The Non‐Motor Symptoms Scale in Parkinson’s disease: Validation and use

The Non‐Motor Symptoms Scale (NMSS) was developed and validated in 2007 as the first instrument for the comprehensive assessment of a range of non‐motor symptoms in Parkinson's disease (PD). Thirteen years have elapsed since its introduction and extensive international validation with good psychometric attributes has been carried out. Here, we review the validation data of the NMSS and its cross‐validity with other scales, and describe the key evidence derived from use of the NMSS in clinical studies. To date, over 100 clinical studies and trials have made use of it as an outcome measure, showing consistent and strong correlations between NMSS burden and health‐related quality of life measures. Moreover, the scale has shown to be capable of detecting longitudinal changes in non‐motor symptoms, where studies have shown differential changes over time of several of the NMSS domains. The scale has become a key outcome in several randomized clinical trials. Highlighting the prevalence and importance of non‐motor symptoms to quality of life in patients with PD, the development of NMSS has also been useful in signposting clinical and biomarker based research addressing non‐motor symptoms in PD.


| VALIDATION
The original validation study of the NMSS enrolled 242 PD patients from Europe, Japan and the USA (mean age 67.2 ± 11 years, disease duration 6.4 ± 6.0 years) and showed a mean NMSS score of 56.5 ± 40.7 (range: 0-243) with no floor and ceiling effects for the NMSS total score, 1 and satisfactory scaling assumptions and internal consistency for most domains. Test-retest study showed satisfactory reproducibility (ICC > 0.80) for all domains except cardiovascular (0.45). The second international validation (411 PD patients from 10 countries across three continents) confirmed that the scale as a whole was free of floor or ceiling effects and had robust clinimetric properties despite its multi-dimensional nature. Similar results were observed in a Chinese cohort and two additional validation studies (Table 1), 9 although certain NMSS domains have less favourable properties in terms of floor and ceiling effects. For example, the sexual dysfunction and perceptual domains in some studies had a higher percentage of patients where a ceiling effect was observed, 8,12 but still well within the acceptable range (around 2%).

| Convergent validity with other instruments addressing NMS
Various studies have either correlated NMSS total score with specific tools or addressed convergent validity against other instruments that include assessment of NMS in PD. The rater-administered NMSS showed a strong positive correlation with the NMSQ self-administered items, confirming the link between patient-reported and physician-gathered outcomes related to NMS in PD, 1 and quality-oflife measures (PDQ-8).
Several studies have shown the link between the NMSS total scores and a range of other tools assessing PD symptoms. The NMSS showed moderate to strong correlation coefficients (r(S) ≥0.3) with: (a) sleep scales, 9,11,12 such as the Pittsburgh Sleep Quality Index, PD Sleep Scale (PDSS) and Epworth Sleepiness Scale (ESS); (b) neuropsychiatric scales, 9,11,[12][13][14] Table 2 and Figure 1. Additionally, the NMSS has been validated against instruments assessing specific NMS such as cognition, sleep, neuropsychiatric symptoms, autonomic symptoms and olfaction, detailed below.
These data show that the NMSS can pick up a broad range of NMS and has the potential to be used to identify specific NMS in PD, which can then be further explored with scales more dedicated to the specific problem.

| Neuropsychiatric features and Cognition
The NMSS mood/apathy domain was strongly associated with SCOPA cognition (SCOPA-COG) total scores, 14 while the self-com-  Table 2.
In terms of links with specific cognitive measures, Koh and colleagues showed a moderate inverse correlation (r(S) = −0.291) between MMSE and NMSS total scores. 7 This was also observed in a Chinese study, where the inverse correlation between MMSE and NMSS was also moderate (r = −0.19), although in the same study the association between NMSS domain 3 and the MMSE was better (r = −0.47). 9 The latter highlights that the cognition domain of the NMSS may prove useful to identify (the risk for) cognitive problems and high domain scores should prompt clinicians to explore cognitive problems in their patients.

| Sleep
NMSS total scores strongly correlate with the PD Sleep Scale (PDSS) total scores. 12  Scale (HAM-A). 9 Wang et al also reported significant associations between the Sleep/fatigue domain of the NMSS and the PSQI and the ESS. 9 Other scales that were significantly associated with the NMSS sleep/fatigue domain were the NPI and BDI scales (

| NMSS in epidemiological studies and progression patterns
The reproducible and validated nature of the NMSS has enabled it to be used as a structured outcome measure in multiple large cohort studies. 19 Several currently active cohort studies are using the NMSS as an outcome measure, for example the Spanish COPPADIS-2015 study. 20 In previous studies, it was shown that NMS and NMS burden are not strongly related either to age or disease duration. 21 Guo et al reported in 616 PD patients that, although the mean affected number of NMS and NMMS score increased with disease duration, NMS progression rate appeared to be largely symptom-specific. 22 On the other hand, specific determinants reported for NMS or NMS burden include sex, Impulse Control Disorder (ICD) (eg ICARUS study) 23 and most recently seasonal variation. 24 In the latter study, it was shown that not only NMSS total scores, but also domain scores for cardiovascular symptoms, perceptual problems and sleep demonstrate seasonal fluctuation. 24 The knowledge gained from some of the here mentioned studies has been instrumental in selecting the relevant outcomes for clinical studies and, moreover, have started to highlight that many factors influence NMS in PD and should be taken into account for proper study interpretation.

| Quality of life: Correlations with QoL scores
The NMSS is not only a useful tool for the identification of specific NMS in PD, but also for the identification of overall NMS burden, underlined by the consistently reported strong link between NMS (burden) and quality of life (QoL) in PD, 19,25 for example between the NMSS total score and the Parkinson's Disease Questionnaire-39 (PDQ-39) and EQ-5D (r(S) 0.57-0.70). 12 Several large studies (n > 500 patients) have confirmed these findings, 26,27 with female sex as an independent predictor for worse QoL related to NMS. 28 NMS burden is not only related to QoL in patients, but also in caregivers where especially disability and mood of PD patients affect caregiver stress and burden assessed through the Zarit Caregiver Burden Inventory and Caregiver Strain Index. 29 The strong link between the NMSS and QoL highlights the need of having a non-motor instrument as an outcome in clinical trials and other clinical studies.

| Relationship with motor features
The relationship between the NMSS, its domains and several motor symptoms, including tremor and postural instability, in PD has been examined and it was reported that these symptoms were moder- ately, yet significantly, associated 15,30 (Table 2) These studies show that many therapies, alongside the often pronounced motor effects, have non-motor effects as well and can be captured through instruments such as the NMSS.

| Open-label and comparative trials
The NMSS was explored as a primary outcome measure in PD for

| ADVANTAG E S AND DISADVANTAG E S OF THE NMSS
The identification and quantification of NMS burden and specific symptoms is of crucial importance as these symptoms are strongly