PD is a progressive, neurodegenerative disorder of the central nervous system.
PD involves the death or impairment of vital nerve cells (neurons) in an area of the midbrain called the substantia nigra. Normally, these cells produce the chemical dopamine, which sends messages to the part of the brain that controls muscles. When dopamine is missing, messages that enable the body to move smoothly and with coordination cannot travel across the nerve connections in the brain. Everyone loses dopamine as they grow older. With PD, the rate of loss is greater.
The cause of the dopamine cell death or impairment is not known. Some possibilities are:
When 80 percent of the dopamine-producing cells are damaged, the symptoms of PD appear.
There are several genes that are known to cause PD, but they account for a very small minority of cases. The most important is a gene called parkin. The parkin gene creates a protein, also called parkin, that helps to break down defective proteins inside brain cells (neurons). When the parkin gene is altered, or mutated, this function is impaired. It is hypothesized that the accumulation of defective proteins contributes to death of neurons. Two mutated copies of parkin are needed to develop PD. This type of inheritance pattern is called "autosomal recessive." One copy of the defective gene is inherited from each parent. Parkin mutations cause young-onset PD, with symptoms beginning usually in the 40s. Parkin mutations are the most common genetic cause of PD, but still account for less than one percent of all cases.
Other known genes for PD include alpha-synuclein, DJ-1, PINK-1, and UCHL-1, but altogether these represent only a small number of PD cases.
More than one million, and perhaps closer to one-and-a-half million, people in the United States have Parkinson’s disease.
The single biggest risk factor for PD is advancing age. Men have a slightly higher risk compared to women. Family history is also an important risk factor. Individuals with an affected first-degree relative (parent or sibling) are estimated to have an approximately doubled risk for developing PD. This increased risk is likely to be a combination of environmental and genetic factors that close relations have in common.
The single factor that has been most consistently associated with a reduced risk of PD is cigarette smoking, which has been demonstrated in numerous studies. It is not known whether smoking confers a genuine protective effect, or whether individuals who are prone to develop PD for other reasons are also prone to avoid smoking. Nonetheless, the negative impact on general health from smoking is enormous, far in excess of any slight reduction in risk for PD. Smoking cannot be recommended as a strategy for avoiding PD.
Caffeine consumption is also associated with a reduced incidence of PD. In women, hormone replacement therapy appears to be associated with a reduced incidence in women who consume only small quantities of caffeine, but may be a risk factor in those who consume more than five cups per day.
The cause of the dopamine cell death or impairment is not known. Some possibilities are:
The presence of at least 2 of the above 4 cardinal features is necessary for the diagnosis of PD.
Parkinson's Disease responds to Levodopa.
Treatments available include medication treatment, non-pharmacological treatments, and surgical options for treatment:
There are six major groups of drugs used to treat PD:
(dopamine precursor) Dopamine does not cross the blood brain barrier and so it can not be used for treatment. Levodopa is converted to dopamine by dopamine decarboxylase. It is the most effective drug in the treatment of PD. Levodopa is used in combination with carbidopa, which blocks its peripheral decarboxylation and allows for higher central bioavailability. The combination preparation is marketed as Sinemet in the US and Madopar in Europe. Sinemet has a short half-life of 3-4 hours, requiring at least three times a day dosing.
On average, at least 75 mg of carbidopa a day are necessary to block peripheral dopamine decarboxylation. Thus, Sinemet 25/100 is the preparation most frequently used. Sustained release preparations of Sinemet (Sinemet CR) have a longer half-life of 4-6 hours and provide steadier levodopa concentrations in the brain. Sinemet CR is usually a better choice for patients with early disease. With advancing disease, it may not give the quick onset of action on which patients depend.
The most common side effect of levodopa is nausea, which can be prevented by increasing the dose of carbidopa as well as instructing patients to take medications 30 minutes after meals. In more severe cases, using more carbidopa (Lodosyn 25 mg tid) may be necessary. Some patients, particularly older patients with underlying cognitive deficits, may experience drug-induced confusion as well as vivid dreams and hallucinations. Patients should be warned of the possibility of positional lightheadedness due to drug induced orthostatic hypotension.
Levodopa as well as all other dopaminergic medications has to be introduced slowly with titration in small increments in order to allow the patient to adjust to the drug. In this way the majority of patients are able to tolerate it.
Compared to levodopa that has to be presynaptically converted to dopamine, dopamine agonists work on postsynaptic dopamine receptors. They are somewhat less effective then levodopa, but are less prone to produce drug-induced dyskinesias (involuntary movements). They have a longer half-life than levodopa, providing more steady dopamine receptor stimulation. Four dopamine agonists are available in the U.S. for PD treatment:
The greatest advantage of dopamine agonists is ability to delay onset of dyskinesias and fluctuations, which makes them a preferred choice of initial treatment for younger patients with relatively mild symptoms. At some point majority of patients will require addition of Sinemet. Comparative efficacy of dopamine agonists is unknown as very few controlled studies have been done. It should be noted that the absence of an adequate response to one dopamine agonist does not predict lack of benefit from another. All dopamine agonists should be started at a low dose and slowly titrated up. The average titration takes 6-8 weeks depending on the drug. The side effect profile of dopamine agonists is very similar to levodopa, but they are more prone to cause GI side effects as well as drug induced confusion. Caution should be exercised in the use of dopamine agonists in elderly or cognitively impaired patients.
Eldepryl (Selegiline, Deprenyl) is an MAO-B antagonist. MAO-B is an enzyme responsible for the metabolism of dopamine. Inhibition of MAO-B allows higher bioavailability of dopamine. This mechanism explains the symptomatic benefit of selegiline, though it is certainly mild when compared to levodopa or dopamine agonists. Selegiline is best known as a potential neuroprotective agent, possibly slowing the progression of early PD based on the results of the DATATOP study. In that study, newly diagnosed PD patients who were placed on selegiline did not require symptomatic treatment with levodopa for a longer period of time when compared to patients treated with placebo. While this could be due to selegiline symptomatic effect, a potential neuroprotective benefit of selegiline could be attributed to its antioxidant properties. Oxidative stress is believed to play a vital role in the degeneration of the SNc cells. Subsequent studies failed to convincingly document a sustained neuroprotective benefit of selegiline in humans although it certainly has such an effect in animal models. In our practice, we use selegiline in early, otherwise uncomplicated PD. Financial considerations should also be taken into the account when prescribing selegiline.
This is the newest group of anti-PD medications. The two available in the US are tolcapone (Tasmar) and entacapone (Comtan). Tasmar is rarely used due to the risk of liver toxicity. COMT is an enzyme that contributes to the metabolism of levodopa and dopamine peripherally and centrally. By inhibiting dopa metabolism in plasma, they allow higher amounts of levodopa to cross the blood brain barrier without actually increasing the dose of levodopa. Comtan increases the dopamine half-life without increasing its peak serum concentration. It is useful in patients with end of dose wearing off when levodopa/carbidopa benefit does not last from one dose to the next. Aside from levodopa-like side effects, Comtan can cause diarrhea.
The ones that are used most commonly are Artane (trihexyphenidyl) and Cogentin (benztropine). This is the oldest group of medications used to treat PD. They are most effective in patients with tremor predominant disease. Great caution should be exercised in the use of anticholinergics in the elderly patients due to their high propensity to cause cognitive side effects. Patients should be warned of the other side effects that include visual blurring, dryness of the mouth and urinary retention. Anticholinergics may be contraindicated in patients with glaucoma.
Amantadine (Symmetrel) is an antiviral drug that was empirically found to be effective in PD. It is used in early tremor predominant PD, but also has been shown to be of benefit as adjunctive treatment in advanced, fluctuating PD with dyskinesias.
Of Note: Antidepressants do not affect PD symptoms per se, but can be quite effective in the management of PD patients with depression, a common consequence of disease. Serotonin reuptake inhibitors, like Paxil or Zoloft are usually effective and well tolerated. Tricyclic antidepressants, like Elavil (amitriptyline) in low doses, can be quite useful for the management of parkinson- related pain.
More information about surgical options is available on our Surgical Management page.