Abstract：
Over recent decades, peripheral sensory abnormalities, including the evidence of cutaneous denervation, have been reported among the non-motor manifestations in amyotrophic lateral sclerosis (ALS). However, a correlation between cutaneous innervation and clinical features has not been found. The aims of this study were to assess sensory involvement by applying a morpho-functional approach to a large population of ALS patients stratified according to King\'s stages and correlate these findings with the severity and prognosis of the disease. We recruited 149 ALS patients and 41 healthy controls. Patients undertook clinical questionnaires for small fibre neuropathy symptoms (Small Fiber Neuropathy Symptoms Inventory Questionnaire) and underwent nerve conductions studies (NCS) and 3-mm punch skin biopsies from leg, thigh and fingertip. We assessed intraepidermal nerve fibre (IENF) and Meissner corpuscle (MC) density by applying an indirect immunofluorescence technique. Moreover, a subset of 65 ALS patients underwent a longitudinal study with repeat biopsies from the thigh at 6- and 12-month follow-ups. Serum NfL levels were measured in 40 patients. Sensory symptoms and sensory NCS abnormalities were present in 32.2% and 24% of patients, respectively, and increased across clinical stages. Analogously, we observed a progressive reduction in amplitude of the sensory and motor ulnar nerve potential from stage 1 to stage 4. Skin biopsy showed a significant loss of IENFs and MCs in ALS compared with healthy controls (all P < 0.001). Across the clinical stages, we found a progressive reduction in MCs (P = 0.004) and an increase in IENFs (all P < 0.027). The increase in IENFs was confirmed by the longitudinal study. Interestingly, the MC density inversely correlated with NfL level (r = -0.424, P = 0.012), and survival analysis revealed that low MC density, higher NfL levels and increasing IENF density over time were associated with a poorer prognosis (all P < 0.024). To summarize, in patients with ALS, peripheral sensory involvement worsens in parallel with motor disability. Furthermore, the correlation between skin innervation and disease activity may suggest the use of skin innervation as a putative prognostic biomarker.
摘要：
在过去的几十年里，周围感觉异常，包括皮肤神经支配的证据，在肌萎缩侧索硬化症（ALS）的非运动表现中有报道。然而,尚未发现皮肤神经支配与临床特征之间的相关性。这项研究的目的是通过对根据King分期分层的大量ALS患者应用形态功能方法来评估感觉受累，并将这些发现与疾病的严重程度和预后相关联。我们招募了149名ALS患者和41名健康对照（HC）。患者接受了小纤维神经病变症状的临床问卷调查（SFN-siq），神经传导研究（NCS）和3毫米的腿部皮肤活检，大腿和指尖。我们通过应用间接免疫荧光技术评估了表皮内神经纤维（IENF）和迈斯纳小体（MC）密度。此外，在随访6个月和12个月时,65例ALS患者中的一个子集接受了一项纵向研究,从大腿重复进行皮肤活检.在40例患者中测量了血清神经丝轻链（NfL）水平。32.2％和24％的患者存在感觉症状和感觉NCS异常，分别,并在临床阶段增加。类似地,我们观察到感觉和运动尺神经电位的幅度从1期到4期逐渐降低。皮肤活检显示，与HC相比，ALS中的IENF和MC明显丢失（均P<0.001）。在整个临床阶段，我们发现MC逐渐减少(P=0.004)和IENF增加(所有P<0.027).纵向研究也证实了IENF的增加。有趣的是,MC密度与NfL水平呈负相关(r=-0.424，P=0.012)，和生存分析显示，低MC密度，更高的NFL水平，随着时间的推移，IENF的增加与预后较差相关（所有P<0.024）。在ALS患者中，外周感觉受累与运动障碍同时恶化。此外，皮肤神经支配与疾病活动之间的相关性可能表明皮肤神经支配可作为推定的预后生物标志物.
