Non-Motor Symptom Management: Insights into Adherence to Treatment Guidelines in Parkinson’s Disease Patients

INTRODUCTION

Parkinson’s disease (PD) is the second most common movement disorder [1], and 98% of PD patients experience at least one non-motor symptom (NMS) [2]. On average, patients experience eight of the NMS monitored by the Non-motor symptom questionnaire, which is three times more than age-matched controls [3]. NMS involves for example cognitive dysfunction [1], constipation, excessive daytime sleepiness, sleep disturbances, depression, anxiety, pain, urinary dysfunction, and orthostatic dysfunction [4]. The exact causes of NMS are likely diverse and not fully understood, but a dysfunction of both dopaminergic and non-dopaminergic neurotransmitter systems are thought to play significant roles in their development [4]. Also, NMS can be side effects of ongoing treatment [4]. For example, degeneration of peripheral autonomic neurons, the medulla oblongata and the olfactory bulb contribute to the development of NMS [5].

Many NMS respond to dopaminergic therapy [6], particularly when NMS are associated with motor fluctuations, such as pain or depression during “Off” state [7, 8]. However, some NMS, like orthostatic hypotension and dopamine dysregulation syndrome, can worsen with the use of dopaminergic treatment [6]. The Swedish National Board of Health and Welfare [9, 10], The Swedish Movement Disorder Society (Swemodis) [7], and The International Parkinson and Movement Disorder Society (MDS) Evidence-Based Medicine committee provide evidence-based treatment guidelines for managing NMS [11]. A recent study assessed the adherence to NMS treatment guidelines in late stage PD patients with a Hoehn and Yahr stage ≥4, using MDS guidelines from 2019, Swemodis guidelines from 2019, and the Swedish National Board of Health and Welfare guidelines from 2016 [12]. The study demonstrated a high prevalence and severity of NMS in advanced stages of PD and emphasized the importance of comprehensive screening and effective management of NMS in patients with late-stage PD. However, it is still unknown to what extent the international and national NMS treatment guidelines are followed for patients with mild to severe PD. This information is crucial for gaining insights into the adherence to NMS treatment guidelines across the entire patient group.

NMS significantly impacts the quality of life for individuals with PD [13, 14], and imposes a considerable financial burden on society due to increased institutional care admissions and premature retirement [8]. Therefore, detecting NMS early and providing appropriate treatment is essential for both individuals with PD and society. However, it appears that clinicians often overlook NMS and fail to inquire about the patients’ problems [13]. Investigating adherence to treatment guidelines can help address this issue by raising awareness of potential gaps and areas for improvement in NMS management. Understanding how NMS guidelines are followed is essential for improving both the guidelines themselves and the NMS treatment approaches. By assessing the current implementation of NMS treatment guidelines, we can work towards improving patient care and outcomes.

Consequently, the aim of this study was to investigate the adherence to pharmacological NMS treatment guidelines among PD patients with a disease severity spanning from mild to severe stages, who were able to walk or stand unassisted (i.e., Hoehn and Yahr stage ≤4).

MATERIALS AND METHODS

RESULTS

DISCUSSION

The primary finding of this study was that among PD patients with a Hoehn and Yahr stage of ≤4, treatment of multiple NMS was limited. On average, only 32% of NMS were treated in adherence to national or international treatment guidelines. Depression showed the highest adherence to guidelines (79%), followed by constipation (77%), while dysphagia had the lowest adherence (0%). These findings highlight the need for improved screening and treatment of NMS among PD patients.

Pain was the most prevalent NMS, with 69% of the participants experiencing symptomatic pain (≥6 points on item 1, 2, or 3 within domain L) and 81% reporting pain symptoms (≥1 point on item 1, 2, or 3 within domain L). This aligns with previous studies showing that 68–95% of PD patients encounter pain-related issues [26]. Pain in PD is often multi-factorial and even though PD is not always the main source of pain, it is often amplified by motor and non-motor PD symptoms [26]. Only 38% of patients received appropriate pain treatment in accordance with the guidelines. However, 27% of patients received pain treatment outside the guidelines, such as paracetamol, or non-steroidal anti-inflammatory drugs. It is possible that these drugs were suitable for specific patients whose primary pain issue was unrelated to PD. Moreover, patients’ ratings indicated that nonsteroidal anti-inflammatory drugs were reported as the most effective analgesic medication [27], despite not being included in the guidelines. This suggests that the guidelines may not address the diverse pain experiences in PD. Optimizing dopaminergic treatment is important for managing PD-related pain [26],but this aspect was not examined in this study due to limitations in assessing treatment optimization over the phone. As specific pain types couldn’t be identified during the phone interviews, any guideline-based treatment was considered appropriate, despite varying guidelines for different pain types. Consequently, less than 38% of patients may have received optimal treatment. These findings indicate a need for physicians to improve recognition and management of pain in PD patients. Further research is warranted to identify effective pain treatments for PD and to enhance the current guidelines.

Consistent with earlier research [28], urinary problems were found to be a prevalent NMS, and 56% of the participants were defined to require treatment. However, only 31 out of 93 patients received treatment in accordance with national or international guidelines. The development of urinary problems has been linked to a notable decline in quality of life [14]. Hence, improved screening and effective management of urinary problems are crucial to enhance patients’ overall well-being. Only 0–2% of patients scored ≥6 points on any item within the “Impulse control disorder” domain. However, previous studies indicate an occurrence rate of approximately 14% for ICD among patients [29]. The limited reporting of ICD symptoms might stem from feelings of embarrassment or reluctance to discuss such issues. Given the significant impact of ICD on quality of life and functioning [29], uncovering these problems is crucial. Encouraging open discussions during clinician meetings, especially with established relationships, could encourage greater openness. Additionally, involving a patient’s relative in the conversation might provide further insights.

Depression and constipation had the highest adherence rates to treatment guidelines, with 79% and 77% compliance, respectively. Among the 29 participants with symptomatic depression, the most common treatments were venlafaxine (45%), mirtazapine (34%), and pramipexole (48%). Pramipexole is prescribed for both depression and motor symptoms, making it unclear if it was specifically intended for depression. Additionally, 10% of symptomatic patients received SSRI, despite only being recommended as an exception according to national guidelines due to contradictory results [10]. However, international guidelines consider SSRI as “possibly useful” for depression treatment [11]. Even though venlafaxine and pramipexole are more strongly recommended in international guidelines it can therefore be argued that the use of SSRI has some support.

Our findings revealed that only 7% of patients reporting cognitive impairment based on the MDS-NMS scale received guideline-based treatment. Often, memantine was prescribed instead of cholinesterase inhibitors, despite being a lower priority in Swedish guidelines and not recommended by the MDS guidelines [7, 9–11]. No validated screening scale for cognitive impairment was utilized in this study, which introduces uncertainty regarding the prevalence of cognitive impairment among participants. It is possible that patients both overestimate and underestimate their problems on the MDS-NMS scale. Cognitive impairment is up to six times more common in individuals with PD than in the healthy population [30]. Over 80% of PD patients progress to dementia in later stages, and around 40% of early stage PD patients experience mild cognitive impairment [31]. Our results indicate that 55% had symptomatic cognitive impairment, aligning well with those numbers, despite relying solely on the MDS-NMS scale. Early identification and targeted treatment of mild cognitive dysfunction is crucial in order to improve cognitive reserve and protect cognitive status [31]. Consequently, it is likely that many of the patients that experienced cognitive problems according to the MDS-NMS scale should be considered for treatment or at least undergo an assessment for cognitive impairment. However, it is important to note that the decision for treatment should not be based solely on the MDS-NMS scale.

Despite available clinical useful treatment, only 38% of men with sexual dysfunction received an appropriate treatment. This finding aligns with previous research indicating that sexual dysfunction is often neglected among PD patients [32]. This undertreatment might be attributed to physicians struggling to address the issue and patients feeling uncomfortable discussing it. Only 20% of men reported sexual dysfunction, although research suggests it affects up to 82% of men with PD, and is about twice as common as in aged matched controls without PD [33]. This indicates a significant stigma surrounding the topic, leading patients to avoid discussing it even when prompted with a direct question. An active and satisfying sex life is associated with improved quality of life and better motor and NMS control in men with PD [34, 35]. Thus, clinicians should probably improve their ability to discuss and address sexual dysfunction in a sensitive and supportive manner, to ensure that patients feel comfortable and receive appropriate treatment and support. Currently, there are no recommended treatments for sexual dysfunction in national guidelines, and international guidelines lack specific recommendations for addressing sexual dysfunction in women with PD, despite its negative impact on their quality of life [36]. However, treatments such as menopause hormone therapy, local estrogen therapy, and vaginal dehydroepiandrosterone are available for women with sexual dysfunctions [37]. Studies on their effectiveness in women with PD are necessary to update the guidelines and provide recommendations for both sexes. Additionally, national guidelines should be revised to include treatment options for sexual dysfunction, aiming to improve the quality of life for PD patients experiencing this symptom.

Some of the symptoms with the lowest adherence to guidelines were apathy (4 out of 58 patients), excessive daytime sleepiness (1 out of 28 patients), and dysphagia (0 out of 22 patients). However, the recommended treatments for these symptoms are based on limited evidence or only a few studies[7, 11]. For apathy, rivastigmine is recommended, and piribedil is recommended after subthalamic nucleus deep brain stimulation (DBS). However, according to the MDS guidelines, both rivastigmine and piribedil have only been evaluated in one positive, small-sized, but high-quality study [11]. The national guidelines also indicate limited evidence for the treatment of apathy[7]. Regarding dysphagia, there are no available international guidelines, and according to the Swedish guidelines, apomorphine may offer temporary relief [7]. Only the MDS guidelines provide recommendations for excessive daytime sleepiness, and while modafinil is considered “possibly useful,” there is insufficient evidence to determine its effectiveness conclusively [11].

Previous studies have revealed that neurologists fail to identify NMS in over 50% of consultations [38], despite the fact that NMS have been shown to have a greater impact on the quality of life of PD patients compared to motor symptoms [39]. In the assessment of NMS, scales such as the NMS Scale (NMSS) and NMSQ are often used [17, 40]. LeWitt et al. [40] examined unmet needs for both motor symptoms and NMS in PD. They identified a lack of unified guidelines for incorporating both patient-completed questionnaires like the NMSQ and clinician-completed tools like the NMSS or MDS-NMS for routine assessment in clinical settings, resulting in NMS often being overlooked and underdiagnosed. Additionally, they identified an unmet need for individualized NMS burden grading to guide personalized management. Moreover, all prevalent and dominant NMS could be shown to be poorly treated, and for many NMS, such as anxiety, apathy and urinary dysfunction, there was no strong evidence for how NMS should be managed the best possible way. These findings align with the results of our study, indicating a frequent oversight and inadequate treatment of NMS, with a limited adherence to treatment guidelines.

The perception of distress or disturbance caused by a symptom can vary significantly among individuals, making it difficult to establish definitive criteria for determining the need for treatment. However, it can be argued that if a patient finds a symptom distressing, it is important to address and alleviate their concerns. In the case of the MDS-NMS scale, there is no predetermined cut-off value. We selected a cutoff of ≥6 to determine when treatment is needed based on the rationale that a score of at least 6 indicates either minor distress or disturbance with frequent problems, or problems occurring sometimes but causing considerable distress or disturbance. In both cases, it can be argued that treatment could be beneficial. Sometimes, treatment for a specific symptom is recommended only if the patient presents with certain accompanying problems. For instance, mirtazapine is recommended for depression treatment when the patient also experiences sleep disturbances. Additionally, the use of low-dose antidiuretic hormone is specifically recommended for patients with nocturia. We considered these recommendations when evaluating adherence to treatment guidelines.

There are several reasons why clinicians may not adhere to NMS treatment guidelines, including prior unsuccessful attempts with the prescribed drug due to ineffectiveness or severe side effects. Additionally, the clinicians’ past experiences might lead them to believe that certain recommended treatments are ineffective, prompting them to avoid them. Also, some patients may experience multiple side effects or be reluctant to take additional medication, while others may be at risk for drug interactions with other medications. Furthermore, some clinicians might prefer to steer clear of polypharmacy. To reduce the risk of polypharmacy while effectively managing patients’ NMS, one approach could be to conduct a thorough assessment of the NMS experienced by the patients and the degree to which they are affected by the NMS, utilizing tools such as the MDS-NMS. This approach enables clinicians to prioritize treatment based on symptom prevalence and subjective severity. Continuous evaluations of both treatment and NMS are also essential, allowing for withdrawal attempts if deemed appropriate.

On average, 32% of NMS were treated in adherence with guidelines for the entire group. There was a trend towards a higher percentage of NMS treated in adherence with guidelines in patients with more severe PD (26% for mild PD, 35% for moderate PD, and 39% for severe PD). One possible reason for the increased adherence to guidelines when treating NMS in more severe disease staged could be a higher awareness of the treating clinician to NMS in those patients as follow-up times might be longer, which provides more patient contact. Furthermore, patients with more severe disease generally exhibited more pronounced NMS, as indicated by a total MDS-NMS score of a median 88 (IQR: 60–118) for mild PD, 119 (IQR: 81–170) for moderate PD, and 133 (IQR: 96–161) for severe PD (data not shown). More pronounced NMS, both reported and visible, is likely to prompt the clinician to initiate treatment. Another explanation could be that clinicians prioritize optimizing dopaminergic treatment during the early stages, rather than introducing additional medications. Optimizing dopaminergic treatment is often recommended before introducing other medications. In some cases, clinicians might be focusing on optimizing dopaminergic treatment or evaluating NMS again after optimizing dopaminergic treatment, which could explain the absence of specific NMS treatments. Furthermore, alternative interventions such as DBS or physiotherapy may have been pursued. For instance, while none of the 22 patients with dysphagia received appropriate pharmacological treatment for this symptom, it is likely that some of them received alternative interventions such as help from a logopedic or gastrostomy to address their swallowing difficulties. Moreover, it is possible that some of the patients with dystonia underwent a DBS procedure, which is also recommended. This study focused on the pharmacological aspects of NMS treatment. However, future research should explore the non-pharmacological aspects of NMS treatment to provide a comprehensive understanding of effective interventions.

A limitation of this study is that some patients may have been symptomatic before receiving treatment but are no longer symptomatic, which could impact the results. However, Table 4 and 5 provide valuable information regarding the number of patients receiving specific treatments, the proportion of patients with a symptom receiving treatment, and the proportion of symptomatic patients receiving each treatment. If patients undergoing treatment have a symptom but are not symptomatic, it sometimes suggests improvement due to treatment. Additionally, incomplete documentation of medical treatments by clinicians may have resulted in the omission of certain treatments from the analysis. The specific indications for prescribing certain treatments are also unclear, such as pramipexole, which can be effective for both depression and motor problems, and catechol-O-methyltransferase (COMT) inhibitors, which has an impact on both motor symptoms and abdominal discomfort. Moreover, the NMS-MDS questionnaire was administered via telephone and translated into Swedish, introducing the potential for translation inconsistencies and varying interpretations of the questions. To address this, a single rater (CJ) conducted all the interviews to maintain translation consistency. Moreover, we included patients with a Hoehn and Yahr stage ≤4, however, 72% of included patients were either in Hoehn and Yahr stage 2 or 3. Importantly, we therefore further analyzed the adherence to guidelines depending on the HY stage. The average number of NMS that were treated in accordance with guidelines was slightly higher for patients with more severe PD, indicating there might be some variations between different disease stages. However, Rosqvist et al. [12] focused on adherence in PD patients with late-stage PD (Hoehn and Yahr ≥4), complementing our study and providing a comprehensive overview of the entire patient group. It is also worth noting that some of the symptoms were only reported by a small number of participants, limiting the ability to draw definitive conclusions from the results. However, these findings still provide valuable insights into the potential inadequacies in the treatment of specific symptoms and highlight the need for further investigation into adherence to guidelines.

In conclusion, this study confirms the high prevalence of NMS among PD patients across the motor severity spectrum. In median, each patient experienced 14 NMS and required treatment for seven different NMS. Moreover, there was a low adherence to national and international pharmacological treatment guidelines for NMS. To optimize the treatment of NMS and improve the quality of life for individuals with PD, it is crucial to enhance the detection of NMS. This can be accomplished by incorporating tools like NMSQ or similar questionnaires regularly during clinical assessments. Furthermore, it is essential to advance our understanding of effective NMS treatment strategies. This can be achieved by enhancing adherence to existing NMS treatment guidelines and by further evaluating and refine these guidelines to enhance their effectiveness. Further research is necessary to explore more effective methods of treating NMS with fewer side effects and drug interactions, as well as developing reliable ways to detect NMS.