Department of Neurosciences, Reproductive Sciences and Odontostomatology, University Federico II of Naples, Via Sergio Pansini, 5, 80131, Naples, Italy.
Istituti Clinici Scientifici Maugeri IRCCS, Neurological Rehabilitation Unit of Telese Terme Institute, 82037, Telese Terme, Benevento, Italy.
J Neurol. 2023 Oct;270(10):4968-4977. doi: 10.1007/s00415-023-11832-w. Epub 2023 Jun 26.
BACKGROUND: Among non-motor symptoms, autonomic disturbances have been described in amyotrophic lateral sclerosis (ALS) and reported as mild to moderate in up to 75% of patients. However, no study has systematically investigated autonomic symptoms as prognostic factors. OBJECTIVES: The main aim of this longitudinal study was to examine the association of autonomic dysfunction with disease progression and survival in ALS. METHODS: We enrolled newly diagnosed ALS patients and a healthy control group (HC). Time from disease onset to disease milestone (King's stage 4) and death were calculated to assess disease progression and survival. Autonomic symptoms were assessed by a dedicated questionnaire. Longitudinal evaluation of parasympathetic cardiovascular activity was performed by the heart rate variability (HRV). Multivariable Cox proportional hazards regression models on the risk of the disease milestone and death were used. A mixed-effect linear regression model was used to compare autonomic dysfunction with a HC group as well as its impairment over time. RESULTS: A total of 102 patients and 41 HC were studied. ALS patients, compared with HC, complained of more autonomic symptoms, especially in bulbar onset patients. Autonomic symptoms occurred in 69 (68%) patients at diagnosis and progressed over time (post-6: p = 0.015 and post-12: p < 0.001). A higher autonomic symptom burden was an independent marker of faster development of King's stage 4 (HR 1.05; 95% CI 1.00-1.11; p = 0.022); whereas, urinary complaints were independent factors of a shorter survival (HR 3.12; 95% CI 1.22-7.97; p = 0.018). Moreover, HRV in ALS patients was lower than in HC (p = 0.018) and further decreased over time (p = 0.003), implying a parasympathetic hypofunction that progressed over time. CONCLUSION: Autonomic symptoms occur in most of the ALS patients at diagnosis and progress over time, implying that autonomic dysfunction represents an intrinsic non-motor feature of the disease. A higher autonomic burden is a poor prognostic factor, associated with a more rapid development of disease milestones and shorter survival.
背景：在非运动症状中，自主神经紊乱已在肌萎缩侧索硬化症（ALS）中被描述，并在多达 75%的患者中报告为轻度至中度。然而，尚无研究系统地研究自主症状作为预后因素。
目的：本纵向研究的主要目的是检查自主功能障碍与 ALS 疾病进展和生存的相关性。
方法：我们招募了新诊断的 ALS 患者和健康对照组（HC）。从疾病发作到疾病里程碑（King 第 4 期）和死亡的时间被计算出来，以评估疾病进展和生存。自主症状通过专门的问卷进行评估。通过心率变异性（HRV）对副交感心血管活动进行纵向评估。多变量 Cox 比例风险回归模型用于疾病里程碑和死亡的风险。混合效应线性回归模型用于比较自主功能障碍与 HC 组以及随时间的损伤。
结果：共研究了 102 名患者和 41 名 HC。与 HC 相比，ALS 患者抱怨更多的自主症状，尤其是在延髓起病的患者中。69 名（68%）患者在诊断时出现自主症状，并随时间进展（post-6：p=0.015 和 post-12：p<0.001）。更高的自主症状负担是 King 第 4 期更快发展的独立标志物（HR 1.05；95%CI 1.00-1.11；p=0.022）；而尿失禁是较短生存的独立因素（HR 3.12；95%CI 1.22-7.97；p=0.018）。此外，ALS 患者的 HRV 低于 HC（p=0.018），并且随时间进一步降低（p=0.003），这意味着随时间进展的副交感神经功能低下。
结论：自主症状在大多数 ALS 患者诊断时出现，并随时间进展，这表明自主功能障碍代表疾病的内在非运动特征。更高的自主负担是预后不良的因素，与疾病里程碑的更快发展和较短的生存相关。
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