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

小纤维多发性神经病作为青少年慢性广泛性疼痛病因的评估

• 批准号: 9278320
• 负责人: Anne Louise Oaklander
• 金额: $ 83.88万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9278320
• 关键词: 21 year old; Address; Adrenal Cortex Hormones; Adult; Affect; Age; Analgesics; Autoimmune Process; Axon; Biological; Biopsy; Blood Tests; Child; Childhood; Clinical; Clinical Trials; Communities; Confocal Microscopy; Cornea; Dangerousness; Data; Degenerative polyarthritis; Devices; Diagnosis; Diagnostic; Diagnostic tests; Disabled Persons; Disease; Distal; Early Diagnosis; Epidemiology; Evaluation; Family; Feasibility Studies; Fiber; Fibromyalgia; Foundations; Future; Goals; Immune; Immunity; Inflammation; Investigation; Iodine; Laboratories; Life; Measurement; Measures; Medical; Methods; Minor; Modeling; Monitor; Morphine; Names; Natural History; Nerve Endings; Nerve Fibers; Neuropathy; Pain; Pain Measurement; Pain Research; Patient Monitoring; Patients; Pharmaceutical Preparations; Polyneuropathy; Population; Predictive Value; Prevalence; Publishing; Questionnaires; Recruitment Activity; Recurrence; Reporting; Research; Resources; Retrospective Studies; Sampling; Schools; Sensitivity and Specificity; Signs and Symptoms; Skin; Specificity; Starch; Sweat; Sweat test; Sweating; Symptoms; Syndrome; Teenagers; Testing; Time; Weaning; Work; Youth; base; chronic pain; chronic widespread pain; cohort; common symptom; cost; cost effective; density; diagnostic biomarker; disabling symptom; early onset; evidence base; evidence based guidelines; immunoregulation; improved; in vivo; prospective; prospective test; public health relevance; tool; treatment trial; university student; young adult

 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.

 描述（由申请人提供）：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，导致一些人无法上学或工作。年轻人的 UCWP 可能会扰乱整个家庭并导致终生障碍。 UCWP 综合征有多种名称，包括纤维肌痛。 2013 年，我们发表了一项回顾性研究，对 41 名 21 岁之前开始的 uCWP 患者进行了回顾性研究。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，这是其症状的生物学合理原因。最有用的测试是 PGP9.5 免疫标记的皮肤活检，它可以定量小纤维神经末梢密度。一些患者的 SFPN 似乎是由免疫失调引起的，但这还远不能确定。本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，并且许多都有免疫失调原因的证据。我们的观察结果需要在更大的社区样本中进行前瞻性测试，以确定诊断早发小纤维多发性神经病（SFPN）的最佳方法，并评估如何随时间监测患者。用于诊断 SFPN 的测试尚未广泛使用，并且尚未针对年轻患者进行标准化。我们提供的证据表明，当基于轴突少得多的老年正常成年人的数据时，超过一半的 35 岁以下 SFPN 患者会得到假阴性诊断。 该项目解决了临床对更好的循证方法的需求，用于诊断目前几乎没有选择的 uCWP 年轻人的 SFPN。它应该具有直接、广泛的临床影响。它还将为研究奠定基础，包括治疗试验和机制的基本研究。两者都需要经过严格诊断和纵向特征描述的患者，而本项目应该提供这些。 目标 1 提议确定年轻 CWP 患者以及从社区招募的阳性和阴性对照中针对早发 SFPN 的最佳客观测试。我们将重点关注推荐的测试、自主神经功能测试和皮肤活检，但也会研究侵入性较小或更便宜的测试，例如体内角膜共聚焦显微镜、次要淀粉碘汗液测试、新问卷和新汗液测量设备 Sudoscan。目标是开发可应用于各种环境（包括资源匮乏的环境）的最佳测试。目标 2 将通过实验室血液检测和社区人群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，即一半早发性 uCWP 患者有 SFPN 的证据。目标 3 将应用上述制定的问卷和最佳测试，以规定的时间间隔前瞻性地跟踪以不同方式治疗的各种原因的 SFPN 患者，并且还将跟踪未经治疗的 SFPN 患者，收集有关早发 SFPN 的第一个自然史数据。这应该提供规划未来有希望的治疗方法的临床试验所需的信息。