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Diagnóstico e tratamento Doença de Parkinson
Convidad Qui Jul 11, 2013 11:04 am
DIAGNOSIS — The practical diagnosis of PD during life is based on clinical impression. There are no physiologic tests or blood tests for confirming the diagnosis, and neurodiagnostic testing with computerized imaging is almost always unrevealing. The true "gold standard" for diagnosis is neuropathologic examination.
It is generally accepted that bradykinesia, plus one of the other two cardinal manifestations (tremor, rigidity) must be present in order to make the diagnosis of idiopathic PD. In addition, an excellent response to dopaminergic therapy is an important criterion for the diagnosis. Other clinical features that are supportive of the diagnosis are unilateral onset, presence of a rest tremor, and a persistent asymmetry throughout the course of the disease with the side of onset most affected.
Response to dopaminergic therapy — As noted above, an excellent response to dopaminergic therapy is an important supportive feature for establishing the diagnosis of PD. The response to dopaminergic therapy in most parkinsonian syndromes is reduced or absent compared with the response in PD. However, up to 20 percent of patients with parkinsonism due to multiple system atrophy may respond initially to levodopa , as may a substantial proportion of those with vascular parkinsonism.
An acute dopaminergic challenge test consists of rater-blinded assessment of parkinsonian symptoms using the Unified Parkinson Disease Rating Scale (UPDRS) before and after a dose of levodopa (eg, carbidopa-levodopa 25/250 mg) or subcutaneous apomorphine (1.5 to 4.5 mg). Although there is no standard definition, a challenge is considered positive if there is a clinically significant improvement in the UPDRS score (usually in the range of 15 to 30 percent or more) one hour after levodopa administration or 20 minutes after apomorphine injection.
A systematic review and practice parameter from the American Academy of Neurology (AAN) published in 2006 concluded that levodopa and apomorphine challenge tests should be considered when the diagnosis of PD is uncertain, as both tests are "probably useful" in distinguishing PD from other parkinsonian syndromes. An earlier systematic review found that both apomorphine and levodopa challenge tests had similar sensitivity and specificity for the diagnosis of idiopathic PD.
However, the exact role of acute levodopa or apomorphine challenge for the diagnosis of PD in clinical practice remains unclear. The problem with challenge testing is illustrated by the following observations:
• Up to 30 percent of patients with PD may not respond to acute dopaminergic challenges
• Approximately 20 to 30 percent of patients with a positive acute dopaminergic challenge will go on to develop another parkinsonian syndrome
In practice, when patients have mild symptoms that do not interfere with daily activities, it may not be advisable to institute dopaminergic therapy purely for diagnostic purposes. When PD symptoms begin to limit a patient's quality of life, a long-term trial of dopaminergic or levodopa therapy may be just as adequate as an acute dopaminergic challenge.
The vast majority of patients with idiopathic PD will enjoy a significant therapeutic response to an adequate trial of moderate doses of levodopa (400 to 600 mg daily). Complete absence of response to a dose of 1000 to 1500 mg/day for at least two months strongly suggests that the original diagnosis of PD was incorrect and that the diagnosis should be revised to one of the other parkinsonian syndromes.
Features suggesting an alternative diagnosis — According to the 2006 AAN systematic review and practice parameter, a number of clinical features in early stages of disease are probably useful for distinguishing other forms of parkinsonism from PD:
• Falls at presentation or early in the course of the disease
• Poor response to levodopa
• Symmetrical motor signs
• Rapid progression to Hoehn and Yahr stage 3 with mild to moderate disease and some postural instability, but physically independent
• Lack of tremor
• Dysautonomia, early in the disease course, as manifested by urinary urgency/incontinence and fecal incontinence, urinary retention requiring catheterization, persistent erectile failure, or symptomatic orthostatic hypotension
Additional historical or clinical features that may suggest a diagnosis other than PD include:
• History of encephalitis
• History of repeated head injury
• History of recurrent strokes and stepwise progression of parkinsonism
• Antipsychotic drug treatment at the onset of symptoms
• Presence of neoplasm or hydrocephalus on neuroimaging
• Cerebellar signs
• Supranuclear gaze palsy
• Dementia preceding or occurring concurrently with parkinsonism
• Babinski sign
• Presence of apraxia
• Strictly unilateral features after three years
Diagnostic accuracy — While the clinical diagnosis of idiopathic PD may seem relatively simple, the accuracy of such a diagnosis can be as low as 75 percent when neuropathological examination is used as the diagnostic gold standard. On the other hand, diagnostic accuracy is increased to as high as 90 percent if patients are followed long-term by movement disorders specialists.
An early diagnostic error rate of approximately 10 percent has been documented in some long-term studies of the natural history of PD . The most likely explanation is that other parkinsonian syndromes, such as progressive supranuclear palsy and multiple system atrophy, can mimic idiopathic PD early in the course of illness, before the later appearance of the signature symptoms, such as disordered eye movements seen with progressive supranuclear palsy or severe autonomic insufficiency that occurs with multiple system atrophy.
Ancillary tests — Neurodiagnostic testing is almost always unhelpful in the evaluation of suspected PD. The AAN systematic review and practice parameter published in 2006 found insufficient evidence to support or refute the value of certain ancillary tests for distinguishing PD from other parkinsonian syndromes, including magnetic resonance imaging (MRI), ultrasound of the brain parenchyma, 18F fluorodeoxyglucose (FDG) positron-emission tomography (PET), urodynamics, autonomic testing, and urethral or anal electromyography.
Conventional MRI — While neuroimaging is usually nondiagnostic in the evaluation of suspected PD, magnetic resonance imaging (MRI) of the brain should be performed to exclude specific structural abnormalities (eg, hydrocephalus, tumor, or lacunar infarcts). Brain MRI may also be helpful in patients with clinical findings that suggest atypical parkinsonism.
As examples, MRI may reveal thinning of the anteroposterior diameter of the midbrain with enlargement of the posterior third ventricle in moderate to advanced-stage progressive supranuclear palsy, and MRI may show atrophy of the brainstem and cerebellum in multiple system atrophy, as well as putaminal hypointensity with a slit-like hyperintensity of the outer margin of the putamen on T2-weighted imaging. However, the sensitivity of conventional MRI is suboptimal for distinguishing other parkinsonian syndromes from PD.
Newer MRI techniques — More advanced MRI techniques, including MR volumetry, MR spectroscopy, magnetization transfer imaging, diffusion-weighted MRI, and diffusion tensor MRI, are promising methods that may offer higher sensitivity than conventional MRI for separating atypical parkinsonian syndromes from idiopathic PD. Further study is needed to establish the diagnostic utility of these methods.
DaTscan — Striatal dopamine transporter imaging using 123I-FP-CIT single photon emission tomography (DaTscan) can reliably distinguish patients with PD and other parkinsonian syndromes (ie, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration) from controls or patients with essential tremor, but it cannot differentiate PD and the other parkinsonian syndromes from one another. The available evidence suggests that the overall accuracy of DaTscan for parkinsonian syndromes is equal to but not better than the accuracy of a carefully obtained clinical diagnosis. If one assumes that the detection of a striatal dopamine deficiency by DaTscan is the diagnostic gold standard for parkinsonian syndromes (a valid assumption since striatal dopamine deficiency always precedes the earliest symptoms of PD by several years), then the sensitivity of the clinical diagnosis is high in both early and advanced PD. However, the specificity varies with the duration of the illness; the clinical diagnosis in advanced PD has a high specificity, while the clinical diagnosis in early PD has a specificity of only 67 percent.
Based upon the data. and our clinical experience, we suggest the use of DaTscan for the following scenarios:
• Patients for whom the diagnosis is unclear after serial clinical evaluations, such as those with long standing essential tremor who later appear to have PD because of a change in the character of the tremor but fail to respond unequivocally to levodopa
• Patients who are possible candidates for deep brain stimulation but for whom the diagnosis of essential tremor versus PD versus some other cause (eg, dystonia) is unclear and where an accurate diagnosis determines the target of deep brain stimulation (eg, thalamic ventral intermediate nucleus versus subthalamic nucleus/globus pallidus interna)
• To firmly establish a diagnosis of a parkinsonian syndrome in equivocal cases when recruiting for a clinical trial, particularly if the focus is neuroprotection
However, there is concern that with widespread use of DaTscan, technical problems in some centers might lead to an increased false positive rate.
PET — Positron emission tomography (PET) shows decreased [18F]-fluorodopa tracer uptake in the caudate and putamen in patients with early PD compared with controls. With [18F]-fluorodeoxyglucose (FDG) PET, which reveals regional cerebral glucose metabolism, patients with PD have a relative increase in metabolism of the pallidum, posterior putamen, and pons along with a relative decrease in metabolism of certain frontal and parieto-occipital regions.
The results of several studies suggest that the diagnostic accuracy of FDG PET is greater than that of striatal dopamine transporter imaging for discriminating PD from atypical parkinsonian syndromes, and that FDG PET has a good specificity for distinguishing the different atypical parkinsonian syndromes. However, the availability of PET is generally limited to research centers.
Sonography — Brain parenchyma sonography (also called transcranial ultrasound) is being studied for its potential role in the diagnosis of PD. Prospective studies in patients with early parkinsonism suggest that hyperechogenicity of the substantia nigra is predictive of the clinical diagnosis of PD. Hyperechogenicity of the substantia nigra has been reported in approximately 90 percent of patients with clinical PD compared with approximately 10 percent of patients with multiple system atrophy, progressive supranuclear palsy, or SWEDD (see 'SWEDD' above). These data suggest that sonography could be a useful tool to distinguish between PD and other parkinsonian syndromes. In addition, in studies of subjects older than age 50 years without evidence of PD or other neurodegenerative disease, hyperechogenicity of the substantia nigra appears to be a risk marker for the development of PD. However, further research is necessary to establish the utility and diagnostic accuracy of this technique.
Olfactory testing — Olfactory testing is another promising method for the early diagnosis of PD, as olfactory dysfunction is common in PD.
In contrast, olfactory dysfunction is not associated with corticobasal degeneration, progressive supranuclear palsy, or essential tremor, and is mild or nonexistent in multiple system atrophy. Furthermore, it is not associated with vascular parkinsonism.
The 2006 AAN systematic review and practice parameter concluded that olfactory testing should be considered and is probably useful for distinguishing corticobasal degeneration and progressive supranuclear palsy (normal olfaction) from PD (impaired olfaction), but not PD from multiple system atrophy. Olfactory testing is seldom used in clinical practice as a diagnostic test for PD, but test materials such as the University of Pennsylvania Smell Identification Test and Sniffin Sticks are commercially available.
Autonomic testing — Testing of autonomic function, including urodynamic testing, urethral or anal sphincter EMG, sympathetic skin responses, Quantitative Sudomotor Axon Reflex Test, tilt table testing, and heart rate variability during forced respirations, has been examined as a potential tool for differentiating PD from other parkinsonian syndromes, especially multiple system atrophy. These tests, however, are generally not widely available, and there is insufficient evidence to recommend their routine use as diagnostic tests for PD.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
• Basics topics
• Beyond the Basics topics
SUMMARY AND RECOMMENDATIONS — An accurate diagnosis of Parkinson disease (PD) rests on the clinician's ability to recognize its characteristic signs and associated symptoms (rest tremor, rigidity, akinesia, and gait disturbance), especially in the early stages.
• The differential diagnosis of PD is extensive. Essential tremor may be confused with PD. Furthermore, parkinsonism can be a prominent feature of several neurodegenerative disorders in addition to idiopathic PD. The most common of these is dementia with Lewy bodies. Less common are the atypical parkinsonian syndromes, such as corticobasal degeneration, multiple system atrophy, and progressive supranuclear palsy.
• A wide variety of conditions can cause secondary parkinsonism. Of these, drug-induced parkinsonism is the most common, and antipsychotic and antiemetics drugs are the most frequent offenders.
• The diagnosis of PD during life is based on clinical impression; neurodiagnostic testing is almost always unhelpful. While a clinical diagnosis of idiopathic PD may seem relatively simple, the accuracy of such a diagnosis can be as low as 75 percent when neuropathological examination is used as the diagnostic gold standard. On the other hand, diagnostic accuracy is increased to as high as 90 percent if patients are followed long-term by movement disorders specialists.
• Bradykinesia, plus one of the remaining two cardinal manifestations (tremor, rigidity), should be present in order to make the diagnosis of idiopathic PD. In addition, an excellent response to dopaminergic therapy is an important criterion for the diagnosis. Other clinical features that are supportive of the diagnosis are unilateral onset, presence of a rest tremor, and a persistent asymmetry throughout the course of the disease with the side of onset most affected.
• Features that are most useful for identifying patients with parkinsonism other than PD are the following.
• Falls at presentation and early in disease
• Poor response to levodopa
• Symmetry at onset
• Rapid progression
• Lack of tremor
• Dysautonomia
• While there are no diagnostic tests for PD, we suggest brain MRI scan to exclude structural lesions. Striatal dopamine transporter imaging (DaTscan) may also be useful for occasional patients for whom the clinical diagnosis is unclear.
PHARMACOLOGIC TREATMENT OF PARKINSON DISEASE
INTRODUCTION — The array of pharmacologic and surgical treatments available for the treatment of idiopathic (or Lewy body) Parkinson disease (PD) is broader than for any other degenerative disease of the central nervous system. Management of individual patients requires careful consideration of a number of factors including the patient's symptoms and signs, age, stage of disease, degree of functional disability, and level of physical activity and productivity. Treatment can be divided into pharmacologic, nonpharmacologic, and surgical therapy. A useful algorithm for the management of PD has been published by the American Academy of Neurology (AAN).
The pharmacologic treatment of PD can be further divided into neuroprotective and symptomatic therapy. In practice, nearly all of the available treatments are symptomatic in nature and do not appear to slow or reverse the natural course of the disease. However, several potential neuroprotective agents for PD have shown some promise in animals and/or humans and are undergoing further investigation. Neuroprotective therapy for PD is discussed in greater detail separately. The routine medical management of PD is reviewed here. The nonpharmacologic management of PD, including education, support, exercise, and nutrition, is discussed separately.
Treatment of advanced PD, particularly the complications associated with long-term levodopa therapy, and management of the comorbid problems including daytime sleepiness, hallucinations, and psychosis are discussed separately.
Correct diagnosis is fundamental to the appropriate therapy of PD, although the same menu of antiparkinson drugs is used to treat all of the various parkinsonian syndromes. The diagnosis of PD is reviewed in detail separately.
SYMPTOMATIC THERAPY — The decision to initiate symptomatic medical therapy in patients with PD is determined by the degree to which the patient is functionally impaired. The timing of this decision varies greatly among patients but is influenced by a number of factors, including:
• The effect of disease on the dominant hand
• The degree to which the disease interferes with work, activities of daily living, or social and leisure function
• The presence of significant bradykinesia or gait disturbance
• Personal philosophy regarding the use of drugs
The major drugs available for symptomatic therapy include:
• Levodopa
• MAO B inhibitors
• Dopamine agonists
• COMT inhibitors
• Anticholinergic agents
• Amantadine
Either levodopa or a dopamine agonist (DA) can be used initially for patients who require symptomatic therapy. Practitioners should always try to find the lowest but still effective dose of dopaminergic medication, either singly or in combination, for patients with PD, each of whom must be evaluated and managed in a highly individual way.
LEVODOPA — Levodopa (L-dopa) is well established as the most effective drug for the symptomatic treatment of idiopathic or Lewy body PD. It is particularly effective for the management of akinetic symptoms and should be introduced when these become disabling and are uncontrolled by other antiparkinsonian drugs. Tremor and rigidity can also respond to levodopa therapy, but postural instability is less likely to do so.
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Dosing — Treatment should begin with small doses, such as carbidopa-levodopa (Sinemet) 25/100 mg, one-half tablet two to three times daily with meals. Tolerance for the appropriate starting dose must be assessed individually. Once initiated without side effects, the total daily dose of carbidopa-levodopa can be titrated carefully upward over several weeks to a full tablet of 25/100 mg three times daily as tolerated. Elderly patients or those with dementia should begin with smaller doses and slower titration because of their increased susceptibility to psychiatric side effects.
The usual practice is to titrate to the lowest levodopa dose that produces a useful clinical response. This varies from patient to patient, but at the start it is typically in the vicinity of 300 to 600 mg of levodopa daily. The vast majority of patients with idiopathic PD will enjoy a significant therapeutic response to moderate doses of levodopa (300 to 600 mg daily). Complete absence of response to a levodopa dose of 1000 to 1500 mg/day suggests that the original diagnosis of PD may be incorrect and that one of the other parkinsonian syndromes, such as multiple system atrophy, progressive supranuclear palsy, or vascular parkinsonism should be considered. Controlled or sustained release levodopa preparations are less completely absorbed and require a dose up to 30 percent higher to achieve an equivalent clinical effect. The peak clinical effect of each tablet is typically less than for immediate release preparations, since controlled release formulations reach the brain more slowly over time. This presents a disadvantage in assessing the response of patients just initiating therapy. As a result, it is recommended that therapy be started with an immediate release preparation with a subsequent switch to controlled release if desired. Both the immediate and the controlled release formulations appear to maintain a similar level of symptom control after several years of use.
Patients taking levodopa for the first time should take each dose with a meal or snack to avoid nausea, a common early side effect. Patients with more advanced disease, especially those with motor fluctuations, often notice that a dose of levodopa is more effective if taken on an empty stomach 30 minutes before or one hour after meals due to reduced competition with other amino acids for gastrointestinal absorption.
Small starting doses of levodopa of less than 25/100 mg three times daily combined with a decarboxylase inhibitor (eg, Sinemet, Madopar, or Prolopa) are more likely to cause nausea because of inadequate amounts of carbidopa; this can be managed by administering supplemental doses of carbidopa or by use of antiemetics such as trimethobenzamide or domperidone (not available in the United States) taken prior to Sinemet. Phenothiazine antiemetics such as prochlorperazine and metoclopramide should be avoided because they are dopamine receptor blockers that can aggravate parkinsonian symptoms.
MAO B INHIBITORS — Selegiline (Eldepryl), a selective monoamine oxidase (MAO) type B inhibitor, is modestly effective as symptomatic treatment for PD and may have neuroprotective properties.
In many individuals, however, selegiline monotherapy does not produce a functionally significant benefit. However, the use of selegiline in early PD is a reasonable option as long as the patient understands its limitations.
The selective MAO B inhibitor rasagiline has neuroprotective properties in animal models and appears modestly effective as symptomatic treatment for PD in human clinical trials. Effectiveness — Evidence supporting the symptomatic effect of MAO B inhibitors for PD comes from a 2004 meta-analysis that examined data from 17 randomized trials involving 3525 patients. These individual trials compared MAO B inhibitors (predominately selegiline) with either levodopa or placebo (predominately placebo) in the treatment of early PD. Many of these trials were limited by short-term follow-up, poor reporting of results, and absence of quality of life data. With these limitations in mind, the following observations were made :
• Data for clinical rating scales were available from six trials of selegiline; treatment with MAO B inhibitors was associated with significantly better total scores, motor scores, and activities of daily living scores on the UPDRS at three months compared with controls.
• Data on the need for levodopa were available from eight studies with a median follow-up of 13 months; treatment with MAO B inhibitors was associated with a reduction in the need for additional levodopa compared with controls.
• Data on motor complications were available from five trials; treatment with MAO B inhibitors was associated with a modest reduction in the development of motor fluctuations compared with controls. However, MAO B treatment was not associated with a significant difference in the incidence of dyskinesia.
• Data on mortality were available from 10 trials, nine of which involved selegiline. MAO B inhibitor treatment was not associated with increased mortality compared with controls, in contrast to one observational study from the United Kingdom that showed increased mortality in patients using selegiline. The results of the UK study have not been confirmed by subsequent reports, including an earlier meta-analysis.
A subsequent (2012) systematic review identified 12 randomized controlled trials comparing MAO B inhibitors (11 trials used selegiline) with placebo for the treatment of early PD in 2514 patients. The findings supported a small symptomatic benefit of treatment on parkinsonian impairment and disability scores at one year.
Additional evidence supporting the long-term symptomatic benefit of selegiline for PD comes from the continuation phase of a randomized controlled trial involving 157 patients with PD, in which patients who were initially assigned to selegiline in the earlier phase of the study were treated with combined selegiline and levodopa, while those initially assigned to placebo were treated with combined placebo and levodopa. At seven years, treatment with the combination of selegiline and levodopa was associated with significantly better symptom control than treatment with placebo and levodopa.
Uncertainty remains about the relative risks and benefits of MAO B inhibitors, as few trials compared them with other antiparkinson medications. Comparative data are particularly lacking for the dopamine agonists.
Dosing — The dose of selegiline used in DATATOP was 5 mg twice daily, with the second dose given at noon to avoid insomnia. However, lower doses are sufficient to induce MAO B inhibition, and 5 mg once daily in the morning is currently recommended. Doses higher than 10 mg daily are of no additional benefit and may result in nonselective MAO inhibition, thereby placing the patient at risk of hypertensive crisis due to dietary interactions with tyramine containing foods.
DOPAMINE AGONISTS — The dopamine agonists (DAs) are a group of synthetic agents that directly stimulate dopamine receptors. The drugs currently approved by the United States Food and Drug Administration (FDA) include bromocriptine, pramipexole, ropinirole, rotigotine, and injectable apomorphine. Pergolide has been voluntarily withdrawn from the United States market and is best avoided because it is associated with a risk of cardiac valve problems.
Apomorphine and lisuride are additional DAs that can be administered parenterally for "rescue therapy" in patients experiencing sudden akinetic episodes. Lisuride is not currently approved in the United States, but is available in Europe. Injectable apomorphine has been approved by the United States FDA for treatment of motor fluctuations in PD. Apomorphine infusion pumps may also be useful, but are not available in the United States.
Unlike carbidopa-levodopa (Sinemet), these drugs are direct agonists that do not require metabolic conversion, do not compete with amino acids for transport across the gut or into the brain, and do not depend upon neuronal uptake and release. An additional advantage over immediate-release forms of levodopa is the longer duration of action of most of these agents.
Monotherapy — Dopamine agonists (DAs) were initially introduced as adjunctive treatment for advanced PD complicated by reduced levodopa response, motor fluctuations, dyskinesia, and other adverse effects of levodopa. However, the hypothetical concern that free radicals generated by the oxidative metabolism of dopamine contribute further to the degeneration of dopaminergic neurons has prompted some investigators, despite lack of conclusive evidence, to advocate the early use of DAs as an levodopa-sparing strategy.
With this approach, treatment with levodopa can be postponed and saved for a later time in the course of the disease, when disability worsens and the less effective agonists no longer provide adequate benefit. This strategy is based upon the unproven concept that the long-term duration of a given patient's responsiveness to levodopa is finite and that the drug, like money in a savings or retirement account, should be rationed. However, whether reduced responsiveness to levodopa over time is due to a decline in drug response or progression of underlying PD is currently uncertain.
Given the potential that DAs are associated with fewer motor fluctuations and the evidence that there is a higher incidence of levodopa-related dyskinesia in young-onset PD, some experts suggest using DAs as initial treatment for PD in patients younger than age 60, and using the more effective agent levodopa in patients 60 and older, although other factors should be weighed in making this treatment decision.
Effectiveness of DAs — Controlled trials have shown that bromocriptine, pergolide, pramipexole, and ropinirole are all effective in patients with advanced PD complicated by motor fluctuations and dyskinesia.
Other studies have found that pramipexole, ropinirole, transdermal rotigotine, and pergolide are effective as monotherapy in patients with early disease. However, DAs are ineffective in patients who have shown no therapeutic response to levodopa.
The utility of DAs in early PD is supported by the results of a systematic review and meta-analysis published in 2008 that identified 29 eligible trials involving 5247 subjects. Included trials compared DA therapy (with or without levodopa) versus placebo and/or levodopa. The following observations were reported:
• In 16 trials that compared a DA (plus or minus supplementation with levodopa) versus levodopa, patients assigned to DA treatment were less likely to develop dyskinesia (odds ratio [OR] 0.51, 95% CI 0.43-0.59), dystonia (OR 0.64, 95% CI 0.51-0.81) or motor fluctuations (OR 0.75, 95% CI 0.63-0.90) than those assigned to levodopa.
• In contrast, symptomatic control of PD appeared to be better with levodopa than with DAs. Inconsistent and incomplete data reporting prevented meta-analysis of motor symptom control. However, patients assigned to levodopa had significantly greater improvement in clinician-rated disability in four of the 11 trials that compared DAs with levodopa, while a nonsignificant improvement favoring levodopa was reported in five of the remaining seven trials.
The reduction in motor complications with DAs compared with levodopa is further illustrated by findings from individual trials.
• One randomized trial found that the cumulative incidence of dyskinesia over five years was 20 percent in patients assigned to ropinirole (plus or minus supplementation with levodopa) and 45 percent in patients assigned to levodopa.
• Another randomized trial found a similar 22 percent absolute reduction in the development of dyskinesia and a 16 percent reduction in wearing "off" in patients assigned to pramipexole compared with those assigned to levodopa. On the other hand, patients assigned to levodopa had lower incidences of freezing, somnolence, and leg edema (the latter two attributable to side effects of pramipexole), and had better symptomatic control than those assigned to pramipexole. Both treatments resulted in similar quality of life.
Thus, there is evidence from several clinical trials and a meta-analysis that early DA monotherapy postpones the future onset of motor complications. This may simply be because DAs are less potent than levodopa in their effects on motor function. In support of this, the benefit occurs at the expense of reduced efficacy when compared with levodopa. In practice, while symptoms can be controlled initially with DAs, few patients with progressive disease can be satisfactorily maintained on DA monotherapy for more than a few years before levodopa is needed.
The few studies that have compared the efficacy of various DAs with each other have found either no significant difference or only mild superiority of one agent over another.
Dosing — The DAs generally require administration at least three times a day at maintenance doses:
• Bromocriptine is usually started at 1.25 mg twice a day; the dose is increased at two to four week intervals by 2.5 mg a day. Most patients can be managed on 20 to 40 mg daily in three to four divided doses, although total daily doses as high as 90 mg can be used.
• Pramipexole is usually started at 0.125 mg three times a day. The dose should be increased gradually by 0.125 mg per dose every five to seven days. Most patients can be managed on total daily doses of 1.5 to 4.5 mg.
• Ropinirole is usually started at 0.25 mg three times a day. The dose should be increased gradually by 0.25 mg per dose each week for four weeks to a total daily dose of 3 mg. Most patients can be managed on this dose. After week four, the ropinirole dose may be increased weekly by 1.5 mg a day up to a maximum total daily dose of 24 mg. Benefit most commonly occurs in the dosage range of 12 to 16 mg per day.
• Pramipexole and ropinirole are now both available in sustained release formulations; these are useful for convenience and for avoiding peaks and troughs in plasma levels.
• Transdermal rotigotine is a once-daily patch that is usually started at 2 mg/24 hours and titrated weekly by increasing the patch size in 2 mg/24 hour increments to a dose of 6 mg/24 hours. Rotigotine should not be stopped abruptly, because sudden withdrawal of DAs has been associated (rarely) with a syndrome resembling neuroleptic malignant syndrome or akinetic crisis.
• Apomorphine may be administered either as intermittent rescue injections or as continuous infusions to treat "off" episodes or levodopa-induced motor fluctuations. A challenge test dose must precede routine use. This is usually done with a 2 mg subcutaneous injection under medical supervision and monitoring of standing and supine blood pressure before the injection, and repeated at 20, 40, and 60 minutes after.
Antiemetic therapy (eg, with trimethobenzamide) is initiated three days prior to starting apomorphine and is usually continued for two months before reassessing need. However, the use of apomorphine is contraindicated with ondansetron and other serotonin receptor agonists commonly used to treat nausea and vomiting, as the combination may cause severe hypotension and loss of consciousness. In addition, dopamine antagonists used to treat nausea and vomiting such as prochlorperazine and metoclopramide should be avoided, as they may reduce the effectiveness of apomorphine.
The usual starting dose for intermittent apomorphine use, if the patient tolerates and responds to the test dose, is 2 mg. The dose may be increased by 1 mg per dose every two to four days to a maximum of 6 mg per dose. The average dosing frequency is three times daily and should not exceed five times a day dosing or a total daily dose of 20 mg.
COMT INHIBITORS — The catechol-O-methyl transferase (COMT) inhibitors tolcapone (Tasmar) and entacapone (Comtan) are useful as levodopa extenders. They are ineffective when given alone, but they may prolong and potentiate the levodopa effect when given with a dose of levodopa. These medications are mainly used to treat patients with motor fluctuations who are experiencing end-of-dose wearing "off" periods. When given to patients without motor fluctuations, entacapone did not improve UPDRS motor scores, but was associated with several improved quality of life measures.
Inhibition of catechol-O-methyl transferase reduces the peripheral (entacapone) and central (tolcapone) methylation of levodopa and dopamine, which in turn increases the plasma half-life of levodopa, produces more stable plasma levodopa concentrations, and prolongs the therapeutic effect of each dose. Use of COMT inhibitors may allow a reduction in the total daily levodopa dose by as much as 30 percent. The net result is an increased levodopa effect.
Dosing — The starting dose of tolcapone is 100 mg three times daily; the clinical effect is evident immediately. The dose of entacapone is one 200 mg tablet with each dose of levodopa, up to a maximum of eight doses per day.
ANTICHOLINERGICS — Dopamine and acetylcholine are normally in a state of electrochemical balance in the basal ganglia. In PD, dopamine depletion produces a state of cholinergic sensitivity so that cholinergic drugs exacerbate and anticholinergic drugs improve parkinsonian symptoms.
Centrally acting anticholinergic drugs such as trihexyphenidyl and benztropine have been used for many years in PD and continue to have a useful role. Other anticholinergic agents such as biperiden, orphenadrine, and procyclidine produce similar effects and are more commonly used in Europe than the United States. Benztropine also may increase the effect of dopamine by inhibiting its presynaptic reuptake, but it is not known whether this contributes to its mechanism of action.
Anticholinergic drugs are most useful as monotherapy in patients under age 70 with disturbing tremor who do not have significant akinesia or gait disturbance. They also may be useful in patients with more advanced disease who have persistent tremor despite treatment with levodopa or DAs.
Dosing — Trihexyphenidyl is the most widely prescribed anticholinergic agent, although there is little evidence to suggest that one drug in this class is superior to another. The starting dose of trihexyphenidyl is 0.5 to 1 mg twice daily, with a gradual increase to 2 mg three times daily. Benztropine traditionally is more commonly used by psychiatrists for the management of antipsychotic drug-induced parkinsonism; the usual dose is 0.5 to 2 mg twice daily.
AMANTADINE — Amantadine is an antiviral agent that has mild antiparkinsonian activity. Its mechanism of action is uncertain; it is known to increase dopamine release, inhibit dopamine reuptake, stimulate dopamine receptors, and it may possibly exert central anticholinergic effects. Amantadine has N-methyl-D-aspartate (NMDA) receptor antagonist properties that may account for its therapeutic effect by interfering with excessive glutamate neurotransmission in the basal ganglia.
In early uncontrolled clinical trials, two-thirds of patients receiving amantadine monotherapy showed an improvement in akinesia, rigidity, and tremor. Subsequent controlled studies demonstrated that it was more effective than anticholinergic drugs for akinesia and rigidity. The benefit induced by amantadine appears to be transient in some patients; it is best used as short-term monotherapy in those with mild disease. Amantadine is of little benefit when added to levodopa, although the addition of levodopa to amantadine causes significant additive improvement.
Amantadine in divided doses of 200 to 400 mg a day may reduce the intensity of levodopa-induced dyskinesia and motor fluctuations in patients with PD. Although the published randomized trials on amantadine in advanced PD are limited by serious methodological flaws and small numbers of patients, experience has shown that individual patients with advanced PD who have motor fluctuations and dyskinesia can benefit dramatically, at least for a while, from the addition of amantadine to a regimen of levodopa.
Dosing — The dose of amantadine in early PD is 200 to 300 mg daily; there is no evidence that larger doses are of additional benefit. The main advantage of this agent is a low incidence of side effects. It is excreted unchanged in the urine and should be used with caution in the presence of renal failure.
ESTROGEN — Low-dose estrogen may be helpful as adjunctive therapy in postmenopausal women with motor fluctuations on antiparkinsonian medication. In one study, administration of Premarin 0.625 mg daily for eight weeks significantly improved "on" time and motor control in such women, although it did not result in global improvement on a scale rating activities of daily living. There is no evidence that estrogen has a specific effect on dopamine receptors; the benefit attributable to estrogen use may be related to an overall sense of well being.
It is not clear if these results would be similar in women taking combined estrogen/progestin therapy (necessary in women with an intact uterus). Furthermore, concerns about adverse effects associated with long-term estrogen/progestin therapy may limit its use in PD.
REFERÊCIAS:
* http://www.uptodate.com/contents/pharmacologic-treatment-of-parkinson-disease?detectedLanguage=gl&source=search_result&translation=parkinson+treatment&search=parkinson+tratament&selectedTitle=1~150&provider=babylon
http://www.uptodate.com/contents/diagnosis-of-parkinson-disease?detectedLanguage=en&source=search_result&translation=parkinson&search=parkinson&selectedTitle=3~150&provider=noProvider
Obs: ESSE ARTIGO DE REVISAO ESTA MUITO BOM PARA O DIAGNÓSTICO CLÍNICO :
*http://www.revistaneurociencias.com.br/edicoes/2005/RN%2013%2003/Pages%20from%20RN%2013%2003-8.pdf
It is generally accepted that bradykinesia, plus one of the other two cardinal manifestations (tremor, rigidity) must be present in order to make the diagnosis of idiopathic PD. In addition, an excellent response to dopaminergic therapy is an important criterion for the diagnosis. Other clinical features that are supportive of the diagnosis are unilateral onset, presence of a rest tremor, and a persistent asymmetry throughout the course of the disease with the side of onset most affected.
Response to dopaminergic therapy — As noted above, an excellent response to dopaminergic therapy is an important supportive feature for establishing the diagnosis of PD. The response to dopaminergic therapy in most parkinsonian syndromes is reduced or absent compared with the response in PD. However, up to 20 percent of patients with parkinsonism due to multiple system atrophy may respond initially to levodopa , as may a substantial proportion of those with vascular parkinsonism.
An acute dopaminergic challenge test consists of rater-blinded assessment of parkinsonian symptoms using the Unified Parkinson Disease Rating Scale (UPDRS) before and after a dose of levodopa (eg, carbidopa-levodopa 25/250 mg) or subcutaneous apomorphine (1.5 to 4.5 mg). Although there is no standard definition, a challenge is considered positive if there is a clinically significant improvement in the UPDRS score (usually in the range of 15 to 30 percent or more) one hour after levodopa administration or 20 minutes after apomorphine injection.
A systematic review and practice parameter from the American Academy of Neurology (AAN) published in 2006 concluded that levodopa and apomorphine challenge tests should be considered when the diagnosis of PD is uncertain, as both tests are "probably useful" in distinguishing PD from other parkinsonian syndromes. An earlier systematic review found that both apomorphine and levodopa challenge tests had similar sensitivity and specificity for the diagnosis of idiopathic PD.
However, the exact role of acute levodopa or apomorphine challenge for the diagnosis of PD in clinical practice remains unclear. The problem with challenge testing is illustrated by the following observations:
• Up to 30 percent of patients with PD may not respond to acute dopaminergic challenges
• Approximately 20 to 30 percent of patients with a positive acute dopaminergic challenge will go on to develop another parkinsonian syndrome
In practice, when patients have mild symptoms that do not interfere with daily activities, it may not be advisable to institute dopaminergic therapy purely for diagnostic purposes. When PD symptoms begin to limit a patient's quality of life, a long-term trial of dopaminergic or levodopa therapy may be just as adequate as an acute dopaminergic challenge.
The vast majority of patients with idiopathic PD will enjoy a significant therapeutic response to an adequate trial of moderate doses of levodopa (400 to 600 mg daily). Complete absence of response to a dose of 1000 to 1500 mg/day for at least two months strongly suggests that the original diagnosis of PD was incorrect and that the diagnosis should be revised to one of the other parkinsonian syndromes.
Features suggesting an alternative diagnosis — According to the 2006 AAN systematic review and practice parameter, a number of clinical features in early stages of disease are probably useful for distinguishing other forms of parkinsonism from PD:
• Falls at presentation or early in the course of the disease
• Poor response to levodopa
• Symmetrical motor signs
• Rapid progression to Hoehn and Yahr stage 3 with mild to moderate disease and some postural instability, but physically independent
• Lack of tremor
• Dysautonomia, early in the disease course, as manifested by urinary urgency/incontinence and fecal incontinence, urinary retention requiring catheterization, persistent erectile failure, or symptomatic orthostatic hypotension
Additional historical or clinical features that may suggest a diagnosis other than PD include:
• History of encephalitis
• History of repeated head injury
• History of recurrent strokes and stepwise progression of parkinsonism
• Antipsychotic drug treatment at the onset of symptoms
• Presence of neoplasm or hydrocephalus on neuroimaging
• Cerebellar signs
• Supranuclear gaze palsy
• Dementia preceding or occurring concurrently with parkinsonism
• Babinski sign
• Presence of apraxia
• Strictly unilateral features after three years
Diagnostic accuracy — While the clinical diagnosis of idiopathic PD may seem relatively simple, the accuracy of such a diagnosis can be as low as 75 percent when neuropathological examination is used as the diagnostic gold standard. On the other hand, diagnostic accuracy is increased to as high as 90 percent if patients are followed long-term by movement disorders specialists.
An early diagnostic error rate of approximately 10 percent has been documented in some long-term studies of the natural history of PD . The most likely explanation is that other parkinsonian syndromes, such as progressive supranuclear palsy and multiple system atrophy, can mimic idiopathic PD early in the course of illness, before the later appearance of the signature symptoms, such as disordered eye movements seen with progressive supranuclear palsy or severe autonomic insufficiency that occurs with multiple system atrophy.
Ancillary tests — Neurodiagnostic testing is almost always unhelpful in the evaluation of suspected PD. The AAN systematic review and practice parameter published in 2006 found insufficient evidence to support or refute the value of certain ancillary tests for distinguishing PD from other parkinsonian syndromes, including magnetic resonance imaging (MRI), ultrasound of the brain parenchyma, 18F fluorodeoxyglucose (FDG) positron-emission tomography (PET), urodynamics, autonomic testing, and urethral or anal electromyography.
Conventional MRI — While neuroimaging is usually nondiagnostic in the evaluation of suspected PD, magnetic resonance imaging (MRI) of the brain should be performed to exclude specific structural abnormalities (eg, hydrocephalus, tumor, or lacunar infarcts). Brain MRI may also be helpful in patients with clinical findings that suggest atypical parkinsonism.
As examples, MRI may reveal thinning of the anteroposterior diameter of the midbrain with enlargement of the posterior third ventricle in moderate to advanced-stage progressive supranuclear palsy, and MRI may show atrophy of the brainstem and cerebellum in multiple system atrophy, as well as putaminal hypointensity with a slit-like hyperintensity of the outer margin of the putamen on T2-weighted imaging. However, the sensitivity of conventional MRI is suboptimal for distinguishing other parkinsonian syndromes from PD.
Newer MRI techniques — More advanced MRI techniques, including MR volumetry, MR spectroscopy, magnetization transfer imaging, diffusion-weighted MRI, and diffusion tensor MRI, are promising methods that may offer higher sensitivity than conventional MRI for separating atypical parkinsonian syndromes from idiopathic PD. Further study is needed to establish the diagnostic utility of these methods.
DaTscan — Striatal dopamine transporter imaging using 123I-FP-CIT single photon emission tomography (DaTscan) can reliably distinguish patients with PD and other parkinsonian syndromes (ie, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration) from controls or patients with essential tremor, but it cannot differentiate PD and the other parkinsonian syndromes from one another. The available evidence suggests that the overall accuracy of DaTscan for parkinsonian syndromes is equal to but not better than the accuracy of a carefully obtained clinical diagnosis. If one assumes that the detection of a striatal dopamine deficiency by DaTscan is the diagnostic gold standard for parkinsonian syndromes (a valid assumption since striatal dopamine deficiency always precedes the earliest symptoms of PD by several years), then the sensitivity of the clinical diagnosis is high in both early and advanced PD. However, the specificity varies with the duration of the illness; the clinical diagnosis in advanced PD has a high specificity, while the clinical diagnosis in early PD has a specificity of only 67 percent.
Based upon the data. and our clinical experience, we suggest the use of DaTscan for the following scenarios:
• Patients for whom the diagnosis is unclear after serial clinical evaluations, such as those with long standing essential tremor who later appear to have PD because of a change in the character of the tremor but fail to respond unequivocally to levodopa
• Patients who are possible candidates for deep brain stimulation but for whom the diagnosis of essential tremor versus PD versus some other cause (eg, dystonia) is unclear and where an accurate diagnosis determines the target of deep brain stimulation (eg, thalamic ventral intermediate nucleus versus subthalamic nucleus/globus pallidus interna)
• To firmly establish a diagnosis of a parkinsonian syndrome in equivocal cases when recruiting for a clinical trial, particularly if the focus is neuroprotection
However, there is concern that with widespread use of DaTscan, technical problems in some centers might lead to an increased false positive rate.
PET — Positron emission tomography (PET) shows decreased [18F]-fluorodopa tracer uptake in the caudate and putamen in patients with early PD compared with controls. With [18F]-fluorodeoxyglucose (FDG) PET, which reveals regional cerebral glucose metabolism, patients with PD have a relative increase in metabolism of the pallidum, posterior putamen, and pons along with a relative decrease in metabolism of certain frontal and parieto-occipital regions.
The results of several studies suggest that the diagnostic accuracy of FDG PET is greater than that of striatal dopamine transporter imaging for discriminating PD from atypical parkinsonian syndromes, and that FDG PET has a good specificity for distinguishing the different atypical parkinsonian syndromes. However, the availability of PET is generally limited to research centers.
Sonography — Brain parenchyma sonography (also called transcranial ultrasound) is being studied for its potential role in the diagnosis of PD. Prospective studies in patients with early parkinsonism suggest that hyperechogenicity of the substantia nigra is predictive of the clinical diagnosis of PD. Hyperechogenicity of the substantia nigra has been reported in approximately 90 percent of patients with clinical PD compared with approximately 10 percent of patients with multiple system atrophy, progressive supranuclear palsy, or SWEDD (see 'SWEDD' above). These data suggest that sonography could be a useful tool to distinguish between PD and other parkinsonian syndromes. In addition, in studies of subjects older than age 50 years without evidence of PD or other neurodegenerative disease, hyperechogenicity of the substantia nigra appears to be a risk marker for the development of PD. However, further research is necessary to establish the utility and diagnostic accuracy of this technique.
Olfactory testing — Olfactory testing is another promising method for the early diagnosis of PD, as olfactory dysfunction is common in PD.
In contrast, olfactory dysfunction is not associated with corticobasal degeneration, progressive supranuclear palsy, or essential tremor, and is mild or nonexistent in multiple system atrophy. Furthermore, it is not associated with vascular parkinsonism.
The 2006 AAN systematic review and practice parameter concluded that olfactory testing should be considered and is probably useful for distinguishing corticobasal degeneration and progressive supranuclear palsy (normal olfaction) from PD (impaired olfaction), but not PD from multiple system atrophy. Olfactory testing is seldom used in clinical practice as a diagnostic test for PD, but test materials such as the University of Pennsylvania Smell Identification Test and Sniffin Sticks are commercially available.
Autonomic testing — Testing of autonomic function, including urodynamic testing, urethral or anal sphincter EMG, sympathetic skin responses, Quantitative Sudomotor Axon Reflex Test, tilt table testing, and heart rate variability during forced respirations, has been examined as a potential tool for differentiating PD from other parkinsonian syndromes, especially multiple system atrophy. These tests, however, are generally not widely available, and there is insufficient evidence to recommend their routine use as diagnostic tests for PD.
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SUMMARY AND RECOMMENDATIONS — An accurate diagnosis of Parkinson disease (PD) rests on the clinician's ability to recognize its characteristic signs and associated symptoms (rest tremor, rigidity, akinesia, and gait disturbance), especially in the early stages.
• The differential diagnosis of PD is extensive. Essential tremor may be confused with PD. Furthermore, parkinsonism can be a prominent feature of several neurodegenerative disorders in addition to idiopathic PD. The most common of these is dementia with Lewy bodies. Less common are the atypical parkinsonian syndromes, such as corticobasal degeneration, multiple system atrophy, and progressive supranuclear palsy.
• A wide variety of conditions can cause secondary parkinsonism. Of these, drug-induced parkinsonism is the most common, and antipsychotic and antiemetics drugs are the most frequent offenders.
• The diagnosis of PD during life is based on clinical impression; neurodiagnostic testing is almost always unhelpful. While a clinical diagnosis of idiopathic PD may seem relatively simple, the accuracy of such a diagnosis can be as low as 75 percent when neuropathological examination is used as the diagnostic gold standard. On the other hand, diagnostic accuracy is increased to as high as 90 percent if patients are followed long-term by movement disorders specialists.
• Bradykinesia, plus one of the remaining two cardinal manifestations (tremor, rigidity), should be present in order to make the diagnosis of idiopathic PD. In addition, an excellent response to dopaminergic therapy is an important criterion for the diagnosis. Other clinical features that are supportive of the diagnosis are unilateral onset, presence of a rest tremor, and a persistent asymmetry throughout the course of the disease with the side of onset most affected.
• Features that are most useful for identifying patients with parkinsonism other than PD are the following.
• Falls at presentation and early in disease
• Poor response to levodopa
• Symmetry at onset
• Rapid progression
• Lack of tremor
• Dysautonomia
• While there are no diagnostic tests for PD, we suggest brain MRI scan to exclude structural lesions. Striatal dopamine transporter imaging (DaTscan) may also be useful for occasional patients for whom the clinical diagnosis is unclear.
PHARMACOLOGIC TREATMENT OF PARKINSON DISEASE
INTRODUCTION — The array of pharmacologic and surgical treatments available for the treatment of idiopathic (or Lewy body) Parkinson disease (PD) is broader than for any other degenerative disease of the central nervous system. Management of individual patients requires careful consideration of a number of factors including the patient's symptoms and signs, age, stage of disease, degree of functional disability, and level of physical activity and productivity. Treatment can be divided into pharmacologic, nonpharmacologic, and surgical therapy. A useful algorithm for the management of PD has been published by the American Academy of Neurology (AAN).
The pharmacologic treatment of PD can be further divided into neuroprotective and symptomatic therapy. In practice, nearly all of the available treatments are symptomatic in nature and do not appear to slow or reverse the natural course of the disease. However, several potential neuroprotective agents for PD have shown some promise in animals and/or humans and are undergoing further investigation. Neuroprotective therapy for PD is discussed in greater detail separately. The routine medical management of PD is reviewed here. The nonpharmacologic management of PD, including education, support, exercise, and nutrition, is discussed separately.
Treatment of advanced PD, particularly the complications associated with long-term levodopa therapy, and management of the comorbid problems including daytime sleepiness, hallucinations, and psychosis are discussed separately.
Correct diagnosis is fundamental to the appropriate therapy of PD, although the same menu of antiparkinson drugs is used to treat all of the various parkinsonian syndromes. The diagnosis of PD is reviewed in detail separately.
SYMPTOMATIC THERAPY — The decision to initiate symptomatic medical therapy in patients with PD is determined by the degree to which the patient is functionally impaired. The timing of this decision varies greatly among patients but is influenced by a number of factors, including:
• The effect of disease on the dominant hand
• The degree to which the disease interferes with work, activities of daily living, or social and leisure function
• The presence of significant bradykinesia or gait disturbance
• Personal philosophy regarding the use of drugs
The major drugs available for symptomatic therapy include:
• Levodopa
• MAO B inhibitors
• Dopamine agonists
• COMT inhibitors
• Anticholinergic agents
• Amantadine
Either levodopa or a dopamine agonist (DA) can be used initially for patients who require symptomatic therapy. Practitioners should always try to find the lowest but still effective dose of dopaminergic medication, either singly or in combination, for patients with PD, each of whom must be evaluated and managed in a highly individual way.
LEVODOPA — Levodopa (L-dopa) is well established as the most effective drug for the symptomatic treatment of idiopathic or Lewy body PD. It is particularly effective for the management of akinetic symptoms and should be introduced when these become disabling and are uncontrolled by other antiparkinsonian drugs. Tremor and rigidity can also respond to levodopa therapy, but postural instability is less likely to do so.
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Dosing — Treatment should begin with small doses, such as carbidopa-levodopa (Sinemet) 25/100 mg, one-half tablet two to three times daily with meals. Tolerance for the appropriate starting dose must be assessed individually. Once initiated without side effects, the total daily dose of carbidopa-levodopa can be titrated carefully upward over several weeks to a full tablet of 25/100 mg three times daily as tolerated. Elderly patients or those with dementia should begin with smaller doses and slower titration because of their increased susceptibility to psychiatric side effects.
The usual practice is to titrate to the lowest levodopa dose that produces a useful clinical response. This varies from patient to patient, but at the start it is typically in the vicinity of 300 to 600 mg of levodopa daily. The vast majority of patients with idiopathic PD will enjoy a significant therapeutic response to moderate doses of levodopa (300 to 600 mg daily). Complete absence of response to a levodopa dose of 1000 to 1500 mg/day suggests that the original diagnosis of PD may be incorrect and that one of the other parkinsonian syndromes, such as multiple system atrophy, progressive supranuclear palsy, or vascular parkinsonism should be considered. Controlled or sustained release levodopa preparations are less completely absorbed and require a dose up to 30 percent higher to achieve an equivalent clinical effect. The peak clinical effect of each tablet is typically less than for immediate release preparations, since controlled release formulations reach the brain more slowly over time. This presents a disadvantage in assessing the response of patients just initiating therapy. As a result, it is recommended that therapy be started with an immediate release preparation with a subsequent switch to controlled release if desired. Both the immediate and the controlled release formulations appear to maintain a similar level of symptom control after several years of use.
Patients taking levodopa for the first time should take each dose with a meal or snack to avoid nausea, a common early side effect. Patients with more advanced disease, especially those with motor fluctuations, often notice that a dose of levodopa is more effective if taken on an empty stomach 30 minutes before or one hour after meals due to reduced competition with other amino acids for gastrointestinal absorption.
Small starting doses of levodopa of less than 25/100 mg three times daily combined with a decarboxylase inhibitor (eg, Sinemet, Madopar, or Prolopa) are more likely to cause nausea because of inadequate amounts of carbidopa; this can be managed by administering supplemental doses of carbidopa or by use of antiemetics such as trimethobenzamide or domperidone (not available in the United States) taken prior to Sinemet. Phenothiazine antiemetics such as prochlorperazine and metoclopramide should be avoided because they are dopamine receptor blockers that can aggravate parkinsonian symptoms.
MAO B INHIBITORS — Selegiline (Eldepryl), a selective monoamine oxidase (MAO) type B inhibitor, is modestly effective as symptomatic treatment for PD and may have neuroprotective properties.
In many individuals, however, selegiline monotherapy does not produce a functionally significant benefit. However, the use of selegiline in early PD is a reasonable option as long as the patient understands its limitations.
The selective MAO B inhibitor rasagiline has neuroprotective properties in animal models and appears modestly effective as symptomatic treatment for PD in human clinical trials. Effectiveness — Evidence supporting the symptomatic effect of MAO B inhibitors for PD comes from a 2004 meta-analysis that examined data from 17 randomized trials involving 3525 patients. These individual trials compared MAO B inhibitors (predominately selegiline) with either levodopa or placebo (predominately placebo) in the treatment of early PD. Many of these trials were limited by short-term follow-up, poor reporting of results, and absence of quality of life data. With these limitations in mind, the following observations were made :
• Data for clinical rating scales were available from six trials of selegiline; treatment with MAO B inhibitors was associated with significantly better total scores, motor scores, and activities of daily living scores on the UPDRS at three months compared with controls.
• Data on the need for levodopa were available from eight studies with a median follow-up of 13 months; treatment with MAO B inhibitors was associated with a reduction in the need for additional levodopa compared with controls.
• Data on motor complications were available from five trials; treatment with MAO B inhibitors was associated with a modest reduction in the development of motor fluctuations compared with controls. However, MAO B treatment was not associated with a significant difference in the incidence of dyskinesia.
• Data on mortality were available from 10 trials, nine of which involved selegiline. MAO B inhibitor treatment was not associated with increased mortality compared with controls, in contrast to one observational study from the United Kingdom that showed increased mortality in patients using selegiline. The results of the UK study have not been confirmed by subsequent reports, including an earlier meta-analysis.
A subsequent (2012) systematic review identified 12 randomized controlled trials comparing MAO B inhibitors (11 trials used selegiline) with placebo for the treatment of early PD in 2514 patients. The findings supported a small symptomatic benefit of treatment on parkinsonian impairment and disability scores at one year.
Additional evidence supporting the long-term symptomatic benefit of selegiline for PD comes from the continuation phase of a randomized controlled trial involving 157 patients with PD, in which patients who were initially assigned to selegiline in the earlier phase of the study were treated with combined selegiline and levodopa, while those initially assigned to placebo were treated with combined placebo and levodopa. At seven years, treatment with the combination of selegiline and levodopa was associated with significantly better symptom control than treatment with placebo and levodopa.
Uncertainty remains about the relative risks and benefits of MAO B inhibitors, as few trials compared them with other antiparkinson medications. Comparative data are particularly lacking for the dopamine agonists.
Dosing — The dose of selegiline used in DATATOP was 5 mg twice daily, with the second dose given at noon to avoid insomnia. However, lower doses are sufficient to induce MAO B inhibition, and 5 mg once daily in the morning is currently recommended. Doses higher than 10 mg daily are of no additional benefit and may result in nonselective MAO inhibition, thereby placing the patient at risk of hypertensive crisis due to dietary interactions with tyramine containing foods.
DOPAMINE AGONISTS — The dopamine agonists (DAs) are a group of synthetic agents that directly stimulate dopamine receptors. The drugs currently approved by the United States Food and Drug Administration (FDA) include bromocriptine, pramipexole, ropinirole, rotigotine, and injectable apomorphine. Pergolide has been voluntarily withdrawn from the United States market and is best avoided because it is associated with a risk of cardiac valve problems.
Apomorphine and lisuride are additional DAs that can be administered parenterally for "rescue therapy" in patients experiencing sudden akinetic episodes. Lisuride is not currently approved in the United States, but is available in Europe. Injectable apomorphine has been approved by the United States FDA for treatment of motor fluctuations in PD. Apomorphine infusion pumps may also be useful, but are not available in the United States.
Unlike carbidopa-levodopa (Sinemet), these drugs are direct agonists that do not require metabolic conversion, do not compete with amino acids for transport across the gut or into the brain, and do not depend upon neuronal uptake and release. An additional advantage over immediate-release forms of levodopa is the longer duration of action of most of these agents.
Monotherapy — Dopamine agonists (DAs) were initially introduced as adjunctive treatment for advanced PD complicated by reduced levodopa response, motor fluctuations, dyskinesia, and other adverse effects of levodopa. However, the hypothetical concern that free radicals generated by the oxidative metabolism of dopamine contribute further to the degeneration of dopaminergic neurons has prompted some investigators, despite lack of conclusive evidence, to advocate the early use of DAs as an levodopa-sparing strategy.
With this approach, treatment with levodopa can be postponed and saved for a later time in the course of the disease, when disability worsens and the less effective agonists no longer provide adequate benefit. This strategy is based upon the unproven concept that the long-term duration of a given patient's responsiveness to levodopa is finite and that the drug, like money in a savings or retirement account, should be rationed. However, whether reduced responsiveness to levodopa over time is due to a decline in drug response or progression of underlying PD is currently uncertain.
Given the potential that DAs are associated with fewer motor fluctuations and the evidence that there is a higher incidence of levodopa-related dyskinesia in young-onset PD, some experts suggest using DAs as initial treatment for PD in patients younger than age 60, and using the more effective agent levodopa in patients 60 and older, although other factors should be weighed in making this treatment decision.
Effectiveness of DAs — Controlled trials have shown that bromocriptine, pergolide, pramipexole, and ropinirole are all effective in patients with advanced PD complicated by motor fluctuations and dyskinesia.
Other studies have found that pramipexole, ropinirole, transdermal rotigotine, and pergolide are effective as monotherapy in patients with early disease. However, DAs are ineffective in patients who have shown no therapeutic response to levodopa.
The utility of DAs in early PD is supported by the results of a systematic review and meta-analysis published in 2008 that identified 29 eligible trials involving 5247 subjects. Included trials compared DA therapy (with or without levodopa) versus placebo and/or levodopa. The following observations were reported:
• In 16 trials that compared a DA (plus or minus supplementation with levodopa) versus levodopa, patients assigned to DA treatment were less likely to develop dyskinesia (odds ratio [OR] 0.51, 95% CI 0.43-0.59), dystonia (OR 0.64, 95% CI 0.51-0.81) or motor fluctuations (OR 0.75, 95% CI 0.63-0.90) than those assigned to levodopa.
• In contrast, symptomatic control of PD appeared to be better with levodopa than with DAs. Inconsistent and incomplete data reporting prevented meta-analysis of motor symptom control. However, patients assigned to levodopa had significantly greater improvement in clinician-rated disability in four of the 11 trials that compared DAs with levodopa, while a nonsignificant improvement favoring levodopa was reported in five of the remaining seven trials.
The reduction in motor complications with DAs compared with levodopa is further illustrated by findings from individual trials.
• One randomized trial found that the cumulative incidence of dyskinesia over five years was 20 percent in patients assigned to ropinirole (plus or minus supplementation with levodopa) and 45 percent in patients assigned to levodopa.
• Another randomized trial found a similar 22 percent absolute reduction in the development of dyskinesia and a 16 percent reduction in wearing "off" in patients assigned to pramipexole compared with those assigned to levodopa. On the other hand, patients assigned to levodopa had lower incidences of freezing, somnolence, and leg edema (the latter two attributable to side effects of pramipexole), and had better symptomatic control than those assigned to pramipexole. Both treatments resulted in similar quality of life.
Thus, there is evidence from several clinical trials and a meta-analysis that early DA monotherapy postpones the future onset of motor complications. This may simply be because DAs are less potent than levodopa in their effects on motor function. In support of this, the benefit occurs at the expense of reduced efficacy when compared with levodopa. In practice, while symptoms can be controlled initially with DAs, few patients with progressive disease can be satisfactorily maintained on DA monotherapy for more than a few years before levodopa is needed.
The few studies that have compared the efficacy of various DAs with each other have found either no significant difference or only mild superiority of one agent over another.
Dosing — The DAs generally require administration at least three times a day at maintenance doses:
• Bromocriptine is usually started at 1.25 mg twice a day; the dose is increased at two to four week intervals by 2.5 mg a day. Most patients can be managed on 20 to 40 mg daily in three to four divided doses, although total daily doses as high as 90 mg can be used.
• Pramipexole is usually started at 0.125 mg three times a day. The dose should be increased gradually by 0.125 mg per dose every five to seven days. Most patients can be managed on total daily doses of 1.5 to 4.5 mg.
• Ropinirole is usually started at 0.25 mg three times a day. The dose should be increased gradually by 0.25 mg per dose each week for four weeks to a total daily dose of 3 mg. Most patients can be managed on this dose. After week four, the ropinirole dose may be increased weekly by 1.5 mg a day up to a maximum total daily dose of 24 mg. Benefit most commonly occurs in the dosage range of 12 to 16 mg per day.
• Pramipexole and ropinirole are now both available in sustained release formulations; these are useful for convenience and for avoiding peaks and troughs in plasma levels.
• Transdermal rotigotine is a once-daily patch that is usually started at 2 mg/24 hours and titrated weekly by increasing the patch size in 2 mg/24 hour increments to a dose of 6 mg/24 hours. Rotigotine should not be stopped abruptly, because sudden withdrawal of DAs has been associated (rarely) with a syndrome resembling neuroleptic malignant syndrome or akinetic crisis.
• Apomorphine may be administered either as intermittent rescue injections or as continuous infusions to treat "off" episodes or levodopa-induced motor fluctuations. A challenge test dose must precede routine use. This is usually done with a 2 mg subcutaneous injection under medical supervision and monitoring of standing and supine blood pressure before the injection, and repeated at 20, 40, and 60 minutes after.
Antiemetic therapy (eg, with trimethobenzamide) is initiated three days prior to starting apomorphine and is usually continued for two months before reassessing need. However, the use of apomorphine is contraindicated with ondansetron and other serotonin receptor agonists commonly used to treat nausea and vomiting, as the combination may cause severe hypotension and loss of consciousness. In addition, dopamine antagonists used to treat nausea and vomiting such as prochlorperazine and metoclopramide should be avoided, as they may reduce the effectiveness of apomorphine.
The usual starting dose for intermittent apomorphine use, if the patient tolerates and responds to the test dose, is 2 mg. The dose may be increased by 1 mg per dose every two to four days to a maximum of 6 mg per dose. The average dosing frequency is three times daily and should not exceed five times a day dosing or a total daily dose of 20 mg.
COMT INHIBITORS — The catechol-O-methyl transferase (COMT) inhibitors tolcapone (Tasmar) and entacapone (Comtan) are useful as levodopa extenders. They are ineffective when given alone, but they may prolong and potentiate the levodopa effect when given with a dose of levodopa. These medications are mainly used to treat patients with motor fluctuations who are experiencing end-of-dose wearing "off" periods. When given to patients without motor fluctuations, entacapone did not improve UPDRS motor scores, but was associated with several improved quality of life measures.
Inhibition of catechol-O-methyl transferase reduces the peripheral (entacapone) and central (tolcapone) methylation of levodopa and dopamine, which in turn increases the plasma half-life of levodopa, produces more stable plasma levodopa concentrations, and prolongs the therapeutic effect of each dose. Use of COMT inhibitors may allow a reduction in the total daily levodopa dose by as much as 30 percent. The net result is an increased levodopa effect.
Dosing — The starting dose of tolcapone is 100 mg three times daily; the clinical effect is evident immediately. The dose of entacapone is one 200 mg tablet with each dose of levodopa, up to a maximum of eight doses per day.
ANTICHOLINERGICS — Dopamine and acetylcholine are normally in a state of electrochemical balance in the basal ganglia. In PD, dopamine depletion produces a state of cholinergic sensitivity so that cholinergic drugs exacerbate and anticholinergic drugs improve parkinsonian symptoms.
Centrally acting anticholinergic drugs such as trihexyphenidyl and benztropine have been used for many years in PD and continue to have a useful role. Other anticholinergic agents such as biperiden, orphenadrine, and procyclidine produce similar effects and are more commonly used in Europe than the United States. Benztropine also may increase the effect of dopamine by inhibiting its presynaptic reuptake, but it is not known whether this contributes to its mechanism of action.
Anticholinergic drugs are most useful as monotherapy in patients under age 70 with disturbing tremor who do not have significant akinesia or gait disturbance. They also may be useful in patients with more advanced disease who have persistent tremor despite treatment with levodopa or DAs.
Dosing — Trihexyphenidyl is the most widely prescribed anticholinergic agent, although there is little evidence to suggest that one drug in this class is superior to another. The starting dose of trihexyphenidyl is 0.5 to 1 mg twice daily, with a gradual increase to 2 mg three times daily. Benztropine traditionally is more commonly used by psychiatrists for the management of antipsychotic drug-induced parkinsonism; the usual dose is 0.5 to 2 mg twice daily.
AMANTADINE — Amantadine is an antiviral agent that has mild antiparkinsonian activity. Its mechanism of action is uncertain; it is known to increase dopamine release, inhibit dopamine reuptake, stimulate dopamine receptors, and it may possibly exert central anticholinergic effects. Amantadine has N-methyl-D-aspartate (NMDA) receptor antagonist properties that may account for its therapeutic effect by interfering with excessive glutamate neurotransmission in the basal ganglia.
In early uncontrolled clinical trials, two-thirds of patients receiving amantadine monotherapy showed an improvement in akinesia, rigidity, and tremor. Subsequent controlled studies demonstrated that it was more effective than anticholinergic drugs for akinesia and rigidity. The benefit induced by amantadine appears to be transient in some patients; it is best used as short-term monotherapy in those with mild disease. Amantadine is of little benefit when added to levodopa, although the addition of levodopa to amantadine causes significant additive improvement.
Amantadine in divided doses of 200 to 400 mg a day may reduce the intensity of levodopa-induced dyskinesia and motor fluctuations in patients with PD. Although the published randomized trials on amantadine in advanced PD are limited by serious methodological flaws and small numbers of patients, experience has shown that individual patients with advanced PD who have motor fluctuations and dyskinesia can benefit dramatically, at least for a while, from the addition of amantadine to a regimen of levodopa.
Dosing — The dose of amantadine in early PD is 200 to 300 mg daily; there is no evidence that larger doses are of additional benefit. The main advantage of this agent is a low incidence of side effects. It is excreted unchanged in the urine and should be used with caution in the presence of renal failure.
ESTROGEN — Low-dose estrogen may be helpful as adjunctive therapy in postmenopausal women with motor fluctuations on antiparkinsonian medication. In one study, administration of Premarin 0.625 mg daily for eight weeks significantly improved "on" time and motor control in such women, although it did not result in global improvement on a scale rating activities of daily living. There is no evidence that estrogen has a specific effect on dopamine receptors; the benefit attributable to estrogen use may be related to an overall sense of well being.
It is not clear if these results would be similar in women taking combined estrogen/progestin therapy (necessary in women with an intact uterus). Furthermore, concerns about adverse effects associated with long-term estrogen/progestin therapy may limit its use in PD.
REFERÊCIAS:
* http://www.uptodate.com/contents/pharmacologic-treatment-of-parkinson-disease?detectedLanguage=gl&source=search_result&translation=parkinson+treatment&search=parkinson+tratament&selectedTitle=1~150&provider=babylon
http://www.uptodate.com/contents/diagnosis-of-parkinson-disease?detectedLanguage=en&source=search_result&translation=parkinson&search=parkinson&selectedTitle=3~150&provider=noProvider
Obs: ESSE ARTIGO DE REVISAO ESTA MUITO BOM PARA O DIAGNÓSTICO CLÍNICO :
*http://www.revistaneurociencias.com.br/edicoes/2005/RN%2013%2003/Pages%20from%20RN%2013%2003-8.pdf
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