Longitudinal evolution of motor and non-motor symptoms in early-stage multiple system atrophy: a 2-year prospective cohort study

In this prospective observational 2-year follow-up study, we investigated patients with early-stage MSA and observed significant progression of motor symptoms and NMS reflected by the UMSARS-I and II and the NMSS. Additionally, we observed differences between each item of the UMSARS, based on their sensitivity to change. The most sensitive to change items of UMSARS-I were those associated with motor functions, whereas items associated with autonomic dysfunction (orthostatic symptoms, urinary, sexual, and bowel function) showed lesser sensitivity to change over 1- and 2-year follow-ups. Items 3 (ocular motor dysfunction), 4 (tremor at rest), and 5 (action tremor) of UMSARS-II were less sensitive to change at the 1- and 2-year follow-ups.

A previous study reported an increase of 14 points in the median total UMSARS score at the 12-month follow-up and an increase of 22 points at the 24-month follow-up in patients with mild MSA (UMSARS-IV score ≤2) at baseline (n = 44) [14]. These results are consistent with those of our study; we observed a mean increase of 11.90 and 22.54 points at the 1- and 2-year follow-ups in our study. Despite the significant progression of the UMSARS, all items included in this scale did not show good ability to detect changes. We applied a SE (using the mean annual change divided by the SD of the change) to reflect the sensitivity of an item to change, as previously reported [9]. Studies from Western countries have shown that UMSARS-I items associated with motor functions, including speech, swallowing, handwriting, cutting food, hygiene, dressing, and walking were more sensitive to change; this finding concurs with that of our study [7, 9]. These items of the UMSARS-I also showed good ability to detect changes in Chinese patients with early-stage MSA. However, items associated with autonomic dysfunction (orthostatic symptoms, as well as urinary, sexual, and bowel function) were less sensitive to change in our study; these findings are supported by other studies of independent cohorts [7, 9]. Overall, items 9 (orthostatic symptoms), 10 (urinary function), and 12 (bowel function) of the UMSARS-I showed the poorest ability to detect change, which is attributable to the fact that severe autonomic failure is a fundamental clinical feature for diagnosis of MSA [7] or may be secondary to a floor effect in early-stage disease.

With regard to UMSARS-II, most items were sensitive to change, except for items 3 (ocular motor dysfunction), 4 (tremor at rest), and 5 (action tremor), which is consistent with the findings of previous studies [7, 9]. In a small-scale study of 70 patients with MSA, Palma et al. observed that tremor at rest and action tremor had limited ability to detect change [9], which is attributable to the fact that tremors (particularly, tremors at rest) are uncommon in MSA. Krismer et al. reported that in addition to items associated with tremors, oculomotor dysfunction was insensitive to change [7], which may at least partially be explained by an inaccurate description of specific oculomotor abnormalities because of difficulty in assessment.

Our study adds to the evidence that items 9 (orthostatic symptoms), 10 (urinary function), and 12 (bowel function) of the UMSARS-I and items 3 (ocular motor dysfunction), 4 (tremor at rest), and 5 (action tremor) of the UMSARS-II were less sensitive to change even during early-stage MSA. Based on data obtained from Western studies in combination with our findings, it is reasonable to conclude that the UMSARS may have a floor effect in early-stage and a ceiling effect in late-stage MSA. In view of the limitations of the UMSARS, optimization of UMSARS is warranted to improve its sensitivity to change.

This is the first study to use a comprehensive tool (the NMSS) to investigate the early progression of overall NMS in Chinese patients with early-stage MSA; we observed that NMS was prevalent as previously reported [11]. The frequency and severity of NMS significantly increased over the 2-year follow-up. A Spanish study, which used the NMSS to investigate changes in NMS over a 2-year follow-up, observed that only urinary and sexual dysfunction and sleep difficulties showed significant progression [14]. However, the study included only 80 patients with MSA, and only 42 patients successfully completed the 2-year follow-up. The findings of the aforementioned study are inconsistent with our findings; differences in sample size, disease duration at baseline, and ethnicity may have contributed to the discrepancies in results. As previously reported, the frequency and severity of fatigue in patients with MSA increased from baseline to the 1-year follow-up [13]. The results of the current study showed that the prevalence of sleep/fatigue increased from baseline to 1- and 2-year follow-ups, whereas the severity of sleep/fatigue increased from baseline until 2-year follow-up, which is attributable to the fact that we used different scales to evaluate fatigue.

The current study showed that most NMS increased significantly even during early-stage MSA. Accumulating evidence indicates that NMS is closely associated with poor quality of life in patients with MSA [11, 12]. Therefore, the management of NMS in MSA is important, and early intervention with regular monitoring is necessary throughout the course of the disease.

The NMSS and UMSARS have overlapping NMS items, including orthostatic, urinary, sexual, and bowel symptoms. Those items in the UMSARS and NMSS were less sensitive to change, particularly from baseline until the 1-year follow-up. Additionally, attention/memory, gastrointestinal, urinary, and sexual function domains of NMSS were more sensitive to change from baseline until the 2-year follow-up. NMSS contains more comprehensive NMS such as sleep/fatigue, mood/apathy, and attention/memory. Thus, we propose that NMSS can be used as a supplementary scale to evaluate various NMS of MSA in the clinical trials. Furthermore, the International Parkinson and Movement Disorder Society (MDS) task force is planning to revise the UMSARS and transform it into the MDS-UMSARS, which is a comprehensive scale covering the entire spectrum of MSA-specific symptoms, a patient-centered scale, and a set of virtually assessable items [18]. Taken together, the results of the current study may provide useful data to support the revision of the UMSARS, contributing to clinical trials in the future.

The following are the limitations of the current study: (a) The follow-up duration was relatively short. Long-term follow-up is difficult because MSA is a rare and rapidly progressive condition. (b) The single-center design of our study is likely to introduce systemic bias; multicenter studies are warranted in the future. However, we included patients from across more than five provinces of western China to reduce bias. (c) All patients were diagnosed clinically without postmortem confirmation.

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