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体内共聚焦显微镜对转甲状腺素蛋白家族性淀粉样蛋白多发性神经病变的角膜神经成像的潜在作用

Rousseau A, Cauquil C, Dupas B, et al.

期刊名称:JAMA Ophthalmology

卷期:2016年第134卷第9期

摘要

小纤维神经病变(SFN)是转甲状腺素蛋白家族性淀粉样蛋白多发性神经病变(TTR-FAP)的一个重要特征。目前亟需一种实用且客观的SFN临床评价方法来提高对这种疾病的管理。角膜神经的体内共焦显微镜(IVCM)成像技术是一种快速无创成像技术,可作为SFN的一种替代指标。研究目的:本研究旨在确定TTR-FAP 患者的SFN与IVCM检测结果之间的关联性。试验设计,地点和参与者:我们设计一项前瞻性、单中心、横断面对照研究,时间从2013年6月1日到2014年6月30日,研究地点在法国国家TTR-FAP参比中心。我们对15名TTR-FAP患者进行完整的神经系统检查,包括下肢功能的神经功能缺损评分、握力、营养功能障碍评价,以及电生理学研究(神经传导和电化学皮肤电导)和表皮神经纤维密度的定量检测。我们还对患者和15名正常对照者(年龄和性别均相匹配)进行了眼科评估,包括角膜触觉测量法和IVCM。主要观察指标:角膜神经纤维长度(CNFL)与SFN严重程度之间的相关性。研究结果:在本研究招募的15名患者中,6名为女性(40%);平均(SD)年龄为54.4岁 [ 13.7 ]。患者组较比对照组的CNFL要短(13.08 vs 17.57mm/ mm2;偏差为4.49 [95% CI,0.72到8.27 ];P =0.02)。患者组的CNFL与复合自主神经功能障碍测试(rs = 0.66 [95% CI,0.22到0.87 ];P =0.008)或电化学皮肤电导测试(rs = 0.80 [95% CI,0.50到0.93 ];P<0.001)所评估的自主神经病变的严重程度以及下肢功能的神经功能缺损评分(rs = 0.58 [ 95% CI,-0.84到 - 0.11 ];P =0.02)所评估的感觉运动神经病变的严重程度均相关。感觉神经动作电位和表皮神经纤维密度发生变化的患者具有较短的CNFL(分别为P =0.04和P =0.02)。较比感觉神经动作电位(11名患者[ 73%;95% CI,44%~92% ];P<0.001)和表皮神经纤维密度(4名患者[ 27%;95% CI,8%~55% ];P <0.001)这两个参数而言,所有患者的CNFL都可以测量出来。研究结论及相关性:在这15名TTR-FAP患者中,IVCM测量手段可以快速无创性评价患者的小纤维变化情况,并且可用于评估该情况下的SFN。所有患者的CNFL都可以通过这种方法测定,从而避免从其他病变测量方法中观察到的地板效应。此外,还需对更多病例进行纵向研究,来确定IVCM监测TTR-FAP患者的体内放置位置。

IMPORTANCE:Small fiber neuropathy (SFN) is an important feature of transthyretin familial amyloid polyneuropathy (TTR-FAP). A practical and objective method for the clinical evaluation of SFN is needed to improve the management of this disease. In vivo confocal microscopy (IVCM) of the corneal nerves, a rapid noninvasive technique, may be used as a surrogate marker of SFN.OBJECTIVE:To determine the correlation of SFN with IVCM in patients with TTR-FAP.DESIGN, SETTING, AND PARTICIPANTS:A prospective, single-center, cross-sectional controlled study was conducted at the French National Reference Center for TTR-FAP from June 1, 2013, to June 30, 2014. Fifteen patients with TTR-FAP underwent a complete neurologic examination, including Neuropathy Impairment Score of the Lower Limbs, hand grip strength, and evaluation of vegetative dysfunction, as well as electrophysiologic studies (nerve conduction and electrochemical skin conductance) and intraepidermal nerve fiber density quantification. Patients and 15 controls (matched for age and sex) underwent ophthalmologic assessments, including corneal esthesiometry and IVCM.MAIN OUTCOMES AND MEASURES:Correlation of corneal nerve fiber length (CNFL) with the severity of SFN.RESULTS:Of the 15 patients enrolled in the study, 6 were women (40%); mean (SD) age was 54.4 [13.7] years. The CNFL was shorter in the patients than in controls (13.08 vs 17.57 mm/mm2; difference of 4.49 [95% CI, 0.72 to 8.27]; P=.02). The patients' CNFL correlated with the severity of both autonomic neuropathy assessed by the Compound Autonomic Dysfunction Test (rs=0.66 [95% CI, 0.22 to 0.87]; P=.008) or electrochemical skin conductance (rs=0.80 [95% CI, 0.50 to 0.93]; P<.001) and sensorimotor neuropathy assessed using the Neuropathy Impairment Score of the Lower Limbs (rs=-0.58 [95% CI, -0.84 to -0.11]; P=.02). Patients with altered sensory nerve action potentials and intraepidermal nerve fiber density had a shorter CNFL (P=.04 and P=.02, respectively). The CNFL could be measured in all patients compared with sensory nerve action potentials (11 patients [73%; 95% CI, 44% to 92%]; P<.001) and intraepidermal nerve fiber density (4 patients [27%; 95% CI, 8% to 55%]; P<.001).CONCLUSIONS AND RELEVANCE:In these 15 patients with TTR-FAP, IVCM measurement permitted rapid, noninvasive evaluation of small-fiber alterations in patients and could be used to assess SFN in this setting. The CNFL could be measured in all patients, thus avoiding the floor effect seen with other neuropathy measures. Longitudinal studies with more cases evaluated are needed to define the place of IVCM in monitoring patients with TTR-FAP.

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