Prevalence and incidence of Parkinson’s disease and drug-induced parkinsonism in Korea

This study used the Korean Health Insurance Review and Assessment (HIRA) Service database from 2011 to 2015, which is the data of the universal health insurance system in South Korea that covers the entire population [4]. If patients are diagnosed with PD or DIP, all of these patients are included in this database. This database contains patients’ demographics and the medical and pharmacy claims of approximately 50 million Koreans [4]. Diagnoses in this database were coded according to the Korean Standard Classification of Diseases (KCD), which is based on the International Classification of Diseases 10th Revision (ICD-10) [4]. HIRA provided the data after de-identification.

Patients with PD from 2012 to 2015 were identified if they met all of the following criteria: (1) at least one claim with all of the available diagnosis codes (i.e., primary and all sub-diagnosis codes) of PD (ICD-10 code: G20); and (2) at least 60 days of supply of antiparkinsonian drugs prescribed by neurologists. The definition of PD was based on the expert opinions of Korean neurologists and previous Korean research published in 2007 [5].

Among all antiparkinsonian drugs [6], only antiparkinsonian drugs that are specifically used for the treatment of PD were included, based on the expert opinions of Korean neurologist. These include entacapone, levodopa combinations, pergolide, pramipexole, rasagiline, ropinirole, and selegiline (Additional file 1 Table S1). Other antiparkinsonian drugs, which were available in Korea during the analysis period, such as amantadine, apomorphine, benzatropine, biperiden, bromocriptine, cabergoline, dihydroergocryptine, orphenadrine, piribedil, procyclidine, rotigotine, and trihexyphenidyl, were excluded from analysis as these drugs can be used for indications other than PD.

Patients with DIP from 2012 to 2015 were identified if they met all of the following criteria: (1) at least one prescription for a drug that is known to be frequently related with DIP (i.e., offending drug); (2) the date of earliest claim with primary or secondary diagnosis code of DIP (ICD-10 code: G21.1, G25.1) occurred during the prescription period of the offending drug. Offending drugs include antiemetics (levosulpiride and metoclopramide), atypical antipsychotics (risperidone, olanzapine, and aripiprazole), typical antipsychotics (haloperidol, perphenazine, and chlorpromazine), and calcium channel blockers (flunarizine). The definition of DIP and the drugs that are known to be frequently related with DIP were based on the expert opinions of Korean neurologists and the published literature [2, 7].

A patient with PD or DIP was considered to be incident if it was preceded by a 12-month disease-free period; otherwise, it was considered to be prevalent.

We estimated prevalences in a retrospective cross-sectional study design, whereas incidences were estimated based on the retrospective cohort study design. To estimate prevalences, we counted the number of patients with disease within a certain time frame in a cross-sectional way instead of following up patients. On the contrary, to estimate incidences, new cases have to be identified, thus we looked back a certain period of time to examine whether these patients are newly diagnosed without prior history. Prevalence was calculated as the number of cases of the disease divided by all population and expressed as number per 100,000 persons. Incidence density was calculated as the number of new cases of the disease divided by the person-year and expressed as number per 100,000 person-years. Age- and sex-specific annual prevalence and incidence density of PD and DIP in each of the 4 years (from 2012 to 2015) were calculated using denominators derived from mid-year Korean population of the respective stratum [8]. Because, as mentioned above, HIRA database covers the entire Korean population, numerator of prevalence and incidence were also derived from entire Korean population. In addition, we calculated the average prevalence and incidence over 2012–2015. For international comparison, age-standardized rates were calculated using direct standardization with age distribution of the US 2000 and WHO 2000–2025 population as reference populations [9, 10]. The female-to-male ratio for PD and DIP was also calculated. The differences in the prevalence and incidence density of PD and DIP between sexes were analyzed using the chi-square test [11]. To evaluate the significance of changes in the prevalence or incidence of PD and DIP over time, Poisson regression adjusted by sex was used [12] and a test for trend (i.e., the P-value for whether the coefficient for calendar year was significantly different from 0) was performed. All analyses were performed using SAS version 9.4 (SAS Inc., Cary, NC, USA). A P-value of less than 0.05 was considered to be statistically significant.

First, to evaluate whether the prevalence and incidence of PD were influenced by the definition of PD, we assessed the prevalence and incidence of PD by restricting patients who met all of the following criteria to exclude patients with multiple system atrophy, DIP, or progressive supranuclear palsy: (1) had a primary diagnosis of PD without any secondary diagnosis of cerebellar ataxia (ICD-10 code: G111, G112, G113, G119, G312, R270), DIP (ICD-10 code: G211, G251), and Steele-Richardson-Olszewski syndrome (ICD-10 code: G231); and (2) received at least 60 days of supply of antiparkinsonian drugs at the Department of Neurology. This definition was based on the expert opinions of Korean neurologists.

Second, to assess whether patterns of prevalence or incidence of DIP changed after excluding antipsychotics, we assessed the prevalence and incidence of DIP by not including antipsychotics in the analysis. Antipsychotics were reported as the major causes of DIP in published literature [3].

The average prevalence of PD between 2012 and 2015 was 171.01 per 100,000 persons. The average age-standardized prevalence of PD according to the WHO 2000–2025 and US 2000 standard population between 2012 and 2015 was 114.13 and 176.21 per 100,000 persons, respectively. In contrast, the average prevalence of DIP between 2012 and 2015 was 9.78 per 100,000 persons and the average age-standardized prevalence of DIP according to the WHO 2000–2025 and US 2000 standard population between 2012 and 2015 was 7.99 and 8.95 per 100,000 persons, respectively (Table 1).

A higher average prevalence of PD between 2012 and 2015 was observed in the older age groups and the peak prevalence was observed in the over-80 age group, with a higher prevalence in males. In contrast, the average prevalence of DIP between 2012 and 2015 showed a bimodal distribution in the age groups of 45–49 years and 75–79 years, with a higher prevalence in females (Fig. 1).

The average female-to-male ratio of prevalence of PD between 2012 and 2015 was higher than 1.0 in the age group of 60–79 years, while the average female-to-male ratio of prevalence of DIP between 2012 and 2015 was higher than 1.0 in the age group of 50–79 years and the values of female-to-male ratios were higher than those of PD (Table 1; Fig. 2).

The prevalence of PD significantly increased from 156.90 to 181.33 per 100,000 persons from 2012 to 2015 (p < 0.0001; Additional file 1 Table S2). The prevalence of DIP also significantly increased from 7.32 to 15.37 per 100,000 persons from 2012 to 2015 (p < 0.0001; Additional file 1 Table S3).

In all of the studied age groups, the trends in the prevalence of PD were quite similar between the sexes by calendar year but an increasing trend of PD prevalence was observed particularly in the age group of over-80 years old. In contrast, the trends in the prevalence of DIP were substantially different among the sexes by calendar year. In both men and women, the prevalence of DIP was the highest in 2015 and the degree of the increase was the highest in middle-aged men and women.

The mean age of incident patients with PD increased from 70.89 in 2012 to 71.33 in 2015, while the mean age of incident patients with DIP decreased from 48.78 in 2012 to 47.39 in 2015. DIP incident patients were younger than PD incident patients. However, when excluding antipsychotics as a sensitivity analysis, the mean age of incident patients with DIP was 64.31 in 2012 and 63.58 in 2015.

The average incidence of PD between 2012 and 2015 was 34.97 per 100,000 person-years, while the average age-standardized incidence of PD according to the WHO 2000–2025 and US 2000 standard population between 2012 and 2015 was 23.49 and 35.79 per 100,000 person-years, respectively. In contrast, the average incidence of DIP between 2012 and 2015 was 8.69 per 100,000 person-years, and the average age-standardized incidence of DIP according to the WHO 2000–2025 and US 2000 standard population between 2012 and 2015 was 7.13 and 7.98 per 100,000 person-years, respectively.

A higher average incidence of PD between 2012 and 2015 was observed in both male and females in the older age groups. The peak incidence was reached in the age group of over-80 years old, with a higher incidence in males. In contrast, the average incidence of DIP between 2012 and 2015 showed a bimodal distribution in the age group of 45–49 and 75–79 years, with a higher incidence in females (Fig. 1).

The average female-to-male ratio of incidence of PD between 2012 and 2015 was higher than 1.0 in the younger aged groups (younger than 25 years). The older aged groups (over 45 years) had a female-to-male ratio of approximately less than or equal to 1.0. The average female-to-male ratio of the incidence of DIP between 2012 and 2015 was higher than 1.0 in patients aged over 45 years (Table 1; Fig. 2).

The incidence of PD significantly decreased from 35.39 to 33.25 per 100,000 person-years from 2012 to 2015 (p < 0.0001; Additional file 1 Table S4). In contrast, the incidence of DIP significantly increased from 7.09 to 13.85 per 100,000 person-years from 2012 to 2015 (p < 0.0001; Additional file 1: Table S5).

In all age groups, the trends in the incidence of PD were approximately similar between the sexes and calendar year but a decreasing trend of PD incidence was observed particularly in the age group of 75–79 years. In contrast, the trends in the incidence of DIP substantially differed between the sexes and calendar year. In both men and women, the incidence of DIP was highest in 2015 and the degree of this increase was highest in middle-aged men and women (Fig. 3).

In the all of the incident cases, among offending drugs (i.e., levosulpiride, metoclopramide, risperidone, olanzapine, aripiprazole, haloperidol, perphenazine, chlorpromazine, flunarizine), the most commonly used offending drug from 2012 to 2015 was risperidone. In addition, most people used only one offending drug when they were diagnosed as having DIP (Fig. 4).

When restricting the study population to patients without any secondary diagnosis of cerebellar ataxia, DIP, or Steele-Richardson-Olszewski syndrome for the sensitivity analysis for PD, the results generally align with the main analysis. However, the prevalence and incidence levels were relatively lower than the main analysis (181.33 per 100,000 persons versus 149.56 per 100,000 persons for the prevalence of all age groups in 2015; 33.25 per 100,000 person-years versus 23.41 per 100,000 person-years for the incidence of all age groups in 2015).

When we excluded antipsychotics as a sensitivity analysis for DIP, the bimodal distributions observed in the prevalence and incidence appeared to disappear. In addition, the trends in the prevalence and incidence of DIP from 2012 to 2015 by age groups and sexes remained rather constant (Additional file 2: Figure S1). The average female-to-male ratios between 2012 and 2015 were larger than those in the primary findings (1.21 versus 1.93 for the female-to-male ratios of incidence of DIP of all age groups). Among all of the incident cases, levosulpiride was the most commonly used drug from 2012 to 2015. Furthermore, most people used only one offending drug when they had a diagnosis of DIP (Additional file 3: Figure S2). The results of the prevalence are not shown due to the similarity in the overall details to those of the incidence.