Levodopa-induced dyskinesia is one of the most difficult problems facing patients with Parkinson’s disease. With more treatment options available for Parkinson’s disease, physicians need to understand the pathogenetic mechanisms underlying levodopa-induced dyskinesia. Better understanding of the pharmacological actions of dopaminergic drugs in the basal ganglia will lead to better management of patients with levodopa-induced dyskinesia. This article reviews recent developments in research and discusses strategies for the prevention and management of levodopa-induced dyskinesia.
PD patients often pose challenging problems given the many treatment options available—levodopa-induced dyskinesia can be one of the most troublesome.
The management of Parkinson’s disease (PD) today is a complex and demanding task as more treatment options become available. The patient often poses challenging problems, which may be derived from either their PD or its treatment. Levodopa-induced dyskinesia is one of most vexing problems facing physicians. This paper reviews recent developments on this issue and discusses the management of levodopa-induced dyskinesia.
Levodopa-induced dyskinesia refers to involuntary adventitious movements that usually occur after prolonged treatment with levodopa in PD patients. The term dyskinesia is applied to any involuntary movement, such as chorea, ballism, dystonia, tic, or myoclonus. The most common types of levodopa-induced dyskinesia are chorea and dystonia, which often coexist. Myoclonus, ballism, tics, or stereotypy are far less common.
The appearance of levodopa-induced dyskinesia is closely related to plasma levels of levodopa. Most levodopa-induced dyskinesia occurs when antiparkinsonian effects of levodopa are maximal, hence the term peak dose dyskinesia. Less common than peak dose dyskinesia is diphasic dyskinesia. This presents as both chorea and dystonia, often in the legs at both the beginning and end of the dosing period. In these patients dyskinesias may appear soon after a single dose of levodopa before any symptomatic effect takes place. Early morning dystonia is another type of dyskinesia in PD patients. This presents as dystonic posturing of the foot, usually occurring unilaterally on the more parkinsonian side, at night or in the early morning, that is, in an unmedicated state during an "off" period. This "off" dystonia is frequently painful and may also present as leg cramps at night. It is distinguished from peak dose dystonia since it is relieved by adding or increasing the dose of antiparkinson drugs.
There are wide individual variations in the nature, severity, and topographical pattern of levodopa-induced dyskinesia. It has been estimated that the annual incidence of levodopa-induced dyskinesia is approximately 10% in treated patients. However, at least 10% to 20% of patients with levodopa-responsive PD never develop dyskinesia. Once levodopa-induced dyskinesia has developed, its severity increases but the topographical pattern tends to remain constant.
During early levodopa treatment, peak dose dyskinesia may be apparent only during the maximum antiparkinsonian effect of levodopa. With a longer duration of treatment the dyskinetic phase expands to the whole "on" period, with the severity varying little throughout. Even during the "off" state, a brief episode of dyskinesia may be provoked by stress. This square wave response usually accompanies the development of sudden "on-off" responses. The threshold dose of levodopa for dyskinesia decreases with a longer duration of disorder, but not for antiparkinsonian effects. Ultimately, patients develop dyskinesia even at the dose at which the patient is in an "off" state. Furthermore, many patients with PD develop dyskinesia in one part of the body while another part remains parkinsonian. In these cases treatment is very difficult; the patient is often left with a choice of either dyskinesia with less parkinsonism or more parkinsonism with less dyskinesia.
Preclinical and clinical observations provide evidence that the development of levodopa-induced dyskinesia requires nigrostriatal dopaminergic denervation, intact postsynaptic basal ganglia neurons, and exogenous administration of levodopa.
Levodopa-induced dyskinesia appears sooner on the side first affected and is worse on the more affected side. Similar observations were made in primates with unilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesions. In contrast, primates with intact nigrostriatal dopaminergic neurons develop dyskinesia only if the dose of levodopa is very high.[5,6] These observations clearly indicate a pathogenetic role of nigrostrial dopamine denervation in levodopa-induced dyskinesia.
Dyskinesia generally occurs in patients who have a good therapeutic response to levodopa. Patients with Parkinson-plus syndromes have a poorer response and seldom develop dyskinesia.
Repeated levodopa dosing is necessary to induce dyskinesia, implying the development of sensitization to levodopa. Evidence on whether delaying levodopa treatment would also delay appearance of dyskinesia is inconclusive.[3,8] The prevalence of levodopa-induced dyskinesia is greater with a longer duration of treatment, increasing about 10% per year during the first 7 years. On the other hand, it has been shown that the cumulative levodopa dose used prior to the manifestation of dyskinesia is not significantly different between patients who have dyskinesia and those who do not.
Recent clinical studies show that monotherapy with D2 agonist induces less dyskinesia than with levodopa in PD patients.
Preclinical studies show that continuous administration of levodopa induces less dyskinesia than intermittent administration. Clinical studies comparing immediate-release and controlled-release forms of levodopa have not shown significant differences between the two treatment groups in the development of dyskinesia. However, these studies were not designed to test the concept of non-pulsatile levodopa administration.
Normal motor function is dependent on a highly regulated balance between neurotransmitters in the basal ganglia circuitry. A growing body of evidence indicates that levodopa-induced dyskinesia is caused by conflicting, uneven regulatory changes in the basal ganglia circuitry, resulting from both dopamine depletion and drug treatment.
The basal ganglia receive signals from the cortex and send the signals back to the cortex through the thalamus. Striatal neurons give rise to two major output pathways: the direct pathway innervating the output nuclei of the basal ganglia, and the indirect pathway innervating the output nuclei of the basal ganglia via the lateral globus pallidus and the subthalamic nucleus. In the indirect pathway, striatal projection neurons provide inhibitory inputs to the lateral globus pallidus, which in turn provides inhibitory input to the subthalamic nucleus. The subthalamic nucleus generates excitatory input to the lateral globus pallidus and the output nuclei of the basal ganglia. Recent evidence from anatomical and physiological studies, however, shows that signals originating in the cortex enter the basal ganglia circuitry through the striatum and the subthalamic nucleus and converge onto the output nuclei of the basal ganglia, indicating that the subthalamic nucleus functions as more than a relay station.
Pharmacological actions of dopamine in the basal ganglia are notoriously complicated. This complexity derives from multiple modes of actions of dopamine as a neuromodulator. First, the outcome of dopamine action is different depending on the receptors to which it binds. Binding to D2 receptors suppresses neuronal activity, whereas binding to D1 receptors facilitates neuronal activity. Second, dopamine modulates both the release and synthesis of neurotransmitters. Since the former is mediated by neuronal activity, and the latter by immediate early genes, the time course is different in these two actions. For instance, dopamine actions on the neurotransmitter release are concurrent with the binding to dopamine receptors, whereas dopamine actions on the neurotransmitter synthesis are prolonged, not concurrent with the stimulation of dopamine receptors. Third, dopamine has opposing actions on striatal projection neurons in the direct and indirect pathways. Striatal projection neurons are GABAergic in both the indirect and direct pathways, but are distinguished by the expression of dopamine receptor subtypes and different opioid peptides. Most striatal projection neurons in the indirect pathway express D2 receptors, whereas striatal projection neurons in the direct pathway express D1 receptors. Thus, in the dopamine-denervated striatum, gene expression for neurotransmitters in the striatal projection neurons is upregulated in the indirect pathway and downregulated in the direct pathway. Pulsatile administration of levodopa upregulates gene expression for neurotransmitters in the striatal projection neurons in the direct pathway while it does not normalize upregulated gene expression in the indirect pathway. Recent experimental observations have shown that the induction of dyskinesia during the course of levodopa treatment is associated with these regulatory changes in neurotransmitters, in particular, opioid peptides.[13,14] Similar observations have been made in patients with Parkinson’s disease.
Management of levodopa-induced dyskinesia is directed to two levels: prevention of the development of dyskinesia and reduction of the severity of established dyskinesia. Since levodopa-induced dyskinesia is difficult to reverse once it is established, it is preferable to attempt to prevent it. Strategies preventing the development of dyskinesia include the use of dopaminomimetics with a relatively long half-life to minimize pulsatile stimulation of dopamine receptors, such as a controlled release levodopa preparation, and early use of a D2 agonist, especially in patients with young-onset PD. It has been consistently observed that levodopa-induced dyskinesia occurs more frequently in patients with younger age of onset.[3,9] Some reports suggest that patients who are treated initially with higher doses of levodopa, more than 600 mg per day, may be at increased risk for developing dyskinesia.
Reducing specific doses or the total daily dose of levodopa will reduce the severity of peak dose dyskinesia in already primed patients. Since patients with dyskinesia often also experience motor fluctuations, spreading the daily dose of levodopa into smaller but more frequent doses can also help to reduce the severity of peak dose dyskinesia. A D2 agonist may be added to the regimen to spare the dose of levodopa. The dose of levodopa can be further reduced by adding a COMT inhibitor in selected cases. However, the first such agent, tolcapone, has been withdrawn from the market, and entacapone is still under consideration by Health Canada. Recently, amantadine, given as an adjuvant to levodopa, has been shown to improve dyskinesia and motor fluctuations. If dyskinesia is medically intractable, surgical treatment may be considered.
2. Nutt JG. Levodopa-induced dyskinesia: Review, observations, and speculations. Neurology 1990;40:340-345.[PubMed Citation]
3. Grandas F, Galiano ML, Tabernero C. Risk factors for levodopa-induced dyskinesias in Parkinson’s disease. J Neurol 1999; 246:1127-1133.[PubMed Abstract]
4. Clarke CE, Boyce S, Robertson RG, et al. Drug-induced dyskinesia in primates rendered hemiparkinsonian by intracarotid administration of MPTP. J Neurol Sci 1989;90:307-314.[PubMed Abstract]
5. Sassin JF, Taub S, Weitzman ED. Hyperkinesia and changes in behavior produced in normal monkeys by L-dopa. Neurology 1972;22:1122-1125.[PubMed Citation]
6. Jenner P. Factors influencing the onset and persistence of dyskinesia in MPTP-treated primates. Ann Neurol 2000;47: S90-9; discussion S99-104.[PubMed Abstract]
7. Cotzias GC, Van Woert MH, Schiffer LM. Aromatic amino acids and modification of parkinsonism. N Engl J Med 1967; 276:374-379.[PubMed Citation]
8. Friedman A. Levodopa-induced dyskinesia: Clinical observations. J Neurol 1985; 232:29-31.[PubMed Abstract]
9. Blanchet PJ, Allard P, Gregoire L, et al. Risk factors for peak dose dyskinesia in 100 levodopa-treated parkinsonian patients. Can J Neurol Sci 1996;23:189-193.[PubMed Abstract]
10. Rascol O, Brooks DJ, Korczyn AD, et al. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. 056 Study Group. N Engl J Med 2000;342:1484-1491.[PubMed Abstract]
11. Koller WC, Hutton JT, Tolosa E, et al. Immediate-release and controlled-release carbidopa/levodopa in PD: A 5-year randomized multicenter study. Carbidopa/ Levodopa Study Group. Neurology 1999; 53:1012-1019.[PubMed Abstract]
12. Gerfen CR, Engber TM, Mahan LC, et al. D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons. Science 1990;250: 1429-1432.[PubMed Abstract]
13. 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;155:204-220.[PubMed Abstract]
14. Lee CS, Cenci MA, Schulzer M, et al. Embryonic ventral mesencephalic grafts improve levodopa-induced dyskinesia in a rat model of Parkinson’s disease. Brain 2000;123:1365-1379.[PubMed Abstract]
15. Piccini P, Weeks RA, Brooks DJ. Alterations in opioid receptor binding in Parkinson’s disease patients with levodopa-induced dyskinesias. Ann Neurol 1997; 42:720-726.[PubMed Abstract]
16. 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;50:1323-1326.[PubMed Abstract]
Chong S. Lee, MD, FRCPC
Dr Lee is an assistant professor of neurology at the Neurodegenerative Disorders Centre, Vancouver Hospital and Health Sciences Centre.
Above is the information needed to cite this article in your paper or presentation. The International Committee
of Medical Journal Editors (ICMJE) recommends the following citation style, which is the now nearly universally
accepted citation style for scientific papers:
Halpern SD, Ubel PA, Caplan AL, Marion DW, Palmer AM, Schiding JK, et al. Solid-organ transplantation in HIV-infected patients. N Engl J Med. 2002;347:284-7.
About the ICMJE and citation styles
The ICMJE is small group of editors of general medical journals who first met informally in Vancouver, British Columbia, in 1978 to establish guidelines for the format of manuscripts submitted to their journals. The group became known as the Vancouver Group. Its requirements for manuscripts, including formats for bibliographic references developed by the U.S. National Library of Medicine (NLM), were first published in 1979. The Vancouver Group expanded and evolved into the International Committee of Medical Journal Editors (ICMJE), which meets annually. The ICMJE created the Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals to help authors and editors create and distribute accurate, clear, easily accessible reports of biomedical studies.
An alternate version of ICMJE style is to additionally list the month an issue number, but since most journals use continuous pagination, the shorter form provides sufficient information to locate the reference. The NLM now lists all authors.
BCMJ standard citation style is a slight modification of the ICMJE/NLM style, as follows:
- Only the first three authors are listed, followed by "et al."
- There is no period after the journal name.
- Page numbers are not abbreviated.
For more information on the ICMJE Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, visit www.icmje.org