Parkinson’s Disease
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.
SIGNS, SYMPTOMS, AND DIAGNOSIS
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.
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.
