Use of a novel physiologic measure for the assessment and monitoring of vincristine induced peripheral neuropathy (VIPN) in children and adolescents.

在本申请中，我们提出了一种新的生理措施长春新碱诱导的检查 周围神经病变（VIPN）的儿科患者。制定这样一项措施将有助于实现以下目标： 儿童患者神经病变的阳性和阴性症状的表征， 长春新碱，以便能够早期发现和管理由此产生的发病率。急性淋巴细胞 白血病（ALL）是最常见的儿童癌症，但由于以下原因，儿童的5年存活率为90%： 目前的治疗方案，其中长春新碱是一个关键组成部分。依地斯汀主要诱导大的 通过破坏微管相关轴突运输的纤维周围神经病。临床上，这表现为 肌肉无力、反射丧失、神经性疼痛和感觉丧失。临床评估和研究 长春新碱神经毒性的患病率和风险因素受到不同敏感性的阻碍 神经病变评估工具。VIPN通常在治疗期间出现，但在治疗后可持续数年。 导致生活质量下降的治疗。因此，迫切需要开发一种临床工具来检测VIPN 在出现明显症状之前在这个建议中，我们定义和评估VIPN的度量，神经病变 指数，由一种新的技术，可以产生一个客观的评估神经纤维的敏感性。这 技术利用了我们的变革性发现， 每种感觉神经纤维类型（C、Aδ和Aβ）的电刺激诱导瞳孔扩张（nPRD） 响应反映了光纤的灵敏度。比较了三种光纤的nPRD响应 以生成将用于评估VIPN的复合指数，神经病指数。完成 为此，我们提出了以下目标：目标1：评估一种新的生理终点的性能， 神经病指数，用于表征VIPN患者的伤害性处理。我们计划 入组20例年龄6 - 18岁诊断为ALL并接受（或计划接受）长春新碱治疗的患者。我们计划 在8个月的时间里定期收集数据，这将使我们能够测量不同的水平， VIPN的严重性。还将使用TNS©-PV对参与者进行评估。利用这种方法，我们计划应用 神经病指数（即，[AUCAδ-AUCAβ]/AUCC）与每次测试期间收集的数据进行比较。然后我们 我计划将神经病变指数与TNS-PV进行比较，以确定两者之间的关系 措施我们还计划通过测试/重测范式评估该指数的可靠性，并评估患者 报告了与TNS-PV相比，我们的试验的可接受性。里程碑： 指数和TNS-PV之间的关系（相关性至少为0.7）和可靠性（测试- 重测信度系数至少为0.58）。最终，在这个应用中开发的技术 能够早期检测VIPN，优化长春新碱剂量以获得最大疾病缓解， 干预的目的是尽量减少慢性功能缺陷的风险。

In this application, we propose the examination of a novel physiologic measure of vincristine-induced peripheral neuropathy (VIPN) in pediatric patients. Establishment of such a measure will enable the objective characterization of both the positive and negative symptoms of neuropathy in pediatric patients treated with vincristine in order to enable early detection and management of the resulting morbidity. Acute lymphoblastic leukemia (ALL) is the most common childhood cancer but has a 90% 5-year survival rate in children due to current treatment protocols, of which vincristine is a critical component. Vincristine induces primarily a large fiber peripheral neuropathy by disrupting microtubule associated axonal transport. Clinically, this manifests as muscle weakness, loss of reflexes, neuropathic pain and loss of sensation. Clinical assessments and research of the prevalence and risk factors for vincristine neurotoxicity have been hampered by the differing sensitivities of neuropathy assessment tools. VIPN often manifests during treatment but can be present for years following therapy leading to a diminished quality of life. It is therefore imperative to develop a clinical tool to detect VIPN before the onset of overt symptoms. In this proposal, we define and assess a metric of VIPN, the Neuropathy Index, informed by a novel technology that can produce an objective assessment of nerve fiber sensitivity. This technology leverages our transformative finding that an innocuous, transcutaneous neuroselective electrical stimulus of each sensory nerve fiber type (C, Aδ and Aβ) induces a pupillary dilation (nPRD) response reflecting the sensitivity of the fiber. The nPRD responses of the three fiber types are compared to generate a composite index, Neuropathy Index, that will be used for the assessment of VIPN. To accomplish this, we propose the following aim: Aim 1: Assess the performance of a novel physiologic endpoint, the Neuropathy Index, for the characterization of nociceptive processing in patients with VIPN. We plan to enroll 20 patients ages 6y-18y diagnosed with ALL and receiving (or scheduled to receive) vincristine. We plan to collect data at regular intervals over the course of 8 months, which will allow us to measure different levels of VIPN severity. Participants will also be evaluated using the TNS©-PV. Using this approach, we plan to apply the Neuropathy Index (i.e., [AUCAδ-AUCAβ]/AUCC) to the data collected during each testing session. We then plan to compare the Neuropathy Index to the TNS-PV to determine the relationship between these two measures. We also plan to assess the reliability of the index via a test/retest paradigm and assess the patient reported acceptability of our test compared to that of the TNS-PV. Milestone: Demonstration of a relationship between the Index and the TNS-PV (a correlation of at least 0.7) and of reliability (a test- retest reliability coefficient of at least 0.58). Ultimately, the technology being developed in this application would enable early detection of VIPN, optimizing vincristine dosing for maximum disease response and early intervention with the goal of minimizing the risk of chronic functional deficits.