Is it Dementia or Delirium? - PowerPoint Presentation

1. Is it Dementia or Delirium?Why this topic, relevance?Because we see delirium frequently in our patients.Delirium is frequently missed.When delirium is detected, it’s significance can be undersestimated.We may diagnose delirium but not the underlying dementia.We confound overlapping symptoms of these disorders

2. What is Delirium? Common parametersPreviously: “Acute confusional state” too narrow! It is a global brain disorder.Combined disturbance of Attention, Consciousness, Cognition, Perception, Psychomotor functions, Emotional regulation, Sensory perception, Hypothalamic homeostatic functions (circadian, appetite, blood pressure, pulse, temperature and hormonal dysregulation)Acute or rapid onset, fluctuating and reversibleIt is a significant departure from a previous baseline level of functionManifest in disturbances in behavior with associated symptoms of usually an underlying condition or diseaseInformation at the ADS American Delirium Society

3. What is Dementia? (Simplified Definition)A specific set of symptoms resulting from injury or disease affecting the brainMost are progressive Neurodegenerative Disorders eventually affecting the entire brain. There are many varietiesDecline in cognition (thought, memory) is commonly recognized, however, it also affects Emotional regulation, Perception, Psychomotor activity, hypothalamic homeostatic functions! (just not all right away), attention and consciousness are preserved except in sundowner syndromeOnset is usually gradualIt is a non-reversible, significant departure from previous baseline functionIt is manifest in disturbances of behavior with or without manifestations of disease comorbidities.

4. Epidemiology: Delirium InpatientAbout 30% prevalence in patients in acute care get delirium (when tested) (1,2)About 20% of Post-operative cases in a large meta-analysisIncidence 10-20% after major surgery, 50% in high-risk/complex procedures (2)Up to 60% cases go unrecognized in hospitals (3)Mortality risk estimates vary more: 30 Day Mortality about 10% by Hospital Day 2-3 with Delirium (4)70 % risk of death at 6 months if presenting to ED with Delirium (5)Costs: Annual additional health costs in ICU 6.6-20 BillionAbout 40-160 Billion in Non-ICU costs (1,3) (counting readmits?)Independent risk factor for hospital readmission

5. Delirium PathophysiologyTheory of Acute Brain Failure (6,7): Substrate: The Patient:Specific physiological characteristics:Pre-existing conditions: Dementia, TBI, MS, Sickle cell, CHF, COPD…Physiological Event precipitating delirium: Surgery, Trauma, PE, UTI, Intoxication, Pain, etc.…Environmental Context contributing: Noise, Light, Comfort, Psychological stressors

6. Delirium PathophysiologySystems Integration Failure: Systems that affect the entire brainComplex web of interrelated pathophysiological pathways (6,7): Breakdown of energy supply and waste removalUnmitigated Free Radical damageDisruption of the BBBNeuroinflammationGlial DysfunctionDirect Toxin influence (e.g. Alcohol, Anesthesia, Chemotherapy)

7. Clinical ManifestationsThree conventional subtypes: Hypoactive, Hyperactive and MixedSymptom Subcategories based on brain regions affected:Prefrontal- Cognitive/ExecutiveTemporal/Occipital- Illusions/Hallucinations/MisperceptionParietal-Association/Integrative/Cognitive/ParanoiaCentral/Striatal/Cerebellar- Abnormal movements/IncoordinationHypothalamic- Circadian/Temp/Appetite/BP/HR/HormonalHippocampal/Amygdala- Emotion/Memory

8. ImpactPatient: High Risk Behaviors, Subjectively Traumatizing, Lasting impairment and damage and disability, Increased vulnerabilityFamily: Highly distressing to family, Interpersonal conflicts, Acting out behaviors, Psychiatric problems, Financial losesDirect Care Team: Caregiver frustration, Errors, Increased staffing for safety, Interventions worsening condition, Sedating the patientCommunity/Hospital/ECF: Large Cost increases, Readmissions, Falls, Affect on other patients

9. Epidemiology: DementiaVast Majority of patients are in the communityThere is no official surveillance system tracking numbers in US (8)Estimated 10-12% of US population affected (8) (Alz assn 2020)Estimated 25% of inpatients, 40-50% inpatients over 70 (9)Estimated 80-90% of ECF patients (10)

10. Epidemiology: DementiaDementia Subtype Estimates: Figures inexact and variable with age, population typeAlzheimer’s 60-80%Lewy-Body/Parkinson’s 30% (Lower in some studies)Vascular 20%Other 5-10%Mixed etiology increasingly documented (10%), ischemic disease is very common in elderly patients, especially those with dementiaCosts: 160-215 Billion annually (Rand.org 2013)

11. Dementia: Pathophysiology Complex, varied and requiring significant further investigationCertain common features predispose to delirium and shared with delirium:NeuroinflammationDisruption of the Blood Brain BarrierNerve Cell damage/toxicity/injury/death from Free RadicalsDisruptions in oxidative metabolismMalfunctioning of neuronal networks with resulting symptoms

12. Dementia PathophysiologyFailure of Central Neurological SystemsMemory and Cognition (attention, concentration, plasticity) Emotional Regulation (response to cues, context, attribution)Perception (association, integration, interpretation)Motor bioregulation (balance, rigidity, tremor, accuracy, fluidity)Homeostatic bioregulation (temp, BP, HR)Hormonal bioregulation (appetite, sleep, thyroid, immunity)

13. Dementia PathophysiologyNeurological System failure involves changes in NT (neurotransmitter) levels and ratios (DA, Ach, 5HT etc.)Typically begins in one or two systems predominantly, then progressesInitial symptoms presentations are insidiousProgression punctuated by exacerbations causing delirium, with or without a clear cause, with acceleration of progressionVulnerability to co-morbid illness increases concomitantlyBlending of symptoms of Delirium and Dementia

14. Dementia Pathophysiology (abbreviated)AD, Deposition of amyloid plaques and neurofibril tangles of hyperphosphorylated Tau protein (P-Tau), with cellular apoptosisLBD, Intracellular accumulation of ubiquitin and alpha-synuclein in neurons mainly in the cortexFTD, Deposition of ubiquitin TDP-43 and P-Tau mainly in frontal-temporal cortical distributionVD, Ischemic brain injury, stroke and small vessel ischemic disease with permanent neuronal cell deathMixed Dementia (low confirmation on rates) (15)

15. Clinical confounders?Significant overlap in symptoms of Dementia with complications and progression punctuated by deliriumReflected ambiguity in historical literature and in past diagnosesReflected in consultations for assessment and management, geriatrics, neurology and psychiatry, predicted by presentationDifferences found in natural history of the disorder, test results and response to treatment effortsLimitations in understanding the disorder reflected in treatment, planning, response by hospital and community systems

16. BPSD (NPS)Behavioral and Psychiatric Symptoms of DementiaPsychiatry called upon to assess and treatSundown Syndrome is part of BPSDProgressive and/or periodicConfusion, agitation/restlessness, irritability, paranoia, hallucinations, maniaCombativeness, threats, purposeless behavior, screaming, calling out, wandering, disrupted circadian rhythm and appetite

17. Sundown Syndrome (SS)(13,14)Significant historical debate as to whether a valid clinical construct: Senile Nocturnal Delirium 1941 (16)High prevalence in dementia careSignificant contribution from social and environmental factorsAbrupt onset, afternoon, evening and/or nightAgitation, confusion, anxiety, pacing, aggression, cognitive and perceptual symptoms, impaired circadian rhythmAssociated with advancing disease and may accelerate decline

18. Sundown Syndrome: PathophysiologyHypothalamic contribution: Degeneration of the suprachiasmatic nucleus with reduced production of melatoninHypothalamic nuclei very sensitive to social and environmental cues through CNS, endocrine balance and inflammation via ependymal cells (tanicytes) in floor of 3rd Ventricle, where BBB is absent/differentPowerful changes in appetite, energy balance, circadian rhythm and stress/anxiety regulation and behavior

19. Sundown Syndrome: Differential (16,17)Sundown syndrome strongly resembles deliriumDistinguish from other BPSD: Avolition, apathy, inattention to social cues, depression and cognitive errorsIs Sundown Syndrome a form of Delirium or just progression of the Dementia? Problem: SS has not been systematically studied, data inconsistent on definitions, incidence, prevalence, needed screening and assessment tools2005 American Sleep Disorder Association defined SS as a sleep disorder with NPS of wandering and confusion

20. Sundown Syndrome: Differential (cont’d)Treatment focusing on supporting the SCN/Pineal-Melatonin system reduce SSMorning exposure to daylight, maintaining routines, exercise, good sleep at night and short naps in early afternoon can helpDaytime sedating medications, sleep and light deprivation and melatonin too late at night can worsen the conditionDelirium is also triggered by sleep deprivation without being considered a sleep disorder, triggered by many other factors as well

21. Sundown Syndrome: Differential (cont’d)Studies are limited but indicate:SS does represent disease progressionSS is pernicious and a severe aspect of BPSDSS likely represents a form of Delirium where no clear classification as yet existsSS may represent Delirium Superimposed on Dementia (DSD)SS requires much more study for nosological reasons, assessment of burden and as a target of treatment and indicator of progression and recovery

22. Clinical ThinkingDementia and Delirium are complex and interrelated disordersIn context of one, look for unrecognized presence/episodes of the otherRecovery from Delirium can be protracted and often only partial and contribute to readmissionTherapeutic approaches are difficult, even treacherous due to unwanted adverse effects of medicationsTreatment requires a full team approach, which can vary according to availability (CM,MDs,RN,Psy)

23. Clinical thinkingBearing in mind associated morbidity and mortality, focus should be on safety and life qualityManaging expectations of family can be challenging when they are unrealistic, education neededOften appropriate to consult palliative care and sometimes hospiceSedated or quiet patients are not safer and life quality is not there, a temporary respite for caregivers may exist

24. Therapeutics: Delirium/BPSD/DementiaPrinciples: Prevent/Treat/ComplicationsSleep/Hydrate/Ambulate/Nutrition/Stress ReductionEliminate all non-essential medicationsAvoid sedating agents with long half-life and during the daytimeImpaired/slowed metabolism prolongs medication effectsWatch for combinations that suppress respirationNo diuretics at night, reduce antihypertensives unless neededTreat pain, avoid opioids wherever possibleBrain imaging with comparisons when possible

25. Therapeutics: Delirium/BPSD/DementiaPrinciples continuedInvolve family, POA, Advance directives to be discussedReduce excess noise, light, dark, intrusions, unfamiliar peopleEliminate catheters, tubes, leads and wires whenever possibleMonitor labs and vitals as appropriate to settingFalls preventionAmbulate as soon as able, PT/OT assessment and careNutrition consultOnce clear of a Delirium and at Baseline: screen for Dementia

26. Therapeutics: Delirium/BPSD/DementiaAntipsychotics:Historically treatment has been dominated by antipsychotics and benzodiazepines to treat dangerous agitation/behaviors/psychosisDementia and Delirium are not exclusively psychiatric diagnosesPatients tend to stay on these medications after dischargeNursing homes are fined if more than a certain percentage of patients are on antipsychotics without a psychiatric diagnosis/indication Elderly patients with Dementia getting diagnosed with schizophrenia and Bipolar so the medication can continueLimited alternatives studied

27. Therapeutics: Delirium/BPSD/Dementia (18)Antipsychotics:Haldol: Most recommended due to history/familiarity and best studied, considered standardComes in Oral, IM,IV, can micro dose if needed, Rec: 0.25-0.5 mg every 4 hrsAvoid in LBD and PD, increase risk EPS, TD (SGA better)Long QT syndrome, monitor ECG/telemetry (IV,IM)Less sedation and hypotension than with some SGAs

28. Therapeutics: Delirium/BPSD/DementiaAntipsychotics:Second Generation Antipsychotics (SGAs)Adverse effects (AE) vary with indication, drug profile, dosingAbout equivalent effectiveness, choose in part for AEUse much lower doses than needed for other psychoses Can combine less sedating during day, more sedating at nightShort term use recommended, slow tapers

29. Therapeutics: Delirium/BPSD/Dementia (18)Benzodiazepines:Used in benzodiazepine/barbiturate/alcohol withdrawal deliriaUsed in Deliria with seizures and catatonia (and NMS)Worsen other forms of Delirium and Dementia/BPSDFavor Lorazepam (dual hepatic/renal metabolism), short acting, metabolites not activeLow dosing/slow taperingRespiratory suppression/drug interactionsCan combine with AP if patient hallucinating

30. Therapeutics: Delirium/BPSD/DementiaAlpha-2 Agonist Dexmetomidine (IGLAM): Reduces agitation in Delirium without respiratory suppressionReduces Norepinephrine release in the Locus CoeruleusAnxiolytic and analgesic marketed for Delirium in ICU5 Double-Blind Randomized Controlled TrialsMeta-Analysis found superior to placebo and Antipsychotics in reducing symptoms of Delirium and reduced length of ICU stay (22)

31. Therapeutics: Delirium/BPSD preventionMelatonin: SCN-Pineal natural hormone regulating circadian rhythm, via MT1 and MT2 at SCNRamelteon: MT1 and MT2 Agonist at the SCNSuvorexant: Orexin (OX1 and OX2) receptor antagonist, sleep inducer, blocking the wake promoting effects of hypocretin Melatonin is affordable OTCNewer medications are expensive and often require trials with other medications and prior authorizationsAll these medications have studies indication prevention of Delirium (25,26,27)

32. Therapeutics: Delirium/BPSDAnticholinesterase Medications:No demonstrated evidence for treating DeliriumMay reduce BPSD, studies inconclusive and limited in scope and applicabilityCan be initiated and/or continued when Dementia is establishedCan contribute unnecessary adverse effectsIn case of delirium may be best to wait until symptoms clearMemantine: No clear evidence, controversy as to benefit (23,24)

33. Therapeutics: BPSD/DementiaDextromethorphan-Quinidine:3 studies: One open label pilot study 2020, One RCT 2015, one Review ArticleFindings indicate beneficial effects for treatment of agitation in dementia/BPSDReview concluded that study limitations restrict generalizability in NH settings (19,20,21)

34. Therapeutics: Search continues for novel and combined strategiesSome weak evidence for Gabapentin/Pregabalin in BPSD/DeliriumPimavanserin for Dementia Related Psychosis (DRP) (28)Some medications if incorrectly dosed or in drug-drug interactions can worsen BPSD and DeliriumSuccess in treating these disorders will rest on understanding the medical triggers/causes and understanding the psychoneuropharmacology and neurophysiology of these disorders

35. Therapeutics:Due to limited understanding and research in physiology and pharmacology:Current focus should be on early prediction through risk factors analyses in care and prevention through modifications in careFocus on education at all levels: Patients, families, community care givers, ECF and hospital-based providersBetter epidemiological monitoring and tracking, which can influence funding streamsAn evolving and important endeavor!

36. References1. A Hospital-wide Evaluation of Delirium Prevalence and Outcomes in Acute Care Patients-A Cohort Study. Shubert et al.BMC Health Serv Res 2018; 18:550. DOI 10.1186/s12913-018-3345-x2. Epidemiology, Mechanisms, Diagnosis of Delirium: A Narrative Review. Ospina et al. Clin Medicine and Therapeutics 2018; 1(1):3 DOI 10:24983/scitemed.cmt.2018.000853. Delirium. Echeverria et al. 09/30/2022. NCBI Bookshelf4. Perioperative Assessment, Risk Reduction and Management British Journal of Anesthesiology. Hu et al. 2020.Oct; 125(4):492-5045. Delirium in the Elderly. Clin Geriatric Med. Hsieh et al 2020, May; 36(2): 183-199. DOI:10.1016/j.cger2019.11.0016. Neuropathogenesis of Delirium: Review of current etiologic theories and common pathways. Maldonado et al. 2013. Am J Ger Psychiatry. 2013 Dec;21(12):1190-222. DOI:10.1016/j.jagp2013.09.005

37. References7. An Updated Hypothesis of the Etiology of Acute Brain Failure. Maldonado et al. 2018. Int J Geriat Psychiatry 2018 Nov.;33(11):1428-1457. DOI:10.1002/gps.48238. Alz Dem. Bennet et al 2021.DOI:10.1002/tcz.122379. Prevalence of Dementia and Cognitive Impairment in Hospital. Bickel et al 2018. Dtsch Arztebl 2018.Nov;115(44):733-740. DOI:10.3238/arztebl.2018.073310. Nationwide Survey of Dementia Prevalence in Long-term Care Facilities I Taiwan. Kao et al. J Clin Med 2022. DOI:10.3390/jcm.1.06.55411. A Systemic Review of the Prevalence and Incidence of Dementia with Lewy-Body. Zaccai et al. Age Aging.2005 Nov:34(6):561-612. The Interrelationship between Delirium and Dementia: The importance of Delirium Prevention. Fong et al. Nature Reviews Neurology 18,579-596. 2022

38. References13. Sundowner Syndrome. Psy Investig 2011 Dec;8:275-287. Khachiyants et al. 2011. DOI:10.4306/pi.2011.8.4.27514. Sundowning in Dementia; Clinical Relevance, Pathophysiological Determinants and Therapeutic Approaches. Front Med (Lausanne) 2016;3:73 DOI:10.3389/fmed.2016.0007315. Mixed Dementia: A Review of the evidence: Dementia Neuropsychology Custodio et al. 2017. Oct-Dec;11(4):364-370. DOI:10.1590/1980-57642016dn11-04000516. Studies in Senile Delirium. Psychiatr Quarterly 1941;15:47-53 Cameron D.17. Sundown Syndrome in patients with Alzheimer’s Disease Dementia. Dement Neuropsychol 2019 Oct-Dec;13(4):469-474. DOI:10.1590/1980-57642018dn13-04001518. Clinical Practice Guidelines for Management of Delirium in Elderly. Grover et al 2018. Indian J Psychiatry 2018 Feb;60(suppl(3):S329-s340

39. References19. Dextromethorphan for the treatment of agitation in Dementia: A Pilot Study. Drug Dev. Huang et al. 07 Dec 2020. DOI:10.1002/alz.04579120. Evidence for using Dextromethorphan-Quinidine for Treatment of Agitation in Dementia. World J Psychiatry Tampi et al. 2020 Apr19;10(4):29-33. DOI:10.5498/wjp.v10.4.2921. Effect of Dextromethorphan-Quinidine on agitation in patients with Alzheimer’s Disease Dementia: A Randomized Controlled Trial. Cummings et al. JAMA 2015 Sep 22-29(12):1242-54. DOI:10.1001/jama.2015.1021422. Pharmacological and Non-Pharmacological Interventions to prevent Delirium in Critically Ill patients: a systemic review and network meta-analysis. Intensive Care Med: Burry et al 2021. DOI:10.1007/s00134-021-0649-323. Cholinesterase Inhibitors for the Treatment of Delirium in Non-ICU settings. Alan Y et al 2018. Cochrane Data Base Syst Rev. 2018. DOI:10.1002/14651858.cd.012494.pub2

40. References24. Pilot Randomized Trial of Donepizil Hydrochloride for Delirium after Hip-Fracture. J Am Ger Soc 2011 Nov;59(suppl2). DOI:10.1111/j.1532.2011.03691.x25. Preventative Effects of Ramelteon on Delirium: A Randomized Placebo Controlled Trial. Hatta et al. Randomized Controlled Trial>JAMA Psychiatry.2014.Apr. DOI:10.1001/jamapsychiatry.2013.332026. Melatonin for Delirium Prevention in hospitalized patients: A systemic review and meta-analysis. J Psychiatr Res 2021 Jan;133:181-190. DOI:10.10116/j.psychres2020.12.02027. Suvorexant for the Prevention of Delirium. Xu et al 2020. Medicine 2020 Jul24;99(30):e21043. DOI:10.1097/MD000000000002104328. Phase III Harmony Trial. Pimavanserin a novel Antipsychotic with potential to address an unmet need of older adults with Dementia related psychosis. Front Pharmacol. Yunusa et al.2020.11:87,DOI:10.3389/fphar.2020.00087