Stuart H. Isaacson, MD, FAAN, offers insight into the challenges faced when attempting to achieve long-term symptom control for patients with Parkinson disease.
Matt Hoffman: I'm Matt Hoffman with NeurologyLive®, and I'm here with Stuart Isaacson, MD, FAAN, at the 75th Annual American Academy of Neurology meeting. Dr. Isaacson, thanks so much for sitting down with me.
Stuart Isaacson, MD, FAAN: Great to be with you today.
Matt Hoffman: Today, we're gonna talk a little bit about optimizing the control of Parkinson disease, specifically optimizing the symptoms of disease with novel treatment options. A lot of things have entered the market in the last 5 to 10 years, so lots to talk about. But of course, we would be remiss not start with the gold standard, levodopa. Right now, levodopa, and obviously, several other therapies, are available to treat Parkinson disease. But long-term symptom control is still a challenge for many patients. Can you explain why currently that's still the case and the clinic and what some of those challenges are?
Stuart Isaacson, MD, FAAN: Well, in Parkinson disease, the motor symptoms at least reflect this depletion of dopamine in the motor pathways of the brain. And the miracle of levodopa when it was identified as a therapy for Parkinson in the mid-1960s, was that after swallowing levodopa, 20 minutes later, these motor symptoms robustly improve. The irony of levodopa was that you have to swallow it, and when you swallow levodopa, it enters the GI tract, which is plagued by dysmotility caused by involvement of the degenerative process of the enteric nervous system and the autonomic nervous system. And once you begin to slowly the dope is esophageal dysmotility, delayed gastric emptying or gastroparesis, and then it has to get into the small intestine where it's absorbed. It's not absorbed until it gets there, so there can be a big delay to when it arrives at where it's absorbed. And that is absorbed in active transport, by large neutral amino acids transport. And this is difficult because this also transports small amino acids from dietary proteins, so there could be competition there that can make this absorption levodopa, even to the intestine, variable.
When we look at individual doses of levodopa, we see a great variability in the time to entry into the plasma, and how much was there. And then only stays in the plasma, circulating, for about 90 minutes, that is its elimination half-life. So we have a gold standard therapy that can be delayed in onset with variable absorption, and that has a short duration of effect in the circulation. Then, when it gets to the brain, it has a long-duration response, but after a few years that is lost and replaced by the short-duration response because of progressive striatal denervation and the loss of these nerve terminals that can uptake levodopa and recycle it and release it, perhaps, and postsynaptic changes.
So, very rapidly, we moved to trying to treat the motor symptoms of Parkinson, to try to treat motor complications, OFF episodes, and dyskinesia onset.
Matt Hoffman: When those things happen, how does that inform what you need to do to adjust treatment in order to improve some of these difficulties and patients deal with?
Stuart Isaacson, MD, FAAN: Before motor complications emerge, we just need to take more. We can take more levodopa to get more benefit, we can take add-on and other medicines to enhance the benefit, but when motor complications occur, we have to begin thinking about not exceeding a peak when dyskinesia occurs, and not falling below a threshold where symptom benefit is lost from a dose of levodopa and symptoms reemerge. We also have to think about the onset of action, we have to think about whether we want to focus on oral medicines or nonoral medicines, and whether we want short-acting levodopa or extended-release preparations, an extender type medication or an on-demand type medication, the intermediate therapies or advanced therapies—we have so many different choices.
Once patients go beyond 2, 3, 4, or 5 years—at 5 years, almost all patients experience motor complications. We have to begin thinking about getting a more consistent duration of benefit for doses of levodopa without the disruptions of OFF and dyskinesia.