Current Treatment Options in Neurology

, Volume 12, Issue 3, pp 186–199

Parkinson’s Disease and Motor Fluctuations

Authors

    • Medical University of South Carolina
Movement Disorders

DOI: 10.1007/s11940-010-0067-8

Cite this article as:
Hinson, V.K. Curr Treat Options Neurol (2010) 12: 186. doi:10.1007/s11940-010-0067-8

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.

Introduction

Levodopa and other dopaminergic drugs are effective symptomatic treatments for the motor signs of early Parkinson’s disease (PD). Appropriately treated patients usually do well for a number of years, with relatively little disability and few medication side effects. After several years of dopaminergic therapy, motor fluctuations start to develop. Motor fluctuations are changes in the response to dopaminergic drugs with the development of episodes when parkinsonian symptoms re-emerge. In this scenario, periods of good function (“on” periods) are followed by “off” periods, and involuntary hyperkinetic movements (dyskinesias) also may occur. Motor fluctuations are estimated to develop in 40% to 50% of patients after 4 to 6 years of levodopa therapy, according to a cumulative literature review [1]. The longer-acting dopamine agonists produce a lower prevalence of motor fluctuations than levodopa [2, 3, Class I].

There are several clinically distinct patterns of motor fluctuations, which differ in phenomenology and timing as to their occurrence in the dosing cycle; they progress from more to less predictable (Table 1). The earliest pattern is that of the end-of-dose wearing-off phenomenon, in which patients develop breakthrough parkinsonian symptoms before their next dose of medication is due. The patient becomes more dependent on frequent doses of medication and eventually may require medication at intervals of 2 to 3 h. Unlike these predictable off periods at the end of a medication dose, some patients experience off time in a more unpredictable manner. These unpredictable off periods come on rather suddenly (over a few seconds) and can be quite disabling, with severe akinesia or freezing of gait. Some patients also notice that their medication will take longer to take effect or sometimes may fail to work at all (delayed “on” or dose failure). This pattern is often due to gastrointestinal factors, such as poor levodopa absorption due to competition with dietary amino acids or slow gastric emptying secondary to PD-associated dysautonomia. On the other end of the spectrum of motor fluctuations are dyskinesias, which are drug-induced, hyperkinetic, involuntary movements, most commonly choreiform or dystonic. Dyskinesias usually occur at peak dose of the dopaminergic drug, but they sometimes last throughout the entire on period (square-wave dyskinesias). When dyskinesias occur at the end of a dose, they are often dystonic and most frequently affect the lower limbs; a commonly encountered example is early-morning foot dystonia. Finally, some patients with advanced PD fluctuate briskly between on periods with dyskinesia and parkinsonian off periods, an effect also known as yo-yoing.
Table 1

Phenomenology of motor fluctuations in Parkinson’s disease

Term

Definition

Wearing off

End-of dose wearing off with increased parkinsonian symptoms

Unpredictable “off”

Off symptoms without apparent relationship to drug dosing cycle

Delayed “on”

Delayed kicking in of Parkinson’s disease medications

Dose failure

No effect from last medication dose

Peak-dose dyskinesia

Choreiform or dystonic movements when plasma levels of Parkinson’s disease drugs peak

Diphasic dyskinesia

Dyskinesia at beginning and end of dosing cycle

Square-wave dyskinesia

Dyskinesia persisting throughout the entire dosing cycle

End-of-dose dyskinesia

Most commonly dystonic movements with predominant limb involvement, often painful. (Example: Early-morning foot dystonia)

On-off fluctuations (“yo-yoing”)

Rapid switching between being “off” and immobile and “on” and dyskinetic

Risk factors for the development of motor fluctuations include longer disease duration, greater disease severity, higher doses of levodopa, longer duration of treatment, and younger onset of PD [4, Class IV]. The pathophysiology of motor fluctuations is not entirely clear but is believed to be related to peripheral pharmacokinetic and central pharmacodynamic processes. Peripheral factors include the short plasma half-life of levodopa (about 90 min) and problems related to absorption, with interfering dietary factors and gastrointestinal dysmotility secondary to PD itself. In early PD, these peripheral factors are less relevant, as the dopaminergic neurons can synthesize enough dopamine from exogenous levodopa and store it, shielding the postsynaptic dopamine receptors from oscillations in circulating levodopa levels. As the number of dopaminergic neurons in the substantia nigra decreases, striatal dopamine receptors are increasingly exposed to fluctuations in plasma and brain levels of levodopa and dopamine. This nonphysiologic stimulation is believed to underlie the altered pharmacodynamics of the levodopa response and leads to biochemical and molecular aberrations on striatal medium spiny neurons, thus altering striatal output and motor behavior [5]. A great obstacle for treatment of motor fluctuations is that the underlying changes in basal ganglia function appear to be permanent, so prevention of the onset of motor fluctuations would be preferable to treating already-established fluctuations [6•].

The concept of providing “continuous dopaminergic stimulation” in the treatment of PD has become increasingly popular. Based on the idea that dopamine replacement with short-acting drugs such as levodopa provides nonphysiologic pulsatile stimulation of postsynaptic dopamine receptors, the use of drugs that have a prolonged duration of effect and novel ways of drug administration have been explored. Longer-acting dopamine agonist drugs (e.g., pramipexole and ropinirole) can reduce the prevalence of motor fluctuations, but patients eventually require the addition of levodopa, with its increased risk of dyskinesia. In animal models, the addition of entacapone, a catechol-O-methyltransferase (COMT) inhibitor, to carbidopa/levodopa for the initial treatment of parkinsonism led to improved motor disability with less-intense dyskinesia than occurred with the use of carbidopa/levodopa alone [7]. However, a phase 3 clinical trial, STRIDE-PD [8, Class I], failed to show any delay in the onset of dyskinesia with the use of the triple combination levodopa/carbidopa/entacapone compared with the standard levodopa/carbidopa formulation. Time to dyskinesia was significantly shorter in the group treated with the entacapone combination, but wearing-off was reported more frequently in carbidopa/levodopa-treated patients. Preclinical models point to the fact that the delivery mode (continuous versus pulsatile delivery) is a greater determinant of the induction of motor fluctuations than the actual therapeutic agent [6•]. Continuous infusion of the dopamine agonist apomorphine via a modified insulin pump and enteral levodopa infusion systems are available in Europe but not in the United States. These infusion therapies require a surgical procedure for catheter implantation and replacement. The use of such infusion systems in clinical practice, where available, is part of the treatment of advanced PD with established motor fluctuations; it is not a practical preventive measure.

In summary, even though certain treatment strategies in early PD can delay the onset of motor fluctuations, these fluctuations will ultimately occur in most patients, adding to the disability in advanced stages of the illness. Treatment options for motor fluctuations include medical, surgical, and emerging therapies.

Treatment

Diet and lifestyle

  • PD patients with motor fluctuations should be encouraged to avoid large, high-fat meals, which slow gastric emptying and may interfere with drug absorption.

  • Large, neutral dietary amino acids compete with levodopa for absorption in the gut. It is therefore generally recommended that patients with motor fluctuations take levodopa 30 to 60 min before mealtime or 60 to 120 min after mealtime, to avoid delayed on periods or dose failures. Some patients may require a protein-redistribution diet, limiting most protein intake to the evening meal [9, Class II].

Pharmacologic treatment

  • The goal of pharmacologic treatment of motor fluctuations is to decrease off time and increase the amount of on time without disabling dyskinesias.

  • Strategies include manipulation of the medication dosing schedule, change of levodopa dose and formulation, addition of longer-acting drugs to achieve more continuous dopaminergic stimulation, and the use of antidyskinetic agents (Table 2). Cost estimates (average wholesale prices) for the pharmacologic agents discussed below are derived from the Drug Topics Red Book, 2009 edition (Medical Economics Co., Montvale, NJ).
    Table 2

    Pharmacologic treatment of motor fluctuations

    Problem

    Treatment

    Wearing off

    Modify dosing schedule (smaller dosing intervals)

    If not effective

    Add on adjunctive treatment to levodopa with dopamine agonist, COMT inhibitor, or MAO-B inhibitor

    If not effective

    Evaluate for deep brain stimulation (DBS)

    Dyskinesias

    Attempt levodopa dose reduction

    If not tolerated

    Add on levodopa sparing agent (dopamine agonist, COMT inhibitor, or MAO-B inhibitor) with concomitant levodopa dose reduction

    If not effective

    Add on amantadine

    If not effective

    Evaluate for deep brain stimulation (DBS)

    COMT catechol-O-methyltransferase; MAO-B monoamine oxidase-B

Change of medication dosing schedule

Once wearing-off symptoms occur as the first sign of motor complications, medication is usually dosed on a strict every-4-h schedule. More advanced patients will ultimately transition to an every-3-h schedule, and some will have to take medication even more often. Increasing dosing frequency does not necessarily mean increasing the total daily dose of the drug, which could escalate dyskinesias. Motor complications will often improve if the same total daily dose of medication is distributed into a number of smaller doses.

Levodopa

Wearing-off phenomenon: For patients with simple end-of dose wearing off without the presence of dyskinesias, an increase in levodopa dosing frequency is usually effective. For nocturnal akinesia and early-morning off time (often in the form of painful foot dystonia), a bedtime dose of controlled-release (CR) carbidopa/levodopa is helpful. CR carbidopa/levodopa can be used in conjunction with immediate-release carbidopa/levodopa to decrease off time. The use of CR carbidopa/levodopa by itself is problematic, as absorption is often poor and unpredictable, and it has the potential to escalate dyskinesias later in the day.

Dyskinesias: Reduction of the total daily levodopa dose can reduce dyskinesias but often it is not tolerated because it increases off time. CR carbidopa/levodopa can potentiate dyskinesias. A change to immediate-release carbidopa/levodopa may therefore diminish dyskinesias. Giving smaller doses of levodopa on a more frequent basis can be helpful.

Liquid carbidopa/levodopa: Rapidly absorbed liquid carbidopa/levodopa taken on a half-hourly to hourly basis is sometimes used to provide more continuous dopaminergic stimulation in the treatment of motor fluctuations. Liquid levodopa can improve on time without escalation of dyskinesias and can reduce the amount of daily off time [10, Class III]. The major disadvantage is its short duration of action, requiring cumbersome 30-min to 90-min dosing intervals. Although not commercially available, the liquid formulation can easily be prepared by dissolving 10 tablets of carbidopa/levodopa (25/100 mg) and 1 g of ascorbate in 1 L of water. This generates a levodopa concentration of 1 mg/mL. To calculate the liquid formulation dosing schedule, the patient’s total daily levodopa dose is divided by the number of waking hours, thus providing the required amount of liquid levodopa for each hourly dose. Each dose can be adjusted in increments of 10 to 20 mL to achieve an optimized dose response. The dosing interval can be individualized as well, commonly ranging between 30 and 90 min.
Standard dosage

Immediate-release carbidopa/levodopa is available in 10/100-mg, 25/100-mg, and 25/250-mg tablets. Standard doses range between 300 and 1500 mg of levodopa per day in divided doses. Dose intervals for patients with motor fluctuations usually range between 2 and 4 h. CR carbidopa/levodopa is available in 25/100-mg and 50/200-mg tablets. Standard doses range between 300 and 2000 mg per day in divided doses. Typical dose intervals range between 3 and 4 h. CR carbidopa/levodopa is equivalent to 75% of the corresponding dose of immediate-release carbidopa/levodopa. Orally disintegrating carbidopa/levodopa is available for patients with swallowing problems. It does not reach the systemic circulation faster than standard tablets, so its effects are equivalent to those of standard immediate-release levodopa [11, Class I].

Contraindications

No absolute contraindications. Caution is advised in patients with history of malignant melanoma, narrow-angle glaucoma, active psychosis, and orthostatic hypotension.

Main drug interactions

Nonselective monoamine oxidase (MAO) inhibitors may produce a hypertensive crisis, dopamine receptor blockers (antipsychotics, metoclopramide, certain antiemetics) may block the levodopa effect, iron salts and isoniazid may reduce the levodopa effect.

Main side effects

Nausea, orthostatic hypotension, somnolence, psychosis, and dyskinesias are the most common.

Special points

Levodopa therapy remains the most effective treatment for PD despite the motor fluctuations seen with long-term use. Earlier speculations that levodopa may accelerate the neurodegenerative process in PD have not been substantiated, and evidence from a recent clinical trial suggests that it may slow disease progression [12, Class I].

Cost

Carbidopa/levodopa immediate-release (100 tablets): 10/100 mg, $70.00 (generic); 25/100 mg, $90.00 (generic), $116.74 (brand); 25/250 mg, $100.00 (generic), $148.75 (brand). Carbidopa/levodopa CR (100 tablets): 25/100 mg, $90.00 (generic), $130.56 (brand); 50/200 mg, $160.00 (generic), $251.53 (brand). Carbidopa/levodopa orally disintegrating tablet (100 tablets): 10/100 mg, $129.73; 25/100 mg, $146.50; 25/250 mg, $186.65.

Dopamine agonists

Dopamine agonists are often used as adjuncts to levodopa in advanced PD. The non-ergot-derivative dopamine agonists ropinirole and pramipexole are most commonly prescribed in clinical practice because of their more favorable side effect profile versus older ergot derivatives (bromocriptine, pergolide).

Apomorphine is a dopamine agonist given subcutaneously for prolonged or unpredictable off time and severe morning akinesia [13, Class I]. Apomorphine has a rapid onset of action and duration of benefit of about 90 min. It is a good rescue therapy for severe motor fluctuations, but it is also a potent emetic, so pretreatment with trimethobenzamide is recommended.

Wearing off: The addition of a dopamine agonist to levodopa therapy can reduce end-of-dose wearing-off symptoms [14•, 15, Class I]. This strategy is most helpful for daytime off symptoms. Nighttime akinesia is preferably addressed with the use of CR carbidopa/levodopa, as dopamine agonists can disrupt sleep architecture with bedtime dosing.

Dyskinesias: Dopamine agonists can be added or increased in exchange for a reduced dose of levodopa, thus improving dyskinesias.
Standard dosage

Ropinirole: Ropinirole is available in tablets of 0.25, 0.5, 1, 2, 3, 4, and 5 mg. The drug is initiated at a dose of 0.25 mg three times per day and slowly increased to effectiveness. The average dose in clinical trials for ropinirole was 8 to 9 mg per day in divided doses. Doses up to 24 mg per day were used. Ropinirole extended-release: Available in tablets of 2, 4, 6, 8, and 12 mg. The starting dose is 2 mg every morning. The dose can be titrated up to a maximum of 24 mg per day (average dose 4–8 mg/d in this setting) given as a single dose, most commonly in the morning. Pramipexole: Pramipexole is available in tablets of 0.125, 0.25, 0.5, 1, and 1.5 mg. The usual starting dose is 0.125 mg three times per day, with a slow up-titration to effect. The average effective dose is 1.5 to 4.5 mg per day in divided doses.

Contraindications

No absolute contraindications. Relative contraindications include dementia, psychosis, and orthostatic hypotension.

Main drug interactions

Ciprofloxacin and other p450 inhibitors can increase ropinirole serum concentrations. Cimetidine may increase pramipexole levels.

Main side effects

The most common side effects of the nonergot dopamine agonists are sedation, orthostatic hypotension, peripheral edema, and psychosis. Sudden sleep attacks with the use of dopamine agonists have been reported and may impair driving safety. Some patients also develop what has been termed the “dopamine dysregulation syndrome” with various impulse-control behavioral problems such as pathologic gambling, hypersexuality, or hyperreligiosity [14•]. In general, dopamine agonists tend to be poorly tolerated by the elderly (>70 years) and demented patients. Apomorphine can have serious side effects because of its fast onset of action, including acute orthostasis or syncope and severe nausea and vomiting. The first apomorphine injection should therefore be given under physician supervision at a PD center. Pretreatment with trimethobenzamide for 3 days is recommended to reduce gastrointestinal side effects.

Special points

Pramipexole and ropinirole have similar efficacy and side effect profiles in the setting of advanced PD. Data from double-blind, placebo-controlled trials for both agents show about 30% improvement in the amount of daily on time, 15% to 25% improvement in measures of activities of daily living, and a 30% decrease in levodopa requirements [15, 16, Class I].

Cost

Ropinirole (100 tablets, independent of tablet strength): $250.00 (generic); $300.00 (brand). Ropinirole, extended-release (100 tablets): 2 mg, $260.30; 4 mg, $478.60; 8 mg, $717.90; 12 mg, $1183.00. Pramipexole (100 tablets): $312.00 independent of tablet strength. No generic available.

COMT inhibitors

Entacapone and tolcapone are catechol-O-methyltransferase (COMT) inhibitors that are used in addition to levodopa to reduce off time by inhibiting levodopa metabolism. Tolcapone has been associated with liver failure, so monitoring of hepatic enzymes is recommended for the first 6 months [17].

A combination drug of 200 mg of entacapone with various doses of carbidopa/levodopa is available in a single tablet.
Standard dosage

Entacapone: Entacapone is available in 200-mg tablets. The usual dose is 200 mg with each dose of carbidopa/levodopa, up to a maximum dose of 1600 mg per day. Tolcapone: Available as 100-mg and 200-mg tablets. The usual initiation dose is 100 mg three times per day. This may be increased to 200 mg three times per day. Carbidopa/levodopa/entacapone: Available as tablets with doses of 25/50/200 mg, 25/75/200 mg, 25/100/200 mg, 25/125/200 mg, and 25/150/200 mg. If a patient’s current levodopa dose is no more than 600 mg per day and there are no dyskinesias, the patient may transfer to the corresponding carbidopa/levodopa/entacapone fixed-dose combination product. If the current levodopa dose exceeds 600 mg or there are dyskinesias, then a reduction of the levodopa dose is recommended with a switch to the entacapone combination product.

Contraindications

Hepatic disease.

Main drug interactions

COMT inhibitors should be avoided in patients taking norepinephrine reuptake inhibitors because of the risk for cardiovascular side effects.

Main side effects

Entacapone: Diarrhea (5%-10%), abdominal pain, nausea, urine discoloration. Tolcapone: Diarrhea (10%–20%), nausea, elevation of alanine transaminase (ALT) or aspartate transaminase (AST) in 1% to 3% of patients, rarely liver failure.

Special points

The addition of COMT inhibitors to levodopa increases on time by 1.3 to 1.8 h per day [18, 19, Class I]. Development of dyskinesias may necessitate levodopa dose reduction.

Cost

Entacapone (100 tablets): 200 mg, $307.24. No generic available. Tolcapone (100 tablets): $574.53 independent of tablet strength. No generic available. Carbidopa/levodopa/entacapone (100 tablets): $305.95 independent of tablet strength. No generic available.

MAO-B inhibitors

Monoamine oxidase type B (MAO-B) inhibitors can reduce off time in patients with PD motor fluctuations [20, Class III; 21, Class I].

Selegiline is an MAO-B inhibitor that has been used in the treatment of PD since 1989. Because of its primary metabolites, L-amphetamine and L-methamphetamine, it is often poorly tolerated and can lead to increased dyskinesias, insomnia, confusion, and hallucinations.

Rasagiline, which was developed more recently, is not metabolized to amphetamine derivatives and thus has greater tolerability.
Standard dosage

Selegiline: Available as a 5-mg tablet, selegiline is initiated at 5 mg every morning and may be increased to 5 mg twice daily, with the second dose given no later than early afternoon, to avoid insomnia. An orally disintegrating 1.25-mg tablet is available. This is started at a dose of 1.25 mg per day and may be increased to 2.5 mg per day, given once a day before breakfast. Rasagiline: Available as 0.5-mg and 1-mg tablets, rasagiline is started at 0.5 mg every morning and may be increased to 1 mg per day. The development of dyskinesias may necessitate a levodopa dose reduction.

Contraindications

Presence of pheochromocytoma, concomitant treatment with medications listed below under drug interactions.

Main drug interactions

Ciprofloxacin: Increases rasagiline blood levels. Dextromethorphan: Associated with psychosis or unusual behavior. Meperidine, methadone, propoxyphene, tramadol: Associated with severe hypertension or hypotension, malignant hyperpyrexia, coma. Sympathomimetic amines: May cause severe hypertensive reactions. Local and general anesthesia containing sympathomimetics: Increases risk of serious cardiovascular side effects. Antidepressants: Concomitant use of MAO-B inhibitors with many classes of antidepressants (e.g., selective serotonin reuptake inhibitors [SSRIs], serotonin-norepinephrine reuptake inhibitors [SNRIs], tricyclic or tetracyclic antidepressants) is not recommended because of concern about the occurrence of the serotonin syndrome. However, selegiline and rasagiline are selective MAO-B inhibitors when used at the doses recommended for the treatment of PD. Because selective MAO-B inhibitors have not been implicated in causing serotonin syndrome in conjunction with antidepressants, coadministration of antidepressants with selegiline or rasagiline is common practice. Tyramine-rich foods: Traditional nonselective MAO inhibitors have been associated with dietary tyramine interactions that can induce hypertensive reactions. At therapeutic doses, selegiline and rasagiline (both selective MAO-B inhibitors) do not produce interactions with dietary tyramine [22].

Main side effects

Selegiline: Headache, orthostasis, diarrhea, confusion, insomnia, hallucinations. Rasagiline: Nausea, orthostasis, headache.

Special points

Rasagiline improves off time by about 1 hour. The effect of selegiline has been less vigorously studied.

Cost

Selegiline (100 tablets): 5 mg, $200.00 (generic), $300.00 (brand). Orally disintegrating selegiline (100 tablets): $430.00. No generic available. Rasagiline (100 tablets): 1 mg, $1100. No generic available.

Amantadine

Amantadine has a prodopaminergic and antiglutaminergic effect. Its role in advanced PD is in the treatment of dyskinesias.
Standard dosage

Available as 100-mg capsules and tablets. Starting with 100 mg twice daily, the dose may be increased to 400 mg per day in divided doses. Avoid evening and bedtime dosing, as amantadine can disrupt sleep.

Contraindications

No absolute contraindications. Relative contraindications are renal insufficiency, dementia, and psychosis, which may be exacerbated by amantadine.

Main drug interactions

Triamterene and trimethoprim may reduce the clearance of amantadine, thus increasing the risk for toxic reactions.

Main side effects

Anticholinergic side effects (constipation, dry mouth, blurry vision, memory loss, psychosis), pedal edema, livido reticularis.

Special points

Amantadine can reduce dyskinesia severity by about 60% [23, Class III]. This effect is often transient and may subside after about 1 year. The other problem with the use of amantadine in advanced PD is poor tolerability because of neuropsychiatric side effects. Withdrawal after chronic use can lead to delirium.

Cost

100 capsules or tablets (100 mg), $90.00 (generic).

Surgery

Should medical management of motor fluctuations fail, an evaluation for surgical treatment of PD is indicated. Patients with disease duration greater than 5 years, robust (≥30%) improvement with levodopa, and absence of dementia and gait dysfunction may be good surgical candidates. A thorough presurgical evaluation should be conducted at a movement disorders specialty center.

Deep brain stimulation

Standard procedure

Bilateral deep brain stimulation (DBS) of the subthalamic nucleus or the internal segment of the globus pallidus is the preferred surgical treatment for Parkinson’s Disease [24]. DBS entails continuous high-frequency electrical stimulation and seems to be a functional inhibitor of these two structures. “Maintenance” of DBS therapy requires regular programming sessions and interval generator replacements. For patients who have difficulty accessing medical centers for continuous post-DBS care, ablative lesioning of the globus pallidus is an alternative to DBS.

Contraindications

Electrode location and proper patient selection are important determinants in the outcome of DBS. Exclusion criteria for DBS include dementia, unstable psychiatric disease, poor functional status in the on state, severe brain atrophy on MRI, and significant medical history increasing the risk for intraoperative and postoperative complications.

Complications

Intraoperative hemorrhage (1.7%-3.4% of cases [25]), postoperative transient confusion, lead breakage, infection at the implantation site, worsening cognition, depression, dysarthria, stimulation-related adverse effects (contralateral paresthesias, weakness, or spasms).

Special points

DBS can improve bradykinesia, rigidity, and tremor, decrease off time, and eliminate dyskinesias. In addition, Parkinson medication can be reduced and occasionally discontinued altogether. Nonmotor symptoms, as well as gait and balance failure, are usually unresponsive to subthalamic and pallidal DBS therapy.

Cost/cost-effectiveness

DBS is considered a cost-effective intervention for advanced PD, as the cost savings achieved through medication reduction offset the cost of the procedure [26•, 27, Class III].

Emerging therapies

New therapies under investigation aim at preventing motor fluctuations and improving their treatment. The main areas of ongoing research are new delivery methods for established drugs, novel nondopaminergic approaches, and cell-based and gene-based therapies.

New delivery methods for established drugs

Infusion systems

With the goal of providing continuous dopaminergic stimulation, infusion therapies of dopamine agonists and levodopa have been explored over the past decade. Data from open-label clinical trials and many case series suggest that subcutaneous infusions of the dopamine agonists lisuride and apomorphine, as well as enteral infusion of levodopa (levodopa gel), reduce motor fluctuations and dyskinesias [28, 29, Class III; 30•, Class IV]. However, data from randomized clinical trials are lacking, and infusion systems are not currently available for clinical use in the United States, although they are used in many European countries. Problems with the subcutaneous delivery of dopamine agonists include the continued need for adjunct oral levodopa therapy in most patients, injection site reactions, and the need for concomitant administration of domperidone for blockade of peripheral side effects. Enteral levodopa therapy, on the other hand, requires an invasive surgical procedure for percutaneous enteric gastrostomy placement and is rather cumbersome to manage for the patient and caregiver. Ongoing research is aimed at developing improved infusion systems and evaluating the safety and efficacy of levodopa gel infusions in double-blind clinical trials.

Transdermal delivery

Patches provide a means of continuous transdermal delivery of a drug. Transdermal delivery of levodopa has proven difficult, because levodopa must be administered in large volumes and is maintained in an acidic concentration. Rotigotine, a novel nonergot dopamine agonist, was developed for delivery via a transdermal patch system and was in clinical use until its recall in early 2008. The recall became necessary after the discovery of crystal formation on the patches. Clinical trials of rotigotine showed similar efficacy to other dopamine agonists but failed to show superiority over other dopamine agonist agents in the treatment of advanced PD with motor fluctuations [31, Class I]. Efforts are under way to resolve the crystallization and patch delivery problems and bring this drug back to market.

Novel nondopaminergic approaches

Glutamate antagonists

Based on a body of scientific evidence implicating glutamate-mediated plastic changes in the pathogenesis of dyskinesias, a variety of glutamate antagonists are currently being studied. Riluzole and talampanel showed promising effects in preclinical evaluations but no efficacy in preliminary human clinical trials [32, Class III; 33], and they have a narrow therapeutic window because of neuropsychiatric side effects. A more promising avenue of research may be the study of drugs that are more specific to NMDA receptor subunits localized to the striatonigral dopamine system, such as the NR2B subunit, which has been shown to be relevant in the development of levodopa-induced dyskinesias [34].

5-HT1A agonists

Studies in animals and open-label clinical trials showed promise with the use of sarizotan, a 5-HT1A agonist and D3/D4 antagonist [35, Class IV]. Dyskinesia reduction in the open-label trials was approximately 40% but was accompanied by worsening parkinsonism at higher doses. This antidyskinetic effect was not duplicated in a double-blind placebo-controlled trial, and worsening parkinsonism was again problematic [36, Class I]. Current research is investigating whether concomitant levodopa dosage adjustments would allow for a higher dose of sarizotan, thus inhibiting dyskinesias without worsening parkinsonism.

Antiepileptic drugs

Zonisamide is thought to activate dopamine synthesis, provide central MAO-B inhibition, and reduce glutamate release [37]. A double-blind, placebo-controlled trial of this drug in advanced PD showed improvement in motor scores and a decrease in daily off time without worsening dyskinesias [38•, Class I]. This trial was conducted in an Asian population using relatively small doses of levodopa; it should be replicated in a more diverse population with higher doses of concomitant dopaminergic drugs.

Levetiracetam is another antiepileptic drug with potential for use in PD. Levetiracetam has shown antidyskinetic properties in animal models of PD and in small, open-label human studies [39, Class IV], but it seems to be poorly tolerated in patients with advanced PD because of sedation.

Cell-based therapies

Cell-based therapies are being explored under the assumption that implanted cells from various sources can integrate into the nigrostriatal system and manufacture dopamine, thus compensating for the loss of dopaminergic cells in PD. The use of fetal nigral mesencephalic neurons for this purpose has lead to disappointing results in two double-blind clinical trials. Patients implanted with fetal cells failed to show clinical improvement, and some developed unusual and severe “runaway dyskinesias” in the off state [40, Class I]. Furthermore, the implanted neurons were found to develop Lewy body-like pathology and other characteristics of parkinsonian degeneration in follow-up autopsy studies [41, Class IV].

Transplantation of human retinal pigment epithelial (hRPE) cells attached to microcarriers (Spheramine; Bayer Schering Pharma, Berlin, Germany) looked promising in an open-label study [42, Class IV] but ultimately led to disappointing results in a human phase-2b clinical trial. There was no statistically significant difference in the off state between Spheramine-implanted and sham-implanted patients at 12 months. There were also no differences in secondary outcomes, including on-state motor scores, levodopa reduction, or activities of daily living scores.

More recent laboratory work has focused on using stem cells as a starting point for exogenous or endogenous derivation of the optimal dopamine cells for repair purposes. The largest body of work has been done with the use of embryonic stem cells in animal models of PD. However, many questions in regards to survival of transplanted cells in the host tissue, the appropriate neurons, correct brain locations for repair, and possible long-term complications such as tumor formation remain unanswered. Clinical trials using stem cells have not yet been performed in humans.

Gene therapy

Gene therapy is another approach to deliver therapeutic molecules to the human brain. DNA is inserted into host cells by using viral vectors encoding for specific proteins, enabling the transfected cell to make the desired protein. One approach, using a viral vector to deliver the dopamine-synthesizing enzymes tyrosine hydroxylase and aromatic amino acid decarboxylase into the striatum, has led to the reversal of motor dysfunction in parkinsonian rodents and primates [43].

Another line of research has tried to enhance dopaminergic function with the delivery of trophic factors. Glial cell line-derived neurotrophic factor (GDNF) and neurturin have both been successfully inserted into the striatum of monkeys using viral vectors, and robust behavioral, imaging, and histologic results have been obtained. These results, together with positive data from the first open-label clinical trial in humans [44•, Class IV], paved the way to an ongoing double-blind, placebo-controlled clinical trial.

Disclosure

Dr. Hinson has received consulting honoraria from Novartis.

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