The levels of evidence (class I-IV) supporting the recommendations and ratings of recommendations (A-C, good practice point) are defined at the end of the "Major Recommendations" field.
Symptomatic Control of Motor Complications
Motor Fluctuations
Wearing-off
- Adjust levodopa dosing. In an early phase, when motor fluctuations are just becoming apparent, adjustments in the frequency of levodopa dosing during the day, tending to achieve four to six daily doses, might attenuate the wearing-off (good practice point).
- Switch from standard levodopa to controlled release (CR) formulation. CR formulations of levodopa can also improve wearing-off (level C).
- Add catechol-O-methyltransferase (COMT) inhibitors or monoamine oxidase isoenzyme type B (MAO-B) inhibitors. No recommendations can be made on which treatment should be chosen first – on average, all reduce OFF time by about 1 to 1.5 h/day. The only published direct comparison (level A) showed no difference between entacapone and rasagiline. Tolcapone is potentially hepatotoxic, and is only recommended in patients failing on all other available medications (see Part I of the original guidelines). Rasagiline should not be added to selegiline (level C) because of cardiovascular safety issues.
- Add dopamine agonists. Oral dopamine agonists are efficacious in reducing OFF time in patients experiencing wearing-off. Currently, no dopamine agonist has proven better than another, but switching from one agonist to another can be helpful in some patients (level B/C). Pergolide* and other ergot agonists are reserved for second-line treatment, because of their association with valvulopathy.
*Note from the National Guideline Clearinghouse (NGC): On March 29, 2007, Permax (pergolide) was withdrawn from the market in the U.S. and worldwide due to safety concerns of an increased risk of cardiovascular events. See the U.S. Food and Drug Administration (FDA) Web site for more information.
- Add amantadine or an anticholinergic. In patients with disabling recurrent OFF symptoms that fail to improve further with the above mentioned strategies, the addition of an anticholinergic (in younger patients), or amantadine, may improve symptoms in some cases (good practice point).
Most patients will eventually receive a combination of several of these treatments because a single treatment fails to provide adequate control of fluctuations. There is insufficient evidence on the combination of more than two strategies and the choice of drugs is mainly based on safety, tolerability and ease of use. All the above options may provoke or increase dyskinesias, but usually this can be managed by decreasing the levodopa dose.
Note: Reduction or redistribution of total daily dietary proteins may reduce wearing-off effects in some patients. Restricting protein intake to one meal a day may facilitate better motor responses to levodopa following other daily meals during the day. A more practical approach could be to take levodopa on an empty stomach about 1 h before or at least 1 h after, each meal (class IV).
If oral therapy fails, the following strategies can be recommended.
- Deep brain stimulation (DBS) of the subthalamic nucleus (STN) (level B).
- Subcutaneous apomorphine as penject (level A) or pump (level C).
- Alternative delivery routes or alternative formulations of levodopa:
- Oral dispersible levodopa might be useful for delayed ON (level C).
- Levodopa/carbidopa enteric gel administered through percutaneous gastrostomy (PEG) can also be considered to stabilize patients with refractory motor fluctuations (level B).
Unpredictable ON-OFF
In the large studies of wearing-off, patients with unpredictable ON–OFF were either not included or constituted <5% of the total population. Therefore, insufficient evidence exists to conclude whether the results that are valid for wearing-off are also valid for unpredictable ON–OFF. There are only a few small studies specifically including patients suffering from unpredictable ON–OFF, although studies evaluating continuous dopaminergic stimulation also include patients suffering concomitantly from wearing-off and unpredictable ON–OFF. The same is true for concomitant dyskinesia, which frequently occurs during the ON phase of ON–OFF. Thus, there is insufficient evidence to conclude on specific strategies for ON–OFF, although the strategies described for dyskinesia and for wearing-off should be considered for unpredictable ON–OFF (good practice point).
Unpredictable ON–OFF can have several components, one of which is delayed ON and, for which, oral dispersible levodopa formulations could have some value (level C).
Note: By shortening the interval between levodopa doses to prevent wearing-off, the relation between the moment of intake of each dose and the subsequent motor effect can become difficult to disclose, especially when inadequate absorption also occurs. The resulting pattern of fluctuation and dyskinesia may falsely suggest unpredictable ON–OFF. In such patients, the actual mechanism of wearing-off and peak-dose dyskinesia may reappear by increasing the levodopa intake interval to about 4 h. However, in some patients, the benefit may wane after weeks or months.
Dyskinesias
Peak-Dose Dyskinesia
- Add amantadine (level A) – most studies use 200 to 400 mg/day. The benefit may last <8 months. The use of other antiglutaminergic drugs is investigational.
- Reduce individual levodopa dose size, at the risk of increasing OFF time. The latter can be compensated for by increasing the number of daily doses of levodopa or increasing the doses of a dopamine agonist (level C).
- Discontinue or reduce dose of MAO-B inhibitors or COMT inhibitors (good practice point), at the risk of worsening wearing-off.
- Add atypical antipsychotics, clozapine (level A), with doses ranging between 12.5 and 75 mg/day up to 200 mg/day, or quetiapine (level C). However, clozapine is associated with potential serious adverse events (agranulocytosis and myocarditis), which limits its use (good practice point).
- DBS of the STN, which allows reduction of dopaminergic treatment (level B).
- Apomorphine continuous subcutaneous infusion, which allows reduction of levodopa therapy (level C).
Biphasic Dyskinesia
Biphasic dyskinesias can be very difficult to treat and have not been the subject of specific and adequate class I to III studies. Usually, the strategies described for peak-dose dyskinesias can also be considered for biphasic dyskinesia (good practice point). Another option is increasing the size and frequency of levodopa dose, at the risk of inducing or increasing peak-dose dyskinesia. This latter strategy can be helpful, generally transiently, in those cases without peak-dose dyskinesia, or where they are considered less disabling than the biphasic type. A further option could be larger, less frequent doses, to give a more predictable response, which would better enable patients to plan daily activities (good practice point).
Off-Period and Early Morning Dystonias
- Usual strategies for wearing-off can be applied in cases of off-period dystonia (good practice point).
- Additional doses of levodopa or dopamine agonist therapy at night may be effective for the control of dystonia appearing during the night or early in the morning (good practice point).
- DBS of the STN (level B).
- Botulinum toxin can be employed in both off-period and early morning dystonia (good practice point).
Freezing
Freezing, particularly freezing of gait, often occurs during the OFF phase and less frequently in both OFF and ON. The latter scenario often does not respond to dopaminergic strategies.
Options for OFF freezing are the same as those described for wearing-off. In addition, the use of visual or auditory cues is empirically useful for facilitating the start of the motor act once freezing has occurred (level C).
In ON freezing, trying a reduction in dopaminergic therapy is recommended, although this may result in worsening of wearing-off.
Neuropsychiatric Complications
Dementia
- Discontinue potential aggravators. Anticholinergics (level B), amantadine (level C), tricyclic antidepressants (level C), tolterodine and oxybutynin (level C) and benzodiazepines (level C).
- Add cholinesterase inhibitors. Rivastigmine (level A), donepezil (level C), galantamine (level C). Given the hepatotoxicity of tacrine, its use is not recommended (good practice point).
Psychosis
- Control triggering factors (good practice point). Treat infection and metabolic disorders, rectify fluid/electrolyte balance, treat sleep disorder.
- Reduce polypharmacy (good practice point). Reduce/stop anticholinergic antidepressants, reduce/stop anxiolytics/sedatives.
- Reduce antiparkinsonian drugs (good practice point). Stop anticholinergics, stop amantadine, reduce/stop dopamine agonists, reduce/stop MAO-B and COMT inhibitors, lastly, reduce levodopa. Stopping antiparkinsonian drugs can be at the cost of worsening motor symptoms.
- Add atypical antipsychotics. Clozapine (level A) – although it can be associated with serious haematological adverse events, requiring monitoring. There is insufficient data on quetiapine, but it is possibly useful (good practice point). Quetiapine is thought to be relatively safe and does not require blood monitoring. Olanzapine (level A) and risperidone (level C) are not recommended (harmful).
- Typical antipsychotics (e.g. phenothiazines, butyrophenones) should not be used because they worsen parkinsonism.
- Add cholinesterase inhibitors. Rivastigmine (level B), donepezil (level C). However, it must be noted that the cognitive improvements are only modest, whilst tremor worsened in some patients.
Depression
- Optimize antiparkinsonian therapy (good practice point).
- Tricyclic antidepressants (good practice point).
- SSRIs (good practice point). SSRI's are less probably to produce adverse effects than tricyclic antidepressants (good practice point).
- 'New' antidepressants – reboxetine, venlafaxine (no recommendation can be made).
Autonomic Dysfunction
Orthostatic Hypotension
- General measures:
- Avoid aggravating factors such as large meals, alcohol, exposure to a warm environment and drugs known to cause orthostatic hypotension such as diuretics or antihypertensive drugs. Levodopa and dopamine agonists may also induce orthostatic hypotension.
- Increase salt intake in symptomatic orthostatic hypotension.
- Head-up tilt of the bed at night, which may be helpful.
- Wear elastic stockings.
- Highlight postprandial effects. In some patients, hypotension occurs only postprandially. Warning the patient about this effect and taking frequent small meals may be helpful.
- Drug therapy:
- Add midodrine (level A).
- Add fludrocortisone (good practice point: possibly effective, but note side-effects).
Urinary Disturbance
- General measures for treating urinary urgency and incontinence. Avoid coffee before bedtime, limit water ingestion before bedtime, etc.
- Add peripherally acting anticholinergic drugs (good practice point).
- Add intranasal desmopressin spray for nocturnal polyuria (insufficient evidence, no recommendation can be made).
Gastrointestinal Motility Problems
- Apply general measures for treating constipation. Diet, laxatives, etc.
- Reduce or discontinue drugs with anticholinergic activity (good practice point).
- Add domperidone (level B).
Erectile Dysfunction
- Add sildenafil (level A).
- Add dopamine agonists. Apomorphine and pergolide (insufficient evidence, no recommendation can be made).
Definitions:
Evidence Classification Scheme for a Therapeutic Intervention
Class I: An adequately powered prospective, randomized, controlled clinical trial with masked outcome assessment in a representative population or an adequately powered systematic review of prospective randomized controlled clinical trials with masked outcome assessment in representative populations. The following are required:
- Randomization concealment
- Primary outcome(s) is/are clearly defined
- Exclusion/inclusion criteria are clearly defined
- Adequate accounting for dropouts and crossovers with numbers sufficiently low to have minimal potential for bias
- Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences
Class II: Prospective matched-group cohort study in a representative population with masked outcome assessment that meets a–e above or a randomized, controlled trial in a representative population that lacks one criteria a–e
Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment
Class IV: Evidence from uncontrolled studies, case series, case reports, or expert opinion
Rating of Recommendations
Level A rating (established as effective, ineffective, or harmful) requires at least one convincing class I study or at least two consistent, convincing class II studies.
Level B rating (probably effective, ineffective, or harmful) requires at least one convincing class II study or overwhelming class III evidence.
Level C rating (possibly effective, ineffective, or harmful) requires at least two convincing class III studies.
Good practice points In cases where there is insufficient scientific evidence, a consensus statement ('good practice point') is made.
