Hostname: page-component-848d4c4894-jbqgn Total loading time: 0 Render date: 2024-06-16T14:12:49.989Z Has data issue: false hasContentIssue false

The Fluctuating Parkinsonian Patient - Clinical and Pathophysiological Aspects

Published online by Cambridge University Press:  02 December 2014

Pierre J. Blanchet*
Affiliation:
Department of Stomatology, Faculty of Dentistry, Universite de Montreal, and Andre-Barbeau Movement Disorders Unit, Hôtel-Dieu du CHUM, Montreal, QC, Canada
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Although levodopa-related motor response complications remain challenging from a pathophysiological and therapeutic standpoint, major advances have been made in the last decade, supporting the development of several promising drugs. Eventually, these drugs may help us to prevent, alleviate, or even “deprime” these frequent and disabling complications. Knowledge of the basic mechanisms and hypotheses underlying this fascinating conversion in the parkinsonian brain allows neurologists to understand the rationale behind emerging treatment strategies.

Résumé

RÉSUMÉ

Les complications motrices associées à la dopathérapie chez le Parkinsonien constituent toujours un défi au plan théorique et thérapeutique mais des progrès majeurs ont été réalisés durant la dernière décennie, favorisant le développement de plusieurs médications prometteuses. Il n’est peut-être pas loin le jour où ces nouveaux agents pourront prévenir, soulager ou même renverser pour de bon (“déprogrammer”) ces complications fréquentes et handicapantes. Une connaissance des mécanismes fondamentaux à l’origine de cette fascinante conversion dans le cerveau parkinsonien et des hypothèses explorées permet aux neurologues de mieux comprendre la logique entourant les stratégies correctrices en émergence.

Type
Research Article
Copyright
Copyright © The Canadian Journal of Neurological 2003

References

1. Fahn, S. The spectrum of levodopa-induced dyskinesias. Ann Neurol 2000;47(Suppl 1):S2-S11.Google Scholar
2. Riley, DE, Lang, AE. The spectrum of levodopa-related fluctuationsin Parkinson’s disease. Neurology 1993;43:14591464.Google Scholar
3. Hillen, ME, Sage, JI. Nonmotor fluctuations in patients with Parkinson’s disease. Neurology 1996;47:11801183.Google Scholar
4. Witjas, T, Kaphan, E, Azulay, JP, et al. Nonmotor fluctuations in Parkinson’sdisease: frequentand disabling. Neurology 2002;59:408413.Google Scholar
5. Papa, SM, Engber, TM, Kask, AM, Chase, TN. Motor fluctuations inlevodopa treated parkinsonian rats: relation to lesion extent and treatment duration. Brain Res 1994;662:6974.Google Scholar
6. Merello, M, Lees, AJ. Beginning-of-dose motor deteriorationfollowing the acute administration of levodopa and apomorphine in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1992;55:10241026.CrossRefGoogle ScholarPubMed
7. Blanchet, PJ, Allard, P, Grégoire, L, et al. Risk factors for peak dosedyskinesia in 100 levodopa-treated parkinsonian patients. Can J Neurol Sci 1996;23:189193.Google Scholar
8. Muenter, MD, Sharpless, NS, Tyce, GM, Darley, FL. Patterns ofdystonia (“I-D-I” and “D-I-D”) in response to L-dopa therapy for Parkinson’s disease. Mayo Clin Proc 1977;52:163174.Google Scholar
9. Marconi, R, Lefebvre-Caparros, D, Bonnet, AM, et al. Levodopa-induced dyskinesias in Parkinson’s disease. Phenomenology and pathophysiology. Mov Disord 1994;9:212.CrossRefGoogle ScholarPubMed
10. Togasaki, DM, Tan, L, Protell, P, et al. Levodopa induces dyskinesiasin normal squirrel monkeys. Ann Neurol 2001;50:254257.Google Scholar
11. Daras, M, Koppel, BS, Atos-Radzion, E. Cocaine-inducedchoreoathetoid movements (“crack dancing”). Neurology 1994;44:751752.CrossRefGoogle ScholarPubMed
12. de la Fuente-Fernandez, R, Pal, PK, Vingerhoets, FJG, et al. Evidencefor impaired presynaptic dopamine function in parkinsonian patients with motor fluctuations. J Neural Transm 2000;107:4957.Google Scholar
13. de la Fuente-Fernandez, R, Lu, J-Q, Sossi, V, et al. Biochemicalvariations in the synaptic level of dopamine precede motor fluctuations in Parkinson’s disease: PET evidence of increased dopamine turnover. Ann Neurol 2001;49:298303.Google Scholar
14. Blanchet, PJ, Grondin, R, Bédard, PJ. Dyskinesia and wearing-offfollowing dopamine D1 agonist treatment in drug-naive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned primates. Mov Disord 1996;11:9194.Google Scholar
15. Nutt, JG, Carter, JH, Lea, ES, Sexton, GJ. Evolution of the response tolevodopa during the first 4 years of therapy. Ann Neurol 2002;51:686693.CrossRefGoogle ScholarPubMed
16. Rascol, A, Guiraud, B, Montastruc, JL, David, J, Clanet, M. Long-termtreatment of Parkinson’s disease with bromocriptine. J NeurolNeurosurg Psychiatry 1979;42:143150.Google Scholar
17. Lees, AJ, Stern, GM. Sustained bromocriptine therapy in previouslyuntreated patients with Parkinson’s disease. J Neurol Neurosurg Psychiatry 1981;44:10201023.Google Scholar
18. Hely, MA, Morris, JGL, Reid, WGJ, et al. The Sydney MulticentreStudy of Parkinson’s disease: a randomised, prospective five year study comparing low dose bromocriptine with low dose levodopa-carbidopa. J Neurol Neurosurg Psychiatry 1994;57:903910.Google Scholar
19. Bedard, PJ, Di Paolo, T, Falardeau, P, Boucher, R. Chronic treatment with L-DOPA, but not bromocriptine induces dyskinesia in MPTP-parkinsonian monkeys. Correlation with [3H]spiperonebinding. Brain Res 1986;379:294299.CrossRefGoogle ScholarPubMed
20. Blanchet, P, Bédard, PJ, Britton, DR, Kebabian, JW. Differential effectof selective D-1 and D-2 dopamine receptor agonists on levodopa-induced dyskinesia in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-exposed monkeys. J Pharmacol Exp Therap 1993;267:275279.Google Scholar
21. Muriel, M-P, Bernard, V, Levey, AI, et al. Levodopa induces acytoplasmic localization of D1 dopamine receptors in striatal neurons in Parkinson’s disease. Ann Neurol 1999;46:103111.Google Scholar
22. Gomez-Mancilla, B, Bédard, PJ. Effect of D1 and D2 agonists andantagonists on dyskinesia produced by L-dopa in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys. J PharmacolExp Ther 1991;259:409413.Google Scholar
23. Engber, TM, Susel, Z, Juncos, JL, et al. Continuous and intermittentlevodopa differentially affect rotation induced by D1 and D2 dopamine agonists. Eur J Pharmacol 1989;168:291298.CrossRefGoogle Scholar
24. Engber, TM, Susel, Z, Kuo, S, et al. Levodopa replacement therapyalters enzyme activities in striatum and neuropeptide content in striatal output regions of 6-hydroxydopamine lesioned rats. Brain Res 1991;552:113118.Google Scholar
25. Henry, B, Crossman, AR, Brotchie, JM. Effect of repeated L-DOPA,bromocriptine, or lisuride administration on preproenkephalin-A and preproenkephalin-B mRNA levels in the striatum of the 6-hydroxydopamine-lesioned rat. Exp Neurol 1999;155:204220.Google Scholar
26. Blanchet, PJ, Calon, F, Martel, J-C, et al. Continuous administrationdecreases and pulsatile administration increases behavioral sensitivity to a novel dopamine D2 agonist (U-91356A) in MPTP-exposed monkeys. J Pharmacol Exp Therap 1995;272: 854859.Google ScholarPubMed
27. Blanchet, PJ, Grondin, R, Bédard, PJ, et al. Dopamine D1 receptordesensitization profile in MPTP-lesioned primates. Eur J Pharmacol 1996;309:1320.CrossRefGoogle Scholar
28. Mouradian, MM, Heuser, IJE, Baronti, F, Chase, TN. Modification ofcentral dopaminergic mechanisms by continuous levodopa therapy for advanced Parkinson’s disease. Ann Neurol 1990;27:1823.CrossRefGoogle Scholar
29. Blanchet, PJ, Calon, F, Morissette, M, et al. Regulation of dopaminereceptors and motor behavior following pulsatile and continuous dopaminergic replacement strategies in the MPTPprimate model. In: Calne, D, Calne, SM, (Eds). Parkinson’s Disease: Advances in Neurology, vol. 86, Philadelphia, Lippincott Williams & Wilkins, 2001: 337344.Google Scholar
30. Herrero, MT, Augood, SJ, Asensi, H, et al. Effects of L-DOPA-therapy on dopamine D2 receptor mRNA expression in the striatum of MPTP-intoxicated parkinsonian monkeys. Mol Brain Res 1996;42:149155.Google Scholar
31. Turjanski, N, Lees, AJ, Brooks, DJ. In vivo studies on striataldopamine D1 and D2 site binding in L-dopa-treated Parkinson’s disease patients with and without dyskinesias. Neurology 1997;49:717723.Google Scholar
32. Bordet, R, Ridray, S, Carboni, S, et al. Induction of dopamine D3receptor expression as a mechanism of behavioral sensitization tolevodopa. Proc Natl Acad Sci USA 1997;94:33633367.Google Scholar
33. Hurley, MJ, Stubbs, CM, Jenner, P, Marsden, CD. D3 receptorexpression within the basal ganglia is not affected by Parkinson’s disease. Neurosci Lett 1996;214:7578.Google Scholar
34. Ryoo, HL, Pierrotti, D, Joyce, JN. Dopamine D3 receptor is decreased and D2 receptor is elevated in the striatum of Parkinson’s disease. Mov Disord 1998;13:788797.CrossRefGoogle ScholarPubMed
35. Calon, F, Goulet, M, Blanchet, PJ, et al. Levodopa or D2 agonistinduced dyskinesia in MPTP monkeys: correlation with changes in dopamine and GABAA receptors in the striatopallidal complex. Brain Res 1995;680:4352.Google Scholar
36. Calon, F, Morissette, M, Goulet, M, et al. 125I-CGP64213 binding toGABAB receptors in the brain of monkeys: effect of MPTP and dopaminomimetic treatments. Exp Neurol 2000;163:191199.CrossRefGoogle ScholarPubMed
37. Mitchell, IJ, Boyce, S, Sambrook, MA, Crossman, AR. A 2 -deoxyglucose study of the effects of dopamine agonists on the parkinsonian primate brain. Brain 1992;115:809824.Google Scholar
38. Soghomonian, J-J, Pedneault, S, Blanchet, PJ, et al. L-dopa regulatesglutamate decarboxylases mRNA levels in MPTP-treated monkeys. Molec Brain Res 1996; 39:237240.Google Scholar
39. Laitinen, LV, Bergenheim, AT, Hariz, MI. Leksell’s posteroventralpallidotomy in the treatment of Parkinson’s disease. J Neurosurg 1992;76:5361.CrossRefGoogle ScholarPubMed
40. Baron, MS, Vitek, JL, Bakay, RA, et al. Treatment of advancedParkinson’s disease by posterior GPi pallidotomy: 1-year results of a pilot study. Ann Neurol 1996;40:355366.Google Scholar
41. Lang, AE, Lozano, AM, Montgomery, E, et al. Posteroventral medialpallidotomy in advanced Parkinson’s disease. N Engl J Med 1997;337:10361042.Google Scholar
42. Volkmann, J, Sturm, V, Weiss, P, et al. Bilateral high-frequencystimulation of the internal globus pallidus in advanced Parkinson’s disease. Ann Neurol 1998;44:953961.Google Scholar
43. Krack, P, Pollak, P, Limousin, P, et al. Inhibition of levodopa effectsby internal pallidal stimulation. Mov Disord 1998;13:648652.Google Scholar
44. Kumar, R, Lang, AE, Rodriguez-Oroz, MC, et al. Deep brainstimulation of the globus pallidus pars interna in advanced Parkinson’s disease. Neurology 2000;55(12 suppl 6):S34-S39.Google Scholar
45. Duty, S, Brotchie, JM. Enhancement of the behavioral response toapomorphine administration following repeated treatment in the 6-hydroxydopamine-lesioned rat is temporally correlated with a rise in striatal preproenkephalin-B, but not preproenkephalin-A, gene expression. Exp Neurol 1997;144:423432.Google Scholar
46. Piccini, P, Weeks, RA, Brooks, DJ. Alterations in opioid receptorbinding in Parkinson’s disease patients with levodopa-induceddyskinesias. Ann Neurol 1997;42:720726.Google Scholar
47. Henry, B, Fox, SH, Crossman, AR, Brotchie, JM. µ- and δ-opioidreceptor antagonists reduce levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson’s disease. Exp Neurol 2001;171:139146.Google Scholar
48. Henry, B, Brotchie, JM. Potential of opioid antagonists in thetreatment of levodopa-induced dyskinesias in Parkinson’s disease. Drugs Aging 1996;9:149158.Google Scholar
49. Chase, TN, Engber, TM, Mouradian, MM. Contribution ofdopaminergic and glutamatergic mechanisms to the pathogenesis of motor response complications in Parkinson’s disease. In: Battistin, L, Scarlato, G, Caraceni, T, Ruggieri, S, (Eds). Advances in Neurology, vol 69: Drugs for the Treatment of Parkinson’s disease. Philadelphia: Lippincott-Raven, 1996;62: 497501.Google Scholar
50. Brotchie, JM. Advances in understanding the neural mechanismsunderlying L-dopa-induced dyskinesia. In: Stern, GM, (Ed.) Parkinson’sDisease. Advances in Neurology, Vol. 80. Philadelphia: Lippincott Williams & Wilkins 1999: 7185.Google Scholar
51. Calon, F, Morissette, M, Ghribi, O, et al. Alteration of glutamatereceptors in the striatum of dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys following dopamine agonist treatment. Prog Neuropsychopharmacol Biol Psychiatry 2002;26:127138.Google Scholar
52. Papa, SM, Chase, TN. Levodopa-induced dyskinesias improved by aglutamate antagonist in Parkinsonian monkeys. Ann Neurol 1996;39:574578.CrossRefGoogle Scholar
53. Blanchet, PJ, Konitsiotis, S, Whittemore, ER, et al. Differing effectsof N-methyl-D-aspartate receptor subtype selective antagonists on dyskinesias in levodopa-treated 1-methyl-4-phenyl-tetrahydropyridine monkeys. J Pharmacol Exp Ther 1999;290: 10341040.Google Scholar
54. Konitsiotis, S, Blanchet, PJ, Verhagen, L, Lamers, E, Chase TN.AMPA receptor blockade improves levodopa-induced dyskinesiain MPTPmonkeys. Neurology 2000;54:15891595.Google Scholar
55. 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;50:13231326.CrossRefGoogle ScholarPubMed
56. Oh, JD, Vaughan, CL, Chase, TN. Effect of dopamine denervationand dopamine agonist administration on serine phosphorylationof striatal NMDAreceptor subunits. Brain Res 1999;821:433442.CrossRefGoogle Scholar
57. Marin, C, Papa, SM, Engber, TM, et al. MK801 prevents levodopa-induced motor response alterations in parkinsonian rats. Brain Res 1996;736:202205.Google Scholar
58. Doucet, J-P, Nakabeppu, Y, Bédard, PJ, et al. Chronic alterations indopaminergic neurotransmission produce a persistent elevation of AFosB-like protein(s) in both rodent and primate striatum. Eur J Neurosci 1996;8:365381.Google Scholar
59. Andersson, M, Hilbertson, A, Cenci, MA. Striatal fosB expression iscausally linked with L-dopa-induced abnormal involuntary movements and the associated upregulation of striatal prodynorphin mRNA in a rat model of Parkinson’s disease. Neurobiol Dis 2000;6:461474.Google Scholar
60. Brotchie, JM. Adjuncts to dopamine replacement: a pragmaticapproach to reducing the problem of dyskinesia in Parkinson’s disease. Mov Disord 1998;13:871876.Google Scholar
61. Sieradzan, KA, Fox, SH, Hill, M, et al. Cannabinoids reducelevodopa-induced dyskinesia in Parkinson’s disease: a pilot study. Neurology 2001;57:21082111.Google Scholar
62. Brotchie, JM. The neural mechanisms underlying levodopa-induceddyskinesia in Parkinson’s disease. Ann Neurol 2000;47(Suppl 1):S105-S114.Google Scholar
63. Bibbiani, F, Oh, JD, Chase, TN. Serotonin 5-HT1A agonist improvesmotor complications in rodent and primate parkinsonian models. Neurology 2001;57:18291834.CrossRefGoogle Scholar
64. Grondin, R, Bédard, PJ, Hadj Tahar, A, et al. Antiparkinsonian effectof a new selective adenosine A2a receptor antagonist in MPTP-treated monkeys. Neurology 1999;52:16731677.Google Scholar
65. Filion, M, Tremblay, L, Bédard, PJ. Effects of dopamine agonists onthe spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism. Brain Res 1991;547:152161.Google Scholar
66. Papa, SM, Desimone, R, Fiorani, M, Oldfield, EH. Internal globuspallidus discharge is nearly suppressed during levodopa-induceddyskinesias. Ann Neurol 1999;46:732738.Google Scholar
67. Albin, R, Young, A, Penney, J. The functional anatomy of basalganglia disorders. Trends Neurosci 1989;12:336374.Google Scholar
68. Hutchison, WD, Levy, R, Dostrovsky, JO, et al. Effects ofapomorphine on globus pallidus neurons in parkinsonianpatients. Ann Neurol 1997;42:767775.Google Scholar
69. Obeso, JA, Rodriguez-Oroz, MC, Rodriguez, M, et al. Pathophysiology of levodopa-induced dyskinesias in Parkinson’s disease: problems with the current model. Ann Neurol 2000;47(Suppl 1):S22-S34.Google Scholar
70. Filion, M. Physiologic basis of dyskinesia. Ann Neurol 2000;47(Suppl 1):S35-S41.Google Scholar
71. Benabid, AL, Benazzouz, A, Limousin, P, et al. Dyskinesias and thesubthalamic nucleus. Ann Neurol 2000;47(Suppl 1):S189-S192.Google Scholar
72. Caparros-Lefebvre, D, Blond, S, Feltin, MP, Pollak, P, Benabid, AL. Improvement of levodopa induced dyskinesias by thalamic deep brain stimulation is related to slight variation in electrode placement: possible involvement of the centre median and parafascicularis complex. J Neurol Neurosurg Psychiatry 1999;67:308314.Google Scholar