ORIGINAL ARTICLE - NEUROLOGY Non motor symptoms of Parkinson s Diseaseits prevalence across the various stages of Parkinson s disease and its correlation with the severity and duration of the disease Chandrasekaran P (1), Mugundhan K (2) Abstract Background: The non classical features of Parkinson s disease like nonmotor symptoms are often poorly recognized but dominate the clinical picture of advanced Parkinson s disease and contribute to severe disability, impaired quality of life, and shortened life expectancy. Aim: To study the prevalence of nonmotor features across the various stages of Parkinson s disease and to correlate it with the severity and duration of the disease. Methods: 50 Patients with Idiopathic Parkinson s disease who attended the Neurology outpatient clinic and was inpatients at Neuromedicine ward at GOVT RAJAJI HOSPITAL, MADURAI were enrolled and underwent a detailed and complete neurological examination. The motor symptoms were assessed through the Unified Parkinson s Disease Rating Scale (UPDRS) and the disease staged according to the Hoehn and Yahr staging from stage 0 to stage 5.The nonmotor features were assessed through the Nonmotor Symptoms Questionnaire (NMS QUEST) which contains 30 items. CT AND MRI brain was done to exclude Parkinson plus syndrome, vascular Parkinsonism and secondary Parkinsonism. Results: Non motor symptoms were prevalent across all stage of Parkinson s disease. The most prevalent ones were autonomic which includes constipation, urgency, orthostatic hypotension, erectile dysfunction, and drooling and the most prevalent neurobehavioral abnormalities were depression, fatigue, recent memory loss, and anxiety. The number of NMS increased as the disease severity progressed. The number of NMS in stages 1 and 1.5 were the least. It increased through stages 2 and 2.5 and was highest reported in stages 3 and 4. Conclusions: The early recognition of these non motor symptoms may well perhaps lead to an earlier diagnosis of Parkinson s disease and treatment of NMS may go long way in improving the quality of PD patients as well as the economic burden on the care givers. Key words: Non motor symptoms, Parkinson s disease, Nonmotor symptom questionnaire. Introduction The clinical diagnosis of Parkinson s disease rests on the identification of the characteristics related to dopamine deficiency that are a consequence of degeneration of the substantia nigra pars compacta.1 However, non dopaminergic and nonmotor symptoms are sometimes present before diagnosis and almost inevitably emerge with disease progression. Indeed, non motor symptoms dominate the clinical picture of advanced Parkinson s disease and contribute to severe disability, impaired quality of life, and shortened life expectancy.2-4 By contrast with dopaminergic symptoms of the disease, for which treatment is available, nonmotor symptoms are often poorly recognised and inadequately treated.3 However, attention is now being focused on the recognition and quantization of non motor symptoms which will form the basis of improved treatments. The nonmotor symptoms include neuro behavioural and cognitive symptoms, sleep disorders, autonomic symptoms, sensory symptoms and miscellaneous symptoms like diplopia, fatigue and seborrhoea, hair loss, leg edema.5 The nonmotor symptoms questionnaire (NMS Questionnaire) and the nonmotor symptom scale (NMSS) were developed to assess the frequency and severity of nonmotor symptoms in Parkinson s patients across all stages.3 The nonmotor symptoms Questionnaire was validated in March 2007 by the Movement Disorder Society. It covers 9 domains and includes 30 items, including sleep / fatigue, cardiovascular, mood/cognition, perceptual problems, attention / memory, gastrointestinal, urinary, sexual functions and miscellaneous. The nonmotor symptoms Questionnaire does not provide an overall score or disability and is not a graded rating instrument. It is a screening tool designed to draw attention to the presence of nonmotor symptoms and to initiate further investigation. Recent studies using the Nonmotor Symptoms Quest for Parkinson s patients have highlighted the significant occurrence of a range of different nonmotor symptoms in PD patients. Further studies validating the nonmotor symptom scale (NMSS) also indicated a strong relationship between the burden of nonmotor symptoms in Parkinson s disease and health related quality of life (QOL). The development of tools such as the Nonmotor Symptoms Please Scan this QR Code to View this Article Online Article ID: 2017:04:03:03 Corresponding Author: Mugundhan K e-mail : mugundhan69@gmail.com 13 1, Department of Neurology,Govt. Mohan Kumaramangalam Medical College Hospital, Salem, Affiliated to Tamilnadu Dr.MGR Medical University 2,, Department of Neurology,Govt. Stanley Medical College Hospital, Salem, Affiliated to Tamilnadu Dr.MGR Medical University
14 Quest and Nonmotor Symptoms Scale alongside the re vamped Unified Parkinson s Disease Rating Scale which includes a specific nonmotor domain will help define research and therapy to improve the recognition and management of nonmotor symptoms of Parkinson s disease.6 Some nonmotor symptoms, including depression, constipation, pain, genitourinary problems, and sleep disorders, can be improved with available treatments. Other non motor symptoms can be more refractory and need the introduction of novel non dopaminergic drugs. Inevitably, the development of treatments that can slow or prevent the progression of Parkinson s disease and its multicentric neurodegeneration provides the best hope of curing nonmotor symptoms. Methodology This is a cross sectional descriptive study involving 50 patients with Idiopathic Parkinson s disease who attended the Neurology outpatient clinic and who were inpatients at Neuro medicine ward at GOVT RAJAJI HOSPITAL, MAD- URAI were studied. A detailed and complete neurological examination was done. The motor symptoms were assessed through the Unified Parkinson s Disease Rating Scale (UP- DRS) and the disease staged according to the Hoehn and Yahr staging from stage 0 to stage 5.7 The nonmotor features were assessed through the Nonmotor Symptoms Questionnaire (NMS QUEST) which contains 30 items. This included cognitive dysfunction, depression, sleep disorders, fatigue, sensory and autonomic abnormalities. CT AND MRI brain was done to exclude Parkinson plus syndrome, vascular Parkinsonism and secondary Parkinsonism. The prevalence of these Non motor symptoms across the various stages of the disease was studied and its correlation with the disease severity and duration assessed. Adult patients with idiopathic Parkinson s disease were included. Parkinson s Plus Syndromes like Progressive Supranuclear Palsy (PSP), Multi System Atrophy (MSA), and Corticobasal Degeneration (CBD), diffuse lewy body dementia (DLBD), patients with Vascular Parkinsonism, secondary Parkinsonism, Young onset Parkinson s disease were excluded. Results This study included 50 patients with Idiopathic Parkinson s Disease and the baseline characteristics of these patients are shown in table 1-4 and the analysis of nonmotor symptoms of Parkinson s disease is shown in table 5-8. Table.1 - Demographic profile of the patients Characteristic sex Male 33 66 Female 17 34 Age distribution in years 40 50 9 18 51 60 19 38 61 70 21 42 71 80 1 2 Duration of disease < 5 years 31 62 5 10 years 16 32 > 10 years 3 6 Table.2 - Drug history of the patients Drug prescribed Dopamine precursors 50 100 Anticholinergics 50 100 Dopamine agonist 4 8 COMT inhibitors 1 2 Antidepressants 6 12 Anxiolytics 2 4 Laxatives 4 8 MAO-B inhibitors 1 2 Table 3 - Family History And Co-Morbidities Of The Patients Family history Positive PD 3 6 Negative PD 47 94 Co-morbidities Smoker 4 8 Alcoholic 6 12 Hypertension 4 8 Diabetes 4 8 IHD 1 2 No Comorbid conditions 31 62 Discussion: The present study when compared to Chaudhari et al showed similarly high prevalence of the following non motor symptoms namely depression, constipation, sleep,
taste and smell disturbances. The next prevalent NMS were sexual disturbances, urinary urgency, memory loss, cramps in legs, anxiety and fatigue which were less when compared to Chaudhari et al. 3 Hallucinations, weight loss and dreams were least prevalent when compared to Chaudhari et al. The most prevalent NMS were autonomic symptoms namely constipation, urgency, orthostatic hypotension, sexual dysfunction, swallowing difficulties, sweating disturbances and sialorrhea. Table 4: Hoehn and Yahr Staging of the patients Hoehn and Yahr Staging Stage 1 4 8 Stage 1.5 5 10 Stage 2 9 18 Stage 2.5 15 30 Stage 3 16 32 Stage 4 1 2 The analysis of nonmotor symptoms of Parkinson s disease Autonomic features Table 5: Enumeration of autonomic features of the patients Orthostatic hypotension 8 16 Sweating dysfunction Hypohydrosis 3 6 Hyperhydrosis 3 6 Urologic symptoms Urgency 10 20 Precipitancy 1 2 Hesitancy 2 4 Sexual impotence Erectile dysfunction 8 16 Premature ejaculation 3 6 GIT symptoms Sialorrhea 5 10 Decreased salivation 2 4 Reflex esophagitis 7 14 Constipation 16 32 Weight loss 1 2 Dermatological features Seborrhea 1 2 Hair loss 1 2 Table 6: Enumeration of Neurobehavioral and Cognitive Abnormalities of the patients Neurobehavioral and Cognitive Abnormalities Anxiety 5 10 Fatigue 7 14 Akathisia 2 4 Depression 19 38 Memory loss 8 16 Auditory hallucinations 3 6 Excessive eating 3 6 Euphoria 2 4 Hyper sexuality 1 2 Aggression 2 4 Phobias 1 2 Addictive personal 2 4 Table 7: Enumeration of Sleep disorders of the patients Sleep disorders Excessive day drowsiness 6 12 REM sleep behavior 12 24 Cramps in the legs 10 20 Vivid dreams 3 6 Table 8: Enumeration of Sensory abnormalities of the Sensory abnormalities patients Parathesia 5 10 Anosmia 5 10 Hyposmia 8 16 Others 4 8 Autonomic symptoms study in Parkinson s disease by D.Verbaan et.al, studied 420 patients with Parkinson s disease found gastro intestinal, urinary symptoms are common with increasing age, disease severity and with higher doses of dopaminergic medications.8 The present study when compared to D.Verbaan et al study showed constipation, swallowing difficulties, other gastro intestinal symptoms were common in stage 2.5, stage 3 and in patients aged more than 60 years. Urinary symptoms like urgency were common in stages 2, 2.5, 3and in patients aged more than 50 years. Next common NMS in the present study were Neuropsychiatric symptoms like depression, memory disturbances, anxiety and hallucinations followed by sleep disturbances which include insomnia, sleepiness, cramps in legs, REM sleep behaviour disorder and dreams. Fatigue and weight loss, seborrhoea, hair loss, addictive behaviour, aggression, 15
16 decreased sweating were reported in a small of patients. Lisa M.Shulman, MD, et al, studied co-morbidity of NMS and their relation to Parkinson s disease severity in 118 patients. Depression, anxiety, fatigue, sleep disturbances, sensory symptoms. Increased co-morbidity of the five or more non motor symptoms was associated with greater PD severity.9 The present study showed depression, sleep disturbances, sensory disturbances which are almost same with M.Shulman et al study. Anxiety and fatigue were less compared with above study. And more NMS symptoms occurred in HOEHN YAHR stage 2.5,3 and 4. The number of NMS ranged between 3 to 4 in stage 1, 4to 9 in stage 1.5, 3 to 13 in stage 2, 7 to 21 in stage 2.5, and finally 7 to 23 in stage 3 and 4. In the Indian context, Arindam Ghosh et al, have studied 34 patients of idiopathic PD. 10 Depression(58%), sleep disturbances such as excessive day time somnolence, insomnia (44.1%), autonomic symptoms such as constipation(76.4%), urgency(67.6%), sweating(47%), sexual dysfunction(64.7%), drooling(61.8%) were the NMS noted. NMS add to the morbidity of PD, and may even precede the onset of motor symptoms. Early identification and treatment is imperative to improve quality of life in such patients. The present study compared with above study following NMS like depression, constipation, urgency, sleep disturbances, sexual disturbances were less prevalent. The NIMS study had NMS scores between 6 to 20. The most common symptoms identified were dribbling of saliva, swallowing difficulty, urinary urgency, sexual dysfunction, unexplained pains, anxiety, dreams, insomnia, sweating disturbances, memory disturbances and falls. Alteration in taste and smell, bowel and urinary incontinence, weight loss and hallucinations were seen in fewer patients. In another study carried out at SCIMT, Thiruvananthapuram, NMS was assessed by the NMS Scale (9 domains) in 100 consecutive PD patients.11 The Mood / cognition domain was most frequently involved (84.2%), while the cardiovascular domain was the least affected (22.4%). Four of the domains namely, cardiovascular, perceptual problems- hallucinations, gastrointestinal and urinary showed significant correlation with the duration of the disease and severity of PD. There was a significant correlation between the overall severity of NMS and duration of disease and severity of PD. And NMS in PD differ from those in aging in frequency, severity, sex predilection, and domain involvement. As compared to above study the present study showed cognitive and behavioural, GIT domains were more frequently involved than cardiovascular, sensory, urinary domains and there were significant correlation between duration of disease and severity of NMS in PD patients. Manmohan Mehindiratta et al12 concluded that the NMS are universal features of idiopathic PD. They add significantly to the overall disability caused by PD and critical determinants of health related quality of life of affected patients. There was evidence that many NMS may antedate the onset of motor symptoms of PD by years or even decades. Early recognition and treatment of NMS may go long way in improving the quality of life of PD patients as well as the economic burden of carers. Deepthi Varma et al, AIMS. Delhi showed that patients with REM sleep behaviour disorder had significantly higher prevalence of insomnia, nocturnal awakening, early morning awakening and snoring.13 Most clinical events confined to limb or vocalisation. REM sleep behaviour disorder may proceed or follow PD onset.rem sleep behaviour has higher occurrence of hallucination and other nocturnal problems. The present study compared with above study, REM sleep behaviour disorder had a higher prevalence(20%), when compared with other sleep related problems. D. Verbaan et al has characterised these non motor domains in patients of the Profiling Parkinson s Disease (PROPARK) cohort and describes their relation with other domains of the disease as well as their impact on disability and quality of life. Of the domains evaluated olfaction is the only domain that seemed unrelated to any of the other impairment domains. All other nonmotor symptoms were related to symptoms of other domains. The strongest relation was found between night time sleep problems and depressive symptoms and between psychotic and autonomic symptoms. As compared with previous study, the present study showed high prevalence of sleep problems and depression and strong correlation with autonomic symptoms like urgency. The relation found between the different impairment domains may emerge through different causes. First two domains may be related because of a shared underlying mechanism that is inherent to the disease or may be induced by medication or by a combination of both. Second a relation between impairment domains may emerge because different brain regions are simultaneously affected by the disease process. The pathological staging system of Braak, in which the upper brainstem, midbrain and limbic system become involved as the disease progresses, may explain the co-occurrence of features from two different domains. Of the nonmotor domains in PD depressive symptoms and autonomic dysfunction were the most important contributors to health
related quality of life. Our study has also demonstrated relation between insomnia, depression and autonomic symptoms. Conclusion Non motor symptoms were prevalent across all stage of Parkinson s disease and the most prevalent were autonomic disturbances which included constipation, urgency, orthostatic hypotension, erectile dysfunction, and drooling. The most prevalent neurobehavioral abnormalities were depression, fatigue, recent memory loss, and anxiety. The number of NMS increased as the disease severity progressed and the number of NMS in stages 1 and 1.5 were the least. It increased through stages 2 and 2.5 and was highest reported in stages 3 and 4.The early recognition of these symptoms may well perhaps lead to an earlier diagnosis and treatment of NMS may go long way in improving the quality of PD patients as well as the economic burden on the care givers. bout AM, Hilten JJ van. Patient-reported autonomic symptoms in Parkinson disease. Neurology. 2007 Jul 24;69(4):333 41. 9. Shulman LM, Taback RL, Bean J, Weiner WJ. Comorbidity of the nonmotor symptoms of Parkinson s disease. Mov Disord. 2001 May 1;16(3):507 10. 10. Manmohan Mehndiratta, Rohit K Garg, Sanjay Pandey. Nonmotor Symptom Complex of Parkinson s Disease An Under-recognized Entity. JAPI-VOL-59,2010 11. Krishnan S, Sarma G, Sarma S, Kishore A. Do nonmotor symptoms in Parkinson s disease differ from normal aging? Mov Disord Off J Mov Disord Soc. 2011 Sep;26(11):2110 3. 12. Arindam Ghosh, Bhattacharya AK, Dutta A, Sengupta SB, Kumar T. Non-Motor manifestations of Parkinson s Disease- A Hospital based study. JAPI,december 2011 13. Vibha D, Shukla G, Goyal V, Singh S, Srivastava AK, Behari M. RBD in Parkinson s disease: a clinical case control study from North India. Clin Neurol Neurosurg. 2011 Jul;113(6):472 6. References 1. Ehringer H, Hornykiewicz O. Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system. Parkinsonism Relat Disord. 1998 Aug;4(2):53 7. 2. Schrag A, Jahanshahi M, Quinn N. What contributes to quality of life in patients with Parkinson s disease? J Neurol Neurosurg Psychiatry. 2000 Sep;69(3):308 12. 3. Chaudhuri KR, Healy DG, Schapira AHV, National Institute for Clinical Excellence. Non-motor symptoms of Parkinson s disease: diagnosis and management. Lancet Neurol. 2006 Mar;5(3):235 45. 4. Aarsland D, Larsen JP, Tandberg E, Laake K. Predictors of nursing home placement in Parkinson s disease: a population-based, prospective study. J Am Geriatr Soc. 2000 Aug;48(8):938 42. 5. Poewe W. Non-motor symptoms in Parkinson s disease. Eur J Neurol. 2008 Apr 1;15:14 20. 6. Ramaker C, Marinus J, Stiggelbout AM, van Hilten BJ. Systematic evaluation of rating scales for impairment and disability in Parkinson s disease. Mov Disord. 2002 Sep 1;17(5):867 76. 7. Goetz CG, Poewe W, Rascol O, Sampaio C, Stebbins GT, Counsell C, et al. Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord Off J Mov Disord Soc. 2004 Sep;19(9):1020 8. 8. Verbaan D, Marinus J, Visser M, Rooden SM van, Stiggel- 17