EP 36 - Think Gut: Why Parkinson’s Medication Sometimes Stops Working

🎙️ Parkinson Weekly – Episode 36

In Episode 36 of Parkinson Weekly, Prof. Bas Bloem explores one of the most overlooked reasons why oral Parkinson’s medications can become unreliable: the gut.

Drawing on his presentation at the European Academy of Neurology (EAN) Congress in Geneva, Prof. Bloem explains why fluctuating symptoms are not always caused by disease progression alone. While predictable “wearing-off” episodes can often be managed by adjusting medication schedules or adding adjunctive therapies, he highlights the importance of recognising delayed ONs, dose failures and unpredictable OFF periods—all of which may point towards impaired gastrointestinal function.

The episode examines how Parkinson’s disease affects the digestive tract long before diagnosis in many people, including delayed gastric emptying (gastroparesis), constipation and small intestinal bacterial overgrowth (SIBO). Prof. Bloem discusses how these conditions can prevent levodopa from reaching the small intestine for absorption or even cause the medication to be broken down before it reaches the brain, leading to inconsistent symptom control.

He also reviews practical management strategies, including treating constipation, understanding the current evidence surrounding SIBO, and recognising when it may be appropriate to bypass the gut altogether using device-aided therapies such as deep brain stimulation, continuous infusion therapies, or emerging on-demand treatments like inhaled levodopa.

This practical and clinically focused episode provides valuable insights into recognising gastrointestinal causes of motor fluctuations and highlights how addressing the gut can help restore more reliable symptom control, improve mobility, and ultimately enhance quality of life for people living with Parkinson’s disease.

Tune in now to discover why, when Parkinson’s medications stop working as expected, the answer may lie in the gut rather than the brain.

Have a question you’d like Bas to answer in a future episode? Email us at parkinsonweekly@gmail.com – we’d love to hear from you.

Transcript

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Welcome back at Parkinson Weekly, recording live here in Geneva at the uh EAN where I gave a series of talks, and one of my talks is about how the gut interferes with the efficacy of oral medication and what to do when you see a patient like this. And I will give you the quick summary here. The key point that I want you to remember is that if the symptoms of Parkinson's start to fluctuate, they can do this either predictably, people take their medication, they feel better, the medication wears off and they feel worse, and the symptoms return. So you get this cycling predictable curve. That is to a large extent, and at least for a certain amount of time, treatable. For example, by fractionating levatopa doses or by adding add-on therapies that will extend the working time of oral levatopa. But there is also such a thing as unpredictable fluctuations. Sometimes this is random on-offs when people quite unpredictably out of the blue switch from a good on to a bad off. That is fairly rare in my experience. But what is very, very common is delayed on's. So people take an oral medication, and the time for them to switch from a bad off to a good on is not your typical 20-30 minutes, but it could be an hour, an hour and a half. This is called a delayed on. Sometimes the oral medication doesn't even work at all. These are people who will tell you that the first morning dose works fine, maybe the second morning dose works well, but the doses later in the day sometimes don't seem to be working at all. It's as if they're taking water instead of leave it opa. These are called dose failures. And what is essential, and this was part of my talk, is that if you have random on-offs, if you have delayed ons, or if you have dose failures, think about the gut. The gut is affected early on in the course of Parkinson's, probably years before we make the diagnosis in many individuals, and it spans all the way from the mouth till the anus. Everything is literally affected. It's swallowing problems, it is delayed gastric emptying, gastroparesis, and gastroparesis, delayed gastric emptying is common. It affects, according to some studies, some 70% of people with Parkinson's. If you measure the speed at which the stomach empties, it may be up to 100% of people with Parkinson's. And the problem is you swallow the pills, and the pills just hover in the stomach and never transcend to the small intestine where they are being absorbed. And I showed an image really compelling by Alfonso Fasano of a patient who had a gastroscopy and where there was a levadopa, a cinemat pill, intact in the stomach one and a half hour after the patient had swallowed that pill. So if that pill doesn't work, you can say, Oh well, I need more pills, more pills, more pills, but that won't work. A third problem, of course, is constipation, slow bowel movements, often compounded by farting. Not a pretty story, but it happens. And farting happens because, secondary to constipation, there is bacterial overgrowth called small intestinal bacterial overgrowth or SIBO. And these bacteria start to produce enzymes, TDC and AADC, that will convert levadopa into dopamine in the lumen of the gut. And that dopamine will never arrive in the brain of the patient, explaining why these gut issues are correlated to an unreliable, unpredictable response to oral pharmacotherapy. Sometimes people even develop paradoxical diarrhea, secondary to chronic constipation, which is why they are often reluctant to take laxatives, because they think it will make the diarrhea worse, and yes, it will make it worse in the short term, but eventually you obviously need to treat the constipation. Key point that you should really remember is if you see these signs, either the bad response to oral pharmacotherapy that I pointed out, or gastrointestinal symptoms such as bloating, farting, constipation, paradoxical diarrhea, think gut. And either you treat the gut, which in many cases is difficult, or you bypass the gut. Treating the gut is possible. I think constipation is treatable. Drinking ample fluids, having lexatives, ample exercise, a diet rich in fibers can help. Small intestinal bacterial overgrowth can theoretically be treated with antibiotics, but this is still part of research and trials, and not something you should try as part of your daily clinical practice. But I have seen people where the oral pharmacotherapy didn't work, people started increasing the dose and more pills and more pills and more pills, still no response. Came to me, tertiary referral. We did a trial of vancomycin, which people know from intenous use. If you give vencomycin orally, it stays exclusively in the lumen of the gut, so there are no systemic side effects. It will kill off the wrong bacteria, keeping the good boys alive. Patient came back to me after a week of vancomycin treatment, wildly dyskinetic, because suddenly the same dose of levatopa was now reaching the brain. But the problem is within six weeks the small intestinal bacterial overgrowth returns. In the acute phase, you need to reduce levitopa because people are now over-treated. Then you need to increase levadopa again. So you're hovering between control of the gut versus over-treatment. So oftentimes it's difficult. Delayed gastric emptying, difficult to treat. Sometimes scissorprite, be aware of the long QT intervals, sometimes erythromycin, but in general, difficult to treat. Be aware of meals high in fats that can worsen delayed gastric emptying. So think low threshold about ways to bypass the gut if you cannot correct the gut. Ways to bypass the gut could be a subcutaneous pump therapy, which is available with apomorphin and levadopa, or of course, deep brain stimulation, which is also a wonderful way of bypassing the gut. But there's another way of doing it now, and this is an on-demand rescue treatment, and this is inhalable levadopa. And the symposium that I was seeing and where I was speaking is about this new inhalable form of levadopa, which is interesting because it is inhaled via the lungs. People know this from asthma treatment, for example, and it goes directly into the bloodstream, and from there it goes directly into the brain. And it's a very good way of creating an on period within about 10 minutes with a peak at about 30 minutes, and it will last for about 60 minutes. So, this is theoretically a wonderful way for these unpredictable off periods that deprive people from their independence. It causes anxiety. People don't dare to go out and about, they don't dare to go to a theater, to a mall, because they fear these random offs. If you now have an inhalable form of Levi Dopa to quickly bring you back on, that will restore independence and mobility for people with Parkinson's. Now, in all honesty, I've read the papers, I've seen it, I haven't used it myself. We are starting in my university medical center, but it is an interesting concept to keep an eye out for. In summary, random on-offs, random fluctuations, delayed-ons, dose failures, think gut, treat the gut if you can. If you fail, think about bypassing the gut, and keep that in your mind to improve quality of life for people with Parkinson's disease.

SPEAKER_00 8:57

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