Keywords: Parkinson Disease - Therapeutics - Levodopa
Palavras-chave: Doença de Parkinson; Terapêutica - Levodopa
INTRODUCTION
Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide.
PD prevalence ranges from 102 to 190 per 100,000 in Western countries[1 ], affecting both men and women, but being slightly more common in men. The disease
typically develops after the age of fifty and may affect up to 2% of the population
older than 65 years old[2 ]. From 1900 to 2015 the projection of the number of people with PD doubled to over
6 million, mainly due to ageing population. The number of people affected is projected
to a staggering 12.9 million people affected by 2,040[3 ]. Early-onset PD denotes disease onset below age 40, and juvenile PD when age of
disease onset is below 21 years.
PD is a complex disorder with a broad spectrum of motor and non-motor features that
require an individualized therapeutic approach. Several guidelines for the treatment
of PD are available in the literature[4 ]. The main drugs used for the treatment of motor manifestations of the disease are:
levodopa, dopamine agonists, catechol-o-methyltransferase inhibitors, monoamine oxidase
inhibitors, amantadine and anticholinergics[5 ].
LEVODOPA
Levodopa is the most effective drug for the treatment of symptoms of Parkinson disease.
In the 1970s, it was discovered that adding a dopa decarboxylase inhibitor to levodopa
to reduce its peripheral metabolism would lessen treatment side effects and show better
symptom control. Levodopa treatment contributes to greater activity levels, independence,
employability and consequently improved patient’s quality of life[6 ]. Levodopa dose should be kept as low as possible to maintain good function in order
to reduce the risk of motor complications.
For patients with prolonged off periods or severe dysphagia an encapsulated levodopa
powder can be administered orally via an inhaler, but this preparation is not available
in our country[7 ].
Levodopa may lead to the development of longterm motor complications, including abnormal
involuntary movements such as dyskinesias, dystonia, and response fluctuations.
The pathogenesis of motor complications associated with chronic levodopa therapy is
still not fully understood. Theories include: presynaptic neuronal degeneration leading
to insufficient buffering of released levodopa; postsynaptic changes in dopamine receptor
number and its sensitivity, partially caused by presynaptic changes; and pharmacokinetic
and pharmacodynamics changes of chronic dopaminergic therapy. Motor complications
may be also related to the pulsatile use of levodopa, which leads to an imbalance
of basal ganglia opioid concentrations and resetting of voltage gated channels in
N-methyl-D-aspartate (NMDA) receptors[8 ],[9 ].
Different levodopa formulations have been developed to provide more desirable delivery
to avoid or prevent levodopa-related complications, but most of them are ineffective
for these goals. A continuous intrajejunal infusion of levodopa-carbidopa intestinal
gel has been found effective in smoothing out motor fluctuations[5 ].
DOPAMINE AGONISTS
Dopamine agonists (DA) act directly stimulating dopamine brain receptors in There
are two DA subclasses: ergoline and non-ergoline agonists. Ergoline dopamine agonists
include bromocriptine, pergolide, lisuride, and cabergoline, whereas ropinirole, pramipexole
and rotigotine (patch application) are non-ergoline agonists. Apomorphine was the
first DA shown to improve parkinsonian symptoms, but it has to be administered subcutaneously
(not available in our country). Only non-ergot dopamine agonists, such as pramipexole
and rotigotine, both available in Brazil, should be used because ergot agonists may
cause pulmonary and cardiac fibrosis.
DA has been used as monotherapy in de novo patients with the intention of delaying
levodopa treatment. DA are also used as adjunct to levodopa treatment in patients
exhibiting motor fluctuation. DA rather than levodopa use appears to postpone onset
of motor complications and dyskinesias, since motor complications may be related to
the pulsatile use of levodopa as previously mentioned. DA display longer half-lives
and differences in receptor selectivity, while dopaminergic therapy may lead to the
development of Impulse control disorders, more common in patients on dopamine agonists
therapy.
For patients with severe off periods and delayed onset with subsequent dosing, self-administered
subcutaneous apomorphine injections (available outside Brazil) can be used to obtain
a faster motor response.
CATECHOL-O-METHYLTRANSFERASE INHIBITORS (COMTI)
CATECHOL-O-METHYLTRANSFERASE INHIBITORS (COMTI)
When peripheral decarboxylation is blocked by carbidopa or benserazide, the next n
metabolic pathway of levodopa is O-methylation by COMT. COMTIs block dopamine degrading
enzymes, prolonging the benefits of levodopa by improving its bioavailability and
inhibiting the formation of 3-O-methyldopa.
Entacapone (the only COMTI available in Brazil) inhibits COMT peripherally and tolcapone
inhibits it both centrally and peripherally. Opicapone is a new generation once-daily
administration COMTI, not yet available in Brazil. These drugs prolong the antiparkinsonian
effect of levodopa and also allow levodopa dose reduction. Combination of COMT inhibitors
and levodopa is indicated in patients with wearing off.
MONOAMINE OXIDASE INHIBITORS (MAOI)
MONOAMINE OXIDASE INHIBITORS (MAOI)
Most of the MAO in the brain are type B and play an important role in the monoamine
breakdown, such as dopamine. Three MAO inhibitors are available for the treatment
of PD: selegiline, rasagiline and safinamide.
Although selegiline and rasagiline are most frequently used in early and mild PD,
these MAOI are also effective in patients with moderately advanced PD with levodopa-related
motor complications. A third generation of MAOI, safinamide, administered once daily
(50-100 mg/day), has been found to increase patients‘ on time without troublesome
dyskinesia and to reduce daily and morning off times[10 ]. Safinamide is a reversible MAOI, it also reduces neuronal dopamine reuptake and
blocks voltage-dependent activated sodium channel and intracellular calcium entry,
reducing neuronal glutamate release.
AMANTADINE
Amantadine, originally used as an antiviral drug, was fortituitously recognized to
be a treatment for PD despite being a weak therapeutic agent. This drug increases
dopamine release and blocks dopamine reuptake. Recent studies have demonstrated that
amantadine is a weak NMDA glutamate receptor antagonist. Thus, amantadine can influence
glutamatergic neurotransmission in corticostriatal synapses or at the subthalamic-internal
pallidal synaptic level. Moreover, recent randomized clinical trials have also shown
that amantadine reduces dyskinesias and motor fluctuations in patients receiving levodopa[11 ]. Immediate-release amantadine is used off label for dyskinesia. Extended-release
amantadine preparations was approved by the FDA for dyskinesia[12 ].
ANTICHOLINERGICS
The oldest class of medicines to treat PD is the anticholinergic (ACH) drugs. Biperiden
and trihexyphenidyl reduce cholinergic activity contributing to reestablish the balance
between striatal cholinergic and dopaminergic activity. The most recognized ACH drug
use is to treat tremor in early or young onset PD, but ACH drugs do not significantly
affect bradykinesia or rigidity. The most common side effects of ACH include dry mouth,
blurred vision, constipation, and difficulty voiding the bladder. ACH can cause confusional
states in elderly patients.
SURGICAL TREATMENT
Deep brain stimulation (DBS) of the subthalamic nucleus or internal globus pallidus
are indicated to manage patients with severe dyskinesias and motor fluctuations. In
the topic “Treatment of the advanced phase of PD” additional brief comments about
this subject will be made. Details about the indications criteria and complications
related to this procedure will be discussed in another article of this issue.
MODIFYING-DISEASE THERAPIES
MODIFYING-DISEASE THERAPIES
Multiple lines of research point to several pathways which may contribute to neurodegeneration
in PD: mitochondrial dysfunction, defective autophagy, abnormal protein accumulation
of α-synuclein and synaptic impairment. Although effective therapies are available
for the symptomatic control of PD treatments to halt the progression of the neurodegeneration
process do not exist so far. Development of disease-modifying therapies to slow, mitigate
or prevent PD is crucial ,and new approaches to development of these agents have been
proposed recently by Kieburtz et al.[13 ].
MANAGEMENT OF EARLY PD
Early stage PD begins when the first motor symptoms are noticed and the diagnosis
is established. This stage may last for months or a few years, until symptoms begin
to interfere with daily activities and quality of life is affected.
There are many treatment options to control symptoms in early stages of PD. Optimal
management in individual patients depends on a number of variables such as age, cognitive
status, symptom severity, predominance of bradykinesia or tremor, degree of dominant
hand involvement, functional disability and employment status, among others. Medical
treatment of early PD consists of dopamine replacing strategies to relieve motor symptoms,
but eventually, other medical interventions may be required to treat nonmotor symptoms,
such as depression or bowel constipation. No neuroprotective therapy is currently
available to treat PD.
Four main classes of drugs are currently considered to be useful for initial PD: monoamine
oxidase type B (MAO-B)) inhibitors, amantadine, dopamine agonists (DA) and levodopa.
Occasionally, anticholinergic drugs may be used in young patients with predominant
tremor. These drugs have different pharmacological profiles, potencies and side effects.
None of them has been found to be neuroprotective. MAO-B inhibitors and amantadine
are less poten,t and can be used in patients with mild symptoms. Side effects are
usually mild and well tolerated. DAs have a more potent dopaminergic effect and a
longer half-life than levodopa. There is a lower risk of producing motor complications
compared to levodopa, but adverse effects can be troublesome and include somnolence,
hallucinations and impulse control disorders. Levodopa is the most effective drug
and all patients will use this drug at some point in the course of the disease. However,
short half-life and higher risk of development of dyskinesias are limitations to be
considered[14 ],[15 ].
Some clinicians have advocated that levodopa should be used as the initial therapy
in spite of the known risk of producing motor fluctuations and dyskinesias[16 ]. The main argument is that there is no proof that levodopa is toxic to the brain
or that the cause of motor complications is levodopa itself. In fact, there are reasons
to indicate that dyskinesias correlate with disease severity and duration and not
with duration of levodopa therapy. Moreover, it may be reasonable to argue that the
most effective drug should be used in the early stages to provide the best quality
of life from the start. Furthermore, the increasing recognition of severe impulse
control disorders have cautioned against the use of DAs in more vulnerable patients[17 ].
Moreover, those who prefer to delay the introduction of levodopa in favor of other
dopamine-sparing drugs do not recommend postponing its use beyond the patient clinical
requirement.
Two pivotal studies deserve mention regarding early levodopa treatment. The ELLDOPA
study was a controlled clinical trial aimed to evaluate the effect of levodopa on
the clinical course of PD. Results showed that subjects treated with levodopa had
less clinical progression after a two-week washout period compared to the placebo
group, and that this effect was dose-dependent. In spite of some discordance between
clinical results and ligand imaging findings suggesting increased degeneration in
dopamine terminal neurons in the levodopa arms, the overall conclusion of this study
was that levodopa is not toxic[18 ].
The other trial was the LEAP study, which was a delayed-start clinical trial to investigate
whether early treatment with levodopa had a beneficial disease modifying effect on
PD. The results showed no differences between groups and the authors concluded that
levodopa does not have a disease modifying effect[19 ].
A recent report of the American Academy of Neurology reviewed the current evidence
on the options available for initiating treatment of motor symptoms in early-stage
PD. The main recommendations are summarized below: (Pringsheim)[20 ].
Levodopa vs. DAs vs. MAO-B inhibitors
Clinical trials have failed to provide evidence of disease modifying effects when
therapy is initiated with any class of drugs. Studies comparing treatment with levodopa
with treatment with MAO-B inhibitors demonstrate greater improvement with levodopa
and > 60% of individuals randomized to MAO-B inhibitors will require additional therapy
within two to three years. (PD MED)[21 ].
Initial treatment of early PD with levodopa provides greater benefit for motor symptoms,
but is more likely to induce dyskinesias than initial treatment with DAs. Treatment
with DAs may be more likely to cause more hallucinations compared with levodopa, but
the difference is small for the first five years. Treatment with DAs in early PD carries
a higher risk of impulse control disorders. Patient characteristics may provide clues
to the risk of adverse effects. Younger age at onset, lower body weight, female gender
and disease severity are predisposing factors for levodopa-induced dyskinesias. Predisposing
factors for impulse control disorders are younger age, male gender and history of
previous mood disorders. Cognitive and behavioral adverse effects are more common
in older patients treated with DAs.
Overall recommendations regarding comparison studies among drugs are as follows:
In patients who seek treatment for motor symptoms, levodopa should be the initial
dopaminergic therapy;
DAs may be prescribed as initial drug in patients < 60 years, whio are at higher risk
for dyskinesias;
DAs should not be prescribed to patients older than 70 years, or with a history of
impulse control disorders, cognitive impairment, daytime sleepiness or hallucinations.
Recommendations for levodopa
Studies comparing immediate-release, extended release or levodopa/carbidopa/entacapone
formulations did not detect significant differences. Recommendations for levodopa
prescription are:
Immediate-release should be preferred over extended release or association with entacapone
formulations in patients with early PD;
Lowest effective doses should be prescribed to minimize risk of adverse effects;
Patients should be advised that higher dosages increase the risk of dyskinesias;
Patients should be advised that taking levodopa with meals may decrease levodopa effect,
butthis is usually not a problem in early disease stages.
Recommendations for DAs
Patients and caregivers should be informed of side effects of Das, such as impulse
control disorders, sudden-onset sleepiness, postural hypotension and hallucinations;
Patients should be screened for the above symptoms and for cognitive impairment;
There is no compelling evidence that pramipexole extended-release vs. pramipexole
immediate-release was associated with more favorable UPDRS scores;
There are preliminary reports that long-acting and transdermal formulations of DAs
have lower rates of impulse control disorders than short-acting formulations;
The lowest effective dose of DAs should be prescribed.
Recommendations for MAO-B inhibitors
Most patients on monotherapy with a MAO-B inhibitor will require additional therapy
after two to three years. This class of drug is associated with higher risk of adverse
effects on discontinuation compared to levodopa treatment;
There are no studies comparing the efficacy of selegiline, rasagiline and safinamide;
Both drugs are superior to placebo for the treatment of motor symptoms;
Although serotonin syndrome is rarely reported in PD, prescribing information cautions
against concomitant use of MAO-B inhibitors and serotonin reuptake inhibitors.
TREATMENT OF ADVANCED PARKINSON’S DISEASE
TREATMENT OF ADVANCED PARKINSON’S DISEASE
Definition of advanced PD and its challenges
Advanced stage PD is defined by the presence of functional limitation despite optimized
treatment, and occurrence of motor complications associated with dopamine replacement
therapy (DRT), such as motor fluctuations, dyskinesias and psychosis. Postural instability
and/or regular falls, gait freezing, postural abnormalities (camptocormia, Pisa syndrome)
and cognitive impairment are the main conditions associated with disability at this
stage, negatively affecting quality of life of affected individuals. The term end
stage PD is also used by some authors when there is significant disability and poor
response to available treatments[22 ]. In the Hoehn and Yahr (H&Y) classification, advanced PD is classified as stages
4 or 5[23 ].
In the advanced stage of the disease most patients present with symptoms that are
not improved by levodopa. Hely and colleagues showed that after 15 years of disease
progression the main motor symptoms affecting individuals with PD are: motor complications
of dopamine replacement treatment (dyskinesias and wearing-off), regular falls and
choking. The main nonmotor symptoms (NMS) are cognitive decline, depression, hallucinations,
urinary incontinence and postural hypotension[24 ]. Periodic consultations with a movement disorders neurologist could help manage
the complications of DRT and guide treatment decisions, particularly concerning advanced
therapies, such as infusion therapies and surgical procedures[25 ].
Non-pharmacological treatment of advanced PD
Physical therapy and exercise can improve PD symptoms not usually ameliorated by DRT,
such as gait impairment and freezing, postural instability, falls, and non-motor symptoms,
such as depression, constipation, apathy, and fatigue[26 ]. It is good practice to recommend physical exercise to all patients with a recent
diagnosis of PD. Individuals with advanced PD, on the other hand, are at greater risk
of injury from exercising and need a personalized approach. At this stage, physical
therapy should focus on prevention of falls, improving transfers, posture, balance,
and gait. This could be achieved by assisted active exercising and training of cognitive
movement strategies. In patients with H&Y 5 physical therapy can help preventing contractures
and pressure sores as well as help with postural adjustments[27 ]. An occupational therapist could contribute to caregiver education, helping to reduce
caregiver burden, to improve quality of care, and to advise environmental adaptations
to reduce risk of falls and injuries[28 ].
Speech problems such as hypophonia and dysarthria frequently fail to improve with
levodopa, and can worsen as the disease progresses, being a significant source of
distress for individuals with PD, particularly in the advanced stage. Speech rehabilitation
can improve dysarthria and possibly increase voice pitch, and should therefore be
offered to any patient suffering from these symptoms[29 ]. Dysphagia is a common symptom in advanced PD3 and should prompt referral to a speech
therapist.
Pharmacological treatment of advanced PD
Motor complications of dopaminergic treatment
Motor fluctuations are the main complications of levodopa therapy in advanced PD.
Motor fluctuations are predictable: end of dose (wearing-off), unpredictable: OFFs,
ON-OFF phenomenon, delayed-on and dose failures. Troublesome motor fluctuations affect
43% of patients with PD after five years of disease progression[30 ]
, and become more frequent with time, affecting approximately 80% of individuals 10
years after diagnosis. Motor fluctuations are associated with younger age at disease
onset, longer disease duration and higher doses of levodopa[31 ],[32 ]. Unpredictable ON-OFF phenomenon usually occurs later in disease course[33 ].
Dyskinesias are involuntary movements that occur in an individual with PD showing
a temporal relationship to levodopa ingestion[34 ]. Dyskinesias are associated with longer disease duration, affecting 59% of individuals
after 10 years of disease progression. Risk factors for development of levodopa-induced
dyskinesias (LID) are younger age at PD onset, higher levodopa dose and presence of
motor fluctuations[35 ].
Different types of dyskinesias are seen in PD. Dyskinesias that occur at peak levodopa
serum concentration are the most common, these dyskinesias are choreiform, appear
initially in the more affected body side, and do significantly impact on quality of
life.1 Dystonia is commonly painful, can affect as many as 30% of individuals with
PD, and is seen in OFF periods[35 ],[36 ]. Diphasic dyskinesias are rare, occur a few moments before levodopa kicks in and
wears off, and are usually manifested as stereotyped movements of one or both legs[22 ].
Treatment of motor complications
The likelihood of developing complications from dopamine replacement therapy is substantially
increased in the advanced stage of PD. The treating physician faces complex choices
in the trade-off between motor control and treatment adverse effects. Considering
that levodopa is more effective and safer than the other dopaminergic drugs, it should
be the preferred treatment for motor symptoms at this stage[25 ]. Reinforcing the recommendation to take levodopa away from meals can help reduce
delayed ONs. Soluble levodopa tablets, which are absorbed faster, are also useful
to improve delayed ON[37 ]. Reduction of OFF periods can be achieved by increasing levodopa dose or adding
catechol-O-methyltransferase inhibitors (iCOMT), however both strategies can lead
to supratherapeutic levels of levodopa, contributing to adverse effects and peak-dose
dyskinesias[25 ],[38 ].
Controlled release formulations of levodopa have longer bioavailability and could
theoretically improve ON time, however it is still unclear whether these are helpful
in controlling motor fluctuations. Night time rigidity and akinesia, on the other
hand, could be improved by a bedtime dose of controlled release levodopa.16 Sudden
OFF periods and morning akinesia could be improved by rescue apomorphine injections[39 ].
TREATMENT OF LEVODOPA-INDUCED DYSKINESIAS (LID)
TREATMENT OF LEVODOPA-INDUCED DYSKINESIAS (LID)
Correct identification of the type of dyskinesias is of paramount importance for treatment
success. Diphasic and dystonic dyskinesias could be improved by increasing levodopa
dosage, whereas peak-dose dyskinesias usually respond to a reduction in levodopa dose
or the total amount of dopamine replacement therapy[25 ]. When treating peak-dose dyskinesias it is important to consider that most patients
are not bothered by the involuntary movements nor perceive any functional impairment
related to peak dose dyskinesias. A reduction of levodopa dosage is not always necessary
and could lead to motor deterioration[40 ].
When levodopa dose reduction with the goal of ameliorating dyskinesias results in
inadequate motor control, add-on therapy, with dopamine agonists or MAOi, is usually
recommended to patients in earlier stages of PD. However, due to potential side effects,
these medications are not recommended for individuals with advanced disease. Controlled
release levodopa has not been shown to be superior to standard release levodopa in
controlling dyskinesias[35 ],[37 ].
Amantadine is the only medication that acutely improves peak-dose dyskinesias without
worsening motor symptoms. The initial dose is 100 mg daily, which can be increased
up to 400 mg daily, depending on tolerability. In advanced PD amantadine should be
used with caution, because of higher propensity to side effects, particularly visual
hallucinations and executive dysfunction. In the presence of cognitive impairment,
an alternative treatment should be sought[35 ].
Safinamide, a drug with dopaminergic and anti-glutamatergic properties appears to
improve dyskinesias in a long-term scenario at a dose of 100 mg daily, but it appears
to show no acute effect in reducing the severity of peak dose dyskinesias[41 ]. Clozapine, an atypical antipsychotic drug, can improve peak-dose dyskinesias. However,
the need to monitor white blood cells count and cardiovascular risk makes it an unsuitable
option for most patients[35 ].
INFUSION THERAPIES
Infusion therapies can deliver levodopa to the brain in a more constant way, bypassing
the gastrointestinal tract and minimizing absorption rate variability. Potential benefits
are reduction of OFF periods and adverse events associated with suprathreshold levels
of levodopa, such as peak-dose dyskinesias, making these therapies suitable for individuals
with advanced PD. Two types of infusion therapies are available, levodopa-carbidopa
intestinal gel (LCIG) and apomorphine continuous infusion.
LCIG is administered continuously via a percutaneous endoscopic gastrostomy-jejunostomy
feeding tube and has the inconvenience of relying on an infusion system[34 ]. Apomorphine is a short-acting dopamine agonist with pharmacological properties
akin to levodopa, with higher affinity for dopaminergic D1 and D2 receptors, that
can also be administered via subcutaneous continuous infusion. Both LCIG and apomorphine
infusion are effective in reducing OFF time in individuals with advanced PD and motor
complications[42 ],[43 ] making them good therapeutic options for individuals who are not candidates for
deep brain stimulation. These drugs are safe for individuals with a present or past
history of impulse control behaviours[44 ],[45 ].
SURGERY
Many of the complications of advanced stage PD, such as postural instability, falls
and cognitive impairment, make individuals at this stage of the disease unsuitable
for deep brain stimulation (DBS)[1 ]. In a recent systematic review, DBS was superior to best medical treatment and similar
to LCIG in controlling motor symptoms of advanced PD. In suitable patients the decision
to undergo DBS should be individualized, considering risks, potential benefits, costs
and life expectancy[46 ]. Lesioning procedures can also be considered if surgical risk permits. Pallidotomy,
for instance, is effective in reducing levodopa-induced dyskinesias and OFF period
disability[47 ],[48 ].
TREATMENT OF NONMOTOR SYMPTOMS
TREATMENT OF NONMOTOR SYMPTOMS
Comprehensive treatment of nonmotor symptoms is beyond the scope of this section,
which will focus on the NMS more frequently seen in advanced PD. NMS are a significant
source of distress and have a negative impact on the quality of life of individuals
with PD, particularly in advanced disease stages[22 ]. NMS can e be a consequence of the disease or a complication of DRT. When NMS occurs
in association with OFF symptoms (nonmotor OFF), NMS could be improved using the same
strategies used to minimize motor OFF periods[22 ],[25 ]. The most common nonmotor OFF symptoms are pain, akathisia, depression, anxiety,
dysphoria and dysautonomia[22 ].
Considering that many NMS are worsened by DRT and/or difficult to distinguish from
complications of treatment, individuals with advanced PD and significant NMS benefit
from dose reduction and simplification of treatment regimen (favoring levodopa over
other classes of medication). This is particularly true for individuals with psychosis
or cognitive impairment[25 ]. If cognitive impairment remains an issue in patients on levodopa monotherapy, the
treating physician should attempt to establish the minimum levodopa dose necessary
to control motor symptoms. Cholinesterase inhibitors could be prescribed, if motor
deterioration prevents further reduction of levodopa in individuals with significant
cognitive impairment. Rivastigmine and donepezil have both been shown to improve cognitive
function and psychosis in PD[49 ]. If psychosis in advanced PD fails to improve with the measures discussed above,
antipsychotics can be prescribed. Quetiapine and clozapine are the only antipsychotics
that do not worsen parkinsonian symptoms, and are both useful to treat psychosis and
visual hallucinations[25 ].
Orthostatic hypotension is common in advanced PD. Reduction of levodopa and other
contributing medication should be attempted, if possible, in addition to non-pharmacological
measures, such as increased fluid and salt intake, avoiding carbohydrate rich meals,
and preferring smaller, more frequent meals. There is still no consensus guiding the
decision to initiate pharmacological treatment. The drugs available to treat orthostatic
hypotension are domperidone, fludrocortisone, droxidopa and midodrine[50 ].
Impulse control behaviors (ICB) mainly affect individuals with young onset PD, but
a significant proportion of patients remain symptomatic in thr long run [51 ]. Reduction of DRT and/or initiation of infusion therapies are treatment options
for individuals with advanced PD and troublesome ICBs[52 ].
PALLIATIVE CARE
Palliative care in PD focuses on improving quality of life and autonomy, planning
advance care, and supporting caregivers. In advanced PD it should be seen as a complementary
treatment strategy that could be used in parallel to other treatments. Decision to
start palliation is difficult considering the variability in clinical phenotypes.
Generally, limited lifetime expectancy, rapid disease progression, malnutrition, impaired
breathing, or the occurrence of life-threatening complications in the previous year
are clues that could be used to identify individuals who would benefit from palliative
care. Palliative care can also be indicated with the prescription of a new intervention
or when end of life is approaching[53 ].
PARKINSON DISEASE REHABILITATION
PARKINSON DISEASE REHABILITATION
Although pharmaceutical treatments improve PD manifestations, optimal management requires
a multidisciplinary approach. Independently of the stage of the disease, patients
and caregivers may benefit from tailored rehabilitation programs according to their
needs[54 ]. Many rehabilitation interventions have been proven to improve PD symptoms[55 ] and clinical practice guidelines have been published to help therapists and neurologists
to provide best decision making for the management of PD patients treatment[56 ].
A recent meta-analysis evaluated the effect of different physical therapy (PT) interventions
on motor symptoms, balance, gait and quality of life (QoL)[57 ]. The authors concluded that conventional PT improved motor symptoms, gait, and QoL.
Resistance and treadmill training improved gait, hydrotherapy improved balance, and
strategy training improved balance and gait. Dance, Nordic walking, martial arts,
and balance and gait training improved motor symptoms, balance, and gait. Dual task
training (DT) did not improve motor symptoms, balance, gait and QoL. Although this
last finding might seem conflicting with proven benefits of DT [55 ],[58 ],[59 ], DTT should be implemented in PD rehabilitation, because of the motor learning principle[60 ]. Patients improve mobility and cognitive function when both motor and cognitive
activities are integrated during DT training[55 ]. Caution should be taken with people with higher falling risk, freezing of gait
or mild cognitive impairment,. Good strategies and tailoring exercises to each patient’s
personal and physical cognitive abilities[61 ] may reduce or avoid risks during training.
Many studies suggest that aerobic and high intensity exercises may attenuate PD symptoms[62 ]. Resistance training improves muscle strength, mobility, balance, functional capacity,
QoL and reduces the risk of falls of PD patients[63 ]. Exercise may improve cognitive functions of PD patients at a mild to moderate stage
of the disease[64 ]. Exergaming and virtual reality training can be useful to improve gait in PD[65 ]. Whether these effects are merely symptomatic or reflective of a possible disease-modifying
effect requires further study[66 ]. Overall, there are long-term effects with exercise training[67 ] but there is no consensus about which types of exercises are better for PD, and,
therefore, individualized prescription, similarly to pharmacotherapeutic interventions,
such as frequency, duration, and intensity, is required[68 ].
Recent meta-analysis demonstrated the efficacy of the Lee Silverman Voice Treatment
in increasing vocal loudness and functional communication among individuals with PD[69 ]. Speech language therapy (SLT) has potential benefits for PD dysphagia[70 ]. Intensive SLT is effective for hypophonia and can lead to some improvement of voice
pitch but behavioral speech rehabilitation in PD still needs validation[71 ].
Although occupational therapy (OT) has a perceived possibly beneficial role for PD,
studies about the effect of OT in PD are scarce. In 2014, Sturkenboom et al.[72 ] demonstrated that OT can improve the self-perceived performance of PD patients in
daily activities. Different OT interventions may be effective in improving QoL in
patients with PD. Because of the lack of high-quality studies, further investigations
are needed to establish firm conclusions about OT efficacy in PD[73 ].
AN ALGORITHM FOR THE TREATMENT OF MOTOR SYMPTOMS OF PD AND RECENT GUIDELINES FOR THE
TREATMENT OF PARKINSON’S DISEASE
AN ALGORITHM FOR THE TREATMENT OF MOTOR SYMPTOMS OF PD AND RECENT GUIDELINES FOR THE
TREATMENT OF PARKINSON’S DISEASE
Based on this review, we propose an algorithm as a guide for the treatment of motor
symptoms in PD [Figure 1 ], Moreover, it is important to mention three recently published guidelines with recommendations
concerning the treatment of PD: the Canadian guideline[4 ], the Brazilian guideline of the Movement Disorders Scientific Department of the
Brazilian Academy of Neurology[74 ] and the American Academy of Neurology guideline[75 ]. They review the current evidence of available treatment options for PD. Additionally,
an update on the management of PD for general neurologists was recently published
by Pyrtosek et al[76 ]. These written materials can help doctors to improve treatment strategies for PD
patients.
Figure 1 Treatment of PD motor symptoms.
