HISTORY OF PARKINSON'S DISEASE
Parkinson's Disease is due to the insufficient formation and action of dopamine. Human beings have always had the potential for insufficient dopamine. So although Parkinson's Disease has increased in its prevalence over time, it must have existed to some extent for as long as human beings. There are references to Parkinson's Disease symptoms throughout history.
An ancient civilisation in India practiced their medical doctrine called Ayurveda. Ayurveda is claimed to be a divine revelation of the ancient Indian creator God Lord Brahma as he awoke to recreate the universe. They described the symptoms of Parkinson's Disease, which they called Kampavata as far back as 5000 B.C.. To treat Kampavata, they used a tropical legume called Mucuna Pruriens, which they called Atmagupta. Mucuna Pruriens seeds are a natural source of therapeutic quantities of L-dopa. Mucuna pruriens is the oldest known method of treating the symptoms of Parkinson's Disease, and is still being used today.
The Huang di nei jing su wen (often known as the Su wen), is the oldest existing Chinese medical text. It was written in around 500 B.C.. It is composed of two texts each of eighty one chapters or treatises in a question and answer format between the mythical Huang di (Yellow Emperor) and his ministers. The first text, the Suwen, also known as Plain Questions, covers the theoretical foundation of Chinese Medicine, diagnosis methods and treatment methods. It also describes the symptoms of Parkinson’s Disease.
It is claimed that there are references to the symptoms of Parkinson’s Disease in both the old and new testaments of the Bible. Often cited as possible references to Parkinsonism is the following depiction of old age in the Old Testament : "When the guardians of the house tremble, and the strong men are bent" (Ecclesiastes 12 : 3), and the following description in the New Testament "There was a woman who for eighteen years had been crippled by a spirit.....bent and completely incapable of standing erect" (Luke 13:11).
In the Illiad, which, along with the Odyssey are claimed to have been written by Homer in the eighth century B.C., the septuagenarian King Nestor describes symptoms that appear to be those of Parkinson's Disease. He remarks that, despite the fact he still partakes of the armed struggle, he can no longer compete in athletic contests : my limbs are no longer steady, my friend, nor my feet, neither do my arms, as they once did, swing light from my shoulders.
Erasistratus of Ceos (310BC- 250BC) was a Greek anatomist and royal physician under Seleucus I Nicator of Syria. Along with fellow Greek Philosopher Herophilus, he founded a school of anatomy in Alexandria. Caelius Aurelianus wrote that Erasistratus of Ceos appeared to be describing the freezing that occurs in Parkinson's Disease when he termed paradoxos a type of paralysis in which a person walking along must suddenly stop and cannot go on, but after a while can walk again.
Aulus Cornelius Celsus (c25BC-c50AD), although apparently not a physician himself, compiled an encyclopedia entitled De artibus (25AD-35AD) that included De medicina octo libri (The Eight Books of Medicine). He advised against administering those who suffered tremor of the sinews with emetics or drugs that promoted urination, and also against baths and dry sweating. Relief from worry, rubbing of the limbs and their exercise by ball games and walking were indicated. The patient could eat whatever he wanted, but sexual activity should be restricted. If he should succumb, he should afterwards be rubbed in bed with olive oil, by boys, not men. Fine tremor was distinguished from a coarser shaking, which was independent of voluntary motion. So it resembled resting tremor. It could be alleviated by the application of heat and by bloodletting.
Pedanius Dioscorides (c40-c90) was an ancient Greek physician, pharmacologist and botanist from Anazarbus, Cilicia, Asia Minor, who practised in ancient Rome during the time of Nero. Dioscorides is famous for writing De Materia Medica, which is a precursor to all modern pharmacopeias, and is one of the most influential herbal books in history. Dioskorides wrote that beaver testes, prepared with vinegar and roses was helpful not only for the "lethargicall" but was also good for tremblings and convulsions, and for all diseases of the Nerves, being either drank or anointed on, and that it had a warming faculty.
Symptoms of Parkinson’s Disease were described by the ancient Greek physician Galen (129-200) who worked in ancient Rome. He wrote of tremors of the hand at rest. He wrote extensively on disorders of motor function, including the book On tremor, palpitation, convulsion and shivering. He distinguished between forms of shaking of the limb on the basis of origin and appearance. The aged, he noted, exhibited tremor because of a decline in their power to control motion of their limbs. The key to overcoming tremor was to abolish the proximal cause, but for the aged, this was impractical. He related that a person suffering from "catoche" has wild, wide open eyes, that he lies rigid in bed, as if he were made of wood. He also suffers from tremor, constipation and certain psychiatric symptoms.
Paul of Aigina (c625-c690) the Byzantine Greek physician, wrote the medical encyclopedia "Medical Compendium in Seven Books". For many years in the Byzantine Empire, this work contained the sum of all Western medical knowledge and was unrivaled in its accuracy and completeness. Paul of Aegina noted in his work On trembling that tremor was characteristic of alcoholism and what Mettler interpreted as "senile paralysis agitans".
An ancient Syrian medical text listed among its prescriptions for nervous diseases a complex unguent for "pains in the excretory organs and in the joints, and in cases of gout and palsy, and for those who have the tremors, and for all the pains which take place in the nerves". It consists of thirty-five components, including frankincense, rosemary, several types of cypress, cardamom, peppercorns, myrrh, mandragora and frogs. It was to rubbed on the paralysed or rigid limb.
Ibn Sina (c980-1037), the Persian polymath and foremost physician of his time discussed the various forms of motor unrest in his chapter on nervous disorders in the "Canon of Medicine". The description of tremor is not unexpectedly similar to that of Galen, as it was based on previous works including that of Galen. A range of measures are proposed according to the cause of the disorder. Bathing in sea-water or mineral baths (nitrate, arsenic, asphalt, sulphur) was recommended, as was the ever popular evacuation; composite preparations including made from the excretion of the anal gland of the beaver mixed with honey and cold oil, to which pills formed from rue (Ruta graveolens) and scolopendrium (Scolopendrium vulgare; hart's tongue).
The Italian artist, engineer and scientist Leonardo da Vinci (1452-1519) also studied anatomy, physiology and medicine. Leonardo da Vinci kept secret notebooks in which he wrote and sketched his ideas and observations. He saw people whose symptoms coincided with the tremors seen in Parkinson's Disease. Leonardo wrote in his notebooks that "you will see.....those who.....move their trembling parts, such as their heads or hands without permission of the soul; (the) soul with all its forces cannot prevent these parts from trembling."
There are examples of references to the symptoms of Parkinson's Disease in the plays of William Shakespeare (1564-1616). There is a reference to shaking palsy in the second part of Henry VI, during an exchange between Dick and Say. Say explains to Dick that it is shaking palsy rather than fear that was causing his shaking. Dick asks Say : "Why dost thou quiver, man ?" Say responds : "The palsy, and not fear, provokes me."
John Gerard (1545-1611/12)
botanist famous for his
herbal garden. He studied medicine and
travelled widely as a ship's
1597, he published a list of plants
cultivated in his
Holborn. It was basically a translation
of a 1583 Latin herbal illustrated. In Gerard's Herbal he writes of Sage
that it "strengthneth the sinewes, restoreth health to those that have the
palsie upon a moist cause, takes away shaking or trembling of the
members". He also mentioned cabbage, pellitory and mugwort for treating
trembling of the sinews.
Nicholas Culpeper (1616-1654) was an English botanist, herbalist, physician and astrologer. He published books, The English Physitian (1652) and the Complete Herbal (1653). The Complete Herbal contains both pharmaceutical and herbal knowledge. Among the recommendations in Complete Herbal, he suggests sage for "sinews, troubled with palsy and cramp". For centuries prior to this, Sage had also been recommended for tremor in the hands. Amongst other plant remedies Culpepper suggested for palsy and trembling were bilberries, briony (called "English mandrake"), and mistletoe. In the 1696 edition of his Pharmacopoeia Londinensis, a variety of substances were claimed to be useful in the treatment of "palsies", the "dead palsy", and "tremblings". These included "oil of winged ants" and preparations including earthworms.
The writer and antiquary, John Aubrey (1626-1697) wrote a biography of the philosopher Thomas Hobbes (1588-1679) titled "Life of Mr Thomas Hobbes of Malmesbury". In it, he used the term "Shaking Palsey" in his description of the progressive disability that had afflicted Thomas Hobbes. John Aubrey wrote of Thomas Hobbes that he "had the shaking Palsey in his hands.....and has grown upon him in degrees", and that ".....Mr Hobbs wase for severall yeares before he died so Paralyticall that he wase scarce able to write his name".
The Hungarian doctor Ferenc Pápai Páriz (1649-1716) described in 1690 in his medical text Pax Corporis not only individual signs of Parkinson's Disease, but all four cardinal signs : tremor, bradykinesia, rigor and postural instability. This was the first time that all the main symptoms of Parkinson's Disease have been formally described. The book was published in Hungarian, which because it is understood by so few people, has resulted in his description of Parkinson's Disease being ignored in the medical literature in favour of later descriptions of Parkinson's Disease wrongly being claimed to be the first.
George Cheyne (1671-1743) was a Scottish physician, psychologist, philosopher and mathematician. It is possible to interpret a disorder described in chapter XII of his The English Malady (1734) as parkinsonian. The subject of his discussion is the vaguely defined "Palsy", or "Paralytick Symptoms". "Palsy" was then defined as "a disease wherein the body, or some of its members lose their motion, and sometimes their sensation of feeling. The disease is never acute, often tedious, and in old people, almost incurable; and the patient for the most part drags a miserable life.....he totters and shakes, and becomes a dismal sight; as if no longer a man, but an animal half dead".
Francois Boissier de Sauvages de la Croix (1706-1767) provided one of the clearest descriptions of a parkinsonism-like condition in 1763. He spoke of a condition that he named "sclerotyrbe festinans" in which decreased muscular flexibility led to difficulties in the initiation of walking. Both of the cases he observed were in elderly people. His observations, along with those of Jerome David Gaubius (1705-1780) and Franciscus de la Boë (1614-1672) were subsequently cited by James Parkinson, because none of them described the whole syndrome, but they all described aspects of it.
John Hunter (1728-1793) was a distinguished Scottish surgeon. In his Croonian lecture in 1776, John Hunter gave a description of Lord L. that was similar to paralysis agitans. He wrote that "Lord L's hands are almost perpetually in motion, and he never feels the sensation in them of being tired. When he is asleep his hands, &c., are perfectly at rest; but when he wakes in a little time they begin to move". It has been suggested that James Parkinson may have attended this lecture. If he did, it may have had little influence on his subsequent description of Parkinson's Disease over thirty years later.
Parkinson's disease was first formally described in modern times in "An Essay on the Shaking Palsy," published in 1817 by a London physician named James Parkinson (1755-1824). James Parkinson described the medical history of six individuals who had symptoms of the disease that eventually bore his name. Unusually for such a description, he did not actually examine all these patients himself but observed them on daily walks. The purpose of his essay was to document the symptoms of the disorder, which he described as "Involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forwards, and to pass from a walking to a running pace : the senses and intellect being uninjured."
THE FIRST CLAIMED CURE
The English physician John Elliotson (1791-1868) published pamphlets concerning the disorder from 1827 to 1831 in the Lancet, which largely consisted of case reports, although some of those he described probably did not actually have Parkinson’s Disease. Amongst his preferred methods of treatment were bleeding, induction and maintenance of pus building, cauterization, purging, low diet and mercurialization, silver nitrate, arsenic, zinc sulphate, copper compounds, and the administration of iron as a tonic with some porter, which is a kind of dark beer. Elliotson made the first known claimed cure. He suggested that many young patients could be cured, although unreliably, using the carbonate of iron. On another occasion, he reported that the “disease instantly and permanently gave way” when he treated with iron a patient who had proved resistant to all other forms of therapy. This was well over a century before iron was found to be essential for the formation of L-dopa.
The first named patient
Wilhelm von Humboldt (1767-1835), a philosopher and diplomat, described in his letters from 1828 until his death in 1835, his own medical history, which gave a more complete description of the symptoms of Parkinson's Disease than had James Parkinson. They included resting tremor and especially problems in writing, called by him "a special clumsiness" that he attributed to a disturbance in executing rapid complex movements. In addition to lucidly describing akinesia, he was also the first to describe micrographia. He furthermore noticed his typical parkinsonian posture. There were incidental references in the following decades to what may (or may not) have been some of the symptoms of Parkinson’s Disease by Toulmouche (1833), Hall (1836, 1841), Elliotson (1839), Romberg (1846). However, the syndrome remained hardly known.
The naming of Parkinson's Disease
It was not until 1861 and 1862 that Jean-Martin Charcot (1825-1893) with Alfred Vulpian (1826-1887) added more symptoms to James Parkinson's clinical description (Charcot and Vulpian, 1861, 1862) and then subsequently confirmed James Parkinson's place in medical history by attaching the name Parkinson's Disease to the syndrome. Charcot added to the list of symptoms the mask face, various forms of contractions of hands and feet, akathesia as well as rigidity. It was quite difficult to understand from his description what was meant by referring to rigidity. It was only after Charcot gave a clinical lesson in 1868 that the difference became clear (Charcot, 1868). In 1867 Charcot introduced a treatment with the alkaloid drug hyoscine (or scopolamine) derived from the Datura plant, which was used until the advent of L-Dopa a century later. In 1876 Charcot described a patient suffering from Parkinson's disease in the absence of tremor, while rigidity was present. In this case there was no paralysis, so Charcot rejected the term paralysis agitans. Instead he suggested that the disease be referred to in future as Parkinson's disease.
THE FIRST KNOWN DEPICTIONS OF PARKINSON'S DISEASE
Paul Marie Louis Pierre Richer (1849-1933) was a French anatomist, physiologist, sculptor and anatomical artist. Paul Richer was an assistant to Jean-Martin Charcot at the Salpêtrière. In 1880, Jean-Marie Charcot completed a full clinical description of Parkinson's Disease. The symptoms were depicted by Paul Richer in drawings and a statuette of people with Parkinson's Disease. Along with a photograph, these are the first known depictions of Parkinson's Disease.
THE USE OF ELECTROTHERAPY
In 1868, Jean-Martin Charcot wrote that the French doctor Guillame Benjamin-Amand Duchenne (1806-1875), had reported a case in which he had cured paralysis agitans by application of galvanism. Duchenne had popularized the use of electrical means with his 1855 publication "On localized electrification, and on its application to pathology and therapy". The Irish physician U.S.L.Butler also claimed in 1869 that it cured a patient of paralysis agitans. William Sanders had mentioned in his paper in 1865 that the application of "galvanism" was without benefit for his patient. Hughlings Jackson, and William Gowers in 1893, who also tried it in paralysis agitans, were unstinting in their deprecation of the practice as "useless". Despite this, electrical stimulation in Parkinson’s disease continued to be used for decades more. In the 1924 edition of his handbook on electrotherapy, Toby Cohn commented that "remarkable results could not be expected", and that what benefits he had seen were largely psychological. In his 1941 review of the "modern treatment of parkinsonism", Critchley specifically warned against electricity and other spurious claims of curing the disease.
Expanding the known symptoms
After Charcot initiated the research of incomplete forms of Parkinson's disease, rigidity as a symptom grew in importance. In 1892 Béchet made the remark that all symptoms of Parkinson's disease were secondary to rigidity, tremor being an exception. Although Charcot and Parkinson pointed out that patients are moving slowly and with difficulty, they did not see this as a symptom in its own right. The slowness of movement was firstly taken into account by Claveleira and it became a new element of the definition. Jaccoud referred to this symptom in 1873 as akinesia. In 1886, the neurologist and artist, Sir William Richard Gowers, drew an illustration in 1886 as part of his documentation of Parkinson's Disease. Cruchet introduced the word bradykinesia and emphasized that this symptom should be mentioned in the first place in any definition of Parkinson's disease. Jules Froment, a French neurologist from Lyon, contributed to the study of parkinsonian rigidity during the 1920s.
In 1915, epidemics of Encephalitis Lethargica broke out around the world. It was first described in 1917 by the Austrian neurologist Constantin von Economo. It started off as an influenza like fever, and then developed in to symptoms such as headache, depression, delirium, confusion, motor disturbances, psychosis and stupor. Its symptoms were thought to encompass almost anything imaginable. Encephalitis Lethargica could cause death in a short period, or a type of sleep that might last days, weeks or months, but could also cause insomnia. Many of those that survived developed Postencephalitic Parkinsonism. Encephalitis Lethargica consequently led to a huge increase in the number of people with Parkinsonism. In the 1920's, the majority of Parkinsonian patients had Postencephalitic Parkinsonism.
THE USE OF ALKALOIDS
The first widespread use of the alkaloid atropine was in the 1920's. High dose atropine therapy dominated in the first half of the 1930's, achieving significant results, but it was accompanied by serious side effects. In 1926, the Bulgarian Ivan Raeff introduced in to the treatment of post encephalitic Parkinsonism what was later called the "Bulgarian treatment", which was white wine extract of the belladonna root. It was the belladonna root that was the effective part. The alkaloid content of the extract included varying amounts of hyoscyamine, atropine and, in lesser quantities, scopolamine and belladonnine. By the beginning of the 1940's most patients were being treated using belladonna alkaloids.
THE USE OF NEUROSURGERY
The first specific attempt to treat Parkinsonism surgically was reported by Leriche in 1912, via section of the posterior roots. The method relieved tremor or rigidity. Delmas-Marsalet claimed success in the treatment of rigidity with lesions of the cerebellum. Improvements in tremor were subsequently achieved by cortectomy, but often at the price of other functional losses. Cordotomy was directed against unilateral tremor and rigidity, and associated with fewer side effects. Meyers reported in 1951 that sectioning of pallidofugal fibres achieved the best results for relieving tremor and rigidity, but most surgeons chose to undertake a more direct attack on the pallidum, with equal success and a lower fatality rate. The publication of the first stereotactic atlas of the human brain by Spiegel and Wycis in 1952 increased the popularity of stereotactic surgery. The thalamus gradually became the preferred target, as the impact on tremor was greater and the operation was safer. By 1969, only 15% of patients were suitable for stereotactic operations, but up to 90% of those could expect relief from tremor and rigidity. After a sharp decline in stereotactic surgery, thalamotomy was revived in the 1970's for patients whose tremor was not helped by L-dopa. Laitinen and colleagues resumed operations on the medial pallidum in 1985.
NEW SYNTHETIC DRUGS
During the 1950's, synthetic drugs became the main methods of treating Parkinson's Disease. Due to their side effects and limited efficacy, the plant derived treatments were almost completely replaced by these synthetic drugs. The main type of drugs used were anti-cholinergics because of their ability to reduce muscle contraction. The most widely used of them was Benzhexol HCl, which had anti-cholinergic activity. It was marketed as Artane in the U.S.A.. It was then the primary choice for treating Parkinson's Disease. To a lesser extent anti- histaminergics were also used for Parkinson's Disease. They lessened the effect of allergic reactions, but also reduced muscle contraction. Anti-histaminergic drugs were sold commercially, but only two of them, diphenhydramine (Benadryl) and phenindamine (Theophorin), were widely used in Parkinson's Disease.
The biochemistry of L-dopa
The underlying biochemical changes in the brain were identified in the 1950s, due largely to the work of Swedish scientist Arvid Carlsson (born 1923). In the 1950s, Arvid Carlsson demonstrated that dopamine was a neurotransmitter in the brain and not just a precursor for norepinephrine, as had been previously believed. He developed a method for measuring the amount of dopamine in brain tissues and found that dopamine levels in the basal ganglia, a brain area important for movement, were particularly high. He then showed that giving animals the drug reserpine caused a decrease in dopamine levels and a loss of movement control. These effects were similar to the symptoms of Parkinson's disease. Arvid Carlsson subsequently won the Nobel Prize in Physiology or Medicine in 2000 along with co-recipients Eric Kandel and Paul Greengard.
The therapeutic use L-dopa
These findings led other doctors to try L-Dopa with human Parkinson's patients and found it to alleviate some of the symptoms in the early stages of Parkinson's. Unlike dopamine, its precursor L-Dopa could pass the blood brain barrier. The validity of the approach was shown by the transient benefit seen after injection of L-dopa. However, it was not of practical value as a treatment because of the severe toxicity associated with the injection. At this point, George C. Cotzias (1918-1977) made a critical observation that converted the transient response into a successful, large scale treatment. By starting with very small doses, given orally every two hours under continued observation, and gradually increasing the dose he was able to stabilize patients on large enough doses to cause a dramatic remission of their symptoms. The first study reporting improvements in patients with Parkinson's disease resulting from treatment with L-dopa was published in 1968.
SINEMET AND MADOPAR
There were efforts to improve on the administration of L-dopa in order to lessen its side effects. Dopa decarboxylase inhibitors reduced the metabolism of L-dopa. L-dopa combined with the decarboxylase inhibitor carbidopa was commercially launched in 1972 as Sinemet. Carbidopa made the product more effective by delaying the conversion of L-dopa into dopamine until the drug passed into the brain. The product was improved in 1991 when approval was given for Sinemet CR, which is a controlled release version. The combination of L-dopa with the decarboxylase inhibitor benserazide was commercially launched by Hoffmann-LaRoche in 1973 as Madopar. It was eventually produced in a controlled release version called Madopar CR.
During the 1970's, MAO inhibitors were introduced in order to prolong the effect of L-dopa by delaying its breakdown. By inhibiting Monoamine Oxidase, MAO inhibitors were shown to be able to raise dopamine levels, but the side effects were severe. In 1968 it was shown that there were two MAO enzymes, MAO-A and MAO-B. Inhibition of MAO-B was suitable for Parkinson's Disease. The inhibition of MAO-B was not subject to the same risks as MAO generally. The most suitable drug for use as a MAO-B inhibitor, called at the time E-250, was launched commercially in 1977. Its use gradually spread to other countries, but it was not approved in the U.S.A. until 1989. It came to be known as Selegiline. Since then, other MAO-B inhibitors such as Rasagiline have been used in Parkinson's Disease.
Despite L-dopa initially being seen as a major breakthrough, as many as 25% of people taking L-dopa did not respond to it. Other people were being caused widespread side effects due to using it, including dsykinesia. Consequently, directly stimulating the dopamine receptors using dopamine agonists appeared to some to be a better option. Cotzias demonstrated efficacy using apomorphine in the treatment of Parkinsonism. When used alongside L-dopa, its effects appeared to be additive. In 1974, another dopamine agonist, bromocriptine, for the treatment of Parkinson's Disease, was introduced. Following the initial success of bromocriptine, other dopamine agonists were clinically trialled, including cabergoline, lisuride, pergolide, pramipexole, ropinirole, and eventually, rotigotine. However, all of the dopamine agonists caused side effects of their own.
FROM 2000 ONWARDS
From 2000 onwards, L-dopa primarily as Sinemet and Madopar was already being widely used in the treatment of Parkinson's Disease, as were MAO-B inhibitors and dopamine agonists. Even more variants of each or them were being used, assessed or introduced. The primary new means of treating Parkinson's Disease were different formats of L-dopa, Deep Brain Stimulation, and COMT inhibitors. Although Stem cell surgery had been claimed capable of curing Parkinson's Disease it subsequently failed all its clinical trials. Besides these methods there was a proliferation of new approaches to the treatment of Parkinson's Disease that have become progressively more diverse and scientifically unsound.
After thousands of years of describing and treating Parkinson's Disease, and despite the enormous resources used in developing new treatments, each method of treating Parkinson's Disease has been found to have serious inadequacies. The ultimate therapy, one that was able to rid symptoms without side effects is still to be revealed.