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CES – shedding light on a misunderstood condition

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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

Spinal

Clinical trial gives hope to spinal cord injury patients

If successful animal studies translate into patients, NVG-291 could be set to redefine the treatment of spinal cord injury

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A revolutionary treatment designed to help redefine the future of people with spinal cord injury (SCI) is to embark on a clinical trial. 

The NVG-291 treatment has previously indicated its huge potential through two independent studies, which resulted in significant recovery in mobility and/or bladder function in animals with spinal cord injury. 

Now, NervGen Pharma, the biotech company behind NVG-291, has announced a Memorandum of Understanding the Shirley Ryan AbilityLab, with the intention of progressing the first clinical trial of the treatment. 

The single site trial is expected to start in the second half of this year and will assess the safety and effect of NVG-291 in treating acute and subacute, as well as chronic SCI, patients. 

NVG-291 is based on the by Dr Jerry Silver at Case Western Reserve University of a class of molecules (chondroitin sulphate proteoglycans, or CSPGs) that are up-regulated in response to nervous system damage and that inhibit repair. 

NVG-291 was designed to bypass this inhibition by CSPGs, thereby enhancing the body’s natural repair mechanisms, including plasticity, regeneration and remyelination.

“We have been following Dr Silver’s work for years and are very excited to be the first centre working with NervGen on this important spinal cord injury study,” said Dr Monica A. Perez, scientific chair of the Arms + Hands Lab at Shirley Ryan AbilityLab.

“One of the important aspects of this single-centre, placebo-controlled trial is the use of advanced electrophysiology to assess transmission in cortical and subcortical neuronal pathways as well as behavioural outcomes. 

“The ability of NVG-291 to demonstrate meaningful recovery in motor function, sensory function and bladder control in animal models is exceptional. 

“If these results translate to patients, NVG-291 could redefine the treatment of spinal cord injury.”

“NervGen and Shirley Ryan AbilityLab are planning a very unique and intriguing trial design, into which I have been fortunate to provide input,” stated Dr James Guest, professor of neurological surgery at the University of Miami and member of NervGen’s Spinal Cord Injury Clinical Advisory Board.

“The rationale to include acute and chronic patients in a study underscores the broad potential of the mechanism of NVG-291 in SCI. 

“Using Shirley Ryan AbilityLab in a single-centre study that implements advanced electrophysiological techniques to monitor connectivity across the site of injury will allow reproducible testing to explore NVG-291’s effects on motor recovery, possibly shaping the impact of subsequent studies.

“Partnering with Shirley Ryan AbilityLab, a leading institution in spinal cord injury research and management of patients with spinal cord injury, is an exceptional opportunity for NervGen.”

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World-first stem cell trial for spinal cord injury

Keio University hailed the implant of cells as a ‘huge step forward’ in the quest to cure paralysis

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The world’s first successful transplant of stem cells in a patient with a spinal cord injury (SCI) has been hailed as a “huge step forward” in efforts to cure paralysis. 

Surgeons at Tokyo’s Keio University are studying whether induced pluripotent stem (iPS) cells can be used to treat SCI. 

And it has been announced than in the first step in the trial, more than two million iPS-derived cells have been implanted into a patient’s spinal cord in an operation which took place last month.

Keio University Professor Masaya Nakamura, who leads the research, said this marked a “huge step forward” but there remains “lots of work to be done” before the treatment can be put to use. 

iPS cells are created by stimulating mature, already specialised, cells back into a juvenile state.

They can then be prompted to mature into different kinds of cells, with the Keio University study using iPS-derived cells of the neural stem.

The breakthrough follows significant progress in moving closer to finding a cure for paralysis, with tech company ONWARD underway with its international Up-LIFT trial and a groundbreaking project to develop a biomaterial bridge to regrow nerve fibres being backed by a $24m investment.

The initial stage of the Keio University study aims to confirm the safety of the transplant method, the researchers said.

The patient will be monitored by an independent committee for up to three months to decide whether the study can safely continue and others can receive transplants.

The team also hopes to see whether the stem cell implants will improve neurological function and quality of life.

The number of cells implanted into the patient was determined after safety experiments in animals, said the researchers. While they will  be monitoring for therapeutic effects, the study’s main goal is to study the safety of injecting the cells, they added. 

The study has been planned since 2019, when the Keio University School of Medicine and Keio University Hospital were given clearance to start a clinical study into regenerative medicine for SCI. 

However, recruitment to the trial was suspended after research begun in December 2020 due to the COVID-19 pandemic. Patient recruitment for a subsequent trial is expected to resume in April. 

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Groundbreaking spinal cord injury project backed by $24m

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Groundbreaking work will see the development of a biomaterial bridge to help regrow nerve fibres, giving new hope to people living with spinal cord injury (SCI).

A key challenge in treating traumatic spinal cord injury SCI is repairing the gap that is formed when the spine is broken. This gap, typically a few centimetres wide, essentially blocks nerve impulses from getting through, leading to serious health issues that may include paralysis, loss of blood pressure, bladder and bowel control, sexual dysfunction, and chronic pain.

Now a new, multidisciplinary team—aptly named Mend the Gap—is working on a novel approach that may help people with SCI.

The Mend the Gap team recently received $24million from Canada’s New Frontiers in Research Fund 2020 Transformation stream to investigate using biomaterials—and soft gels in particular—to heal the injury.

The soft gel will be injected into the site of the injury to serve as a bridge for growing nerve fibres.

“A biomaterials bridge is compatible with other systems and structures in the body and is minimally disruptive,” explains principal investigator Dr John Madden, a professor of electrical and computer engineering in the faculty of applied science at the University of British Columbia (UBC).

“The soft gel that our team plan to use contains tiny magnetic rods that are aligned using an external magnet, creating guide rails that support the nerve fibres to grow in the right direction, eventually crossing the gap.”

Previous treatments for spinal cord injuries used solid bridges, which have the drawback of risking injury to any remaining healthy nerve fibres and bodily functions, explains co-principal investigator Dr Wolfram Tetzlaff, a professor of surgery and zoology at UBC and director of ICORD, a world-leading centre for spinal cord injury research within the UBC faculty of medicine and the Vancouver Coastal Health Research Institute.

“A soft gel can be moulded into the shapes of the many different lesions seen in the body, and thus provide personalised treatment,” said Dr. Tetzlaff. 

“Since the surgery will be minimally invasive, we can potentially see shorter recovery times and minimal damage to the patients.”

Co-principal investigator Dr Dena Shahriari adds that thus far, research in SCI has been largely focused on biomaterials that need to be implanted through invasive surgery.

“Here, we shift the focus to injectable biomaterials to potentially protect any residual function that those living with SCI heavily rely on and treasure,” says Dr Shahriari, a biomaterials scientist and neural engineer, and an assistant professor at UBC’s department of orthopaedics and school of biomedical engineering. She also leads a team at ICORD that develops neuroelectronic devices, sensors and smart biomaterials to interface with biological tissues and provide new capabilities for tissue regeneration and improving organ function.

One reason repairing the spinal cord is so difficult is the presence of scar tissue, so the soft gel will contain drugs that can modify that tissue and revive the nerve fibres. The gel will be injected into the spinal cord by a machine-vision-equipped surgical robot for enhanced precision.

“Every week we admit a new patient whose life has been turned upside down after suffering a spinal cord injury,” says co-principal investigator, Dr Brian Kwon, a professor of orthopaedics at UBC’s faculty of medicine, the Canada Research Chair in Spinal Cord Injury and Dvorak Chair in Spine Trauma.

“It serves as a stark reminder that we have to be pushing the boundaries of science and innovation in initiatives like Mend the Gap to establish novel ways of repairing the injured cord.”

While the primary goal of Mend the Gap is repairing the spinal cord in recently injured individuals, the team does not rule out eventually applying the results to those who have chronic injuries in the future.

The 32-member project includes researchers, engineers and surgeons from Canada, the United States, Europe and Australia. In Canada, the network includes UBC, ICORD, the University of Alberta, Western University, McGill University and University of Toronto.

Co-principal investigator Dr Karen Cheung says the project highlights the unique advantages of bringing together medical and engineering knowledge to tackle the complexity of spinal cord injuries.

“Biomedical engineers play a central role in addressing grand challenges in health, because they analyse, interpret, transform and recombine knowledge and information from all of these domains—materials engineering, electrical engineering, neuroscience, chemistry, physics—to generate new technologies and make impactful discoveries,” says Dr. Cheung, a bioengineering professor at UBC’s school of biomedical engineering.

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