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Considerations for the Maintenance of ON Time in Parkinson Disease - Episode 4

OFF Episodes During Progression of PD

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Robert A. Hauser, MD, MBA, discusses the appearance of OFF episodes throughout progression of Parkinson disease.

Stuart Isaacson, MD: Bob, I was going to say, what role does the progression of Parkinson disease play in the emergence of OFF episodes, as opposed to some of these other factors? Who in your mind is at greater risk of experiencing OFFs? Should we pay closer attention to asking about OFFs earlier in certain patients?

Robert A. Hauser, MD, MBA: Yes. One thing I’d like to point out is at the basis of motor fluctuations is the fact that our main treatment, oral carbidopa/levodopa, has a short half-life. Levodopa alone has a half-life of 60 minutes, and when given with carbidopa, its half-life is only 90 minutes. When I think about how long it stays in the therapeutic zone by itself, it’s only about 2 to 2.5 hours or so. Why does it last 6 hours when we give it early on? The answer is because early on, there’s still enough remaining dopamine neurons that levodopa finds its way up to the remaining dopamine neurons, is converted to dopamine, and importantly is stored and slowly released over many hours. But here’s where disease comes in. As the disease progresses and people lose more dopamine neurons, they lose that ability to convert levodopa to dopamine, and most importantly, to store and release that levodopa-derived dopamine over time. That’s when they start to say, “Hey, doctor, the levodopa is now only lasting 5 hours, and then 4.5 hours, and then 4 hours, etc.” That’s one part of disease progression.

The other part of disease progression, of course, is that Parkinson disease is not only in the brain, it’s in the body, it’s in nerves to the autonomic system, including to the gut. Patients begin to get more GI [gastrointestinal] dysfunction, including gastroparesis and delayed gastric emptying. Remember that levodopa is not absorbed in the stomach. It must get past the stomach to get absorbed, so patients more and more frequently get this delay in levodopa getting to the small intestine where it gets absorbed. Those 2 things together, GI dysfunction and the inability of the brain to convert, store, and release levodopa as dopamine are the main ways that disease over time brings forth fluctuations. You’ve also asked who’s most at risk. The main answer is that younger patients in particular are at high risk for both fluctuations and dyskinesia. It’s in those individuals we need to think about what ways do we have to monitor clinical response, and potentially how do we minimize the development of fluctuations of dyskinesia over time?

Transcript Edited for Clarity