1. Neuropsychiatric symptoms of Dementia and behavioral problems in Delirium.
Haroon Burhanullah, MD
Faculty, Geriatric Neuropsychiatry
Department of Psychiatry and Behavioral sciences
Johns Hopkins University School of Medicine
Presented by: Name goes here
July 29th, 2017

2. Disclosures
Nothing to disclose.
September 19, 2018

3. Learn to reduce the duration of delirium and possibility sitter use
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.
September 19, 2018

5. Delirium Transient organic mental syndrome Acute onset
Global impairment of cognitive functions
Reduced level of consciousness
Fluctuating
Increased or decreased psychomotor activity
Disordered sleep-wake cycle.

6. 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 patients
Mixed delirium
September 19, 2018

7. Etiology
Disease induced syndrome- organ dysfunction in sepsis, cirrhosis .
Withdrawal from drug/ alcohol – usually hyperactive delirium
Iatrogenic-medication(benzo,opioids,etc
Environmental – Sleep disturbance, immobilization and sensory deprivation(eye glasses, hearing aids)
September 19, 2018

8. Pathophysiology
Neurotransmitter imbalances: Deficiency in acetylcholine and serotonin and activation of dopamine and glutamate
Inflammation: IFN alpha or beta, CRP, IL 6, 8, 10 – not measured in clinical practice
September 19, 2018

9. Pathophysiology- contd.
Cortisol: has delirious effects on memory when in excess
Oxidative impairment: Decrease oxygen supply to brain- inadequate oxidative metabolism and cerebral dysfunction
September 19, 2018

10. Delirium diagnosis
Predisposing Factors- age >65 , chronic pathology- HTN, stroke, Dementia
Precipitating Factors: Acute illness, infection, seizure, TIA, infarcts, metabolic imbalance, medications, NMS or serotonin syndrome etc.
Environmental factors, restraints, immobilization, sleep disturbance
September 19, 2018

11. Patient history (acute onset, fluctuating course, decrease cognition)
Behavioral observation (delusion, hallucinations, mood lability,)
Cognitive assessment (scales)
September 19, 2018

12. WORK UP
Physical exam
CBC, CMP, UA, Blood and urine culture, O2 sat, EKG, Chest X ray, CT scan head and Lumbar puncture
EEG
September 19, 2018

13. Behavioral symptoms in Delirium
Sleep wake cycle (falling asleep during conversation, circadian fragmentation)
Perceptual disturbances
Lability of affect
Motor agitation/retardation
Orientation
Attention
September 19, 2018

14. Agitation ( removing tubes etc) Memory (STM and LTM)
Visuospatial ability
- Fluctuation of symptom severity
September 19, 2018

15. 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 )
September 19, 2018

16. MMSE ( minimental scale)
Delirium rating scale
MMSE ( minimental scale)
EEG ( good for nonconvulsive or subclinical seizures)
September 19, 2018

17. Prevention of Delirium
Act early- Triage Nurse to do 4AT on confused patients.
Review Medications.
Manage pain, infection, dehydration, constipation and hypoxia
Early mobilization may reduce the incidence and duration of delirium (early Physical therapy and OT)
September 19, 2018

18. Prevention Appropriate day/ night light exposure Orient the patient
Consider cognitive stimulating activities, family visits, promotion of good sleep
Avoid benzodiazepine, minimize narcotics,
Manage withdrawal
September 19, 2018

19. Medication considerations for hyperactive delirium / agitation
American delirium society clinical guideline states that antipsychotics can shorten the duration of delirium
American geriatric society guidelines recommends lowest possible dose of antipsychotic for agitation in delirium
Haldol 1-2 mg Q12 or Zyprexa 2.5mg Q12 hr
September 19, 2018

20. Withdrawal symptoms associated with delirium
Delirium tremens : combination of CNS excitation (agitation, delirium, seizures) and hyperadrenergic symptoms (HTN, increased HR)
Valium, lorazepam
Non FDA approved Gabapentin, Depakote
September 19, 2018

22. Dementia
Global impairment of cognitive functions in the setting of a clear sensorium
Cortical Dementias
e.g. Alzheimer’s disease
4 As: amnesia, aphasia, apraxia, agnosia
Subcortical Dementias
e.g. HD, PD
4 Ds: dysmnesia, dysexecutive, delay, depletion

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

24. Cortical Dementias e.g. Alzheimer’s disease 4 As:
Amnesia: a partial or total loss of memory
Aphasia: loss of ability to understand or express speech
Apraxia: inability to perform particular purposeful actions
Agnosia: inability to interpret sensations and hence to recognize things

25. Subortical Dementias e.g. HD, PD 4 Ds:
Dysamnesia: memory impairment, patients may benefit from cues
Dysexecutive: related to troubles with decision-making
Delay: related to slowed thinking and moving
Depletion: reduced complexity of thought

26. NPS in dementia Disorders of connectivity
Inferences from brain lesions have not been very enlightening into NPS mechanisms
NPS likely due to changes in brain circuitry (connectivity)
Structural connectivity
Reflected in gray and white matter changes
Diffusion tensor imaging particularly helpful
Functional connectivity
Alterations in neurotransmission
Resting state fMRI
PET imaging of neurochemistry

27. 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

28. 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)

29. Problem behaviors Uncooperativeness
Combativeness with care or assistance
Refusal of redirection
Wandering
Hitting and other violence
Tearfulness
Beseeching
Yelling, profanity, verbal aggression
Pacing
Exit-seeking, trying the doors
Hoarding of objects
Repetitive behaviors
Apathy, lack of motivation
Social withdrawal

30. Common causes of disturbance
Delirium
Medical problem
UTI, pain, constipation, dehydration, other
Medication
Anticholinergics, benzodiazepines, opioids, lithium, anticonvulsants, slow increase in serum drug levels,
Cognitive impairment
Disorientation
I.e., sundowning
Frustration with functional deficits
Unwilling to accept help
Comprehension deficits
Apraxia
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

31. Find the cause
Due to general medical condition or medication (delirium)?
Treat the cause
Harder 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 events
Use supportive care
Due to environmental stressor or precipitant?
Modify the environment
Educate caregivers

32. Find the cause (2) Closely linked to the cognitive impairment?
Avoid precipitants
Intervene early during escalation
Distraction and activity therapy
Educate caregivers
Due to difficulties in patient caregiver relationship or unsophisticated care?
Evaluate, educate, support the caregiver
Develop new routines, activities, structure
Recurrence of a pre-morbid psychiatric illness?

33. 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 skills
May be related to disordered circadian rhythm
May 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 approach
May simply consist of changing aides or time of care
69y.o. woman who barricades in her room and says others are stealing from her (“psychosis”)
Treat delusions with antipsychotics when affectively charged
77y.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

34. Common issues in dementia care (Dementia Care Needs Assessment)
Patient
Caregiver
Primary care!
Safety measures
Driving, wandering, falling, self harm
Oversight of medication administration
Daily structure
Recreational activities
Day care
Behavioral program
Highly individualized
Play to individual’s strength and history
Intact remote memory
Hobbies
Sleep and eating routines
? Cognitive rehabilitation
Decision making
Capacity evaluations
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

35. Common patient issues in dementia care (Dementia Care Needs Assessment)
Primary care
Safety measures
Driving, wandering, falling, self harm
Oversight of medication administration
Daily structure
Recreational activities
Day care
Friends
Retained skills
Sleep and eating routines
Decision making
Capacity evaluation
Behavioral 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

36. 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

37. Treatment of depression in Alzheimer’s Disease
Prior to 2003, antidepressant studies split about between positive and null effect of medication
Depression of Alzheimer’s Disease (DIADS)
Johns Hopkins RCT of sertraline for major depressive episode in AD (N=44)
12-week trial
Achieved dose close to 100 mg daily
Better mood and functional outcomes with sertraline

38. Treatment of apathy in AD
Loss of motivation, initiative, and interest
Can be distinguished from depression
Major quality-of-life issue for caregivers
May be related to deficient dopaminergic neurotransmission
ADMET
6 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., 2012
Also trend toward improved attention (digit span)
Well tolerated
ADMET-2
More robust 6-month RCT with larger N (200), more sites (10), and more thorough cognitive assessment
Currently recruiting

39. 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:
6-week RCT of methylphenidate for apathy in AD
Target dose 10 mg breakfast and lunch
Most patients tolerated this dose

40. Treatment of agitation and psychosis in AD
Are medications needed? (often not)
Severity of agitation/affective component
Caregiver stress
Interference with daily care
Target symptoms
Specific agitated behaviors
Affective component of delusions

41. Medications for agitation and psychosis in AD
Antidepressants
Suggestion 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 rarely
Anticonvulsants
Depakote
Trileptal
Similar to Tegretol but adverse events less common
Avoid benzodiazepines except for emergencies

42. Antipsychotics and mortality in dementia
Small but significantly increased mortality in elderly demented patients
50% increase in mortality in 8-12 week trials
Likely applies to typical as well as atypical agents
Increase from 2 to 3% mortality, for example
Depending on age and medical comorbidity
Need to balance this small risk against benefit
Quality of life/comfort care issues
This is important to discuss with families!
Caution in prescribing and in dosing
Try to taper patients off antipsychotics once they are stable
Lancet article 1/09
RCT 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

43. SSRIs for agitation in AD Citalopram (CitAD trial)
SSRIs appear inherently safer than antipsychotics
no mortality signal
worry 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 America
MMSE 10-26, no antipsychotics allowed
Primary outcomes Neurobehavioral Rating Scale + Clinical Global Impression

45. 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 fold
Reasonable results for narrow indication
Alzheimer’s with agitation phase II trial
220 participants
two-stage Bayesian design
Significant superiority over placebo in both stages
There is a new variant which is deuterated and has lower quinidine dose

46. Pimavanserin 5HT2A inverse agonist
Targeting antipsychotic efficacy without EPS
No dopaminergic antagonism.
“The good half” of atypical antipsychotic mechanism
Phase III trial for psychosis in Parkinson’s disease (PD)
199 participants randomized for 6-week RCT
Psychosis decreased with significant superiority over placebo
No worsening of motor function
Most 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 psychosis
There is a similar drug with great results in early phase schizophrenia trials

47. Treatment of insomnia in AD
Behavioral
Medications
Sleep hygiene
Calm, quiet, dark environment
Minimize caffeine
Daytime exercise
Minimize naps (if extreme)
Daily nap is normal
Look for medical cause
Antipsychotics if “sundowning” and agitation associated with insomnia
Trazodone mg
Mirtazapine (Remeron) mg

48. Questions?
Thank you!

49. Intervention/study procedures Seeking individuals with
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
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)
Trials in FTD
Various (lithium, oxytocin)
Frontotemporal dementia
All ages

50. Alzheimer’s Association TrialMatch Brain Health Registry
Resources:
NIH
Clinicaltrials.gov
Alzheimer’s Association TrialMatch
Brain Health Registry
Alzheimer’s Prevention Registry
Sarah Lawrence