Management of Motor Fluctuations in Parkinson Disease

1. Management of Motor Fluctuations in
Parkinson Disease
Ade Wijaya, MD

2. Outline
• Motor fluctuations as a complication of Parkinson Disease (PD)
• Management of motor fluctuations: non pharmacological and
pharmacological
• How to choose the most suitable medication for our patients

3. Introduction
• Approximately one-third of PD patients will experience motor
complication(s) after 2 years of levodopa exposure  this may
be difficult to treat and may significantly increase disability
• Motor complications: motor fluctuations and dyskinesia
• Motor fluctuations are alterations between periods marked by a
positive response to medication ("on") and periods marked by
reemergence of Parkinsonian symptoms ("off")

4. Course of PD Progression

5. Honeymoon Period

6. Motor Complications
Motor fluctuations
• Predictable wearing-off
• Delayed ‘on’ or partial ‘on’ response
or dose failures
• Complex fluctuations or on/off
fluctuations or ‘yo-yo-ing’
• ‘On’ and ‘off’ period freezing
• Beginning-of-dose worsening (super
‘off’)
• End-of-dose rebound
• Unpredictable sudden ‘off’
Dyskinesias
• Peak-dose
dyskinesia/Square
wave dyskinesia
• Diphasic dyskinesia
• ‘Off’ period
dystonia
Others
• ‘Tachyphemia/
stuttering speech
• Running gait

7. Pathophysiology
• Progressivity of the disease – nigrostriatal degeneration
• Dopamine desensitization and downregulation
 dopaminergic nerve terminals in the striatum   storage capacity of
dopamine and an immediate dependency on dopamine despite a
sufficiently high level of levodopa available
• Delayed gastric emptying in late PD

8. Wearing-Off

9. Wearing-Off Prevalence

10. Classification of Levodopa-Related Motor
Fluctuations in PD

11. Risk Factors
• Younger onset of PD
• Duration of the disease
• Duration of medication (levodopa and dopamine agonist)

12. Wearing-Off Symptoms

13. Wearing-Off Questionnaire

14. Management

15. Management of Motor Fluctuations
• Evaluate the patient’s adherence/compliance to therapy (which
might be influenced by conditions such as depression, apathy,
and cognitive impairment)
• Evaluate dietary factors (quantity and timing of protein intake)
and gastrointestinal absorption (H. pylori status, constipation)
• Evaluate other factors such as insomnia and depression,
infections, post surgery, adverse effects of some other
medications

16. Management of Motor Fluctuations
- Dietary Modification
• Constipation:  fiber and fluid intake, exercise, laxatives
• Delayed gastric emptying/gastroparesis: small frequent feeding,
low-fat diet, domperidone
• 40-min delay between levodopa dosing and protein intake; low-
protein intake
• Protein redistribution

17. Management of Motor Fluctuations
- Pharmacological
• Levodopa fractination (compliance ?)
• Increase the dose of levodopa (dyskinesia ?)
• Controlled-release formulation (delayed on, lack of on)
• Add COMT inhibitor (opicapone, tolcapone, entacapone)
• Add dopamine agonist (levodopa dose should be maintained until clinical
response to DA is achieved)
• Add MAO-B inhibitor
• Zonisamide, amantadine

18. Therapeutic
Options for
Management:
Evidence-Based
vs. Experience
Selection

19. PD Medications

20. Management of Motor Fluctuations
- Advanced Therapies
• Deep brain stimulation
• Levodopa/carbidopa intestinal gel
• Continuous subcutaneous apomorphine infusion

21. Which medication should we choose
first?
COMT inhibitor?
Dopamine agonist?
MAO-B inhibitor?
No therapeutic strategy has been proven to be better

22. There is no one-size-fits-all in PD
management
EBM
Patients’ profile
Symptoms/
fluctuation
patterns

23. Special condition COMT INHIBITOR DOPAMINE AGONIST MAO-B INHIBITOR
Risk of dyskinesia + + -
Postural hypotension + + +
Cognitive impairment - + +
Impulsivity or psychosis - + +
Confusion or hallucination - + +
Fatigue or EDS - + -
Dark discoloration/staining of
urine, sweat, and saliva
+ (entacapone)
not harmful
- -
Diarrhea, GI effect + (entacapone) - -
Hepatotoxicity + (tolcapone)
Restless leg syndrome   
Arrhythmia   
Frailty   
Early morning off -  

24. • Patients with PD who take levodopa chronically are increasingly
likely to develop motor fluctuations and dyskinesia as the disease
progresses
• Management:
oDetermine the fluctuation patterns
oNon pharmacological vs pharmacological
• There is no one-size-fits-all; certain medications for certain
patients
Take Home Messages

25. • Perepezko, K., Hinkle, J., Mills, K., & Pontone, G. (2020, September). Frequency of Wearing-
Off Symptoms in Parkinson's disease Fluctuators: An on/off evaluation. In MOVEMENT
DISORDERS (Vol. 35, pp. S344-S344). 111 RIVER ST, HOBOKEN 07030-5774, NJ USA: WILEY.
• Fackrell R, Carroll CB, Grosset DG, Mohamed B, Reddy P, Parry M, Chaudhuri KR, Foltynie T.
Noninvasive options for ‘wearing-off’in Parkinson's disease: a clinical consensus from a
panel of UK Parkinson's disease specialists. Neurodegenerative disease management. 2018
Sep;8(5):349-60.
• Raja K, Ramrakhia S, Dev K, et al. (September 30, 2020) The Risk Factors for the Wearing-Off
Phenomenon in Parkinson's Disease. Cureus 12(9): e10729. doi:10.7759/cureus.10729
• Fabbri, M., Barbosa, R. & Rascol, O. Off-time Treatment Options for Parkinson’s
Disease. Neurol Ther (2023). https://doi.org/10.1007/s40120-022-00435-8
• Goel A, Sugumaran R, Narayan SK. Zonisamide in Parkinson’s disease: a current update.
Neurological Sciences. 2021 Oct;42(10):4123-9.
• Buku Ajar Neurologi FKUI/RSCM Edisi ke-2
References

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27. THANK YOU