Novel Deployable Diagnostic Use of 4-Aminopyridine for Peripheral Nerve Injury
Abstract
Traumatic peripheral nerve injury (TPNI) is a common cause of permanent paralysis and disability. When trauma is significant enough to paralyze a limb, there are many factors that play a critical role in the clinical assessment and prognosis for recovery. Nowadays, surgeons have many advanced tests to assess one or another tissue type so that we can make a plan to manage injuries to bone, muscle, skin, and most other tissues. However, we do not have any test for nerve tissue status that we can use before weeks of watchful waiting. Nerves control everything in a limb, and without nerve input, a paralyzed limb is non-functional. The critical question to answer early is whether the nerve has been severed or not – because even mild nerve injuries often result in an insensate limb that does not move. 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. Unless the nerve endings are visible in an open wound, no one knows if the nerve was crushed or severed. Without any definitive information on nerve continuity, we must guess whether the nerve is intact and not functioning or completely severed. If we guess a nerve is intact, we wait for spontaneous recovery, and if we are wrong, we sacrifice potential recovery of those who actually had a severed nerve. In effect, two groups of TPNI patients exist (those with severed and those with intact nerves); each with conflicting needs and each indistinguishable from the other. What benefits one patient harms the other. This is the current state-of-the-art in nerve injury. Currently available diagnostics cannot be used for 6 weeks (EDX, electrodiagnostic testing). We have discovered that a commonly used multiple sclerosis drug, 4-aminopyridine (4AP), has the previously unrecognized effect of recovering function in nerves that were not severed. We are pursuing clinical trials to see if we can use this drug as an oral pill to awaken nerves in patients who do not have complete nerve lacerations – in effect distinguishing them for the first time from those requiring urgent nerve repair surgery. The problem is that systemic treatment with an oral pill cannot be used in the field, because some patients have complicating injuries that make an oral pill unsafe, even at doses approved for use by the Food and Drug Administration (FDA). Trauma patients are often evaluated in the field in forward medical facilities, and these patients sometimes have distracting injuries that make the use of systemic 4AP unfavorable. What is needed is a more specific, local injection usable at the site of a suspected nerve injury to deliver a small dose of 4AP to wake up a non-severed nerve and confirm that nerve repair is not emergently needed. Such a treatment would be safe, and could be used at several sites in multiple limbs without the fear of systemic side effects because of the low doses used. Moreover, such a treatment might be critical in telling which patients need transport to facilities where complex nerve microsurgery can be performed. We made a locally administrable version of 4AP that is liquid at room temperature and solidifies only when injected into the body (by a process called thermoregulation) out of FDA-approved components and we want to test local-4AP in different battlefield-relevant nerve injuries of increasing severity. This will allow us to see what dose is needed to awaken nerves. Perhaps local-4AP is best suited for nerve injuries from high pressure blasts, or penetrating projectiles that partially sever the nerve but leave a part intact. Human trials of local-4AP must have injury-severity-based inclusion and exclusion criteria and this proposal specifically tests battlefield relevant nerve injuries that leave the nerve in continuity but dysfunctional enough to seem completely severed. Our experiments have a natural 18-month timeline, and in each controlled experiment, we
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910773
Entities
People
- John C Elfar
Organizations
- Penn State Milton S. Hershey Medical Center
- United States Army