102 Parkinson’s Disease

Several species of the genus Paragonimus, the lung flukes, can parasitize human beings. The most impor­tant, Paragonimus westermani, is found in China, Japan, Korea, Southeast Asia, Papua New Guinea, and parts of India and Central Africa.

Motile larvae hatch, penetrate an appropriate type of snail, undergo two reproductive cycles, and emerge to seek the second intermediate host, a crab or crayfish. Here they penetrate between the joints of the crustacean’s exoskeleton, and encyst there to await ingestion by humans or other definitive host. They then burrow through the intestinal wall and the diaphragm and enter the lungs, where they may survive for many years. Slow, chronic lung damage may become very serious in heavy infestations. Mi­grating flukes sometimes wander widely lost and reach atypical (ectopic) sites like the brain, where they cause a variety of neurological symptoms and may prove fatal.

Diagnosis of paragonimiasis depends on detection of the eggs in sputum or feces. Treatment of the lung form of the disease is usually effective, but may be prolonged. Prevention is achieved by avoidance of raw, poorly cooked, pickled, or marinated freshwater crabs and crayfish.

K. David Patterson

Bibliography

Burton, K. 1982. Pulmonary paragonimiasis in Laotian refugee children. Pediatrics 70: 246—8.

Kean, B. H., et al. eds.

Nwokolo, C. 1974. Endemic paragonimiasis in Africa. Bul­letin of the World Health Organization 50: 569-71.

Yokagama, M. 1965. Paragonimus and paragonimiasis. In Advances in Parasitology, ed. B. Dawes, Vol. II, 99— 158. New York.

Parkinson’s disease, or parkinsonism, is a syndrome (i.e., a constellation of clinical signs and symptoms) consisting of four cardinal features: resting tremor, bradykinesia (physical and mental sluggishness), ri­gidity, and impaired postural reflexes. The diagnosis is made on the basis of finding any three of the four cardinal features.

Distribution and Incidence

This disease occurs throughout the world, with no population protected against the condition. Most sur­veys have investigated Caucasian populations of northern European or of Anglo-Saxon descent, and few studies have been done on the occurrence of Parkinson’s disease in other populations. In Cauca­sians the prevalence is 84 to 187 per 100,000 of population, with no geographic patterns and no clus­ters of increased incidence. Two studies seem to indi­cate a lower prevalence in blacks; this has been the clinical experience as well, probably indicating a decreased risk of Parkinson’s disease for blacks. The annual incidence varies from 5 to 24 per 100,000 of the white population. These figures, of course, de­pend on the methods of ascertainment, the popula­tion studied, the length of time that data have been collected, and many other factors. If the prevalence is divided by the annual incidence, the average dura­tion of the illness is approximately 10 years.

Epidemiology

Parkinson’s disease usually occurs in late middle life or beyond. The mean age of onset is 58 to 62. Onset before age 30 is rare but is not unknown, and there is a juvenile form of Parkinson’s disease. The great­est incidence is in the decade age 70 to 79 years, with an incidence of 1 to 2 per 1,000 population per year.

In 1917 an epidemic of encephalitis Iethargica started in Vienna and spread throughout the world. Following this illness, about half of the victims devel­oped Parkinson’s disease with tremor, bradykinesia, and rigidity often associated with oculogyric crises, parkinsonian crises (sudden episodic worsening of signs and symptoms), behavioral abnormalities, cra­nial nerve palsies, and a host of other central nervous system abnormalities. The age of onset of the post­encephalitic Parkinson’s disease is early compared to other types of Parkinson’s disease. A popular and now discarded theory, the Cohort theory, hypothesized that all Parkinson’s disease was caused by the en­cephalitis Iethargica agent and that Parkinson’s dis­ease would therefore disappear in the 1980s. Since 1961 when the Cohort theory was promulgated, evi­dence against it has been overwhelming, and we now know that there is no decrease in the prevalence of Parkinson’s disease, but of course, the postencepha­litic Parkinson’s disease has almost disappeared.

Mortality

The mortality rate from parkinsonism varies from 0.5 to 3.8 per 100,000 of population, and the duration averages about 10 years, with a large range of 1 to 33 years, depending on the age of onset, the rate of progression, the patient’s general health, and the treatments received.

Etiology

The signs and symptoms of parkinsonism are caused by a decrease in striatal dopamine due to the loss of dopaminergic neurons in the substantia nigra of the midbrain. At the present time, environmental agents are the primary known cause of parkinson­ism; exposure to manganese, carbon disulfide, and carbon monoxide are recognized environmental tox­ins that can produce the disorder. It is also known that drugs that interfere with dopaminergic pathways or receptors — such as phenothiazines, reserpine, and alpha-methyldopa - can produce the Parkinson’s syndrome, and multiple head traumas, probably causing atrophy of the substantia nigra, also may do the same. The recent discovery that 1-methyl- 4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), a com­mercially available chemical intermediate used in the synthesis of organic compounds, induces parkinsonism, has again supported the concept that environmental chemicals play a major role in the pathogenesis of this disorder. Varying amounts of MPTP may be formed as a byproduct in the synthesis of potent analgesic drugs, one of which is MPPP (l-methyl-4-phenyl-4-proprionoxypiperi- dine), the reverse ester of meperidine, a strong anal­gesic drug similar to heroin and morphine. The self­administration of small amounts of MPTP by young drug abusers who were using MPPP as an alterna­tive to heroin has resulted in a severe and perma­nent Parkinson’s syndrome that resembles Park­inson’s disease in its clinical, pathological, and biochemical features as well as its responsiveness to the drugs usually used in the treatment of Parkin­son’s patients.

Pathology

Nigrostriatal dopaminergic system failure is the im­portant pathological feature of parkinsonism. Loss of pigment cells in the substantia nigra and the dopaminergic neurons associated with them results in a deficiency of dopa in the striatum and produces the clinical signs and symptoms of the disease.

Clinical Manifestations

The cardinal features of Parkinson’s disease are rest­ing tremor, bradykinesia, rigidity, and postural in­stability. The resting tremor usually is 4 to 6 cycles per second and is present at rest and decreases with

Figure VIII. 102.1. Scheme illustrating the mechanism of MPTP toxicity at nigral dopamine neurons in primates. MPTP, which is lipophilic, enters the brain where it is transformed into MPP⁺ by monoamine oxidase B located in glial cells or in serotonergic neurons. MPP⁺ is taken up into the dopaminergic (DA) neurons, where it accu­mulates, by dopamine reuptake mechanisms. The bind­ing of MPP⁺ to neuromelanin might assist in the accu­mulation of MPP⁺, or might contribute to its toxicity. MPP⁺ within the neurons is assumed not to undergo redox cycling to reproduce free radical species but, rather, to be actively accumulated by mitochondria, where it inerferes with mitochondrial energy metabo­lism, leading to cell death. The precise mechanism of MPP⁺ toxicity remains unknown.

action. The tremor usually starts in the upper ex­tremity on one side and then spreads to the lower extremity on the same side. Upper and lower ex­tremities are usually time-locked, with the lower extremity a half cycle behind the upper extremity. Once the tremor has spread to one side of the body, the opposite upper extremity is usually involved, and then the opposite lower extremity. Postural tremor is also present in the majority of Parkinson’s patients, and postural tremor is usually slightly faster than the resting tremor. Bradykinesia, which literally means “slow movement,” is not the same as hypokinesia, meaning “decreased movement,” or akinesia, “no movement.” All of these movement disorders can be part of Parkinson’s disease. The bradykinesia shows up as a delay in the execution and initiation of voluntary movement, and also there is difficulty arresting the movement once it has been started. Akinesia is simply an extreme state of immobility, and some Parkinson’s patients, particularly before treatment with Ievodopa became available, eventually ended their days totally rigid and immobilized. Rigidity is resistance to passive stretch of muscle, and the patients with parkin­sonism have a characteristic stiffness of the muscles of the body. This stiffness can be brought out by passive rotation of the wrist or flexion-extension at the forearm. It is also present in the truncal muscles and can be examined by placing one’s hands on the dorsal aspect of the patient’s back muscles and hav­ing the patient flex and extend the body at the waist. The rigidity that is characteristic of parkinsonism is the rigidity that usually gives way in little catches and, hence, has been called cogwheel rigidity. The most disabling of the cardinal features of parkin­sonism is the postural instability. This one symptom alone accounts for most of the falls that occur in this disease. The instability results in loss of balance with propulsion and retropulsion, and such patients are unable to anticipate a change in their posture and thereby correct for the change, and thus they often follow their center of gravity as they fall to the ground. Little postural corrections that are normally made automatically cannot be done, and this is the major motor defect in the disease. Other clinical features of parkinsonism include masked facies and decreased blinking, increased saliva production called sialorrhea, hyperhidrosis (profuse sweating) or oily skin, a low-pitched monotonous voice, stooped posture, scoliosis, decreased upward gaze, a ten­dency toward low blood pressure, micrographia, and a shuffling and small-stepped gait.

History

Tremor was mentioned in the writings of Hippo­crates, Celsus, and Galen, but the real history of Parkinson’s disease does not start until 1817, the year Parkinson’s essay on the shaking palsy was published - when he was 62 years old. Parkinson called the disease the “shaking palsy,” but he also provided a Latin term: paralysis agitans. He re­ported on six patients. The first was personally ob­served, two others were noticed casually in the street; case 4 had an abscess on the chest wall but was lost to follow-up; case 5 was evidently seen at a distance, and there are no details of that patient available; and case 6 was a 72-year-old man who was visually inspected but evidently not examined.

In other words, by modern standards Parkinson’s great essay on Parkinson’s disease would not have passed muster. It is clear that the information he conveys in his essay is basically from visual inspec­tion: He did not examine the patients personally. Despite that his paper was well received by the medi­cal community, and subsequently, clinicians added to his description.

Armand Trousseau, in 1859, included a lecture in clinical medicine on parkinsonism and discussed the rigidity and the bradykinesia. The great French neu­rologist Jean Martin Charcot considered Parkinson’s disease a neurosis because there was no proper cen­tral nervous system lesion to explain it, and the condi­tion was characteristically worsened by stress or emo­tion. Charcot frequently commented that everything possible had been used to treat parkinsonism but with very little effect. He recommended belladonna alkaloids, especially hyoscyamine, an etropine iso­mer, now known to us as scopolamine. According to our modern biochemical understanding of parkin­sonism, this agent should have a partial effect in improving the signs and symptoms of Parkinson’s disease. In an interesting paper in 1893, Paul Oscar Blocq reported the case of a patient with hemiparkin­sonism, who at autopsy was found to have a lesion in the inferior peduncle with complete destruction of the substantia nigra. This, of course, suggested that the neuroanatomic substrate of Parkinson’s disease was the substantia nigra and probably is the first descrip­tion in the medical literature of a lesion that produces parkinsonism. Many other descriptions were made by William R. Gowers and other famous physicians, but these merely added to the fundamental and origi­nal observations of Parkinson.

The road to effective therapy was paved in the 1960s by A. Carlsson, who showed in animals that reserpine produces a bradykinesia that could be re­versed by the administration of L-dopa, a dopamine precursor. Because it was known that reserpine ad­ministration to humans produces a condition that resembles parkinsonism, L-dopa was administered to reserpinized humans to ameliorate the signs and symptoms of the reserpine-induced parkinsonism. O. Homykiewicz and colleagues then studied the con­centration of dopamine in patients dying of parkin­sonism, comparing the results to those in normal controls, and reported that there was a marked de­crease in dopamine in the caudate nucleus. In 1962 Andre Barbeau tried the oral administration of L- dopa (100 to 200 mg), and in 1961 W. Birkmayer and Hornykiewicz experimented with intravenous levo­dopa (50 to 150 mg), both reporting temporary bene­fits in parkinsonism. Others, however, were unable to confirm any major effect until George C. Cotzias and colleagues initiated the modern era of therapy in parkinsonism by showing that much larger oral doses of the L-dopa, 1.6 to 12.6 grams per day, re­sulted in dramatic improvement in many patients. The improvements were so dramatic that the effi­cacy of Ievodopa treatment was established beyond any doubt, and a new era in the management of Parkinson’s disease began.

Geography

As was previously mentioned, an increased incidence of Parkinson’s disease has not been shown anywhere in the world. However, there is an increased inci­dence of a complex of parkinsonism, dementia, and amyotrophic lateral sclerosis (ALS) in Guam, the Kii Peninsula of Japan, Rota, and the western highlands of New Guinea. This peculiar disease, in which pa­tients manifest abnormalities referable to almost ev­ery level of the neuraxis, resembles a combination of parkinsonism, Alzheimer’s disease, and ALS. Two major theories have emerged to explain the increased incidence of this condition in areas of the world bor­dered by the Mariana volcanic fault. The first theory implicates a secondary hyperparathyroidism, which increases the deposition of toxic environmental met­als in the nervous system. This theory is supported by the finding of increased manganese and calcium lev­els in nervous tissue taken from patients dying of this condition. The secondary theory implicates the inges­tion of two toxic amino acids - beta-oxaloamine-1- alanine (BOAA) and beta-methylamino-l-alanine (BMAA) - by people in this area of the world. This theory is supported by the finding that infusions of toxic amino acids can produce nervous system disease in primates that does seem to resemble some of the degenerative diseases including parkinsonism, ALS, and Alzheimer’s disease. Further work needs to be done to clarify the role of these toxic amino acids, if any, in the pathogenesis of the Parkinson’s disease- ALS-dementia complex on Guam. Both theories, im­plicating environmental factors as the cause, are sup­ported by the fact that the incidence of this peculiar combination of disorders is steadily decreasing.

Bernard M. Patten

Bibliography

Barbeau, Andre. 1962. The pathogenesis of Parkinson’s disease. Canadian Medical Association Journal 87: 802-7.

Birkmeyer, W., and O. Homykiewicz. 1961. The l-3,4- Jioxyphenylalanine (DOPA) effect in Parkinson- akinesia. Wiener Klinische Wochenschrift 37: 787-8.

Cotzias, G. C. et al. 1967. Aromatic amino acids and the modification of parkinsonism. New England Journal OfMedicine 276: 347.

Duvoisin, R. C. 1984. Parkinson’s disease: A guide for patient and family. New York.

Duvoisin, R. C. et al. 1963. Parkinsonism before and since the epidemic of encephalitis lethargica. Archives of Neurology 8: 232.

Hoehn, M. M., and M. D. Yahr. 1967. Parkinsonism: Onset, progression, and mortality. Neurology 17: 427.

Homykiewicz, O. 1966. Dopamine (3-hydroxytyramine) and brain function. Pharmacological Reviews 18: 925.

Koller, W. C., ed. 1987. Handbook of Parkinson’s disease. New York.

Parkinson, J. 1817. An essay on the shaking palsy. London.