|Year : 2021 | Volume
| Issue : 3 | Page : 121-130
Burden of nonmotor symptoms in Parkinson’s disease patients from eastern India
Sulagna Sahu1, Adreesh Mukherjee1, Samar Biswas1, Valentina Leta2, Katarina Rukavina2, Shyamal Kumar Das1, Atanu Biswas1
1 Department of Neurology, Institute of Post Graduate Medical Education & Research (IPGME&R) and Bangur Institute of Neurosciences, Kolkata, West Bengal, India
2 Parkinson’s Foundation Centre of Excellence at King’s College Hospital and King’s College London, London, UK
|Date of Submission||06-Mar-2021|
|Date of Decision||22-May-2021|
|Date of Acceptance||18-Jun-2021|
|Date of Web Publication||13-Nov-2021|
Prof. Atanu Biswas
Department of Neurology, Bangur Institute of Neurosciences and IPGME&R, 52/1A, S.N. Pandit Street, Kolkata 700025, West Bengal.
Source of Support: None, Conflict of Interest: None
BACKGROUND: Parkinson’s disease (PD) is classically characterized by motor features. However, nonmotor symptoms (NMSs) represent an important aspect of the disease with a significant impact on quality of life (QoL). OBJECTIVES: The aim of this study was to evaluate NMS in patients with PD, to determine their various correlates, and to assess the impact on QoL. METHODS: This cross-sectional study included 150 consecutive patients with PD and 150 age- and sex-matched healthy controls. NMSs were assessed using the NMS Questionnaire (NMSQuest) and NMS Scale (NMSS). QoL was evaluated by the 8-item Parkinson’s Disease Questionnaire scored as summary index (PDQ-8-SI). RESULTS: Every patient experienced NMS and 90% had more than five NMSs. Patients with PD had a significantly higher prevalence of NMS compared to healthy controls. The most common NMSs in patients with PD were unexplained pain, anxiety, constipation, insomnia, and memory impairment. Miscellaneous was the most prevalent domain of NMSS, followed by sleep/fatigue, gastrointestinal tract, and mood/cognition. Attention/memory impairment and pain were greater in females. Cardiovascular/falls and perceptual/hallucination showed a positive correlation with duration of disease. Sexual dysfunction decreased with increasing age. In the young-onset group (YOPD), mood/cognition involvement was higher. PDQ-8-SI showed a significant correlation with total NMSS score and most of the individual domain scores. Contrary to other Indian studies, our patients reported restless legs more frequently, whereas urinary symptoms were less common. Our observations showed a greater prevalence of pain and constipation compared to the Western studies. CONCLUSIONS: All of our patients experienced NMS. The prevalence of various NMS in our study showed differences with previous reports. NMS had a significant impact on QoL.
Keywords: Hoehn and Yahr stage, nonmotor symptoms, nonmotor symptoms questionnaire, nonmotor symptoms scale, Parkinson’s disease, Parkinson’s disease questionnaire-8
|How to cite this article:|
Sahu S, Mukherjee A, Biswas S, Leta V, Rukavina K, Das SK, Biswas A. Burden of nonmotor symptoms in Parkinson’s disease patients from eastern India. Ann Mov Disord 2021;4:121-30
|How to cite this URL:|
Sahu S, Mukherjee A, Biswas S, Leta V, Rukavina K, Das SK, Biswas A. Burden of nonmotor symptoms in Parkinson’s disease patients from eastern India. Ann Mov Disord [serial online] 2021 [cited 2022 Jan 18];4:121-30. Available from: https://www.aomd.in/text.asp?2021/4/3/121/330445
FNx01Sulagna Sahu and Adreesh Mukherjee should be considered joint first author,
FNx08Dr Shyamal Kumar Das was deeply involved with the study; however, he met an untimely demise.
| Introduction|| |
Parkinson’s disease (PD) is a progressive neurodegenerative disorder classically characterized by motor features of bradykinesia, rigidity, and tremor-at-rest. Postural impairment along with gait difficulty might also occur. In addition, nonmotor symptoms (NMSs) are an important feature of the disease, which might occur even before the appearance of motor symptoms, and have a significant effect on the quality of life (QoL) of patients with PD. Although the prevalence of some of the NMS shows a similar trend in various reports, there is heterogeneity across studies around the world. For example, although some described nocturia as the most common NMS, others have reported sleep/fatigue issues to be the commonest. There is also a wide variation in the prevalence of different NMS among previous studies, and both gender and ethnicity-related differences have been observed.
To evaluate NMS, holistic tools such as the patient-completed Non-Motor Symptoms Questionnaire (NMSQuest) and the clinician-administered Non-Motor Symptoms Scale (NMSS) were introduced., These tools have been used widely in various studies to identify and quantify NMS. Although the NMSQuest identifies the presence or absence of different NMS, the NMSS is used to assess the severity and frequency of several nonmotor domains to provide a composite score.
Although the NMS burden in the population of patients with PD from certain parts of India has recently been reported, no study from eastern India on the detailed spectrum of NMS in PD has been published yet. Considering the ethnic variability inherent to this country, there appears to be incomplete representation; hence, we undertook this study to evaluate the NMS in patients with PD in eastern India, determine their various correlates and assess the impact on QoL.
| Methods|| |
This cross-sectional study included 150 consecutive patients with PD diagnosed as per the International Parkinson and Movement Disorder Society (MDS) clinical diagnostic criteria, recruited from the Movement Disorders clinic of Bangur Institute of Neurosciences, IPGMER, Kolkata, India from February 2016 to June 2017, after obtaining written informed consent from patients/ guardians. Patients with advanced dementia, severe psychosis, and stroke were excluded from the study. The study was approved by the institutional ethics committee.
NMSs were assessed by using the NMSQuest and NMSS, and symptoms were considered within a time span of 1 month preceding the interview. NMSQuest consists of 30 questions and was used to document the presence of various NMS. In the NMSS, there are nine domains with a total of 30 questions. For every patient, demographic details were collected followed by a thorough history and clinical examination according to a semistructured proforma. Patients were classified according to the modified Hoehn and Yahr (HY) staging. Cognitive function was measured by the Bengali Mental Status Examination (BMSE). QoL was evaluated by the 8-item Parkinson’s Disease Questionnaire (PDQ-8)., The total scoring was done in the form of summary index (PDQ-8-SI), standardized on a scale of 0–100, with higher scores indicating worse QoL.
We compared the NMS between male and female patients and across the HY stages and evaluated the correlation of NMS with age of the patients and duration of disease. Patients with age at onset ≤40 years constituted the young-onset PD (YOPD) group, and the NMS in these patients were compared with later-onset patients with PD (age at onset >40 years). We also assessed the effect of NMS and other disease parameters on QoL (PDQ-8-SI).
In addition, 150 age- and gender-matched healthy controls who gave consent to participate in the study were selected from healthy relatives attending the Neurology outpatient department, if they did not have any neurological or psychiatric illness, cognitive impairment, or other nonmotor features that might be attributable to side-effects of medication. The controls were also matched for diabetes mellitus and hypertension. Benign prostatic hyperplasia (BPH) was ruled out by relevant investigations in both patients and controls who complained of urinary symptoms. The NMS in controls were evaluated by the NMSQuest and comparison was done with that of the patients with PD.
Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) software program, version 20.0. Categorical variables are expressed as number and percentage and compared across the groups using the chi-square test/ Fisher’s exact test. Continuous variables are expressed as mean, median, and standard deviation and compared across the groups using Mann–Whitney U test/ Kruskal–Wallis test as appropriate. Associations between continuous variables were obtained by the Spearman rank correlation coefficient. Multiple linear regression analysis was performed to assess the effect of duration of disease, HY stage, and total NMSS score on PDQ-8-SI. An alpha level of 5% was taken, and a value of P ≤ 0.05 was considered significant.
| Results|| |
Of total 150 patients, majority (72.7%) were male and the median HY stage was 2.5 (IQR= 0.625) (demographic details are given in [Table 1]). The higher stages consisted of older patients, and expectedly, longer disease duration. Although overall the male:female ratio was 2.7:1, this reversed in stages 4/5.
Every patient in this study experienced at least one NMS. In total, 135 (90%) patients had more than 5 NMS based on the NMSQuest (highest being 24), and the average number of NMS was 11.18 (± 5.003). According to the HY stages, >5 NMS were present in 83.3% in stage 1, 81.3% in stage 1.5, 88% in stage 2, 92.6% in stage 2.5, 92.3% in stage 3, and 100% in stages 4 and 5, respectively. The most common NMSs were unexplained pain, anxiety, constipation, insomnia, and memory impairment, whereas the least common NMSs were bowel incontinence, nausea/ vomiting, and double vision [Figure 1].
A total of 121 (80.7%) healthy controls reported one or more NMS and the number of NMS varied from 1 to 4. The average number of NMS in the healthy controls (mean ± standard deviation [SD] = 1.69 ± 0.876) was much lower compared to PD subjects (P = <0.001). The most common NMSs in healthy controls were anxiety, insomnia, constipation, nocturia, and unexplained pain, and all NMSs were more prevalent in patients with PD except vomiting/ nausea and bowel incontinence [Table 2].
|Table 2: Nonmotor symptoms in Parkinson’s disease patients and Healthy controls|
Click here to view
On the NMSS, 93.3% patients showed involvement of ≥4 domains. The average number of domains involved was 5.74 ± 1.599 (mean ± SD) and it was similar in males and females (P = 0.586), and across the HY stages (P = 0.711). The total NMSS score was 59.31 (± 24.93) (range 12–164), and there was no significant difference regarding gender of the patients or stage of the disease [Table 3]. Total NMSS score increased with increasing duration of disease (rs = 0.297, P = <0.001). There was no significant difference of total NMSS score (P = 0.358) or number of NMSS domains involved (P = 0.932) between YOPD and later-onset PD.
Miscellaneous was the most prevalent NMSS domain followed by sleep/ fatigue, gastrointestinal tract, mood/ cognition and attention/ memory, whereas least common were sexual function and perceptual/ hallucination [Table 3]. Domain score for attention/ memory was significantly higher in females (P = 0.014) and in stages 4/5 (P = 0.028).
Prevalence (frequency) of the individual domains was similar in males and females, and across the different HY stages. However, taken separately, prevalence of unexplained pain in females (92.7%) far exceeded that of males (65.1%) (P = <0.001). Approximately 35.33% (53/150) showed Levodopa-induced dyskinesia. There was no significant difference in the various NMS domains regarding the presence of dyskinesia. Domain scores for cardiovascular/ falls and perceptual/ hallucination showed a positive correlation with duration of disease, and that of sexual function showed a negative correlation with age. In the YOPD group, mood/ cognition score was significantly higher compared to later-onset PD (10.24 ± 6.4 vs. 6.51 ± 4.96, P = 0.017).
The PDQ-8-SI score showed a significant correlation with duration of disease (rs= 0.259, P = 0.001), but not age at evaluation. There was also no significant difference between YOPD and later-onset PD (P = 0.11). PDQ-8-SI score was higher in HY stage 4 and especially stage 5 (P = 0.015). It was also greater in females, but not statistically significant (31.63 ± 22.41 vs. 23.68 ± 18.49, P = 0.077). PDQ-8-SI showed a significant correlation with total NMSS score and all the individual domain scores except urinary and sexual function [Table 3]. On multiple linear regression analysis (with duration, HY stage, and total NMSS score), only total NMSS score was found to be a significant predictor of PDQ-8-SI.
| Discussion|| |
NMS is an important aspect of PD and forms an integral part of the disease. In our study, each patient had at least one, and most of them had multiple NMS. This is concurrent with previous studies showing high prevalence of NMS, with some studies documenting NMS in nearly 100% patients.,, Although nearly 80% of healthy controls in our study reported the presence of NMS, the number of NMS was much lower than the patients with PD, and all NMS were more frequent in patients with PD except vomiting/ nausea and bowel incontinence. Interestingly, 12.7% of the controls reported unexplained pain. A previous Indian study showed a prevalence of 19.3% for chronic pain among adults. There may be several causes of chronic pain in the general population, including musculoskeletal, hypovitaminosis D, fibromyalgia, and psychogenic. However, it was not possible to identify these factors in the controls of the present study.
Similar to our study, where 90% of the patients had more than 5 NMS and majority had ≥ 4 NMS domains involved, others have also reported multiple NMS in their patients with PD, and the average number was estimated in a recent review to be 8.3 per patient. This possibly indicates concomitant dysfunction of multiple neurotransmitter pathways, both dopaminergic and nondopaminergic.
Comparison with other Indian studies
The most prevalent NMSs in our study (present in >60% of patients) were unexplained pain, anxiety, constipation, insomnia, and memory impairment; and the most commonly affected domains were miscellaneous, sleep/ fatigue, gastrointestinal tract, mood/ cognition, and attention/ memory (present in >70% of patients). Although previous Indian studies have produced some differing results, there seems to be a definite trend for some NMS having higher prevalence [Table 4].,,,,,,, Overall, the more common NMS were constipation, pain, urinary urgency, and nocturia. Other common NMS were fatigue, insomnia, memory impairment, anxiety, and lightheadedness. Similarly, data from Indian studies regarding involvement of NMS domains indicate a greater prevalence of sleep/ fatigue, mood/ cognition, urinary and miscellaneous. Involvement of the gastrointestinal tract and attention/ memory was also found to be common in some Indian studies. The least common NMSs in our study were bowel incontinence, nausea/ vomiting, double vision, and delusion; and the domains with the lowest prevalence were sexual function and perceptual/ hallucination. In general, other Indian studies have documented the following NMS being involved least frequently- sexual function, double vision, delusion, and hallucination. Bowel incontinence and leg swelling, were also less common.
Hence, our findings were commensurate with this general trend. However, there were some discrepancies. Bowel incontinence was present in nearly 25% of patients in an Indian study. Some of the studies found a lower prevalence of restless legs (< 20%),,, compared to ours (> 50%). Similarly, the prevalence of RBD was much lower in a study. Although urinary symptoms were quite frequent in our study (54%), it was still lower than some of the other Indian studies which showed >75% presence of such symptoms.,, There was a change in smell/ taste in nearly 50% of our patients, whereas the same was found in only 7.5% of patients in the study by Mridula et al. Interestingly, the same study showed high prevalence (> 60%) of several domains, but cognitive impairment/ apathy in only 32% patients (on medical management), compared to our study where attention/ memory was involved in nearly 75% patients. One possible explanation for this may be the correlation of hyposmia with cognitive impairment in PD as observed in recent studies. However, similar inference could not be drawn from another Indian study, which showed considerable memory impairment without significant change in smell/ taste. Hence, this association should be investigated in larger cohorts with detailed objective assessment of smell to arrive at a definite conclusion.
Comparison with studies outside the Indian subcontinent
NMSs in PD have been investigated in various populations across the globe. In Asian countries outside the Indian subcontinent (henceforth termed as Asian), several studies have been reported. Despite the differences in prevalence of NMS, overall, these studies show the frequent occurrence of nocturia, constipation, and memory impairment. Some studies reported depression, restless legs, vivid dreams, and orthostatic dizziness as well. The most commonly affected domains were sleep/ fatigue, attention/ memory, mood/ apathy, and also miscellaneous and urinary. The least common NMS was bowel incontinence, whereas other infrequent symptoms were delusion, double vision, and sexual dysfunction. In terms of domains, perceptual disturbance was by far the least frequent. Findings of our study were similar to quite a few of these observations. However, in our patients, unexplained pain was much higher and nocturia was relatively less common. Similar to the other Asian studies, the domains of sleep/ fatigue, mood/ cognition, and attention/ memory were common in our study too. However, miscellaneous was the most commonly affected domain in our study, possibly driven to some extent by the increased prevalence of pain which is included under this domain.
In the international multicenter study of NMSQuest comprising mainly Caucasian patients, the most frequent NMS were nocturia, urgency, and constipation, followed by depression, memory impairment, and insomnia (> 40%), whereas the least common NMSs were bowel incontinence, vomiting, and delusion. In the multicenter PRIAMO study from Italy, the most common NMSs were fatigue and anxiety (present in >50%), followed by leg pain, insomnia, and urgency/ nocturia, whereas the least prevalent was bowel incontinence. Data from different studies analyzing Western population showed certain differences. Although nocturia/ urgency was present in >60% of patients in one study, it was present in only approximately 35% in the other. In our study, prevalence of nocturia/ urgency (54%) was about mid-way between these two. Constipation was less frequent than our study., The other NMS clearly more common in our study than the Western population was unexplained pain. The high prevalence of pain in patients with PD might be linked to depression and anxiety. Motor features such as bradykinesia and rigidity might contribute as well. There might also be a role of co-existent conditions such as osteoporosis and vitamin D deficiency; however, it was not possible to establish the exact reason. Further studies evaluating the various aspects of pain in patients with PD in our population are required. In an American survey of NMS in PD, the highest reported symptoms (present in >60%) were sleep problems/ excessive tiredness, cognitive impairment, and anxiety. However, unlike our study, they reported much higher prevalence of hallucination (40%) and delusion (23%). We have represented graphically an overview of the most common NMS present consistently in the Asian and Western studies vis-à-vis our present study in [Figure 2].
|Figure 2: Comparative overview of the most common nonmotor symptoms of Parkinson’s disease in studies done outside India (relative to the present study)|
Click here to view
Relation of nonmotor symptoms with age and gender
Sexual dysfunction was higher in younger age. Similar observation was made in a survey that revealed a higher prevalence of sexual function, sleep, depression, and memory impairment in younger age group (< 45 years) compared to older patients (> 85 years). Interestingly, our YOPD patients had higher mood/ cognition problems. A study found greater forgetfulness, loss of interest, anxiety, and difficulty in sexual activities in late-onset PD (onset ≥ 55 years), whereas their YOPD (onset between 21 and 45 years) patients experienced more restless legs and sweating. In another study, sexual dysfunction was more common in early-onset PD (< 50 years) compared to late-onset PD (> 50 years); however, there was no difference in mood/apathy. The higher prevalence of mood disorders in young patients with PD might be due to an increased concern about the disease because they were usually the working member of their family. It might also be related to the disease itself with a possible genetic component; however, our study could not document genetics of the patients with PD.
Attention/ memory problems and unexplained pain were greater in female patients. The greater attention/ memory involvement in female patients contradicts previous reports which indicate a male predominance. One possible explanation for this may be linked with the disproportionate gender distribution in our study regarding the HY stages. Although, overall, we had male predominance, in the advanced HY stages 4 and 5, there was clear female majority, and these two stages also showed higher memory impairment. A study on gender-related differences of NMS showed mood/apathy, pain and miscellaneous domain, fatigue, constipation, and restless legs to be more common in female, and sexual dysfunction in male.
Relation of nonmotor symptoms with duration and stage of the disease
Our patients experienced more cardiovascular and perceptual disturbances as well as overall NMS burden as the duration of disease increased. Along with that, the attention/ memory domain was higher in the advanced stages of HY 4 and 5, although the total NMS burden did not show a statistically significant difference among the HY stages. In addition, more than 80% of patients experienced >5 NMS even in the early stages (HY 1 and 1.5) of the disease. This indicates the possibility of a greater impact of duration of disease on the NMS total burden than stage of the disease. However, our study population consisted of less than 10% of patients in the advanced HY stages 4 and 5, and hence, this aspect should be evaluated in larger cohorts with a greater number of advanced patients with PD. Nevertheless, previous studies documented greater NMS with longer disease duration and higher HY stage.,, Toyama et al. reported greater odds ratios in higher HY stages compared with lower stages for several NMS domains including attention/memory.
Impact on quality of life
NMSs were associated with worse QoL. The total NMSS score proved to be a significant predictor of QoL (PDQ-8-SI score). All the individual domains, except urinary and sexual function, were also linked with worse QoL. NMSs are recognized as an important contributor to QoL and this has been documented in various studies.,, Interestingly in our study, QoL correlated with NMS burden rather than HY stage or disease duration. This highlights the impact of NMS in patients with PD.
Limitations of the study
As all the patients were on one or more antiparkinsonian drugs, the comparison between drug naïve and those on medication could not be done. Moreover, in some cases, whether the NMS were attributable to antiparkinsonian drugs or the disease per se could not be differentiated. We do not have data of Levodopa equivalent daily dose (LEDD) of all our patients and could not correlate this with NMS. A larger cohort with long-term follow-up would have been helpful to better delineate the temporal profile of NMS in PD.
In conclusion, NMS was present in every patient and majority experienced multiple NMS. Our findings showed some dissimilarities from previously published studies, signifying possible ethnicity-related variations. Moreover, some of the NMS showed differences regarding age and gender of the patients as well as duration and stage of the disease. Importantly, the presence of NMS was significantly associated with poorer QoL.
We acknowledge Prof. Kallol Ray Chaudhuri for his kind help in reviewing the manuscript.
Sulagna Sahu: Research project: Organization,Execution; Manuscript preparation: Writing of the first draftAdreesh Mukherjee: Research project:Organization; Statistical analysis: Design, Execution; Manuscript preparation: Review and critiqueSamar Biswas: Research project: Organization; Statistical analysis: Review and critique; Manuscript preparation: Review and critiqueValentia Leta: Statistical analysis:Review and critique; Manuscript preparation: Review and critiqueKatarina Rukavina: Statistical analysis: Review and critique; Manuscript preparation: Review and critiqueShyamal Kumar Das: Research project: Conception; Statistical analysis: DesignAtanu Biswas: Research project: Conception; Statistical analysis: Execution,Review and critique; Manuscript preparation: Review and critique
Ethical compliance statement
The study has been approved by the institutional ethics committee and has been performed in accordance with the ethical standards of the Declaration of Helsinki. All subjects gave informed consent before their inclusion in the study.
Financial support and sponsorship
This study did not receive any financial grant from any organization.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]