Mortality of Epilepsy in Chinese Populations: A Comprehensive Review

Epilepsy is one of the most common neurological disorders characterised by recurrent and unprovoked epileptic seizures [1, 2]. Epilepsy can vary in frequency, duration, type, and severity and is associated with multimorbidity, disability, and premature mortality, as well as social stigma and reduced life quality [2, 3].

Premature mortality is a significant part of the epilepsy burden. Studies of the mortality of people with epilepsy aim to estimate the mortality rates, case fatality ratios (CFRs), causes of death, proportionate mortality ratios (PMRs), standardised mortality ratios (SMRs), and risk factors for death in this population. These studies can provide valuable information about the disease burden, natural history, prognosis, and healthcare needs. They can also help identify modifiable risk factors and potential interventions to reduce mortality and improve survival outcomes.

Worldwide, epilepsy affects over 50 million individuals [4]. China accounts for approximately one-fifth of the global population with diverse socioeconomic, cultural, and educational backgrounds and medical conditions across the different Chinese regions. It is estimated that around 10 million people have epilepsy in China [5]. Features of the risk of premature mortality in this population may differ from those in other populations, especially in high-income countries (HICs), due to the diversity of genetic background, culture, environment, aetiologies, and risk factors for epilepsy. Variations in diagnostic and treatment access may also matter. Several studies have reported on the premature mortality of epilepsy in different regions of China without consistent results. These may not represent the overall situation in China due to inconsistencies in design, methods, sample size, follow-up time, and other inherent population differences [5].

Based on available data in the last 6 decades (shown in online suppl. Fig. 1; for all online suppl. material, see https://doi.org/10.1159/000540426), we comprehensively reviewed existing evidence on the mortality rate, causes of death, sudden unexpected death in epilepsy (SUDEP), risk factors, and mortality in status epilepticus (SE) and symptomatic epilepsy in people with epilepsy in China, aiming to provide an overview of this topic, particularly in terms of causes of death and risk factors. We also discussed the limitations of the current evidence and suggested directions for future research in this area.

We defined a report of interest as any article providing data on the mortality of people with epilepsy. We used this definition for items of interest in the reports, such as epilepsy [1, 6, 7], convulsive epilepsy [6], SE [8‒10], SUDEP [11], mortality rate [12], SMR [12], CFR [12], and PMR [12]. These definitions are provided in online supplementary Table 1.

We searched the following electronic databases from January 1, 1959, to July 31, 2023: Web of Science, Scopus, Embase, PubMed (English), and Wanfang (Chinese) Database (there was no report on epilepsy before this date in the databases). We used a combination of keywords and MeSH terms related to epilepsy, mortality, and China/Chinese. We also searched the reference lists of relevant articles and reviews for additional studies. We restricted our search to publications in English or Chinese.

The search terms we used in Web of Science, Scopus, Embase, and PubMed were (epilepsy OR seizure) AND (mortality OR death OR survive OR fatality OR “sudden unexpected death in epilepsy” OR SUDEP) AND (China OR Hong Kong OR Taiwan OR Macau); the search formula in Wanfang (in Chinese) is “Epilepsy AND (death OR mortality OR survival OR sudden unexpected death in epilepsy)”.

We included population-based and hospital-based studies that reported mortality rates, causes of death, risk factors, or SMRs in Chinese people with epilepsy. We excluded case reports, case series, reviews, editorials, commentaries, letters, conference abstracts, those with sample sizes <30, and those without sufficient data on mortality outcomes. Two reviewers (X.W.Z. and D.D.) independently screened the titles and abstracts of the retrieved records for eligibility. Any discrepancies were resolved by consensus or in consultation with a third reviewer (J.W.S.). The reviewers had access to the full texts of potentially eligible articles.

We identified 2,866 articles of potential interest, of which 2,056 were in English and 810 in Chinese. After applying the inclusion and exclusion criteria, we included 83 articles (64 English and 19 Chinese) (shown in Fig. 1 and online suppl. Fig. 1).

We employed a standardised extraction process that was used to collect information from included studies by extracting the first author, year of publication, study design, study setting (region, urban or rural), study period, data source (population registry, hospital registry, cohort study), sample size, age range, gender distribution, epilepsy type and severity (if available), definition and diagnosis of epilepsy and mortality outcomes, follow-up duration, mortality rates (overall and age-specific), causes of death and their proportions, risk factors for mortality (if available), and SMRs (overall and age-specific). Two reviewers (D.D. and X.W.Z.) independently extracted and cross-checked the data for accuracy and consistency. Discrepancies were resolved by discussion or consultation with a third reviewer (J.W.S.). We also checked the reference list of the papers or contacted the authors of the original studies for additional or missing data when necessary.

Twenty studies covering 50,316 cases were included in the analysis of mortality rate and SMR. We found 15 population-based studies reporting on mortality rates, all prospective. The median mortality rate of population-based studies was 14.7 (range: 6.8–74.4)/1,000 person-years and SMRs were reported with a median of 4.4 (range: 2.6–12.9), indicating that the excess mortality in people with epilepsy was 2–13 times greater than the reference population [13‒19]. The highest mortality rate was reported in central China (Henan and Guizhou) (range: 51.2–74.4/1,000 person-years) [20, 21], with relatively poor socioeconomic conditions (shown in Table 1).

We found five hospital-based Chinese studies that reported data on the mortality rate, with only one prospective study and the other four retrospective from electronic data. In hospital-based registrations in South China (Guangdong province, Hong Kong, and Taiwan) [27‒31], the median mortality rate was 12.3 (range: 9.5–101.5)/1,000 person-years and the median SMR was 3.0 (range: 1.5–5.1) [27, 28, 30, 32]. High mortality rate (101.5/1,000 person-years) and SMR (5.1) were found in a Hong Kong study where most participants were older adults [27].

SMRs also varied in terms of sex and age. The SMR in females (median: 2.9) was higher than that in males (median: 2.6) [13, 15, 17, 18, 30]. The highest SMR in young adults (range: 23.3–40.2) was reported in a multicentre study [15]. High SMRs were found in children, especially among those aged 0–9 years, reported in West China (SMR: 97), Northwest China (SMR: 38), and Southern Taiwan (SMR: 34) [17, 18, 30]. A similar result was also identified in a study from public hospitals in Hong Kong, indicating a higher mortality in children aged 1–4 years (SMR: 42.3) and 5–9 years (SMR: 46.4) compared with the general population [27]. A significantly low SMR among older adults was also reported in most studies [13, 17, 18, 30, 27].

As shown in Fig. 2b, comorbidities and other unrelated causes accounted for three-quarters of the deaths. The most common cause was cardiovascular and cerebrovascular diseases, accounting for approximately one-fifth of all causes, followed by complications of diabetes (median PMR: 9.4%), neoplasm (median PMR: 9.4%, among this, median PMR of brain tumours: 3.2%; median PMR of other neoplasms: 5.5%), malnutrition (median PMR: 8.3%), etc. In addition, neurological diseases, suicide, and other diseases (such as infectious diseases, respiratory diseases, diseases of the digestive system, diseases of the genitourinary system, and congenital anomalies) also accounted for deaths. Still, they had a low PMR of <5%. Epilepsy-related causes accounted for approximately one-quarter of the total, among which the most common were accidental injuries (median PMR: 22.0%). The remaining were SUDEP and SE with PMR <3% of the epilepsy-related cause.

As shown in Fig. 2a, people with epilepsy had an over tenfold increased risk of death from several causes, including complications of diabetes (SMR: 28.2), drowning (median SMR: 23.9), brain tumour (SMR: 21.4), toxic effects of carbon monoxide and pesticides (SMR: 17). Other causes of death showing a higher risk were falls (median SMR: 9.8), transport accidents (median SMR: 8.6), and suicide (median SMR: 5). SMRs <5 were found in chronic obstructive pulmonary disease, digestive system diseases, ischaemic heart disease and myocardial infarction, pneumonia and influenza, cerebrovascular disease, cardiac disease, liver cirrhosis, neoplasms, and malignant neoplasm except for brain tumour.

A few studies reported sex differences in SMR: women had a higher risk of drowning (female 51.6 vs. male 31.2), toxic effects of carbon monoxide and pesticides (37.0 vs. 7.8), transport accidents (6.3 vs. 5.7), myocardial infarction (5.6 vs. 2.4), and suicides (8.6 vs. 8.1) but lower SMR for falls (6.7 vs. 15.4) [15, 16], cerebrovascular disease (1.7 vs. 2.5), and diseases of the digestive system (2.5 vs. 5.1) [15].

The median incidence of SUDEP was 1.49 (range: 0.17–2.57)/1,000 person-years, as shown in Table 3. The highest SUDEP incidence was found in Central China (median: 2.03/1,000 person-years) [15, 16, 22, 35] and the lowest in Northeast China (median: 0.5/1,000 person-years) [14] (shown in Table 2).

Male (HR: 1.88), onset age of epilepsy >50 years old (HR: 2.28), hypertension comorbidity (HR: 3.07), and polytherapy of anti-seizure medications (ASMs) (HR: 2.07) were significant risk factors associated with SUDEP as indicated in a study from insurance database [31]. However, other factors, such as sex, onset age, duration, aetiology, seizure type, ASM treatment, seizure frequency, phenobarbital (PB) dosage from baseline to death, final PB doses, and learning disability were also reported but without statistical significance [18, 22, 33‒35].

Main risk factors identified for all-cause death were older age at onset or death (OR/HR: 1.08–18.20) [18, 22, 31, 54], presence of comorbidities or complications (OR/HR: 1.40–22.10) [26, 28, 31, 55‒59], generalised or drug-resistant epilepsy type or severity (OR/HR: 2.55–4.90) [28, 56, 60, 61], longer duration before therapy (HR: 4.37) [55], drug resistance (OR: 3.90) [56], rural residence (HR: 3.64) [55], higher frequency of seizures (HR: 1.43–2.41) [22, 26], male (OR/HR: 1.20–2.28) [18, 22, 26, 28, 54], and polytherapy (HR: 0.51–2.07) [26, 62]. Other risk factors included C-reaction proteins or blood glucose, a history of mechanical ventilation, and bilateral lesions or diffuse cerebral oedema in neuroimages [56, 63, 64].

Certain factors may affect the risk of cause-specific death. Long duration since diagnosis was a risk factor for death due to drowning (HR: 6.2), SE (HR: 22.8), and suicides (HR: 38.1), while duration <3 years was also reported as a risk factor for death due to drowning [16, 26]. Older epilepsy onset age was associated with an increasing risk for mortality due to cerebrovascular disease (HR: 7.2) and SUDEP (HR: 2.28), but onset age of epilepsy before 12 years old was a risk factor for SE death (HR: 10.2) [16, 18, 31]. Living in a waterside area was associated with death due to drowning (HR: 2.8) [16]. Not being seizure-free with higher seizure frequency were risk factors for dying from injury (HR: 1.15–2.17) and drowning (HR: 1.63–2.40) [26].

Studies showed that the median CFR in hospitalisation was 15.8% (3.0%–28.6%), and the CFR for post-discharge follow-up ranged from 1.5% during 5-year follow-up to 55.4% during 20.3 months follow-up [56, 64‒76] (shown in online suppl. Table 2). As shown in Fig. 3, the CFR of adults was higher than that of children, but both increased with follow-up duration.

The CFR of refractory SE (14.4%–75%) was higher than that of non-refractory SE (1.3%–21.7%) [57, 60, 67]. The CFR of acute symptomatic SE (48.9%) was also higher than remote symptomatic SE (19.4%) and idiopathic SE (0) [67]. It was higher in females (11.1%) than in males (7.4%) [77]. Studies also identified the main risk factors for death as older age at onset (OR/HR: 1.08–18.2), male (OR/HR: 0.54–2.28), longer duration or higher frequency of seizures (OR/HR: 1.43–2.41), drug-resistant epilepsy type or severity (OR/HR: 2.55–4.9), and presence of comorbidities or complications (OR/HR: 0.16–22.1) [55‒60, 63, 64, 67, 75, 77, 78].

The CFR in people with epilepsy after cerebrovascular diseases ranged from 1.9% to 48.9% [36‒41, 79, 80] (shown in Table 3), and the leading causes of death were cardiovascular diseases, such as ischaemic heart disease, cerebrovascular disease, cardiac arrhythmias, and early seizures after stroke [40, 41, 80]. The CFR ranged from 10.4% to 39.1% after infection or immunologic diseases [42‒45, 69, 81, 82] (shown in Table 3), and the leading causes of death were secondary neurological injury and infectious diseases like pneumonia and sepsis [42‒44, 81]. CFRs were 28.6%–37.5% [46‒48] and 51.1%–62.3% after head injury and high-grade glioma [49, 50] (shown in Table 3). Table 3 also showed the CFR of 42.8% at 1 year and 68.9% at 5 years in patients with symptomatic epilepsy due to allogeneic haematopoietic stem cell transplantation [52]. One study reported a CFR of 1.3% in 75 pregnant women with epilepsy [51]. Another study also reported 11 deaths of 30 people with epilepsy and COVID-19. It showed CFRs of 38.5% (5 of 13) for the new-onset seizure group, 50% (5 of 10) for the recurrent seizure group, and 14.3% (1 of 7) for the epilepsy history group in the 3-month follow-up after discharge [53].

We provide a comprehensive and updated overview of the premature mortality that affects Chinese people with epilepsy, including causes and risks. Our median SMR was higher than reported in an existing meta-analysis for population-based premature mortality from LMICs [12, 83, 84]. Most population-based studies we identified were from the Global Campaign against Epilepsy (GCAE) demonstration project and the later National Epilepsy Prevention and Control Management project in Mainland China [5]. These results may reflect the poor healthcare conditions for people living in resource-poor areas, especially in less-developed regions with the highest mortality rates. These regional differences may be related to socioeconomic and healthcare factors that impose different levels of hazards and comorbidities on people with epilepsy and their access to health services.

We found the SUDEP incidence higher than in reports from HICs (range: 0.33–1.35/1,000 person-years) [83, 85, 86]. In contrast to HICs, where SUDEP was one of the most important causes of death [85, 87‒89] (even ranking second in some evidence [87, 89]), SUDEP ranked merely seventh and accounted for less than 3% of all deaths in Chinese people with epilepsy.

The incidence of SUDEP may be underestimated as postmortem examinations are hardly carried out in China because of cultural conventions, especially in rural areas [22]. Thus, the lack of autopsy accounts for the fact that most of the incidence estimation in China is usually based on probable and possible cases, and it may be overshadowed by other more prevalent causes of death in China. Some studies, however, used detailed verbal autopsy questionnaires [22]. They indicate challenges in SUDEP diagnosis in such resource-poor settings, and more research on the risk of SUDEP in China is needed.

Our study suggests that epilepsy-related deaths accounted for approximately one-quarter of total deaths, comparable to reports in HICs like Denmark [89]. Accidental injuries were the most common causes of epilepsy-related deaths in our study, accounting for more than 80% of all cases. This was rare in HICs and other countries [89, 90], where SUDEP was the predominant cause, comprising 80% of epilepsy-related deaths [89]. Possible reasons for this discrepancy may be the higher occupational and life exposure to hazardous environments due to poorer socioeconomic levels and educational conditions among people with epilepsy in less-developed areas.

Regarding epilepsy-unrelated deaths, cerebrovascular and cardiovascular diseases were common causes of death, ranking second and accounting for approximately one-fifth of all deaths and one-third of epilepsy-unrelated deaths. This was lower in Denmark but more comparable to Korea [89, 91]. This may be explained by the higher incidence of stroke and cardiovascular diseases in China, which is a significant risk factor for epilepsy and premature mortality. There may be some SUDEP cases reported as ischaemic heart diseases or strokes without careful investigation, especially in rural areas, due to the lack of accurate and immediate examinations and diagnosis.

We found that complication of diabetes was a significant cause of death, ranking third and accounting for almost 10% of all deaths. In comparison with the general population, people with epilepsy had a markedly higher risk of death from complications of diabetes. Previous epidemiological studies have shown a bidirectional association between epilepsy and diabetes mellitus (DM), T1DM, and T2DM [92‒99]. In the current stage, no studies have directly examined the mortality in people with epilepsy who also have DM; thus, some evidence suggests that there is a higher risk of complications of diabetes, such as pneumonia, urinary tract infection, and septicaemia in people with epilepsy [100].

We also found that neoplasm was a significant cause of death, ranking fourth and accounting for almost 10% of all deaths. Unlike other countries where brain neoplasm is the most common cancer in people with epilepsy [89, 90, 101], in China, there were more deaths from other types of neoplasm, such as lung cancer, liver cancer, and gastric cancer. These types were found to account for approximately 58% of neoplasm deaths.

One study reported that the mortality rate of pregnant Chinese women with epilepsy was significantly higher than those reported in the USA and Denmark [102, 103]. This indicates that pregnant women require better clinical management, which needs public health attention.

Another study investigated the post-COVID-19 mortality of people with epilepsy, which was higher than other studies [104‒107]. While some studies found no association [105, 107], the impact of epilepsy on COVID-19 outcomes is still uncertain and requires more research.

Our work has several limitations. First, due to study design heterogeneity, varying data sources, population characteristics, epilepsy types, definitions, and confounder adjustments, a meta-analysis was infeasible. Consequently, we cannot ascertain whether mortality rates differ significantly between different types of studies. Second, most of the included studies were retrospective and relied on existing death certificates, hospital records, or verbal autopsies, making assumptions about accuracy challenging. Only prospective studies provide reliable and valid estimates of mortality risks [15‒17]. Third, existing studies capture more data from adults and adolescents than from children and older adults with epilepsy. This significant gap needs attention as epilepsy is more prevalent in children and older adults. Fourth, we found that the mortality rate of children and young people with epilepsy was higher than that of adults, primarily in studies that reported SMR, typically in resource-poor areas. This aligns with previous studies showing higher mortality rates in younger groups than in older age groups in LMICs [12, 83, 108]. SMRs use indirect standardisation since the reference population for each SMR has a different demographic distribution that affects the expected deaths [109]. Therefore, comparisons of SMRs from different studies should be handled with caution. Fifth, symptomatic epilepsy accounts for a large proportion of epilepsy cases, especially in the older population. The prognosis and death characteristics of people with symptomatic epilepsy may vary depending on the severity and extent of brain injury or structural abnormality caused by primary diseases. For these reasons, we excluded several articles without a clear aetiology of epilepsy. Lastly, most of the studies were from rural areas in Mainland China, and only a few were from Hong Kong and Taiwan. The results, therefore, cannot be extrapolated due to significant regional disparities in socioeconomic conditions, healthcare services, and medical supply systems across regions.

We summarised the evidence on the mortality in Chinese people with epilepsy characteristics in the last 6 decades. More studies are needed to improve the understanding of premature mortality of people with epilepsy in China to reduce such risks. The research directions include (1) linking big data to estimate mortality; (2) obtaining more accurate information (including verbal autopsy and autopsy) to define the causes of death and particularly SUDEP; (3) identifying and providing preventative intervention to reduce preventable causes of death, such as accidental injuries, SUDEP, and suicide; (4) exploring the potential predisposing mechanisms of common comorbidities such as cerebrovascular/cardiovascular diseases, diabetes, and cancer; (5) improving the treatment of primary diseases which may be associated with symptomatic epilepsy.

X.Z., D.D., W.W., and D.Z. declare no competing interests. J.W.S. reports personal fees from Eisai, UCB, and Angelini Pharma and grants from Eisai, UCB, Angelini Pharma, and Jazz Pharma, outside the submitted work.

D.D. received funding from the National Nature Science Foundation of China (82173599), the Ministry of Science and Technology of China (SQ2021AAA010157), and the Shanghai Huashan Hospital Project (3030537176). D.Z. received funding from the National Nature Science Foundation of China (U21A20393), the Sichuan Science and Technology Bureau Program (2019YFH0196), the Chengdu Science and Technology Bureau Program (2019-YF09-00215-SN), the 1.3.5 project for disciplines of excellence and Brain Science project of West China Hospital, Sichuan University (ZYJC21001), and the West China Nursing Discipline Development Special Fund Project (HXHL20004). J.W.S. is partly based at University College London Hospital Comprehensive Biomedical Research Centre, which receives a proportion of funding from the UK Department of Health’s National Institute for Health Research Centres funding scheme, and receives support from the Dr. Marvin Weil Epilepsy Research Fund, UK Epilepsy Society, and Christelijke Vereniging voor de Verpleging van Lijders aan Epilepsie.

X.Z., D.D., W.W., D.Z., and J.W.S. conceptualised the review. X.Z. and D.D. did the search, data collection, and analysis and drafted the manuscript. X.Z., D.D., D.Z., and J.W.S. evaluated the quality of the included studies. All authors were involved in the interpretation of data, critically reviewed the manuscript, and approved the final version. During the initial draft of this article, the authors used Copilot to improve the readability. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the publication’s content.