孤立球部表型肌萎缩侧索硬化的临床及预后分析

研究背景：肌萎缩侧索硬化（amyotrophic lateral sclerosis，ALS）是一种以上、下运动神经元同时受累为主要临床表现的神经系统退行性疾病，临床表现为肌肉无力、萎缩及锥体束征。病因及临床表现具有很强的异质性。ALS 起病部位可为球部或者四肢，球部起病的ALS 多表现为进行性延髓麻痹（progressive bulbar palsy，PBP），疾病进展迅速、预后较差；亦有部分球部起病的ALS 患者表现为起病六个月内症状局限于球部，无突出肢体受累表现，称为孤立球部表型ALS 或孤立球麻痹（isolated bulbar palsy，IBP），该类患者症状相对局限、进展缓慢、预后相对较好。目前针对孤立球麻痹研究较少，其临床及预后特征尚不明确。
研究目的：本研究分析并比较孤立球部表型ALS 与进行性延髓麻痹的临床及预后特征。
研究方法：本研究纳入2013 年10 月至2022 年4 月期间就诊于中国医学科学院北京协和医院神经科门诊并诊断为散发型肌萎缩侧索硬化且球部起病的患者共402 名，收集其人口学信息、基线临床信息及随访信息，包括但不限于性别、起病年龄、就诊时病程、身体质量指数（body mass index，BMI）、进展至第二部位时间、临床症状与体征、肌电图特征、肺功能、基线及随访改良肌萎缩侧索硬化功能评价量表（ALS functional rating scale- reivised，ALSFRS-R）得分、治疗情况等，根据起病后6 个月内临床症状是否局限于球部分为IBP 及PBP 两组，分析并比较两组患者人口学、临床及预后特征。
研究结果：本研究纳入402 名球部起病的ALS 患者，其中男性194 人（48.3%），女性208 人（51.7%）。平均起病年龄为56.4 岁，中位起病年龄为57（49，64）岁，就诊时中位病程为12（8.0，18.8）个月。总生存期（Overall survival, OS）平均为30.4 个月，中位27.8（22.3，36.5）个月。IBP 组与PBP 组的人在性别构成、起病时及就诊/基线时BMI 无有统计学意义的差异。在起病年龄上，IBP 组显著晚于PBP 组（p<0.05），就诊时病程上，IBP 组显著长于PBP 组（p<0.0001）。临床表现上，IBP 组患者的舌肌纤颤及舌肌轻瘫的发生率显著高于PBP（p<0.05），但两组在其他球部症状及体征如构音障碍、吞咽困难/饮水呛咳、颈部无力、饮食食物粘稠度、咽反射、下颌反射、舌肌萎缩、肺功能等项目上无显著差异。IBP 组基线ALSFRS-R 得分显著高于PBP 组（p<0.0001），但二组球部得分上无有统计学意义的差异。IBP 患者相比PBP 患者，无论是球部得分下降速率还是其他部位得分下降速率，均显著减慢（p 均<0.0001）。IBP 组患者使用力如太比例更高（p<0.05)。IBP 组患者进展至第二部位显著晚于PBP 组患者（p<0.0001），两组患者进展至第二部位中位时间分别为11.47 个月和3.03 个月。两组患者在总生存期上存在显著统计学意义差异（p<0.0001），IBP 中位生存期为30.5 个月，PBP 中位生存期为24.3 个月。
研究结论：孤立球部表型ALS 是一类特殊球部起病的ALS，其起病年龄晚、进展至第二部位慢、功能损伤速度较慢、总生存期相对长。但难以从临床症状及体征上区分孤立球部表型ALS及进行性延髓麻痹。

Research Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of the nervous system characterized by simultaneous involvement of upper and lower motor neurons, with clinical manifestations including muscle weakness, atrophy, and pyramidal signs. The etiology and clinical manifestations of ALS exhibit strong heterogeneity. ALS can onset at the bulbar or limb regions. ALS with bulbar onset mostly presents as progressive bulbar palsy (PBP), which has rapid disease progression and poor prognosis. Additionally, some patients with bulbar-onset ALS show symptoms limited to the bulbar region within 6 months of onset without prominent limb involvement, which is termed isolated bulbar palsy (IBP) or isolated bulbar phenotype ALS. This subgroup of patients has relatively localized symptoms, slow progression, and relatively good prognosis. Currently, there are few studies on isolated bulbar palsy, and its clinical and prognostic features remain unclear.
Research Objective: This study aims to analyze and compare the clinical and prognostic characteristics of isolated bulbar phenotype ALS and progressive bulbar palsy.
Research Methods: A total of 402 patients with sporadic amyotrophic lateral sclerosis and bulbar onset who attended the neurology outpatient clinic of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences between October 2013 and April 2022 were enrolled. Demographic information, baseline clinical data, and follow-up information were collected, including but not limited to gender, age at onset, disease duration at first visit, body mass index (BMI), time to progression to the second affected region, clinical symptoms and signs, electromyography features, pulmonary function, baseline and follow-up scores of the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), treatment status, etc. Patients were divided into IBP and PBP groups based on whether their clinical symptoms were limited to the bulbar region within 6 months after onset. Demographic, clinical, and prognostic characteristics of the two groups were analyzed and compared.
Research Results: A total of 402 bulbar-onset ALS patients were enrolled in this study, including 194 males (48.3%) and 208 females (51.7%). The mean age at onset was 56.4 years, with a median age at onset of 57 (49, 64) years, and the median disease duration at first visit was 12 (8.0, 18.8) months. The overall survival (OS) had a mean of 30.4 months and a median of 27.8 (22.3, 36.5) months. There were no statistically significant differences in gender distribution, BMI at onset and at first visit/baseline between the IBP and PBP groups. Regarding age at onset, the IBP group was significantly older than the PBP group (p<0.05). For disease duration at first visit, the IBP group was significantly longer than the PBP group (p<0.0001). In terms of clinical manifestations, the incidence of tongue muscle fibrillation and tongue muscle paresis in the IBP group was significantly higher than that in the PBP group (p<0.05), but there were no significant differences between the two groups in other bulbar symptoms and signs such as dysarthria, dysphagia/water choking, neck weakness, dietary consistency, pharyngeal reflex, jaw reflex, tongue muscle atrophy, and pulmonary function. The baseline ALSFRS-R score of the IBP group was significantly higher than that of the PBP group (p<0.0001), but there was no statistically significant difference in bulbar subscores between the two groups. Compared with PBP patients, IBP patients had significantly slower decline rates of both bulbar subscores and other regional subscores (both p<0.0001). A higher proportion of IBP group patients received riluzole treatment (p<0.05). The time to progression to the second affected region in the IBP group was significantly later than that in the PBP group (p<0.0001), with median times to progression to the second region being 11.47 months and 3.03 months, respectively. There was a statistically significant difference in overall survival between the two groups (p<0.0001), with a median OS of 30.5 months in the IBP group and 24.3 months in the PBP group.
Research Conclusions: Isolated bulbar phenotype ALS is a special subgroup of bulbar-onset ALS, characterized by later age at onset, slower progression to the second affected region, slower rate of functional impairment, and relatively longer overall survival. However, it is difficult to distinguish isolated bulbar phenotype ALS from progressive bulbar palsy based on clinical symptoms and signs.