Neuropsychiatric symptoms of Dementia and behavioral problems in Delirium. - PowerPoint Presentation

Neuropsychiatric symptoms of Dementia and behavioral problems in Delirium. Haroon Burhanullah, MDFaculty, Geriatric NeuropsychiatryDepartment of Psychiatry and Behavioral sciencesJohns Hopkins University School of Medicine July 29th, 2017 1 Presented by: Name goes here

Disclosures Nothing to disclose.July 17, 2017 2

To Identify delirium in early stages and be able to differentiate from dementia. Learn to reduce the duration of delirium and possibility sitter use To identify neuropsychiatric symptoms of dementia and treatment of behavioral symptoms of dementia Info on some clinical trials. July 17, 2017 3

Delirium Transient organic mental syndromeAcute onset Global impairment of cognitive functionsReduced level of consciousnessFluctuating Increased or decreased psychomotor activity Disordered sleep-wake cycle.

Delirium subtypes Hyperactive delirium : agitation, restlessness, attempts to remove medical devices. Hypoactive delirium: decreased responsiveness, lethargy, apathy, withdrawal and flat affect- Its under appreciated in ICU patientsMixed delirium July 17, 20176

Etiology Disease induced syndrome- organ dysfunction in sepsis, cirrhosis .Withdrawal from drug/ alcohol – usually hyperactive deliriumIatrogenic-medication(benzo,opioids,etcEnvironmental – Sleep disturbance, immobilization and sensory deprivation(eye glasses, hearing aids) July 17, 2017 7

Pathophysiology Neurotransmitter imbalances: Deficiency in acetylcholine and serotonin and activation of dopamine and glutamateInflammation: IFN alpha or beta, CRP, IL 6, 8, 10 – not measured in clinical practice July 17, 2017 8

Pathophysiology- contd. Cortisol: has delirious effects on memory when in excessOxidative impairment: Decrease oxygen supply to brain- inadequate oxidative metabolism and cerebral dysfunction July 17, 20179

Delirium diagnosis Predisposing Factors- age >65 , chronic pathology- HTN, stroke, DementiaPrecipitating Factors: Acute illness, infection, seizure, TIA, infarcts, metabolic imbalance, medications, NMS or serotonin syndrome etc.Environmental factors, restraints, immobilization, sleep disturbance July 17, 201710

Patient history (acute onset, fluctuating course, decrease cognition) Behavioral observation (delusion, hallucinations, mood lability,)Cognitive assessment (scales)July 17, 2017 11

WORK UP Physical examCBC, CMP, UA, Blood and urine culture, O2 sat, EKG, Chest X ray, CT scan head and Lumbar punctureEEGJuly 17, 2017 12

Behavioral symptoms in Delirium Sleep wake cycle (falling asleep during conversation, circadian fragmentation)Perceptual disturbancesLability of affectMotor agitation/retardationOrientationAttention July 17, 2017 13

Agitation ( removing tubes etc) Memory (STM and LTM)Visuospatial ability - Fluctuation of symptom severity July 17, 201714

Cognitive assessment scales CAM ICU ( great sensitivity for ICU patients) assess acute onset and fluctuating course, inattention, disorganized thinking and altered level of consciousness.4AT (rapid delirium assessment, no copyright ) July 17, 2017 15

Delirium rating scale MMSE ( minimental scale) EEG ( good for nonconvulsive or subclinical seizures) July 17, 201716

Prevention of Delirium Act early- Triage Nurse to do 4AT on confused patients.Review Medications.Manage pain, infection, dehydration, constipation and hypoxiaEarly mobilization may reduce the incidence and duration of delirium (early Physical therapy and OT) July 17, 201717

Prevention Appropriate day/ night light exposureOrient the patient Consider cognitive stimulating activities, family visits, promotion of good sleepAvoid benzodiazepine, minimize narcotics, Manage withdrawal July 17, 201718

Medication considerations for hyperactive delirium / agitation American delirium society clinical guideline states that antipsychotics can shorten the duration of deliriumAmerican geriatric society guidelines recommends lowest possible dose of antipsychotic for agitation in deliriumHaldol 1-2 mg Q12 or Zyprexa 2.5mg Q12 hr July 17, 2017 19

Withdrawal symptoms associated with delirium Delirium tremens : combination of CNS excitation (agitation, delirium, seizures) and hyperadrenergic symptoms (HTN, increased HR)Valium, lorazepamNon FDA approved Gabapentin, Depakote July 17, 2017 20

Dementia Global impairment of cognitive functions in the setting of a clear sensoriumCortical Dementias e.g. Alzheimer’s disease4 As: amnesia, aphasia, apraxia, agnosia Subcortical Dementias e.g. HD, PD4 Ds: dysmnesia, dysexecutive, delay, depletion

Memory Ability to learn, retain, and recall information and experiencesGetting information via sensory organs ( registration)Processing the information ( encoding) – requires attention Storing the information (retention)Recalling the information (recall)

Cortical Dementias e.g. Alzheimer’s disease4 As: Amnesia: a partial or total loss of memoryAphasia: loss of ability to understand or express speechApraxia: inability to perform particular purposeful actions Agnosia: inability to interpret sensations and hence to recognize things

Subortical Dementias e.g. HD, PD4 Ds: Dysamnesia: memory impairment, patients may benefit from cuesDysexecutive : related to troubles with decision-making Delay: related to slowed thinking and movingDepletion: reduced complexity of thought

NPS in dementiaDisorders of connectivity Inferences from brain lesions have not been very enlightening into NPS mechanismsNPS likely due to changes in brain circuitry (connectivity)Structural connectivity Reflected in gray and white matter changes Diffusion tensor imaging particularly helpfulFunctional connectivityAlterations in neurotransmissionResting state fMRIPET imaging of neurochemistry

Agitation/aggression in AD Clinical characteristics (CitAD ) derived from NPI Emotional agitation : distress, upheaval, anger, tension, anxiety, inability to relax Lability: rapid changes in mood, easily irritable, unexpected outbursts, overreacting, catastrophizing Psychomotor agitation : pacing, rocking, gesticulating, pointing fingers, restless Verbal aggression : yelling, excessively loud voice, screaming, uses profanity, threatens, "in your face" Physical aggression : grabs, shoves, pushes, resists, hits, kicks, gets in the way Perceptual disturbance

Clinical examples 72 y.o. man who paces and asks to go home, most days starting at about 4pm, while at home with his wife (sundowning) 87y.o. woman who becomes combative with whomever tries to help her take a bath in the nursing home (agitation with personal care)69y.o. woman who barricades in her room and says others are stealing from her (persecutory delusions)77y.o. man who refuses to eat or stop watching TV becomes angry and upset when asked to do otherwise (depression) 91y.o. woman who starts screaming every time she looks at herself in a mirror ( agnosia)75y.o. woman who suddenly has trouble getting to sleep and becomes mixed up and very scared at night (delirium)

Problem behaviors UncooperativenessCombativeness with care or assistanceRefusal of redirection Wandering Hitting and other violenceTearfulnessBeseeching Yelling, profanity, verbal aggression Pacing Exit-seeking, trying the doorsHoarding of objectsRepetitive behaviorsApathy, lack of motivation Social withdrawal

Common causes of disturbance DeliriumMedical problem UTI, pain, constipation, dehydration, otherMedicationAnticholinergics, benzodiazepines, opioids, lithium, anticonvulsants, slow increase in serum drug levels, Cognitive impairment Disorientation I.e., sundowningFrustration with functional deficitsUnwilling to accept helpComprehension deficitsApraxia Mood or psychotic disorder Recurrence of prior illness Caused by AD 25-50% of demented persons have significant mood disorder Environment Wrong level of care Change in environment Disorientation Agnosia Unsophisticated care-giving Just as likely with paid staff as with family

Find the cause Due to general medical condition or medication (delirium)?Treat the causeHarder to stop medications than start them To start them you just need a bright idea To stop them you must monitor response and think (creatively) of possible adverse eventsUse supportive care Due to environmental stressor or precipitant?Modify the environment Educate caregivers

Find the cause (2) Closely linked to the cognitive impairment?Avoid precipitantsIntervene early during escalation Distraction and activity therapyEducate caregiversDue to difficulties in patient caregiver relationship or unsophisticated care? Evaluate, educate, support the caregiverDevelop new routines, activities, structure Recurrence of a pre-morbid psychiatric illness?

Clinical examples 72 y.o. man who paces and asks to go home, everyday starting at about 4pm, while at home with his wife (“sundowning”) More disoriented as he becomes fatigued, less able to access intact cognitive skillsMay be related to disordered circadian rhythmMay benefit from antidepressant or antipsychotic 87y.o. woman who becomes combative with whomever tries to help her take a bath in the nursing home (“care specific”) Individualized approachMay simply consist of changing aides or time of care69y.o. woman who barricades in her room and says others are stealing from her (“psychosis”)Treat delusions with antipsychotics when affectively charged77y.o. man who refuses to eat or stop watching TV becomes angry and upset when asked to do otherwise (“depression”) Antidepressants (although efficacy not proven) Activity therapy Environmental changes 91y.o. woman who starts screaming every time she looks at herself in a mirror (“ agnosia ”) Tends to be seen in more advanced disease Start with environment change (remove mirror) 75y.o. woman who suddenly has trouble getting to sleep and becomes mixed up and very scared at night (“delirium”) The clue is time course (sudden change) Look hard for medical cause Start with medication review, labs

Common issues in dementia care(Dementia Care Needs Assessment) PatientPrimary care! Safety measuresDriving, wandering, falling, self harmOversight of medication administration Daily structureRecreational activities Day careBehavioral programHighly individualizedPlay to individual’s strength and historyIntact remote memoryHobbiesSleep and eating routines? Cognitive rehabilitationDecision making Capacity evaluations Caregiver Realistic expectation re disease and stage Skills training Respite Problem solving help Crisis availability Emotional support Slow pace of grief – different than death Treat depression Decision making Advance directives POA/guardianship When to change level of care When to give up 24 /7 caregiving Caregiver support groups Access to experienced specialists

Common patient issues in dementia care(Dementia Care Needs Assessment) Primary careSafety measures Driving, wandering, falling, self harmOversight of medication administrationDaily structure Recreational activitiesDay care FriendsRetained skillsSleep and eating routinesDecision makingCapacity evaluationBehavioral programs Highly individualized Play to individual’s strengths and history Often utilizes intact remote and procedural memory Hobbies Therapeutic Activity Plan (TAP) Laura Gitlin , JHU Familiar tasks Housekeeping Home maintenance

Symptom constellation of dAD Comparison with major depression More common Less common Anhedonia Depressed mood Anxiety Guilt Irritability Hopelessness Lack of motivation Suicidality Agitation Delusions Hallucinations

Treatment of depression in Alzheimer’s Disease Prior to 2003, antidepressant studies split about 50-50 between positive and null effect of medicationDepression of Alzheimer’s Disease (DIADS)Johns Hopkins RCT of sertraline for major depressive episode in AD (N=44) 12-week trialAchieved dose close to 100 mg dailyBetter mood and functional outcomes with sertraline

Treatment of apathy in AD Loss of motivation, initiative, and interestCan be distinguished from depressionMajor quality-of-life issue for caregiversMay be related to deficient dopaminergic neurotransmissionADMET6 week RCT of methylphenidate 20 mg daily (divided doses) in 60 AD patients with apathy Significant improvement in 2 of 3 outcomes Rosenberg et al., 2012Also trend toward improved attention (digit span)Well tolerated ADMET-2More robust 6-month RCT with larger N (200), more sites (10), and more thorough cognitive assessmentCurrently recruiting

Safety and Efficacy of Methylphenidate for Apathy in Alzheimer’s Disease: A Randomized, Placebo-Controlled Trial Paul B. Rosenberg, MD; Krista L. Lanctôt, PhD; Lea T. Drye, PhD; Nathan Herrmann, MD; Roberta W. Scherer, PhD; David L. Bachman, MD; and Jacobo E. Mintzer, MD, MBA, for the ADMET investigators J Clin Psych 2013;74:810-816.6-week RCT of methylphenidate for apathy in ADTarget dose 10 mg breakfast and lunchMost patients tolerated this dose

Treatment of agitation and psychosis in AD Are medications needed? (often not)Severity of agitation/affective componentCaregiver stressInterference with daily care Target symptomsSpecific agitated behaviorsAffective component of delusions

Medications for agitation and psychosis in AD AntidepressantsSuggestion of efficacy for citalopram CITAD – NIH-funded trial of citalopram for agitation in AD (RECRUITMENT ONGOING)Antipsychotics Atypicals are best tolerated Risperidone (start 0.25 mg)Olanzapine (start 2.5 mg)Seroquel (start 25 mg)Abilify, Geodon , Invega used rarelyAnticonvulsants Depakote Trileptal Similar to Tegretol but adverse events less common Avoid benzodiazepines except for emergencies

Antipsychotics and mortality in dementia Small but significantly increased mortality in elderly demented patients50% increase in mortality in 8-12 week trialsLikely applies to typical as well as atypical agents Increase from 2 to 3% mortality, for exampleDepending on age and medical comorbidity Need to balance this small risk against benefitQuality of life/comfort care issues This is important to discuss with families!Caution in prescribing and in dosingTry to taper patients off antipsychotics once they are stableLancet article 1/09RCT of antipsychotic discontinuation in demented nursing home patients Little difference seen in 12-month trial But mortality higher in medicated group after blinded trial ended Equivocal result But suggest utility of discontinuation

SSRIs for agitation in ADCitalopram (CitAD trial)SSRIs appear inherently safer than antipsychoticsno mortality signalworry about prolonged QT intervals (FDA caution on citalopram) Citalopram for agitation in AD trial (CitAD trial)9-week RCT of citalopram 30 mg daily N=188 at 8 academic medical centers in North AmericaMMSE 10-26, no antipsychotics allowed Primary outcomes Neurobehavioral Rating Scale + Clinical Global Impression

Nuedexta Dextromethorphan/quinidine involuntary and uncontrollable expressed emotion that is exaggerated and inappropriate, and also incongruent with the underlying emotional state. Avanir developed dextromethorphan/quinidine combination for PBA (Nuedexta)Tiny quinidine dose (10 mg) inhibits dextromethorphan catabolism, raising blood and brain levels 10-20-foldReasonable results for narrow indication Alzheimer’s with agitation phase II trial220 participantstwo-stage Bayesian design Significant superiority over placebo in both stagesThere is a new variant which is deuterated and has lower quinidine dose

Pimavanserin 5HT2A inverse agonist Targeting antipsychotic efficacy without EPSNo dopaminergic antagonism. “The good half” of atypical antipsychotic mechanismPhase III trial for psychosis in Parkinson’s disease (PD)199 participants randomized for 6-week RCTPsychosis decreased with significant superiority over placebo No worsening of motor functionMost discontinuation was due to VH (i.e., didn’t work for psychosis in some patients)Now being studied in AD phase III trial I think target symptom is agitation not psychosisThere is a similar drug with great results in early phase schizophrenia trials

Treatment of insomnia in AD BehavioralSleep hygieneCalm, quiet, dark environment Minimize caffeineDaytime exerciseMinimize naps (if extreme) Daily nap is normalLook for medical cause MedicationsAntipsychotics if “sundowning” and agitation associated with insomniaTrazodone 25-50 mgMirtazapine (Remeron ) 7.5- 15 mg

Questions? Thank you!

Study Intervention/study procedures Seeking individuals with A4 Solanezumab administered every 4 weeks via infusion No dementia dx/normal cognition Age 65-85 Positive amyloid PET (performed on site during screening) BDPP Nuetraceuticals (resveratrol, grape seed extract) taken every day MCI High blood sugar or DM type 2 Age 50-90 PATH-MCI Talk therapy administered every week MCI Mild depression Age 60-85 ADMET II Ritalin administered daily Alzheimer ’ s Disease (MMSE ≥10) Apathetic Navigate-AD (Eli Lilly and Company) BACE-inhibitor administered daily Mild Alzheimer ’ s disease (MMSE 26-20) Age 55-85 AbbVie Anti-tau antibody administered every 4 weeks via infusion Mild Alzheimer ’ s disease (confirmed by PET) Age 55-85 Trials in FTD Various (lithium, oxytocin) Frontotemporal dementia All ages

Sarah Lawrence 410-550-9020 swoody1@jhmi.edu Resources: NIH Clinicaltrials.gov Alzheimer ’ s Association TrialMatch Brain Health Registry Alzheimer ’ s Prevention Registry