Risk Factors for Dyskinesia in Patients With Parkinson Disease

EP: 1.Treatment Options for Parkinson Disease

EP: 2.Use of Parkinson Disease Treatments and Identification of OFF Episodes in Clinical Practice

EP: 3.Challenges With Parkinson Disease Treatments

EP: 4.Pathophysiology of Dyskinesia in Parkinson Disease

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EP: 5.Risk Factors for Dyskinesia in Patients With Parkinson Disease

EP: 6.Diagnosis of Dyskinesia and Impact on Quality of Life of Patients With Parkinson Disease

EP: 7.Challenges in Balancing Treatment of OFF Episodes and Dyskinesia in Parkinson Disease

EP: 8.Treatment of Dyskinesia in Patients with Parkinson’s Disease

EP: 9.Amantadine Formulations in Treatment of Dyskinesia in Parkinson Disease

EP: 10.Studies With Amantadine-DR/ER for Treatment of Dyskinesia

EP: 11.Amantadine DR/ER for Dyskinesia in Parkinson Disease: Safety Profile and Ideal Patient

EP: 12.Use of Other Amantadine Formulations in Parkinson Disease

EP: 13.Surgical Options and Emerging Treatments for Parkinson Disease

EP: 14.Unmet Needs and Improving Diagnosis of Dyskinesia in Parkinson Disease

Daniel E. Kremens, MD, JD: Typically, how long after a patient starts their dopaminergic therapy, do we see the dyskinesia emerge?

Robert A. Hauser, MD, MBA: It can occur quite early. In the L-Dopa study, which was conducted by the Parkinson Study Group, they were looking at patients with early Parkinson disease randomized to placebo or levodopa. Just in the first 9 months, there was significantly more dyskinesia observed in patients on the highest dose of levodopa, which was 600 mg per day. So, dyskinesia can emerge quite early, and this increases over time such that 60% to 70% of patients develop dyskinesia through about 10 years or so.

Daniel E. Kremens, MD, JD: There was an interesting paper from the PPMI [Parkinson’s Progression Markers Initiative] project recently. In their first cut, their data looked at dyskinesia emerging in most of the patients in that study at 3 years. I think there’s a perception among many physicians that dyskinesia is a late problem, but among those folks who see a lot of Parkinson disease, we realize that some patients can get it early. Speaking of patients getting it early, Raj, what are the risk factors? I know Bob touched on a couple of these, but what are the risk factors for developing dyskinesia?

Rajesh Pahwa, MD: There are certain patients who might be at high risk to have dyskinesia. Bob brought up the issue of age. Of course, the younger the patient, the more likely they would have dyskinesia. We know that the longer the disease duration, the more likely the patients will develop it. Like you said, at 3 years compared to 10 years, you’re going to see a lot more dyskinesia. Then, there’s the dose of levodopa. Like Bob mentioned with the L-Dopa study, we saw at 9 months, the patients who are getting 600 mg are much more likely to have dyskinesia than patients who are getting 300 mg a day. The other thing we have found is that women are more likely to have dyskinesia. For some reason, that is another one. We believe it might be related to their weight, but we don’t know why women are more likely to have dyskinesia.

Daniel E. Kremens, MD, JD: In the recent PPMI paper that I was talking about, that was confirmed and it was independent of weight, so it’s a fascinating thing. Could it somehow be estrogen related, something like that? We don’t know the answer to that, but again, just showing how complex dyskinesia can be.

Rajesh Pahwa, MD: These are some of the risk factors. That does not mean that because of these risk factors, we need to give them a lower dose. We still use the dose that is going to provide them with the best efficacy to help with their symptoms.

Daniel E. Kremens, MD, JD: In the old days, we would give them dopamine agonists rather than levodopa to start with, on the thought that you could somehow delay dyskinesia. Fernando, were you about to say something?

Fernando Pagan, MD: Yes. I want to point out how you deliver the medicine, how much you give. You brought that up, Dr Kremens, that if you look at the L-Dopa study, just within 40 weeks of treatment, you could see at the higher dose group, the 600-mg group, they got 2 tablets 3 times a day, there was already 16% of the patients with dyskinesia. It was almost a 5-fold increase in dyskinesia compared to the 300 and 150 mg in the placebo group. They already developed dyskinesia within 40 weeks of treatment. So how much and how you deliver it matters. Then when you go further out with other studies, like the STRIPE or FIRST-STEP, again, every time you go higher with the amount of levodopa, you see a higher incidence of dyskinesia. The more pulsatile, the higher the dose, it’s definitely one of the contributing factors we’ve seen in clinical trials. I think what Dr Pahwa brought up is very important. All those different risk factors, the body weight, young individuals, and women, are some of our most challenging cases we have in our clinics.

Rajesh Pahwa, MD: It’s interesting, patients are having more OFF time, so we are trying to give them more levodopa, and what is resulting is more dyskinesia.

Daniel E. Kremens, MD, JD: Another other interesting thing that there is emerging evidence for is that it may also be related to how long the patient has had their Parkinson disease, independent of the dosing of the levodopa and things like that. I think we always point to a high dose of levodopa. But there was this fascinating study where patients in Ghana were compared to patients in Italy. Patients in Ghana don’t have access to essential medications such as levodopa, and so they were not started on treatment for some time compared to Italian patients, who had full access to levodopa. But once the patients from Ghana were started on levodopa, they developed their dyskinesia very quickly. They had had disease for a long time, relatively little levodopa exposure, but nevertheless developed dyskinesia quickly. So, there may be another independent risk factor of just length of time with disease also increasing your risk of dyskinesia.

Rajesh Pahwa, MD: Dan, I think we need to point to 2 things. One is many patients and physicians try to delay the use of levodopa, hoping that they can delay the onset of dyskinesia. But all they’re doing is that the dyskinesia is going to come on earlier rather than later, and that should not be a reason. The other thing is, even though we are talking about the dose of levodopa, that the higher dose causes more dyskinesia, I don’t want physicians to take the message that I would rather have my patient be undertreated, because it’s the same issue. Then you are having the patient have more OFF time and they’re not functioning well. We should not restrict the levodopa for the person who needs it. We still need to give them good control of their symptoms.

Fernando Pagan, MD: That’s an important point that Dr Pahwa brought up. When we look at the studies that show a higher dose, in most of those studies the medications were given in a pulsatile fashion, because we can give the same dose in a more controlled-release fashion or more continuous delivery, and we see more ON time with reduction in dyskinesia, so that’s an important point. I would not withhold the dose that a patient needs in order to move. In fact, most patients who have dyskinesia, they’d rather be dyskinetic than be OFF. As Dr Ondo pointed out, sometimes those OFF periods can be accompanied by very painful dystonia or pain, whereas dyskinesias are not painful.

Daniel E. Kremens, MD, JD: Bob, you want to say something?

Robert A. Hauser, MD, MBA: Yes. I want to bring up one another interesting thing, which is that when you do analyses, motor fluctuations are an important risk factor for the development of dyskinesia, and dyskinesia is an important risk factor for the development of motor fluctuations. That shows that these 2 things are opposite sides of the same coin, and they’re intimately related. As you suggested, these may have to do with the changes going on over time in Parkinson disease, and may be related to increased glutamatergic stimulation. It’s an interesting phenomenon.

Transcript Edited for Clarity