Treatment of Parkinson’s Disease Dementia (PDD)

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

2. Outline • Background • Neurobiology • Different studies • Methodology • Results • Side effects • Evaluation • Conclusion Rivastigmine for Parkinson’s Disease Dementia

3. Background • 40-70 % of patients with Parkinson’s Disease develop dementia • atleast 2 years after Parkinson’s diagnosis • If before or within 2 years  diffuse Lewy-body disease (DLB) • Both considered subtypes of more inclusive diagnosis of dementia with lewy bodies • Risk Factor  Mainly aging – usually over 65 • Increasing cholinergic function is beneficial Rivastigmine for Parkinson’s Disease Dementia

4. Neurobiology • The presence of Lewy bodies •  Intracytoplasmic neuronal inclusion containing alpha-synuclein • Found in neocortical and paralimbic regions • Lewy body counts increased neocortex & limbic areas (10 fold) • Majority of patients with PDD have pathological finding characteristic of alzheimer’s disease • *** In parkinson’s without dementia  lewy bodies are generally restricted to subcortical structures such as substantia nigra Rivastigmine for Parkinson’s Disease Dementia

5. Neurobiology Deficits 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 Rivastigmine for Parkinson’s Disease Dementia

6. Rivastigmine Background • Since, cholinesterase breaks down acetylcholine, a cholinesterase inhibitor will suppress the action of the enzyme   increases acetylcholine • Cholinesterase inhibitor  Rivastigmine • . • First Developed by Novartis Pharmaceuticals • Initially used for the treatment of mild to moderate Alzheimer's • In 2006, it became the first product approved by the US FDA for the treatment of mild to moderate PDD Rivastigmine for Parkinson’s Disease Dementia

7. Study 1 - Giladi et al (2003) • Conducted study on effects of rivastigmine on cognitive functions and other clinical features • 28 consenting patients with PD and Dementia (17M/11F), (mean age – 75 +/- 4.6 yrs), (symptoms duration – 7.0 +/- 5.3 yrs) • Had atleast 2 years of PD symptoms with a clear response to levodopa for more than 1 year • Excluded patients with: •  Cognitive changes in first year •  Psychotic features prior to or during first year after levodopa being introduced •  Other Psychiatric disorders Rivastigmine for Parkinson’s Disease Dementia

8. Study 1 - Giladi et al (2003) • ASSESSMENT • Unified Parkinsons’ Disease Rating scale (UPDRS) • Alzheimer’s Disease Assessment Scale (ADAS cog) DOSAGE • Week 1-4  1.5mg twice daily • Week 5-8  3mg twice daily • Week 8-12  4.5mg twice daily • Week 13-26  6mg twice daily (maximum dose) • Week 26  Dose tapered down over 2 weeks • Week 34  Final assessment Rivastigmine for Parkinson’s Disease Dementia

9. Study 1 - Giladi et al (2003) • RESULTS • Tolerated rivastigmine well - (mean dose at week 12  7.3 +/- 3.3 mg/day) • Significant improvement at weeks 12 and 26 (P < 0.0001) • Improvement disappeared at end of washout period (week 34) • Significant improvement in total UPDRS score from baseline (from 67.5 +/- 12 to 64.3 +/- 13.8) • Significant improvement in total ADAScog score - remembering, recognition and concentration Rivastigmine for Parkinson’s Disease Dementia

10. Study 1 - Giladi et al (2003) • LIMITATIONS • Adverse Side effects – Increased salivations and tremor • 17 experienced side effects, 11 decreased their dose • 8 Patients discontinued due to: • motor worsening, palpitations, confusional state, acute psychosis, heart attack and one found dead • Deterioration after 26 weeks was only picked up by mental part of UPDRS  low sensitivity • Limited sample size • Alternative explanations – placebo effect & training effect Rivastigmine for Parkinson’s Disease Dementia

11. Study 1 - Giladi et al (2003) • EVALUATION • Provided significant effects • Did improve cognitive decline • Positive behavioural changes • Did not really cause any major motor disturbances • SUGGESTIONS • Use better measurement • Requires long term study • Requires larger sample size • Requires double blind Rivastigmine for Parkinson’s Disease Dementia

12. Study 2 – Emre et al (2004) • Conducted double blind, randomized, placebo-controlled study on effects of rivastigmine on PDD. • Total of 541 patients – 410 completed the study. • 2:1 ratio of rivastigmine group to placebo group • Onset – At least 2 years after diagnosis of PD • 24 week treatment started off with 1.5 mg of rivastigmine or placebo daily. – Increased by 3 mg per day every 4 weeks until highest well-tolerated dose. Until 16 week dose escalation period. • The highest well tolerated dose was maintained for each patient. Rivastigmine for Parkinson’s Disease Dementia

13. Study 2 – Emre et al (2004) • RESULTS • Mean dose  8.6 mg per day • Moderate but significant improvements in global rating of dementia, cognition, and behavioural symptoms (ADAScog and ADCS-CGIC) • More patients in treatment group improved and more patients in placebo group worsened Rivastigmine for Parkinson’s Disease Dementia

14. Study 2 – Emre et al (2004) • DISCONTINUATION • Adverse events, withdrew consent, lost to follow up, protocol violation, died, unsatisfactory therapeutic results and abnormal test results • ADVERSE EVENTS • Primary reason for discontinuation • Nausea, tremor, anorexia, dizziness, constipation, confusion • Tremor was more frequent in the rivastigmine-treated patients but rarely resulted in withdrawal. Rivastigmine for Parkinson’s Disease Dementia

15. Study 2 – Emre et al (2004) • EVALUATION • Did have placebo, randomized, double blind study • Did have large size • Provided significant effects • Did improve cognitive decline • Positive behavioural changes • SUGGESTIONS • Use better measurement as there is a problem with low sensitivity. • Requires long term study Rivastigmine for Parkinson’s Disease Dementia

16. Quantitative EEG - Fogelson et al (2003) • 19 Patients, suffering from PD atleast one year before dementia. • In PDD, there is a slowing of background activity • Rivastigmine increases higher frequency activity in the qEEG and decrease in slow-wave activity with concomitant improvement in cognitive state • Increase in alpha activity (greater in left hemisphere) and increase in beta activity • Decrease in delta and theta ** could be in an indication of arousal rather than improvement in cognitive state *** Problems with placebo effects, training and not blinded. Rivastigmine for Parkinson’s Disease Dementia

17. Efficacy • Efficacy must be looked at in 3 domains: • Cognition • Neuropsychiatric symptoms • Parkinsonian symptoms • Cognition - rivastigmine produced a moderate effect on cognitive symptoms • Neuropsychiatric – Did improve but not clear if improvement is clinically significant • Parkinsonian – Rivastigmine does worsen parkinsonian symptoms but the tests may not detect deterioration (may be considered not significant) Rivastigmine for Parkinson’s Disease Dementia

18. Conclusion & Suggestions • Rivastigmine may only have a mild to moderate effect on PDD • Tolerability is an issue (high dropout rates) • Worsening of parkinsonian symptoms • However, not much choices as of now since there are not many options for PDD • May have underestimated improvements due to the lack of sensitivity in measurements • Rivastigimine and cholinesterase inhibitors should be closely monitored for response and adverse events and physicians should evaluate each patient individually before initiating treatment Rivastigmine for Parkinson’s Disease Dementia