This review evaluated medical and surgical treatments for Parkinson disease with levodopa-induced motor fluctuations and dyskinesia, and found the highest evidence was for the effectiveness of entacapone and rasagiline in reducing off time; treatment recommendations were reported. This is a well-conducted review and the authors' conclusions are likely to be reliable.

To evaluate medical and surgical treatments for patients with Parkinson disease (PD) with levadopa-induced motor fluctuations and dyskinesia, and to answer the following questions:

1. Which medications reduce off time?

2. What is the relative efficacy of medications in reducing off time?

3. Which medications reduce dyskinesia? 4. Does deep brain stimulation (DBS) of the subthalamic nucleus (STN), globus pallidus interna (GPi), or ventral intermediate (VIM) nucleus of the thalamus reduce off time, dyskinesia and antiparkinsonian medication and improve motor function?

The review also examined the factors that predict improvement after DBS, but this abstract does not include predictive factors.

MEDLINE and EMBASE were searched from 1965 to 2005 for English language reports; the search terms were reported. In addition, bibliographies of identified studies were screened and the views of experts in the review panel were sought.

Study designs of evaluations included in the review

For studies evaluating medical treatment (questions 1, 2 and 3), masked randomised controlled trials (RCTs) with at least 20 patients and with at least 3 months' follow-up were eligible for inclusion. In the absence of studies meeting the criterion for duration of condition, studies of patients with a shorter duration were included. Placebo-controlled, crossover and comparator studies were included.

For studies of surgical treatment (question 4), studies with at least 20 participants and with at least 6 months' follow-up were eligible for inclusion. In the included studies, the duration of follow-up ranged from 6 months to 5 years.

Specific interventions included in the review

For questions 1, 2 and 3, studies that evaluated medications available in the USA, or those with a letter of approval from the U.S. Food and Drug Administration, were eligible for inclusion. The review compared the following medications with placebo or each other: pergolide, pramipexole, ropinirole, apomorphine, bromocriptine, cabergoline, selegiline, rasagiline, tolcapone, entacapone, sustained release carbidopa/levadopa, amantadine and clozapine. The duration of treatment ranged from 3 to 40 weeks.

For question 4, studies that evaluated DBS of the STN, GPi, or VIM nucleus of the thalamus were included.

Participants included in the review

For questions 1, 2 and 3, studies of patients with motor fluctuations or dyskinesia were eligible for inclusion. It is clear that the review focused on patients with PD with levadopa-induced motor fluctuations and dyskinesia.

Outcomes assessed in the review

There were no stated outcome criteria. The review assessed dyskinesia, on time, off time, change in the Unified PD Rating Scale (UPDRS) activities of daily living (ADL) and motor scales, global impression, adverse effects and reduction in medication.

How were decisions on the relevance of primary studies made?

Panel members assessed the relevance of identified studies and any disagreements were resolved through recourse to a third panel member.

At least two panel members reviewed the included studies and any disagreements were resolved through recourse to a third panel member. It is not clear whether this referred to the validity assessment. Studies were graded from class I to class IV using a hierarchy of study design. Class I represented blinded RCTs with a clearly defined primary outcome, clearly reported inclusion and exclusion criteria, adequate accounting for drop-outs and baseline comparability of treatment groups or statistical adjustment. Class IV represented uncontrolled trials, case series, case reports or expert opinion. The grading system is presented in an appendix on the Neurology website, but a subscription may be required for access. The review also assessed the percentage of patients completing the trials.

At least two panel members reviewed the included studies and any disagreements were resolved through recourse to a third panel member. It is not clear whether this referred to the data extraction. Where possible, the percentage (absolute) decrease in off time was reported for each treatment group in medication studies, and the baseline and follow-up UPDRS ADL and motor scores and percentage reduction in medication were extracted for surgical studies.

How were the studies combined?

Studies were grouped under the specific question which the review sought to address and combined in a narrative. The level of evidence for each intervention was graded using a hierarchy: level A indicated effective, ineffective or harmful evidence from at least 2 consistent blinded RCTs; level B indicated probably effective, ineffective or harmful evidence from at least 1 RCT or at least 2 consistent matched-group cohort studies; level C indicated possibly effective, ineffective or harmful evidence from at least 1 matched-group cohort study or 2 consistent non- randomised and non-matched studies and level U indicated inadequate or conflicting evidence where there were inadequate data. The grading system is presented in an appendix on the Neurology website, but a subscription may be required for access.

How were differences between studies investigated?

Results for each medication and each surgical treatment were discussed separately. Other differences were described in the text and tables.

Twenty-six RCTs (n=4,595) evaluated the effect of medications on off time. Twenty class III or class IV studies (n=776) evaluated surgical treatments.

Only results for level A evidence are reported in detail below. Results for the other studies were reported in the text of the review.

1. Which medications reduce off time?

Two class I studies showed that entacapone was effective in reducing off time. One double-blind RCT (n=205) reported that on time increased by 5% in patients taking entacapone, but dyskinesia was significantly more commonly found in patients taking entacapone compared with placebo (53% versus 32%, p=0.002). The other RCT (n=687) compared rasagiline and entacapone separately with placebo. It reported that entacapone was associated with a significant decrease in off time (21% versus 7%, p<0.0001), and a significant improvement in UPDRS ADL off time, UPDRS motor scores and global impression compared with placebo. There were no differences between treatment groups in the percentage of patients with dyskinesia. Three class II studies also compared entacapone with placebo and found that entacapone significantly decreased off time (2 studies) and was associated with increased rates of dyskinesia (3 studies).

Two class I studies showed that rasagiline was effective in reducing off time. One double-blind RCT (n=472) reported that rasagiline was associated with a significant decrease in off time (decrease of 29% with a 1-mg dose and 23% with a 0.5-mg dose versus decrease of 15% with placebo, p<0.0001 and p=0.02, respectively) and an improvement in global impression, UPDRS ADL off time and UPDRS motor scores compared with placebo. Thirty-two per cent of the increase in on time was reported to include troublesome dyskinesia in patients taking rasagiline 1.0 mg (p=0.048). The other class I RCT (n=687) compared rasagiline, entacapone and placebo. It reported that rasagiline was associated with a significant decrease in off time (21% versus 7%, p<0.0001), significant improvement in UPDRS ADL off time, UPDRS motor scores and global impression compared with placebo. There were no differences between treatment groups in the on time with troublesome dyskinesia or the percentage of patients with dyskinesia.

There was evidence that the following drugs are probably effective: pergolide (1 class I study), pramipexole (1 class I and 1 class II study), ropinirole (2 class II studies) and tolcapone (2 class II studies). Caution and monitoring may be required with tolcapone (for hepatotoxicity) and pergolide (for valvular fibrosis).

Apomorphine (1 class II study), carbergoline (2 class III studies) and selegiline (1 class III study) may reduce off time. There was evidence that neither sustained-release carbidopa/levadopa (4 class III studies) nor bromocriptine (1 class II study) reduced off time.

Adverse events with dopamine agonists: nausea was reported in 18 to 36%, symptomatic orthostatic hypotension in 5 to 48%, dizziness in 11 to 37%, somnolence in 10 to 35% and hallucinations in 10 to 19%.

2. What is the relative efficacy of medications in reducing off time? Many of the comparative studies were inadequately powered to detect a treatment difference. Ropinirole was possibly more effective than bromocriptine (1 class II study). The following pairs of drugs were of similar efficacy: rasagiline and entacapone; bromocriptine and pramipexole; tolcapone and pergolide; cabergoline and bromocriptine; and tolcapone and entacapone (level U).

3. Which medications reduce dyskinesia?

Amantadine is possibly effective in reducing dyskinesia (1 class II study). There was insufficient evidence to evaluate clozapine (1 class III study).

4. Does DBS of the STN, GPi, or VIM nucleus of the thalamus reduce off time, dyskinesia and antiparkinsonian medication?

DBS of the STN is possibly effective in improving motor function, dyskinesia and antiparkinson medication (4 class III studies), although adverse events may impose limited application. There was insufficient evidence about DBS of the GPi (1 class III and 2 class IV studies) and DBS of the VIM nucleus of the thalamus (4 class IV studies).

Entacapone and rasagiline should be used to reduce off time (level A evidence); pergolide, pramipexole, ropinirole and tolcapone can be considered to reduce off time (level B evidence). Patients taking tolcapone and pergolide should be carefully monitored for adverse effects.

Apomorphine, cabergoline and selegiline (level C evidence) may be considered to reduce off time (level C evidence). There was insufficient evidence to determine the most effective medication for reducing off time (level B evidence) and no evidence to support the use of sustained-release carbidopa/levadopa (level C evidence). Amantadine may be considered to reduce dyskinesia (level C evidence).

DBS of the STN may improve motor function and reduce off time, dyskinesia and use of medication (level C evidence), but adverse events may limit its use. There was insufficient evidence about DBS of the GPi or VIM nucleus of the thalamus.

The review addressed a clear question that was defined in terms of the participants, intervention, outcomes and study design. Relevant literature sources were searched but no attempts were made to reduce language bias and there were no reported attempts to minimise publication bias. Study validity was assessed using defined criteria and a hierarchy of study design. Methods were used to minimise reviewer error and bias in the selection of studies; this also appears to have been the case in the assessment of validity and extraction of data. In view of the diversity of the studies, a narrative synthesis that highlighted the higher quality evidence identified was appropriate. Overall, this was a well-conducted review and the authors' conclusions are likely to be reliable.

Practice: The authors made the following recommendations. Entacapone and rasagiline should be used to reduce off time. Pergolide, pramipexole, ropinirole and tolcapone can be considered to reduce off time, but patients taking tolcapone and pergolide should be carefully monitored for adverse effects. Apomorphine, cabergoline and selegiline can also be considered to reduce off time, but there is no evidence supporting the use of sustained-release carbidopa/levadopa. Amantadine may be considered to reduce dyskinesia. DBS of the STN may improve motor function and reduce off time, dyskinesia and the use of medication, but adverse events may limit its use.

Research: The authors stated that there is a need for double-blind RCTs to determine the most effective medications for reducing off time in patients with moderate to advanced PD. Outcome measures should be standardised and diaries should be used to measure on time, off time and dyskinesia. Other outcomes should also be assessed including non-motor fluctuations, PD quality of life and neuropsychiatric measures. There is also a need for the following: to perform further and long-term evaluation of DBS of the STN, GPi and VIM nucleus of the thalamus using objective measures and blinded assessment; to compare surgical versus optimal medical management; to provide a cost-benefit analysis; and to take account of regional disparities in terms of access.

American Academy of Neurology; Michael J Fox Foundation.

Suchowersky O, Gronseth G, Perlmutter J, Reich S, Zesiewicz T, Weiner WJ. Practice parameter: neuroprotective strategies and alternative therapies for Parkinson disease (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;66:976-82. (DARE abstract number 12006002836).

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.