A Single Dose Pharmaco-Diagnostic for Peripheral Nerve Continuity After Trauma

摘要 神经损伤可以影响任何人，并带来永久的后果，外周创伤 神经损伤(TPNI)可由各种环境引起，从战场或机动车创伤，到医源性 其他严重情况下的外科治疗所致的损伤。对于其他组织类型，预后和治疗 计划很简单。然而，当神经衰竭时，医生几乎没有工具来帮助指导治疗计划 患者永远记得他们疼痛和瘫痪的经历。如果神经损伤可能发生在 原因很多，最能预测好结果的决定因素是什么？ 答案是神经的连续性。被子弹割断的神经，如果没有子弹，永远不会痊愈 手术修复，然而，同样的神经，被子弹擦伤，或被经过的子弹的冲击波缠住， 和子弹割伤的神经没什么区别。这两种神经都不起作用，但后者却没有被切断 最好让神经自行恢复，不需要手术。存在两种类型的神经损伤，两种类型都会产生 都同样功能失调，但我们需要手术修复其中一个，而手术对另一个是有害的。 在受伤后的几周内，还没有测试来区分这些神经。几周过去了，我们 使用电诊断(EDX)来判断哪些神经被切断。这是TPNI诊断的最新技术。 因为神经的连续性本身在受伤后的几周内是不可能定义的，目前的标准是 治疗正在等待自然恢复，我们猜大多数患者都没有被切断的神经。在……里面 在医学的每个领域，都有以这种方式监测的神经损伤--没有明确诊断的工具， 基于我们的临床怀疑。 我们最近发现，目前FDA批准的一种药物(4-氨基吡啶，4AP)，以前有 立即允许诊断创伤性瘫痪神经的效果未知。小剂量可以 将需要立即手术的切断的神经与未切断的神经区分开来，后者可能是 安全监控。已经在人类身上使用的药物4AP的这种新特性可能会在我们等待的过程中被探索 以使函数自发返回。根据我们的初步数据，我们打算重新调整4AP的用途以诊断 神经不连续，而不是仅仅猜测神经是否被切断并希望恢复。 我们希望在有神经损伤的患者中尝试4AP，在这些患者中，我们无法判断神经是被切断还是 不。我们获得了FDA的批准，可以在人类身上进行4AP试验，以研究神经连续性，并有 机构IRB批准继续进行。我们希望以一种新的方式在携带TPNI的人类身上测试4AP：作为一种 药理学诊断，药物挑战的结果揭示了关于 潜在的神经连续性。凭借从这次试验中获得的知识，我们希望提供可靠的信息 这可以证实或驳斥临床对神经连续性这一关键问题的猜测。

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.