dementia syndromes • Alzheimer's disease (AD) 60-80% • Vascular dementia (VaD) 10-20% • Dementia with Lewy bodies (DLB) 10% • Parkinson's disease with dementia (PDD) 5% • Fronto-temporal dementia (FTD) • Reversible dementias • Others eg alcoholic

21. Cholinergic Deficit Alzheimer's disease (AD) sufferers have reduced cerebral production of choline acetyl transferase & impaired cortical cholinergic function

22. Cholinesterase inhibitors • MOA: increase cholinergic transmission by inhibiting cholinesterase at the synaptic cleft • Tacrine (abn LFTs), donepezil od, rivastigmine bd, and galantamine • s/e: insomnia; nausea; diarrhoea; syncope; BP changes; arrhythmias • Int: anticholinergics; antipsychotics

23. Evidence of Efficacy • 13 RCTs • treatment for 6 months - 1 year • mild, moderate or severe dementia due to Alzheimer's disease • improvements in cognitive function • -2.7 points (95%CI -3.0 to -2.3), in the midrange of the 70 point ADAS-Cog Scale • ↑ clinical global measures • Delay disease progression • Conflicting data on cost effectiveness

24. NMDA Receptor antagonists Excessive N-methyl-D-aspartate (NMDA) receptor stimulation can be induced by ischemia and lead to excitotoxicity

25. Memantine • MOA: low affinity glutamate NMDA receptor antagonist • Ind: Moderate to severe VaD, AD • small beneficial effect at six months • 1.85 ADAS-Cog points, 95% CI 0.88 to 2.83 • Agents that block pathologic stimulation of NMDA receptors may protect against further damage in patients with vascular dementia • s/e Dizziness, agitation, delusions

26. Antioxidants • Vitamin E • Selegiline (MAO-B inhibitor) • Delayed nursing home placement • No evidence of benefit on cognition Selegiline and Vitamin E: Delay in Clinical Progression of Alzheimer's Disease

27. Ginkgo Biloba • Chinese herbal medicine • Contains flavoglycosides • potent free radical scavengers • inhibit platelet-activating factor (PAF) • May improve regional circulation • May improve cholinergic neurotransmission

28. Ginkgo Biloba • Ginkgo Biloba (Meta-analysis of RCTs) • Four studies with 212 subjects in each placebo and drug groups using EGb 761 120–240 mg/day • Results: small but significant effect of 3–6 month treatment 120–240 mg of Gingko biloba extract on objective measures of cognitive function • Side effects: four reports of hemorrhage • Caution: in patients taking anticoagulants, antiplatelets or with bleeding diathesis • lack of regulation, including variability in the dosing and contents of herbal extracts

29. Agents with no clear benefit or evidence of harm • Oestrogen/testosterone replacement • NSAIDS • immunization with amyloid beta peptide (6% meningoencephalitis)

30. Behavioral symptoms • Agitation • Aggression • Delusions • Hallucinations • wandering

31. Behavioral symptoms • depression and sleep disturbances • depressive pseudodementia • concomitant medical illness • medication toxicity • behavioral methods

32. Treatment of behavioral symptoms • Non-pharmacological - look for medical cause eg: constipation, urinary retention, infection, drug toxicity, pain, delirium - look for an environmental cause eg: fear of unrecognized caregivers, trigger of the behavior, sensory deprivation

33. Treatment of behavioral symptoms • Antipsychotic agents • Atypical 1.6- to 1.7 fold increase in mortality compared with placebo • Typical agents have problems with extrapyramidal s/e • Antidepressants • SSRIs preferable • Benzodiazepines worsening gait, potential paradoxical agitation, and possible physical dependence

34. Insomnia

35. Insomnia • inadequate quantity or quality of sleep • difficulty initiating or maintaining sleep • Non-restorative sleep/impaired daytime functioning • Persistent insomnia is usually a consequence of medical, neurologic or psychiatric disease

36. Assessment • Alcohol and drug history - central nervous system stimulants - withdrawal of CNS depressant drugs • Treatment of co-morbid insomnia is unlikely to be successful unless the primary cause of the disturbance is diagnosed and properly remedied • Nonpharmacologic measures in conjunction with the judicious use of hypnotics

39. Who should be prescribed hypnotics? • Judicious use of hypnotics may be helpful when treating transient or short-term idiopathic or psychophysiologic insomnia • Short courses to alleviate acute insomnia after causal factors have been established • Some patients with insomnia benefit from long term hypnotics without evidence of tolerance or abuse

40. Who should not? • Contraindicated in pregnancy • Avoid or use judiciously in patients with alcoholism or renal, hepatic, or pulmonary disease • Avoid in patients with sleep apnea syndrome • Avoid concomitant alcohol ingestion • Avoid where high risk of abuse/dependence • Avoid where altered performance may be detrimental eg driving, on-call, carers

41. Historical agents • Laudanum • Bromide 19th C • Chloral hydrate • Clomethiazole • Barbiturates • Chlordiazepoxide 1960s

44. Hypnotic agents • Benzodiazepines • Nonbenzodiazepine drugs • Sedating antidepressants eg, amitriptyline, trazodone • Antihistamines diphenhydramine • Valerian – no clear evidence of effectiveness • Melatonin - large doses sold over-the-counter may be associated with side effects, such as hypothermia, gynecomastia, seizures • Melatonin receptor agonists - unpublished trials

45. Benzodiazepines • Low capacity to produce fatal CNS depression • MOA: enhance effects of the inhibitory neurotransmitter, GABA on the GABA A receptor • Sedative, hypnotic, muscle relaxant, anxiolytic, anticonvulsant, anterograde amnesia • Increase total sleep time but shortened time in REM sleep • Most have active metabolites with long t1/2

46. Adverse effects of BZDs • Can get rebound insomnia on withdrawal esp with short-acting agents • Residual somnolence esp with long-acting agents • Tolerance • Dependence and abuse • ↑ falls risk in elderly • Delirium in elderly • Withdrawal – confusion, convulsions, DTs • Up to 3 weeks after long-acting agent • Paradoxical effects • Anterograde amnesia

49. Nonbenzodiazepine hypnotics • nonbenzodiazepine drugs • eg zolpidem, zaleplon, zopiclone • also activate the benzodiazepine receptor, although they do not have a benzodiazepine structure

50. Nonbenzodiazepine hypnotics • at hypnotic doses less muscle relaxation or memory-disrupting effects • ↓ tolerance and dependence • Less effects on REM sleep • Short half-life of ±2 hours and elimination by liver metabolism - minimal sedation the next day after administration