Treatment of Parkinson’s Disease Dementia (PDD) Shanil Ebrahim

Treatment of Treatment of Parkinson’s Disease Parkinson’s Disease

Dementia (PDD)Dementia (PDD)

Shanil EbrahimShanil Ebrahim

OutlineOutline

Rivastigmine for Parkinson’s Disease Dementia

Background

Neurobiology

Different studies

Methodology

Results

Side effects

Evaluation

Conclusion

BackgroundBackground

• 40-70 %40-70 % of patients with Parkinson’s Disease develop of patients with Parkinson’s Disease develop dementia dementia

• atleast 2 years after atleast 2 years after Parkinson’s diagnosisParkinson’s diagnosis

• If before or within 2 years If before or within 2 years diffuse Lewy-body diffuse Lewy-body disease (DLB)disease (DLB)

• Both considered subtypes of more inclusive diagnosis Both considered subtypes of more inclusive diagnosis of dementia with lewy bodiesof dementia with lewy bodies

• Risk Factor Risk Factor Mainly Mainly aging – aging – usually over 65usually over 65

• Increasing cholinergic function is beneficialIncreasing cholinergic function is beneficial



NeurobiologyNeurobiology

• The presence of LThe presence of Lewy bodiesewy bodies

Intracytoplasmic neuronal inclusion containing alpha-Intracytoplasmic neuronal inclusion containing alpha-synucleinsynuclein

• Found in Found in neocortical and paralimbic neocortical and paralimbic regions regions

• Lewy body counts increased neocortex & limbic areasLewy body counts increased neocortex & limbic areas (10 fold)

• Majority of patients with PDD have pathological finding Majority of patients with PDD have pathological finding characteristic of alzheimer’s diseasecharacteristic of alzheimer’s disease

*** In parkinson’s *** In parkinson’s withoutwithout dementia dementia lewy bodies are generally lewy bodies are generally restricted to subcortical structures such as restricted to subcortical structures such as substantia nigrasubstantia nigra


NeurobiologyNeurobiologyDeficits in multiple neurotransmitters:

- Serotonergic & noradrenergic lead to cognitive symptoms

- Dopaminergic and particularly cholinergic lead to dementia

*Dopaminergic agents – little improvement, also frequently worsen hallucinations and cognitive symptoms.

PDD is associated with the cholinergic cell loss in the nucleus basalis of Meynert

** Increasing Cholinergic activity may alleviate cognitive dysfunction

• Since, cholinesterase breaks down acetylcholine, Since, cholinesterase breaks down acetylcholine, a cholinesterase inhibitor will suppress the action a cholinesterase inhibitor will suppress the action of the enzyme of the enzyme increases acetylcholineincreases acetylcholine

• Cholinesterase inhibitor Cholinesterase inhibitor Rivastigmine Rivastigmine ..

• First Developed by Novartis PharmaceuticalsFirst Developed by Novartis Pharmaceuticals

• Initially used for the treatment of mild to moderate Initially used for the treatment of mild to moderate Alzheimer'sAlzheimer's

• In 2006, it became the first product approved by In 2006, it became the first product approved by the US FDA for the treatment of mild to moderate the US FDA for the treatment of mild to moderate PDDPDD

Rivastigmine BackgroundRivastigmine Background


Study 1 Study 1 - Giladi et al (2003)- Giladi et al (2003)


• Conducted study on effects of rivastigmine on cognitive Conducted study on effects of rivastigmine on cognitive functions and other clinical featuresfunctions and other clinical features

• 28 consenting patients with PD and Dementia (17M/11F), 28 consenting patients with PD and Dementia (17M/11F), (mean age – 75 +/- 4.6 yrs), (symptoms duration – 7.0 +/- (mean age – 75 +/- 4.6 yrs), (symptoms duration – 7.0 +/- 5.3 yrs)5.3 yrs)

• Had atleast 2 years of PD symptoms with a clear Had atleast 2 years of PD symptoms with a clear response to levodopa for more than 1 yearresponse to levodopa for more than 1 year

• Excluded patients with:Excluded patients with:

Cognitive changes in first yearCognitive changes in first year

Psychotic features prior to or during first year after Psychotic features prior to or during first year after levodopa being introducedlevodopa being introduced

Other Psychiatric disordersOther Psychiatric disorders


Study 1 Study 1 - Giladi et al (2003)- Giladi et al (2003)ASSESSMENTASSESSMENT

Unified Parkinsons’ Disease Rating scale (UPDRS)Unified Parkinsons’ Disease Rating scale (UPDRS)

Alzheimer’s Disease Assessment Scale (ADAS cog)Alzheimer’s Disease Assessment Scale (ADAS cog)

DOSAGEDOSAGE

• Week 1-4 Week 1-4 1.5mg twice daily 1.5mg twice daily

• Week 5-8 Week 5-8 3mg twice daily 3mg twice daily

• Week 8-12 Week 8-12 4.5mg twice daily 4.5mg twice daily

• Week 13-26 Week 13-26 6mg twice daily (maximum dose) 6mg twice daily (maximum dose)

• Week 26 Week 26 Dose tapered down over 2 weeks Dose tapered down over 2 weeks

• Week 34 Week 34 Final assessment Final assessment



RESULTSRESULTS

Tolerated rivastigmine well - (mean dose at week 12 Tolerated rivastigmine well - (mean dose at week 12 7.3 +/- 3.3 mg/day) 7.3 +/- 3.3 mg/day)

Significant improvement at weeks 12 and 26 (P < Significant improvement at weeks 12 and 26 (P < 0.0001)0.0001)

Improvement disappeared at end of washout period Improvement disappeared at end of washout period (week 34)(week 34)

Significant improvement in total UPDRS score from Significant improvement in total UPDRS score from baseline (from 67.5 +/- 12 to 64.3 +/- 13.8)baseline (from 67.5 +/- 12 to 64.3 +/- 13.8)

Significant improvement in total ADAScog score Significant improvement in total ADAScog score - remembering, recognition and concentration- remembering, recognition and concentration



LIMITATIONSLIMITATIONS

Adverse Side effects – Increased salivations and tremorAdverse Side effects – Increased salivations and tremor

17 experienced side effects, 11 decreased their dose17 experienced side effects, 11 decreased their dose

8 Patients discontinued due to:8 Patients discontinued due to:

motor worsening, palpitations, confusional state, motor worsening, palpitations, confusional state, acute psychosis, heart attack and one found deadacute psychosis, heart attack and one found dead

Deterioration after 26 weeks was only picked up by Deterioration after 26 weeks was only picked up by mental part of UPDRS mental part of UPDRS low sensitivitylow sensitivity

Limited sample sizeLimited sample size

Alternative explanations – placebo effect & training Alternative explanations – placebo effect & training effecteffect



EVALUATIONEVALUATION

• Provided significant effectsProvided significant effects

• Did improve cognitive declineDid improve cognitive decline

• Positive behavioural changesPositive behavioural changes

• Did not really cause any major motor disturbancesDid not really cause any major motor disturbances

SUGGESTIONSSUGGESTIONS

Use better measurementUse better measurement

Requires long term studyRequires long term study

Requires larger sample sizeRequires larger sample size

Requires double blindRequires double blind


Study 2 Study 2 – Emre et al (2004)– Emre et al (2004)

• Conducted Conducted double blind, randomized, placebo-double blind, randomized, placebo-controlled study controlled study on effects of rivastigmine on PDD.on effects of rivastigmine on PDD.

• Total of 541 patients – 410 completed the study.Total of 541 patients – 410 completed the study.

• 2:1 ratio of rivastigmine group to placebo group2:1 ratio of rivastigmine group to placebo group

• Onset – At least 2 years after diagnosis of PDOnset – At least 2 years after diagnosis of PD

• 24 week treatment started off with 1.5 mg of rivastigmine 24 week treatment started off with 1.5 mg of rivastigmine or placebo daily. – Increased by 3 mg per day every 4 or placebo daily. – Increased by 3 mg per day every 4 weeks until highest well-tolerated dose. Until 16 week weeks until highest well-tolerated dose. Until 16 week dose escalation period.dose escalation period.

• The highest well tolerated dose was maintained for each The highest well tolerated dose was maintained for each patient.patient.

RESULTSRESULTS

Mean dose Mean dose 8.6 mg per day 8.6 mg per day

Moderate but significant improvements in global Moderate but significant improvements in global rating of dementia, cognition, and behavioural rating of dementia, cognition, and behavioural symptoms (ADAScog and ADCS-CGIC)symptoms (ADAScog and ADCS-CGIC)

More patients in treatment group improved and More patients in treatment group improved and more patients in placebo group worsenedmore patients in placebo group worsened



DISCONTINUATIONDISCONTINUATION

• Adverse events, withdrew consent, lost to follow Adverse events, withdrew consent, lost to follow up, protocol violation, died, unsatisfactory up, protocol violation, died, unsatisfactory therapeutic results and abnormal test resultstherapeutic results and abnormal test results

ADVERSE EVENTSADVERSE EVENTS

• Primary reason for discontinuationPrimary reason for discontinuation

• Nausea, tremor, anorexia, dizziness, constipation, Nausea, tremor, anorexia, dizziness, constipation, confusionconfusion

• Tremor was Tremor was more frequentmore frequent in the rivastigmine- in the rivastigmine-treated patients but rarely resulted in withdrawal.treated patients but rarely resulted in withdrawal.



EVALUATIONEVALUATION

• Did have placebo, randomized, double blind studyDid have placebo, randomized, double blind study

• Did have large sizeDid have large size

• Provided significant effectsProvided significant effects

• Did improve cognitive declineDid improve cognitive decline

• Positive behavioural changesPositive behavioural changes

SUGGESTIONSSUGGESTIONS

Use better measurement as there is a problem with low Use better measurement as there is a problem with low sensitivity.sensitivity.

Requires long term studyRequires long term study



Quantitative EEGQuantitative EEG - - Fogelson et al (2003)Fogelson et al (2003)


19 Patients, suffering from PD atleast one year before 19 Patients, suffering from PD atleast one year before dementia.dementia.

In PDD, there is a slowing of background activityIn PDD, there is a slowing of background activity

Rivastigmine increases higher frequency activity in the Rivastigmine increases higher frequency activity in the qEEG and decrease in slow-wave activity with qEEG and decrease in slow-wave activity with concomitant improvement in cognitive stateconcomitant improvement in cognitive state

Increase in alpha activity (greater in left hemisphere) Increase in alpha activity (greater in left hemisphere) and increase in beta activityand increase in beta activity

Decrease in delta and thetaDecrease in delta and theta

** could be in an indication of arousal rather than ** could be in an indication of arousal rather than improvement in cognitive stateimprovement in cognitive state

*** Problems with placebo effects, training and not blinded.*** Problems with placebo effects, training and not blinded.

EfficacyEfficacy


Efficacy must be looked at in 3 domains:Efficacy must be looked at in 3 domains:

1)1) CognitionCognition

2)2) Neuropsychiatric symptomsNeuropsychiatric symptoms

3)3) Parkinsonian symptomsParkinsonian symptoms

CognitionCognition - rivastigmine produced a moderate effect on - rivastigmine produced a moderate effect on cognitive symptomscognitive symptoms

NeuropsychiatricNeuropsychiatric – Did improve but not clear if – Did improve but not clear if improvement is clinically significantimprovement is clinically significant

ParkinsonianParkinsonian – Rivastigmine does worsen parkinsonian – Rivastigmine does worsen parkinsonian symptoms but the tests may not detect deterioration symptoms but the tests may not detect deterioration (may be considered not significant)(may be considered not significant)


Conclusion & SuggestionsConclusion & Suggestions Rivastigmine may only have a mild to moderate effect Rivastigmine may only have a mild to moderate effect

on PDDon PDD

Tolerability is an issue (high dropout rates)Tolerability is an issue (high dropout rates)

Worsening of parkinsonian symptomsWorsening of parkinsonian symptoms

However, not much choices as of now since there are However, not much choices as of now since there are not many options for PDDnot many options for PDD

May have underestimated improvements due to the May have underestimated improvements due to the lack of sensitivity in measurementslack of sensitivity in measurements

Rivastigimine and cholinesterase inhibitors should be Rivastigimine and cholinesterase inhibitors should be closely monitored for response and adverse events closely monitored for response and adverse events and physicians should and physicians should evaluate each patient evaluate each patient individually individually before initiating treatmentbefore initiating treatment

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Treatment of Parkinson’s Disease Dementia (PDD) Shanil Ebrahim