Published: May 2013
Parkinson disease (PD) is a common neurodegenerative condition. Typically beginning in the sixth or seventh decade of life, it is characterized by the unilateral onset of resting tremor in combination with varying degrees of rigidity and bradykinesia. PD was originally described by James Parkinson (1755-1824), a man of many talents and interests. Parkinson published works on chemistry, paleontology, and other diverse topics. Early in his career he was a social activist championing the rights of the disenfranchised and poor. His efforts in this area were enough to result in his arrest and appearance before the Privy Council in London on at least one occasion. In collaboration with his son, who was a surgeon, he also offered the first description in the English language of a ruptured appendix. His small but famous publication, "Essay on the Shaking Palsy," was published in 1817, seven years before his death. The clinical descriptions of 6 cases was remarkable in part because he never actually examined the people he described. Instead, he had simply observed these people on the streets of London.
PD ranks among the most common late-life neurodegenerative diseases, affecting approximately 1.5% to 2.0% of people aged 60 years and older.
Although the etiology of PD is not completely understood, the condition likely results from a confluence of factors. The first is an age-related attrition and death of the approximately 450,000 dopamine-producing neurons in the pars compacta of the substantia nigra.1 For every decade of life there is estimated to be a 9% to 13% loss of these neurons. Patients who live long enough are destined to lose 70% to 80% of these neurons before the first signs and symptoms of the disease appear. This age-related attrition may also be the explanation for the subtle extrapyramidal findings that are often observed in the octogenarian patient.
The discovery in the 1980s of the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine–1-methyl-4-phenylpyridinium), a precursor of MPP+ and a byproduct of illicit drug synthesis, has contributed prominently to proposed etiologies for PD.2 MPTP may be accidentally produced during the manufacture of MPPP, a synthetic opioid drug with effects similar to those of morphine and meperidine. The Parkinson-inducing effects of MPTP were first discovered following accidental ingestion as a result of contaminated MPPP.
After the original description of the effects of MPTP on the dopamine-producing cells of the substantia nigra, a number of other environmental neurotoxins were described that can contribute to the development of parkinsonian symptoms. These discoveries have led to the suggestion that PD might arise as a result of the combined effects of aging and environmental exposures that accelerate the process of nigral cell death. The unusual clustering of persons who had worked in a Canadian recording studio who later developed PD (including the actor Michael J. Fox) is thought to emphasize the possible relation of environment to disease development.
The third component of the puzzle is the possibility that some people might have a predetermined genetic susceptibility to environmental insults.3 Although PD has been observed to occur throughout the world and in virtually all ethnic groups, there is a low incidence among Asians and Africans as opposed to Caucasians. This observation suggests that genetic factors might have a role in disease development. Other evidence involves twin studies, which initially failed to show a high concordance rate among monozygotic twins but is now being reconsidered in light of new evidence.4
In addition, family history appears to be a strong predictor, after age, for development of the disease. A number of families in Greece and Italy with a high penetrance of PD were shown to have a mutation on chromosome 4 for the alpha-synuclein gene.5 Another gene abnormality on the long arm of chromosome 6 has been identified in patients with a peculiar autosomal recessive form of young-onset PD. The protein product of this gene has been named Parkin and seems to promote the degradation of certain neuronal proteins. It is closely related to the ubiquitin family of proteins involved in several neurodegenerative disease states.6 Research continues in an effort to shed additional light on the genetics and to identify genes that contribute to susceptibility and for PD.
The diagnosis of PD is a clinical one. A useful starting point is to begin by identifying parkinsonism as definite, probable, or possible. Using several clinical extrapyramidal features (resting tremor, rigidity, bradykinesia, postural instability, and freezing) the clinician can confidently say that a patient has definite parkinsonism if any 2 of the 5 features are present, with 1 of the 2 being tremor or bradykinesia.
Once a diagnosis of parkinsonism is made, it is imperative for the physician to exclude pharmacologic causes. Since the recognition that reserpine can produce extrapyramidal side effects, the list of medications that can cause parkinsonism continues to grow each year (Table 1). In addition, unexplained extrapyramidal disease in a young person should always prompt exclusion of Wilson's disease, a metabolic disorder of copper metabolism that can lead to degenerative changes in the brain.
|Selective serotonin reuptake inhibitors|
The asymmetrical and unilateral onset of a pill-rolling resting tremor is probably the single best clinical clue to suggest PD, although some of the parkinsonisms can manifest in a similar fashion. A robust response to levodopa is also considered a strong indicator of true PD. Atypical features that may suggest parkinsonism are listed in Table 2. The difficulty in accurately distinguishing between neurodegenerative diseases that have parkinsonian extrapyramidal features (multiple system atrophy, progressive supranuclear palsy [PSP], etc.) is reflected in statistics showing a high rate of misdiagnosis among movement disorder experts when patients are followed throughout the course of their illness to autopsy.7,8 Two case series, one conducted in Europe and one in North America, suggest a roughly 24% misdiagnosis rate.
|Absence of tremor|
There is a growing body of literature on the utility of magnetic resonance imaging (MRI) of the head for distinguishing parkinsonism from true PD. Perhaps the most reliable and consistent findings are in vascular parkinsonism, wherein the discovery of multiple prior strokes provides a clear diagnosis.
In 2011, the United States Food and Drug Administration (FDA) approved the use of a new imaging compound for single-photon emission computed tomography (SPECT) imaging which allows visualization of dopamine transporter neurons in a patient's brain.9 This provides an imaging technology that enables the clinician to differentiate between patients with essential tremor and those with PD based on the pattern of transporter loss. Authors of a recent case series reported that the use of this technology in patients with clinically uncertain parkinsonian syndromes resulted in a change in the clinical diagnosis in 45% of cases.10
At least 2 overriding principles should guide therapy in PD patients: education and individualization. With regard to education, there are abundant free resources to which the treating physician can refer a patient. Among them are the Cleveland Clinic Center for Consumer Health Education, the National Parkinson's Disease Foundation, and the American Parkinson's Disease Association which offer pamphlets, booklets, and online information to patients and families. Patient education, as an adjunct to medical therapy, has been studied by Montgomery and has been shown to improve intermediate-term outcomes.11
The second guiding principle should be individualization of treatment based on the specific patient and disease stage. It is useful to conceptualize at least 2 staging epochs: early and advanced disease. The widely used Hoehn and Yahr scale offers some landmarks to help the physician stage a patient's disease (Table 3). In this scheme, purely unilateral disease is designated as stage I. Stage II represents bilateral disease no matter how trivial. Stages III and IV indicate increasing degrees of postural instability and falling. Stage V disease generally reflects a patient who no longer independently ambulates and is essentially wheelchair confined.
|I: Unilateral disease|
|II: Bilateral disease|
|III: Postural instability—mild|
|IV: Postural instability—marked|
|V: No independent ambulation|
An algorithm has recently been proposed for the symptomatic management of PD. It recommends the following steps: 1) consider neuroprotective therapies immediately upon diagnosis; 2) administer dopamine agonists to control symptoms; 3) add levodopa if agonists alone are not effective; 4) use a catechol-O-methyltransferase (COMT) inhibitor in conjunction with levodopa for longer-lasting treatment; and 5) consider surgery after exhausting all medical options.12
In terms of medical treatment and understanding of basic disease mechanisms, PD has fared better than many of the other well-known neurodegenerative diseases, such as Alzheimer disease. If one compares past seminal reviews of medical therapy, such as those offered by Yahr13 and Calne,14 with a more current overview offer by Lang,15 one can appreciate the progress in this area.
With regard to neuroprotective therapy, the hope that the selective MAO-B inhibitor selegiline offered neuroprotection was dashed by the results of the DATATOP study.16 Although the drug does provide some symptomatic relief, there is no clear evidence from this study that it offers any neuroprotection. Likewise, the antioxidant properties of vitamin E were hoped to be neuroprotective but were shown to be ineffective against PD. Future advances in neuroprotection in Parkinson disease will come only with a more complete understanding of the etiology of the disease. Medications that modulate formation of free radicals through oxidative phosphorylation and stabilizing calcium homeostasis will likely play important roles in this area. The selective MAO-B inhibitor, rasagiline is now available for patients. This drug as monotherapy in a dose of 1 mg a day has been found to be effective in early PD.17
Symptomatic therapy depends on the stage of the disease at diagnosis. For mild disease, one strategy is to treat the patient with the triad of amantadine, the selective MAO inhibitor rasagiline, and, some cases, with one an anticholinergic agent, found to be effective for tremor, in order to provide modest relief (Table 4).
|Amantadine||100 mg twice daily|
|Selegiline (oral disintegrating formulation)||1.25-2.5 mg/day|
|Trihexyphenidyl||2 mg 3-4 times daily|
With advancing disease, the main classes of medication are either the dopamine agonists or levodopa itself. Since its introduction in the late 1960s, levodopa, the immediate precursor of dopamine, has been the standard of effective treatment for Parkinson symptoms. Levodopa is combined with the peripheral decarboxylase inhibitor carbidopa. This combination reduces the decarboxylation of levodopa to dopamine outside of the blood-brain barrier, thereby allowing more efficient dosing of levodopa. Before the discovery of this drug combination, high doses of levodopa were required because 98% of a given levodopa dose was converted to dopamine in the periphery, and because dopamine does not cross the blood-brain barrier it was effective.
Some controversy surrounds the appropriate time to initiate levodopa therapy. Early use (ie, in the patient with minimal symptoms and signs) leads to predictable treatment complications after several years of therapy. These include wearing off, on-off motor fluctuations, and the development of dyskinesias. The half-life of levodopa is only about 60 minutes, resulting in multiple peaks and valleys of drug level during a typical day of therapy. It is now believed that this pulsed stimulation of the dopamine receptors is non-physiologic when compared with the more constant and tonic physiologically normal state. After years of treatment, diminished efficacy, dyskinesias, or on-off periods (radical swings between functioning and nonfunctioning states) begin to appear. For this reason, it is current practice to initiate treatment with one of the dopamine agonists, which have longer half-lives than levodopa, when the patient's quality of life demands more aggressive treatment.
All of the agonists contain a dopamine-like ring moiety, which is believed to be the portion of the molecule that actually stimulates the dopamine receptor. Historically, dopamine agonists were first used only for symptomatic treatment when the traditional therapy began to fail. The use of this class of drug earlier in the treatment cycle represents current theory, suggesting that many of the late treatment complications associated with PD treatment are a result of the short half-life of levodopa. The agonists currently available in the United States, are ropinirole and pramipexole. Most recently, in the summer of 2012, the FDA approved release of the dermal patch formulation of the agonist Rotigotine, allowing for a once-a-day application of the drug as a patch.
It is believed that the long duration of action of these drugs, as compared with levodopa, is the main reason for the less frequent development of dyskinesias and fluctuations in response. Table 5 lists the dopamine agonists as well as levodopa preparations and dosing schedules for these medications.
|Drug||Dosing form||Dosing (average)|
|3-4 times per day|
|Levodopa-carbidopa CR||25-100 mg
|3-4 times per day|
|Levodopa-carbidopa-entacapone|| 50 mg
|6-8 tablets per day|
|15 mg 3 times per day titrated|
|3-5 mg 3 times per day titrated|
|Daily patch application, titrated|
CR, controlled release
In mid 2007, the newest dopamine agonist appeared on the market in patch form. The rotigotine patch provides a constant 24-hour drug level with very stable stimulation of the dopamine receptors. The drug was withdrawn from the US market in 2008 due to formulation issues and returned to the market in 2012.
In recent years, much research has been directed toward inhibiting the COMT enzyme system that breaks down levodopa in the periphery. Currently, 2 COMT inhibitors are available, with the most widely used being entacapone. When administered as a 200-mg tablet with each levodopa-carbidopa dose, entacapone increases the elimination half-life of levodopa and prolongs its action. Thus, the strategy of prolonged and continuous stimulation of the dopamine receptor is maximized by combining levodopa with carbidopa and entacapone. In a large study of 255 patients with fluctuations, the addition of entacapone resulted in an increase in on-time of about 1 hour and allowed a reduction of the levodopa dose.18 Using the controlled-release preparation early in the course of levodopa therapy may provide additional prolongation. Currently, the recommendation for use of entacapone is limited to patients who are experiencing a wearing off of treatment efficacy when taking combined levodopa and carbidopa.
A transmucosal form of selegiline, referred to as the Zydis formulation is absorbed directly through the buccal mucosa into the systemic circulation, bypassing the gut and, therefore, first-pass hepatic metabolism. Compared with regular selegiline, this results in higher blood levels of the medication but with marked reduction in the amphetamine-like metabolites of selegiline. Water is not required to aid in swallowing, because the medication dissolves completely in the saliva.
The combination of carbidopa-levodopa and entacapone is available as a single tablet. Each of the 4 dosages contains 200 mg of entacapone with 50, 100, 150, or 200 mg of carbidopa-levodopa. The physical size of the 50- and 100-mg tablets is smaller than that of the carbidopa-levodopa tablet in order to facilitate therapy in patients who have difficulty swallowing. Levodopa is also available in a rapidly disintegrating formulation in the same strength as regular carbidopa-levodopa tablets for those with difficulty swallowing.
With the use of entacapone dyskinesias may become more prominent and a corresponding reduction in levodopa dosing is indicated. About 5% to 10% of patients taking this drug experience a benign urine discoloration (orange tint) which does not require any modification of the therapy.
The benefit of adding folic acid to the drug regimen of patients taking levodopa has been discussed.19,20 Administration of levodopa results in hyperhomocysteinemia with resulting potential for vascular endothelial damage. The addition of folic acid reduces the concentration of homocysteine.
Finally, the value of daily exercise for the Parkinson patient cannot be over emphasized. Alberts has demonstrated the remarkable ability of forced aerobic bicycle exercise to improve overall function in patients with PD.21 A 35% improvement in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score was achieved using this technique without a change in the patients drug regimen.
The understanding of the etiology and neurobiology of PD continues to evolve. Matching knowledge gained in these areas with similar progress in neurotherapeutics might one day offer treatments to completely alleviate the burdens of this disease.
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