Evaluation of small-fiber polyneuropathy as a cause of chronic widespread pain in youth

 描述(申请人提供)：医学上无法解释的慢性广泛性疼痛(UCWP)是一种常见的致残症状，甚至会影响儿童和年轻人，导致一些残疾人士无法上学或工作。年轻人的UCWP可能会扰乱整个家庭，并导致终生残疾。UCWP综合征有各种不同的名称，包括纤维肌痛。2013年，我们发表了一项针对41名uCWP患者的回顾性研究，该研究始于21岁之前。我们报告说，大多数患者都有小纤维多发性神经病(SFPN)的客观证据，这是他们症状的生物学原因。最有用的测试是PGP9.5免疫标记皮肤活检，它允许对小纤维神经末梢密度进行定量。一些患者似乎有SFPN的免疫障碍原因，但这一点还远未确定。这项拟议研究的目的是严格检验我们的假设，即SFPN是儿童和年轻人CWP的常见原因，而且许多人有免疫障碍原因的证据。我们的观察需要在更大的社区样本中进行前瞻性测试，以确定诊断早发性小纤维多发性神经病(SFPN)的最佳方法，并评估如何随着时间的推移监测患者。用于诊断SFPN的测试并不广泛使用，而且还没有被年轻患者正常化。我们提供的证据表明，超过一半的35岁以下的SFPN患者，当他们基于轴突少得多的老年正常成年人的数据时，会收到假阴性诊断。该项目解决了临床上需要更好的循证方法来诊断患有uCWP的年轻人的SFPN，这些年轻人目前几乎没有选择。它应该会立即产生广泛的临床影响。它还将为包括治疗试验在内的研究奠定基础，对机制进行基础调查。两者都需要严格诊断和纵向特征良好的患者，这是本项目应该提供的。目的1探讨青年煤工尘肺患者以及社区招募的阳性和阴性对照早发SFPN的最佳客观检测方法。我们将专注于推荐的测试、自主功能测试和皮肤活检，但也将研究侵入性较小或成本较低的测试，如活体角膜共焦显微镜、少量淀粉碘汗液测试、新的问卷调查以及一种新的汗液测量设备--Sudoscan。我们的目标是开发最好的测试，可以在不同的情况下应用，包括低资源环境。目标2将通过实验室血液测试和社区队列中皮肤活检的皮肤病理学研究，更严格地定义SFPN的医学原因。我们还将看看这些测试是否支持我们之前的发现，即一半的早发性uCWP患者有SFPN的证据。目的3将以规定的间隔应用上面开发的问卷和最佳测试来前瞻性地跟踪各种原因的SFPN患者以不同的方式接受治疗，并将跟踪未经治疗的SFPN患者收集关于早发性SFPN的第一批自然病史数据。这应该为计划未来有希望的治疗方法的临床试验提供所需的信息。

 DESCRIPTION (provided by applicant): Medically unexplained chronic widespread pain (uCWP) is a common and disabling symptom that can even affect children and young adults, leaving some disabled from school or work. UCWP in the young can disrupt entire families and cause life-long handicap. UCWP syndromes go by various names including fibromyalgia. In 2013 we published a retrospective study of 41 of our patients with uCWP that began before age 21. We reported that most had objective evidence of small-fiber polyneuropathy (SFPN), a biologically plausible cause of their symptoms. The most useful test was PGP9.5 immunolabeled skin biopsies, which permit quantitation of small-fiber nerve ending density. Some patients appeared to have dysimmune causes of their SFPN, but this was far from certain. The goal of the proposed research is to rigorously test our hypothesis that SFPN is a common cause of CWP in children and young adults and that many have evidence of dysimmune causes. Our observations need prospective testing in a larger community-based sample with determination of best methods for diagnosis of early-onset small-fiber polyneuropathy (SFPN) and assessment of how to monitor patients over time. The tests used to diagnose SFPN are not widely available, and have not been normed for young patients. We provide evidence that more than half of SFPN patients under age 35 receive false-negative diagnoses when they are based on data from older normal adults with far fewer axons. This project addresses the clinical need for better evidence-based methods for diagnosing SFPN in young people with uCWP who currently have few options. It should have immediate, widespread clinical impact. It will also lay foundations for research including treatment trials an basic investigation of mechanisms. Both require rigorously diagnosed and longitudinally well-characterized patients, which this project should provide. Aim 1 proposes to identify the best objective tests for early onset SFPN in young patients with CWP and in positive and negative controls recruited from the community. We will focus on the recommended tests, autonomic function testing and skin biopsy, but will also investigate less invasive or cheaper tests such as in vivo corneal confocal microscopy, the Minor starch-iodine sweat test, a new questionnaire, and Sudoscan, a new sweat-measuring device. The goal is to develop the best tests that can be applied in diverse circumstances, including low-resource settings. Aim 2 will more rigorously define the medical causes of SFPN using laboratory blood tests and dermatopathologic study of skin biopsies in community-based cohorts. We will also see if these tests support our prior finding that half of people with early-onset uCWP have evidence of SFPN. Aim 3 will apply the questionnaire and best tests developed above at defined intervals to prospectively track SFPN patients with various causes being treated in different ways, and will also follow untreated SFPN patients to gather the first natural history data about early-onset SFPN. This should provide the information needed to plan for future clinical trials of promising treatments.