Introduction
Cervical dystonia (CD) is the commonest idiopathic focal dystonia (Albanese et al.
2013; LeDoux et al.
2016) and is one of the most frequently treated movement disorders (Defazio et al.
2013b; Group
2000). Non-motor symptoms (NMS) are common in CD and can range from pain perception, sleep dysfunction to neuropsychiatric symptoms such as depression and are considered as a research priority (Jinnah et al.
2013). However, the results from these studies vary in relation to the reported frequencies of various NMS and in their impact on health-related quality of life (HRQoL). One explanation for the reported variabilities could be related to diverse and non-standard methodologies of assessment of NMS. The Dystonia Non-Motor Symptoms Questionnaire (DNMSQuest (Klingelhoefer et al.
2019,
2020)) is a newly described 14-item self-completed questionnaire listing the presence of a range of NMS in patients with craniocervical dystonia during the past month. The overall load of the seven different relevant non-motor domains of the DNMSQuest can be calculated as an estimation of the symptoms burden [similar to NMS questionnaire for Parkinson’s disease (PD) (Chaudhuri et al.
2006)] (Klingelhoefer et al.
2019).
In this case–control study we report on the association and the impact of non-motor burden and motor symptoms on HRQoL in CD patients using the DNMSQuest.
Discussion
In this multicenter observational case–control study, we describe the non-motor and motor profiles as well as their impact on HRQoL in CD patients in comparison to age- and sex-matched HC using the newly validated DNMSQuest.
The majority of investigated CD patients has intermediate motor severity, a combination of different dystonic postures and dystonic head tremor as previously described (Chan et al.
1991; Defazio et al.
2013a; Jankovic et al.
1991; Jost et al.
2020; Tomic et al.
2016; van den Dool et al.
2016; Werle et al.
2014). Importantly, our study cohort consisted of mainly middle-aged females and thus is representative for the CD population (Defazio et al.
2013b; Group
2000). Furthermore, patients of all disease durations and in all CGI stages were included.
NMS were significantly more common in CD patients with 95% reporting at least one NMS; in line with other publications (Klingelhoefer et al.
2014; Smit et al.
2017a). While in HC the NMS burden only became relevant with increasing age and comorbidities, in CD patients, the investigated NMS were independent of age, sex, disease duration, duration of BoNT therapy and socio-economic status. Further, there was no association of general NMS burden and motor severity.
Pain is common in dystonia (57–89% of CD patients), mainly in the neck and shoulder area (Comella and Bhatia
2015; Klingelhoefer et al.
2019; Sheehy and Marsden
1980; Tinazzi et al.
2020; Werle et al.
2014). In our study pain was reported by 77% of CD patients and there was a strong correlation between pain and other NMS, especially emotional well-being and depression whereas the correlation between pain and motor severity was low. This observation is therefore of interest as we also report that pain is only partly related to motor severity with the duration of head deviation being the most relevant factor. Our overall results support observations in relation to lack of correlation between pain and motor severity (Kutvonen et al.
1997; Novaretti et al.
2019). Emotional well-being, comprising symptoms of depression and anxiety, was highly prevalent and reported by 59% of CD patients in DNMSQuest; in line with other observations (Comella and Bhatia
2015; Fabbrini et al.
2010; Smit et al.
2016). Even though 37% of CD patients fulfilled the DSM criteria of mild depression (Beck et al.
1996; Kühner et al.
2007) only half of the CD patients had a documented diagnosis of depression/anxiety disorder and only a quarter was treated with anxiolytics or antidepressants. Our results indicate a marked underreporting of psychiatric comorbidities in CD patients. This is of special interest as our study and other publications reported no association of emotional well-being and motor severity (Gundel et al.
2001; Skogseid et al.
2007; Slawek et al.
2007) emphasising the need of recognition and appropriate treatment of NMS. Perceived Stigma was prevalent in around half of the investigated CD patients, especially in younger adults. Stigmatisation was mainly related to worse motor severity but also to a higher NMS burden. In our study, CD patients reporting stigmatisation were more likely to present with depressive symptoms and be treated with antidepressants or anxiolytics as described previously (Lewis et al.
2008; Papathanasiou et al.
2001). Sleep dysfunction was the second most common NMS with various presentation (66% of CD patients reporting insomnia, 41% a feeling of impaired sleep quality, 49% daytime sleepiness/fatigue). These findings are in line with other studies reporting impaired sleep in 44–72% of CD patients (Avanzino et al.
2010; Klingelhoefer et al.
2014; Paus et al.
2011). Sleep impairment was associated with reduced emotional well-being and more often reported by CD patients treated with anxiolytics or antidepressants. Importantly, sleep problems were not related to motor severity. Furthermore, our study revealed for the first time that CD patients with sleep problems had a higher pain burden than those with regular sleep and pain symptoms were reported more often during the day. Overall, sleep dysfunction and pain seem to aggravate each other independent of motor severity of CD and point out the need of specific treatment.
CD patients were significantly more impaired in their ADLs than HC. Relevant influencing factors on ADL were mainly other NMS like pain, emotional well-being, sleep dysfunction and autonomic symptoms but also motor severity. Van den Dool et al. (
2016) showed that psychiatric features and pain have the largest contribution to disability in CD patients. We confirm these findings with more than half of our CD patients reporting pain as a source of disability.
NMS have a relevant influence on HRQoL in movement disorders, especially in PD (Martinez-Martin et al.
2011). In dystonia, NMS and their impact on HRQoL is topical (Ben-Shlomo et al.
2002; Camfield et al.
2002; Paracka et al.
2020; Pekmezovic et al.
2009; Smit et al.
2017b). The present study reports the impact of NMS burden, assessed by DNMSQuest, on HRQoL in CD patients (Fig.
3). HRQoL was measured by CDQ-24, a specific validated self-reported questionnaire for the assessment of HRQoL in craniocervical dystonia (Fig.
3c) and by EQ-5D, a more general validated self-reported questionnaire for the assessment of HRQoL in any kind of disease (Fig.
3a).
Based on the defined symptom complexes, emotional well-being had the highest impact on HRQoL followed by pain. Emotional well-being was also found relevant for HRQoL in CD patients in other studies (Ben-Shlomo et al.
2002; Drexel et al.
2020; Muller et al.
2002; Skogseid et al.
2007; Slawek et al.
2007). Pain as the second most relevant factor for HRQoL in the investigated CD patients, explained 41% of reduced HRQoL in a study by Werle et al. (
2014). Stigma and motor severity were closely linked and relevant for HRQoL but were not significant in this study. Stigma was reported as the most relevant factor for HRQoL when using the CDQ-24 (Muller et al.
2004; van den Dool et al.
2016). This is in line with the finding of Drexel et al. reporting reduced HRQoL even under BoNT treatment (Drexel et al.
2020). Further NMS such as sleep problems and impaired ADL were associated with reduced HRQoL in this and previous studies (Smit et al.
2016,
2017b; Soeder et al.
2009; Tomic et al.
2016; Wagle Shukla et al.
2016) but were not significant within our regression model.
The potential limitations of this study are
1.
The symptom complex “sleep/fatigue” covers the sleep and fatigue domain of the DNMSQuest even though fatigue is not a sleep-related problem. There are no disease-specific sleep/fatigue scales in dystonia but “sleep/fatigue” are clustered together in other NMS measures, e.g. the Non-Motor Symptom assessment scale for PD (Chaudhuri et al.
2007). Thus we used the combined symptom complex in our analysis.
2.
The symptom complex “cognition” should be evaluated with caution as participants with a history of dementia or evidence of significant cognitive impairment were excluded. Nevertheless, the greater impairment of cognition and attention in CD patients compared to HC, both in subjective and objective evaluation, is an interesting finding, supported by other investigations (Czekoova et al.
2017) and needs further investigation.
3.
The effect of BoNT therapy cannot be evaluated as study assessments were performed at the end of a BoNT treatment cycle (Table
2). However, we observed that a shorter positive BoNT effect is associated with a higher amount of NMS and a longer positive BoNT effect is associated with better HRQoL. This may provide a hint that BoNT has a positive effect on NMS, at least on those NMS secondary to motor symptoms. These observations need to be studied further, e.g. by re-assessment of NMS at the most effective time point after BoNT treatment. An assessment of de-novo patients would also be desirable to fully exclude any BoNT effects.
In summary, we report that NMS are highly prevalent in CD patients with 95% reporting at least one NMS. Pain, sleep problems, stigma, anxiety and depression being most common NMS. Furthermore, NMS are present throughout the whole course of dystonia and appear independent of age, sex, disease duration, duration of BoNT therapy and socio-economic status. In general, NMS burden and especially emotional well-being and pain have a major impact on HRQoL which may be a greater determinant of QoL compared to the motor symptoms in CD patients. Further, most NMS with the exception of pain, stigma and ADL occurred independent of motor severity of CD. Therefore, in line with previous publications, our data suggests that most NMS could be a primary phenomenon of dystonia. This is of major importance as a diagnostic consideration and for a holistic treatment approach of CD patients. In contrast to the diagnostic criteria for PD including NMS both as supportive and as exclusion criteria (Postuma et al.
2015), the current definition of dystonia does not consider any NMS (Albanese et al.
2013). The DNMSQuest therefore, could be an useful screening tool empowering CD patients to declare relevant NMS and thus personalise and improve holistic care.
Compliance with ethical standards
Conflict of interest
Information concerning all sources of financial support and funding, regardless of relationship to current manuscript: Lisa Klingelhoefer: reports academic grants from EU Horizon 2020 and habilitation funding for women from the Medical Faculty of the Technical University Dresden, Germany. Robert Untucht: reports a grant from the Stiftung Hochschulmedizin (medical university foundation) Dresden and travel costs to a conference by Merz Pharma (Frankfurt, Germany). Björn Falkenburger: received payment for consultations, talks or articles from Desitin, UCB, Thieme; research support from Deutsche Forschungsgemeinschaft and Merz. K. Ray Chaudhuri: Advisory board: AbbVie, UCB, GKC, Bial, Cynapsus, Novartis, Lobsor, Stada, Medtronic, Zambon, Profile, Sunovion, Roche, Therevance, Scion, Britannia. Honoraria for lectures: AbbVie, Britannia, UCB, Mundipharma, Zambon, Novartis, Boeringer Ingelheim. Grants (Investigator Initiated): Britania, AbbVie, UCB, GKC, Bial. Aacdemic grants: EU (Horizon 2020), IMI EU, Parkinson’s UK, NIHR, PDNMG, NPF, MRC, Kirby Laing Foundation, Wellcome Trust. Heinz Reichmann: was acting on Advisory Boards, gave lectures and received research grants from Abbott, Abbvie, Bayer Health Care, Bial, Boehringer/Ingelheim, Brittania, Cephalon, Desitin, GSK, Lundbeck, Medtronic, Merck-Serono, Novartis, Orion, Pfizer, TEVA, UCB Pharma, Valeant, Zambon, and Kyowa. Maximilian Kaiser, Anna Sauerbier, Miriam Wienecke, Könül Mammadova, Olaf Gregor: None.
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