Patients with new spinal cord injuries (SCI) whose blood pressure is maintained within a newly-defined range during surgery may stand a better chance of regaining some mobility and functionality – even in patients with the most devastating injuries.
Using a novel machine-learning technique called topological data analysis (TDA), researchers at UC San Francisco were able to identify patterns in large datasets to find previously unknown connections that explain why some people recover some motor control after a significant injury, while others are left with total paralysis.
The study also may have ramifications for patients undergoing spinal surgeries for more common conditions, the researchers said, although further investigation is needed.
“Without the use of TDA, data would be heterogenous, overwhelming and beyond human comprehension,” said co-corresponding author Dr Adam Ferguson, director of data science at the UCSF Brain and Spinal Injury Center.
“Topological data analysis helped us to ‘see’ patterns that are difficult for humans to see,” he added.
Ferguson was the first scientist to harness machine learning as a tool to uncover the connection between spinal cord injury recovery and blood pressure, using data from both published and unpublished studies.
For one particular participant in the research, a father of two injured in a surfing accident, the innovative insight and bench-to-bedside research that followed meant the difference between total paralysis and resuming his life.
The study also may have ramifications for patients undergoing spinal surgeries for more common conditions, the researchers said, although further investigation is needed.
The study, which draws from retrospective data from hospital operating rooms, follows preclinical research by Dr Ferguson, using data from both published and unpublished studies.
In the current study, the researchers tracked data from 118 patients at two hospitals with Level 1 trauma centres: Zuckerberg San Francisco General Hospital and Trauma Center (ZSFG) and Santa Clara Valley Medical Center.
They compared the estimated grade of injury on admission with the estimated grade of injury at discharge.
Grades followed the American Spinal Injury Association Impairment Scale and ranged from A, denoting complete motor and sensory function loss below the level of injury, to E for normal sensation and full motor function.
The same machine-learning technique used by Ferguson with preclinical data in the earlier study was applied to the current study using clinical data collected at one-to-five-minute intervals while the patients were in the operating room.
Of the 42 patients whose injuries had improved by at least one grade from admission to discharge, 18 had had a grade A injury, eight grade B, 11 grade C and five grade D.
These TDA patterns were then verified by spinal cord injury experts and statisticians, who developed rigorous statistical models that “assessed their truth,” Dr Ferguson said.
“This is an ideal use case for how machine learning could be implemented in biomedicine – it’s a partnership between machines and humans with clinical domain knowledge,” he said.
“In essence, we are machine learning-assisted cyborgs.”
Patients with blood pressure that was too high or too low during surgery had poorer neuromotor recovery after surgery, the researchers concluded.
Maximal recovery was associated with mean arterial blood pressure maintained between 76 mmHg and 104-117 mmHg, a range that is narrower than the current guidelines that have followed smaller clinical studies.
“Damage to neurons in spinal cord injuries leads to dysregulation of blood pressure, which in turn limits the supply of blood and oxygen to stressed spinal cord tissue, exacerbating spinal neuron death,” said co-lead author Dr Abel Torres-Espin, of the UCSF Department of Neurological Surgery and of the UCSF Weill Institute for Neurosciences.
“Thus, precise blood pressure management is a key target for spinal cord injury care.”
For patients with the most severe grade A injuries, optimal blood pressure during surgery may be a key factor in demoting those injuries to grade C, the researchers noted.
CES – shedding light on a misunderstood condition
Cauda equina syndrome (CES) is a rare and severe type of spinal stenosis where all the nerves in the lower back suddenly become severely compressed
Speaking at the CES Festival 21, Dr Nish Srikandarajah, neurosurgery registrar at the Walton Centre, Liverpool, explained more about this hard-to-diagnose condition.
How is CES diagnosed?
To confirm CES, we need both a clinical and radiological diagnosis, with the clinical signs supported by the correct imaging.
The cauda equina refers to the end of spinal cord, where roots have developed – known the horse’s tail, hence the name. These supply sensation and power to your leg muscles as well as control to your bladder, your bowel and your sexual function.
So when there’s a disc pressing on that area, which happens in most cases of CES, invariably over time you get a dysfunction of these nerves.
Therefore the clinical signs would be leg weakness and loss of sensation, which could also lead to paralysis of the legs. A patient may also experience problems with their bladder and bowel function and may also experience sexual dysfunction, loss of ejaculation or orgasm.
These are all serious signs and symptoms that would point to the need for imaging.
What are the problems with CES diagnosis?
There are two main issues. The first is in terms of picking up the clinical signs, because the first port of call for most people would be a GP or A&E, who may find it hard to differentiate CES from more common lower back and leg pain.
However, there are some red flags that would alert a medical professional, such as issues with the bowel or bladder, or feeling numb in the genitals or backside. Symptoms like that would make clinicians consider CES.
The second issue is with getting an MRI scan, which is very difficult as very few institutions offer it out-of-hours. Because MRI is only available out of hours in tertiary centres, patients find it very difficult to get a scan and so do clinicians. In cases like this, they need to be calling through to us, the neurosurgeons, to verify if it’s important enough.
It is subjective as to what degree of compression requires urgent surgery. What is your opinion?
The general thinking with surgeons is that, if significant canal compromise is seen on the imaging, this would constitute compressive CES. However, as to what degree that is in terms of a percentage is always argued about in studies, so ultimately it comes down to clinicians’ personal experience.
In fact, this is an area we need to look at – is it that you need a significant canal compromise before calling it CES? Or if there’s a smaller amount of compression, maybe a local reaction, it’s still causing compromise of the nerves – does that count? That’s why research is still needed in this area.
What do you look for in a CES referral?
If I get a call, there are some important questions I would ask: do you have lower back pain? How long have you had it? Has it got worse recently? Do you have leg pain associated with it? Is it one side or both? Where does leg pain travel to? This is to figure out which nerves might be affected.
The next question would be are there any issues with the bladder or bowel? These issues can range from patients with incomplete CES, who have bit of an issue passing urine, feel a bit of numbness down there, a change in bowel habits, to those with full blown CES. In those cases, the patient will be retaining urine, they’ll be unable to fully empty their bladder, although it won’t be painful. They’ll also have considerable numbness on their backside – we would test this by asking if they can feel a pin prick.
In fact, that’s shown to be the most likely thing to go wrong if you go on to have an MRI positive diagnosis of CES; the perianal sensation starts to go.
We would also run a bladder scan to find what the post-void bladder residual is. So, once you’ve passed urine to do a bladder scan, if you’re found holding a lot of urine, even after voiding, it suggests the bladder is not functioning as well as it should. This gives a stronger indication that something’s going wrong and need to get further imaging.
What are your recommendations for rehab?
During my PhD, I interviewed quite a few patients with CES and the impression I got from them is that after having their surgery, their care tends to be quite disjointed.
So in essence, once the surgery’s done, if you have a bladder issue, you tend to see a urologist, if you have a bowel issue, you’ll see general surgeons and if you have any sort of psychiatric issues, you’ll see a psychiatrist, but there’s nobody overseeing all of this.
What we have at the Walton Centre is a CES clinic where one person acts holistically, looking at all these features that need to be fed into your care and I think that’s what’s needed.
Because the second thing I found with patients is that they were really anxious about what they could do after the operation. Could they even go for a walk? Pick up their child? Bend over?
They’re all simple things that we take for granted, but they were worried that doing them might make the CES might come back.
Obviously, it’s different depending on each patient; you have to look at what they’ve been through and what sort of operation or imaging they had before and what their outcome was to give them that advice. That’s why we need a more tailored advice, reassurance and a more holistic service for CES patients.
What are your thoughts on the current research available for CES?
We published a study a few years back looking at all the literature that’s out there and we found that people are generally conducting low quality studies, because they’re doing it only at single institutions and they’re not looking at the outcomes that matter to patients and healthcare professionals.
I think the landscape needs to change for CES in terms of research and services. One way is to develop a solid database for this syndrome, which collects outcomes that matter to patients over a long period of time, so we can follow it up and figure out the best way to manage patients with CES.
See more on the CES Festival 21 here.
Could dancing molecules cure paralysis?
The therapy has the potential to repair tissue damage after serious spinal cord injury, say researchers
Researchers in the United States have developed an injectable therapy that harnesses ‘dancing molecules’ to repair tissue after severe spinal cord injuries, which is said to have the potential to cure paralysis.
In a new study, researchers at Northwestern University administered a single injection to tissues surrounding the spinal cords of paralysed mice.
Just four weeks later, the animals regained the ability to walk.
By sending bioactive signals to trigger cells to repair and regenerate, the breakthrough therapy dramatically improved severely injured spinal cords in five key ways:
- The severed extensions of neurons, called axons, regenerated;
- scar tissue, which can create a physical barrier to regeneration and repair, significantly diminished;
- myelin, the insulating layer of axons that is important in transmitting electrical signals efficiently, reformed around cells;
- functional blood vessels formed to deliver nutrients to cells at the injury site;
- more motor neurons survived.
After the therapy performs its function, the materials biodegrade into nutrients for the cells within 12 weeks and then completely disappear from the body without noticeable side effects.
This is the first study in which researchers controlled the collective motion of molecules through changes in chemical structure to increase a therapeutic’s efficacy.
“Our research aims to find a therapy that can prevent individuals from becoming paralyzed after major trauma or disease,” said Northwestern’s Samuel I. Stupp, who led the study.
“For decades, this has remained a major challenge for scientists because our body’s central nervous system, which includes the brain and spinal cord, does not have any significant capacity to repair itself after injury or after the onset of a degenerative disease.
“We are going straight to the FDA to start the process of getting this new therapy approved for use in human patients, who currently have very few treatment options.”
According to the National Spinal Cord Injury Statistical Center, nearly 300,000 people are currently living with a spinal cord injury in the United States.
Less than three per cent of people with complete injury ever recover basic physical functions, and approximately 30 per cent are re-hospitalised at least once during any given year after the initial injury, incurring significant lifetime health care costs per patient.
“Currently, there are no therapeutics that trigger spinal cord regeneration,” said Stupp, an expert in regenerative medicine.
“I wanted to make a difference on the outcomes of spinal cord injury and to tackle this problem, given the tremendous impact it could have on the lives of patients.
“Also, new science to address spinal cord injury could have impact on strategies for neurodegenerative diseases and stroke.”
The science behind Stupp’s new breakthrough therapeutic is tuning the motion of molecules, so they can find and properly engage constantly moving cellular receptors.
Injected as a liquid, the therapy immediately gels into a complex network of nanofibres that mimic the extracellular matrix of the spinal cord.
By matching the matrix’s structure, mimicking the motion of biological molecules and incorporating signals for receptors, the synthetic materials are able to communicate with cells.
“Receptors in neurons and other cells constantly move around,” Stupp said. “The key innovation in our research, which has never been done before, is to control the collective motion of more than 100,000 molecules within our nanofibres.
“By making the molecules move, ‘dance’ or even leap temporarily out of these structures, known as supramolecular polymers, they are able to connect more effectively with receptors.”
While the new therapy could be used to prevent paralysis after major trauma as well as from diseases, Stupp believes the underlying discovery — that “supramolecular motion” is a key factor in bioactivity — can be applied to other therapies and targets.
“The central nervous system tissues we have successfully regenerated in the injured spinal cord are similar to those in the brain affected by stroke and neurodegenerative diseases, such as ALS, Parkinson’s disease and Alzheimer’s disease,” Stupp said.
“Beyond that, our fundamental discovery about controlling the motion of molecular assemblies to enhance cell signalling could be applied universally across biomedical targets.”
Christopher & Dana Reeve Foundation: A Legacy of Hope
The inspiration Christopher Reeve gave to people living with spinal cord injury during his life is being continued by the Foundation that bears his name, with the quest to find a cure for paralysis moving closer by the day. NR Times speaks to Maggie Goldberg, President and CEO of the Christopher & Dana Reeve Foundation, about its world-leading research to change the future, coupled with a commitment to supporting people who need help today
“So many of our dreams at first seem impossible, then they seem improbable, and then, when we summon the will, they soon become inevitable.”
Christopher Reeve’s words, while applicable to so many situations in life, resonate more closely with the spinal cord injured community with every passing day.
Once regarded as a permanent status, with little to no hope of recovery, pioneering research now underway into finding cures and treatments for paralysis is helping to change the outlook of millions of people around the world.
And from being widely credited as putting a human face on spinal cord injury since his equestrian accident in 1995, bringing the issue to the fore globally and laying bare the reality of paralysis, the role Christopher – known and loved by so many as Superman – played in challenging the accepted norm during his lifetime is being carried forward by the Foundation that bears his name.
Now synonymous with fighting the cause of people living with spinal cord injury, the Christopher & Dana Reeve Foundation continues to break down barriers in what is possible, delivering on its dual mission statement of Today’s Care. Tomorrow’s Cure. ®
Offering a wealth of practical support and resources to individuals and caregivers across the world via its website, as well as making grants to non-profit organisations across the United States, for the past 19 years, it has been changing lives through its National Paralysis Resource Center (PRC).
Co-founded by Dana Reeve to support the millions of people – like herself – seeking information and a centralised place to seek practical and emotional support in their day-to-day lives, the PRC continues to be the only national program that directly serves the 5.4 million Americans living with paralysis.
Each year, the Foundation supports three million people virtually, with around 110,000 people receiving one-on-one personal support since the establishment of the PRC.
But in its quest to change the future, its support of research – to which it has committed approximately $140 million – is giving hope and accelerating progress across a full spectrum of spinal cord research from basic science to clinical trials and real-world treatments.
“At one time, spinal cord injury was really seen as the graveyard of neuroscience. People didn’t have hope,” Maggie Goldberg, President and CEO of the Reeve Foundation, tells NR Times.
“We believe spinal cord injury is curable, and we’re now taking multiple ‘shots on goal.’ We’ve always been very traditional in funding academic research, but now we are trying to get into humans as quickly as possible. This is a very exciting time.”
And through its approach, more wide-ranging than ever before, the Reeve Foundation is stepping up its efforts to bring this new-found hope for people with paralysis to reality.
Investments have been made in some of the most promising businesses in neuroscience and biotech – from ONWARD, creators of the spinal cord stimulation ARC Therapy, whose first device is set to be launched within the next two years, through to early-stage Axonis Theraputics in support of its research in breakthrough drug discoveries.
And through the groundbreaking, The Big Idea project, the next generation of neuromodulation is being fast-tracked and brought closer to reality every day. From its launch in 2014, the first epidural stimulation implant was made in 2018 – 22 people to date, all of whom live with paralysis, have now received such implants. The study will be fully enrolled with 36 patients by July 2022.
“The study was designed with stakeholders in mind, individuals living with paralysis due to spinal cord injury, with a goal to improve cardiovascular ability and provide advances in stepping and standing,” says Maggie, who recently became President and CEO of the Foundation after long being part of its leadership team.
“But what we are seeing, even though it was not initially part of the study, are improvements in the secondary complications which affect quality of life. There is someone in The Big Idea study who, since being implanted, hasn’t been in hospital in six months.
“This is extremely exciting, and patients are reporting it themselves. We are now seeing what a hugely important component implantables and technology are in both spinal cord injury and the health implications.
“We want to bring this therapy to the wider community, but that is easier said than done. There are a lot of steps. It’s not one size fits all as every single injury is different, but we are focused on continuing our work and providing the evidence.”
With world-leading research underway, the Reeve Foundation continues to do all it can to maximise its potential to the full, and is exploring more opportunities for collaboration.
“We are a big proponent of coalition building and are excited by work being done by other foundations and we want to work with them. We want to get the most promising therapies into humans as quickly as possible, and are looking at how we can deliver that in a holistic way,” says Maggie.
But while looking to change the future for people with spinal cord injury, the Reeve Foundation is equally committed to supporting individuals and families now in every way they can.
“We want to be available to assist when someone is affected by paralysis. We know the devastating impact it has on the individual, their caregivers, family and professionals. Whether it’s providing information, answering questions, peer mentoring, advocacy, we want to give people hope and tools,” says Maggie.
“In the United States, the type of insurance a person has may determine what therapy, assistance or nursing one may receive once they are integrated back into society, sometimes that varies between state. No matter the situation, our resource center can help connect people with services. Our goal is to help the individual have the highest quality of life through employment, sports, education, or advocacy.
“This is such a large country and so diverse, some areas are so rural that access to transport is a real issue. In some areas like New York City, we can focus on accessibility for people with paralysis, but in rural Montana or Wyoming, there may not be access to public transport, they may not have access to a rehabilitation facility or to employment if they can’t physically get there. It can be very isolating.
“We believe social connections are important. After you have a spinal cord injury, you go through a grieving process. In an instant, everything changes, and the way you interact with society may not be the same. Some people may not even be able to go back to their home. We look at every aspect of how we can be available to assist.”
And while delivering support and, crucially, hope to people living with spinal cord injury around the world, the Reeve Foundation is also committed to continuing the work of Christopher Reeve in raising awareness and changing perceptions of paralysis.
Both Christopher, who passed in 2004, aged only 52, and Dana, who tragically lost her life to lung cancer at 44 just two years later, worked tirelessly to change the lives of millions of people, and alter the awareness around paralysis for millions more.
Maggie shares this priority and is committed to ensuring this continues to be at the heart of the Reeve Foundation.
“My passion is to help others understand why this cause is so important, why they should care about it,” she says.
“When I was 16, I broke my neck in a car accident and had to wear a brace for six months. Doctors told me it was a matter of centimeters, or my injury could have been the same as Christopher Reeve.
“Spinal cord injury is still not well understood, and there is the civil rights issue too. We have an incredible team, and we’re all doing all we can to address the myriad components of care and cure within our community.”
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