Introduction
Measles, a highly contagious viral disease, poses a substantial public health threat due to its potential for severe complications. Among these complications, subacute sclerosing panencephalitis (SSPE) is particularly devastating and often fatal. SSPE is caused by persistent measles virus infection within the central nervous system, which can reactivate years after the initial infection, leading to progressive neurological deterioration and ultimately death. The interval between primary measles infection and the onset of SSPE can vary significantly, ranging from several months to multiple decades, underscoring the long-term neurological impact of measles infection [
1]. Additionally, previous studies have reported that SSPE predominantly affects young adults [
2,
3]. This epidemiological characteristic highlights the necessity of maintaining high measles vaccination coverage not only to protect children but also to mitigate long-term consequences in later life.
Although the introduction of effective measles vaccination programs has significantly reduced the incidence of measles and associated complications, including SSPE, the growing trend of vaccine hesitancy and declining herd immunity threaten the gains achieved through vaccination efforts. A resurgence of measles cases could result in a considerable increase in SSPE incidence, emphasizing the critical need for continued vaccination.
The Republic of Korea experienced a notable measles outbreak in 2000–2001 and subsequently implemented a nationwide measles elimination program, providing a unique opportunity to investigate the long-term impact of measles control on SSPE occurrence [
4]. This study aimed to determine the incidence of SSPE following the 2000–2001 measles outbreak and evaluate the effectiveness of measles elimination efforts in preventing this devastating complication.
Materials and Methods
Study Design and Data Source
This nationwide, population-based retrospective cohort study utilized claims data from the National Health Insurance (NHI) system, which is administered by the Health Insurance Review and Assessment Service (HIRA). In the Republic of Korea, all measles cases must be reported to local community health centers, after which they are recorded by the Korea Disease Control and Prevention Agency (KDCA) and the Korean Statistical Information Service (KOSIS). The KOSIS database provided data on measles incidence covering the period from 1974 to 2022, which were included in this study. The NHI system offers universal health coverage to approximately 98% of the Korean population, ensuring that the analyzed sample is highly representative. Claims data from January 2007 through December 2022 were extracted from the HIRA database. This timeframe was selected to reflect the most recent epidemiological trends, thus ensuring an analysis based on current and representative public health data. Data on measles incidence were obtained from both HIRA and KDCA databases. HIRA provides information derived from insurance claims, whereas KDCA data are based on officially reported cases. Discrepancies between these datasets likely result from variations in case definitions and reporting practices. Notably, SSPE cases have only been captured in the HIRA database since 2007; consequently, data on SSPE prior to 2007 were unavailable. Cross-sectional analyses were conducted to evaluate annual temporal trends.
Study Population
This study analyzed national epidemic data for measles among individuals aged 0 to 20 years, as well as SSPE cases, using NHI claims data collected between January 2007 and December 2022. Cases were identified based on inpatient and outpatient claims data that included the relevant International Classification of Diseases, 10th Revision codes: B05 (measles) and A81.1 (SSPE). Patients were included in the study only if these disease codes appeared as the primary diagnosis on their claims. Cases where these codes were listed as accessory diagnoses were excluded. Population data for the Republic of Korea, imported from KOSIS census data provided by Statistics Korea, were utilized to calculate the incidence rates of measles and SSPE relative to the entire population.
Statistical Analysis
Population-based incidence rates for measles and SSPE were calculated per 100,000 individuals. Specifically, SSPE incidence was calculated as the annual number of newly diagnosed SSPE cases per 100,000 individuals in the population. The chi-square test was used for categorical variables, while the independent t-test was employed for continuous variables. Statistical significance was set at p<0.05. All statistical analyses were conducted using SAS software ver. 9.4 (Enterprise Guide; SAS Institute Inc.).
Ethics Approval
This study was approved by the Institutional Review Board of Korea University Anam Hospital (IRB No. 2023AN0395).
Results
During the observation period, the HIRA database recorded 236 cases of measles and 2,736 cases of SSPE. Surveillance data from the KDCA identified 1,168 measles cases. Reported SSPE cases varied substantially, ranging annually from approximately 93 cases (0.19 per 100,000 individuals) to 333 cases (0.66 per 100,000 individuals). A significant decline in reported measles cases was observed over the study period, from 442 cases (3.87 per 100,000 individuals) in 2014 to zero cases reported by both HIRA and KDCA since 2021 (
Table 1). According to the KOSIS database, measles incidence gradually declined from 20.4 per 100,000 individuals in 1976, experienced a sharp increase to 69.4 per 100,000 individuals in 2000, decreased to 48.7 per 100,000 individuals in 2001, and ultimately reached zero in 2021. Conversely, SSPE incidence exhibited an upward trend, rising from 0.24 per 100,000 individuals in 2007 to 0.63 in 2013, and further increasing to 0.66 in 2014. Notably, the peak incidence of SSPE occurred approximately 12 to 14 years after the measles epidemic, with incidence declining thereafter (
Figure 1). In
Figure 1, the absence of SSPE cases before 2007 is due to the analysis being limited to data available from January 2007 onward, when HIRA’s systematic collection of claims data commenced. The mean age at SSPE onset was 21.2 years, ranging from 6 to 30 years. The sex distribution was significantly skewed, exhibiting a male-to-female ratio of 13.0:1. Notably, the age at onset of SSPE increased following significant reductions or cessation of measles transmission (
Table 2).
Among measles patients, 57.2% were male and 42.8% were female. In contrast, SSPE patients showed a distinct male predominance, with 92.8% male and 7.2% female. Measles patients had a mean age of 4.8 years, with a median age ranging from 1 to 7 years. Conversely, SSPE patients had a mean age of 21.2 years, with a median age ranging from 19 to 24 years. Healthcare coverage differed substantially between the 2 groups. Most measles patients (96.2%) were enrolled in the NHI system, with only 3.8% benefiting from medical assistance. In contrast, SSPE patients primarily depended on medical assistance, with 72.4% enrolled in this program and only 27.6% covered by NHI.
The treatment costs associated with SSPE patients were markedly higher than those for measles patients, averaging 328,315 Korean won (
Table 3).
Discussion
The most significant finding of this study is the remarkably low incidence of SSPE in the Republic of Korea following the measles outbreak of 2000–2001. This observation underscores the profound impact of effective public health interventions in mitigating the long-term consequences of infectious diseases. The successful implementation of a nationwide measles elimination program, primarily driven by widespread vaccination, drastically curtailed measles transmission [
5]. This reduction in measles incidence directly translated to a decreased population at risk of developing SSPE, a rare but devastating complication that can manifest years after the initial measles infection.
The temporal association observed between the measles outbreak and the subsequent peak in SSPE cases, followed by a sharp decline, further supports the causal link between measles control and SSPE prevention [
4]. The findings of this study resonate with observations from other countries that have achieved high measles vaccination coverage [
3]. For instance, in the United Kingdom, robust vaccination programs led to a dramatic reduction in SSPE incidence, from 5 to 10 cases per year in the 1990s to near elimination in recent years [
6]. This remarkable progress highlights the global impact of measles vaccination in preventing not only acute measles infections but also protecting against the long-term neurological consequences of the virus. The virtual disappearance of SSPE in countries with sustained low measles incidence serves as strong evidence of the enduring benefits of vaccination, underscoring the importance of maintaining high immunization rates [
7]. It is noteworthy that SSPE typically develops 7 to 10 years after measles infection, suggesting that SSPE incidence observed in a given year likely corresponds to measles cases from several years earlier.
In this study, we reported the incidence of SSPE per 100,000 individuals in the general population rather than per 100,000 measles cases. This approach reflects our aim to assess the population-level impact of measles and SSPE in the context of a nationwide measles elimination program. Reporting SSPE incidence at the population level provides a clearer understanding of the disease burden within the broader public health context and allows for a direct evaluation of measles control measures’ effectiveness in preventing this rare but severe complication. Our findings emphasize the importance of maintaining low measles incidence to prevent SSPE. The study revealed no concerning trends or indications of increased SSPE risk in the post-outbreak period, emphasizing the effectiveness of sustained measles control efforts. This observation aligns with findings from other countries, such as Finland and the United Kingdom, where sustained low measles incidence has led to an almost complete disappearance of SSPE cases [
6,
8]. The temporal relationship between the 2000–2001 measles outbreak and the SSPE incidence peak around 2014 further emphasizes the delayed yet significant impact of measles infection on SSPE development [
4]. This lag underscores the necessity of long-term surveillance even after successful measles control. The continued decline in SSPE cases following the peak provides reassurance about the sustained effectiveness of vaccination programs.
Our study supports previous research demonstrating a pronounced male predominance among SSPE patients. For instance, a German study covering the period from 2003 to 2009 reported similar sex-related disparities, suggesting males may be more susceptible to SSPE or its clinical manifestations [
9]. Although the underlying mechanisms remain unclear, factors such as hormonal differences, genetic predispositions, or variations in immune responses might contribute to this phenomenon [
10]. In our study, the male-to-female ratio was approximately 13:1, further highlighting this significant gender difference. Additionally, the observed pattern of SSPE incidence peaking after a measles outbreak and subsequently declining aligns with trends observed in other countries [
11], reinforcing the strong association between effective measles control and SSPE prevention [
12].
This study has some limitations. First, as a retrospective analysis utilizing national health insurance claims data, it is inherently subject to potential coding errors and underreporting of SSPE cases. Second, the study did not assess measles vaccination status or the severity of primary measles infection, both of which could influence SSPE risk. Third, because the study relied solely on reported and claims data, it does not provide insights into the clinical long-term risk of SSPE development; moreover, since our data cover only from 2007 to 2022, they may not fully represent broader epidemiological trends observed since 1974. Although our study identifies a significant male predominance among SSPE cases, we could not compare this finding with the sex distribution of measles cases during the 2000–2001 outbreak due to data limitations. Consequently, further research is needed to determine whether this disparity reflects inherent sex-based susceptibility to SSPE or merely reflects demographic characteristics of the initial measles outbreak.
Despite these limitations, the study’s strengths include its large nationwide sample size and comprehensive coverage through the national health insurance database, minimizing selection bias and providing a representative depiction of SSPE incidence in the Republic of Korea. Measles immunization primarily targets reducing measles cases, and the associated decline in SSPE incidence represents an important, though indirect, benefit of effective measles control.
While KDCA surveillance data offer valuable insights into overall measles trends, our analysis primarily relied on HIRA and KOSIS data. Differences in data collection methods and case ascertainment among these sources limit direct comparisons. The inclusion of KDCA data provides broader historical context regarding the measles outbreak, facilitating interpretation of SSPE incidence trends in light of overall measles control efforts. The findings hold significant implications for global public health, particularly for countries aiming to eliminate measles and prevent SSPE. The Republic of Korea’s success in controlling measles and subsequently reducing SSPE incidence serves as a compelling example of the long-term benefits derived from effective vaccination programs and public health interventions. By highlighting the effectiveness of measles control efforts in preventing SSPE, this study contributes valuable evidence supporting global measles elimination initiatives and vaccination campaigns.
In conclusion, our study demonstrates a remarkably low incidence of SSPE in the Republic of Korea following a significant measles outbreak, attributable primarily to a successful nationwide measles elimination program. Although reduced SSPE incidence is an encouraging outcome, it remains an indirect benefit of measles control efforts, which primarily aim to reduce measles cases. By highlighting this indirect impact, our findings provide valuable support for global initiatives promoting measles elimination and robust vaccination campaigns.
Article information
Ethics Approval
This study was approved by the Institutional Review Board of Korea University Anam Hospital (IRB No. 2023AN0395).
Conflicts of Interest
Jong-Koo Lee has been the editor-in-chief of Osong Public Health and Research Perspectives since October 2021. Young June Choe was not involved in the editorial process or review of this manuscript, despite being a member of the Editorial Board of the Osong Public Health and Research Perspectives. The other authors have no conflicts of interest to declare.
Funding
This study was supported by Korea University (Research No. K2327151).
Availability of Data
All data generated or analyzed during this study are included in this published article. For other data, these may be requested through the corresponding author.
Authors’ Contributions
Conceptualization: YHL, JHB, YJC; Data curation: YHL, JHB; Formal analysis: YHL, CRK, JKL, YJC; Investigation: YHL, YJC; Methodology: YHL, YJC; Project administration: CRK, YJC; Resources: YJC; Supervision: JKL; Validation: YJC; Visualization: YJC; Writing–original draft: YHL, JHB, YJC; Writing–review & editing: all authors. All authors read and approved the final manuscript.
Acknowledgements
We gratefully acknowledge the dedication of public health workers across the Republic of Korea, whose commitment to measles prevention and control has significantly contributed to the low incidence of subacute sclerosing panencephalitis observed in this study.
