EP 23 - Papers on 'Response Fluctuations'

🎙️ We’re back with the twenty third episode of Parkinson Weekly, hosted by Prof. Bas Bloem.

In Episode 23 of Parkinson Weekly, Prof. Bas Bloem explores the phenomenon of response fluctuations, where the benefits and side effects of oral Parkinson’s medications vary throughout the day. Rather than focusing on a single new study, this episode revisits several influential papers that have reshaped how clinicians understand these fluctuations and their underlying mechanisms.

Listeners will learn about key concepts including “on” and “off” states, predictable wearing-off, dose failures, and different types of dyskinesias—including peak-dose and biphasic dyskinesias. The episode also highlights how Parkinson’s disease progression narrows the brain’s therapeutic window, making it increasingly difficult to maintain stable symptom control.

Prof. Bloem also discusses an often overlooked factor: the gut. Gastrointestinal issues such as delayed gastric emptying, constipation, small intestinal bacterial overgrowth (SIBO), and Helicobacter pylori infection can significantly affect how levodopa is absorbed, leading to delayed or unpredictable medication responses.

Finally, the episode explores treatment strategies—from adjusting dosing schedules and adding adjunct medications to the role and limitations of continuous dopaminergic therapies, while emphasising the importance of realistic treatment goals and expectation management.

This episode offers practical insights for clinicians, people living with Parkinson’s disease, and caregivers seeking to better understand and manage medication fluctuations.

Listen now to discover how evolving research is shaping the way we approach response fluctuations in Parkinson’s disease.

Articles mentioned can be found here:

1. https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(15)00007-1/abstract
2. https://movementdisorders.onlinelibrary.wiley.com/doi/10.1002/mds.870120304
3. https://pmc.ncbi.nlm.nih.gov/articles/PMC2865731/

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

SPEAKER_01 0:01

After several years of treatment with levadopa or other dopaminergic medications, the response to the treatment starts to fluctuate. What precisely are these fluctuations? And how can these be managed? Listen to episode 23, where I will discuss a few older papers that have really changed my thinking about response fluctuations in people with Parkinson's disease. So today's topic in Parkinson Weekly is about response fluctuations, the fluctuating efficacy and adverse effects in response to oral pharmacotherapy. This is very common in people with Parkinson's disease. There are many different types of response fluctuations. And instead of discussing a recent article today, I'm going to discuss a few articles, older ones, that have really changed my mind about what is happening in the field. And for those of you who are not just listening but who are also watching the show notes, there is a PowerPoint presentation coming with this where I drafted a cartoon for this lecture where in a graph you can see on the y-axis the theoretical brain level of Levadopa, and on the horizontal axis you see Levi Dopa administration. And the response to the treatment will fluctuate. It is like a sinusoidal wave. It goes up and down, just like the waves in the ocean. It goes up and it goes down. And the reason it fluctuates is the short half-life of a drug such as levatopa. It takes a bit of time for the effects to kick in, and then the effects taper off. You take a next dose and the cycle resumes. Now, in the early days of treatment, people will be more or less stable on typically three doses of levitopa per day. And this is probably because the brain will absorb the oral levitopa into the substantia nigra and from there on disseminate the dopamine into the place where it is supposed to work in the brain. So there is a built-in buffer within the brain. So three times a day, people are pretty much stable across the day and will also be stable during the night. The problem is that Parkinson's is a progressive disease, and that progression means that there are increasingly fewer dopaminergic neurons left in the substantia nigra to buffer the fluctuations, the short half-life of the oral leafodopa. And that means that after a couple of years of treatment, typically happens a bit earlier in people with young onset Parkinson's disease, tends to come on a bit later in people with late onset Parkinson's disease. People will start to notice these fluctuations. After several years of treatment, people will notice that after a good time on, and we call this an on time when the medication is working well, they feel that their body tells them it's about time to take their next dose of medication. They feel that the Parkinsonian symptoms are returning, for example, more tremor, more shuffling gait, more stiffness. And a state when the symptoms are poorly controlled is called an off state. A state when the symptoms are reasonably well controlled is an on state. And people will notice that difference. So we've understood now the difference between an on-state and an off-state. And this is all because the therapeutic window progressively narrows over time, and it becomes increasingly difficult to squeeze in those fluctuations, that sinusoidal wave, into that increasingly narrow therapeutic window. Now, the type of response fluctuation that we see typically first is what we call a predictable wearing off. Predictable meaning that people take the pill, feel better, and they can predict that after a certain amount of time, say two to three hours, the symptoms will begin to return. And because this happens in a very time-locked fashion to the intake of medication, we call this a predictable wearing off. And this is typically one of the earliest response fluctuations that we see. A bit later in the course of the disease, if you can envision this window which has a bottom and a ceiling, the medication starts to cause adverse effects at the peak of the efficacy. So this is a time when the symptoms are relatively well controlled, but now the medication is working too well and it causes involuntary jerky movements that we call dyskinesias. They tend to have a chorietic character, meaning these are dancing movements, shifting from body segment to body segment, and these peak dose dyskinesia occur at the time when the medication is working well. But here becomes something really important. And again, this is a paper that has really changed my thinking, and it is by one of my heroes. I always tell the young residents in our clinical training program: find your heroes and incorporate whatever you find good about them into your own repertoire. And Jay Nott, a world-famous neurologist who used to work at the Department of Neurology of Oregon Health and Science University in Portland, who's now retired, still active though. Jay Nott is one of my heroes. And he did a study that really changed my thinking because he demonstrated in a paper published in Neurology already way back in 2010 that, and there's a graph in the show notes to show you what he found, is that the anti-Parkinson effect of Lever Dopa inevitably started to coincide with the presence of dyskinesia in people who had developed dyskanesias. In other words, what I used to believe until I read this paper was that there was such a thing as an off time. We talked about wearing off. There was a good time called on, and there was a good time accompanied by dyskinesias. What J. Nott was showing in this paper is that once you have dyskinesias, there is no such thing as a good on without any dyskinesias anymore. They become an inevitable part of the efficacy of Levadopa, and this is so important to understand and appreciate. What we do need to distinguish is relatively benign, you might say, acceptable dyskinesias and unacceptable dyskanesias. The unacceptable dyskinesias, which we used to see in the old days when we treated people with high doses of levadopa, even though they had long-standing Parkinson's disease. If you want to appreciate this, you can see the film Awakenings after Oliver Sachs's book, where people with long-standing post-encaphyletic Parkinsonism were for the first time treated with high doses of levadopa and developed violent dyskinesias. Dyskinesias can be really cumbersome. They can cause weight loss because they consume energy, they can cause sweating, they can cause fatigue, tiredness, and of course they look not very nice, so they can be socially debilitating. But mild wobbliness, dyskines that do not interfere with, for example, eating your meals or that that may cause falls. That's another reason why dyskines can be terrible. But mild wobbliness becomes an intrinsic part of the efficacy of Levadopa, and that should be accepted. So the reality is, and you see that in the cartoon in the show notes, is that there is such a thing as wearing off, an off state. There is an unstate in the therapeutic window with mild slash acceptable dyskinesias, and there is such a thing as unacceptable dyskinesias, the violent movements that interfere with eating, that may cause falls, that cause you to lose weight, etc. So once there are dyskinesias, it is an optimal state if there is gentle wobbliness and the holy grail of a good on state where all the dyskines have miraculously disappeared, no longer exists. So that's important to recognize. So let's move on to the other response fluctuations. There is also such a thing as a delayed on. Typically, once people have fluctuations, they will notice that when they take their drug, the medication will typically kick in within, say, 20, 30, maybe at most 45 minutes. But if it takes unacceptably long, hours for the medication's effects to kick in, we call this a delayed-on. And a delayed on in its extreme form is in fact a dose failure. This happens to people who take Levadopa multiple times a day, and they say first dose of the of the day works really well, maybe the second dose works, but in the afternoon medication is no longer working at all. It is almost as if I'm taking water. And please remember that a delayed on, a slow onset of the efficacy of Levadopa, or sometimes even a dose failure, failure of the drug to achieve anything good for you, is very often related to gastrointestinal issues. We know that the gut is a very important factor that hampers the efficacy of oral drugs. This relates to constipation, the slow bowel movements, which in turn may lead to intestinal bacterial overgrowth. We call this SIBO, small intestinal bacterial overgrowth, and these bacteria can cause all sorts of discomfort, frequent winds, for example, but importantly, they can also produce enzymes which we think can annihilate the effects of oral levadopa, already convert levadopa into dopamine in the lumen of the gut, so that the dopamine leaves your body without ever having reached the brain. So the gut is an important factor explaining unpredictable responses to the medication and think gut when there is a delayed on or a dose failure. And one element, and I'm again referring to a beautiful, slightly older paper by Alfonso Fassano and colleagues, and it's on gastrointestinal dysfunction in Parkinson's disease. If you want to understand all the complex GI issues in people with Parkinson's, read this beautiful paper that was published in the Lancet Neurology in 2015. And I mentioned constipation, I mentioned bacterial overgrowth. One element that is addressed by Alfonso Fassano and his colleagues in the Lancet Neurology is delayed gastric emptying. And I'm mentioning this because there is increasing attention to this phenomenon. It is common in people with Parkinson's. I think it is actually very common. We don't nearly address this often enough. Delayed gastric emptying means that food, but importantly also pills, that are swallowed enter the stomach and just lie there idle in the stomach without ever being passed on to the small intestine where they are resorbed into the bloodstream. And there is a beautiful image in the Lancer Neurology of an intact Levadopa capsule lying in the gut several hours after intake of oral medication. And you can easily see how patients might say, Oh, the drug is no longer working. It's still working, it just never left the gut. It's a very striking photograph that I'm sharing in the show notes. Delayed gastric emptying happens in up to 70 to maybe even 100% all people with Parkinson's disease. Symptoms that are suggestive are nausea, rapid satiety after foods, bloating, and importantly, delayed passage of medication into the small intestine, causing these delayed-ons. It worsens with fatty meals, so this is best avoided. And certain types of medication, such as proton pump inhibitors, I'll come to that in a minute, can also make things worse. What the paper is also mentioning, and this is important, is that a certain bacteria called Helicobacter pillari, which people may know as a bacteria that causes gastric ulcers, can also have a negative effect on gastric motility. And conversely, eradicating this Helicobacter bacteria can sometimes improve gastric motility. A confounder here is that those antibiotics that you use to kill the Helicobacter pylori bacteria also kill off other bacteria, including the ones that are overgrowing in the small intestine as part of the SIBO. But regardless, antibiotics are sometimes a possible treatment for delayed gastric emptying, and so they are for the intestinal bacterial overgrowth. There is little evidence how to treat delayed gastric emptying. Frequent small meals is recommended, up to four, maybe ten small meals per day. So avoid three big meals per day, which we typically do, but resort to small frequent meals. Avoid high-fat solid foods, which I mentioned before makes things worse. Adequate fluid intake is mandatory for every person with Parkinson's disease. Two liters of water per day, if possible. Try to avoid carbonated drinks. This can also make things worse. Avoid alcohol. Try a diet enriched in fibers and again lots of fluids, as I mentioned before. This also helps for constipation. If you do not know what a high fiber diet means, then speak to your dietitian. Avoid insoluble fibers or gas-forming fibers. And those are recommendations that you can consider doing yourself. Treatment is difficult. I mentioned before that the proton pump inhibitors are best avoided. Examples are omeprozol or pentaprozol. Those are brands that are best avoided if you are considering this. So speak to your physician about this. These make the delayed gastric emptying worse. They can also promote bacterial overgrowth in the intestine and are associated with a higher prevalence of the helicobacter pillary bacteria. Are there any drugs that can promote the release of whatever is in the gut? Domperidone is a drug that is used for this purpose. Sisopride is also sometimes used for this purpose. So those are drugs to consider. They can have adverse effects on heart rhythms, so an ECG is mandatory prior to start, and this should always be discussed with your physician. So back to the scheme. What happens over time is that not only becomes the therapeutic window smaller, but also the duration of the response becomes progressively smaller. So the number of hours in a good on state are reduced at the expense of more hours in a bad on-off state. And of course, one of the treatment strategies is to enhance the frequency of the medication doses. Sometimes there are people taking six, seven, eight times levadopa per day in order to fight this reduction in the duration of the efficacy of levatopa. There's another type of response fluctuation that I briefly want to mention, and these are called diphasic dyskinesia. So the dynesia that happen at the peak of the sinusoidal wave are called peak dose dyskinesia. They're peak dose because they happen at the peak of the wave. If you now imagine a rocket, like the moon rocket, leaving the earth going for space, if you go, if you leave the earth, you go through the atmosphere, and that transition period can be likened to the phase when diphasic dyskinesias happen. This is dyingsias that happen on during the rise in the dose or the levels of levadopa uh in the body, um, and also happen when the levadopa levels are declining again. So they happen both at the upward going slope of the sinusoidal curve and they also happen during the downward curve of the downward slope of the curve. And because they happen twice, once during the upward phase, once during the downward phase, we call them biphasic dyskinesias. These tend to happen a bit more often in younger men, can have a more dystonic character, and they should be recognized because the treatment strategy is different compared to the peak dose dyskinesias. They are much more rare, so if in doubt, it is usually peak dose dyskinesias, but diphasic or biphasic dyskines also happen. If you again think of the rocket leaving the earth, you want to leave the earth as quickly as possible, break through the atmosphere as quickly as you can and reach outer space. So slow-acting drugs would lead the rocket to depart the earth on a more shallow curve, so you stay in the atmosphere for a longer period of time. So once you have diphasic or biphasic dskinesia, the solution is typically rapid-acting drugs rather than slow release formulations, such as slow-acting levadopa, or the controlled release or the slow release dopamine agonists. And finally, there's such a thing as unpredictable offs. Everything I mentioned, most of the stuff I mentioned so far, is more or less predictable, except for the dose failures. Sometimes people will tell you that in the midst of a cycle where they know when they turned on and they know when they turned off, suddenly there's a switch in their condition, and this is called an unpredictable off. And an unpredictable off happens at a time when you wouldn't expect it based on the timing of the intake of the medication. And again, in my experience, this is often related to gastrointestinal issues, although with these unpredictable offs, cerebral mechanisms, changes in the responsiveness of the dopamine receptors in the brain can also play a role. So there's a little cartoon showing all of these response fluctuations in one summary slide for you in the show notes, which you might be able to review. And then finally, in closing, because this is something that again has really changed my mind. I mentioned as one of these solutions more frequent dosing, that's definitely a good option. Adding drugs that prolong the half-life of Levadopa, such as MEOB inhibitors or COMT inhibitors, are also a good solution. A dopamine agonist can be a solution because they also tend to have a longer half-life. But of course, there is a great interest in continuous dopaminergic treatments, a pump therapy with, for example, subcutaneous levadopa, or a pump therapy with subcutaneous apomorphin. And again, a paper that really changed my mind was again by my hero John Knott from Portland, published in Movement Disorders in 1997, where, and this is really fascinating, what he did is he gave people with Parkinson's disease a constant intravenous infusion of Levadopa. So now the plasma levels of Levadopa were perfectly straight lines, continuous, stable levels of Levadopa in blood. And what he monitored as people were on this drug for a long period of time, I believe they were on it for 36 to even 110 hours, and he carefully monitored the change in their clinical response. And there are two, in the show notes, I'm showing two examples. One is patient A, who has a constant level of Levadopa in blood, and is indeed very stable in the clinical response. But the second patient, even though the plasma levels of levodopa are completely stable in blood, is still turning off, and particularly in the afternoon. And although the mechanism is still not fully understood, the idea is that continuous levadopa is not a physiological way of stimulating dopamine receptors. The brain does it in its own unique way with a certain rhythm. And our non-physiological way of stimulating these receptors ultimately leads these receptors to say, hang on, this is not the normal situation. I won't respond to anything you're telling me to do for the next few hours or so. And what I hear all the time in my clinical practice is people saying, I'm good in the morning, I'm good during lunch still, but after lunch, in the afternoon, I'm worse. And for many, many folks with Parkinson's disease, the afternoon is worse. And I'm saying this because, yes, I'm a fan of continuous dopaminergic therapies in people who fluctuate a lot and where oral pharmacotherapy can no longer solve the issue. But even on an intravenous continuous levadopa infusion, people still turn off. And this is related to the central changes in the responsiveness of the dopamine receptors. So I use this in my clinical practice to tell people if you go on a continuous dopaminergic stimulation therapy, there will be fewer bad moments and there will be more good moments, but the bad moments will always persist. And that deep learning and managing expectations, I think, is quite critical. So, in conclusion, I will as always end with you know my the impact on clinical practice for tomorrow. One important take-home message is think gut when there is a delayed on, when there are dose failures, when there are random off fluctuations, when the response overall is much less than you would anticipate based on the dose of the treatment. And even when there are no dyskinesias in people, even after years and years of high dose levadopa treatment, in those people think about impaired absorption from the gut, either through constipation, bacterial overgrowth, or as I mentioned today, delayed gastric emptying. When it comes to the dyskinesias, the involuntary wobbly movements, remember these become an intrinsic part of the effect of Levi Dopa once they are present, so getting fully rid of them is a holy grail that you shouldn't strive for. Yes, you have to distinguish acceptable from unacceptable dyskinesias. Acceptable dyskinesias is the desired situation, mild wobbliness, unacceptable dyskinesias should be treated. And distinguish peak dose dyskinesia from biphasic dyskines because they require a different treatment goal. And finally, set the treatment goals clearly and realistically. Eradicating all fluctuations is, to my mind, a myth, but strive for a treatment that gives you a greater proportion of good on during the day at the expense of less bad off time. But remember that even on an intravenous levitopa infusion, which would theoretically be the best way of stimulating, there will there are still bad off moments, so you can never fully get rid of them. I hope this was helpful. You don't have to remember everything. Typically, the neurologist or the Parkinson nurse specialist will know a lot about this. But I think if you understand as a person with Parkinson's or a family member how it works, then I think the treatment overall will be better. And as I said before, it helps in managing and setting the expectations right. So this was Parkinson Weekly. This was episode 23. I hope you enjoyed it, and I'll see you again next week.

SPEAKER_00 27:52

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