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Table of Contents

Revised
January 19, 2005

Patrick J.
Sweeney, MD

Department
of Neurology

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James Parkinson (1755-1824), while best remembered for the disease state named after him by Charcot, was a man of many talents and interests. Publishing on chemistry, paleontology and other diverse topics, he was, early in his career, 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", appeared in 1817, 7 years before his death in 1824. The clinical description of 6 patients was a remarkable masterpiece testifying to his prodigious powers of observation for most of the 6 were never actually examined by Parkinson himself; rather, they were simply observed walking on the streets of London.

Definition

Prevalence

Pathophysiology

Signs and
Symptoms

Diagnosis

Therapy

Outcomes

References

DEFINITION

While the etiology of Parkinson's disease is not completely understood, the condition probably results from a confluence of several 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 Per decade of life there is estimated to be a 9% to 13% loss of these dopamine-producing neurons. If carried to its logical extreme, those patients achieving very great age are destined to lose approximately 70% to 80% of these critical 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 found in the octogenarian patient.

Since the early 1980s and the discovery of a potent neurotoxin (MPTP-MPP+), a byproduct of illicit drug synthesis, the environment has figured prominently in proposed etiologies for Parkinson's disease.^2,3 After the original description of this environmental "insult" to the dopamine-producing cells of the substantia nigra, a number of other environmental neurotoxins have been described, which have led to the Parkinsonian state. These discoveries have led to the suggestion that Parkinson's disease may arise as a combined consequence of the ongoing aging process coupled with environmental exposure(s) that accelerate the process of nigral cell death. The unusual clustering of individuals who later developed Parkinson's Disease (including Michael J. Fox), in a Canadian recording studio, emphasizes the possible relation of environment to disease development.

The third component of the puzzle is the possibility that some individuals may have a predetermined genetic susceptibility to these environmental "insults." While Parkinson's disease has been observed to occur throughout the world and in virtually all ethnic groups, there is a very low incidence among Asians and African patients as opposed to white patients. This observation suggests that genetic factors may possibly have an important role in disease production. Other evidence involves twin studies which initially failed to show a high concordance rate among monozygotic twins but are now being reconsidered in light of new evidence.⁴ In addition, family history appears to be a very strong predictor, after age, for development of the disease. Recently, a number of families in Greece and Italy with a very high penetrance of Parkinson's disease were shown to have a mutation on chromosome 4 for the alpha-synuclein gene.⁵ This is a presynaptic protein of unknown function but with the potential, upon further study of this muted gene, to provide insights into the pathogenesis of this form of autosomal dominant Parkinson's disease. Another gene abnormality on the long arm of chromosome 6 has been identified in patients with a peculiar autosomal recessive form of young onset disease. The protein product of this gene is 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 at a very high level to identify susceptibility genes and shed additional light on the genetics of Parkinson's disease.

The diagnosis of Parkinson's disease is a clinical exercise. A useful starting point begins by identifying Parkinsonism at a definite, probable, and possible level. Utilizing 5 clinical extrapyramidal features (resting tremor, rigidity, bradykinesia, postural instability, and freezing) one can confidently say a patient has definite Parkinsonism if he has any 2 of those 5 features with 1 of the 2 being tremor or rigidity. Probable Parkinsonism is suggested by isolated tremor or rigidity alone and possible Parkinsonism by either bradykinesia, postural instability, or freezing.

Once a diagnosis of Parkinsonism is made it is imperative for the physician to exclude pharmacological causation. Since the recognition, decades ago, that reserpine can produce extrapyramidal side effects, the list of medications that can cause parkinsonism continues to increase 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 leading to degenerative changes in the brain.

The asymmetrical and unilateral onset of resting tremor is probably the single best clinical clue that one is dealing with true Parkinson's disease, although some of the Parkinsonisms can present in a similar fashion. A robust response to levodopa is also considered a strong indicator of true Lewy Body Parkinson's disease. Atypical features that may suggest Parkinsonism rather than the true disease 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 actual autopsy.^7,8 Both of these series, one from Europe and the other from North American, point out a roughly 24% misdiagnosis rate at autopsy.

There is a growing literature on the usefulness of MRI head imaging in distinguishing Parkinsonism from Parkinson's disease. While there are reports of distinctive features for many of these conditions, perhaps the most reliable and consistent findings are to be found in vascular Parkinsonism, where the discovery of multiple prior strokes gives the clinician a diagnosis.

There are at least two overriding principles that should guide therapy in Parkinson's disease; education and individualization. With regard to education, there are abundant free resources to which the treating physicians can refer patients. The National Parkinson's Disease Foundation as well as the American Parkinson's Disease Association offer pamphlets, booklets, and resource information to patients and their families simply for the asking. (National Parkinson's Disease Foundation, 1-800-327-4545; American Parkinson's Disease Association, 1-800-223-2732). Patient education, as an adjunct to medical therapy of Parkinson's disease, has been studied by Montgomery⁹ and has been shown to improve the intermediate term outcomes.

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 versus more advanced disease. The widely used Hoehn and Yahr scale offers some landmarks to help the physician "stage" a patient (Table 3). In this scheme, purely unilateral disease is designated as Stage I. Stage II is represented by bilateral disease no matter how trivial. Stages III and IV add increasing amounts of postural instability and falling. Stage V describes that patient who no longer independently ambulates and is essentially wheelchair confined.

An algorithm has recently been proposed for the symptomatic management of Parkinson's disease. The algorithm suggests the following steps in treating Parkinson's. 1.) Consider "neuroprotective therapies" immediately following diagnosis, (see below) 2.) Administer dopamine agonists to control symptoms; 3.) Add levodopa if agonists alone do not work; 4.) Use a COMT inhibitor in conjunction with levodopa for longer-lasting treatment; 5.) Consider surgery after exhausting all medical options.¹⁰

In terms of medical treatment and understanding of basic disease mechanisms, Parkinson's disease has fared better than many of the other well-known neurodegenerative diseases, such as Alzheimer's disease. If one compares past seminal reviews of medical therapy, such as those offered by Yahr¹¹ and Calne,¹² with the most current overview offer by Lang,¹³ one can appreciate the state of progress in this area. Comments here will be limited to a) neuroprotective therapy and b) symptomatic therapy.

With regard to neuroprotective therapy, the hope that the selective Mao-B inhibitor selegiline HCl offered neuroprotection was dashed by the results of the DATATOP study.¹⁴ While the drug does have some symptomatic benefit, there is no clear evidence from this study that it offers any neuroprotection. Likewise, high expectations for the antioxidant properties of vitamin E as being neuroprotective were also shown to be ineffective. Future chapters on neuroprotection in Parkinson's disease will come only with a more complete understanding of the etiology of the disease. It is likely that medications which modulate free radical formation through oxidative phosphorylation as well as stabilizing calcium homeostasis will play important roles in this area. In the near future a second selective MAO-ß inhibitor, Rasagiline, is expected to be available for patients. The use of this drug as monotherapy in dosages of 1 or 2 mg a day has been found to be effective in early Parkinson's Disease.¹⁴

Symptomatic therapy is dependent on the stage of the disease when the patient is first diagnosed. For early, mild disease this practitioner prefers using one or more of the triad of amantadine (Symmetrel), selegiline HCl (Eldepryl), and one of the anti-cholinergic agents (the latter often effective for tremor) which frequently provide modest relief. Examples and dosing schedules for these medications are listed in Table 4. The use of dopamine agonists in early disease will be discussed later in this review.

With advancing disease progressing into the later stages of disability, the main classes of medication are either the dopamine agonists or levodopa itself. Since its introduction into the physicians' armamentarium nearly 35 years ago, levodopa, the immediate precursor of dopamine, remains the gold standard in terms of effective treatment for Parkinson symptoms. Levodopa is combined with a peripheral decarboxylase inhibitor (carbidopa); this combination reduces the decarboxylation of levodopa to dopamine outside of the blood brain barrier (BBB), thereby allowing for a more efficient dosing of levodopa. Prior to this drug combination very large doses of levodopa were required because 98% of a given dose of levodopa was converted to dopamine in the periphery, and since dopamine does not cross the BBB, it was effectively wasted.

Currently, however, some controversy surrounds just when to initiate levodopa therapy because early and inappropriate use of levodopa (ie, 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 unwanted movements (dyskinesias). Levodopa's half-life is only about 90 minutes, which results 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 to the more constant and tonic physiologically normal state. After several years of treatment (even earlier when the Parkinsonian pathology is at a more advanced state), loss of efficacy before the next dose (wearing off), dyskinesias (unwanted movements of the head, shoulders, or limbs), or "on-off" periods (radical swings between functioning and nonfunctioning states) appear. Because of this, it is current practice to initiate 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 have contained within their structure 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 patient began to fail traditional therapy. The earlier use of this class of drug represents current theory which suggests many of the late treatment complications associated with Parkinson's disease treatment are due to the short half-life of L-dopa.

Perhaps the newest application of the agonists involves the issue of neuroprotection. For a number of reasons, one of which is that, as a class, agonists do not undergo oxidative metabolism, trials are planned to see if patients treated initially with agonists and levodopa progress in their disease more slowly than patients treated with levodopa alone. Presently, of the four agonists available in the United States, the "new generation" (since 1997) agonists ropinirole (Requip) and pramipexole (Mirapex) are very popular.¹⁵ It is believed that the long duration of actions of these drugs, as compared with levodopa, is the seminal reason for the less frequent development of dyskinesias and fluctuations when these are employed initially as major therapy. Table 5 lists the dopamine agonists as well as levodopa preparations and dosing schedules for these medications.

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In recent years, much research has been directed toward inhibiting the other major enzyme system that breaks down levodopa outside of the BBB in the periphery; COMT or catechol-O-methyltransferase. At present, 2 medications are available for this purpose with the most widely used being entacapone (Comtan). When administered (200 mg tablets) with each levodopa-carbidopa dose, it increases the elimination half-life of levodopa by up to 85%. 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 a significant increase in "on-time" of about 1 hour and allowed for a reduction of levodopa dosage.¹⁶ In addition, using the controlled release preparation (CR) early in the course of levodopa therapy may provide additional prolongation. At present the recommendation for use of Comtan is limited to those patients who are experiencing "wearing off."

New developments in the mechanism of drug delivery have resulted in a transmucosal form of Selegeline which is expected to be available in the near future. The technique is referred to as the Zydis formulation and utilizes a method that rapidly freezes the drug so that it becomes interlaced as tiny crystals in a medium of gelatin spindles. This allows disintegration of the pill/wafer on the contact with saliva in the mouth. Using this technique Zydis Selegiline is absorbed directly through the buccal mucosa into the systemic circulation. Bypassing the gut and therefore first pass hepatic metabolism. Compared to regular Selegeline this results in higher levels of the medication but with marked reduction in the amphetamine like metabolites of Selegeline. Water is not required to aid in swallowing as the medication dissolves completely in the saliva of the mouth.

The combination of Sinemet and Entacapone is now available as a single tablet referred to as Stalevo. Each of the three dosage strengths contains 200mg of Entacapone with 50, 100, or 150mg of Sinemet. This convenience allows the patient to take just one pill rather than two. For those who have difficulty swallowing the physical size of the 50 and 100mg tablets of Stalevo is actually smaller than the Sinemet by utilizing the Zydis technology. L-Dopa is also available in a formulation called Parcopa, in the same strength as regular Sinemet tablets allowing the convenience of instant pill dissolution in the saliva.

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 will experience a benign urine discoloration (orange tint) which does not require any drug modification.

The benefit of adding folic acid to the drug regimen of patients taking L-dopa has been increasingly commented on.^17,18 Administration of L-dopa results in hyperhomocysteinemia with resulting potential for vascular endothelial damage. The addition of folic acid lowers the concentration of homocysteine.

At the beginning of this new century our understanding of the etiology and neurobiology of Parkinson's disease continues to evolve. Matching knowledge gained in these areas with similar progress in neurotherapeutics may, one day, offer treatments to completely alleviate the burdens of Parkinson's disease.

Return to Medicine Index

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