How an FDA-Approved Neuromodulation Device Fits into Modern Restless Legs Syndrome Care

Emerging research is shedding new light on the relationship between multiple sclerosis (MS) and restless legs syndrome (RLS), suggesting that patients with MS may face a substantially higher risk of developing the sleep-related movement disorder. Prior epidemiologic studies and meta-analyses have shown that RLS occurs significantly more frequently in individuals with MS compared with the general population, with pooled analyses estimating approximately a 3- to 4-fold increased odds of RLS among patients with MS.¹ Recent investigations have continued to explore this relationship, highlighting the potential role of genetic predisposition, spinal cord involvement, and other neurologic factors that may contribute to the development of RLS in this population.²

Jonathan Charlesworth, PhD, co-founder and chief scientific officer at Noctrix Health in Pleasanton, California, recently spoke with NeurologyLive^® about these findings and the evolving treatment landscape for RLS. In the interview, Charlesworth discussed the increased incidence of RLS among patients with MS and provided an overview of the FDA-cleared Nidra wearable neuromodulation device, highlighting its potential role in addressing unmet needs in RLS care. Furthermore, he discussed limitations of the device and broader considerations for the future of RLS management.

NeurologyLive: Can you provide a general overview of the new research linking MS to an increased likelihood of developing RLS?

Charlesworth, PhD: This is a really interesting paper, and I find that some of the secondary findings are actually more interesting than the primary conclusion. This is a study from a group in Spain indicating that the incidence of RLS is about twice as high in patients with MS than in a control group. That’s not the first time that’s been reported, which is similar to the odds ratio reported previously.

With their methodology, they were able to do some interesting secondary analyses. Probably the most interesting part of this for me was looking at family history, which is basically a surrogate for genetic predisposition.

RLS is multifactorial, and genetic factors can lead to increased risk. What they found is that family history of RLS was a risk factor for developing RLS in MS patients. It was a really strong risk factor, with an odds ratio of 5, meaning MS patients are 5 times more likely to develop RLS if they have a family history.

Why is this important? Because 20 years ago, if you asked experts about RLS, they’d say there are two different types. There’s primary RLS, where there’s no other condition that could have led to the RLS, and then there’s secondary RLS. If you had MS, Parkinson disease, end-stage renal disease, or iron deficiency anemia, they’d call that secondary RLS.

That thinking has evolved tremendously over the past 10 or 20 years and that terminology is no longer used. It’s now well understood that, like most other chronic conditions, there’s a complex interplay between environmental and genetic factors and other health conditions. That’s what the authors here see as well.

It supports this shift from seeing RLS as primary or secondary to seeing it as a spectrum. Even in patients where RLS was partially due to MS, or where MS played a contributing factor, they were still more likely to have this genetic predisposition. They were still more likely to have a family history, indicating that RLS in most patients is not driven by a single factor.

On the flip side, they also did analyses showing that a family history of RLS was less common in the MS patients who developed RLS than in matched controls who developed RLS. That shows that MS is likely playing a role here and likely leading to a higher incidence of RLS in those patients. I think it’s really strong data showing that MS plays a role, but genetics play a role too.

One potential limitation, but something I also found very interesting, is that they looked at the frequency of patients taking drugs known to exacerbate or induce RLS symptoms. This is an important factor for the clinical management of RLS and is in the guidelines. One of the first things clinicians are instructed to do is ask whether there are drugs that could exacerbate RLS. There are psychiatric drugs, especially SSRIs like fluoxetine, that are well known to exacerbate or induce RLS.

The authors found that approximately twice as many patients in the MS group were taking these medications compared with the control group. To their credit, they did follow-up analyses and showed that this wasn’t purely responsible for the higher rate of RLS in MS patients, but the P value was 0.07. It’s a notable factor, and the authors probably could have dug into it further—looking at which specific SSRIs were more common. Some drugs have very strong evidence indicating that they exacerbate RLS symptoms, while others have weaker evidence. If they had looked into that more deeply, they might have gotten more precision on that odds ratio. It’s probably a little bit of both: MS likely plays most of the role in the increased odds ratio, but these medications may contribute as well.

The final finding, which again, to their credit with their methodology, was looking at pyramidal tract involvement. They showed that MS patients with pyramidal tract involvement were much more likely to develop restless leg syndrome. That’s particularly interesting for me, having developed a therapeutic that interacts with the spinal cord. One of our inspirations was a hypothesis from David Rye, Stephan Clemens, and Sean Hoffman back in 2006 that spinal hyperexcitability plays a key role in the pathophysiology of RLS.

There’s tremendous evidence that there’s motor involvement in RLS, periodic limb movements during sleep, and the relief patients get from walking. But it’s interesting to see this dissociation between sensory involvement and pyramidal tract involvement, and to see that there’s a specific relationship with MS patients who have pyramidal tract involvement being much more likely to develop RLS.

Q: How does the Nidra device operate and what advantages does it hold?

Charlesworth: Our inspiration for developing this technology was one of the core diagnostic criteria for RLS. There are four main diagnostic criteria, and one of them is that if a patient has symptoms and they get out of bed and walk around, it leads to very temporary relief from those symptoms.

If you dig into that and talk to patients and clinicians, it’s not just walking. If you get on a stationary bike, or activate your leg muscles in other ways, you can get relief. What we learned, and this is well known among clinicians, is that it’s really any voluntary activation of the leg muscles that relieves the symptoms.

That means activation of the neuromuscular circuitry involving the lower spinal cord and the peripheral nerves of the legs has therapeutic value. What we sought to do, and what we developed with Nidra, was to create a device that activates those same circuits but can do so persistently for a long time, leading to long-lasting relief—and in a way that’s compatible with falling asleep and staying asleep.

The limitation of walking or getting on a stationary bike is that as soon as you stop, the symptoms come back quickly, and you can’t fall asleep. We developed a very high-frequency form of neurostimulation, about 4000 pulses per second with very narrow pulses. What that does is essentially short-circuit the outer layer of skin. It allows us to develop a wearable, noninvasive device while selectively activating the peroneal nerve without activating pain fibers or free nerve endings in the outer layers of skin which makes it much more comfortable.

The device selectively activates the neuromuscular circuitry that provides relief without activating extraneous nerve fibers. It resembles a wearable device, similar to a Fitbit worn on the leg, and is placed just below the knees where the peroneal nerve is closest to the skin’s surface. Patients apply the device themselves at home as an on-demand treatment. When symptoms begin in the evening, they put the device on and turn it on, and it runs for 30 minutes. Relief typically lasts for a couple of hours afterward, and patients can use the device multiple times per day if needed.

What we’ve also found is that continued use over several weeks or months leads not only to on-demand relief but also to a reduction in the overall severity of the condition. Even on days when patients are not using it, they have fewer symptoms. That’s a contrast with medications, which typically don’t provide that continued benefit.

Q: Why do you think wearable neuromodulation devices are becoming increasingly popular compared with traditional medication?

Charlesworth: It’s an intriguing question, and you’re starting to see this across multiple conditions. There’s a very good reason for RLS specifically, but before I get into that, I think part of what we’re seeing across multiple health conditions is that the value of medications is that they’re very easy to use. You go home, take a pill, and you get effectiveness if you’re on the right dose. That can be very appealing.

For RLS, there is a class of medications that fit that category. Those are the dopamine agonists, generally targeting dopamine pathways. They’re even used diagnostically, in that if you don’t respond to these on night one, you probably didn’t have RLS. Twenty years ago, everybody was taking these and everybody recommended them. For the first year of taking these medications everything looks great.

Unfortunately, what happens in the long term—specifically with dopamine agonists for RLS—is that they make RLS worse. If you take away nothing else from my interview here, it’s to look at the latest guidelines from the American Academy of Sleep Medicine, which now recommend against using dopamine agonists in the standard treatment of RLS. They acknowledge that if you look at the trials for these medications, the immediate effectiveness is fantastic. But long-term use, even at fairly low doses compared with Parkinson disease treatment, leads to medication-induced worsening.

We’re talking about doses like half a milligram of pramipexole leading to medication-induced worsening. The specific answer is that the drugs most commonly used to treat RLS can make the condition worse in the long term.

More broadly, when you talk to patients, there’s a growing skepticism and apprehension about the long-term risks of drugs. Yes, you’re getting immediate value, but do we know all the long-term risks? RLS is a chronic health condition and patients will be on treatment for the rest of their lives. If you’re a patient in your late 80s, that may not bother you. You may have several other health conditions you’re managing, and you may want a pill that makes this go away.

But if you’re a patient—and many RLS patients are like this—they’re otherwise healthy. RLS may be the first chronic health condition they develop, and it often starts in their 40s. Do you want to be on a medication for 50 years that may make the condition worse or may have other side effects that people don’t even realize yet?

Q: Are there any limitations that come from treating patients with this device?

Charlesworth: I think it’s something prescribers and patients need to be well educated about before choosing this therapy. The most important factor is proper use. A good analogy for sleep neurologists would be CPAP therapy for obstructive sleep apnea. If a patient is willing to take the first week and learn how to use the device properly, follow the instructions, place it in the right location, and develop the habit of using it consistently, there really aren’t many limitations.

But it’s not something where you take it straight out of the box like a Fitbit, put it on your leg, and you’re automatically doing better. You do need to learn how to use it properly. We find that if a patient is willing to spend a couple of hours with our team to get titrated and set up properly, the overwhelming majority experience a strong benefit.

But the patients who don’t go through that process generally do not experience the same benefit and that’s a trade-off. If a patient doesn’t have the time for that, or if they’re managing many other health conditions and aren’t able to follow through with the setup process, it may not be the right choice for them.

There are also some limitations related to insurance coverage, although many are temporary. Currently, the FDA indication for Nidra applies to patients who have tried at least one medication and had an insufficient response. This includes patients who required a dose increase after taking pramipexole because it was no longer effective—often indicating augmentation—as well as those who discontinued medications such as pregabalin or gabapentin due to side effects like daytime sleepiness or edema. The device may also be used as an adjunct for patients still taking medication but experiencing breakthrough symptoms several times per week. All of these scenarios fall within the current FDA indication.

However, first-line use is not currently included. If a patient has never taken medication for RLS, they would not meet the current FDA indication. That’s important not only for staying on label but also for insurance coverage. Medicare coverage is very strong today, but only for patients who meet the FDA indication.

Another important consideration is contraindications. The device is contraindicated for patients with implanted neurostimulators, such as spinal cord stimulators or pacemakers. Those patients would not meet the indication statement, which again affects both labeling and insurance coverage.

Q: How will the inclusion of this device affect the care paradigm for patients with RLS going forward?

Charlesworth: When we talk to clinicians, especially neurologists who have been practicing for 20 or 30 years, they often compare this to the early days of CPAP therapy for obstructive sleep apnea. CPAP offers a low-risk device that works for most patients if they use it properly.

What we’re seeing in real-world clinical evidence with Nidra is something very similar. The biggest predictive factor for success is simply whether the device is used consistently and used correctly. Unlike CPAP, though, patients often notice relief fairly quickly. It acts somewhat like a pain reliever in that sense, which makes adherence easier.

Right now, most prescribers are incorporating the device into their existing continuum of care. They’re essentially looking at their standard treatment pathway and asking where this device can fill gaps for patients who need additional relief.

In the future, we may see a shift where clinicians move device therapy earlier in the continuum of care. Instead of increasing the dose of a dopamine agonist, adding a second medication, or considering opioids, which are sometimes used for severe RLS, they may consider a low-risk device therapy first.

The worst-case scenario with a device therapy is that a patient tries it for a month and it doesn’t work well for them. The worst-case scenario with certain drugs is that a patient may never be able to stop taking them and they may actually worsen the condition over time. Today, we’re seeing the device used primarily as an adjunct to existing care; tomorrow, we may see it moving much earlier in the treatment continuum for RLS.

Q: Do you have any final thoughts on the Nidra device or RLS care in general that we haven’t covered?

Charlesworth: I would encourage every prescriber who manages patients with restless leg syndrome to look at the latest clinical practice guidelines from the American Academy of Sleep Medicine. I’d also encourage them to read some of the latest position papers from the International Restless Legs Syndrome Study Group. These papers outline the long-term consequences and the role of dopamine agonists for patients with RLS.

This can be surprising for some clinicians in the neurology community who have used these drugs very successfully for Parkinson disease. The story is very different for RLS. The doses that can lead to negative consequences are much lower in RLS than they are in Parkinson disease.

As a company, we want to support education around this topic because it’s ultimately in the best interest of patients. Whenever I have the opportunity to speak about this, I try to spread awareness about augmentation and the long-term consequences of dopamine agonists as much as possible.

REFERENCES:
1. Zali A, Motavaf M, Safari S, et al. The prevalence of restless legs syndrome in patients with multiple sclerosis: a systematic review and meta-analysis—an update. Neurol Sci. 2023;44(1):67-82. doi:10.1007/s10072-022-06364-6.
2. Aladro Y, Álvarez-Sáenz de Tejada C, Díaz-Díaz J, et al. Prevalence of restless legs syndrome in patients with multiple sclerosis, as confirmed by sleep disorders specialists. J Neurol. 2026;273(2):96