Levodopa-Induced Dyskinesia: Medical and Surgical Management

In the 1960s, the treatment of Parkinson disease (PD) was revolutionized by the introduction of levodopa. Soon after its discovery, however, it was observed that continuous treatment was complicated by the emergence of choreoathetoid movements and off episodes.¹

Although levodopa therapy remains the most effective symptomatic treatment for PD, its usefulness may be limited by these motor complications, which result in deterioration in quality of life.

Levodopa-induced dyskinesia (LID) is characterized by a variety of hyperkinetic movements. Although chorea and dystonia are the most common manifestations of LID, stereotypies, tics, myoclonus, or ballism may occur. LID commonly starts in the lower extremity ipsilateral to the side first affected by PD, usually the most affected side. Early in LID, patients may not notice subtle hyperkinetic movements; however, as LID worsens it may interfere with activities of daily living, resulting in functional impairment, disability, and poor quality of life.^2-5

LID occurs in 3 temporal patterns related to timing of levodopa dosing.¹ Peak-dose dyskinesias are the most common and are characterized by the sequence of "improvement-dyskinesia-improvement." Diphasic dyskinesias are characterized by "dyskinesia-improvement-dyskinesia" and are often manifested clinically by dystonia and stereotypies.⁶

Diphasic dyskinesia accounts for 15% to 20% of LID.⁷ Some hyperkinetic movements occur in the functional off state in which patients may experience off dystonia characterized by painful sustained contractions. Off-dystonia occurs when plasma levodopa concentrations are low; therefore, off-dystonia frequently manifests itself before the first dose of levodopa is taken in the early morning on awakening, although it can occur during any off state.⁸

EPIDEMIOLOGY OF DYSKINESIA

The risk of developing LID has been linked to disease severity, younger age at onset, female sex, duration of levodopa treatment, and total levodopa exposure.^9,10 The use of different methods to recognize LID has resulted in variations in the frequency rate reported in the literature. A literature survey of more than 2000 publications identified LID in almost 40% of patients with PD treated with levodopa for 4 to 6 years.¹¹ Another review found a prevalence of LID in up to 85% of patients with PD.³

In the DATATOP (Deprenyl and Tocopherol Antioxidative Therapy for Parkinson's Disease) study, LID was observed in almost 30% of patients after 20.5 months of levodopa therapy.¹² In a community study, LID was present in 28% of patients with PD, with a mean time to onset of 6.7 years.¹³

PATHOGENESIS OF LID

In the dopamine-denervated state, striatal dopamine levels depend on exogenously administered levodopa. With the short half-life of levodopa, fluctuating plasma and striatal dopamine concentrations and nonphysiological pulsatile striatal stimulation occur.¹⁴ The pulsatile stimulation results in abnormal basal ganglia firing patterns,¹⁵ altered striatal neurotransmitter receptors,¹⁶ abnormalities in neuropeptide levels,¹⁶ and immediate early gene expression.¹⁷

These alterations lead to functional changes in the basal ganglia input and output pathways. The direct striatal output pathway provides g-aminobutyric acidergic inhibitory input to the globus pallidus interna (GPi) and substantia nigra pars reticulata. Overactivity of the direct pathway drives the development of LID.¹⁸ The direct pathway is modulated by excitatory glutaminergic corticostriatal projections.¹⁹ In addition, serotonergic 5HT_1A20 and 5HT_2A α-receptors,²¹ and α₂-adrenergic receptors¹⁹ influence the direct pathway. These provide potential targets for novel therapeutic discovery.

MEDICAL MANAGEMENT

When approaching the medical management of LID, it is important to recognize its clinical pattern; peak-dose and diphasic dyskinesia are managed differently. Treatment of peak-dose dyskinesia includes levodopa-based strategies or optimizing non-levodopa treatments.

Levodopa-based strategies are aimed at providing more constant dopaminergic delivery to the striatum while reducing peak plasma dopamine concentrations, including using smaller, more frequent doses of levodopa, reducing the individual doses, or changing formulations. Agents that might be considered in the management of dyskinesia include the following:

• Adjunctive dopamine agonists. A reduction in total levodopa dosage may be complicated by an increase in off time. The addition of dopamine agonists, which are less likely to result in LID, may allow for reduction in total levodopa dosage without inducing an off state.^22-24 An example of this was illustrated by an open-label trial of 36 patients with advanced PD and severe dyskinesia who were treated with a high dose of the dopamine agonist ropinirole (Requip) to miminize levodopa use and reduce LID.²⁵ At 12 months' follow-up, there was a reduction in total daily levodopa dosage (734.1 ± 254.8 mg/d to 502 ± 228.4 mg/d); the mean ropinirole dosage was 34.7 ± 5.5 mg/d. This correlated with improvements in LID during on and off time. Eleven patients withdrew from the study because of intolerable adverse effects or worsening motor function.
• Sustained-release levodopa. Sustained-release levodopa can result in worsening dyskinesia at the end of the day because plasma levels of the drug accumulate. Substituting a sustained-release formulation of levodopa for an immediate-release formulation may be required. When converting from controlled-release levodopa to immediate- release, the dosage will need to be reduced to account for the relative reduction in controlled-release levodopa bioavailability.²⁶
• Liquid levodopa. Liquid levodopa may be required when immediate-release oral levodopa preparations, used with frequent dosing, fail to adequately control LID. Liquid levodopa allows for tailoring the doses when doses smaller than those achieved with standard oral preparations are required.

To prepare liquid levodopa at a concentration in which 1 mL is equivalent to 1 mg of levodopa, dissolve 10 tablets of 25/100 mg of carbidopa/levodopa and 2 g of ascorbic acid with 1 L of water.^27,28 Continuous levodopa infusion delivered into the duodenum results in stable plasma levodopa levels and reduction in motor fluctuations and dyskinesia.^29-31 Liquified levodopa has been shown to improve on time without increasing dyskinesia.^32,33

• Amantadine. Amantadine (Symmetrel) is a N-methyl-d-aspartic acid receptor antagonist. It was the only pharmacological agent found to be beneficial for the treatment of dyskinesia in a recent evidence-based review.³⁴ An open-label study⁵ also showed that the agent has a small benefit in improving off time.

Several studies have documented the benefits of amantadine in controlling dyskinesia.^35-38 A 45% reduction in total dyskinesia in patients with advanced PD and LID was reported in one randomized, placebo-controlled, double-blind study.³⁵ A 60% reduction in dyskinesia without exacerbation of motor function was observed in another randomized placebo-controlled trial with crossover design.³⁶ In the 1-year open-label follow-up, 13 of the 17 study participants continued taking amantadine. A sustained reduction in dyskinesia of 56% was seen,³⁷ a find- ing that was in contrast to that of another study in which a shorter duration of benefit was reported.³⁵

In another study, intravenous amantadine at a dose of 200 mg in patients with PD and LID resulted in a marked improvement of 50% without worsening motor function.³⁸ (Rimantadine [Flumadine], an a-methyl derivative of amantadine, may be an alternative for patients who experience peripheral adverse effects [eg, lower extremity edema and livedo reticularis] from amantadine.^39,40)

• Clozapine. Clozapine, an atypical neuroleptic, has been associated with a reduction in LID without worsening of motor symptoms in patients with PD in open-label trials.^41-43 In a double-blind, randomized, placebo-controlled study of 50 patients with PD and LID, the effectiveness of clozapine was assessed using self-evaluation and levodopa challenge.⁴⁴ After 10 weeks, a significant reduction in total LID and a maximal LID score after levodopa challenge was seen. Rarely, clozapine is associated with agranulocytosis; nevertheless, its use requires frequent white blood cell count monitoring.

Other agents have been tried as well. Two recently published randomized controlled trials failed to confirm the open-label antidyskinetic properties of the novel serotonin-5HT_1A agonist sarizotan.^45,46 Other agents reported to reduce LID in preclinical animal studies or open-label trials include riluzole (Rilutek),⁴⁷ memantine (Namenda),⁴⁸ dextromethorphan,³⁶ propranolol (Inderal),⁴⁹ levetira-cetam (Keppra),^50-52 remacemide,⁵³ and topiramate (Topamax).⁵⁴

Diphasic dyskinesia is more difficult to treat than peak-dose dyskinesia. Higher doses of levodopa may be successful in ameliorating diphasic dyskinesia.⁵⁵ In addition, converting controlled-release levodopa to standard-release formulations may alleviate symptoms because controlled-release levodopa has lower bioavailability and reduced intestinal absorption. Patients may need to take frequent doses of levodopa to maintain adequate plasma dopamine concentrations; however, this may exacerbate peak-dose dyskinesia.

Apomorphine has been shown to be effective in temporarily reducing the duration of diphasic dyskinesias.⁵⁶ The dose required was higher than needed to induce the on state. Although not available in the United States, lisuride, apomorphine infusion, and duodenal levodopa infusion may be future treatment options.