Prediagnostic presentations of Parkinson's disease in primary care: a case-control study

Abstract

Background: Parkinson’s disease (PD) has an insidious onset and is diagnosed when typical motor features occur. A number of motor and non-motor features may occur during a “pre-diagnostic” phase, reflecting the early disease process. Previously there has been no comprehensive analysis in the general population of the relative magnitude and timing of their association with PD diagnosis. Aim: To assess the association of first presentation of several pre-diagnostic features in primary care with a subsequent diagnosis of PD, and to chart the timeline of these first presentations before diagnosis of PD. Methods: 8,166 individuals with a first diagnosis of PD and 46,755 individuals without PD were identified from 1st January 1996 to 31st December 2012 from The Health Improvement Network, United Kingdom primary care database. Codes were extracted for a wide range of possible pre-diagnostic or early symptoms comprising motor features (tremor, rigidity, balance impairment, neck pain and shoulder pain), autonomic features (constipation, hypotension, dizziness, erectile dysfunction, urinary dysfunction), mental disturbances (memory problems, depression, anxiety) and additional features (fatigue, insomnia) in the years prior to diagnosis. Incidence rates for symptoms recorded in more than 1% of cases per 1000 person years and incidence risk ratio (RR) were calculated and compared for individuals with and without PD at two, five and ten years before diagnosis. Findings: At two years before PD diagnosis the incidence of all examined pre-diagnostic features except neck pain was higher in patients (n=7,232) than in controls (n=40,541). At five years before diagnosis, patients with PD (n=4,769) had higher incidence rates of tremor (RR 13.70 (95%CI 7.82-24.31), balance impairment (RR, 2.19 (95%CI 1.09-4.16), depression (RR 1.76 (95%CI 1.41-2.17), anxiety (RR 1.41 (95%CI 1.09-1.79), constipation (RR 2.24 (95%CI 2.04-2.46), postural hypotension (RR 3.23 (95%CI 1.85-5.52), dizziness (RR 1.99 (95%CI 1.67-2.37), erectile dysfunction (RR 1.30 (95%CI 1.11-1.51), fatigue (RR 1.56 (95%CI 1.27-1.91), and urinary dysfunction (RR 1.96 (95%CI 1.34-2.80) than controls (n=25,544). At ten years before diagnosis of PD the incidence of constipation (RR 2.01 (95%CI 1.62-2.49) and tremor (RR 7.59 (95%CI 1.1-44.8) was already higher in those with later diagnosis with PD (n=1,680) than in controls (n=8,305). Interpretation: This study for the first time provides evidence for a range of pre-diagnostic features that can be detected several years before diagnosis of PD in primary care, estimating the comparative magnitude of risk for each and where they fit in the prodromal timeline. These data on the pre-diagnostic symptoms of PD can be incorporated into ongoing efforts to identify individuals at the earliest stages of the disease in future trials and help understand progression in the earliest phase of PD