Neonatal brachial plexus injury (NBPI) is the most common birth injury and the most common cause of paralysis in children. Usually diagnosed at birth, NBPI is characterized by a loss of movement or weakness in the arm or hand due to damaged nerves around the shoulder. Most children with NBPI recover, but 20 percent to 30 percent sustain permanent disability. In those who do not recover, the weakness can be complicated by joint contractures that persist even if the nerves are repaired.

Now, with the help of a 2013 Career Development Grant from the Orthopaedic Research and Education Foundation (OREF), pediatric orthopaedic surgeon Roger Cornwall, MD, is conducting a first-of-its-kind research study that may provide new hope for NBPI patients with such contractures.

Treating contractures
For the last 100 years, orthopaedic surgeons have treated all contractures for all patients—from newborns to mature adults, regardless of the specific disease condition—with essentially the same surgical procedures. It wasn’t until the 1970s that orthopaedic surgeons began to be trained to treat NBPI contractures at all.

“Many senior surgeons were taught to assume that NBPI doesn’t need any treatment at all,” Dr. Cornwall explained.

In 2005, Dr. Cornwall modified a surgical technique specifically to relieve NBPI muscle contractures. His innovation showed great promise. Patients recovered more range of motion in their arms. Dr. Cornwall’s practice was thriving. His contribution to pediatric orthopaedics was being acknowledged.

But it soon became clear that this new technique was still merely palliative, leading to slight improvements in flexibility and muscle function, but no more. Further, Dr. Cornwall couldn’t establish any scientific logic for the results.

Effective, but why?
The surgical innovation that Dr. Cornwall developed involved cutting the paralyzed portion of a partially denervated subscapularis to relieve the contracture without further weakening the muscle.

Dr. Cornwall stated his dilemma: “It’s the working muscle that’s supposedly causing the contracture, so how does cutting the paralyzed part of that muscle relieve the contracture?”

Dr. Cornwall took a deep dive into the scientific literature and found a few studies that suggested muscle growth could be impeded after damage at birth, but nothing that looked at impaired muscle function. “I realized I needed to investigate this,” he said.

As hard as orthopaedic surgeons try, “we can’t fix this surgically,” Dr. Cornwall said. “There’s something much more global and biologically wrong with these muscles.”

The role of satellite cells
The OREF grant gives Dr. Cornwall the opportunity to test his hypothesis that disturbances in muscle satellite cell behavior are responsible for NBPI contractures.

Dr. Cornwall explained that muscle tissue includes a population of stem cells known as satellite cells because they reside on the periphery of muscle fiber. The satellite cells are plentiful and replicate freely. However, in muscles denervated by NBPI, satellite cells fail to receive—or respond to—signals that command them to make muscle.

Dr. Cornwall’s study aims to identify ways to counteract these cellular signaling problems so that treatment for NBPI might be more effective and prevent secondary contractures.

“If we can understand why the satellite cells aren’t doing what they’re supposed to be doing, then we can identify the signals that are missing or the signals that are actively suppressing them. Maybe we could reverse those signals or add the missing signals to harness that population of satellite cells,” he said.

Using a mouse model he developed in earlier studies, Dr. Cornwall is performing a series of experiments with control and test subjects with paralyzed muscles to answer the following questions:

• What accounts for the disproportionate number of dormant satellite cells in denervated muscles?
• How do satellite cells behave following muscle paralysis?
• How does that behavior differ depending on the severity of paralysis?
• What cellular processes trigger the manufacture of fat and fibrous tissue in place of muscle?
• How might those processes be interrupted?

Innovative research
Building on a series of firsts from Dr. Cornwall’s previous research, the OREF-supported study is the first to investigate the biologic mechanisms that lead to NBPI contractures. This research is leading the way in looking at alterations in satellite cell proliferation and differentiation following paralysis at birth and in correlating these abnormalities with muscle growth.

The study will also investigate the relationship between the function of nerve fibers and postnatal muscle development. This will expand what is currently known about other childhood neuromuscular and musculoskeletal disorders, such as cerebral palsy.

OREF support indispensable
Basic science research like Dr. Cornwall’s study has game-changing potential, but it needs sustained funding. The OREF Career Development Grant provides $75,000 per year for 3 years. That gives researchers time to assemble the preliminary data crucial to obtaining the long-term grant support necessary to fully answer both questions that have already emerged and those that will surface as the research continues.

“There’s a great deal of faith involved,” Dr. Cornwall said. “Faith that this research will amount to something such as actual findings that will help kids. It’s a daunting prospect for a surgeon to compete against scientists for National Institutes of Health (NIH) dollars, especially as those dollars get thinner and thinner.”

That’s why, he said, funding from OREF is key. OREF funding is free of bias inherent in monies from industry and more robust than the smaller and sometimes narrowly focused grants available through specialty societies.

“OREF is certainly the biggest funding source for orthopaedic research that I know and is well-recognized as impartial,” said Dr. Cornwall. “OREF awards come with a certain degree of prestige that gives credibility to the research itself—and to my ability to perform it. That can be useful in achieving the ultimate goal of NIH funding.”

Sharon Johnson is a contributing writer for OREF. She can be reached at communications@oref.org

References:

1. Foad SL, Mehlman CT, YingJ: The epidemiology of neonatal brachial plexus palsy in the United States. J Bone Joint Surg Am 2008;90(6):1258–1264.
2. Pondaag W, Malessy MJ, van Dijk JG, Thomeer RT: Natural history of obstetric brachial plexus palsy: A systematic review. Dev Med Child Neurol 2004;46(2):138–144.