Parkinson’s disease (also known as Parkinson disease or PD) is a degenerative disorder of the central nervous system that often impairs the sufferer’s motor skills and speech.
Parkinson’s disease belongs to a group of conditions called movement disorders. It is characterized by muscle rigidity, tremor, a slowing of physical movement (bradykinesia), and in extreme cases, a loss of physical movement (akinesia). The primary symptoms are the results of excessive muscle contraction, normally caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain. Secondary symptoms may include high level cognitive dysfunction and subtle language problems. PD is both chronic and progressive.
PD is the most common cause of parkinsonism, a group of similar symptoms. PD is also called “primary parkinsonism” or “idiopathic PD” (“idiopathic” meaning of no known cause). While most forms of parkinsonism are idiopathic, there are some cases where the symptoms may result from toxicity, drugs, genetic mutation, head trauma, or other medical disorders.
Symptoms of Parkinson’s disease have been known and treated since ancient times. However, it was not formally recognized and its symptoms were not documented until 1817 in An Essay on the Shaking Palsy by the British physician James Parkinson. Parkinson’s disease was then known as paralysis agitans, the term “Parkinson’s disease” being coined later by Jean-Martin Charcot. The underlying biochemical changes in the brain were identified in the 1950s, due largely to the work of Swedish scientist Arvid Carlsson who later went on to win a Nobel Prize. L-dopa entered clinical practice in 1967, and the first study reporting improvements in patients with Parkinson’s disease resulting from treatment with L-dopa was published in 1968.
The cardinal symptoms are:
Other motor symptoms include:
There are currently no blood or laboratory tests that have been proven to help in diagnosing PD. Therefore the diagnosis is based on medical history and a neurological examination. The disease can be difficult to diagnose accurately. The Unified Parkinson’s Disease Rating Scale is the primary clinical tool used to assist in diagnosis and determine severity of PD. Indeed, only 75% of clinical diagnoses of PD are confirmed at autopsy. Early signs and symptoms of PD may sometimes be dismissed as the effects of normal aging. The physician may need to observe the person for some time until it is apparent that the symptoms are consistently present. Usually Doctors look for shuffling of feet and lack of swing in the arms. Doctors may sometimes request brain scans or laboratory tests in order to rule out other diseases. However, CT and MRI brain scans of people with PD usually appear normal.
Most people with Parkinson’s disease are described as having idiopathic Parkinson’s disease (having no specific cause). There are far less common causes of Parkinson’s disease including genetic, toxins, head trauma, and drug-induced Parkinson’s disease.
In recent years, a number of specific genetic mutations causing Parkinson’s disease have been discovered, including in certain populations (Contursi, Italy). These account for a small minority of cases of Parkinson’s disease. Somebody who has Parkinson’s disease is more likely to have relatives that also have Parkinson’s disease. However, this does not mean that the disorder has been passed on genetically.
Genetic forms that have been identified include:
One theory holds that the disease may result in many or even most cases from the combination of a genetically determined vulnerability to environmental toxins along with exposure to those toxins. This hypothesis is consistent with the fact that Parkinson’s disease is not distributed homogenously throughout the population: rather, its incidence varies geographically. It would appear that incidence varies by time as well, for although the later stages of untreated PD are distinct and readily recognizable, the disease was not remarked upon until the beginnings of the Industrial Revolution, and not long thereafter become a common observation in clinical practice. The toxins most strongly suspected at present are certain pesticides and transition-series metals such as manganese or iron, especially those that generate reactive oxygen species, and or bind to neuromelanin, as originally suggested by G.C. Cotzias. In the Cancer Prevention Study II Nutrition Cohort, a longitudinal investigation, individuals who were exposed to pesticides had a 70% higher incidence of PD than individuals who were not exposed.
MPTP is used as a model for Parkinson’s as it can rapidly induce parkinsonian symptoms in human beings and other animals, of any age. MPTP was notorious for a string of Parkinson’s disease cases in California in 1982 when it contaminated the illicit production of the synthetic opiate MPPP. Its toxicity likely comes from generation of reactive oxygen species through tyrosine hydroxylation.
Other toxin-based models employ PCBs, paraquat (a herbicide) in combination with maneb (a fungicide) rotenone (an insecticide), and specific organochlorine pesticides including dieldrin and lindane. Numerous studies have found an increase in Parkinson disease in persons who consume rural well water; researchers theorize that water consumption is a proxy measure of pesticide exposure. In agreement with this hypothesis are studies which have found a dose-dependent an increase in PD in persons exposed to agricultural chemicals.
Past episodes of head trauma are reported more frequently by sufferers than by others in the population. A methodologically strong recent study found that those who have experienced a head injury are four times more likely to develop Parkinson’s disease than those who have never suffered a head injury. The risk of developing Parkinson’s increases eightfold for patients who have had head trauma requiring hospitalization, and it increases 11-fold for patients who have experienced severe head injury. The authors comment that since head trauma is a rare event, the contribution to PD incidence is slight. They express further concern that their results may be biased by recall, i.e., the PD patients because they reflect upon the causes of their illness, may remember head trauma better than the non-ill control subjects.
These limitations were overcome recently by Tanner and colleagues, who found a similar risk of 3.8, with increasing risk associated with more severe injury and hospitalization.
Antipsychotics, which are used to treat schizophrenia and psychosis, can induce the symptoms of Parkinson’s disease (or parkinsonism) by lowering dopaminergic activity. Due to feedback inhibition, L-dopa can also eventually cause the symptoms of Parkinson’s disease that it initially relieves. Dopamine agonists can also eventually contribute to Parkinson’s disease symptoms by increasing the sensitivity of dopamine receptors.
The most widely used form of treatment is L-dopa in various forms. L-dopa is transfomed into dopamine in the dopaminergic neurons by L-aromatic amino acid decarboxylase (often known by its former name dopa-decarboxylase). However, only 1-5% of L-DOPA enters the dopaminergic neurons. The remaining L-DOPA is often metabolised to dopamine elsewhere, causing a wide variety of side effects. Due to feedback inhibition, L-dopa results in a reduction in the endogenous formation of L-dopa, and so eventually becomes counterproductive.
Carbidopa and benserazide are dopa decarboxylase inhibitors. They help to prevent the metabolism of L-dopa before it reaches the dopaminergic neurons and are generally given as combination preparations of carbidopa/levodopa (co-careldopa) (e.g. Sinemet, Parcopa) and benserazide/levodopa (co-beneldopa) (e.g. Madopar). There are also controlled release versions of Sinemet and Madopar that spread out the effect of the L-dopa. Duodopa is a combination of levodopa and carbidopa, dispersed as a viscous gel. Using a patient-operated portable pump, the drug is continuously delivered via a tube directly into the upper small intestine, where it is rapidly absorbed.
Talcopone inhibits the COMT enzyme, thereby prolonging the effects of L-dopa, and so has been used to complement L-dopa. However, due to its possible side effects such as liver failure, it’s limited in its availability.
A similar drug, entacapone, has similar efficacy and has not been shown to cause significant alterations of liver function. A recent follow-up study by Cilia and colleagues looked at the clinical effects of long-term administration of entacapone on motor performance and pharmacological compensation is advanced PD patients with motor fluctuations. 47 patients with advanced PD and motor fluctuations were followed for six years from the first prescription of entacapone and showed a stabilization of motor conditions, reflecting entacapone can maintain adequate inhibition of COMT over time.
Mucuna pruriens, is a natural source of therapeutic quantities of L-dopa.
The dopamine-agonists bromocriptine, pergolide, pramipexole, ropinirole , cabergoline, apomorphine, and lisuride, are moderately effective. These have their own side effects including those listed above in addition to somnolence, hallucinations and /or insomnia. Dopamine agonists initially act by stimulating some of the dopamine receptors. However, they cause the dopamine receptors to become progressively less sensitive, thereby eventually increasing the symptoms.
Dopamine agonists can be useful for patients experiencing on-off fluctuations and dyskinesias as a result of high doses of L-dopa. Apomorphine can be administered via subcutaneous injection using a small pump which is carried by the patient. A low dose is automatically administered throughout the day, reducing the fluctuations of motor symptoms by providing a steady dose of dopaminergic stimulation. After an initial “apomorphine challenge” in hospital to test its effectiveness and brief patient and caregiver, the primary caregiver (often a spouse or partner) takes over maintenance of the pump. The injection site must be changed daily and rotated around the body to avoid the formation of nodules. Apomorphine is also available in a more acute dose as an autoinjector pen for emergency doses such as after a fall or first thing in the morning.
Selegiline and rasagiline reduce the symptoms by inhibiting monoamine oxidase-B (MAO-B), which inhibits the breakdown of dopamine secreted by the dopaminergic neurons. By-products of selegiline include amphetamine and methamphetamine, which can cause side effects such as insomnia. Use of L-dopa in conjunction with selegiline has increased mortality rates that have not been effectively explained. Another side effect of the combination can be stomatitis. One report raised concern about increased mortality when MAO-B inhibitors were combined with L-dopa; however subsequent studies have not confirmed this finding. Unlike other non selective monoamine oxidase inhibitors, tyramine-containing foods do not cause a hypertensive crisis.
Treating Parkinson’s disease with surgery was once a common practice. But after the discovery of levodopa, surgery was restricted to only a few cases. Studies in the past few decades have led to great improvements in surgical techniques, and surgery is again being used in people with advanced PD for whom drug therapy is no longer sufficient. Deep brain stimulation is presently the most used surgical means of treatment, but other surgical therapies that have shown promise include surgical lesion of the subthalamic nucleus and of the internal segment of the globus pallidus, a procedure known as pallidotomy. The engineer who designed and built the equipment shown in the image is Rex Whitby of Hertfordshire.
The most widely practiced treatment for the speech disorders associated with Parkinson’s disease is Lee Silverman Voice Treatment (LSVT). LSVT focuses on increasing vocal loudness.
A study found that an electronic device providing frequency-shifted auditory feedback (FAF) improved the clarity of Parkinson’s patients’ speech.
Regular physical exercise and/or therapy, including in forms such as yoga, tai chi, and dance can be beneficial to the patient for maintaining and improving mobility, flexibility, balance and a range of motion.