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

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.