MDJ Review Article of the Year Award: How does DBS change the course of Parkinson's?

Thank you for joining us today, and congratulations on your award.

[00:00:49] Dr. Werner Poewe: Thank you, Sara.

[00:00:50] Dr. Philipp Mahlknecht: Thank you very much. 

[00:00:51] Dr. Sara Schaefer: So, Dr. Poewe, let's start with you. What do we know, with relative certainty, that DBS can do for patients with Parkinson's [00:01:00] disease?

[00:01:00] Dr. Werner Poewe: Well, we do know with a lot of certainty that DBS is efficacious in reducing motor complications from chronic levodopa therapy of Parkinson's disease, i. e. reduce motor fluctuations, increase on time, reduce off time, and also reduce dyskinesias in those who suffer from them. There are a number of randomized control trials, both for the STN target, but also to some extent for the GPI target, showing that consistently.

We also do know that in patients who have tremor, which is refractory to medical therapies they are very, very likely to profit to considerable extent from DBS. So we have these certainties and we do know that by this procedure, the drug requirements are dramatically reduced requirements for oral medications. 

And we also know from [00:02:00] extensions of these trials that these effects are long lasting.

[00:02:06] Dr. Sara Schaefer: Now, I've had a lot of conversations with patients in the clinic when we are considering deep brain stimulation, and patients often ask when discussing this, will the effects wear off?

Based on your findings, how would you answer this question?

[00:02:21] Dr. Werner Poewe: Well, I do tell my patients who also ask me that kind of question that no, these effects do not wear off. So even after years and we're talking about it, up to 10 years or more of DBS, these reductions in off time, the reductions in dyskinesias, or, as it were, tremor control, they do persist. However, I also tell my patients, of course, that this is a treatment, a procedure which will not stop the disease in itself from [00:03:00] progressing. So, there will be some degree of increased symptom load when it comes to the on motor function these patients experience with time.

[00:03:12] Dr. Sara Schaefer: Now, Dr. Mahlknecht with regards to the effect on disease progression, can you discuss the animal data and also what theories have been proposed for how DBS could influence neurodegeneration rates in patients?

[00:03:29] Dr. Philipp Mahlknecht: Well, regarding the animal data, I'm really no expert, but there are indeed a couple of studies in rodents, in toxin based rodent models and primates that do suggest that DBS might be neuroprotective in terms of sparing dopaminergic neurons and also increased movement tasks. And also there's a prominent study in alpha synuclein over expressing rat model that showed similar effects on [00:04:00] nigral neuronal sparing and improvement in motor deficits in mice that operated versus mice that were operated but kept off stimulation for about three weeks.

So regarding animal data they have prompted that DBS might be neuroprotective. But whether this translates to humans, of course, It's much more difficult to answer, and we've made an effort in our review to find studies that have assessed patients in the long term of medication, but also of stimulation because off scores are generally accepted as a disease state.

And averaging the scores we found across the five studies that reported such scores, we found an increase of one point per year on the UPDRS 3, which is a bit less than two historical cohorts also in advanced patients which found about two points. But what one has to say is that those studies did not follow patients that late [00:05:00] as the DBS studies.

And also, there might be a survivorship bias. Also, there's uncertainty regarding potential carryover effects of stimulation and the levodopa long duration response. So really, there is no firm conclusion that can be drawn from this. But there are two other studies that can help with this question.

There's a 18F-DOPA PET study in DBS patients. After stimulation commencement they found a decline of stratal dopamine binding of 10 to 12 percent. That's comparable to patients without stimulation. So also this does not point to a disease modifying effect. And there are also postmortem studies, actually two that compared histopathology of the substantial nigra and also stratal dopamine levels and did not find any difference between stimulated and not stimulated patients.

So in summary, we cannot find any evidence in humans that DBS is disease modifying in its true sense. 

[00:05:57] Dr. Sara Schaefer: So I like the little addition that you put [00:06:00] at the end there in its true sense because then in the paper you dive into very important measures such as disability, institutionalization, survival rates in these patients. Can you review what you found there and whether your findings suggest an effect other than what might be expected with just the known improvement in symptoms from DBS?

[00:06:25] Dr. Philipp Mahlknecht: Yeah. So you're basically referring to a more pragmatic approach with a definition of disease modifying. If you also consider this end points such as the mentioned milestones irrespective of the mechanism. So we actually summarized studies that reported late stage disease milestones, such as falls dysarthria, dysphagia on the motor side and dementia or psychosis on the non motor side and found rates of falls of about 61 percent dementia of 38 percent psychosis of 48 [00:07:00] percent and 32 percent of the patients were institutionalized, but these studies were uncontrolled. So there is no conclusion that can be drawn from here either, just as mentioned before. But there are very few comparative studies that matched the DBS patients to patients that were not only under medical treatments and retrospective studies one has to say and found reduced risk for falls, psychosis and nursing home placement.

So we have a little, little evidence there, which is thin, but that's really the only evidence we have that DBS might delay these endpoints. And the very same is true for survival where there are actually five studies. We did a meta analysis over the five studies that were controlled and in the end excluded two studies because they did not really report any baseline variables are confounding, and the remaining three studies actually show a small survival benefit with DBS.

[00:07:57] Dr. Sara Schaefer: Of course, the question of when to [00:08:00] implant patients has an evolving answer. What are the potential advantages and disadvantages of implanting in earlier, less symptomatic patients versus waiting until patients become more symptomatic before considering DBS?

[00:08:15] Dr. Werner Poewe: Well, the bulk of the evidence for the efficacy and outcomes after DBS are based on samples of patients with Parkinson's disease who were into their 10th, 11th or more years of disease or even treatment like 11 years or 10 or more years and on levodopa.

So these patients have advanced Parkinson's disease and they oftentimes have additional non motor problems and have advanced disabilities. So, it's a fair question to ask why wait? If we know this procedure is effective, why not approach earlier populations like was done in the early STIM trial where there was a cutoff of three [00:09:00] years of duration of these motor complications come in much earlier, which means generally speaking, and that was the case in the earliest in trial that we're now approaching younger patients.

And that would obviously have an advantage of having less risks of surgical side effects, having fitter patients. And of course, not surprisingly, demonstrated by early STIM, the procedure works just as well in this earlier stage of the motor complication career of subjects.

But the crucial question is, does it confer benefit that would translate to outcomes longer out? And would these justify the unavoidable surgical risks and also to some extent costs that are necessarily associated with the procedure. And this is where the debate kind of divides movement disorder experts with some people arguing, well, yes, we should go early and we're kind of pushing patients back into earlier disability stages and [00:10:00] prolonging their so called second honeymoon after DBS and others saying, well, we can do that with less invasive therapies, best medical management that would include infusion therapies. We're seeing advances in the field of infusions. We're seeing new delivery modes for oral medications or non oral medications. So it's hard to make a final judgment what is right or wrong here.

And in my experience, a factor that comes in whether you go for DBS earlier. And this is still speaking about people who have motor complications, dyskinesias and or motor fluctuations to go earlier is of course patients themselves, oftentimes want this procedure because they are keen to reduce their pill burden, to gain more independence in their daily routines and activities and this is [00:11:00] sometimes a driving factor that comes into the equation, even if the treating neurologist would say, well, we can do this and that, a patient might say, well I don't want to take further adjunct therapies or number seven, number eight dose of levodopa, or I don't want to have a pump for apomorphin as we do in Europe or intestinal delivery or maybe in future subcutaneous levodopa.

I want DBS. So this is something we're all dealing with and we know it's safe. So there's little reason to not go in earlier if that is the patient perspective on it.

A completely different question is how early we've been talking about, or I've been talking about early STIM type of population, those with the established problem of motor complications, but they have been trials.

And we referred to this in this review paper as well, where the procedure has been used in patients who did not fluctuate or did not have dyskinesis. So prior to any of these classical [00:12:00] indications, even being being present. And personally, I'm very skeptical about this. I think we have very little to say the least, actually, no true evidence that would would justify going in with this procedure in patients without motor complications in the first place. There have been arguments about pill burden and there has been data showing there's reduced drug requirements, but that in itself I think is not a sufficient reason for this procedure to be employed.

[00:12:32] Dr. Sara Schaefer: And I would assume based on what you just said that, that logic would exclude the group of patients that are tremor predominant and non responsive to oral medications. 

[00:12:43] Dr. Werner Poewe: Exactly, Sara, that is an important group of course to think about and I'm glad you're bringing this up. Those with drug resistant tremor. And I want should be careful to be sure one is really dealing with drug resistant tremor [00:13:00] that one is not dealing with under dosing or limited exploitation of the armamentarium.

But let's assume everything reasonably, sensibly possible in terms of drug treatment has been tried and there's no sufficient control of tremor. We have these patients and their regular attendance to our clinic. And for them, obviously, STN DBS is one procedure that comes to hand with robust efficacy, that it is very likely to work and make a big difference for these patients.

But the landscape here again, as you well know, is changing with the advent of focused ultrasound and focused ultrasound as a procedure is targeting just that population. And of course, one has to carefully weigh what to choose. I would personally still, in maybe the majority of such patients prefer a DBS procedure because that will take care of, if you do it because of the trauma control, it will also take care of what might be in store for these [00:14:00] subjects later on in terms of developing more severe symptoms of the bradykinetic rigid domain.

And that will have been dealt with with the DBS and whereas the focus ultrasound target. The thalamus would really only deal with the tremor.

[00:14:16] Dr. Sara Schaefer: Yeah, and of course, there's the mix and match approach, the bridge, the focused ultrasound bridge to DBS, et cetera, et cetera, all things that need to be considered, of course. 

So throughout the paper, you discuss the challenges for studying this and the limitations of all of the papers that you included in the review.

How do you think it would be best to study the effects of DBS on disease progression, on disability, survival, and prolonged effect going forward? Do you think your core question, how does DBS change the course of Parkinson's disease, will ever fully get answered? Dr. Poewe?

[00:14:59] Dr. Werner Poewe: [00:15:00] That's a very difficult question, Sara, to answer. Obviously, what one would love to see is a randomized controlled trial where patients are randomly allocated to best medical management, including everything you can do and DBS, and then they would be followed for 10 years. And, and that is very hard to achieve.

I don't think it's impossible to do that. But if you imagine the career in those who would not be randomized to the DBS arm, they might still end up there in the course of the trial. So it's a challenge, but we have seen large pragmatic trials. And in the medication field, we have had large pragmatic trials going on for seven years like the PD med trial comparing levodopa sparing strategies versus levodopa.

And these trials are less rigorous, maybe methodologically compared to a very strict [00:16:00] randomized controlled trials, but it's feasible. So it's all an issue of who's going to pay for these types of efforts. And is there enough pressing need for it to be done or will we have treatments in a couple of years with all these disease modifying trials ongoing with approaches like antisenuclein approaches, other approaches that will change our whole perspective on what is needed to change the long term outcome and the interest in can DBS do it or not, might undergo a change if any of these disease modifying programs that are ongoing and in clinical development right now would bear fruit.

[00:16:42] Dr. Sara Schaefer: Certainly a lot to think about. Who knows what our subspecialties future holds. Thank you both for taking the time to talk with us today about your paper, and congratulations again on your Review Article of the Year designation and award.[00:17:00] Any final thoughts before we depart?

[00:17:03] Dr. Werner Poewe: Well, first of all, thank you, Sara, for, for hosting this podcast and for interviewing us. I think we're living in wonderful times in the movement disorders and PD world in that there's so many advances both related to our topic today. DBS, the techniques and the new developments are truly exciting in multiple ways.

The hardware advances, the AI advances, the imaging advances, and we're seeing all these related to the question of disease modification, all these new insights into the molecular mechanism. So for everybody young listening, go into the movement disorder specialty as deeply as you can.

That's my recommendation. And join the MDS if you haven't.

[00:17:44] Dr. Sara Schaefer: I second all of those recommendations. 

Dr. Malknecht?

[00:17:49] Dr. Philipp Mahlknecht: Yeah, I can only thank you Sara for having us and I would also like of course to thank the editors of the Movement Disorder Journal for their vote for our paper. We [00:18:00] feel deeply honored.