Earlier this year, UK clinicians hailed a potentially huge breakthrough in the treatment of childhood epilepsy, with the news that a clinical trial of a pioneering brain implant has apparently transformed the life of a British teenager suffering from one of the severest forms of the illness.
According to initial reports, since having the UK-developed Picostim device fitted last October at London’s Great Ormond Street Hospital, thirteen-year-old Oran Knowlson (who suffers from a hitherto treatment resistant form of epilepsy known as Lennox-Gastaut syndrome) has seen an 80 per cent reduction in daytime seizures, which previously sometimes occurred hundreds of times a day.
The development is the latest in a series of trials taking place through the CADET project (The Children’s Adaptive Deep brain stimulation for Epilepsy Trial), a three-year long initiative led by UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital aimed at exploring the effectiveness of deep brain stimulation for children with epilepsy.
At the heart of the story is a sytem known as Picostim, an investigational research device developed by Oxford University startup Amber Therapeutics, which can be used to send electrical signals deep into the brain via a network of precisely placed electrodes. By targeting stimulation at specific areas of the thalamus - the central section of the brain - the researchers believe it could be possible to prevent the propagation of seizures.
We don’t want to just develop something that works, we want to develop something that is effective and available to children in the UK
Described by its developer Professor Timothy Denison (founder and director of Amber Therapeutics) as a ‘general-purpose neural computer’, Picostim is already also being investigated for use in the treatment of a range of conditions including urinary incontinence in women and Parkinson’s disease. Denison said that the technology is also set to play a key role in a chronic pain study about to start in Oxford. “We can move it to different areas of the body, adjust the algorithms that run inside, and have it basically adapt to different types of physiology,” he explained. “Ultimately, we’re trying to restore physiology to a more normative state.”
Around four years ago, researchers began exploring the technology’s potential in pediatric applications where, said Denison, it has some key advantages over other systems, which are unsuitable for a child’s rapidly growing body. “For existing deep brain stimulation systems there’s a lead tunnel down through the neck, and then a device is placed in the chest. Oftentimes, it’s actually too big to go into a child’s chest, so they’ll put it in the abdomen. So the idea of having everything kind of form fit up on the surface of the skull had its attractiveness. Also it’s rechargeable which is good for longevity and can really minimise the number of any replacement surgeries for the device.”
Indeed, developing a device suitable for use in growing children presents a series of design and engineering challenges that are extreme even by the usual standards of medical implants, said Denison. “Implant devices are class three medical devices, and so there are very significant regulatory steps that we have to go through and multiple standards that have to be applied….the pediatric side layers on additional considerations for growth and development.” For instance, whilst brain stimulation systems for Parkinson’s disease, which typically affects much older patients, may be expected to last for around a decade, this would not be enough for pediatric use. “If you’re putting it into a five-year old, a decade is not going to be acceptable,” said Denison.
As a result, there’s been a real focus on built in flexibility that will enable clinicians to wirelessly upgrade the device over its lifetime. “Just like your cell phone gets its operating system upgraded, we need to be flexible as well,” said Denison. “As we get a better understanding of exactly how we might go about treating epilepsy we can actually - within some limits - put enhancements into the device through a non-invasive update.”
Initial implantation of the device and the electrodes is a delicate process, with the team using Neuromate, a robotic neurosurgery system developed by UK manufacturing technology firm Renishaw, to precisely place the electrodes in exactly the right area of the brain. Great Ormond Street Hospital’s Rory Piper, CADET trial fellow and coordinator, explained the process: “It’s a minimally invasive neurosurgical procedure. We make two very small holes in the front of the skull on either side, and through those holes will pass very thin wires down to the thalamus, which is the part of the brain that we’re targeting on the right and the left side. Those wires are connected to the Picostim device.”
Piper added that one of the key drivers of the wider engineering effort has been developing a technology that’s actually affordable enough to have a significant impact: “We don’t want to just develop something that works,” he said. “We want to develop something that is effective and available to children in the UK. We intend to translate this therapy as something that’s going to be available on the NHS. That’s very important to us.”
In the meantime, efforts to expand the capabilities of the technology are already underway. Whilst current applications see the device stimulating constantly at the same level, the longer-term vision is to create a more responsive and adaptive system that can be synchronised with a patient’s circadian rhythms and even monitor and react to brain waves and other activities in real time.
This latter capability - stimulating and measuring at the same time - is particularly challenging from an engineering point of view, explained Denison. “The stimulation signals are on the order of milliamps to hundreds of ohms to maybe a kiloohm for the tissue electrode interface, so that we’re talking about volts oftentimes peak to peak. The signals we’re trying to measure from the brain are on the order of down to microvolts, to tens of microvolts, peak to peak. And so it’s getting to be a part per million measurement problem, and that’s historically been the challenge. Another innovation in our toolkit is to really enable more of a full duplex operation, where we can be stimulating the brain, and in real time also see what that stimulation is doing and make the appropriate adjustments.” The core technologies required to do this are, Denison explained, already embedded in the device, and the capability will be unlocked through a wireless update.
Despite the tantalising potential of this more advanced capability, the CADET team is determined to take things one step at a time. Indeed, according to Denison, the potential of the technology can only be fully understood if it’s deployed in a phased manner. That phased approach, he said, is something that distinguishes the CADET project from earlier efforts to explore the potential of DBS. “Other studies have been strictly open loop or they jumped right to an adaptive mode, and no one’s really methodically built up how each of the different approaches are incrementally impacting the treatment of epilepsy and that’s one of the things we really want to explore.”
Although it’s still early days, the indications so far are that the technology could have profound consequences on the treatment of childhood epilepsy and Piper is cautiously excited about its potential “It was absolutely brilliant to see that he got 80 per cent reduction of his daytime seizures,” he said. “We knew that it could be up to that result but it wasn’t entirely clear what number we were going to get.”
The next stage of the project will be a much larger trial that will assess the efficacy and effectiveness of the therapy in a group of 26 children, and hopefully reinforce these early findings. “To be honest, we’re not entirely sure on the true efficacy of the therapy, and that’s why it’s so important to do this research,” said Piper. “When you look at the data in the current literature (i.e. from previous studies) you see a wide variety of effectiveness rates. We need to get a more accurate result and this will be key to translating it into a therapy available on the NHS.”
Getting it to that point will, said Piper, require a continuation of the kind of cross-disciplinary collaboration and shared sense of purpose that’s been one of the defining features of the project thus far. “It all boils down to a common mission statement, and that’s something we all align to”, he said, “that mission statement is developing technology that’s going to help patients, and that’s what we all rally around. It doesn’t matter whether we talk in academic, engineering or clinical terms, that’s what we all get behind,”.
Alongside the clinical, engineering and academic partners, the other key collaborative partner is - of course - the patient (and their family) and Denison is keen to emphasise the critical role played by these brave individuals: “We always want to thank the family for volunteering to go first because it’s actually quite a pioneering step. The person who volunteers to go first requires a certain level of faith in the team, technology and so I really appreciate them putting their trust in [us].”
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