Premotor Symptoms as Predictors of Outcome in Parkinsons Disease: A Case-Control Study

RESEARCH ARTICLE Premotor Symptoms as Predictors of Outcome in Parkinsons Disease: A CaseControl Study Yu-Hsuan Wu1, Wei-Ju Lee1,2, Yi-Huei Chen3, Ming-Hong Chang1,2☯*, Ching-Heng Lin3☯* 1 Section of Neurology, Taichung Veterans General Hospital, Taichung, Taiwan, 2 Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan, 3 Department of Medical education and Research, Taichung Veterans General Hospital, Taichung, Taiwan ☯ These authors contributed equally to this work. * (M-HC); (C-HL) a11111 Abstract Background OPEN ACCESS Citation: Wu Y-H, Lee W-J, Chen Y-H, Chang M-H, Lin C-H (2016) Premotor Symptoms as Predictors of Outcome in Parkinsons Disease: A Case-Control Study. PLoS ONE 11(8): e0161271. doi:10.1371/ journal.pone.0161271 Editor: Mathias Toft, Oslo Universitetssykehus, NORWAY Received: June 20, 2016 Accepted: August 2, 2016 Published: August 17, 2016 Copyright: © 2016 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: Full financial support for all authors came from the Taichung Veterans General Hospital (TCVGH-1053402C and TCVGH-1053404D). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. To evaluate the association between the premotor symptoms and the prognosis of PD. Methods A total of 1213 patients who were diagnosed of PD from January 2001 to December 2008 were selected from the Taiwan’s National Health Insurance Research Database. Patients were traced back to determine the presence of premotor symptoms, including rapid eye movement sleep behavior disorder (RBD), depression, and constipation. Cox’s regression analysis was used to detect the risks between the occurrence of premotor symptoms and the outcome (including death, psychosis, accidental injury, dementia and aspiration pneumonia). In addition, the association between premotor symptoms and levodopa equivalent dosage (LED) was examined. Results Higher occurrence of death, dementia and aspiration pneumonia were identified in PD patients with premotor symptoms than without premotor symptoms (HR 1
69, 95% CI 1
34– 2
14, p <0
001 for death; HR 1
63, 95% CI 1
20–2
22, p = 0
002 for dementia; HR 2
45, 95% CI 1
42–4
21, p = 0
001 for aspiration pneumonia). In a comorbidities-stratified analysis, PD patients with premotor symptoms showed significantly high risks of mortality and morbidity (dementia and aspiration pneumonia), especially in the absence of comorbidities. Independent predictors of mortality in PD were found to be higher age, male sex, constipation, RBD, RBD with constipation and depression, and diabetes. Furthermore, no significant differences of LED and subsequent accidental injury were noted between PD patient with or without premotor symptoms. PLOS ONE | DOI:10.1371/journal.pone.0161271 August 17, 2016 1 / 10 Premotor Symptoms as Predictors of Outcome in PD Conclusion Premotor symptoms seem to be not merely risk factors, but also prognostic factors of PD. Introduction Survival in patients with Parkinson’s disease (PD) is reduced compared with the general population. Recent reports have revealed hazard ratios (HR) of mortality in PD patients ranging from 1
52 in a community-based Norwegian study to 3
38 in a door-to-door survey in Taiwan [1]. According to the University of Virginia Movement Disorders Database where the cause of death by clinical impression was determined for 197 of the 211 patients, about half of the patients died of PD-related causes, and the remainder of cardiovascular disease (12
3%), cancer (8
5%) and stroke (6
6%). Full autopsies were performed in ten PD patients. The majority of patients died of bronchopneumonia (five of ten patients) with one patient dying of complications related to a hip fracture. This indicated that 60% underwent full autopsy died of PDrelated causes [2]. Higher age, male sex, severity of motor symptoms and gait dysfunction were found to be associated with increased mortality in patients with PD [3]. Non-motor symptoms are also increasing recognized as strong contributing factors of morbidity [4]. Dementia, the presence of psychotic symptoms and depression appear to be independent predictors of mortality in PD [3]. A growing number of articles have reported that certain non-motor symptoms might precede the development of motor symptoms in PD by several years. These premotor symptoms include rapid eye movement sleep behavior disorder (RBD), depression, and constipation. Although the role of premotor symptoms in predicting the subsequent development of PD is well understood [5], reports of the influence on disease progression and prognosis in PD of premotor symptoms are scarce. Our study aimed to indentify whether the premotor symptoms can predict the prognosis in PD patients and also to investigate which of the premotor symptoms is the best predictor of subsequent prognosis in patients with PD. Methods Study design and data sources Taiwan’s National Health Research Insurance (NHRI) program is a health insurance program that was instituted in 1995, and by 2010 it covered nearly 98% of all residents of Taiwan [6]. The National Health Insurance Research Database (NHIRD) contains comprehensive information regarding clinical visits and is managed by the Bureau of National Health Insurance. This study used as the data source the Longitudinal Health Insurance Database 2005, which consists of all comprehensive medical care coverage between 1996 and 2011 of a randomly selected group of beneficiaries (n = one million) in the 2005 Registry of Beneficiaries. The distribution of study subjects were representative of the national population in Taiwan. Standard protocol approvals, registrations and patients consents The release of data was approved by the ethics committee of NHRI and the study protocol complied with the Declaration of Helsinki. Written consent from participants was not obtained because the NHI dataset were analyzed anonymously. PLOS ONE | DOI:10.1371/journal.pone.0161271 August 17, 2016 2 / 10 Premotor Symptoms as Predictors of Outcome in PD Study population Subjects with newly diagnosed PD from January 2001 to December 2008 were selected as the study group. The definition of PD was based on the International Classification of Diseases, 9th revision and clinical modification (ICD-9-CM) code was 332
0 [7]. A previous validation study using a hospital administrative database reported a positive predictive value of more than 90% by using this definition of PD [8]. To further improve diagnostic validity, only subjects whose diagnostic co (...truncated)