Time is of the essence in nerve injury repair, research
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Despite the notion that nerve surgery research has plateaued in the past several decades, some surgeons view timely, precise diagnostics and a new wave of research as a viable path to improved outcomes in nerve repair in the future.
In an interview with Healio | Orthopedics Today, Amy M. Moore, MD, professor and chair of the department of plastic and reconstructive surgery at The Ohio State University Wexner Medical Center, said nerve surgery research is headed in the right direction.
Source: Arjun Gupta
“There is nerve research happening right now that is going to push us forward in the next decade. I cannot compare it to what was being done, but there is more interest in all surgical societies to educate and innovate the treatment of patients with nerve injuries, and I think the nerve field is at its strongest right now,” Moore said. “We have multiple industry partnerships that are interested in nerve outcomes and are helping support this research in advancement and innovation. These are companies designed and committed to helping with the care of patients with nerve injuries.”
Nicholas A. Pulos, MD, assistant professor in the department of orthopedic surgery at the Mayo Clinic, said the future of nerve surgery research will rely on the capacity to expedite nerve healing in a pursuit that is a battle with time.
“In the realm of improving patient’s function, we have a time window in which we are able to perform these surgeries and the time window to restore motor function is related to the speed at which the nerve heals itself and the amount of time that a muscle will sit idle without a nerve signal,” Pulos said.
He added, “Can we get nerves to heal faster, or can we get muscles to stay idle for longer and stay receptive to reinnervation longer?”
Trauma
Nerve injury after a traumatic event can be one of the most debilitating injuries to a patient, leaving scars that extend far beyond the surface, according to Brent R. DeGeorge Jr., MD, PhD, associate professor in the department of plastic surgery and orthopedic surgery at the University of Virginia Health System.
“The issue with these [nerve injuries] is they most commonly occur in people who are in their 20s to 40s, in the peak of their occupational/vocational life,” DeGeorge told Healio | Orthopedics Today. “Imagine someone at work, just a normal day. Then, in an instant, one unfortunate accident, and they lose the use of one of their limbs. Brachial plexus injuries can occur suddenly, severely impacting the ability to perform simple tasks — self-care, work, family. The devastation this inflicts cannot be overstated.”
Ranjan Gupta, MD, professor of orthopedic surgery, anatomy and neurobiology, biomedical engineering and chief of shoulder surgery at the University of California, Irvine, added nerve injury is a primary concern for orthopedic surgeons following a traumatic event.
“Whenever a patient has trauma, like a motor vehicle accident, a nerve injury is one of the things that we are most concerned with,” Gupta said. “These injuries can be as severe as having an arm or leg that is completely insensate, meaning you cannot feel the entire extremity or you cannot move that extremity. The number of traumatic nerve injuries is not decreasing. It is, without a doubt, remaining a constant variable in treating patients based upon how active their lives are.”
Diagnosis
Prior to treating a nerve injury, Moore said diagnosis and the ability to define the mechanism of injury is of utmost importance to determine the most appropriate intervention.
“In the diagnosis, we are trying to understand what was the mechanism of injury. Was it a crush [injury]? Was it a stretch [injury]? Was it a transection [injury]? Was the wound opened or closed?” Moore said. “As a nerve surgeon, I also care about the patient’s pain. If we do not treat or diagnose their pain that is caused from their nerve injury, it does not matter if they get back their function or not, they still will not use their limb.”
DeGeorge said the most important factor in treating a nerve injury is making a conscientious effort to detect it.
“The biggest thing is that if you do not look, you are not going to find it,” DeGeorge said. “An awareness in the public sphere regarding the potential options for nerve repair and nerve regeneration techniques following trauma or amputation is important.”
He added physicians should communicate to colleagues who take care of nerve-related injuries, such as neurology, physical medicine and rehabilitation, trauma surgery, vascular surgery and other areas of medicine, that “there are options available to mitigate the pain, loss of function and sensory deficits in patients who have sustained a nerve-related injury and there are surgeons who take great pride and satisfaction in providing this level of care for nerve injured patients.”
Early evaluation
Another important factor in the diagnosis of nerve injury is early evaluation, according to Peter Yonclas, MD, associate professor in the department of physical medicine and rehabilitation at Rutgers - New Jersey Medical School and chair of physical medicine and rehabilitation at Cooperman Barnabas Medical Center.
“There are more treatment options now than we had in the past, and I think sometimes earlier evaluation is probably more important,” Yonclas told Healio | Orthopedics Today. “Traditionally, we used to wait 3 to 6 months to see if somebody got better before you intervene, but I think you need to do better tracking of their recovery sooner because your window for recovery probably is better if you do something within 6 months rather than waiting that whole year because of the fibrosis that occurs.”
Imaging
Advanced imaging modalities can assist in the diagnostic phase of nerve injury repair, but Moore said developments are still needed.
“Unfortunately, we do not have the holy grail of diagnostic imaging that can detect or delineate where the nerve is injured or how severe it is, but we are seeing innovation or improvements in imaging, such as high frequency ultrasound and MR neurography, where they are focused on the nerve,” Moore said.
According to Gupta, imaging should mainly be used as an adjunct to physical examination.
“Currently, the gold standard remains physical examination, especially after trauma,” Gupta told Healio | Orthopedics Today. “The presumption is that most people, prior to their injury, had normal function. So afterward, a detailed physical examination is the most critical component of making the decision.”
Although patients may undergo MR neurography and ultrasound, Gupta said those imaging modalities are adjuncts to physical examination as these additional studies are “incredibly operator dependent in how sensitive and specific they are.”
“You can add electrodiagnostic studies, but that is usually for patients presenting late to you and most often are not as useful for acute trauma,” Gupta said. “For acute trauma, you are going to make decisions based on the physical examination and a good understanding of anatomy.”
Yonclas said while an electromyography test can be valuable in diagnosing nerve injuries, it is still used as a surrogate to physical examination.
“Imaging is not quite there except for in specialized institutions, and I think we are going to start to have a better understanding where we have more specialized MRIs that can get that little detail and understand it better,” Yonclas said.
Amputation
When an amputation is necessary, surgeons focus on controlling how the nerve is going to grow and preventing pain and minimizing phantom limb pain, according to Moore.
“We now have a few new techniques that, since 2015, have come into play as a surgeon’s tool to treat pain,” Moore said. “One is targeted muscle reinnervation (TMR), and that is where we rewire the cut nerve ends back into a muscle that remains so that the nerve fibers that could otherwise become a painful neuroma now have a target to grow into. The other technique that we use to control pain is regenerative peripheral nerve interfaces (RPNI), which is using a muscle graft. We take a little piece of muscle, we wrap the end of the nerve and the nerve grows into this muscle. Excitingly, these techniques can also be used to provide electrical signals for prosthetic control of the amputated limb.”
Yonclas said TMR and RPNI may become the standard of care in multiple facets of nerve repair.
“It is going to become more of the standard of care going forward,” Yonclas said. “I work with an orthopedic hand surgeon, as well as a plastic surgeon, and I am referring more of my amputees that I see who have had traumatic injury for both of these surgeries.”
In addition, according to DeGeorge, investigators at the University of Virginia are testing the use of electrical stimulation to treat phantom limb and residual limb pain following an amputation.
“One of the new developments we are exploring at the University of Virginia is the use of electrical stimulation at the time of nerve management may improve the speed and quality of nerve regeneration,” DeGeorge said. “Researchers across the country are actively exploring innovation methods to integrate electrical stimulation into existing nerve repair and regeneration modalities to improve function and relieve pain in patients.”
Iatrogenic nerve injury
Nerve injury can also occur intraoperatively or postoperatively, in what is called an iatrogenic nerve injury. In these instances, Gupta said, often, the main battle is with the clock.
“First of all, you have to assess is this a partial injury or a complete injury.” Gupta said. “In those situations, that is where I am going to use the combination of physical examination as well as electromyography. I am going to use electromyography to see if there is electrical activity in the muscle. Is the muscle regenerating? I am going to make a decision because time is of the essence. When they come to me, my goal is to do a surgical exploration as soon as possible. If the nerve is transected, the surgeon will need to suture the ends of the nerves back together or perform a nerve transfer. When the patient presents with a functional deficit, I have to address that functional deficit sooner rather than later.”
Because of the slow regeneration rate of the nerve and the expiration date of the muscle, Moore said iatrogenic nerve injuries should be treated 3 to 6 months after it is detected.
“Detecting [iatrogenic nerve injuries] postoperatively is the best thing you can do for your patients,” Moore said. “Examine the patient, identify the nerve involved and listen to the patients. If the patients have pain out of proportion to what you would expect, you should be thinking that there could be a nerve injury and get those patients to a nerve surgeon early.”
Source: Mayo Clinic
Surgeons should also be “conscientious” of the anatomy during surgery and, instead of avoiding the nerve in areas at high risk of iatrogenic nerve injury, identify it “during the surgical approach and protect it throughout the case,” according to Pulos.
“If you think you may have experienced an iatrogenic nerve injury in surgery, call in someone who is an expert in peripheral nerve treatments to assist in the operating room because there may be an opportunity in the case, if a nerve is cut, to directly repair the nerve,” Pulos told Healio | Orthopedics Today.
Gaps in research
Some surgeons fear nerve surgery research may be at a standstill, according to Pulos.
“At the moment, nerve surgery has plateaued in the past 20 years, whereas prosthetics, in general, have improved greatly over the past 20 years,” Pulos said. “So while in the past 20 years nerve surgery has not had any new major developments, in the prosthetics world, they have made some great strides. Right now, prostheses are outpacing our nerve research and that is where the importance of basic science research is, which is trying to improve the way that we do nerve surgery through discovery science.”
The main reason for the limited progress in nerve repair and nerve regeneration is that the era of doing surgical manipulations has plateaued, according to Gupta.
“This is a field that requires adjuvant therapy. It requires growth factor augmentation. It requires enzyme supplementation. There are multiple different strategies, but there are going to be biological adjuncts that need to be done,” Gupta said.
However, Yonclas said researchers and surgeons do not know what role regenerative medicine plays in relation to nerve injuries.
“We have done some research, but I think we do need some more basic science research to see if that can be beneficial,” Yonclas said.
Future research
But research is pushing the specialty forward, perhaps more than ever, according to Moore. She said some of the research involves maintaining muscle cells so that surgeons do not need to worry about the time it takes for the nerve to regrow and there is a focus on advanced prosthetics which can match function of a regrown nerve-muscle unit.
“There is research dedicated to trying to accelerate the nerve regeneration and make the environment better for the nerve to grow faster. There is research looking at nerve substitutes to make them more effective so that patients do not have to worry about using their own nerves, that they can take this off-the-shelf alternative and have a great result every time. Within each of those realms, it is the advancement of the use of stem cells and growth factors and delivery mechanisms. I think that is where we are pushing hard right now,” Moore said.
In addition, Pulos said future nerve surgical research should clarify the role and use of allografts in repair.
“For devastating injuries, we think that autograft nerves probably outperform allograft nerves, but sometimes there is not enough autograft in the body,” Pulos said. “Would it not be great to find a way to enhance allografts so that [it] functioned as well as autografts so that we did not have to take a patient’s sural nerves? Or maybe we take their sural nerves, and we still need more nerve graft.”
Gupta, an NIH-funded surgeon and scientist, and colleagues are researching how to prevent motor endplate degeneration in a preclinical animal model as well as develop treatments for motor endplate degeneration.
“From a diagnostic perspective, we are doing biopsies of downstream muscles prior to nerve surgery to determine if we can predict what the motor endplate looks like,” Gupta said. “Is it degenerating, and will a nerve transfer be most useful for recovery?”
- References:
- Crowe CS, et al. JBJS Rev. 2023; doi:10.2106/JBJS.RVW.22.00161.
- Thawait SK, et al. AJNR Am J Neuroradiol. 2012; doi:10.3174/ajnr.A2465.
- For more information:
- Brent R. DeGeorge Jr., MD, PhD, of the University of Virginia, can be reached at bd6u@uvahealth.org.
- Ranjan Gupta, MD, of the University of California, Irvine, can be reached at ranjang@hs.uci.com.
- Amy M. Moore, MD, of The Ohio State University Wexner Medical Center, can be reached at amy.m.moore@osumc.edu.
- Nicholas A. Pulos, MD, of the Mayo Clinic, can be reached at pulos.nicholas@mayo.edu.
- Peter Yonclas, MD, of Rutgers – New Jersey Medical School, can be reached at yonclape@njms.rutgers.edu.
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