Keywords:
Parkinson Disease - Antiparkinson Agents - Deep Brain Stimulation - Rehabilitation
Palavra-chave:
Doença de Parkinson - Antiparkinsonianos - Estimulação Encefálica Profunda - Reabilitação
INTRODUCTION
Parkinson's disease (PD), first described by James Parkinson in 1817, is a neurodegenerative
disease characterized by motor (stiffness, bradykinesia, resting tremor and postural
instability) and non-motor symptoms (neuropsychiatric, sleep, autonomic, and sensory
disorders)[1].
The control of PD symptoms is done through pharmacological, non-pharmacological, and
surgical treatment. The Brazilian Academy of Neurology has recognized the need to
disseminate knowledge about PD treatment and adapt the best evidence to the Brazilian
reality.
In recent years, a group of specialists from the Scientific Department of Movement
Disorders of the Brazilian Academy of Neurology has developed a "Guide of Recommendations
for the Treatment of Parkinson's Disease", which had two editions. The constant evolution
of therapy and the need to quickly reach the largest number of specialists with updated
information led this group to the elaboration of two articles in guideline format.
The first part of this guideline addresses the management of motor symptoms (MS),
and the second part addresses the treatment of non-motor symptoms (NMS).
A literature review was carried out in MEDLINE and Cochrane Library databases from
1989 to 2020.
To elaborate this guideline the following topics were searched in relation to PD:
The classification of studies (four classes) and levels of evidence (four levels)
were based on the recommendations of the 2017 Edition of the Clinical Practice Guideline
Process Manual of the American Academy of Neurology[2] ([Tables 1] and [2]).
Table 1
Classification of evidence for therapeutic studies.
|
Class I
|
A randomized, controlled clinical trial of the intervention of interest with masked
or objective outcome assessment, in a representative population. The a to e criteria* is also required.
|
|
Class II
|
A randomized controlled clinical trial of the intervention of interest in a representative
population with masked or objective outcome assessment that lacks one criterion a-e above or a prospective matched cohort study with masked or objective outcome assessment
in a representative population that meets b-e above.
|
|
Class III
|
All other controlled trials (including well-defined natural history controls or patients
serving as own controls) in a representative population, where outcome is independently
assessed, or independently derived by objective outcome measurement
|
|
Class IV
|
Studies not meeting Class I, II, or III criteria including consensus or expert opinion.
|
*a: concealed allocation; b: exclusion/inclusion criteria clearly defined; c: Primary
outcome(s) clearly defined; d: adequate accounting for dropouts (with at least 80%
of enrolled subjects completing the study) and crossovers with numbers sufficiently
low to have minimal potential for bias; e: for noninferiority or equivalence trials
claiming to prove efficacy for one or both drugs, the following are also required:
The authors explicitly state the clinically meaningful difference to be excluded by
defining the threshold for equivalence or noninferiority. The standard treatment used
in the study is substantially similar to that used in previous studies establishing
efficacy of the standard treatment (e.g., for a drug, the mode of administration,
dose and dosage adjustments are similar to those previously shown to be effective).
The inclusion and exclusion criteria for patient selection and the outcomes of patients
on the standard treatment are comparable to those of previous studies establishing
efficacy of the standard treatment.
Table 2
Level of recommendation.
|
A
|
Established as effective, ineffective, or harmful (or established as useful/predictive
or not useful/predictive) for the given condition in the specified population
|
|
B
|
Probably effective, ineffective, or harmful (or probably useful/predictive or not
useful/predictive) for the given condition in the specified population
|
|
C
|
Possibly effective, ineffective, or harmful (or possibly useful/predictive or not
useful/predictive) for the given condition in the specified population
|
|
U
|
Data inadequate or conflicting; given current knowledge, treatment (test, predictor)
is unproven
|
Note that recommendations can be positive or negative.
The interpretation of the results of the study is based upon a per protocol analysis
that takes into account dropouts or crossovers.
CLASSES OF ANTIPARKINSONIAN DRUGS
CLASSES OF ANTIPARKINSONIAN DRUGS
Several drugs are used for treatment of PD and classified into dopaminergic and nondopaminergic.
The dopaminergic drugs include levodopa, dopaminergic agonists (DA), monoamine oxidase-B
enzyme (MAO-B) inhibitors, and catechol-ortho-methyltransferase (COMT) inhibitors.
Nondopaminergic drugs are amantadine and anticholinergics.
In Brazil, antiparkinsonian drugs are available on the Public Health System, except
for extended release pramipexole, safinamide, and rotigotine.
DOPAMINERGIC DRUGS
Levodopa
Levodopa is the primary dopamine precursor and is actively transported from the gut
(duodenum and jejunum), and its plasma half-life varies from 50 to 120 minutes. The
most significant enzymes involved in levodopa peripheral metabolism are dopa decarboxylase
(DDC) and COMT. Levodopa crosses the blood-brain barrier through active transport
and is converted to dopamine by DDC in dopaminergic neurons and stored in the synaptic
vesicles by vesicular monoamine transporter-2 and released to the synaptic cleft[3] ([Table 3]).
Table 3
Levodopa formulations available in Brazil.
|
Levodopa + carbidopa
|
Tablet, 250mg + 25 mg
|
|
Levodopa + benserazide
|
Tablet, 200 mg + 50 mg
|
|
Levodopa + benserazide BD (low dose)
|
Tablet, 100 mg + 25 mg
|
|
Levodopa + benserazide (oral dispersible)
|
Tablet, 100 mg + 25 mg
|
|
Levodopa + benserazide HBS (Hydrodynamically Balanced System)
|
Capsule, 100 mg + 25 mg
|
|
Levodopa + benserazide DR (Dual Release)
|
Tablet, 200mg + 50 mg
|
Dopaminergic agonists (DAs)
DAs act directly on striatal dopamine receptors with preferential affinity for the
D2-receptor subfamily and do not depend on dopamine-converting enzymes to work. DAs
available in Brazil are bromocriptine, pramipexole, and rotigotine. Pramipexole is
available in immediate and extended-release formulation. Rotigotine is formulated
in transdermal patches based on silicone[4].
The main adverse effects of DAs are excessive sleepiness and impulse control disorder.
Bromocriptine, which currently has very limited use, presents risks of peritoneal,
pleural, and pericardial fibrosis and cardiac valve damage[5],[6].
MAO-B inhibitors
MAO-B inhibitors increase extracellular dopamine levels in the striate. The formulations
available are: selegiline, rasagiline, and safinamide. Selegiline is metabolized to
amphetamine derivatives, while one of metabolite of rasagiline is 1-aminoindan that
presents antiparkinsonian action. Rasagiline should not be used in association to
fluoxetine and fluvoxamine. Safinamide is a novel reversible MAO-B inhibitor and has
both dopaminergic and non-dopaminergic effects (inhibits glutamate release by blocking
voltage-dependent sodium and N-type calcium channels).
COMT inhibitors
COMT inhibitors decrease the metabolism of levodopa by increasing its supply to the
central nervous system[7] and then offer more stable levodopa plasma levels[8]. They should not be used as monotherapy but as an add-on drug and must be taken
with each single dose of levodopa[9]. In Brazil, the only COMT inhibitor available is entacapone.
NONDOPAMINERGIC DRUGS
Amantadine
The probable effect of amantadine is increasing the dopamine release and inhibition
on N-methyl-D-aspartate (NMDA) receptors[10]. The main side effects reported are hallucinations, mental confusion, and livedo
reticularis[11].
Anticholinergics
Anticholinergic drugs act by blocking acetylcholine receptors and aim to reestablish
the balance between dopaminergic deficits and striatal cholinergic excess in PD[12],[13].
The main reason for the decline in the use of anticholinergic in current therapy is
closely related to their well-known side effects, especially the increased risk of
dementia[14].
TREATMENT OF EARLY STAGE PD
TREATMENT OF EARLY STAGE PD
Drug treatment of PD must be individualized. There are several therapeutic options.
The use of drugs in the early stage of PD was reviewed according to the scientific
evidence ([Table 4]).
Table 4
Drugs for early-stage PD - levels of evidence.
|
|
Monotherapy
|
Adjuvant Therapy
|
|
Levodopa
|
Level A
|
Level A
|
|
Dopaminergic Agonist
|
|
|
|
Bromocriptine
|
Level C - Ineffective
|
|
|
Pramipexole
|
Level A
|
|
|
Rotigotine
|
Level A
|
|
|
MAO-B Inhibitors
|
|
|
|
Selegiline
|
Level B
|
Level B
|
|
Rasagiline
|
Level A
|
Level B
|
|
Safinamide
|
|
Level C
|
|
Amantadine
|
Level C
|
Level C
|
|
Anticholinergics
|
Level B
|
Level B
|
ANTICHOLINERGICS
A 2003 Cochrane review[15] lists nine heterogeneous studies showing efficacy of anticholinergics compared to
placebo, leading to improved motor function, but data specifically regarding some
tremor benefits were inconclusive[12].
For younger patients, anticholinergics can be used and remain “clinically useful”[16]. There are no reports of anticholinergic class I clinical studies for the treatment
of early stage of PD.
Anticholinergics, both as monotherapy and adjuvant therapy, should not be the first
choice of treatment because of their high rate of adverse effects.
In conclusion, anticholinergics are probably effective in younger patients and in
early stages of PD (Level B).
AMANTADINE
Despite previous studies showing some effectiveness of amantadine in improving motor
function, a 2003 Cochrane review[10] concluded that there was insufficient evidence to support the efficacy of this drug.
Another pharmacological feature of amantadine is the limited duration of clinical
effects. Few nonrandomized studies have shown improvement in motor function, but long
duration response has not been not proven[10].
Only six studies compared amantadine with placebo, either as monotherapy or adjuvant
therapy[17],[18]. Double-blind studies had limitations regarding the number of included patients
(class III).
Conclusion
Amantadine is possibly effective in early stage PD (level C).
MONOAMINOXIDASE-B INHIBITORS
MONOAMINOXIDASE-B INHIBITORS
Selegiline
In the DATATOP study[19], the use of selegiline reduced the need of using levodopa by about 50% (class I).
An extension of this study (class II) showed that the benefit of delaying the use
of levodopa was maintained for nine months in the selegiline group, and an improvement
in the Unified Parkinson's Disease Rating Scale (UPDRS) scores was observed in these
patients compared to the placebo group, although without significance. With the withdrawal
of selegiline for two months, the motor scores worsened, indicating a symptomatic
effect[19].
A meta-analysis of 17 randomized trials[20] concluded that the early use of selegiline delays the need for levodopa, and when
used concomitantly, lower doses are required. A systematic review of the Cochrane
Database [21] had the same conclusion.
Rasagiline
The TEMPO study compared the efficacy of rasagiline monotherapy (class I) in two doses
(1 and 2 mg) with placebo. There was improvement in the UPDRS and in the quality-of-life
scale, showing an effect on PD symptoms[22]. The ADAGIO study (class I) showed a benefit of early-start treatment with rasagiline
1 mg/day versus delayed-start treatment[23].
A randomized (class I), double-blind, placebo-controlled trial of rasagiline 1 mg/d
as an add-on therapy in early PD patients using DA monotherapy (ropinirole or pramipexole)
showed a significant improvement in total UPDRS scores in the rasagiline group compared
with placebo[24]. A meta-analysis including double-blind placebo-controlled trials confirmed the
efficacy of rasagiline as monotherapy or as adjuvant[25].
Safinamide
Stocchi et al. (2012) was a 24-week double-blind placebo-controlled trial that included
270 early-stage PD patients receiving a stable dose of a single DA randomized into
placebo, 100 mg, and 200 mg of safinamide[26]. The difference between 100 mg/day safinamide and placebo was significant, but the
difference between 200 mg safinamide and placebo was not. The reason for the lack
of efficacy of the higher dose of safinamide is unknown, but the authors suggested
that the higher incidence of discontinuations in the 200 mg safinamide group (21.3%
vs. 10% each for safinamide 100 mg and placebo) may have prevented a significant clinical
benefit. However, no clinically meaningful differences from placebo were observed
for any safety variables and the results were considered exploratory.
Shapira et al. (2013) conducted a 12-month randomized double-blind placebo-controlled
trial as pre-planned extension of the Stocchi et al. (2012) study. Of the 227 enrolled
patients, only 182 (82%) completed the trial. Patients were randomized to 200 mg safinamide,
100 mg safinamide, or placebo in association with a single DA. The primary endpoint
was the period between randomization and an additional drug intervention - an increase
in the DA dose, an addition of another DA, levodopa, or another PD treatment, or a
drug discontinuation due to the lack of efficacy. The median time to “intervention”
was not significantly different between the pooled safinamide groups and placebo (559
and 466 days, respectively; p=0.3342). A post-hoc analysis suggested that 100 mg safinamide
could be effective as an add-on treatment for PD, but these results should be considered
exploratory only [27].
Conclusion
Selegiline is probably effective as monotherapy and adjuvant therapy in early-stages
PD (level B).
Rasagiline is effective as monotherapy (level A) and associated with DA (level B)
in early-stage PD.
Safinamide could be effective as adjuvant therapy in early-stage PD (level C).
DOPAMINERGIC AGONIST
Bromocriptine
As for the control of motor symptoms, bromocriptine, when used as monotherapy, does
not show evidence of greater benefit in relation to levodopa (Class I)[28]. A study comparing bromocriptine with another DA does not show a greater efficacy
(Class I)[29].
A Cochrane systematic review that analyzed the efficacy and safety of the early combination
of bromocriptine and levodopa in delaying the onset of motor complications showed
that there is no evidence of the use of this association as a strategy to prevent
or delay the onset of motor complications in PD (Class I)[28].
Pramipexole
A study carried out in 2000 by the Parkinson’s Disease Study Group compared the use
of levodopa with that of pramipexole in the early stages of PD. This was a 2-year
prospective, randomized, levodopa-controlled study that used pramipexole as monotherapy.
One hundred and fifty patients received levodopa and 150 received pramipexole. The
results showed that 53% of the patients who were part of the group using pramipexole
required levodopa supplementation, against 39% of the patients using levodopa (Class
I)[30].
Two randomized studies comparing pramipexole with placebo showed improvement in the
motor response and in the activities of daily living according to the UPDRS (Class
I)[31],[32].
The Parkinson Study Group study CALM-PD, published in 2009[33], evaluated the efficacy and motor complications after six years of pramipexole administration
with levodopa in patients in the early stages of PD. This analysis was initially performed
with 301 individuals, 151 of whom used pramipexole and 150 used levodopa. After six
years, it was observed that the scores of Schwab and England were similar in both
groups. Motor complications were more common in the group that used levodopa initially
(68.4% vs. 50%). There was no statistically significant difference in the UPDRS scores
(Class III).
Rotigotine
A study published in 2007 compared the safety and efficacy of using the rotigotine
patch with placebo in early PD. Participants were randomized to receive either placebo
(n=96) or rotigotine (n=181) starting from 2 mg/24 h, titrated weekly to 6 mg/2 4h,
and then maintained for 6 months. The results showed a significant decrease in the
UPDRS scores, showing that rotigotine when titrated to 6 mg is effective in the treatment
of PD in its early stages[34].
Conclusion
Bromocriptine is possibly ineffective, as monotherapy, compared with levodopa or another
DA in early-stage PD (Level C).
Pramipexole is effective as monotherapy in early-stage PD (level A).
The use of pramipexole in early-stage PD allows the appearance of a lower rate of
motor complications (Level A).
Rotigotine is effective as monotherapy in early-stage PD (level A).
LEVODOPA
The class I study Earlier versus Later Levodopa Therapy in Parkinson Disease (ELLDOPA)
using three different doses of levodopa (150, 300, and 600 mg) in early stages. Subjects
were randomly assigned to receive placebo or carbidopa-levodopa at a dose of 12.5
and 50 mg three times daily, 25 and 100 mg three times daily, or 50 and 200 mg three
times daily, respectively. The doses were increased to the maximum over a period of
nine weeks in a blinded fashion. PD patients showed significant improvement of the
UPDRS scores after 40 weeks compared with the placebo group[35]. One class I and two class II studies compared levodopa with DA in the early stages
of PD. They concluded that levodopa, cabergoline, ropinirole, and pramipexol are effective
in the treatment of motor symptoms and improve activity of daily life scores (levodopa
was more effective than the DA). The final recommendation of the studies was that
both levodopa and DA might be used early in PD.
A class II study of controlled-release levodopa compared to rapid-release levodopa
demonstrated that both formulations can be used, and the frequency of motor complications
is similar in both types (class II)[36].
In 2019, the Levodopa in Early Parkinson's Disease (LEAP) study was conducted to investigate
whether levodopa had a disease-modifying effect. It was designed as an early- vs.
delayed-start study. It included 446 patients observed over 80 weeks, divided into
2 groups: 1) levodopa 300 mg/day for 80 weeks and 2) placebo for 40 weeks followed
by levodopa 300 mg/day for another 40 weeks. There was no difference between the groups
at the end of the study, demonstrating that early or delayed onset of levodopa does
not slow disease progression and that starting treatment at low doses according to
patient need is the best clinical practice[37].
Conclusion
Levodopa is effective in early-stage PD (level A).
Levodopa alone is more effective than pramipexole and ropinirole alone in improving
motor symptoms (level A).
Controlled-release levodopa is probably not effective to prevent the onset of motor
complications (level B).
Higher doses of levodopa are related to higher risk of motor complications, and therefore,
so it is recommended to start with the lowest possible doses (level A).
Levodopa is effective as monotherapy or in combination with other antiparkinsonian
drugs in early-stage PD.
TREATMENT OF ADVANCED-STAGE PD
TREATMENT OF ADVANCED-STAGE PD
Although motor symptoms in PD are highly responsive to dopaminergic drugs, particularly
levodopa, the benefit of the drug during diminished in advanced stages of the disease.
At the same time, fluctuations and dyskinesias appear.
Motor fluctuations
The most important motor fluctuations observed in advanced-stage PD are the wearing-off
phenomenon (WO) (shortening effect), delayed-on (delay of motor effect), and no-on
(no motor effect at all)[38],[39] ([Table 5]).
Table 5
Treatments for motor fluctuations in advanced PD - levels of evidence.
|
|
Fluctuations
|
|
Levodopa controlled release
|
No evidence
|
|
Dopaminergic Agonist
|
|
|
Pramipexole
|
Level A
|
|
Rotigotine
|
Level A
|
|
MAO-B Inhibitors
|
|
|
Selegiline
|
Level A
|
|
Rasagiline
|
Level A
|
|
Safinamide
|
Level A
|
|
COMT Inhibitors
|
Level A
|
|
Amantadine
|
Ineffective
|
|
STN-DBS
|
Level A
|
Fractioning the total dose of levodopa and dietary orientation
Due to levodopa’s short half-life, it is recommended to reduce the interval between
levodopa doses, preferably without increasing the total daily dose[38]. It is also recommended that patients have an interval of at least one hour between
the levodopa intake and a meal so that this kind of regimen overcomes the competition
with dietary proteins[39],[40].
Controlled-released levodopa
There are no controlled studies with enough patients to draw definitive conclusions
regarding controlled-released levodopa, since most studies are open-label trials[41],[42].
The only controlled-release formulation available in Brazil is levodopa/benserazide.
There are few studies with this formulation, and their quality is poor. Levodopa associated
with benserazide (immediate and slow release in the same tablet), known as dual release,
was tested in 61 patients, and there was a decrease in wearing-off, but the exact
time of "off-period" was not quantified. Due to methodological reasons, this study
should not be considered conclusive[43].
Dopaminergic agonists
Pahwa et al. in 2006 and Stocchi in 2008, through a review of current treatments for
fluctuations and dyskinesias, concluded that fluctuations can be minimized by the
use of dopaminergic agonists, but dyskinesias cannot[44],[45].
Pramipexole
In a 1997 multicenter randomized class I study with 360 patients (181 active, 179
control) followed-up for 32 weeks, 83% of the active group and 78% of the control
group completed the study. Off-time decreased by 31% in the active group compared
to 7% in the placebo group (p=0.0006). Levodopa dose was reduced in the active group
(27%) compared to the placebo group (5%) (p=0.0001)[46].
Guttman in 1997, in a multicenter, double masked, randomized, parallel group (class
II study), 79 patients received pramipexole and 83 received placebo for 40 weeks.
The active group had a 15% (2.5 hours) decrease in off-time compared with a 3% reduction
in the control group (p=0.007). In the on state, the active group also experienced
improvements in the UPDRS (p=0.0006)[47].
Mizuno et al. in 2003, performed a randomized, three-arm parallel study (placebo,
bromocriptine and pramipexole) involving 325 patients with advanced PD who had motor
fluctuations and freezing for 12 weeks, and UPDRS scores were significantly lower
in the pramipexole (p <0.001) and bromocriptine groups. Apparently, the group using
pramipexole had a better response, but the study was unable to define this difference[48].
A study by Wong et al., 2003, followed 150 patients for 15 weeks in a double-blind,
randomized, placebo-controlled, parallel group study (levodopa + placebo versus levodopa
+ pramipexole) and found that the off period was shorter in the pramipexole group,
based on UPDRS on and off scores[49].
Rotigotine
Poewe et al. published in 2007 the Clinical Efficacy of Pramipexole and Transdermal
Rotigotine in Advanced PD (CLEOPATRA-PD) study of rotigotine in adjunctive treatment
with levodopa. In this double-blind, randomized, placebo-controlled study, 395 patients
with advanced PD with motor fluctuations were followed for six months. The authors
found a reduction in the off period in the treatment group[50]. Lewitt et al., also in 2007, published the Prospective Randomized Evaluation of
a New Formulation: Efficacy of Rotigotine study (PREFER study). In this randomized,
double-blind, placebo-controlled study, 351 patients with advanced PD and motor fluctuation
were divided into three groups (8 mg, 12 mg, and placebo). All patients were taking
concomitant levodopa. The authors concluded that rotigotine reduces the off time of
PD patients safely and with good tolerability[51]. Lewitt et al. published in 2013 the extension of the two previously cited papers,
the CLEOPATRA-PD and PREFER (class I) studies, conducted to evaluate the safety, tolerability,
and efficacy of rotigotine after several years of follow-up of patients with advanced
PD. In the CLEOPATRA-PD study, 48% of the patients remained under follow-up after
four years, while in the PREFER, 45% continued after six years of follow-up. In both
studies, the rotigotine dose was up to 16 mg. During the whole follow-up, patients
who used rotigotine showed better motor improvement than patients who used placebo,
but with a decline in the difference in scores over time. The authors concluded that
rotigotine is safe, effective, and well-tolerated after six years of follow-up. However,
the data regarding the maintenance of the improvement of the off period were not conclusive[52].
COMT inhibitors
Double-blind studies controlled with COMT inhibitors showed a reduction in the off-period
with an increase of one to two hours in the on-period, and most studies with entacapone
showed improvement in the UPDRS motor score[53].
Li et al. published in 2017 a meta-analysis of 14 studies evaluating the use of entacapone
in PD motor fluctuations. It was demonstrated that the adjuvant use of entacapone
and levodopa was effective in the management of motor fluctuations[54].
MAO-B inhibitors
In two major class I trials (LARGO and PRESTO), rasagiline has been shown to reduce
off-time by around 1 hour in patients with drug-related motor complications[55],[56]. The objective of the PRESTO and LARGO studies was to determine the efficacy and
safety or rasagiline as adjunct therapy for levodopa-treated PD patients with motor
fluctuations. These were randomized and placebo-controlled studies, but the LARGO
study also compared rasagiline with entacapone. The studies showed that rasagiline
was effective and safe in adjunct therapy with levodopa to increase motor fluctuations
in advanced PD.
There are two double-blind placebo-controlled studies about safinamide in advanced
PD: the SETTLE study (50 to 100 mg/day, 24 weeks) and the Borgohain et al., 2014 study
[57],[58]. The primary measure of effectiveness was the change in the “ON” time without problematic
dyskinesia between the beginning and the end of the study. Secondary parameters of
effectiveness were the off-time, and the UPDRS II and III and CGI-C scales were used.
Both indicated a significant superiority of safinamide at the target doses of 50 and
100 mg/day over placebo, concerning the selected primary and secondary efficacy variables.
The on-time effect remained until the end of the 24-month treatment period, with both
doses of safinamide better than placebo.
Conclusion
There is no consensus on the interval between levodopa doses or the time between the
meal and levodopa intake.
There is no evidence that the controlled-release levodopa formulations available in
Brazil are useful to manage fluctuations in advanced-stage PD patients. In clinical
practice, controlled-release levodopa formulations could be indicated to treat or
prevent nocturnal and early morning akinesia (level U).
Dopaminergic agonists are effective in the control of motor fluctuations in advanced-stage
PD (level A).
COMT inhibitors are effective to control motor fluctuations in advanced-stage PD (level
A).
MAO-B inhibitors are effective to control motor fluctuations in advanced-stage PD
(level A).
Levodopa-induced dyskinesia
Dyskinesia is characterized by involuntary movements related to levodopa use and may
appear during the motor benefit of the levodopa effect (square-wave dyskinesia) or
at the peak of the effect (peak-dose dyskinesia). Some patients may present dyskinesia
only during the beginning and/or the end of the motor effect of levodopa (diphasic
dyskinesia) or during the off period (off dyskinesia)[38],[59] ([Table 6]).
Table 6
Treatments for dyskinesias in advanced PD - levels of evidence.
|
|
Dyskinesias
|
|
Amantadine
|
Level B
|
|
Clozapine
|
Level U
|
|
STN-DBS
|
Level A
|
Levodopa management
There are no high-quality studies examining how levodopa is offered to patients to
control dyskinetic movements. In clinical settings, patients with peak-dose or square-wave
dyskinesia are advised to take more frequent and lower single doses of levodopa. In
diphasic dyskinesia, patients are put on a regimen of enhanced dopaminergic stimulation,
either by increasing single levodopa doses or adding dopaminergic drugs (DA, COMT
inhibitors or MAO-B inhibitors)[59].
Amantadine
In 1998, Verhagen Metman et al. recruited 18 patients for a six-week, double-blind,
controlled, crossover study evaluating amantadine at doses ranging from 100 to 400
mg daily and placebo. The authors concluded that amantadine substantially improves
dyskinesias induced by levodopa without improving motor symptoms of PD. These benefits
were sustained for at least 12 months[60]. Amantadine is capable of ameliorating the dyskinesias caused by levodopa use. Amantadine
also significantly decreased the duration of off-periods and improved the quality
of life of patients in the on and off periods.
In 2004, Thomas et al. recruited 40 patients for a 12-month, double-blind, randomized,
placebo-controlled study. After 15 to 30 days of treatment with amantadine, there
was a significant decrease in dyskinesia scores. According to the study, this effect
decreased or disappeared after 3 to 8 months of treatment, but the withdrawal of amantadine
led to a significant increase of dyskinesias in 11 patients[61].
In 2010, Wolf et al. conducted a randomized, double-blinded, placebo-controlled, national
multicenter study that included 32 patients already using amantadine for at least
one year. The authors claimed that amantadine maintains an anti-dyskinetic effect
even many years after its introduction[62].
In 2014, the AMANDYSK study evaluated the effect of withdrawal of amantadine, which
was replaced by placebo. The study was carried out on 57 patients with PD and dyskinesia,
and the patients were followed-up for three months after the withdrawal of amantadine.
It was found that the discontinuation of amantadine significantly worsened dyskinesia
compared with patients who were not discontinued[63].
Clozapine
In 2004, in a double-blind placebo-controlled trial of clozapine, Durif et al. showed
a significant increase of on-time without dyskinesia in the treatment group compared
with placebo[64]. An open naturalistic study evaluated the use of clozapine in dyskinetic patients
with or without psychotic symptoms. It was observed an improvement in both symptoms[65]. A limitation related to the chronic use of clozapine is the need for regular hematological
exams.
Conclusion
There is no consensus about the frequency and doses of levodopa to control induced
dyskinesia (level U).
Amantadine is probably effective for controlling levodopa-induced dyskinesias (level
B).
Clozapine is an alternative for patients who do not respond to amantadine or who cannot
take amantadine (level U).
DEEP BRAIN STIMULATION FOR THE TREATMENT OF PD PATIENTS
DEEP BRAIN STIMULATION FOR THE TREATMENT OF PD PATIENTS
Current surgical indications for PD include reducing motor fluctuations, off time,
dyskinesias, tremor, and improvement of levodopa-responsive symptoms. Deep brain stimulation
(DBS) is probably the most critical advance in treatment of PD since the introduction
of levodopa. The beneficial effects of DBS on motor symptoms and quality of life (QoL)
in advanced PD have been shown in randomized, controlled studies[66],[67].
An excellent individual outcome after DBS for PD patients will depend on appropriate
patient selection, accurate electrode placement in the ideal target area, and effective
programming of DBS devices after surgery[68],[69].
Patients’ inclusion and exclusion criteria
When deciding whether a patient is a good candidate for surgery, numerous factors
must be considered, such as:
Symptomatology
The primary DBS indication should be for disabling PD motor complications that are
not well-controlled with the best available medical treatment and for refractory tremor[70],[71].
Levodopa responsiveness
The levodopa response is reported as the best predictive factor for a positive response
to surgery. The levodopa challenge is used to reproduce the patient’s best on-response
and determine the responsiveness. Tremor is an exemption because it can respond poorly
to levodopa but improves with subthalamic nucleus (STN) DBS surgery[72].
Axial symptoms, especially gait disturbances, postural instability, freezing, and
speech disturbances that do not respond to the peak dose of Levodopa usually do not
respond to surgery. “Off-period” gait freezing can improve with surgery, but “on-period”
freezing shows little improvement.
Disease duration
Patients should have a disease duration of at least five years before being considered
for surgery[72],[73]. Findings from the EARLYSTIM trial have shown better results of STN stimulation
compared with medical treatment at a mean of 7.5 years after disease onset, when patients
are just beginning to experience fluctuations. This study argues for considering DBS
earlier than currently used in carefully selected patients when the benefits of the
treatment are weighed against the surgical risks[74] However, for early-stage PD patients without motor complications, there is “insufficient
evidence”[75].
Age
Although no specific age cutoff has been defined in clinical DBS studies, most studies
use age as an exclusion criterion. Most patients presenting the ideal profile for
surgery have a relatively young onset of PD and are younger than 70 years old. For
older patients, the risk-benefit ratio should consider factors such as comorbidities,
cognitive performance, prevalence of levodopa-resistant symptoms, and overall risk
of surgical complications[72],[76].
Cognitive and psychiatric aspects
A preoperative neuropsychological assessment is mandatory. Regarding cognition, dementia
is an absolute contraindication for surgery. There are no clear recommendations for
mild cognitive impairment[72],[72]. Surgery is contraindicated in patients with unstable psychiatric conditions until
symptoms are adequately managed. Ongoing severe depression with suicidal ideation
should also be considered an absolute contraindication to surgery. The relationship
between DBS and impulse control disorders (ICD) is controversial. STN-DBS has been
identified as an independent risk factor for ICD. However, long-term follow-up of
patients who underwent STN-DBS showed that ICD disappeared in most patients and the
use of dopamine agonist and dopamine dysregulation syndrome were reduced[77].
Preoperative imaging MRI
Severe cortical atrophy increases the risk of postoperative subdural hematomas. Visible
structural lesions on imaging findings should be considered absolute contraindications
to DBS[72],[77].
DBS targets
The two most common DBS targets are the STN and globus pallidus pars interna (GPi).
Randomized trials have demonstrated no significant difference in the degree of motor
improvement or complications between the two targets (with improvement in motor scores
by 25%-60%, measured by UPDRS-III scores)[78].
STN-DBS can reduce the need for dopamine replacement medications by approximately
50%. Therefore, when the primary goal of surgery is to reduce dopaminergic medications,
bilateral STN-DBS procedures should be performed instead of GPi[78],[79]. However, patients with STN-DBS can exhibit decreases in visual-motor processing
speed and worsening depression scores compared to patients with GPi-DBS[78]. Therefore, if there is significant concern about cognitive issues, GPi-DBS should
be considered, rather than STN (76). Similarly, if there is significant concern about
the risk of depression, the GPi target should be selected[78].
Ventral intermediate nucleus (Vim) DBS improves tremor but has no effect on other
symptoms; therefore, Vim DBS should be considered only for severe tremor-dominant
PD without other bothersome cardinal parkinsonian symptoms[68],[80]. Other targets such as the pedunculopontine nucleus have been suggested as options
for DBS, particularly for gait and balance symptoms; however, no trials meeting evidence-based
inclusion criteria have been published to date[75].
Conclusion
DBS is an effective therapeutic option for controlling disabling motor fluctuations
and dyskinesia (Level A).
Because of the risk for adverse events, the procedure is recommended only after consideration
of several pre-operatory factors and an evaluation of the risk-benefit ratio by a
specialized multidisciplinary team.
REHABILITATION IN PD
Physiotherapy
Physical therapy (PT), which includes gait, posture, transfers, balance, physical
capacity, and physical activity, plays a crucial role in the management of axial and
motor symptoms of people with PD[75],[81], [82],[83].
One article showed that in-patient multidisciplinary PT is better than “regular” PT
(Class I)[84]. Some class II studies have shown significant improvement in specific parameters
such as gait speed and step size using external cues (visual and auditory)[85],[86], whereas cognitive strategies (internal cues) and sensory cues (external cues) improved
gait freezing in PD[87],[88].
Two studies demonstrated the efficacy of dual task training in PD. The RESCUE[85] class II randomized clinical trial (RCT) enrolled 153 PD patients who received 3
weeks cued gait training and the authors observed that the use of cues enhanced motor
learning in PD. Rochester and colleagues defined motor learning as increased acquisition,
automaticity, and retention of cued gait after training[89]. The RESCUE trial also indicated the potential for sustained improvement in gait
and dual task performance after training. The other study, the DUALITY trial[90], compared the efficacy of two dual-task training programs for improving dual-task
gait in 121 PD patients. After 6 weeks of at-home physiotherapist-led training, both
modalities led to a similar and sustained effect on motor learning (Class I), improving
dual task gait velocity without increasing the risk of falls. The importance of dual-task
training is also observed in gait freezing. Combining treadmill training with visual
and auditory cues had more benefits on gait than cue training alone (Class II)[91].
Two large trials have demonstrated that balance can be improved with PT interventions[92],[93]. The first study (Class II) included 231 PD patients who were randomized into balance
exercises or usual-care control groups. Exercises were deliveried during 40 to 60
minutes, 3 times a week for 6 months. The results demonstrated that PT improved balance.
However, risk of falls was not reduced in both groups[92]. The second study (Class II) included 100 mild to moderate-stage PD patients and
evaluated the short-term effects of a high-challenge balance training, which incorporates
both dual-tasking and PD-specific balance components, compared with usual care. At
the end of the program, the between group comparison showed significant improvement
on balance and gait performance in the intervention group. The intervention group
also improved the performance of the cognitive task while walking compared with the
control group. No differences between groups were found for falls[93].
Recently, a large prospective, single-blind RCT (Class II) investigated the effectiveness
of multimodal balance training with and without rhythmical auditory cues in 154 PD
patients randomized in 3 groups[94]. Both intervention groups improved balance performance compared to controls (educational
program). Multimodal balance training supported by auditory rhythmical cues was more
effective and had long-term retention effect (6-months). A secondary subgroup analysis
for freezers and non-freezers based on the same study showed that adding rhythmic
auditory stimuli to balance training is beneficial for both freezers and non-freezer[95].
Current physiotherapy guidelines provide no recommendations on the specific approach
for advanced stages of PD[82], since there are few studies targeting this subgroup[96],[97]. Multimodal balance intervention (combined or not with rhythmical auditory cues)
may improve balance and gait in patients at advanced stages of PD (H&Y 4) (Class III).
Conclusion
Physiotherapy is effective in improving motor and axial symptoms in early and moderate
stages of PD (Level A). There are insufficient data to support or refute the effectiveness
of physiotherapy in advanced stages of PD (Level U).
Therapeutic and formalized pattern exercises
The SPARX study (Class I) enrolled 128 de novo patients and compared high- and moderate-intensity
treadmill exercises with a wait-list control group. After six month of 3 days per
week exercise, the results showed that the high-intensity group, who exercised at
80 to 85% maximum heart rate, had less change in motor symptoms (UPDRS motor score)
compared with the usual care group[98]. The Park-in-shape trial (Class I), a home-based study, recruited 130 PD patients
in Hoehn & Yahr stage ≤ 2 who were randomized either to exercise on a stationary cycle
or stretching at least three times per week. After the 6-month program, the MDS-UPDRS
motor score change was smaller in the aerobic group, resulting in a between-group
adjusted mean difference of 4.2 points favoring the cycling group[99].
Conclusion
Aerobic exercises are effective in attenuating symptoms in PD patients in early and
mild stages (Level A). Currently, there are insufficient data to support or refute
the effectiveness of aerobic exercise in moderate or advanced stages of PD. (Level
U).
Speech therapy
Studies have suggested a beneficial effect of speech language therapy (SLT) in PD[75],[100] and a newly published systematic review and meta-analysis study (Class II) assessed
the effect of SLT on hypokinetic dysarthria in PD patients. The RCT selected in this
review compared different SLT in the treatment of three variables, (sound pressure
level, semitone standard deviation, and perceptual intelligibility). Results showed
significant differences in favor of SLT for sound pressure level in sustained phonation
tasks. Significant results were also observed for sound pressure level and semitone
standard deviation in reading tasks. This meta-analysis suggests a beneficial effect
of SLT for reducing hypokinetic dysarthria, improving perceptual intelligibility,
sound pressure level, and semitone standard deviation in PD[101].
Conclusion
Speech therapy is possibly effective in improving voice and dysphagia in PD patients
(Level C).
Occupational therapy
Although occupational therapy (OT) is frequently prescribed in the clinical practice[102], few articles have been published about this intervention in PD patients. In 2014,
Sturkenboom et al. demonstrated the impact of OT in daily activities of PD patients[103]. In this study, 191 patients were randomly assigned to the intervention group (n=124),
which consisted of 10 weeks of home-based OT, or to the control group (n=67). The
primary outcome was self-perceived performance in daily activities, assessed with
the Canadian Occupational Performance Measure (COPM). After 3 months, the intervention
group had better scores on the COPM, meaning that patients improved self-perceived
performance in daily activities.
A recent review assessed the efficacy of OT intervention on quality of life in PD
(Class II). In total, 15 randomized controlled trials were selected for the systematic
review and 4 of these were included in the meta-analysis. Both short follow-up (2
- 3 months) and long follow-up (6-12 months) studies showed that OT interventions
significantly improved the quality of life of patients with PD. However, the strength
of the evidence should be considered moderate because of the limited number of publications
available[104].
Because of the lack of high-quality studies available, further investigations are
needed to make firm conclusions about OT efficacy in PD.
Conclusion
Occupational therapy is probably effective in improving daily life activities in PD
patients (Level B).
