Monday, April 01, 2002

What Triggers the “Shaking Palsy”?

By: Donald Calne D.Sc.

A pioneer of research on the disabling brain disorder that afflicts more than 500,000 Americans urges a new look at Parkinson disease’s causes, clinical features, and even definition. There is a known genetic element to Parkinson’s disease, but also much evidence for what may be called “the environmental trigger”—evidence that may be downplayed in our era of genetics, suggests Calne. He urges a search for an “event” early in life that may set in motion the destruction of dopamine-producing cells in the brain’s substantia nigra that later in life confronts us with the full-blown disorder.

The “shaking palsy” was first characterized by a family physician in nineteenth-century London. Today we most often hear about Parkinson’s disease when it affects prominent figures such as Pope John Paul II, Michael J. Fox, and Muhammad Ali, but it afflicts more than 500,000 Americans.  

Like many brain disorders, Parkinson’s disease continues to baffle scientists and its numbers are underestimated by the public. Canadian neurologist Donald B. Calne, D.M., who has studied Parkinson’s disease for more than four decades, argues that we know too little even to label Parkinson’s a “disease”—an entity with clear causes, symptoms, and outcomes. It is time, he urges us, to take a new look at the causes and mechanisms of Parkinsonism, based on important recent discoveries. He makes the case for an interplay of multiple genes with a highly specific, but still unknown, environmental event—an injury from a toxin or virus wounding nerve cells that may succumb only years later. 

The first known recognition of what we now call Parkinson’s disease was by one of the greatest original minds of all time, Leonardo da Vinci. Fascinated by the structure and functioning of the human body, Leonardo noted in about 1500 that some people experienced abnormal, involuntary movements and, simultaneously, difficulty in performing the movements they did wish to make. “This appears clearly in paralytics—whose trembling limbs move...without permission of the soul; which soul with all its power cannot prevent these limbs from trembling.” 

Some two centuries later, the famous British surgeon John Hunter was probably referring to Parkinson’s disease when he commented on an odd phenomenon: Patients with severe tremor did not complain about tiredness in the muscles that produced the incessant shaking. “For instance,” said Hunter, “Lord L’s hands are almost perpetually in motion, and he never feels the sensation of them being tired. When he is asleep his hands, etc., are perfectly at rest; but when he wakes, in a little while they begin to move.” When Hunter made this point in a London lecture in 1776, his audience may have included a bright, 21-year-old student named James Parkinson, who later published his classic “An Essay on the Shaking Palsy”.

Today, most of us have heard of Parkinson’s disease, but surveys suggest that many people think it is a relatively trivial disorder, the cause of a bit of tremor in elderly folks. In reality, Parkinson’s disease is both common and disabling, a disease attended by major difficulties in balance, speech, and swallowing, and ultimately leading to near total immobility and even death. Well-known figures who have been afflicted include the current pope, former heavyweight champion Muhammad Ali, former attorney general Janet Reno, U.S. Senator Morris Udall, Canadian Prime Minister Pierre Trudeau, press photographer Margaret Bourke-White, and actors Michael J. Fox, Sir Michael Redgrave, and Sir Ralph Richardson. How can we explain the mismatch between public awareness and the truth of its prevalence? Why did physicians, including the renowned healers of antiquity, fail to recognize the condition until 1817, when Parkinson gave the first coherent description of the disease that bears his name? 

The answer may reflect a prime characteristic of Parkinsonism. Its symptoms begin very gradually, progress with extreme subtlety, and in many respects look like an exaggeration of normal aging: a stooped posture, shuffling walk, tremulous hand, and weak voice. In the words of Parkinson: “So slight and imperceptible are the first inroads of this malady, and so extremely slow is its progress, that it rarely happens that the patient can form any recollection of the precise period of its commencement.” What follows is far more grave. As Parkinson wrote:

As time and the disease proceed, difficulties increase: writing can now be hardly at all accomplished; and reading, from the tremulous motion, is accomplished with some difficulty. Whilst at meals the fork not being duly directed frequently fails to raise the morsel from the plate; which, when seized, is with much difficulty conveyed to the mouth. At this period, the patient seldom experiences a suspension of the agitation of his limbs. 

In “An Essay on the Shaking Palsy,” Parkinson described six Londoners who appeared to be afflicted, although he does not seem to have performed a physical examination on them. What he observed was shaking, bending forward, slowness of movement, poor balance, and a curious telltale feature that is almost diagnostic: freezing as if rooted to the ground for a few seconds, followed by a tendency to shuffle in steps that get progressively shorter and quicker until walking is no longer under control. In characteristically elegant prose, he gave readers this graphic image:

It seemed to be necessary that the gentleman should be supported by his attendant, standing before him with a hand placed on each shoulder, until, by gently swaying backward and forward, he had placed himself in equipoise; when, giving the word, he would start in a running pace, the attendant sliding from before him and running forward, being ready to receive him and prevent his falling, after his having run about twenty paces.  

James Parkinson was a fascinating man, a humble family physician, not on the staff of any of the great London teaching hospitals, who published articles as diverse as “Medical Admonitions Addressed to Families Respecting the Practice of Domestic Medicine and the Prescription of Health” (1799), “Hints for the Improvement of Trusses” (1802), “Observations on the Nature and Cure of the Gout” (1805), and “Observations on the Excessive Indulgence of Children” (1807). He was also an expert on fossils whose three-volume work, Organic Remains of a Former World, gained him the Honorary Gold Medal of the Royal College of Surgeons. Parkinson had a social conscience, too, striving to reform inhumane conditions in the mental hospitals of his day, which he described in 1811 in “Observations on the Act for Regulating Mad-houses.” Still more broadly, he urged redistribution of wealth in nineteenth-century England, espousing the principles of the French Revolution to an extent that risked prosecution for sedition under the British monarchy, so that he had to conduct his political work under the pseudonym Old Hubert. 

Parkinson was too modest to call the shaking palsy Parkinson’s disease. It was Jean-Martin Charcot, the legendary nineteenth-century French neurologist, who confirmed the common occurrence of the condition and paid tribute to Parkinson’s salient contribution by naming the disorder after him. Charcot also introduced the first effective treatment for Parkinson’s disease, based on an astute chance observation of the kind that has sparked many crucial advances in treatment. 

Parkinsonian patients sometimes drool, so, in 1867, Charcot tried treating them with hyoscyamine, a drug known to dry up salivary secretions. An unexpected improvement in tremor, observed and seized upon by Charcot, made drugs with properties similar to hyoscyamine the cornerstone of treatment for the next 100 years. Unfortunately, as a later writer put it, overdoses of this drug turned the patient “red as a beet, dry as a bone, and mad as a hen.” The benefits of the drugs were, in fact, quite limited, but other purported remedies were worse. In his classic Manual of Diseases of the Nervous System (1893), W. R. Gowers wrote: “My own experience is to the effect that arsenic and Indian hemp, the latter sometimes combined with opium, are of most use.”

REVISITING SOME CLASSIC NOTIONS 

Until recently, most neurologists agreed on the diagnosis of Parkinson’s disease: a condition characterized by tremor (most commonly of the hands when not in use), rigidity (stiffness of the muscles when a limb is moved by the examiner), bradykinesia/akinesia (difficulty in initiating, and slowness in performing, voluntary movements), and unsteadiness on the feet. These features progress, usually affecting one side of the body more than the other. 

Research into Parkinson’s disease underwent a revolution almost half a century ago. In 1957, Arvid Carlsson and his colleagues showed that dopamine transmits information between certain nerve cells in animals. Then, in 1961, Oleh Hornykiewicz and his colleagues found that dopamine is selectively depleted in the brains of patients with idiopathic (of unknown cause) Parkinsonism. There followed various attempts to correct this depletion. Dopamine itself is not administered because it cannot cross from the body’s blood vessels into brain tissue. But levodopa (L-Dopa) readily crosses the blood-brain barrier, and upon entering the brain is converted into dopamine. Today, L-Dopa is given early in the progression of Parkinson’s disease; its results may appear limited simply because the patient’s symptoms are still mild. When it was first introduced some 35 years ago, patients with severe disability experienced dramatic results. An article in Reader’s Digest recounted “How the wonder drug set me free!”

 art_v4n2calne_2

The characteristically small, cramped handwriting of the Parkinson’s patient (top) can change dramatically after treatment with levodopa (L-Dopa), which converts to dopamine upon entering the brain. Dopamine is selectively depleted in the nerve cells of the substantia nigra of patients with Parkinson’s disease of unknown cause (idiopathic). Courtesy of Donald Calne

Indeed, the impact of L-Dopa can be surprising. Shortly after starting a course of treatment, one of my patients complained of severe hip pain. A bit of detective work on this unexpected problem revealed advanced osteoarthritis in the hip. Before L-Dopa, the patient had been bedridden; his arthritis had been “silent.” After starting the treatment, he regained the use of his legs and the arthritis proclaimed its presence. When another of my patients began to take L-Dopa, her handwriting—often small and cramped in Parkinson’s patients because of their poverty of movement— became so much larger that tellers at her bank questioned the authenticity of the new signature on her checks (see illustration above). 

Integral to the definition of Parkinson’s disease is a change observable by postmortem examination of the brain in the laboratory. Dopamine-producing nerve cells are lost in a very particular site, the substantia nigra; and many surviving nerve cells in the substantia nigra are seen under the microscope to have a characteristic abnormal structure, called a Lewy body, named after Franz Lewy who first described them in 1912. 

The classic definition of Parkinson’s disease, in addition to describing symptoms that must be present, requires the exclusion of two uncommon conditions that mimic Parkinson’s: progressive supranuclear palsy and multiple system atrophy. We also must rule out exposure by the patient to certain dopamine-blocking drugs that can cause clinical features resembling Parkinson’s disease. The early diagnosis of Parkinson’s disease may be difficult, but diagnosis becomes much easier with the passage of time, as its clinical features become more prominent. 

The term Parkinson’s disease has been in use for some 150 years, but new evidence is putting a strain on this traditional nomenclature. The definition of a disease should entail a statement of causation, clinical features, pathological findings, and pattern of progression. For Parkinson’s disease, however, we know a few different genetic causes, while other causes remain unknown. Strictly speaking, therefore, we should refer to the Parkinsonian “syndrome”—which refers to a group of clinical features that “run together” and derive from a variety of causes. In practice, the term “idiopathic Parkinsonism” is used more widely than “Parkinsonian syndrome.” 

As we classify disorders, we normally pass through a stage of defining syndromes and then diseases. For example, meningitis is a syndrome, while meningococcal meningitis (caused by the meningococcus) and tuberculous meningitis (caused by the tubercle bacillus) are diseases. By asking the questions “Why do nerve cells die?” and “How do nerve cells die?” we are making some progress in gathering evidence that could enable us to identify various Parkinson’s diseases that now reside under the umbrella of idiopathic Parkinsonism. The importance of the questions goes far beyond classification; they must be answered before we can develop more effective treatments for patients. 

Today, we have good treatments for the symptoms of idiopathic Parkinsonism, but no way to prevent it or even slow its progress. To do that, we will have to learn why the nerve cells that produce dopamine die—that is, we must identify the biological mechanism that leads to cell death. 

LOOKING BEYOND GENETICS 

In seeking the causes of idiopathic Parkinsonism, the first question to answer is whether we are dealing with genetic factors, environmental factors, or both. The answer is both, but in my view our success in identifying the relative importance of each of these factors has been stymied by a pervasive academic prejudice of our era. Let me explain. 

One rare genetic cause of Parkinson’s disease is a gene that guides the production of an abnormal alpha-synuclein protein. Strangely, the function of normal alphasynuclein is not known, but—as we shall see when we look at how cells die—we do know that the abnormal protein accumulates in Lewy bodies. Another, slightly more common, form of Parkinsonism is associated with the parkin gene. This gene guides production of parkin, a protein that takes part in destroying other proteins in nerve cells. In the genetic defect at issue here, patients have reduced quantities of parkin in their nerve cells. An extensive search of the human genome has led to the identification of six additional mutations that seem to make a person susceptible to Parkinsonism. This, then, is the picture to date of genetic contributions to the causation of idiopathic Parkinsonism: rare mutations of either of the two genes encoding for alpha-synuclein and parkin can cause Parkinsonism, but several genes that we know about confer increased susceptibility to the disorder. Studies of twins indicate that genetic Parkinsonism usually begins to produce symptoms before the age of 50. Most patients, however, first notice their Parkinsonism after the age of 50. From that we infer that, in general, environmental factors must play a prominent role in causing these cases. 

The view that most familial Parkinsonism has environmental causes runs smack into the academic prejudice of our era that everything of importance in the biomedical sphere is genetic.

Population studies of the occurrence of idiopathic Parkinsonism support this inference. In the United States, there is a gradient of prevalence, idiopathic Parkinsonism being more common in the northern areas, regardless of race. This geographical heterogeneity, in a freely mobile society, buttresses the argument for environmental causation. On a much smaller scale, we can find clusters of patients who have lived and worked in the same place at the same time. For example, from 1976 to 1980 three of my patients with idiopathic Parkinsonism worked in a television production crew in Vancouver with Michael J. Fox. The chance of this being coincidental rather than the result of exposure to a common environmental agent, taking into account the young age of onset in two of these patients, is remote. 

Some 15 to 20 percent of patients have a family history of blood relatives with Parkinsonism. One recent study shows that, in these families, the younger a child is when a parent develops Parkinsonism, the higher the risk that the child will also develop Parkinsonism. Why? Because a younger child will share his environment more closely with his parents, and so have a higher chance of being exposed to environmental risk factors, compared with an older child. Thus we suspect that even where the disease runs in the family, its usual cause is environmental. 

The view that most familial Parkinsonism has environmental causes runs smack into the academic prejudice of our era that everything of importance in the biomedical sphere is genetic. For at least two decades, research policy has been dominated by an emphasis on genetic studies— primarily, I believe, because we happen to have developed powerful tools in molecular biology. There are many indications, now, that the pendulum has swung too far in the direction of genetics—not least in the area of neurodegenerative conditions such as idiopathic Parkinsonism. The mistaken prejudice that familial disease is always genetic is hardly new, of course; a century ago, tuberculosis was thought to be a hereditary disorder because it clustered in families. Now we know that the clustering is caused by relatives spreading the tuberculie bacillus by coughing on each other or drinking the same infected milk. 

AN EVENT, NOT A PROCESS? 

We are left with the question that haunts everyone interested in idiopathic Parkinsonism: What, exactly, is the environmental cause? We cannot answer that question, but we have some crucial clues. One is that, as we have seen, there is more than one gene that (albeit rarely) can cause Parkinsonism. This warns us that we should not limit our search to only one environmental risk factor. 

It is my contention that we must look, instead, for brief events that may kill some nerve cells but also damage many others in ways that reduce their life expectancy.

The traditional environmental hypothesis holds that the cause is an organic substance, such as a pesticide, herbicide, or a naturally occurring toxin. Since organic toxins are not likely to persist in the body for the 20 to 30 years over which idiopathic Parkinsonism progresses, this view implied prolonged exposure to the toxin. Several threads of recent evidence suggest that this concept is neither necessary nor sufficient. It is my contention that we must look, instead, for brief events that may kill some nerve cells but also damage many others in ways that reduce their life expectancy. 

Three observations tend to favor this “event” hypothesis while casting doubt on a long-term “process” hypothesis. First, the rate of dopamine cell loss in the brain is faster in the earlier stages of the disease. The simplest explanation for this would be damage by a brief environmental event; a continuous risk factor would be expected to kill the same number of nerve cells each year, resulting in a steady decline in the number of surviving cells. Second, idiopathic Parkinsonism is usually asymmetric, affecting the two sides of the body differently. The less-affected side progresses in parallel with the more affected side, rather than “catching up,” as would be predicted by the conventional notion of prolonged exposure. 

Third, when fetal brain cells are transplanted into the brain of a patient with idiopathic Parkinsonism, these cells do not undergo degeneration, as would happen if a noxious agent were acting as a continuing cause of damage. On the contrary, the transplanted cells flourish, suggesting that whatever caused the brain damage has come and gone—a brief, transient, environmental risk factor. 

The event causing Parkinsonism may occur several years before symptoms appear. We know this because those symptoms are not usually noticeable until about half of the dopamine-producing nerve cells are lost. The notion of an event, followed by a time lag, is entirely in keeping with the occurrence of clusters of Parkinsonian patients—such as those working with Michael J. Fox—who shared their environment for a limited time several years before the onset of symptoms. Perhaps nerve cells are like soldiers in a battle. Some are killed outright, some are wounded, some are unscathed. The wounded soldiers survive the battle, but their lives may be shortened by delayed complications from their injuries. 

Perhaps nerve cells are like soldiers in a battle. Some are killed outright, some are wounded, some are unscathed. The wounded soldiers survive the battle, but their lives may be shortened by delayed complications from their injuries.

The event hypothesis has implications that offer a starting point for research. First, scientists can design novel epidemiological studies able to detect brief environmental risk factors. For example, the synthetic toxin methylphenyltetrahydropyridine (MPTP) was created as a cheap “street” substitute for heroin addicts, and some of those who took it immediately came down with severe, irreversible Parkinsonism. Others taking the drug showed no symptoms at the time, but several years later, long after the toxin had disappeared from their bodies, they developed progressive symptoms of Parkinsonism. We need to understand this mechanism. 

In addition, we can include infections as a possible cause of Parkinsonism, since infections can come and go, leaving behind damage to selective portions of the brain and slowly progressive symptoms. Polio and the postpolio syndrome provide a good example. Von Economo’s encephalitis is also relevant; the virus responsible for it was never identified, but the epidemic occurred at the same time (1919-26) as the severe influenza pandemic that killed more people than World War I. Many argue that the same infectious agent was responsible for both the flu and the encephalitis, but the encephalitis left a time bomb in its wake. After a period—often several years—symptoms of Parkinsonism commonly appeared, at a time when indicators of viral activity were no longer present in the brain. 

Characteristically, the damage to the brain in postencephalitic Parkinsonism was more extensive than that seen in idiopathic Parkinsonism, and, because of this mismatch, the condition attracted little attention. There was not much interest in what exactly happened at the time of infection nor in what was going on over the latent period between encephalitis and Parkinsonism. Now we have intriguing new evidence: Japanese researchers have found that in mice, certain strains of Influenza A virus home in on the substantia nigra, which is the region of the brain selectively attacked in idiopathic Parkinsonism. Furthermore, they have shown that Influenza A can gain access to the brain through the nasal passages. 

The viral hypothesis also receives support from a recent epidemiological report on the relative prevalence of idiopathic Parkinsonism in different occupations. Idiopathic Parkinsonism was found to have more than twice the normal prevalence among teachers, medical workers, loggers, and miners. The simplest explanation would be causation by an infective agent. The increased risk for teachers and medical workers is obvious. Many loggers and miners, in the time frame of this study, shared cramped sleeping quarters in camps, which would also predispose to respiratory infections. 

In short, Lewy bodies can occur without Parkinsonism; Parkinsonism can occur without Lewy bodies; and Lewy bodies do not kill nerve cells. Obviously, the classic views have not withstood the test of time.

NEEDED: A NEW HYPOTHESIS OF NERVE CELL DEATH 

After Franz Lewy reported observing an abnormal microscopic structure in postmortem examinations of the brains of patients with idiopathic Parkinsonism, Lewy bodies were seen so consistently that they came to be regarded as one of the disease’s specific diagnostic features. The classic position was that Lewy bodies were the hallmark of idiopathic Parkinsonism and caused the death of the nerve cells. Modern evidence confounds both tenets. 

On the one hand, we now know that Lewy bodies occur in conditions other than Parkinsonism; on the other, we have seen all the usual clinical features of idiopathic Parkinsonism in patients whose brains had no Lewy bodies. Indeed, large numbers of Lewy bodies have been seen in people with no neurological problems, people in whom there has been no loss of dopamine-producing nerve cells. In short, Lewy bodies can occur without Parkinsonism; Parkinsonism can occur without Lewy bodies; and Lewy bodies do not kill nerve cells. Obviously, the classic views have not withstood the test of time. We urgently need a new hypothesis. 

Perhaps this hypothesis can be erected on recent discoveries about the proteins alpha-synuclein and parkin, mentioned earlier as genetic causes of Parkinsonism. The two central observations are that the accumulation of alpha-synuclein appears to be very damaging to the nerve cells in the brain, and that parkin (which is abnormally scarce in certain genetically caused cases of Parkinsonism) normally facilitates the destruction of alphasynuclein, thereby protecting nerve cells. 

Where do Lewy bodies come in? The simplest explanation may be that when alpha-synuclein starts to accumulate in a nerve cell, the cell organizes a defense by collecting the alpha-synuclein and storing it in vesicles—Lewy bodies—where it can do less harm. Think of this as similar to limiting damage from toxic industrial waste by storing it in containers sealed off from the environment. In this view, the Lewy body represents an attempt at damage control, not a lethal time bomb. 

This model still leaves us asking how the cells die. Since the parkin gene is a rare cause of Parkinsonism, lack of parkin is not usually responsible for the accumulation of alpha-synuclein. What are the more common causes? We must look to the environment. There we find an animal model of Lewy body formation after exposure to the pesticide rotenone. In human subjects, infection of the brain by measles can lead to what is called subacute sclerosing panencephalitis, a condition in which Lewy bodies may be found. Thus toxic exposure or viral infection can lead to accumulation of alpha-synuclein, and the cells respond to the threat by forming Lewy bodies. So it seems that more than one type of environmental risk factor may contribute to idiopathic Parkinsonism. 

If the accumulation of alpha-synuclein kills nerve cells, what are the mechanics? Here we have four main theories:

  1. Experiments in animals with toxins that produce excessive neuronal activity have shown that nerve cells may be literally “excited to death.”
  2. Accumulation of atypical inflammatory cells occurs in various neurodegenerative disorders, including idiopathic Parkinsonism. The inflammatory cells may contribute to neuronal death, or they may be morticians removing dead nerve cells, or both.
  3. Oxidative stress may be the cause, since certain biochemical reactions such as the breakdown of dopamine in the brain lead to the formation of toxic products called free radicals.
  4. When the brain is undergoing development in the fetus, at first too many brain cells appear in certain regions. To solve this problem, the cells activate a built-in program for suicide: programmed cell death, or apoptosis. It has been suggested that the same program is activated in neurodegenerative disorders.

These hypotheses have different levels of scientific support, and none has gained general acceptance as providing a satisfactory explanation of neuronal death in idiopathic Parkinsonism. 

MULTIPLE CAUSES, MULTIPLE POSSIBILITIES FOR HOPE 

Many areas of medicine fully accepted the notion that there can be several causes, even several types of cause, for one kind of disorder. For example, everyone recognizes that cancer can be caused by genes, chemical agents, infective agents, or some combination of these. In the field of neurodegenerative diseases, such as idiopathic Parkinsonism, however, people seem oddly reluctant to draw the same conclusion, in spite of a rather convincing body of evidence. The facts now indicate that, for most patients with idiopathic Parkinsonism, their environment plays a more important role in causation than do their genes, though their genes may contribute to susceptibility. 

This new emphasis on the environment is good news, for it is easier to change our environment than our genes.

This new emphasis on the environment is good news, for it is easier to change our environment than our genes. We cannot yet say whether the environmental risk factors are more often toxic or infective, but the question demands our urgent attention. Once we have the answer, we may be able to develop ways to prevent idiopathic Parkinsonism, just as reducing exposure to certain chemical agents has decreased some cancers, and vaccination programs have virtually eliminated certain viral diseases. Finally, if, as argued here, the usual causes of idiopathic Parkinsonism turn out to be brief events in the environment that occur several years before the onset of symptoms, then transplantation of cells that produce levodopa or dopamine should not be followed by engagement of these cells in any ongoing destructive process. Instead, such a treatment—now the subject of much research—could even be, in a sense, a cure.



About Cerebrum

Bill Glovin, editor
Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board
Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Robert Malenka, M.D., Ph.D., Stanford University School of Medicine
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine

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