James Parkinson (1755-1824), although 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, 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,” appeared in 1817, seven years before his death in 1824. The clinical descriptions of six patients were a remarkable masterpiece testifying to his prodigious powers of observation because most of the six patients were never actually examined by Parkinson himself; rather, they were simply observed walking on the streets of London.

Definition

Parkinson's disease is a common neurodegenerative disease of the elderly. Typically beginning in the 60s or 70s, it is characterized by the unilateral onset of resting tremor in combination with varying degrees of rigidity and bradykinesia.

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Prevalence

Parkinson's disease ranks among the most common late-life neurodegenerative diseases, affecting approximately 1.5% to 2.0% of the population older than age 60 years.

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Pathophysiology

Although 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 For every 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 the potent neurotoxin MPTP/MPP⁺ (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine–1-methyl-4-phenylpyridinium), 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 that have led to the parkinsonian state. These discoveries have led to the suggestion that Parkinson's disease might arise as a combined consequence of the ongoing aging process coupled with environmental exposures that accelerate the process of nigral cell death. The unusual clustering of persons, in a Canadian recording studio, who later developed Parkinson's disease (including the actor Michael J. Fox) emphasizes the possible relation of environment to disease development.

The third component of the puzzle is the possibility that some persons might have a predetermined genetic susceptibility to these environmental insults. Although Parkinson's disease has been observed to occur throughout the world and in virtually all ethnic groups, there is a low incidence among Asians and African patients as opposed to white patients. This observation suggests that genetic factors might 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 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 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, on further study of this mutated 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 to shed additional light on the genetics of Parkinson's disease.

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Signs, symptoms, and diagnosis

The diagnosis of Parkinson's disease is a clinical exercise. A useful starting point begins first by identifying parkinsonism at definite, probable, and possible levels. Using several clinical extrapyramidal features (resting tremor, rigidity, bradykinesia, postural instability, and freezing) one can confidently say a patient has definite Parkinsonism if he or she has any two of those five features, with one of the two being tremor or bradykinesia.

Once a diagnosis of parkinsonism is made, it is imperative for the physician to exclude pharmacologic causes. 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 (Box 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 Parkinson's disease, although some of the parkinsonisms can manifest in a similar fashion. A robust response to levodopa is also considered a strong indicator of true Parkinson's disease. Atypical features that may suggest parkinsonism are listed in Box 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 America, 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. Although 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, wherein the discovery of multiple prior strokes gives the clinician a diagnosis.

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Treatment and outcomes

At least two overriding principles 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 and 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, 800-327-4545; American Parkinson's Disease Association, 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 two staging epochs: early versus more advanced disease. The widely used Hoehn and Yahr scale offers some landmarks to help the physician stage a patient (Box 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 later); (2) administer dopamine agonists to control symptoms; (3) add levodopa if agonists alone do not work; (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.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 are limited to neuroprotective therapy and 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 Although the drug does have some symptomatic benefit, 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. Future chapters on neuroprotection in Parkinson's 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 play important roles in this area. A new selective MAO-B?inhibitor, rasagiline (Azilect), 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 Parkinson's disease.¹⁴ The Adagio study is currently under way to evaluate the neuroprotective potential of rasagiline.

Symptomatic therapy depends on the stage of the disease when it is first diagnosed. For early, mild disease, I prefer using one or more of the triad of amantadine (Symmetrel), one of the two new selective MAO inhibitors (rasagiline or zydis selegiline), and sometimes one of the anticholinergic agents (the last often effective for tremor) that often provide modest relief. Examples and dosing schedules for these medications are listed in Table 1. The use of dopamine agonists in early disease is discussed later.

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 in the late 1960s, levodopa, the immediate precursor of dopamine, remains the 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, thereby allowing more-efficient dosing of levodopa. Before this drug combination, high doses of levodopa were required because 98% of a given dose of levodopa was converted to dopamine in the periphery, and because dopamine does not cross the blood-brain barrier, it was effectively wasted.

Currently, however, some controversy surrounds just when to initiate levodopa therapy because early use of levodopa (i.e., 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). The half-life of levodopa 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 nonphysiologic when compared with 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 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 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 a result of the short half-life of levodopa.

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. At present, of the agonists available in the United States, the new-generation (since 1997) agonists ropinirole (Requip) and pramipexole (Mirapex) are 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 2 lists the dopamine agonists as well as levodopa preparations and dosing schedules for these medications.

In mid-2007, the newest dopamine agonist appeared on the market in patch form. Rotigotine (Neupro) allows a constant 24-hour drug level with very stable stimulation of the dopamine receptors. However, the drug was withdrawn (most likely temporarily) from the U.S. market in 2008 due to formulation issues and is only available in Europe at this time. The drug will return to the US market in early 2010.

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. At present, two 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 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 a significant increase in on-time of about 1 hour and allowed a reduction of levodopa dosage.¹⁶ In addition, using the controlled-release (CR) preparation early in the course of levodopa therapy might provide additional prolongation. At present, the recommendation for use of entacapone is limited to patients who are experiencing wearing off.

New developments in the mechanism of drug delivery have resulted in a transmucosal form of selegiline. The technique is referred to as the Zydis formulation and uses 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 wafer on the contact with saliva in the mouth. Using this technique, Zydis selegiline (Zelepar) 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 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 in the mouth.

The combination of carbidopa-levidopa and entacapone is now available as a single tablet referred to as Stalevo. Each of the four dosage strengths contains 200 mg of entacapone with 50, 100, 150, or 200 mg of carbidopa-levidopa. 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 100 mg tablets of Stalevo is actually smaller than the carbidopa-levidopa tablet. Levodopa is also available in a formulation called Parcopa, in the same strength as regular carbidopa-levidopa tablets, allowing the convenience of pill dissolution in the mouth so the patient does not have to swallow the pill.

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 drug modification.

The benefit of adding folic acid to the drug regimen of patients taking levodopa has been increasingly commented on.^17,18 Administration of levodopa results in hyperhomocysteinemia with resulting potential for vascular endothelial damage. The addition of folic acid lowers the concentration of homocysteine. Finally, last but not least, the value of daily exercise for the Parkinson patient cannot be emphasized enough. A number of exercise programs are available on disk or the Internet. An example is www.delaythedisease.com.

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Conclusion

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 might one day offer treatments to completely alleviate the burdens of Parkinson's disease.

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Summary

• Concepts regarding the cause(s) of Parkinson's disease continue to evolve.
• Effective therapies ranging from education, exercise, and physical therapy, as well as a host of medications exist to manage the symptoms of Parkinson's disease.

In mid to late disease, surgical intervention with deep-brain stimulation rescues many patients from complications that develop in advanced Parkinson's disease.

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Suggested Readings

• Calne DB. Treatment of Parkinson's disease. N Eng J Med. 1993, 329: 1021-1027.
• Fearnley JM, Lees AJ. Ageing and Parkinson's disease: Substantia nigra regional selectivity. Brain. 1991, 114: 2283-2301.
• Hughes AJ, Daniel SE, Blankson S, Lees AJ. A clinical pathologic study of 100 cases of Parkinson's disease. Arch Neurol. 1993, 50: 140-148.
• Kitada T, Asakawa S, Hattori N, et al: Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998, 392: 605-608.
• Lang AE, Lozano AM. Parkinson's disease. N Engl J Med. 1998, 339: 1044-1053.
• Miller JW, Selhub J, Nadeau MR, et al: Effect of L-Dopa on plasma homocysteine in Parkinson's disease patients. Neurology. 2003, 60: 1125-1129.
• Miller T, Woitalla D, Kuhn W. Benefit of folic acid supplementation in Parkinsonian patients treated with levodopa. J Neuro Surg Psychiatry. 2003, 74: 549-551.
• Montgomery EB, Lieberman A, Singh G, et al: Patient education and health promotion can be effective in Parkinson's disease: A randomized controlled trial. Am J Med. 1994, 97: 429-435.
• Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson's disease (2001). Neurology. 2001, 56: (Suppl 5): S1-S88.
• Parkinson Study Group. Entacapone improves motor fluctuations in levodopa-treated Parkinson's disease patients. Ann Neurol. 1997, 42: 747-755.
• Parkinson Study Group. A controlled trial of rasagiline in early Parkinson's disease. Arch Neurol. 2002, 59: 1937-1943.
• Polymeropoulos MH, Lavedan C, Leroy E, et al: Mutation in the α-synuclein gene identified in families with Parkinson's disease. Science. 1997, 276: 2045-2047.
• Rajput AH, Rozdilsky B, Rajput A. Accuracy of clinical diagnosis in parkinsonism-a prospective study. Can J Neurol Sci. 1991, 18: 275-278.
• Shannon KM. New alternatives for the management of early Parkinson's disease. Mov Disord. 1996, 11: S266.
• Tanner CM, Ottman R, Ellenberg JH, et al: Parkinson's disease concordance in elderly male monozygotic and dizygotic twins. Neurology. 1997, 48: (Suppl): A333. (Abstract.)
• Vingerhoets FJ, Snow BJ, Tetrud JW, et al: Positron emission tomographic evidence for progression of human MPTP-induced dopaminergic lesions. Ann Neurol. 1994, 36: 765-770.
• Wood N. Genes and parkinsonism. J Neurol Neurosurg Psychiatry. 1997, 62: 305-309.
• Yahr MD, Duvoisin RC. Drug therapy of parkinsonism. N Engl J Med. 1972, 287: 20-24.