Abstract Nerve injury can affect anyone and carries consequences that last forever, and traumatic peripheral nerve injury (TPNI) can result from settings as diverse as battlefield or motor vehicle trauma, to iatrogenic injury from surgical treatments of other serious conditions. For other tissue types, the prognosis and treatment plan are straightforward. However, when nerves fail, doctors have few tools to help guide the treatment plan and patients forever remember their experiences with pain and paralysis. If nerve injuries can happen from many causes, what is the determinant that most predicts a good outcome? The answer is nerve continuity. A nerve that has been severed, say by a bullet will never heal without surgical repair and yet, that same nerve, grazed by the bullet, or caught in the shockwave of a passing bullet, is indistinguishable from the nerve cut by the bullet. Both nerves do not work, and yet the latter, unsevered nerve is best left to recover on its own without surgery. Two types of nerve injury exist, both yield nerves that are equally dysfunctional and yet we need to surgically repair one whereas surgery is detrimental to the other. No test exists to tell these nerves apart until weeks have passed after the injury. After weeks have passed, we use electrodiagnostics (EDX) to tell which nerves were severed. This is the state of the art in TPNI diagnosis. Because continuity of the nerve is itself impossible to define for weeks after injury, the current standard treatment is waiting for spontaneous recovery in most patients we guess do not have a severed nerve. In every field of medicine, there are nerve injuries monitored in this way - without tools for definitive diagnosis, based on our clinical suspicion. We recently discovered that a current, FDA-approved drug (4-aminopyridine, 4AP), has the previously unknown effect of immediately allowing diagnosis of traumatically paralyzed nerves. Small doses can distinguish the severed nerve, which requires immediate surgery, from the non-severed nerve, which can be safely monitored. This novel property of 4AP, a drug already used in humans may be explored while we wait for function to spontaneously return. Based on our preliminary data, we intend to repurpose 4AP to diagnose nerve discontinuity instead of just guessing if the nerve is severed and hoping for recovery. We want to try 4AP in patients who have nerve injury where we cannot tell if the nerve was severed or not. We obtained FDA approval for a trial of 4AP in humans to investigate nerve continuity and have institutional IRB approval to proceed. We want to test 4AP in humans with TPNI in a novel way: As a pharmacologic diagnostic, where the results of a challenge with the drug reveal something about the underlying nerve continuity. With the knowledge gained from this trial, we hope to provide solid information that can confirm or refute clinical guesswork on the critical issue of nerve continuity.

Project Narrative When trauma is bad enough to paralyze a limb, there are many factors that play into the clinical assessment and prognosis for recovery; and nowadays, clinicians have many tests to assess one or another tissue type – but we do not have any test for the status of the nerve tissue usable before weeks of waiting. Nerves control everything in a limb, and without nerve input, a paralyzed limb is useless; severed nerves require urgent surgery whereas non-severed nerves are best left to recover on their own – and no test can tell the difference at the time of injury. We have found a commonly-used drug (4-aminopyridine), has the previously unknown effect of reactivating only non-severed nerves, and we propose a clinical trial to see if this drug can be used as a single-dose test for severed nerves in our trauma patients.