Treatment of Parkinson

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Rivastigmine
Treatment of Parkinsons Disease Dementia (PDD)
Shanil Ebrahim
Shanil Ebrahim
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Outline

• Background
• Neurobiology
• Different studies
• Methodology
• Results
• Side effects
• Evaluation
• Conclusion

Rivastigmine for Parkinsons Disease Dementia
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Background

• 40-70 of patients with Parkinsons Disease
  develop dementia
• atleast 2 years after Parkinsons 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 Parkinsons Disease Dementia
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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 alzheimers disease
• In parkinsons without dementia ? lewy bodies
  are generally restricted to subcortical
  structures such as substantia nigra

Rivastigmine for Parkinsons Disease Dementia
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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 Parkinsons Disease Dementia
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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

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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 Parkinsons Disease Dementia
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Study 1 - Giladi et al (2003)

• ASSESSMENT
• Unified Parkinsons Disease Rating scale (UPDRS)
• Alzheimers 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 Parkinsons Disease Dementia
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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 lt
  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

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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 Parkinsons Disease Dementia
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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

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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.
• 21 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 Parkinsons Disease Dementia
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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

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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 Parkinsons Disease Dementia
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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

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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.

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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)

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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 Parkinsons Disease Dementia