Geriatrics PRN Focus Session—Shakin’ Not Stirred: … · Geriatrics PRN Focus...

Geriatrics PRN Focus Session—Shakin’ Not Stirred: Movement Disorder Assessment and Management Activity Number: 0217-0000-16-128-L01-P, 1.50 hours of CPE credit; Activity Type: A Knowledge-Based Activity

Monday, October 24, 2016 3:15 p.m. to 4:45 p.m. Great Hall 6

Moderator: Scott Martin Vouri, Pharm. D., MSCI, FASCP, BCPS, CGP Assistant Professor, St. Louis College of Pharmacy, St. Louis, Missouri

Agenda

3:15 PM

4:00 PM

Assessment and Management of Non-Parkinson Movement Disorders Melody Ryan, Pharm. D., MPH, FCCP, BCPS, CGP Professor, University of Kentucky College of Pharmacy, Lexington, Kentucky

Assessment and Management of Movement Disorders with Cognitive and Psychiatric Features Jack. J. Chen, Pharm. D., FCCP, FASHP, FCPhA, BCPS, CGP Professor and Chair, Department of Pharmacy Practice, College of Pharmacy, Marshall B. Ketchum University, Fullerton, California

Conflict of Interest Disclosures Jack J. Chen: Consultancies: (Ipsen), Clinical Investigator: (Lundbeck, LLC), Speaker’s Bureau: (ACADIA Pharmaceuticals), Grants: (Lundbeck, LLC) Scott Martin Vouri: no conflicts to disclose Melody Ryan: no conflicts to disclose

Learning Objectives 1. Compare and Contrast Idiopathic Parkinson’s Disease with drug-induced movement disorders, Essential

Tremor, and Restless Legs Syndrome.2. Discuss best practices for the assessment and management of drug-induced movement disorders.3. Select and Recommend drug and non-drug therapies available to help manage symptoms of Essential

Tremor.4. Select and Recommend drug and non-drug therapies available to help manage symptoms of Restless

Legs Syndrome.5. Compare and Contrast signs and symptoms of Lewy Body Dementia, Parkinson’s Disease Dementia, and

Huntington’s Disease.6. Apply clinical pearls for the management of Lewy Body Dementia.7. Apply clinical pearls for the management of Parkinson’s Disease Dementia.8. Apply clinical pearls for the management of Huntington’s Disease.9. Apply clinical pearls for the management of movement disorders at the end-of-life.

Self-Assessment Questions

Self-assessment questions are available online at www.accp.com/am

© American College of Clinical Pharmacy 1

http://www.accp.com/am

2016 ACCP Annual Meeting

Assessment and Management of Non-Parkinson Movement

DisordersMelody Ryan, PharmD, MPH, BCPS, CGP

University of Kentucky College of PharmacyLexington, KY

October 24, 2016



Conflict of Interest

• None



Learning Objectives

• Compare and contrast idiopathic Parkinson disease with drug-induced movement disorders, essential tremor, and restless legs syndrome

• Discuss best practices for the assessment and management of drug-induced movement disorders

• Select and recommend drug and non-drug therapies available to help manage symptoms of essential tremor

• Select and recommend drug and non-drug therapies available to help manage symptoms of restless legs syndrome



Patient Case 1• MC is a 90 YO F who

develops persistent right lower quadrant pain accompanied by nausea and fever

• After 8 hours, she presents to the ED which she is found to have ruptured appendicitis

• Taken to OR for appendectomy, given antibiotics and remains in hospital for 5 days

• At post-discharge appointment 2 wks later, noted to have slowness, resting tremor, and shuffling gait

• Referred to movement disorder clinic and carbidopa/levodopa started

• Medications:• Atorvastatin• HCTZ• Lisinopril • Metoclopramide• Pantoprazole



What is the most likely cause of MC’s Parkinsonism?A. AtorvastatinB. Idiopathic Parkinson diseaseC. MetoclopramideD. Post-anesthesia effect



Drug-induced Movement Disorders (DIMD)• Akathisia – restlessness, pacing• Dystonia – sustained contractions or spasms• Parkinsonism• Tardive dyskinesia – choreoathetoid, stereotypical

movements; develop ≥ 1 month of treatment • Tremor – usually postural



Causative Agents

Akathisia Dystonia Parkinsonism Tardive Dyskinesia

Tremor

• Antipsychotics• Droperidol• Metoclopramide• Prochlorperazine• SSRI• Tricyclics

• Antipsychotics• Methylphenidate• Metoclopramide• Prochlorperazine• SSRI

• Antipsychotics• Methyldopa• Metoclopramide• Prochlorperazine• Reserpine• Valproic acid• Tetrabenazine

• Antipsychotics• Metoclopramide• Prochlorperazine

• Amiodarone• Antipsychotics• Beta agonists• Caffeine• Levothyroxine• Lithium• SSRI• Stimulants• Theophylline• Valproic acid

And many, many more . . .



Comparison of AntipsychoticsAgent Incidence of EPS EPS Risk Assessment

Typical antipsychotics 20-50% Very high

Aripiprazole 5% Moderate

Asenapine* 10% Moderate

Brexpiprazole 6% Moderate

Clozapine 4% Very low

Iloperidone 4% Very low

Olanzapine* 14-20% Moderate

Paliperidone* 20% High

Quetiapine 4% Very low

Risperidone* 20-35% High

Ziprasidone* 14% Moderate*Likely dose-related; EPS, extrapyramidal symptoms Chen JJ, Swope DM. Drug-induced Diseases. 2010.



Pharmacogenetic Association with Tardive Dyskinesia• CYP2D6 variations• Dopamine, serotonin, GABA and glutamate genes • HSPG2• DPP6• MTNR1A• SLC18A2• PIP5K2A• CNR1 Lanning RK, et al. Pharmacogenetics 2016;12:1339-51.



Assessment of DIMD

• Extrapyramidal Symptoms Rating Scale (ESRS)• Akathisia – Barnes Akathisia Rating Scale (BARS)• Parkinsonism – Simpson-Angus Scale• Tardive dyskinesia – Abnormal Involuntary

Movement Scale (AIMS)

Barnes TR. Br J Psychiatry 1989;154:672-6.Simpson GM, Angus JWS. Acta Psychiatrica Scand 1970;212:11-9.Munetz MR, Benjamin S. Hosp Commun Psych 1988;39:1172-7.



Management of DIMD

Akathisia Dystonia Parkinsonism Tardive Dyskinesia

Change to atypical antipsychotic with low EPS risk

Discontinue agent or use lowest effective dose

• antimuscarinicagents

• antiserotoninergicagents

• benzodiapezine• lipophilic beta

blocker


• baclofen• botulinum toxin• deep brain

stimulation• tetrabenazine


• Parkinson disease medications

• amantadine• benzodiazepine• botulinum toxin• deep brain

stimulation• ginkgo biloba• reserpine• tetrabenazine• vitamin E

Bhidayasiri R, et al. Neurology 2013;81:463-9.



Patient Case 2

• RF is a 76-yo F who is referred to the movement disorders clinic for evaluation of refractory Parkinson’s disease

• She has bilateral upper extremity tremor, worse when holding her arms in front of her and prominent head tremor

• She is currently taking carbidopa/levodopa 25 mg/100 mg TID and ropinerole 2.5 mg TID with no improvement; taking no other medicines



What is the best choice for RF?

A. Discontinue all medicines and re-evaluateB. Discontinue all medicines and start propranolol

20 mg BIDC. Increase carbidiopa/levodopa to controlled

release 50 mg/200 mg TIDD. Increase ropinerole to 3 mg TID



Essential Tremor• Action and postural tremor

• Upper limbs 95%; head 34%, lower limbs 30%, voice 12%, tongue 7%, face 5%, trunk 5%

• Difficulty with writing, drinking, eating, dressing, etc.

• Gait and balance can be affected• Cognitive and psychiatric problems are sometime seen• Pathophysiology unclear, but often hereditary• Alcohol decreases tremor amplitude in 50-90% of cases

• Mechanism unknown, but may involve GABA-A receptorsZesiewicz TA, et al. Neurology 2005;64:2008-20.Louis ED. Curr Opin Neurol 2014;27:461-7.



Nonpharmacologic Treatment

• Weighed utensils, wrist weights• Support groups• Deep brain stimulation of the ventral intermediate

nucleus (Vim) of the thallamus



Deep Brain Stimulation

https://www.youtube.com/watch?v=5T0fUCdZuTI&feature=youtu.be



Essential Tremor: Treatment

1ST LINE: Beta blockers, primadone (50-70% response)

2ND LINE: Gabapentin, topiramate

3RD LINE: Benzodiazepines, botulinum toxin A, deep brain stimulation, nimodipine



Beta Blockers

• Propranolol most frequently used – 50-70% response rate

• Atenolol, nadolol, and sotalol also have efficacy• Lipophilicity? Probably not – atenolol, sotalol not

very lipid soluble• Beta-1 selectivity? Probably not – propranolol

works best • Action might be peripheral at the muscle spindles

Ondo W. Tremor Other Hyperkinet Mov 2016;356.Hedera P, et al. J Cent Nerv Syst Dis 2013;5:43-55.



Primadone

• MOA probably NOT through phenobarbital• Superiority to phenobarbital for essential tremor • Action for tremor within an hour, but phenobarbital

takes longer to form• PEMA does not have action on tremor

• 30-50% response rate

Sasso E, et al. Neurology 1998;38:808.Koller WC, Rloyse VL. Neruology 1986;36:121-4

Calzetti S, et al. J Neurol Neurosurg Psychiatry 1981;44:932-4.



Gabapentin

• 30% response rate• Pregabalin does not work as well• Doses of 1200-1800 mg/day• Only small studies to date

Ondo W, et al. Mov Disord 2000;15:678-82.Gironell A, et al. Arch Neurol 1999;56:475-80.

Pahwa R, et al. Mov Disord 1998;13:465-7.



Topiramate

• 30-40% response rate• 208 patients randomized to placebo or topiramate

for 24 weeks; 29% improvement in Tremor Rating Scale scores, first seen at 100 mg/day (p<0.001)

• 62 patients randomized to cross-over treatment with placebo or topiramate; Tremor Rating Scale significantly improved in topiramate group (p<0.0001)

Ondo WG, et al. Neurology 2006;66:672-7.Connor GS, et al. Clin Neuropharmacol 2008;31:97-103.



Patient Case 3

• FG is a 47-yo M seen in the neurology clinic with an urge to move his legs, most often occurring in the evening. This restless feeling abates when he does move.

• He is currently taking sertraline 50 mg QAM and quetiapine 50 mg QHS for depression, which has been responsive.



Which is your recommendation?

A. Evaluate ferritin concentrationB. Evaluate use of quetiapineC. Evaluate use of sertralineD. All of the above



Restless Legs Syndrome/Willis-Ekbom Disease• Urge to move the legs, especially in evening/night,

relieved by moving legs• Prevalence 4-15%, increases with age, lower in Asia

and Africa• 5 increased genetic risk alleles• Affects 15-25% of pregnant women

• Peak in 3rd trimester; 70% resolution after delivery

Koo BB. Sleep Medicine Clinics 2015;10:189-205.Picchietti DL, et al. Sleep Med Rev 2015;22:64-77.



Restless Legs Syndrome/Willis-Ekbom Disease• Comorbidity with iron deficiency and kidney

disease• Association with CV disease, arterial hypertension,

diabetes, migraine, Parkinson disease

• Negative effects on quality of life• Depression, CV disease, hypertension• Decreased work productivity, economic consequences

Koo BB. Sleep Medicine Clinics 2015;10:189-205.Stevens MS. Sleep Med Clin 2015;10:369-73/



Pathophysiology

• Secondary• Direct result of iron deficiency• Ferritin < 45 mcg/L

• Primary• Brain iron transport/metabolism changes • Disturbed dopamine circadian rhythm

Garcia-Borreguero D, et al. Eur J Neurol 2012;19:1385-96.Allen RP. Sleep Med Clin 2015;10:207-14.



Nonpharmacologic Therapies

• Good sleep hygiene• Exercise/stretching• Maintaining healthy

weight• Control of hypertension• Deep massage• Vibratory

counterstimulation*

• Compression stockings• Near-infared light• Mental activities• Sexual activity• Yoga

*FDA approvedSharon D. Sleep Med Clin 2015;10:263-78.



Treatment

• Dopamine agonists• Rotigotine 1-3 mg/24 hr• Ropinirole 2-3 mg/day• Pramipexole 0.25-0.75

mg/day

• Carbidopa/levodopa ≤ 200 mg/day

• Antiepileptics• Gabapentin• Gabapentin enacarbil

600-1200 mg/day

• Clonazepam• Clonidine• Opioids/tramadol

Garcia-Borreguero D, et al. Eur J Neurol 2012;19:1385-96.De Oliveria CO, et al. Coch Data Syst Rev 2016: CD006941.



Treatment

• During pregnancy• Iron, if serum ferritin < 75 mcg/L• Low-dose clonazepam• Carbidopa/levodopa, if refractory

• Inhibits lactation• Low-dose oxycodone, if refractory and severe

Picchietti DL, et al. Sleep Med Rev 2015;22:64-77.



Augmentation

• Worsening of symptoms secondary to treatment• Occurs in ~ 6% of treated patients

• 27% of levodopa-treated• 6% of dopamine agonist-treated• 0.9% of gabapentin-treated

• May occur because of additional down-regulation of dopamine receptors caused by supplementation of dopamine

Zak RS, Walters AS. Sleep Med Clin 2015;10:279-85.Liu GJ, et al. Medicine 2016;95:e2504.

Allen RP. Sleep Med Clin 2015;10:207-14.



Augmentation• Prevention

• Choose non-dopaminergic agent or lowest dose for shortest time

• Intermittent treatment, if possible

• Treatment• Check serum ferritin and correct if < 50-75 mcg/mL• Use longer acting dopamine agonists• Divide and/or advance the dose• Switch to gabapentin• Switch to low dose, long-acting opioid

Garcia-Borreguero D, et al. Sleep Med 2016;21:1-11.



RLS

Intermittent (<2 x/week)

Carbidopa/ levodopa

Benzodiazepines

Opioids

Chronic/Persistent

Gabapentin/gabapentin enacarbil

Dopamine agonist

Check iron status; mental alerting activities; d/c caffeine; d/c

antidepressants, antidopaminergics, antihistamines



Rebound and Refractory RLS

• Rebound – 25-30% of levodopa-treated patients• Return of symptoms as medication wears off• Controlled-release or second dose

• Refractory• Recheck iron• Combination therapy• High-potency opioid

Guilleminault C, et al. Neurology 1993;43:445.Silber MH, et al. Mayo Clin Proc 2013;88:977-86.



Comparison of Movement Disorders

Characteristic ParkinsonDisease

DIMD Essential Tremor RLS

Prevalence 0.04% 40-49 yrs1.9% 70-79 yrs

Variable 0.3-5.6% 5.5%

Hereditary Rarely No, pharmacogeneticpredictors

Yes, 30-80% of patients

No

Classic Symptoms

Tremor, rigidity,bradykinesia, postural instability

Akesthia,dystonia, parkinsonism, tardive dyskinesia, tremor

Limb, head, voice, tremor

N/A



Comparison of Movement Disorders

Characteristic ParkinsonDisease

DIMD Essential Tremor RLS

Type of Tremor Asymmetrical, resting, hand tremor when walking

Variable Typically bilateral, head, voice,postural, action

N/A

Treatment Dopaminergic,anticholinergic

Discontinue offending agent, directed toward specific issue

Beta blockers, primadone, gabapentin, topiramate

Gabapentin, dopamine agonists, opioids, levodopa,benzodiazepines


2016 ACCP Annual Meeting2016 ACCP Annual Meeting

Assessment and Management of Movement Disorders with Cognitive

and Psychiatric Features

Jack J. Chen, PharmD, FASCP, FCCP, BCPS, CGPProfessor & Chair, College of Pharmacy, Marhsall B. Ketchum University, Fullerton, CA

Professor, Movement Disorders Center, Department of Neurology, Loma Linda University



Conflict of Interests

• Advisory Board: Ipsen• Research Funding: Lundbeck, LLC• Speakers Bureau: ACADIA Pharmaceuticals



Learning Objectives• Compare and contrast signs and symptoms of

dementia with Lewy bodies, Parkinson’s disease dementia, and Huntington’s disease.

• Apply clinical pearls for the management of dementia in parkinsonism.

• Apply clinical pearls for the management of psychosis in parkinsonism.

• Apply clinical pearls for the management of Huntington’s disease


2016 ACCP Annual Meeting2016 ACCP Annual Meeting2016 ACCP Annual Meeting

With permission; video by Jack J. Chen



With permission; video by Jack J. Chen



• Cognitive changes• Memory loss; confusion & disorientation• Difficulty handling complex tasks; planning & organizing• Difficulty with reasoning, problem-solving, spatial planning• Difficulty with language; motor coordination & functions

• Psychological changes• Agitation, anxiety, depression, inappropriate behavior• Hallucinations • Paranoia; personality changes

• Changes interfere with independence in daily activities• Riding on the heels of each other: Dementia and psychosis

Dementia and Psychosis: Partners in Crime



1. Postuma RB et al. Mov Disord. 2015 Oct;30(12):1591-601. 2. Kalia LV & Lang AE. Lancet. 2015 Aug 29;386(9996):896-912. 3. McKeith IG et.al. Neurology. 2005;65(12):1863-72. 4. Walker et al. Lancet. 2015 Oct 24;386(10004):1683-97.5. ACMC/ASHGHDGTWG. Am J Hum Genet. 1998;62(5):1243-7. 6. Kim SD & Fung VS. Curr Opin Neurol. 2014 Aug;27(4):477-83.

Parkinson Disease1,2

Dementia with Lewy Bodies3,4

Huntington’sDisease5,6

Core feature: Clinical: Bradykinesia and rigidity and/or tremor.

Clinical: Dementia with visuo-perceptual / executive dysfxn.

Family Hx + ClinicalGenetic: >35 CAG repeats HTT gene (pathologic)

Other features: • Autonomic dysfxn• Sensory dysfxn• Neuropsychiatric

• Anxiety, depression• Cognitive

impairment• Hallucinations /

delusions

• Hallucinations • visual, well-formed

• Fluctuating cognition• transient confusion,

mumbling, hallucinosis• Parkinsonism within 1 year

• Neuropsychiatric• Aggression, apathy,

anxiety, depression, mania, impulsivity, OCD

• Cognitive impairment• Psychosis

• Parkinsonism, ataxia, dystonia, tics

• Dementia develops in 30-50%

• Parkinsonism present 25-50% at time of dementia

• Dementia develops in 50%

Response to L-dopa

• Excellent for motor • Good for motor• May exacerbate psychosis

• Modest for parkinsonian features

Response to D2neuroleptics

Worsening parkinsonism Worsening parkinsonism / cognition; NMS

Depends on phenotype



• Approximately 50% of patients with PD will develop psychosis1,2

• PDP has a clinical profile that is distinct from other psychotic conditions3

• PDP symptoms increase in severity over time3

1. Forsaa EB, et al. Arch Neurol. 2010;67:996-1001. 2. Fénelon G, et al. Mov Disord. 2010;25(6):763-766. 3. Ravina B, et al. Mov Disord. 2007;22:1061-1068. 4. Goldman JG, et al. Expert Opin Pharmacother. 2011;12:2009-2024.5. Voss T, et al. Parkinsonism Relat Disord. 2013;19:295-299. 6. Fénelon G and Alves G. J Neurol Sci. 2010;289:12-17.7. Chen JJ. Neurol Clin 2004;22(3 Suppl):S63-90.

Parkinson’s Disease Psychosis (PDP)1-6

• Visual: 20 – 70%• Auditory: ≤ 20%• Olfactory: 10-15%• Tactile: 10-15%

• Gustatory: 5%• Somatic: 1%

• Delusions: ≤ 15%



NINDS-NIMH Diagnostic Criteria for PDP1

NINDS-NIMH: National Institute of Neurological Disorders and Stroke-National Institute of Mental Health.1. Ravina B, et al. Mov Disord. 2007;22:1061-1068.

1. Occurs in patients with established diagnosis of PD

2. At least 1 symptom of: hallucinations, illusions, false sense of presence,

delusions

3. Symptoms present for at least 1 month

4. May occur with or without: dementia, insight, PD drugs

Differential diagnoses:

1. Psychosis due to delirium, depression, dementias, schizophrenia,

other psychiatric disorders



Management of Hallucinosis and Psychosis in Parkinson’s Disease1. Rule out 2º causes: environment, fluid/electrolyte disturbances, hypoxemia, infection, pain,

medication toxidrome

2. Simplify antiparkinsonian regimen as much as possible by discontinuing or reducingdosage of medications with the highest risk and least benefit.a. Discontinue anticholinergics, including other nonparkinsonian meds with anticholinergic

activity (e.g., antihistamines, TCAs).b. Reduce dose and/or discontinue amantadine.c. Discontinue monoamine oxidase-B inhibitor.d. Reduce does and/or discontinue dopamine agonist.e. Reduce dose L-dopa and discontinue COMT inhibitors.

3. Consider atypical antipsychotic medication if disruptive symptoms persist.

a. Pimavanserin 34 mg qd (FDA approved)a. Quetiapine 12.5–25 mg at qhs; increase 25 mg each week until improve or side effectsb. Clozapine 12.5–50 mg at qhs; increase 25 mg each week until improve or side effects

(requires REMS compliance)

Expert opinion by Chen JJ, Brandt N, Menza M



Association of Antipsychotic Use With Mortality Risk in Patients With PD.

JAMA Neurol. 2016 May 1;73(5):535-41. Weintraub D, Chiang C, Kim HM, et al.

OBJECTIVE: To determine whether AP use in patients with PD is associated with increased mortality.DESIGN: Retrospective matched-cohort study; VA database 1999 to 2010. Rates of 180-day mortality compared in 7877 patients initiating AP therapy and 7877 patients who did not initiate AP therapy (matched for age, sex, race, index year, presence and duration of dementia, PD duration, delirium, hospitalization, Charlson Comorbidity Index, and new nonpsychiatric medications).RESULTS: Antipsychotic use associated with more than twice the hazard ratio (HR) of death compared with nonuse (ITT HR, 2.35; 95% CI, 2.08-2.66; P < .001). The HR was significantly higher for patients who used typical vs atypical APs (ITT HR, 1.54; 95% CI, 1.24-1.91; P < .001). Among the atypical APs used, HRs relative to nonuse of APs in descending order were 2.79 (95% CI, 1.97-3.96) for olanzapine, 2.46 (95% CI, 1.94-3.12) for risperidone, and 2.16 (95% CI, 1.88-2.48) for quetiapine fumarate.



Pimavanserin: 5-HT2A inverse agonist

Clozapine

Pimavanserin

Quetiapine

Images of a simple structural formula are ineligible for copyright and therefore in the public domain, because it consists entirely of information that is common property and contains no original authorship.



Inverse Agonist:Shifts receptor to inactive state

By Boghog (Own work) [CC BY-SA 4.0 (http://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons/



Pimavanserin: in vitro affinity for 5-HT2A

With permission: Hacksell et al. Neurochem Res 2014;39: 2008-17.



Pimavanserin: Efficacy in PDP

Cumming J et al. Lancet. 2014 Feb 8;383(9916):533-40Figure with permission from: Hacksell et al. Neurochem Res 2014;39: 2008-17.



Pimavanserin: Adverse Effects

40 mg pimavanserin tartrate = 34 mg pimavanserin (free base)Cummings et al. Lancet 2014;383:533-40.

Placebo(n=94)

Pimavanserin 40 mg (n=104)

Nausea 6 (6%) 6 (6%)Peripheral oedema 3 (3%) 7 (7%)UTI 11 (12%) 14 (13%)Fall 8 (9%) 11 (11%)Confusional state 3 (3%) 6 (6%)Headache 5 (5%) 1 (1%)Hallucination (including visual) 4 (4%) 7 (7%)



Types of Movement Disorders with Dementia & Parkinsonism

• Lewy Body Dementias• Parkinson’s disease dementia (PDD)• Dementia with Lewy Bodies (DLB)

• Others• Huntington’s disease• Alzheimer’s with parkinsonism• Corticobasal degeneration (CBD)• Progressive supranuclear palsy (PSP)• Vascular dementia with parkinsonism• FTD with parkinsonism• Dementia-parkinsonism-ALS• And more



1. Goodman RA et al. Alzheimers Dement. 2016 May 10. pii: S1552-5260(16)30052-8. doi: 10.1016/j.jalz.2016.04.002. [Epub ahead of print].

Dementia Subtype

ICD-9 Overall %

Alzheimer’s 331.0 43.5Vascular 290.40, 290.41, 290.42, 290.43 14.5Lewy body 331.82,* 332.0 + 331.0** 5.4Frontotemporal 331.1, 331.11, 331.19 1Alcohol-induced 291.2 0.7Other 046.11, 046.19, 292.82, 333.4† 0.2

Not otherwise specified

290.0, 290.10, 290.11, 290.12, 290.13, 290.20, 290.21, 290.3, 290.9, 294.1, 294.10, 294.11, 294.20, 294.21, 294.8, 331.2, 797

92.9

* 331.82 codes for both DLB and PDD**Diagnosis 332.0 (PD) had to have a diagnosis code of 331.0 (AD) on the same claim to be considered Lewy Body.†Other dementia includes Creutzfeldt-Jakob disease, Huntington's Chorea, and drug-induced dementia

Prevalence of Dementias1U.S. Medicare Fee-For-Service Beneficiaries, 2011-13 (Age >68 yrs; n=21.6 million)

3.1 million (14.4%) with dementia claim



With permission: Walker Z. J Neurol Neurosurg Psychiatry. 2002 Aug;73(2):134-40.

FP-CIT SPECT images of healthy subject and PD, Alzheimer, and DLB patients



60-yr-old woman with depressed mood, negative thoughts, mood-congruent delusions, & visual hallucinations (animals). Mild bradykinesia & rigidity noted; treated as psychomotor symptoms of MDD. Diagnosed MDD with psychotic features; olanzapine + duloxetine given. Also on: gabapentin; tramadol/APAP. Olanzapine increased 10 mg QD due to lack of 5 mg response. Days later, found to be confused with rigidity, dysphagia, masked face, and shuffling gait. Eventually admitted: persistent confusion, tachycardia (137 bpm), severe perspiration, elevated body temperature (38.2°C), severe rigidity; elevated CPK of 5,270 U/liter with leukocytosis (WBC 14,600). Diagnosed NMS.

Workup excluded CNS infection, endocrine problems, and other drug-related toxic effects. Treated with supportive, baclofen, clonazepam, bromocriptine. After NMS resolution, persistent fluctuation in cognitive fxn, recurrent visual hallucinations, and parkinsonism evident. Also, repeated falls & persecutory delusions. Striatal DAT SPECT scan abnormal bilaterally. Diagnosed Probable DLB

Is there undiagonosed DLB in your practice?



• Cholinesterase inhibitors:1• DLB & PDD: Donepezil, rivastigmine

• Effective globally and for cognition• Also some benefit on anxiety, hallucinations, sleep, falls2

• Tolerability: GI; some tremorgenic• No effect on mortality

• Memantine:1• DLB & PPD: Well tolerated but questionable benefit

• Atypical D2 antipsychotics:• Risk of worsening parkinsonism & NMS (DLB > PDD)• Use of antipsychotics in elderly with dementia

• Increased mortality• Black Box• What is your practice?

Management of DLB and PDD

1. Wang et al. J Neurol Neurosurg Psychiatry 2015;86:135-1432. Henderson EJ. Lancet Neurol. 2016 Mar;15(3):249-58



INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS. ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS TREATED WITH ANTIPSYCHOTIC DRUGS ARE AT AN INCREASED RISK OF DEATH. ANALYSES OF SEVENTEEN PLACEBO-CONTROLLED TRIALS (MODAL DURATION OF 10 WEEKS), LARGELY IN PATIENTS TAKING ATYPICAL ANTIPSYCHOTIC DRUGS, REVEALED A RISK OF DEATH IN THE DRUG-TREATED PATIENTS OF BETWEEN 1.6 TO 1.7 TIMES THE RISK OF DEATH IN PLACEBO-TREATED PATIENTS. OVER THE COURSE OF A TYPICAL 10-WEEK CONTROLLED TRIAL, THE RATE OF DEATH IN DRUG-TREATED PATIENTS WAS ABOUT 4.5%, COMPARED TO A RATE OF ABOUT 2.6% IN THE PLACEBO GROUP. ALTHOUGH THE CAUSES OF DEATH WERE VARIED, MOST OF THE DEATHS APPEARED TO BE EITHER CARDIOVASCULAR (e.g., HEART FAILURE, SUDDEN DEATH) OR INFECTIOUS (e.g., PNEUMONIA) IN NATURE. OBSERVATIONAL STUDIES SUGGEST THAT, SIMILAR TO ATYPICAL ANTIPSYCHOTIC DRUGS, TREATMENT WITH CONVENTIONAL ANTIPSYCHOTIC DRUGS MAY INCREASE MORTALITY. THE EXTENT TO WHICH THE FINDINGS OF INCREASED MORTALITY IN OBSERVATIONAL STUDIES MAY BE ATTRIBUTED TO THE ANTIPSYCHOTIC DRUG AS OPPOSED TO SOME CHARACTERISTIC(S) OF THE PATIENTS IS NOT CLEAR. Insert drug name IS NOT APPROVED FOR THE TREATMENT OF PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS (see WARNINGS).

Antipsychotic Black Box Warning



1. Stinton C, et al. Am J Psychiatry. 2015 Aug 1;172(8):731-42.2. Pagano G, et al. J Neurol Neurosurg Psychiatry. 2015;86(7):767-73.3. Yasue I. J Alzheimers Dis. 2015;50(3):733-40.4. Li Y, et al. Cochrane Database Syst Rev. 2015 Mar 3;(3):CD009444.

Dementia with Lewy Bodies1

Parkinson Disease2,3 Huntington Disease4

Cholinesterase Inhibitors

++(cognition and psychosis)

++(cognition and psychosis)

0/+

Memantine 0/+ ++ + (antichorea benefit)

Clozapine ++(psychosis)

+++(psychosis)

+++(psychosis; behaviors)

Quetiapine ++(psychosis)

++(psychosis)

+++(psychosis; behaviors)

Olanzapine,risperidone

Negative +/- ++(psychosis; behaviors)

Pimavanserin ? +++(psychosis)

?

Effect on Cognition & Psychiatric Symptoms



Geropsychiatry Case• 76 year old male with dementia NOS; visual hallucinations.

SNF staff reports “slowness” and tremor both upper extremities• Widow; no children; distant relatives• Meds: donepezil 10mg qd; vortioxetine 10mg qd• Staff concerned tremor getting worse; unable to eat or drink

without spilling• Staff concerned about hallucinations

• What is your approach to address motor issues?• What is your approach to address psych issues?• Discuss your clinical reasoning



Huntington’s disease• Juvenile to adult onset• Diagnosis: Family history + clinical sxs or genetic >35 CAG repeats• Motor and psychiatric clinical features:

• Chorea is a hallmark• Bradykinesia, rigidity, dystonia, tics, myoclonus, spasticity• Dementia, hallucinations, psychosis• Aggression, anxiety, apathy, depression, mania, OCD

• Treatment• Non-pharmacological, behavioral• Tetrabenazine (FDA approved), amantadine, antispasmodics• Antipsychotics, psychotropics• No disease modifying agent• RCTs: CoQ10, creatine futile



Discussion:Huntington’s disease

Chorea and Parkinsonism

• In the chorea phenotype of HD, chorea is a hallmark in early disease;

• Bradykinesia and rigidity are hallmarks in advanced stages

• What is a proposed pathophysiological explanation for this observation?



GABAergic

SNc STN

Motor Cortex

StriatumGPe

Gpi / SNrThalamus

D2

D1GABAergic

GABAergic

GlutamatergicGABAergic

Art work by Jack J. Chen

Early Huntington’s Disease: reduction in post-synaptic striatal D2 “indirect” pathway (inhibitory)



Art work by Jack J. Chen

Reduction of striatal D2 pathway = unopposed D1 activity (stimulatory) = chorea

GABAergic

SNc STN

Motor Cortex

StriatumGPe

Gpi / SNrThalamus

D2

D1GABAergic



Art work by Jack J. ChenSNc STN

Motor Cortex

StriatumGPe

Gpi / SNrThalamus

D2

D1

Advanced Huntington’s Disease: reduction in post-synaptic striatal D1 “direct” pathway + pre-synaptic substantia nigra

neurons = parkinsonism



Huntington’s DiseaseDrug Anti-

chorea effect

Anti-psychotic

effect

Anti-PD

effect

Anti-dystonia

effect

Clinical Pearls

Tetrabenazine Good None • Treat underlying depression• Monitor for parkinsonism

High potency antipsychotic(e.g., haloperidol)

Good Good • Good for psychosis, aggression, depression

• May worsen parkinsonism, dystonia, apathy

• Risk for tardive dyskinesia

Atypicalantipsychotic(e.g., aripiprazole, olanzapine, risperidone, quetiapine)

Modest Good • May improve behaviors: aggression,agitation, mania, motivation.

• Depot formulations helpful for adherence.

Amantadine Modest None Modest

Riluzole Modest(200 mg/day)

None • Monitor LFTs• Antidepressant effect?

L-dopa; DA agonist Mild Mild

Benzodiazepines Good Modest • Monitor cognition; apathy• Modest for myoclonus

Anticholinergics Modest • Monitor cognition, antichol ADRs

Botulinum toxin Good • Good for focal dystonia© American College of Clinical Pharmacy 67


• Sedation (31%)• Insomnia (22%)• Fatigue (22%)• Depression (19%)• Akathisia (19%)• Anxiety (19%)• Parkinsonism (9%)

TBZ for HD Chorea• 12.5 – 50 mg / day• Increase by 12.5 qwk• Max 100mg /day

• Divided bid-tid

• Ave. titration: 3-4 week• Ave. dose: 37.5 – 50 mg• Metabolized by CYP450

2D6Chen JJ et al. Clin Ther 2012;34:1487-1504.Xenazine Prescribing Information 2015



TBZ and CYP2D6testing

“…there were no statistically significant differences between the various groups with regard to adverse effects. Our findings demonstrate that, aside from the need for a longer titration in the ultrarapid metabolizers, there are no distinguishing features of patients with various CYP2D6 genotypes, and therefore the current recommendation to systematically genotype all patients prescribed more than 50 mg/day of tetrabenazine should be reconsidered.”

With permission: Mehanna R et al. Mov Disord. 2013;28(2):210-5.

127 patients: • 100 extensive metabolizers• 14 intermediate metabolizers• 11 poor metabolizers• 2 ultrarapid metabolizers (needed 8 wk titration vs. 3 wk)



Demographics Relevant History

Gender Age Ethnicity Family History PMH Genetic Testing

Current Medications for Movement Disorder

Response to Quetiapine

M 59 African American Pt was adopted HTN Positive

Amantadine 100mg TID Quetiapine 25mg QAM, 75mg

QHS

Improvement; transient sedation

M 37 Caucasian Father died from HD Brother, grandfather &

cousins have HD-- Positive Quetiapine 100mg BID

Improvement;no side effects

F 26 African American

Maternal grandfather, mother, several maternal aunts and uncles, and two nieces all had HD

Son has HD

-- Positive

Amantadine 100mg QID Clonazepam Quetiapine 25mg BID Levetiracetam 1000mg BID

Improvement; no side effects

F 60 Hispanic No known family history of

abnormal movements or neurological disease

HTN Positive Amantadine 100mg TID Quetiapine 200mg BID

Improvement; dry mouth

F 54 Native American

Brother and sister have similar types of uncontrolled movement

DM, HTN Positive Quetiapine 25mg TID

Improvement;but d/c due to diarrhea

Quetiapine in Huntington’s Chorea

Chen JJ. Quetiapine in the treatment of Huntington’s chorea: a case series. California Pharmacist 2016;vol 63 (in press).



Case Discussion: Huntington’s Disease• 38 year old woman• HD x 13 yrs (46/19 CAG); depression x 6 yrs; Tdk x 3 yrs• UHDRS-m score 102• MMSE 24; Clock drawing• Meds: Amantadine 100 mg tid, clonazepam 2 mg qd,

citalopram 20mg qd• Previously on haloperidol for chorea; d/c due to

parkinsonism & Tdk

• Patient reports:• Worsening chorea• Forgetfulness

• Plan?


Presenter

Presentation Notes

Examples of clocks drawn by the three HD mutation carriers. Participants were asked to draw a clock, and set the time at 10 past 11. MMSE = mini‐mental state examination; UHDRS‐m = Unified Huntington's Disease Rating Scale motor section; TFC = Total Functional Capacity.


Conclusions• Treatment of these neurodegenerative conditions of

interest can be challenging due to:• Evidence gaps in efficacy and tolerability for various

dementia phenotypes• Variability in disease phenotype; concurrent symptoms• Drug-disease interactions

• E.g., antipsychotics worsening parkinsonism• E.g., TBZ worsening other HD symptoms

• New drugs:• Recently, pimavanserin approved for PD psychosis• Inverse agonist at serotoninergic 5-HT2A receptors• Role in DLB and other conditions remains TBD


Geriatrics PRN Focus Session—Shakin’ Not Stirred: … · Geriatrics PRN Focus...

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