Background
Parkinson’s disease (PD) is the most common movement disorder of the central nervous system [
1]. It is estimated that PD affects 1–2% of the population above 65 years of age worldwide [
2]. In China, the overall prevalence has been estimated at 190 per 100,000 individuals, with an overall incidence of 362 per 100,000 person years [
3]. PD is characterized by both motor and non-motor system manifestations. Motor symptoms of resting tremors, rigidity and bradykinesia are the cardinal signs of the disease. Along with the disease progress and nonphysiological stimulation of striatal dopamine receptors especially long-term levodopa therapy, motor symptoms could be unstable presented as motor complications including motor fluctuations, dyskinesias [
4]. While the 24-h nature of symptoms is known, focus on the management of nocturnal disturbances is comparatively low [
5‐
7], but studies have reported as many as 96–98% of PD patients being affected by disabling nocturnal symptoms [
5,
7]. Nocturnal symptoms may be classified into three classes using the Revised Parkinson’s Disease Sleep Scale (PDSS-2): 1) “motor problems at night”, such as tremor, early morning dystonia; 2) “PD symptoms at night”, such as pain, cramps, hallucinations and immobility; and 3) “disturbed sleep”, such as insomnia, nocturia, difficulty staying asleep, and general poor sleep quality [
8]. In practice, all classes of nocturnal symptoms may affect quality of life (QoL) and result in disruptions to normal sleep. Some daytime symptoms may also be exacerbated or produced by nocturnal symptoms [
5]. Patients may experience symptom fluctuations associated with the wearing-off of their levodopa dose overnight or in the early morning [
9,
10]. Nocturnal symptoms tend to be exacerbated with disease progression and are associated with a worse prognosis [
11,
12]. However, these symptoms occur outside of healthcare professionals’ contact hours with patients. In addition, patients may not be able to describe their nocturnal symptoms accurately or may not consider the symptom part of their PD pathology. Further, symptoms such as rapid eye movement sleep behavior disorder (RBD) require caregiver or observer reports. This relative inaccessibility to clinicians may be part of the reason of a diminished focus on nocturnal symptoms [
12,
13]. To better understand the unmet needs of nocturnal symptom management from patients’ perspective, a patient-centric approach that allows for a freer expression of certain concerns may be useful.
In recent years, the examination of social media data to better understand a population has become possible through a technique called Social Listening (SL), in which publicly available information can be investigated to determine what topics are being discussed and what attitudes the contributing population holds towards the subjects of discussion [
14]. Aside from creating a large dataset, which strengthens the conclusions that can be drawn from the data, SL has the advantage of collecting data from outlets which patients use voluntarily, and it imposes no additional burden to patients as surveys or other studies might. The technique is also a cost-effective way of collecting a large amount of diverse patient-centric data, which makes SL particularly useful in resource-challenged environments. The extent to which different symptoms are discussed in such public forums can be reasonably assumed to be a proxy for the issues of concern – and therefore unmet needs – of the patients discussing them.
Thus, to understand the unmet needs of nocturnal symptoms from the patients’ perspective, we used SL to analyze large amounts of patient-doctor and patient-patient interaction data in 2016 to 2018 available from clinical practitioners’ consulting platforms, online forums and PD bulletin-board systems in China. We sought to know the characteristics and the burden of nocturnal symptoms from patients’ perspectives. In addition, although dopaminergic therapy, especially levodopa, has improved the treatment of PD symptoms significantly over the past decades, symptoms that persist through day and night and affect non-dopaminergic systems are still of large and of growing concern. In this study, we also explored whether there were any changes in participants’ needs over time by comparing data across 3 years. As a contrast, overall symptom data, including symptoms occurring during the day, were also collected in the study. Even though the primary focus in usual clinical practice is often on motor symptoms, particularly those affecting daytime activities, we investigated whether the unmet needs of nocturnal symptoms and overall symptoms are different from patients’ perspective, which is useful in devising a strategy for symptom management.
Because SL is a relatively new technique, no national guidelines concerning the ethics of SL in a research setting exist in China. Upon registering on the websites that were used as data sources for this study, users gave their e-consent to agree with the collection and use of their provided data. The use of that data for this study was considered legally and ethically proper as it was obtained from publicly accessible platforms, did not contain individually identifiable information, and was analyzed only at the group level.
Discussion
This study represents an attempt to understand the unmet needs of nocturnal symptoms from patients’ perspective. We explored the frequency and the burden of negative sentiment of nocturnal symptoms in a large dataset (15,119 dialogues) using a social listening technique. SOV of motor symptoms was the highest in nocturnal symptoms. For overall symptoms, SOV of motor symptoms was larger significantly than non-motor symptoms and motor complications. The results indicated motor symptoms were still patients’ most concerning problems. The most prominent nocturnal motor symptom was rigidity, a condition whereby patients have restricted or no movement, often to the extent that they cannot turn over or get out of bed. This is consistent with the profile of PD, as rigidity is one of the most difficult symptoms to adequately alleviate [
19].
The SOV of nocturnal symptoms increased over the 3 years studied. Compared with the highest SOV, of nocturnal motor symptoms, the SOV of nocturnal non-motor symptoms increased across the 3-year period. Amongst nocturnal non-motor symptoms, insomnia, pain, and RBD featured with high SOV and CAGRs in our data. Such nocturnal non-motor symptoms may arise for multiple reasons. First, in contrast to motor symptoms which are improved by dopaminergic drugs, nocturnal symptoms may become more prevalent with disease progression [
7,
20] but are less- or un-improved by dopaminergic drugs. Thus, attention on the improvement of non-motor symptoms is growing [
21]. Second, interplay exists between motor and non-motor symptoms [
10]. For example, insomnia and nocturnal pain are associated with nocturnal motor symptoms [
22]. Lower than optimum dopaminergic drug dosages may cause insufficient control of nocturnal akinesia, tremors, which then exacerbate nocturnal non-motor symptoms [
5,
23,
24]. In addition, undesired effects of dopaminergic drugs, or the use of inappropriate medication or dosages may also play a role. The dosage and pharmacokinetics of levodopa are associated with the development of complications [
21]. Reliance on higher doses of levodopa rather than using adjunctive medications or modifying delivery regimens may exacerbate or induce nocturnal symptoms [
5]. However, it is important to note that no data to explain why SOV changed over time were collected in this study. As such, although we speculate that growth in SOV represents an unmet need and increased patient focus on nocturnal symptoms, this question should be addressed in detail in a future work. There is limited research on nocturnal symptoms to date, and our investigation should be considered both tentative and exploratory for these reasons.
Although SOV of motor symptoms was highest in our data, non-motor symptoms evoked higher negative sentiment scores no matter whether they occurred in the daytime or at night (see Fig.
2). Whilst any symptom that impairs daily functioning can be expected to evoke negative sentiment, non-motor symptoms like depression may be particularly debilitating. One reason is that many non-motor symptoms are not reported or enquired about. They are often not recognized by the consulting clinician and may thus go untreated [
6,
13]. Further, the pathological and biochemical mechanisms for many non-motor symptoms involve dopaminergic and non-dopaminergic systems (i.e., noradrenergic, serotoninergic and cholinergic systems). Despite being the major therapy for Parkinson’s disease, the effects of dopaminergic drugs on improving non-motor symptoms remains at least partially unclear [
25,
26]; non-motor symptoms may be more treatment-resistant as well as more troubling. It is worth noting that for symptoms occurring over day and night, negative sentiment toward PD symptoms was more pronounced when they occurred nocturnally (see Fig.
3). Control over nocturnal symptoms may not be as good as daytime symptoms due to nocturnal wearing-off, or reduced attention on nocturnal symptom control. By disrupting sleep initiation or maintenance, these symptoms may exacerbate daytime symptoms as well as being uncomfortable during the night, and thus elicit a higher negative sentiment. Further work should assess this hypothesis.
Implications for managing nocturnal symptoms
With an increasing SOV and a higher negative sentiment of nocturnal symptoms from the patients’ perspective, it is important for healthcare providers to spend more time focusing on the management of these symptoms. Considering the nocturnal inaccessibility of patients, approaches to measure nocturnal symptoms could be more varied. Some wearable devices could provide a continuous objective measurement (COM) to track symptoms over 24 h [
27‐
29], which is good for clinicians seeking to evaluate 24-h symptoms objectively. Communication through various technologies may be beneficial for healthcare providers and patients alike. Increased use of patient-doctor consulting platforms, or even specialized mobile applications for chronic disease management [
30] could be utilized to enhance nocturnal symptoms detection and treatment for patients with PD.
Besides these options,24-h continuous treatment is important. Firstly, the replacement of lost dopamine with dopaminergic drugs in 24 h is necessary for the management of motor symptoms alone – regardless of whether these occur nocturnally or during the daytime. Adjunctive medications [
31‐
33], infusion systems such as DuoDopa (carbidopa/levodopa) [
34], continuous dopamine delivery treatments like the transdermal rotigotine patch [
35‐
39], and oral extended release versions of dopamine agents [
40,
41] have shown significant promise in ameliorating wearing-off effects and symptom fluctuations, in nocturnal as well as daytime symptoms. In a randomized, placebo-controlled study (the RECOVER trial, quality score, 93%), patients with unsatisfactory control of early morning motor symptoms were evaluated on the PDSS-2 and UPDRS III. The study demonstrated that rotigotine could significantly improve early morning motor symptoms and nocturnal symptoms [
35], comparable to levodopa continuous infusion [
42]. The rotigotine patch may thus be recommended for the management of nocturnal symptoms [
43]. In addition, deep brain stimulation (DBS) is another option which can be kept active over a 24-h period. However, to date the proven benefits of DBS are limited to motor symptoms and DBS is most commonly restricted to use in patients with relatively advanced disease [
43,
44]. Secondly, for symptoms which can’t be improved by dopaminergic drugs, especially for non-motor symptoms, there is no standard pharmacological treatment at present. Non-motor symptoms should be improved based on careful assessment of triggering or contributing factors and consideration of other factors, including economic influences, local availability of the drug, local drug approval, the treating physician’s experience and judgment and so on [
26]. Non-pharmacological treatments are helpful in conjunction with 24-h drug treatment. Improved sleep hygiene and cognitive-behavioral therapy may be useful for insomnia [
22]. Regular exercise and physical therapy can also assist with issues such as joint rigidity and flexed posture [
33]. Focused education on symptoms for both patients and families or caregivers is highly recommended. The adoption of non-pharmacological therapies alongside pharmacological treatment early in the disease course is also recommended [
45]. The importance of effective multi-specialty management for patients with PD should not be underestimated.
Limitations
Although powerful, utilizing a social listening technique has some limitations. First, the relative lack of full demographic information constrains the conclusions that can be drawn from the data – general conclusions about the reporting PD population may be valid, but not conclusions about specific groups of PD patients. Further, whilst the candid nature of the interactions makes more information accessible, the available details are constrained by what patients recall, lending itself to potential inaccuracies and skewed data. An ability to further identify and segment patient populations will be an important target in future studies. This study should be considered an early attempt to begin to address these issues.
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