Invent: Health

Epilepsy: Understanding the brain when neurological disorders occur
Speakers: Matthew Parker, Alex Stokoe & Martha Morrell
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Matt: Hello and welcome to Invent Health, a podcast from Technology and Product Development company, TTP. I'm your host, Matt Parker.
Over the course of this season, we're going to be exploring the fascinating future of health technologies.
Today we ask, what will improvements to continuous monitoring devices enable for the diagnosis and treatment of neurological disorders?
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Neurological disorders have a really significant patient burden, with some estimates suggesting the impact as many as 1 billion people across the globe. But simultaneously, these are diseases which are both challenging to treat and still remain relatively poorly understood.
Snapshots of the brain have been available through imaging technologies for a while, but coming up with devices that are able to monitor the brain in real time has proved a huge challenge.
So, what would it enable, if we could see and understand what is happening in the brain when neurological abnormalities occur? Well, it would drastically change the lives of people suffering with these diseases. And the data from constant monitoring would allow us to discover more about when and why they occur.
One neurological disease, which has seen some really exciting work in relation to this, in recent years, is epilepsy. Epilepsy is a spectrum of neurological disorders that often manifests itself in seizures. Events that are caused by abnormal electrical activity in the brain.
The unpredictability of seizures for epilepsy patients is what makes them so challenging to manage. So, what if we're able to not only predict the onset of a seizure, but stop it in its tracks before it occurs?
I wanted to find out some more about the treatments and monitoring devices, which currently exist in this space, as well as the ones coming around the corner. So, I needed to get in touch with some of the people working at the forefront of the field.
First up, I sat down with my friend and colleague, Alex Stokoe. Alex is a neurotechnology consultant at TTP, with a master's degree in Integrated Electrical and Mechanical Engineering from the University of Bath.
Over his time here, Alex has worked on and led the product development of several medical devices and specializes in next generation neuromodulation systems, across biosensing, digital health and neurotechnology markets.
I started off by asking Alex about the notion of continuous monitoring for neurological disorders, because this is the thing which would enable truly exciting treatments in the future.
So, hi Alex. Yeah, welcome to Invent Health, series two.
Alex: Yeah, for sure. It's good to be on the show.
Matt: I guess I’ll kick off with sort of where we're going to be going in this episode. So, what do we mean by continuous monitoring for neurological disorders?
Alex: It's a big field. So, I guess what we mean by continuous monitoring is moving away from this very clinician in the loop style approach to neurological disorders.
So, a lot of the current standard of care is around like cognitive assessment tests, and these are happening like really infrequently, and it involves like traveling to your GP, booking appointments in neurologists’ clinics. And it really doesn't give doctors very good and very clear data to titrate pharmacological treatments or other sorts of interventions.
And so, moving to this like continuous monitoring, we're talking the whole kind of stack of technologies from like wearables and like medical devices, all the way through to like digital health appointments and that whole kind of ecosystem around tracking patient data securely and effectively to enable like real-time healthcare decisions to be made and improving the lives of patients.
Matt: Fantastic. And maybe sort of backing up a little bit, what about the sort of current standard of care, has been so difficult?
Alex: Yeah, so I guess neurological disorders are infinitely hard to treat. A lot of them are quite difficult to diagnose. A lot of them change a lot between different patients. So, it's hard to kind of have a standardized test to do it.
There's loads of drugs and loads of very specific tests for things like infectious diseases. Obviously we're really familiar with like things like PCR diagnostics now.
But that kind of doesn't exist for things like Alzheimer's or epilepsy, where it really changes like patient to patient. And part of that's just the complexity of the human brain. It's like 90 billion neurons.
And with so much we don't understand and some of these disorders present physiologically in different ways and in ways that it's hard to tell, from the symptoms exactly what's going on and exactly how to treat it.
And because of this, it's never really seen the drug pipeline that other slightly easier or more obvious medical treatments have seen.
Matt: So, what are some of the current methods we're using for monitoring these diseases? You sort of said there's a bit of physician monitoring. What kind of things would be maybe in the past and current standard of care?
Alex: Yeah, so a lot of these neurological disorders rely on things like cognitive assessment batteries, where it's almost like if anyone did like an IQ test at school, you are giving patients these like either verbal or written or visual or motor skills tasks you’re your physician or neurologist is there monitoring.
For instance, for Parkinson's, there's a thing called a PEG test where you are taking a block from one slot to another slot and you're seeing sort of how dexterous you are with that. So, it's about your motor function.
For Alzheimer's and dementia and things, you've got more to do with like visual spatial impairment and memory. There's a lot of these kind of patient reported or highly interactive assessments with clinicians, rather than kind of discreet sensor data.
However, that's kind of changing. There's obviously like things like CT scans and MRIs, are used to image the brain, and that can be a really powerful tool to help diagnose, especially later stage.
And then there's tools called EEG, so electroencephalography, so that's where you put electrodes around the surface of the head and you look for kind of electrical activity. So, brain waves as it were.
But all of this, looks for kind of gross activity and you don't really get into the specifics of how the different sort of neuronal circuits work.
Matt: That's super interesting. Could you tell me a little bit more about those technologies? Would you say they've been the sort of major breakthroughs in the field historically?
Alex: Yeah. Actually everything we know today as a neurological disorder was basically discovered due to, maybe besides some really, really obvious traits. Basically due to advances in this kind of brain imaging, nervous system monitoring technologies.
So, in things like epilepsy, the tools to look at these kind of seizure propagation centers for enabling sometimes quite drastic treatment where you need to be very precise about kind of what kind of surgical intervention you make.
There's been some real advances there in using something called OP-MEG, which is essentially taking some of the magnetic physics of MRI in a certain extent. But what you’re instead looking for is electrical activity in the brain using these new sensors which are optically pumped magnetometers, which can look for very precise electrical monitoring.
Matt: Wow.
Alex: And so, instead of a patient needing to be in an MRI scanner to look for this kind of activity, instead they can be in a kind of more comfortable chair and it's a sort of improvement in patient care while still having that specificity about — if in epilepsy where a seizure might be starting, in other neurological disorders, other kind of mapping functionality.
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Matt: The kind of incredibly sophisticated brain imaging that Alex mentioned there, shows how far we've come in terms of understanding and diagnosing neuro diseases. To have that kind of detail has allowed clinicians to create snapshots of what's actually happening in the brain.
But to get that information continuously in real time, when a seizure or similar event occurs, therein lies the issue. Because to effectively treat more aggressive forms of neuro diseases, like epilepsy needs a flow of information that is constantly being tracked and responded to.
And there are now devices which could hold the answer. Before getting into the tech that could potentially fill that gap, I wanted to find out some more about epilepsy itself. What do we know about the disease and what are we still waiting to learn?
Hi Marty, thanks so much for joining us.
Martha: Oh, thank you very much, Matt, for the opportunity.
Matt: Next I spoke with Professor Martha Morrell, someone who spent their entire career working at the absolute forefront of this field, a Clinical Professor of Neurology at Stanford University, since July, 2004. Martha has served on various positions across the university, and she's since authored or co-authored more than 150 publications over that time.
Martha is also the chief medical officer at NeuroPace, a company that has developed a responsive neurostimulator for the treatment of medically uncontrolled partial seizures. And it was this work specifically that I really wanted to get into with her, because it's been really groundbreaking.
But first I asked her to give her some of her thoughts on where we were at with the treatment of neuro diseases before honing in on epilepsy specifically.
We're talking about a very wide range of conditions here, but in terms of the burden to the patient that these types of disorders and these types of diseases present, they can be very significant, can't they? I wonder sort of how does that burden vary across the globe?
Martha: Well, I would say that many neurological diseases are, I would use the word intimate, very personal because they are affecting the brain obviously. And the brain is where we think, where we feel, it's what teaches us how to interact with others.
And most neurological disorders are not because of someone's behavior or because of someone's health habits, most occur despite what an individual does or how they live their life.
They are very impactful, again, because they involve the sight of who we are. And very often because they're chronic, most are chronic, must not only be dealt with by the individual, but by those who love that individual. So, that would include family members and close friends.
Because it is affecting the mind, very often they limit the opportunity to be educated, to have occupation and to really experience the normal events of life. And so, I would say depending on when the disorder occurs, it can very much impact life opportunities.
Matt: And they will be conditions that people would be living with, potentially through their entire lives.
Martha: Very often that is the case.
Matt: I think that links us quite nicely into maybe sort of expanding into epilepsy more specifically. And I wonder if maybe we could kick off by talking about what we currently understand about epilepsy. Is this sort of one homogeneous disease or is this something which there's a spectrum of conditions in how they present?
Martha: There is most definitely a spectrum, and to put this in some context that surprises most people, is epilepsy is the third most common neurological disorder that neurologists see after headache and back pain.
It is highly prevalent. 1 out of 10 people will have a seizure, which is an event that occurs because of abnormal electrical activity in the brain. 1 out of 10 will have a seizure in their lifetime. Epilepsy, however, is a condition in which seizures recur, and there is not a clear reason.
So, for example, if I were to have a seizure, because I struck my head, I would not necessarily go on to continue to have seizures. But if that head trauma led to a condition in which I was susceptible to recurrent seizures, then I would have epilepsy.
Most seizures occur over less than three minutes, and many people have very infrequent seizures. And so, we may know somebody who has seizures, but we've never seen them have a seizure and they may not share it because of the substantial stigma that is associated with epilepsy in many cases.
Matt: And I'm amazed despite that prevalence, that I think probably people's assumptions and misconceptions around epilepsy are probably quite incorrect. So, I'd love to know, what are some of people's misconceptions around epilepsy and epilepsy sufferers?
Martha: Yes. Throughout history, epilepsy has been described since the time of the Babylonians. And throughout history, it has often been seemed to be a religious affliction. But it is not unusual for people to think it's infectious. And that may be part of the stigma; that individuals are concerned that they might catch epilepsy from someone.
The other is that it can be very frightening to see someone have a seizure, to be talking to an individual, and then all of a sudden to have that person not be aware of what's going on. Or in extreme cases to have a generalized tonic-clonic seizure, just also known as grand mal seizures or as convulsions.
But the presentation of seizures, what people experience may be as subtle as a sensation or an odor. And if that were to happen to me, you might not notice that anything was going on. I might be able to be fully aware and to talk and to continue my activities. That may be one end of the seizure spectrum, with the convulsion being the other end.
Matt: You described epilepsy as a abnormal electrical activity in the brain. We described a couple of, I guess, different types of seizure there. Do we sort of fully understand what's actually happening in the brain to cause these different types of seizures? Or is that something that's still not well understood?
Martha: We understand to a large extent what is happening. We don't necessarily know why. And especially why at that moment. The brain communicates electrically. So, the neurons are connected in this exquisite network, and electrical signals from one neuron will impact other neurons to which it is connected.
And think of the most complex wiring diagram, that you can imagine. Yes. And if the abnormal electrical discharge that starts in one neuron or a small group of neurons spreads to other neurons, then that can cause the symptom of the seizures.
And the more neurons that are involved in the abnormal electrical activity, the more pronounced the symptoms will be, or the degree to which the patient perceives or is impacted by the seizure.
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Matt: The misconceptions around epilepsy are pretty stark. When most people think of the disease, they go straight to strobe lights and seizures, but this ignores the nuance of the disease and it's varying scales of severity.
It's this nuance which goes some way to explaining why clinicians have found it so hard to find an effective treatment for some patients with more aggressive forms of epilepsy.
The brain's wiring diagram, as Marty points out, is as exquisite as it is complex. And this brings its own huge challenges.
So, how are clinicians dealing with these challenges at the moment? I went back to Alex to find out and started off by asking about the efficacy of the drugs that many people with epilepsy rely on.
Alex: Yeah. Say about two thirds of patients will respond reasonably well to antiepileptic drugs anti-seizure education. We're not one up saying drugs are bad, seizure control is super important. And for 66% of the population, they will work.
However, they're not without their side effects. A drug might work for some patients for a year, and then the efficacy will fade. And then they'll go onto a new drug. And there's a element of patients or the parents of patients having to track their kind of epileptic seizure activity, to see what the efficacy of the drugs is.
And if you've got seizure activity in the evenings or when you might be asleep or there might be absent seizures or other seizures which come with memory loss, having to keep a physical book, a physical log of that activity can be really challenging and a real big burden on patients or the carers.
Matt: So, if you had, I guess, better monitoring technologies, what would that unlock for patients?
Alex: So, essentially it would unlock this ability for patients on an epileptic medication, it gives doctor's ability to automatically see a whole history of how their disease is progressing. You might be able to tie fine triggers.
So, another common misconception with epilepsy is that people get seizures only when they see like strobe lights. That's only one particular subset of the population. And a whole range of other kind of external factors can be triggers for epileptic seizures.
So, it could be like if you haven't eaten for five hours, combined with if it's hot weather that day, combined with something else.
And so, actually having a accurate log like timestamped of how your brain's doing it can be really powerful in terms of identifying not just whether the drugs you're working and using, but also this kind of whole holistic lifestyle choices that can really compliment any other treatments you might be on.
Matt: And how would that help with sort of matching people to the right treatment? Would there be a benefit there?
Alex: Yeah, so what people are saying at the moment with some of the devices which have leading the wave now purely for epilepsy monitoring, what they're saying is it allowing the neurologist to really make sure people are on the right drugs.
And it allows them to maybe suggest them to go down a neuromodulation or a surgical route of treatment. It allows them to look for those lifestyle choices. And it takes the burden off parents and patients to constantly having to be monitoring themselves.
So, we are seeing at the moment as these device is becoming more prevalent, real world clinicians are making choices that will unlock new pathways, will unlock new modifications to a patient's care that will hopefully help them.
Matt: Fantastic. Yeah, it's super interesting to hear this kind of the range of treatments that are available. And maybe how some of the new technology might help guide people through that process and perhaps either find a treatment that works for them faster or actually more quickly progress onto something that will work.
Alex: Yeah. So, maybe talking a little bit more about the technology then. So, there's the traditional way of monitoring for epilepsy, if you're looking specifically in a very detailed sense is your EEG going from sort of outside of the heads. And then deeper in.
You've got I think your EEG. So, these are the electrodes around the scalp, and sometimes that might also involve shaving a patient's head to get good electoral contact all day round.
Also, there's that OP-MEG that we talked about earlier, that's still really in the kind of research phase, that hasn't reached the mass market yet.
So, you've got those two which kind of sit external to the patient's head. But for severe cases, you actually are looking to get closer to the brain activity itself, in a way that you just can't do through the skull and the skin.
And therefore, in specialist centers, there's these things called epilepsy monitoring wards, where a patient usually has a craniectomy, which means a surgical procedure to take out a part of the skull, to allow equipment to sort of interface directly to the brain tissue itself. And this happens in one of two ways, a thing called ECoG, which is cortical and encephalopathy.
So, looking at the surface of the cortex or the surface of the brain with an electrode array sort of placed on the surface itself.
Or there's a thing called stereo encephalography or SEEG, where you have depth electrodes that actually go all the way into the brain tissue. You might have up to 12 of these placed in different parts of the brain, which is obviously really traumatic for patients, especially pediatric ones.
Matt: And how long would you have to be wearing these? Like is this something that's permanently installed or is this for a period of diagnosis?
Alex: So, this is for the period of diagnosis. This is usually for two weeks, would be a standard stay. Unfortunately though, because of the stochastic nature people might not have a seizure in that two weeks and then they might just have to go home and they can't have any surgical interventions.
So, but basically what we're seeing is this kind of reducing the impact on patients by making things smaller, making them wireless, allows to take some of that really good data and monitoring equipment that they might have on an epilepsy monitoring ward, however traumatic that would be. And actually be able to use some of those techniques and some of that data analysis, be able to pair that with a wireless communication technology. So, the surgeon can close up the skin. You don't have that infection risk and a patient can go about their daily lives.
And so, you're seeing companies like NeuroPace with their RNS System, where you've got the monitoring combined with the stimulation to disrupt the seizures. And it’s giving neurologists a log of the electrical activity in the brain, so they can see when seizure-like activity is happening.
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Matt: Those epilepsy monitoring wards, for all the incredible detail I'm sure they will give, will clearly have a big impact on patients' lives.
Marty told me that due to the trial and error nature of epilepsy medication, the time from initial diagnosis through to getting into one of these specialist facilities can take years. And what's more, an extended period, staying in hospital is unlikely to be a cost effective way to monitor patients at scale.
But the innovations Alex mentioned here could be the key because there are technologies that would allow us to monitor continuously in patient's own homes, with no disruption to the patient's lives. And they would go even one step further, not just detecting the onset of seizures, but preventing them at the source.
This is the device developed by NeuroPace and Martha was key in creating. I went back to her to find out some more about it.
Perhaps you can tell me more about the device that you've created with NeuroPace and how that works.
Martha: Well, this came actually — I'll provide a little of my personal story. I am a neurologist who has specialized my entire career in epilepsy and taken care of many thousands of patients. And felt so frustrated and saddened by the numbers of patients I was not able to help.
Of course, as an epileptologist, people often send me the patients who have not been easy to treat. Still it is very difficult, really heartbreaking to tell someone that there's nothing that you can do.
So, these would be individuals who haven't responded to medication and for whom we could not safely or effectively remove the seizure focus. So, I became very motivated to think about something entirely different.
And given the observations I just mentioned, that it's usually only a very small area of the brain and only a very small percentage of time that there is a problem, to take some of the concepts of cardiac defibrillators and apply them to the brain.
So, the development began 20 years ago of the engineering of a device that could do this. And once that technology was developed, clinical trials began actually back in 2004 and went on for many, many years.
The device was created in order to provide electrodes to that focus, that would sense the electrical activity going on all the time, and would be programmed or instructed by the neurologist to respond to abnormal electrical activity and to provide brief pulses of stimulation, also determined by the neurologist.
In addition, this device was created so that it would collect information and that is to keep a record of every time there was abnormal activity, every time the device had provided stimulation and what had happened because of that.
And also to record actual brain electrical activity similar to the EEGs that we've relied on since the forties, but this time to look at EEGs recorded directly from the brain, which we have not seen before in somebody walking around, living their usual life, waking and sleeping over years.
And so, this is what we would refer to as exquisite temporal sampling, meaning that we are being provided data not at a snapshot or at best a few days, but over time and have learned from that, that this is an extremely dynamic disorder.
Matt: The possibilities seem endless there, but what does this continuous monitoring, I guess, enable us to learn about the condition?
Martha: So, seizures are not equally likely to occur at any one moment in time, but they're clearly cycles. And those cycles very often are related to wakefulness and sleep.
So, some people show increases in abnormal electrical activity and therefore more susceptibility to seizures at certain points during their sleeping cycle. And others during their waking cycle, we can see that there are certain behaviors like alcohol that increase susceptibility or stress or activity that make people more susceptible.
And by learning these patterns, we can actually have a conversation, the individual who is being treated and the physician, about perhaps altering those behaviors or at least understanding times when there may be a greater risk for having a seizure.
Matt: In terms of individualizing that treatment for a specific patient, you get a much better understanding of how the condition manifests for them and how you can potentially tailor other aspects of the treatment to that specific patient as well?
Martha: Absolutely. When we began getting this information, we had no idea what we would see. We did not know whether everybody would be the same or everybody would be different.
And what we found is there is difference from individual to individual, but within an individual what we see is quite consistent. And that was very good for using this treatment.
Because that means that it is fairly straightforward and does not take much more than a few weeks to understand what should be detected, to understand what the abnormal electrical activity is in that individual, that predicts that a seizure is likely to occur.
So, programming or dialing in what should be detected can be done early and that will remain consistent.
But then what we also want to see is the effect of the stimulation. We have an opportunity to change the way stimulation is developed, either how much stimulation or the nature of the stimulation, whether it's very short bursts or longer bursts, whether it's low frequency or high frequency.
But by being able to see, actually what the effect of the stimulation is, then we can make more rapid adjustments to find what is right for that individual. And to create a very personalized approach, which has before not been possible because we haven't really understood enough about exactly what is happening in that individual's brain.
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Matt: Individualization and personalization are some of modern healthcare's biggest priorities across the board. And the kind of progress in treating epilepsy that they could offer if done right, could be really groundbreaking.
NeuroPace having the only FDA approved device in this space, really are leading the way. But would having their devices put out at scale be a kind of panacea for epilepsy? Are there other developments going on in tandem which could help patients even further?
I want to end this episode by seeing what an idealized future for epilepsy might look like. Here's Alex with his thoughts.
Alex: I guess the holy grail of any treatment is to let patients live their lives as if they were condition-free. So, stopping any seizure before it happens would be the holy grail. And to do that, you might want some really rapid dynamic response to seizure starting. There's some literature to show that if you time your neuromodulation exactly right, you can help stop the seizure before it really takes hold.
And so, if you can kind of nip that in the bud and scramble the signal as it were, you could maybe stop that seizure happening at all. Having a sort of device that would monitor and then intervene in time to stop that seizure progression starting, that would be kind of the holy grail and let patients live seizure free.
Matt: I wonder if we were to look a bit more broadly, sort of beyond epilepsy here, how the kind of innovations that we see here, how do they apply to other conditions?
Alex: I think there is so much work going into all kinds of neurological disorders. Everything from psychedelic therapies to new cell and gene therapies. Really recently we started doing similar things in Parkinson's.
So, looking at local field potentials in the brain to titrate the stimulation for Parkinson's, to help that therapy adapt in real time to the patient's needs. We're looking at using neuromodulation for depression.
There's a huge amount of research going into being able to apply some of these neuromodulation techniques for Alzheimer's. And hopefully we'll see some of those progress into later stage clinical trials.
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Matt: The more we understand these complex neurological diseases through increased monitoring, the more clinicians will be able to collaborate and create treatments which work across the board. Martha agrees and even sees a world where people with epilepsy could live their lives completely free of seizures.
Martha: What I imagine, my future would be an intervention to inhibit or prevent epileptogenesis. And then it would be medications that actually are targeted to only those neurons that are firing abnormally.
And then I would look towards not having to remove or destroy a part of the brain, but to manage it and to help it heal by inhibiting the abnormal pathways and promoting healthy pathways.
Matt: And how far do you think we are away from that future?
Martha: I would say (oh my gosh), it could be a very long time because the time it's taken to develop the responsive neurostimulator was a long time. It was a meaningful part of my life.
But in the meantime, with advances in technology and that includes miniaturization, advances in integrated circuits, advances in power, in batteries, and then with the application of AI, I think it's kind of like what we saw with computer chips. And perhaps the development in this area, in medical therapies will not be exponential because of course we have to ensure these are safe and that does take some time. But it could and I think will accelerate.
Matt: Yeah, I think that's brilliant. Yeah. Thank you very much Marty.
Martha: Yeah. I feel very privileged to have been part of this and mostly I feel very privileged to have been able to share my patience journey.
And I must say that it's really gratifying to see that there is a great deal of effort across the board to continue to innovate and to develop not only these devices and new surgical approaches, but also medication.
So, for those who are struggling with epilepsy, there is no reason to lose hope.
Matt: I've been most impressed this week, by the way, in which NeuroPace's RNS System has already forged a path for effective treatment. Is that ability to not only monitor, but to respond directly to seizures, which holds the most promise. Because that would radically alter the lives of patients with severe epilepsy and even other diseases besides.
Interacting with the brain at this fundamental level is the core of tackling neurological diseases. And with these innovations, there should be every hope that the future is one where seizures become a thing of the past.
Thanks so much for listening to this week's episode of Invent Health, from TTP. And a big thanks to both Marty and Alex for the incredible insights. You can find out more about both their work in the show notes.
We'll be back next time with an episode looking at how engineers and programmers are designing for trust in healthcare systems, focusing on the potential of AI, especially.
If you've enjoyed this episode and you want to let us know, please do get in touch on LinkedIn, Twitter or Instagram. You can find us at TTP.
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