von Bischhoffshausen Sofia, Ivulic Dinka, Alvarez Paola, Schuffeneger Victor C, Idiaquez Juan, Fuentes Constanza, Morande Pilar, Fuentes Ignacia, Palisson Francis, Bennett David L H, Calvo Margarita
Facultad de Medicina, Universidad de los Andes, Chile.
Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Chile.
Brain. 2017 May 1;140(5):1238-1251. doi: 10.1093/brain/awx069.
Small fibres in the skin are vulnerable to damage in metabolic or toxic conditions such as diabetes mellitus or chemotherapy resulting in small fibre neuropathy and associated neuropathic pain. Whether injury to the most distal portion of sensory small fibres due to a primary dermatological disorder can cause neuropathic pain is still unclear. Recessive dystrophic epidermolysis bullosa (RDEB) is a rare condition in which mutations of proteins of the dermo-epidermal junction lead to cycles of blistering followed by regeneration of the skin. Damage is exclusive to the skin and mucous membranes, with no known direct compromise of the nervous system. It is increasingly recognized that most RDEB patients experience daily pain, the aetiology of which is unclear but may include inflammation (in the wounds), musculoskeletal (due to atrophy and retraction scars limiting movement) or neuropathic pain. In this study we investigated the incidence of neuropathic pain and examined the presence of nerve dysfunction in RDEB patients. Around three quarters of patients presented with pain of neuropathic characteristics, which had a length-dependent distribution. Quantitative sensory testing of the foot revealed striking impairments in thermal detection thresholds combined with an increased mechanical pain sensitivity and wind up ratio (temporal summation of noxious mechanical stimuli). Nerve conduction studies showed normal large fibre sensory and motor nerve conduction; however, skin biopsy showed a significant decrease in intraepidermal nerve fibre density. Autonomic nervous system testing revealed no abnormalities in heart rate and blood pressure variability however the sympathetic skin response of the foot was impaired and sweat gland innervation was reduced. We conclude that chronic cutaneous injury can lead to injury and dysfunction of the most distal part of small sensory fibres in a length-dependent distribution resulting in disabling neuropathic pain. These findings also support the use of neuropathic pain screening tools in these patients and treatment algorithms designed to target neuropathic pain.
皮肤中的小纤维在代谢或中毒性疾病（如糖尿病或化疗）中易受损伤，导致小纤维神经病变及相关的神经病理性疼痛。原发性皮肤病是否会导致感觉小纤维最远端部分受损进而引发神经病理性疼痛，目前仍不清楚。隐性营养不良性大疱性表皮松解症（RDEB）是一种罕见疾病，真皮 - 表皮交界处蛋白质的突变会导致皮肤反复出现水疱，随后皮肤再生。损伤仅局限于皮肤和黏膜，尚无已知的对神经系统的直接损害。人们越来越认识到，大多数RDEB患者每天都经历疼痛，其病因尚不清楚，但可能包括炎症（伤口处）、肌肉骨骼问题（由于萎缩和收缩性瘢痕限制活动）或神经病理性疼痛。在本研究中，我们调查了RDEB患者神经病理性疼痛的发生率，并检查了神经功能障碍的情况。约四分之三的患者表现出具有神经病理性特征的疼痛，且呈长度依赖性分布。对足部进行的定量感觉测试显示，热觉检测阈值显著受损，同时机械性疼痛敏感性和累积比率（有害机械刺激的时间总和）增加。神经传导研究表明，大纤维感觉和运动神经传导正常；然而，皮肤活检显示表皮内神经纤维密度显著降低。自主神经系统测试显示心率和血压变异性无异常，但足部的交感皮肤反应受损，汗腺神经支配减少。我们得出结论，慢性皮肤损伤可导致小感觉纤维最远端部分以长度依赖性分布受损和功能障碍，从而导致致残性神经病理性疼痛。这些发现也支持在这些患者中使用神经病理性疼痛筛查工具以及针对神经病理性疼痛设计的治疗方案。
