Current Treatment Options in Neurology

, Volume 12, Issue 3, pp 186–199

Parkinson’s Disease and Motor Fluctuations

Movement Disorders

Opinion statement

Many important advances for the treatment of Parkinson’s disease (PD) have been made over the past decade, and quality of life has improved for most patients. Nonetheless, motor fluctuations in the form of wearing off with the re-emergence of parkinsonian symptoms and hyperkinetic movements (dyskinesias) often arise as a complication of long-term dopaminergic therapy and can be disabling. Because treatment of motor fluctuations is difficult, clinicians should attempt to prevent them by using low doses of dopaminergic drugs in early PD, targeting functionally relevant symptoms. Instead of levodopa, dopamine agonists, amantadine, and rasagiline can be used with the aim of delaying the onset of motor fluctuations. Once motor fluctuations arise, off time can initially be addressed with more frequent dosing of levodopa. Later, adjunctive therapy with a dopamine agonist, COMT-inhibitor, or MAO-B inhibitor becomes necessary. For treatment of dyskinesias, reduction of the levodopa dose should be the first step. If this is not tolerated because of increased off time, then adjunctive therapy with levodopa-sparing agents should be attempted. The addition of amantadine (the only currently available antidyskinetic drug) is another useful strategy but is often only a temporary solution. Once medical attempts at treating motor fluctuations fail, deep brain stimulation (DBS) can be considered. Careful patient selection and skilled placement of DBS electrodes are important determinants of the surgical outcome.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Ahlskog JE, Muenter MD: Frequency of levodopa related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 2001, 16:448–458.CrossRefPubMedGoogle Scholar
  2. 2.
    Adler CH, Sethi KD, Hauser RA, et al.: Ropinirole for the treatment of early Parkinson’s disease. The Ropinirole Study Group. Neurology 1997, 49:393–399.PubMedGoogle Scholar
  3. 3.
    Holloway RG, Shoulson I, Fahn S, et al.: Pramipexole vs levodopa as initial treatment for Parkinson’s disease: a 4-year randomized-controlled trial. Arch Neurol 2004, 61:1044–1053.CrossRefPubMedGoogle Scholar
  4. 4.
    Schrag A, Quinn N: Dyskinesias and motor fluctuations in Parkinson’s disease. A community-based study. Brain 2000, 123:2297–2305.CrossRefPubMedGoogle Scholar
  5. 5.
    Chase TN: Striatal plasticity and extrapyramidal motor dysfunction. Parkinsonism Relat Disord 2004, 10:305–313.CrossRefPubMedGoogle Scholar
  6. 6. •
    Jenner P: Preventing and controlling dyskinesia in Parkinson’s disease—a view of current knowledge and future opportunities. Mov Disord 2008, 23(Suppl 3):585–598.CrossRefGoogle Scholar
  7. 7.
    Smith LA, Jackson MJ, Al-Barghouthy G, et al.: Multiple small doses of levodopa plus entacapone produce continuous dopaminergic stimulation and reduce dyskinesia induction in MPTP-treated drug-naïve primates. Mov Disord 2005, 20:306–314.CrossRefPubMedGoogle Scholar
  8. 8.
    Stocchi F, Kakarieka A, Kieburtz K, et al.: The STRIDE-PD (Stalevo Reduction in Dyskinesia Evaluation) study [abstract LB-19]. Presented at the 13th International Congress of Parkinson’s Disease and Movement Disorders. Paris, France; June 7–11, 2009. Available at http://www.movementdisorders.org/congress/congress09/late_breaking_abstracts.pdf.
  9. 9.
    Riley D, Lang AE: Practical application of a low-protein diet for Parkinson’s disease. Neurology 1988, 38:1026–1031.PubMedGoogle Scholar
  10. 10.
    Pappert EJ, Goetz CG, Niederman F, et al.: Liquid levodopa/carbidopa produces significant improvement in motor function without dyskinesia exacerbation. Neurology 1996, 47(6):1493–1495.PubMedGoogle Scholar
  11. 11.
    Parcopa: a rapidly dissolving formulation of carbidopa/levodopa. Med Lett Drugs Ther 2005, 47(1201):12.Google Scholar
  12. 12.
    Fahn S, Oakes D, Shoulson I, Parkinson Study Group, et al.: Levodopa and the progression of Parkinson’s disease. N Engl J Med 2004, 351(24):2498–2508.CrossRefPubMedGoogle Scholar
  13. 13.
    Frankel JP, Lees AJ, Kempster PA, Stern GM: Subcutaneous apomorphine in the treatment of Parkinson’s disease. J Neurol Neurosurg Psychiatry 1990, 53(2):96–101.CrossRefPubMedGoogle Scholar
  14. 14. •
    Fenu S, Wardas J, Morelli M: Impulse control disorders and dopamine dysregulation syndrome associated with dopamine agonist therapy in Parkinson’s disease. Behav Pharmacol 2009, 20(5–6):363–379.CrossRefPubMedGoogle Scholar
  15. 15.
    Lieberman AN, Ranhosky A, Korts D: Clinical evaluation of pramipexole in advanced Parkinson’s disease: results of a double-blind, placebo-controlled, parallel-group study. Neurology 1997, 49:162–168.PubMedGoogle Scholar
  16. 16.
    Lieberman AN, Olanow CW, Sethi K, et al.: A multicenter trial of ropinirole as an adjunct treatment for Parkinson’s disease. Neurology 1998, 51:1057–1062.PubMedGoogle Scholar
  17. 17.
    Olanow CW, Watkins PB: Tolcapone 2007: an efficacy and safety review. J Clin Neuropharm 2007, 30:287–294.CrossRefGoogle Scholar
  18. 18.
    Parkinson Study Group: Entacapone improves motor fluctuations in levodopa-treated Parkinson’s disease patients. Ann Neurol 1997, 42(5):747–755.CrossRefGoogle Scholar
  19. 19.
    Rinne UK, Larsen JP, Siden A, Worm-Petersen J: Entacapone enhances the response to levodopa in parkinsonian patients with motor fluctuations. Nomecomt Study Group. Neurology 1998, 51(5):1309–1314.PubMedGoogle Scholar
  20. 20.
    Golbe LI, Lieberman AN, Muenter MD, et al.: Deprenyl in the treatment of symptom fluctuation in advanced Parkinson’s disease. Clin Neuropharmacol 1988, 11:45–55.PubMedCrossRefGoogle Scholar
  21. 21.
    Parkinson Study Group: A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations. The PRESTO study. Arch Neurol 2005, 62(2):241–248.CrossRefGoogle Scholar
  22. 22.
    deMarcaida JA, Schwid SR, White WB, et al.: Effects of tyramine administration in Parkinson’s disease patients treated with selective MAO-B inhibitor rasagiline. Mov Disord 2006, 21(10):1716–1721.CrossRefPubMedGoogle Scholar
  23. 23.
    Verhagen Metman L, Del Dotto P, van den Munckhof P, et al.: Amantadine as treatment for dyskinesias and motor fluctuations in Parkinson’s disease. Neurology 1998, 50(5):1323–1326.PubMedGoogle Scholar
  24. 24.
    Bronte-Stewart H: Parkinson’s disease: surgical options. Curr Treat Options Neurol 2003, 5(2):131–147.CrossRefPubMedGoogle Scholar
  25. 25.
    Ben-Haim S, Asaad WF, Gale JT, et al.: Risk factors for hemorrhage during microelectrode-guided deep brain stimulation and the introduction of an improved microelectrode design. Neurosurgery 2009, 64(4):754–762.CrossRefPubMedGoogle Scholar
  26. 26. •
    Valldeoriola F, Morsi O, Tolosa E, et al.: Prospective comparative study on cost-effectiveness of subthalamic stimulation and best medical treatment in advanced Parkinson’s disease. Mov Disord 2007, 22(15):2183–2191.CrossRefPubMedGoogle Scholar
  27. 27.
    Fraix V, Houeto JL, Lagrange C, SPARK Study Group, et al.: Clinical and economic results of bilateral subthalamic nucleus stimulation in Parkinson’s disease. J Neurol Neurosurg Psychiatry 2006, 77(4):443–449.CrossRefPubMedGoogle Scholar
  28. 28.
    Stocchi F, Ruggieri S, Vacca L, et al.: Prospective randomized trial of lisuride infusion versus oral levodopa in patients with Parkinson’s disease. Brain 2002, 125(9):2058–2066.CrossRefPubMedGoogle Scholar
  29. 29.
    Nyholm D, Nilsson Remahl AI, Dizdar N, et al.: Duodenal levodopa infusion monotherapy vs oral polypharmacy in advanced Parkinson disease. Neurology 2005, 64(2):216–223.PubMedGoogle Scholar
  30. 30. •
    Garcia Ruiz PJ, Sesar Ignacio A, Ares Pensado B, et al.: Efficacy of long-term continuous subcutaneous apomorphine infusion in advanced Parkinson’s disease with motor fluctuations: a multicenter study. Mov Disord 2008, 23(8):1130–1136.CrossRefPubMedGoogle Scholar
  31. 31.
    Poewe WH, Rascol O, Quinn N, SP 515 Investigators, et al.: Efficacy of pramipexole and transdermal rotigotine in advanced Parkinson’s disease: a double-blind, double-dummy, randomized controlled trial. Lancet Neurol 2007, 6(6):513–520.CrossRefPubMedGoogle Scholar
  32. 32.
    Braz CA, Borges V, Ferraz HB: Effect of riluzole on dyskinesia and duration of the on-state in Parkinson’s disease patients: a double-blind, placebo-controlled pilot study. Clin Neuropharmacol 2004, 27:25–29.CrossRefPubMedGoogle Scholar
  33. 33.
    Konitsiotis S, Blanchert PJ, Verhagen L, et al.: AMPA receptor blockade improves levodopa-induced dyskinesia in MTPT monkeys. Neurology 2000, 54:1589–1595.PubMedGoogle Scholar
  34. 34.
    Gardoni F, Picconi B, Ghiglieri V, et al.: A critical interaction between NR2B and MAGUK in L-DOPA induced dyskinesia. J Neurosci 2006, 26(11):2914–2922.CrossRefPubMedGoogle Scholar
  35. 35.
    Olanow CW, Damier P, Goetz CG, et al.: Multi-center, open-label trial of sarizotan in Parkinson disease patients with levodopa-induced dyskinesias (the SPLENDID study). Clin Neuropharmacol 2004, 27:58–62.CrossRefPubMedGoogle Scholar
  36. 36.
    Goetz CG, Damier P, Hicking C, et al.: Sarizotan as a treatment for dyskinesias in Parkinson’s disease: a double-blind, placebo-controlled trial. Mov Disord 2007, 22:179–186.CrossRefPubMedGoogle Scholar
  37. 37.
    Murata M: Novel therapeutic effects of the anti-convulsant, zonisamide, on Parkinson’s disease. Curr Pharm Des 2004, 10(6):687–693.CrossRefPubMedGoogle Scholar
  38. 38. •
    Murata M, Hasegawa K, Kanazawa I; Japan Zonisamide on PD Study Group: Zonisamide improves motor function in Parkinson disease: a randomized, double-blind study. Neurology 2007, 68(1):45–50.CrossRefPubMedGoogle Scholar
  39. 39.
    Zesiewitz TA, Sullivan KL, Maldonado JL, et al.: Open-label pilot study of levetiracetam (Keppra) for the treatment of levodopa-induced dyskinesias in Parkinson’s disease. Mov Disord 2005, 20:1205–1209.CrossRefGoogle Scholar
  40. 40.
    Olanow CW, Goetz CG, Kordower JH, et al.: A double blind controlled trial of bilateral fetal nigral transplantation in Parkinson’s disease. Ann Neurol 2003, 54:403–414.CrossRefPubMedGoogle Scholar
  41. 41.
    Kordower JH, Chu Y, Hauser RA, et al.: Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat Med 2008, 14(5):504–506.CrossRefPubMedGoogle Scholar
  42. 42.
    Bakay RA, Raiser CD, Stover NP, et al.: Implantation of Spheramine in advanced Parkinson’s disease (PD). Front Biosci 2004, 9:592–602.CrossRefPubMedGoogle Scholar
  43. 43.
    Muramatsu S, Fujimoto K, Ikeguchi K: Behavioral recovery in a primate model of Parkinson’s disease by triple transduction of striatal cells with adeno-associated viral vectors expressing dopamine-synthesizing enzymes. Hum Gene Ther 2002, 13:345–354.CrossRefPubMedGoogle Scholar
  44. 44. •
    Marks Jr WJ, Ostrem JL, Verhagen L, et al.: Safety and tolerability of intraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson’s disease: an open-label, phase I trial. Lancet Neurol 2008, 7(5):400–408.CrossRefPubMedGoogle Scholar

Copyright information

© US Government 2010

Authors and Affiliations

  1. 1.Medical University of South CarolinaCharlestonUSA

Personalised recommendations