Treatments and drugs

Your initial response to Parkinson's treatment can be dramatic. Over time, however, the benefits of drugs frequently diminish or become less consistent, although symptoms can usually still be fairly well controlled. Your doctor may recommend lifestyle changes, such as physical therapy, a healthy diet and exercise, in addition to medications. In some cases, surgery may be helpful.

Medications
Medications can help manage problems with walking, movement and tremor by increasing the brain's supply of dopamine. Taking dopamine itself is not helpful, because it is unable to enter your brain.

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Levodopa. The most effective Parkinson's drug is levodopa, which is a natural substance that we all have in our body. When taken by mouth in pill form, it passes into the brain and is converted to dopamine. Levodopa is combined with carbidopa to create the combination drug Sinemet. The carbidopa protects levodopa from premature conversion to dopamine outside the brain; in doing that, it also prevents nausea. In Europe, levodopa is combined with a similar substance, benserazide, and is marketed as Madopar.

As the disease progresses, the benefit from levodopa may become less stable, with a tendency to wax and wane ("wearing off"). This then requires medication adjustments. Levodopa side effects include confusion, delusions and hallucinations, as well as involuntary movements called dyskinesia. These resolve with dose reduction, but sometimes at the expense of reduced parkinsonism control.
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Dopamine agonists. Unlike levodopa, these drugs aren't changed into dopamine. Instead, they mimic the effects of dopamine in the brain and cause neurons to react as though dopamine is present. They are not nearly as effective in treating the symptoms of Parkinson's disease. However, they last longer and are often used to smooth the sometimes off-and-on effect of levodopa.

This class includes pill forms of dopamine agonists, pramipexole (Mirapex) and ropinirole (Requip), as well as a patch form, rotigotine (Neupro). Pergolide (Permax) has been withdrawn from the market because of its association with heart valve problems. A short-acting injectable dopamine agonist, apomorphine (Apokyn), is used for quick relief.

The side effects of dopamine agonists include those of carbidopa-levodopa, although they're less likely to cause involuntary movements. However, they are substantially more likely to cause hallucinations, sleepiness or swelling. These medications may also increase your risk of compulsive behaviors such as hypersexuality, compulsive gambling and compulsive overeating. If you are taking these medications and start behaving in a way that's out of character for you, talk to your doctor.
* MAO B inhibitors. These types of drugs, including selegiline (Eldepryl) and rasagiline (Azilect), help prevent the breakdown of both naturally occurring dopamine and dopamine formed from levodopa. They do this by inhibiting the activity of the enzyme monoamine oxidase B (MAO B) — the enzyme that metabolizes dopamine in the brain. Side effects are rare but can include serious interactions with other medications, including drugs to treat depression and certain narcotics.
* Catechol O-methyltransferase (COMT) inhibitors. These drugs prolong the effect of carbidopa-levodopa therapy by blocking an enzyme that breaks down levodopa. Tolcapone (Tasmar) has been linked to liver damage and liver failure, so it's normally used only in people who aren't responding to other therapies. Entacapone (Comtan) doesn't cause liver problems and is now combined with carbidopa and levodopa in a medication called Stalevo.
* Anticholinergics. These drugs have been used for many years to help control the tremor associated with Parkinson's disease. A number of anticholinergic drugs, such as trihexyphenidyl and benztropine (Cogentin), are available. However, their modest benefits may be offset by side effects such as confusion and hallucinations, particularly in people over the age of 70. Other side effects include dry mouth, nausea, urine retention — especially in men with an enlarged prostate — and severe constipation.
* Antivirals. Doctors may prescribe amantadine (Symmetrel) alone to provide short-term relief of mild, early-stage Parkinson's disease. It also may be added to carbidopa-levodopa therapy for people in the later stages of Parkinson's disease, especially if they have problems with involuntary movements (dyskinesia) induced by carbidopa-levodopa. Side effects include swollen ankles and a purple mottling of the skin.

Physical therapy
Exercise is important for general health, but especially for maintaining function in Parkinson's disease. Physical therapy may be advisable and can help improve mobility, range of motion and muscle tone. Although specific exercises can't stop the progress of the disease, improving muscle strength can help you feel more confident and capable. A physical therapist can also work with you to improve your gait and balance. A speech therapist or speech pathologist can improve problems with speaking and swallowing.

Surgery
Deep brain stimulation is the most common surgical procedure to treat Parkinson's disease. It involves implanting an electrode deep within the parts of your brain that control movement. The amount of stimulation delivered by the electrode is controlled by a pacemaker-like device placed under the skin in your upper chest. A wire that travels under your skin connects the device, called a pulse generator, to the electrode.

Deep brain stimulation is most often used for people who have advanced Parkinson's disease who have unstable medication (levodopa) responses. It can stabilize medication fluctuations and reduce or eliminate involuntary movements (dyskinesias). Tremor is especially responsive to this therapy. Deep brain stimulation doesn't help dementia and may make that worse.

Like any other brain surgery, this procedure has risks — such as brain hemorrhage or stroke-like problems. Infection also may occur, requiring parts of the device to be replaced. In addition, the unit's battery beneath the skin of the chest wall must be surgically replaced every few years. Deep brain stimulation isn't beneficial for people who don't respond to carbidopa-levodopa.

23andMe already testing for rare Parkinson's mutations?

23andMe already testing for rare Parkinson's mutations?

Posted on: March 23, 2009 9:15 AM, by Daniel MacArthur
This casual aside on a recent post on personal genomics company 23andMe's corporate blog caught my eye:

Mutations in several other genes have also been associated with Parkinson's disease, but these are extremely rare. Many have been found only in one or two families. While these mutations are so rare that they are not covered by 23andMe (to date we have found no customers with any of them), studying them could help scientists better understand the mechanisms of Parkinson's generally... [my emphasis]

In other words, the company already has probes on its custom chip targeting these variants, but it isn't yet reporting results back to customers.

Why isn't it reporting back? If you'd asked me a couple of months ago, I'd say the motivation was probably to avoid the regulatory hassles associated with testing overtly clinical markers - but the company's willingness to provide results for large-effect variants associated with breast cancer pretty much rules that out.

Instead, the most likely reason to hold back on giving results back to consumers is (perfectly reasonable) caution about the reliability of the test. Screening for extremely rare variants is tricky for two reasons: firstly, since there are very few individuals around who carry the mutation, obtaining positive controls is difficult; and secondly, screening accuracy needs to be extremely high to keep down the rate of false positives.

To illustrate that last point, let's say there was a genetic variant with a population frequency of just 0.1% (1 in every 1000 people carry it)*. Now, let's say you have a test with false positive and false negative rates of just 1 in every 1000 tests, and you run that test on one million people. Of the 1000 carriers in the population, the test will only miss one; but it will also give a positive result for 999 people who are non-carriers. In other words, even for this extremely accurate hypothetical test, only 50% of the people who test positive are actually carriers.

This means that testing for rare variants requires exceptionally high standards of accuracy, probably higher than could reasonably be expected from chip-based assays. Given the risks of reporting potentially unreliable results back to customers for serious risk variants it makes good sense for 23andMe to hold off until it has developed extra assays for quality control; and it's unlikely to do this until it has seen at least a few customers who actually do test positive for the variant in question.

As for obtaining samples from real carriers to enable the development of validation assays: what better way to do that than to recruit 10,000 customers suffering from Parkinson's? Targeted recruitment of customers with other diseases will no doubt follow.

It is now abundantly clear that 23andMe is intent on moving into the overtly clinical domain; Navigenics' purchase of its Affymetrix testing lab and deCODE's move into disease-specific genetic tests are other signs that this is a shift that will involve the entire personal genomics industry.

Personal genomics is getting serious.