Non-motor symptoms in an Indian cohort of Parkinson's disease patients and correlation of progression of non-motor symptoms with motor worsening
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.156276
Source of Support: None, Conflict of Interest: None
Aim: To document the frequency and prevalence of non-motor symptoms (NMS) in an Indian cohort of Parkinson's disease (PD) patients.
Keywords: Non-motor symptoms; Parkinson disease; UPDRS
Parkinson's disease (PD) is one of the commonest neurodegenerative motor disorders, affecting 1% of the population over the age of 50 years.
Non-motor symptoms (NMS) of PD are those manifestations that are not related to difficulties associated with movement. ,, Although PD is traditionally defined as a movement disorder, it is also associated with a wide range of behavioral/neuropsychiatric and physical NMS that can severely impact the quality of life. ,,, These can occur at any point in the disease from the very early stages, even before motor symptoms are recognized, to a very late stage of PD. ,,,,,, These probably result due to the involvement of the serotonergic and noradrenergic pathways impacting the quality of life and patient mortality. ,,,,,,,,, Numerous studies have now identified different NMS encompassing the cardiovascular, urogenital, autonomic, gastrointestinal, neuropsychiatric and cognitive domains that are frequent accompaniments of PD. ,,,,,,,,,,,,,,,,,
The fact that many of these symptoms are also seen in the elderly population has been addressed, and it has been proven that the NMS are statistically more commonly seen in the PD patients as compared with the age- and sex-matched elderly subjects. 
In the presence of effective symptomatic therapies for the motor symptoms of PD, the non-motor symptoms have become the major prognostic factors determining the overall disease burden and everyday function in PD. ,, Furthermore, there is evidence that many NMS antedate the onset of motor symptoms of PD by up to decades and may thus turn out to be the critical target for the early diagnosis and identification of populations at risk of developing this disease. ,
Various scales are available for the identification and monitoring of motor symptoms. However, for NMS, scales for individual symptoms have been used as there were no comprehensive tools available. This shortcoming has only recently been remedied by Chaudhari et al., who unveiled the Non-Motor Scale Quest (NMS Quest) and the Non-Motor Symptom scale (NMSS). ,,, These scales have been validated and used in various populations for recording, identifying and monitoring the treatment of NMS in PD. ,,,
Despite the importance of NMS in the patients suffering from PD, there is scant data on the various parameters of NMS in the Indian context, with there being just one other study of NMS using the NMSS as the tool in the Indian setting.  This study is an attempt to utilize the NMSS to document and profile NMS in Indian PD patients and to identify the differences amongst them.
This was a cross-sectional, single-center, open-label, one -point-in-time evaluation study conducted from 2009 to 2011.
Patients were enrolled from the movement disorder wing of the neurology outpatient department of a tertiary care hospital from 2010 to 2011. Patients satisfying the UK PD brain bank criteria for idiopathic PD were included after their clinical evaluation by a movement disorder specialist. The inclusion criteria included bradykinesia and at least one of the following: Muscular rigidity, 4-6 Hz resting tremor, postural instability not caused by a primary visual, vestibular, cerebellar or proprioceptive dysfunction following the exclusion of other causes of Parkinsonism More Details; as well as, three or more features that supported a diagnosis of PD including: a unilateral onset and the presence of a resting tremor, a progressive disorder, persistent asymmetry maximally affecting the side of onset, excellent (70-100%) response to levodopa, and the presence of severe levodopa-induced chorea.
The exclusion criteria included a history of repeated strokes with stepwise progression of features resembling that of Parkinson's disease; a history of repeated head injury; a history of definite encephalitis, oculogyric crisis, or of being given neuroleptic treatment at the onset of symptoms; having more than one affected relative; the presence of a sustained remission or of strictly unilateral features even after 3 years; the presence of supranuclear gaze palsies, cerebellar signs, early severe autonomic involvement, early severe dementia with disturbances of memory, language and praxis; the presence of Babinski's sign; the presence of a cerebral tumor or communicating hydrocephalus; a negative response to large doses of levodopa (if malabsorption is excluded); the exposure to 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP); and, patients who refused or were unable to give consent.
The controls were the relatives of the patients visiting the outpatient department. They were age and sex matched with the cases. Controls suffering from a chronic disorder that was causing any of the above mentioned symptoms were excluded.
Ethical approval was obtained from the Institutional Review Board of the hospital after submission of the study proposal and design.
The patients were initially evaluated in the general neurology department. Thereafter, they were examined and interviewed by a clinician from the movement disorder clinic. The demographic data, the clinical manifestations, Unified Parkinson's Disease Rating Scale III (UPDRS III) and NMSS (after explanation of the study aims and proper consent as per format) were recorded in each patient. The NMSS was translated in the local language whenever needed. Thirty-five controls were enrolled for validation of the NMSS from amongst the patients' attendants, who were age and sex matched and did not have PD based on their examination. The UPDRS was recorded for 45 patients.
The NMSS includes nine domains and a total of 32 questions. The NMSS not only assesses whether or not NMS are present but also rates their frequency (range of 0-4) and severity (range of 0-3). If the product of the frequency and severity is 1 or greater, then 1 point is assigned. The NMSS was specifically designed for the patients to help them in assessing their own symptoms; thus, it was not specifically constructed for the caregiver's assessment of their patients.
Using the NMSS form, the subsets were divided as follows: Questions 1-2 were grouped under the cardiovascular/falls symptom subset; questions 3-7 were grouped under the sleep/fatigue symptom subset; questions 8-14 were grouped under the mood symptom subset; questions 15-17 were grouped under the perceptual symptom subset; questions 18-20 were grouped under the cognition symptom subset; questions 21-23 were grouped under the gastrointestinal symptom subset; questions 24-26 were grouped under the urinary symptom subset; questions 27-28 were grouped under the sexual dysfunction symptom subset; and questions 29-32 were grouped under the miscellaneous symptom subset. Thus, the domains are the cardiovascular symptoms (two items), sleep/fatigue (four items), mood/cognition (six items), perceptual symptoms/hallucination (three items), attention/memory (three items), gastrointestinal symptoms (three items), urinary symptoms (three items), sexual functions (two items) and miscellaneous (four items).
The UPDRS III is a motor examination scale consisting of 14 items to assess the motor disability in PD patients.
The data was analyzed after the conclusion of the study. The NMSS is a non-parametric scale. The data did not fit a normal distribution; therefore, the non-parametric data was analyzed using non-parametric statistics. It was assessed for the following:
The study population included 81 patients with idiopathic Parkinson's disease, satisfying the UK PD Brain Bank criteria. Of these patients, 50 patients were male and 31 patients were female. The age ranged between 36 and 84 years among the male patients, and the mean age was 62.93 years, with a standard deviation (SD) of 10.932 years. Among the 31 female patients, the age ranged from 30 to 80 years, with a mean of 63.5 years and an SD of 9.723 years. One patient was less than 40 years old. The mean total NMSS score was 35.31 (SD: 21.853), with the maximum score being 99 and the minimum score being 5. Higher scores were noted in the mood/cognition, sleep/fatigue and urinary domains. The NMSS in male patients ranged from 5 to 94 points, with a mean of 34.96 points and SD of 21.3 points. For female patients the ranges extended from 5 to 99 points, with the mean being 35.87 and SD being 23.01 points.
All patients reported the presence of atleast a few NMS (with a minimum of two and a maximum of 20 symptoms being reported). Only nine patients reported the existence of five or less symptoms and 33 patients reported five to 10 symptoms. As many as 11 of the 81 patients reported between 16 and 20 symptoms [Chart 1].
The most common symptom reported in the study population was nocturia (74 patients, 91%), followed by constipation in 48 patients and fatigue in 41 patients. Males reported nocturia in 46 patients, urgency in 27 patients, nervousness in 26 patients, sadness in 24 patients and forgetting to do things in 23 patients; while females had nocturia in 28 patients, nervousness and fatigue in 20 patients, frequency of micturition in 19 patients and constipation in 18 patients [Table 1].
Descriptive data of NMS scores and complaints
Thirty-five control patients were enrolled to validate the NMSS. The analysis revealed that the highest reported complaints were in the urinary domain and a few complaints were in the gastrointestinal and sleep domains. One control subject reported cognition and memory-related complaints [Table 2].
Score distribution of the NMSS of controls
The reliability was computed with the Cronbach's alfa score, which revealed that the cardiovascular, mood/cognition and urinary domains showed a Cronbach's coefficient higher than the criterion, 0.70 (cardiovascular = 0.7367, mood/cognition = 0.7192, urinary = 0.7309). Three domains reached values near 0.70 (perceptual problems = 0.6784, attention/memory = 0.6141). The remainder of the results were under the limit; however, the total Cronbach's alfa value was 0.7570 thus signifying that the NMSS was valid for the Indian population as a tool for scoring NMS [Table 3].
Chronbach's alfa reliability scores (value of Cronbach's alfa >0.7 is considered significant)
NMS were universally reported, ranging from 2 to 20. Only nine patients reported 5 or less symptoms, 33 patients reported 5 to 10 symptoms and 11 of the 81 patients reported between 16 and 20 symptoms. The correlation between domains and between each item in each domain was found to be significant in the two-tailed analysis. The correlation between the total NMS score and each domain was found to be very significant, with the P value being less than 0.01 for most of the domains. The interdomain correlation between each item in each domain was found to be significant, with the P value being less than 0.01 in the two-tailed analysis. The correlation between the total NMS score and each domain was found to be very significant, with the P value being less than 0.01 for most of the domains except for sexual problems, where the P value was less than 0.05, and the miscellaneous domain where the P value was not significant (P = 0.097).
Correlation between the UPDRS and NMSS (UPDRS, n = 45; NMSS, n = 81)
The UPDRS III scores were available for 45 of the cases and the analysis revealed a definite correlation between the total NMSS score and UPDRS-III. The P value for the correlation was 0.001 [Table 4].
Many studies and clinical observations have suggested that NMS such as sleep disorders, cognitive problems and bowel and bladder disorders are frequent in PD. ,,,,,,,,, However, research has only recently focused on the effect of NMS on quality of life, institutionalization rates, health economics and mortality rates in PD. , The fact that NMS correlate with advancing age and disease severity suggests that these symptoms and their management will become increasingly important as the average life expectancy of the population increases. ,
The NMS complex is frequently unrecognized and/or neglected by healthcare professionals, as reported by Shulman and colleagues.  This may be because physicians or nurses concentrate more on the motor manifestations, there may be lack of awareness that NMS are related to PD, or, there is a possiblity that the symptoms may not be declared to the healthcare professionals. Another recent international survey showed that up to 65.2% of NMS in PD might remain undeclared to health care professionals because patients are either too embarrassed to reveal them or are unaware that the symptoms are linked to PD. 
This unawareness of NMS coupled with the absence of a single composite tool for the assessment and documentation of NMS has resulted in an incomplete and piecemeal approach to an effective therapy for PD, resulting in patient distress, rising economic costs and disease burden. ,, Neurologists commonly fail to identify the major NMS, such as depression, sleep disturbances, anxiety and fatigue, in more than half of their patients.  In a study using the NMS Questionnaire (NMSQ), PD patients reported nine to 12 different NMS in their clinic visits, many of which had not been discussed with the doctor before being flagged by the NMSQ. 
In addition, a clinician-administered scale, the NMS scale, that allows easy identification of the NMS by the physician has also been introduced.  This clinician-administered scale not only identifies the NMS more exhaustively but also rates them on scores for severity and frequency thus providing a composite and accurate scoring for them. The introduction of this tool has been validated by studies across populations. ,,,, NMS are almost universal in prevalence among PD patients.  NMS are also highly prevalent in PD patients across all stages and the duration of the disease. Compared with age-matched controls, some patients of PD reported more than 10 NMS symptoms each, respectively. 
This study also showed that the number of symptoms correlates with disease duration and severity. As compared with control patients, PD patients had significantly higher scores than controls for complaints of dribbling, impaired taste/smell, impaired swallowing, constipation, urinary urgency, weight loss, forgetfulness, sadness, impaired concentration, hallucinations, anxiety, sexual dysfunction, falling, daytime sleepiness, vivid dreams and sweating.
Another large, multicenter study comprising 545 patients using the NMSQ data in the UK, USA, Germany, Israel, Japan and Italy, reported that the mean total NMS (NMSQ-T) was 10.3 ± 5.4 (SD), with nocturia (61.9%) being reported as the most frequent symptom while incontinence of faeces was the least prevalent (8.21%).  Only eight (1.6%) patients in this study declared that they had no NMS at all. There were no significant differences in NMS scores by gender, with the exception that depression/anxiety, sexual dysfunction, and cardiovascular and miscellaneous NMS were more prevalent in women. 
The NMS scale (NMSS), that rates the symptoms in terms of frequency and severity, has also been validated in two major international studies in over 600 patients. The NMSS was introduced in a landmark study involving 242 patients across centers in the UK, Italy, Germany, USA and Japan by Chaudhuri et al.  The mean NMSS score reported was 56.5 ± 40.7. Maximum scores were recorded for the sleep, mood and perceptual disorders, attention/memory, and urinary and sexual function domains. Four domains (mood/cognition, attention/memory, and urinary and sexual function) showed Cronbach's α-coefficient higher than the criterion 0.70. The NMSS was not significantly associated with age; correlation with measures related to PD resulted in low to moderate affinity in this study.
The first report from India and among the few from Asia by Krishnan et al., which compared 174 patients and 128 normal controls to assess the prevalence of NMS and document its relation to disease progression measured by the Hoehn and Yahr scale, reported a higher frequency of NMS in all nine domains in patients with PD compared with controls.  All patients had at least one NMS. Women with PD had higher scores in the cardiovascular, sleep/fatigue, mood/cognition and urinary domains, whereas men had higher scores for the sexual domain. The total NMSS was significantly higher in women (men, 50.8 ± 37.5; women, 67.4 ± 39.0; P = 0.009) thus indicating that women with PD had more severe NMS and more involvement of the cardiovascular, sleep/fatigue, mood/cognition and urinary domains. Li et al. reported a cross-sectional study of 82 Chinese patients with PD and found that NMS were very common in Chinese patients with PD, with a prevalence of the whole spectrum of NMS being 100%, and the NMSS significantly correlated with disease duration.  Wang et al. have also reported similar findings from China in addition to validating the Chinese version of the NMSS.  A multicenter survey, the PRIAMO study, using a semistructured interview in 1072 consecutive patients with PD from Italian centers to assess the prevalence of NMS found that 98.6% of the patients with PD reported the presence of NMS.  The most common symptoms were fatigue (58%), anxiety (56%), leg pain (38%), insomnia (37%), urgency and nocturia (35%), drooling of saliva and difficulties in maintaining concentration (31%). The mean number of NMS per patient was 7.8 (range, 0-32).
The concept of a six-stage pathological process, beginning at "induction sites" with degeneration of the olfactory bulb and the anterior olfactory nucleus (clinically manifesting as olfactory dysfunction) at stage 1 was introduced by Braak and colleagues.  Stage 2 reflected progression of the pathological process to the lower brainstem involving the brainstem nuclei, that are key areas mediating NMS such as olfaction, sleep homeostasis, constipation and central autonomic control. Several of these symptoms have now been recognized as possible pre-motor features of PD. The classical clinical motor triad of PD is postulated to emerge at Braak stages 3 and 4, with the involvement of the substantia nigra and other deep nuclei of the mid- and forebrain. However, limitations of the Braak hypothesis include the fact that Braak based his classification on the Lewy body pathology and not on neuronal cell loss. Moreover, unlike motor symptoms, most NMS have a poor response to dopaminergic therapy, and other pathways, including the serotonergic and noradrenergic pathways, have been implicated in their pathogenesis. The precise pathology is obviously conjectural and postulated to involve neuronal loss in other areas in the central nervous system.
This study population comprised 50 males with a mean age of 62.9 years and 31 females with a mean age of 63.5 years. The mean NMS score was 35.31, with males scoring 34.96 and females scoring 35.8. The difference between the genders was not significant. These results were consistent with those of Song et al.  Chaudhari et al. reported a much higher score of 56.5, which is due to the more advanced disease stage of their study population as brought out by higher Hoehn and Yahr stages scores among the cases in that study.
The control population of 35 patients was included to primarily validate the NMSS in an Indian setting. The comparison revealed urinary complains to be the most common symptom, as expected in an elderly population. Previous studies by Krishnan et al. and Chaudhari et al. have reported similar pattern of complaints among a normal elderly population. , In fact, Krishnan et al. report a much higher prevalence of these symptoms in their control population. They confirmed that the prevalence of these complaints is predominated by the urinary, perceptual and memory domains in the normal elderly. However, the NMS were significantly more common in the PD patients.  The Cronbach's alfa scores were overall significant in the cardiovascular, mood/cognition and urinary domains and showed near-significant values in the other two domains. This finding is similar to that obtained in previous reports, stating that mood/cognition, attention/memory, urinary and sexual function having Cronbach's alfa scores >0.70.  This study found near-significant Cronbach's alfa scores in perceptual problems and in the attention/memory domains.
NMS have been universally reported by patients, and previous studies have reported 90% or more patients accepting their NMS irrespective of the disease stage. Most patients reported multiple NMS and a remarkable number of them reported between 16 and 20 complaints; this is in agreement with reports that most patients exhibit up to 10 symptoms. , All patients complained that NMS were distressing either in terms of frequency or severity. The most common symptoms were reported in urinary domain (nocturia), constipation and fatigue; the other Indian study has reported disturbances in sleep/fatigue in 89%, mood/cognition in 88% and miscellaneous NMS in 80% of these patients. These results are very similar to those obtained by the international, multicenter study by Chaudhari et al. ,,, This report also had controls reporting higher values in the same domains, although the values were non-significant.  Almost all previous studies indicate the predominance of symptoms in the sleep, mood, memory, urinary and sexual domains. ,, However, the studies do report minor differences in various domains as far as frequency is concerned; the PRIAMO study, for example, reports fatigue, anxiety and insomnia as the most common symptoms, followed by urinary complaints and difficulties in concentration.  This study also does not report olfaction as being as common as seen in some other reports. Chaudhuri et al. reported urinary complaints as being the most common, followed by constipation, depression and sleep complaints. Thus, there are minor differences among the various studies regarding the relative frequency of the symptoms. ,, Krishnan et al. report insomnia/fatigue as being the most common symptom followed by mood and cognitive disturbances as well as the miscellaneous, urinary and memory domains. This is in contrast to our findings of the predominance of the urinary domain, followed by the constipation, sleep and mood/cognition domains in that order. The profile, prevalence and pattern of the NMS appear to be congruous with the previous reports. ,,, The variation in some domains in our patients may be due to underreporting of symptoms in the sleep and olfactory domains. Olfaction and sexual dysfunction thus appear to be much less prevalent. The cultural and societal behavior is probably responsible for the underreporting of sexual dysfunction. The sample size and differences in sample characteristics may also be responsible for this difference. Thus grossly, the pattern of NMS in Indian subjects seems to be similar to that of the PD population surveyed elsewhere.
The UPDRS data was available for 45 cases as this evaluation was initiated later on in our study. The maximum UPDRS III score was 43, with a mean score of 22.8. The data analysis revealed that there was a definite and significant correlation using Spearman's coefficient analysis, between the UPDRS III and NMSS scores. Previous studies have correlated NMSS scores with the Hoehn and Yahr stages only and found a definite correlation between these scales.  This is an important finding of our study, signifying the increasing burden of NMS with disease advancement and severity, most comprehensively brought out by the UPDRS III scale that specifically assesses motor disability alone. This was also assessed in the study by Chaudhary et al. and was found to have a low to moderate association with the UPDRS III scale. They had, however, not analyzed individual symptoms. In our study, the subgroup analysis revealed that the NMS symptoms such as mood/cognition, memory, urinary complaints and miscellaneous symptoms worsened with worsening of the motor symptoms [Table 4]. Of these urinary complaints, loss of smell and changes in mood are seen early in the disease, and are persistent throughout the disease. Memory disturbances and cognition worsen with progression of motor disturbance, and probably contribute to motor disability as well. This study is the first attempt to correlate individual NMS symptoms with the UPDRS III scale.
The study reiterates the universal nature of NMS. The profile of NMS in India does not grossly differ from that of rest of the world. The NMSS is a validated and useful tool for identifying and following the progression of idiopathic PD. This study has also compared the NMSS scores with the UPDRS scores and has demonstrated a correlation between non-motor and motor symptoms in the progression of PD. The routine use of these symptom-evaluation tools in movement disorder clinics will go a long way in following the progress of NMS in PD patients.
There is a need for a large and well-designed prospective, adequately powered, community-based study on the prevalence, the symptom stratification based on NMSS and UPDRS III, the efficacy of treatment, and the progression over time, of NMS in PD. This will provide a basis for improving the quality of care of these patients by health professionals.
[Table 1], [Table 2], [Table 3], [Table 4]