MDS Evidence-Based Medicine Review: Motor Symptoms of PD (2018)
This is a condensed summary of the 2018 International Parkinson and Movement Disorder Society Evidence-Based Medicine Review (Fox et al.), updating the 2011 review with 143 new Level I studies through December 2016. Interventions are classified by efficacy (efficacious, likely efficacious, insufficient evidence, nonefficacious) and clinical practice implication (clinically useful, possibly useful, investigational, not useful).
Bottom Line: Key Conclusions
- No disease-modifying therapy: No intervention prevents or delays PD progression (pramipexole, CoQ10, creatine all nonefficacious)
- Early PD monotherapy: Nonergot dopamine agonists, levodopa (IR and ER), selegiline, and rasagiline are all clinically useful
- Levodopa remains most effective: Superior motor improvement and quality of life vs dopamine agonists and MAO-B inhibitors (PD MED trial)
- Motor fluctuations: Many clinically useful options -- nonergot DAs, levodopa ER, LCIG, entacapone, opicapone, rasagiline, zonisamide, safinamide, bilateral STN/GPi DBS
- Dyskinesia: Amantadine, clozapine (with monitoring), bilateral STN DBS and GPi DBS are clinically useful
- Physiotherapy: Clinically useful as adjunct for motor symptoms; exercise-based movement strategies and formalized patterned exercises are possibly useful
- LCIG intestinal infusion: Upgraded to clinically useful for motor fluctuations (new high-quality evidence)
- Opicapone: New COMT inhibitor -- clinically useful for motor fluctuations, no liver monitoring needed
- Safinamide: New MAO-B/glutamate inhibitor -- clinically useful for motor fluctuations (but not useful in early, non-fluctuating PD)
- Ergot DAs (pergolide, cabergoline, bromocriptine): Downgraded due to fibrosis risk -- require specialized monitoring
1. Disease Modification: Slowing or Preventing Progression
No intervention has demonstrated efficacy for slowing PD progression. The agents below are evaluated specifically for disease-modifying (neuroprotective) effects — not symptomatic benefit. Many of these same drugs are effective for symptom control (see Section 2) but do not alter the underlying disease course.
| Agent | Disease Modification Evidence | Conclusion |
|---|---|---|
| Pramipexole | Nonefficacious (PROUD trial — high-quality negative delayed-start study) | Not useful for slowing progression |
| Rasagiline | Insufficient evidence (ADAGIO 3-year follow-up inconclusive) | Investigational |
| Selegiline | Insufficient evidence | Investigational |
| Coenzyme Q10 | Nonefficacious (2 high-quality negative studies) | Not useful |
| Creatine | Nonefficacious (1 high-quality negative study) | Not useful |
| Vitamin D | Insufficient evidence | Investigational |
| Exercise | Insufficient evidence (mixed low-quality studies) | Investigational |
Disease modification remains an unmet need. Clinical rating scales are confounded by symptomatic effects, and PD heterogeneity (including genetic subtypes) may mask benefits in unstratified populations. Studying prodromal PD may offer a better window for future neuroprotective interventions.
2. Symptomatic Monotherapy in Early PD
Multiple options exist for initial monotherapy. Both levodopa and dopamine agonists significantly improve motor symptoms vs placebo. The choice depends on disability level, tolerability, age, and risk of motor complications.
Nonergot Dopamine Agonists
- Pramipexole IR: Efficacious -- clinically useful
- Pramipexole ER: Efficacious -- clinically useful
- Rotigotine (transdermal): Efficacious -- clinically useful
- Ropinirole IR: Efficacious -- clinically useful
- Piribedil: Efficacious -- clinically useful
- Ropinirole PR: Likely efficacious -- possibly useful
Ergot Dopamine Agonists
- Cabergoline, DHEC, Pergolide: Efficacious but require specialized monitoring (cardiac fibrosis risk)
- Bromocriptine: Likely efficacious -- possibly useful, same safety concerns
Levodopa Preparations
- Levodopa IR (standard): Efficacious -- clinically useful
- Levodopa CR (controlled release): Efficacious -- clinically useful
- Levodopa ER (IPX066): Efficacious -- clinically useful (new study)
MAO-B Inhibitors
- Selegiline: Efficacious -- clinically useful
- Rasagiline: Efficacious -- clinically useful
Other
- Anticholinergics: Likely efficacious -- clinically useful (limit to young, cognitively intact patients)
- Amantadine: Likely efficacious -- possibly useful
- Istradefylline (A2A antagonist): Nonefficacious as monotherapy -- not useful
Choosing Initial Therapy: Levodopa vs Levodopa-Sparing
- Levodopa provides superior motor improvement and quality of life (PD MED trial)
- Dopamine agonists delay motor complications (dyskinesia, fluctuations) but with more nonmotor side effects (sleepiness, ICDs, edema, postural hypotension)
- Long-term follow-up shows no clinically relevant difference in motor function, troublesome complications, or mortality by initial therapy choice
- Starting with levodopa and adding a DA later to reduce dyskinesia is a viable strategy
- Younger patients with high motor complication risk may favor levodopa-sparing initial treatment
- Patients needing rapid improvement (e.g., employment) favor initial levodopa
3a. Adjunct Therapy in Early/Stable PD
For patients on levodopa needing additional benefit without increasing levodopa dose, particularly younger patients aiming to delay motor complications.
Nonergot Dopamine Agonists
- Pramipexole IR/ER, Ropinirole IR, Rotigotine, Piribedil: All efficacious -- clinically useful
- No evidence of clinical superiority of one DA over another
- Choice based on local availability, cost, and individual tolerability
COMT Inhibitors
- Entacapone: Nonefficacious in non-fluctuating patients -- not useful (increased motor complications)
- Tolcapone: Efficacious but redesignated unlikely useful (liver toxicity risk, not recommended without fluctuations)
MAO-B Inhibitors
- Rasagiline: Efficacious as adjunct to DA -- clinically useful
- Zonisamide: Efficacious -- clinically useful
- Safinamide: Nonefficacious in early, non-fluctuating PD -- not useful
Surgery
- Early bilateral STN DBS (without motor complications, <4 years disease): Insufficient evidence -- investigational (EARLYSTIM: primary outcome was safety)
3b. Adjunct Therapy for Specific Motor Symptoms (Optimized Patients)
Gait and Balance (Pharmacological)
- Rivastigmine: Likely efficacious (improved step-time variability, reduced falls) -- possibly useful
- Donepezil: Insufficient evidence (1 positive study, lower quality) -- investigational
- Methylphenidate: Insufficient evidence (conflicting data) -- investigational
- Memantine: Insufficient evidence (no effect on stride length) -- investigational
- Cannabidiol: Insufficient evidence -- investigational
Physiotherapy
- Physiotherapy (treadmill, aerobic, strengthening, balance): Likely efficacious -- clinically useful
- 31 new RCTs reviewed; any active physiotherapy intervention appears beneficial
- Optimal frequency, intensity, duration, and setting remain unknown
Movement Strategy Training
- Exercise-based (cueing, balance training, postural rehabilitation): Insufficient evidence but generally positive -- possibly useful
- Technology-based (virtual reality, robotics, biofeedback): Insufficient evidence, conflicting outcomes -- investigational
Formalized Patterned Exercises
- Tai Chi: Conflicting results (2 high-quality studies, 1 positive, 1 negative)
- Dance (tango, Irish): Positive but low quality
- Power Yoga: Positive but low quality
- Overall: Insufficient evidence -- possibly useful
Other Therapies
- Speech therapy (LSVT): Insufficient evidence -- possibly useful (widely used clinically)
- Occupational therapy: Insufficient evidence -- possibly useful
- rTMS: Insufficient evidence (variable techniques, conflicting results) -- investigational
- tDCS: Insufficient evidence -- investigational
- Acupuncture: Insufficient evidence -- investigational
- Bee venom: Nonefficacious (high-quality negative study) -- not useful
Tremor-Specific Interventions
- Unilateral thalamotomy: Likely efficacious -- possibly useful (requires specialized monitoring)
- Thalamic DBS (uni/bilateral): Likely efficacious -- possibly useful
- STN DBS and GPi DBS are efficacious for tremor (see Motor Fluctuations section)
4. Prevention/Delay of Motor Complications
No new studies since the 2011 review. Previous conclusions remain unchanged.
Preventing Motor Fluctuations
- Pramipexole IR: Efficacious -- clinically useful
- Cabergoline: Efficacious -- clinically useful (ergot monitoring)
- Ropinirole IR: Insufficient evidence for fluctuations -- investigational
- Entacapone: Nonefficacious -- not useful
- Selegiline: Nonefficacious for dyskinesia, insufficient for fluctuations
Preventing Dyskinesia
- Pramipexole, Ropinirole, Cabergoline: Efficacious or likely efficacious for delaying dyskinesia vs initial levodopa
- Bromocriptine, Pergolide: Possibly useful but limited by ergot properties
- Note: DAs delay dyskinesia but with more nonmotor side effects; long-term outcomes do not differ
5a. Treatment of Motor Fluctuations
Nonergot Dopamine Agonists
- Pramipexole IR/ER: Efficacious -- clinically useful
- Ropinirole IR/PR: Efficacious -- clinically useful
- Rotigotine: Efficacious -- clinically useful
- Apomorphine s.c. (intermittent): Efficacious -- clinically useful (rapid OFF rescue)
- Apomorphine infusion: Likely efficacious -- possibly useful (no published double-blind RCT at time of review)
- Piribedil: Likely efficacious -- possibly useful
- No evidence of superiority of one nonergot DA over another
Levodopa Preparations
- Levodopa ER (IPX066): Efficacious -- clinically useful (reduced OFF time vs IR and IR/entacapone)
- LCIG (levodopa-carbidopa intestinal gel): Efficacious -- clinically useful (upgraded; new high-quality evidence)
- LCIG safety: acceptable risk with specialized monitoring (device-related complications)
COMT Inhibitors
- Entacapone: Efficacious -- clinically useful
- Opicapone: Efficacious -- clinically useful (new; 2 high-quality positive studies, no liver monitoring needed)
- Tolcapone: Efficacious -- possibly useful (liver toxicity requires specialized monitoring)
MAO-B Inhibitors
- Rasagiline: Efficacious -- clinically useful
- Safinamide: Efficacious -- clinically useful (new; 2 high-quality positive studies with 18-month extension)
- Zonisamide: Efficacious -- clinically useful (upgraded; new high-quality study; approved in Japan)
- Selegiline: Insufficient evidence -- investigational (prior low-quality studies only)
Adenosine A2A Antagonist
- Istradefylline: Likely efficacious (6 positive, 1 negative high-quality study) -- possibly useful (approved in Japan)
Surgery
- Bilateral STN DBS: Efficacious -- clinically useful (new positive studies including earlier PD with fluctuations)
- Bilateral GPi DBS: Efficacious -- clinically useful
- Unilateral pallidotomy: Efficacious -- clinically useful
- Safety for all surgical interventions: acceptable risk with specialized monitoring
- No RCTs directly comparing device-aided therapies (LCIG vs apomorphine vs DBS)
Clinical Approach to Motor Fluctuations
- First-line: Oral/transdermal agents -- adjust levodopa timing, add DA, COMT-I, or MAO-B-I
- Practical first steps: Shorten levodopa dosing interval, ensure empty stomach, treat constipation
- Second-line: Parenteral/surgical -- apomorphine, LCIG, or DBS for advanced patients with bothersome complications
- No head-to-head data comparing relative efficacy of oral add-on agents
- Entacapone vs rasagiline showed comparable OFF time reduction in prior study
5b. Treatment of Dyskinesia
Pharmacological
- Amantadine: Efficacious -- clinically useful (3 new high-quality positive studies; NMDA antagonist)
- Clozapine: Efficacious -- clinically useful (5-HT receptor target; requires blood count monitoring -- acceptable risk with specialized monitoring)
- Levetiracetam: Insufficient evidence (conflicting results) -- investigational
- Zonisamide: Insufficient evidence -- investigational
Levodopa-Based Strategies
- LCIG intestinal infusion: Likely efficacious for dyskinesia disability -- clinically useful for overall motor complications (continuous stimulation reduces pulsatile dyskinesia)
- Optimizing oral levodopa doses may help but risks worsening motor symptoms
Surgery
- Bilateral STN DBS: Efficacious -- clinically useful (reduces dyskinesia primarily through levodopa dose reduction)
- Bilateral GPi DBS: Efficacious -- clinically useful (direct stimulation effect on dyskinesia; levodopa dose unchanged)
- Unilateral pallidotomy: Efficacious -- clinically useful
Ergot Dopamine Agonists -- Safety Warning
- Pergolide, cabergoline, bromocriptine, and DHEC carry risk of cardiac valve fibrosis
- Safety designation: acceptable risk with specialized monitoring
- Use is greatly restricted worldwide; nonergot agents preferred
- Regular echocardiographic screening required if used
Summary Table: Clinically Useful Interventions
- Early PD monotherapy: Levodopa (IR/CR/ER), pramipexole (IR/ER), ropinirole IR, rotigotine, piribedil, selegiline, rasagiline
- Adjunct in early/stable PD: Nonergot DAs (all), rasagiline, zonisamide
- Adjunct for motor symptoms: Physiotherapy
- Motor fluctuations: Nonergot DAs, levodopa ER, LCIG, entacapone, opicapone, rasagiline, safinamide, zonisamide, apomorphine s.c., bilateral STN DBS, bilateral GPi DBS
- Dyskinesia: Amantadine, clozapine, bilateral STN DBS, bilateral GPi DBS
Reference
Fox SH, Katzenschlager R, Lim SY, et al. International Parkinson and Movement Disorder Society Evidence-Based Medicine Review: Update on Treatments for the Motor Symptoms of Parkinson's Disease. Mov Disord. 2018;33(8):1248-1266. doi: 10.1002/mds.27372