Introduction

Epilepsy is a long-standing neurological disorder, identified by the brain’s persistent tendency to generate repeated seizures, impacting individuals across various geographies, ages, and ethnicities [1,2]. Although there have been therapeutic advancements, the majority of people with active epilepsy, over 75%, remain untreated, with the treatment gap being especially wide in low- and middle-income countries [3]. In the context of global population ageing, late-onset epilepsy (LOE), defined as seizure onset at ≥65 years [4], is gaining prominence as a clinical and public-health priority due to its links with vascular and neurodegenerative comorbidity. Although its pathogenesis remains incompletely resolved, converging evidence implicates cerebrovascular injury, neurodegenerative processes, multimorbidity, and frailty as key contributors to susceptibility and poorer outcomes [3,5]. Current management in older adults remains largely symptomatic, targeting seizure suppression rather than underlying pathophysiology [6,7]. Importantly, LOE is associated with substantially higher mortality than in age-matched populations without epilepsy, with excess deaths frequently linked to comorbid conditions such as stroke and dementia [8]. Thus, premature mortality is a critical issue for LOE patients worldwide, placing a heavy load on healthcare systems and impacting the patients and their families. It is vital for healthcare experts in every discipline to have a thorough understanding of this condition [9–12].

The burden of LOE is largely affected by social determinants of health, aside from clinical mechanisms. Older adults with epilepsy are disproportionately affected by poverty, limited educational attainment, and social isolation, which restrict access to timely diagnosis, sustained treatment, and newer antiseizure medications (ASMs) [3,10,13]. Stigma and discrimination act as barriers to seeking help and maintaining adherence, thereby reducing quality of life and well-being. The economic consequences surpass direct medical expenses, involving caregiver load, productivity losses, and long-term care costs, especially in places with insufficient social protection. The ongoing treatment gap in elderly populations in many low- and middle-income countries is due to a deficit of neurologists, limited diagnostic capabilities, and the unaffordability of vital ASMs, which intensifies cross-country health outcome disparities [14,15]. Considering LOE in the broader societal and public health context reveals the need for holistic strategies that incorporate social, economic, and health system interventions, in addition to seizure control.

Even though it is becoming more common and impactful, LOE is still relatively underexplored in the field of geriatric neurology. Prior investigations are usually limited to specific regions, apply different age criteria, or are missing long-term data, which results in poorly defined global trends.To address these gaps, we leveraged data from the Global Burden of Disease (GBD) 2021 study to quantify the prevalence, incidence, mortality, and disability-adjusted life years (DALYs) attributable to LOE among adults aged 65 years and older, disaggregated by age, sex, and Sociodemographic Index (SDI), across 204 countries and territories from 1990 to 2021. This study, by combining temporal trends with sociodemographic context, offers the first systematic, thirty-year assessment of the global LOE burden, providing insights to inform prevention strategies, optimize clinical management,and guide resource allocation in ageing societies.

Methods

Results

Global trends

Between 1990 and 2021, the global prevalence of LOE among individuals aged 65 years and older increased significantly by 193.62%, rising from 1.22 million to 3.57 million cases. The ASPR of LOE grew by 21.82%, from 388.06 per 100,000 population in 1990 to 472.74 per 100,000 population in 2021 (Table 1, S2 Fig), with an AAPC of 0.65% (Table 1, S3 Fig). The global incidence of LOE in this age group reached 0.25 million in 2021, reflecting a 212.84% increase since 1990. The ASIR of LOE experienced a modest rise of 30.71%, climbing from 25.04 per 100,000 population in 1990 to 33.12 per 100,000 population in 2021(Table 1, S2 Fig), with an AAPC of 0.84% (Table 1, S3 Fig). Over the past three decades, the GBD, as measured by DALYs attributable to LOE, increased by 142.37%, rising from 0.59 million to 1.43 million. The age-standardized DALY rate for LOE grew by 2.8%, from 183.90 per 100,000 population in 1990 to 189.08 per 100,000 in 2021 (Table 2, S2 Fig), reflecting an AAPC of 0.10% (Table 2, S3 Fig). In 2021, LOE-related mortality was estimated at 35,181.86 deaths, with the ASMR rising by 7.94%, from 4.41 per 100,000 population in 1990 to 4.76 per 100,000 in 2021 (Table 2, S2 Fig), representing an AAPC of of 0.29% (Table 2, S3 Fig). Compared to the trends in ASPR and ASIR, the increases in the age-standardized DALY rate and ASMR for LOE among individuals aged 65 and older were less pronounced over the same period.

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Table 1. ASPR and ASIR of LOE in individuals aged ≥65 years and Their AAPC from 1990 to 2021 at Global and SDI levels.

https://doi.org/10.1371/journal.pone.0336588.t001

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Table 2. ASMR and age-standardized DALYs rate and AAPC of LOE in individuals aged ≥65 years from 1990 to 2019 at Global and SDI levels.

https://doi.org/10.1371/journal.pone.0336588.t002

National trends

At the national level, between 1990 and 2021, Equatorial Guinea experienced the largest increase in the ASPR of LOE among individuals aged 65 years and older, with an AAPC (AAPC) of 2.62% (S5 Table) (Fig 1). This was followed by Germany (AAPC 2.06%) and the United States (AAPC 1.67%). Germany also reported the highest increase in the ASIR for LOE in this age group, with an AAPC of 2.68%, followed by Equatorial Guinea (AAPC 2.47%) and Oman (AAPC 2.07%) (S5 Table) (Fig 2). During this period, Japan exhibited the largest increase in the ASMR among older adults with LOE, at an AAPC of 5.34% (S5 Table) (Fig 3). Meanwhile, Germany also recorded the most substantial rise in the age-standardized DALYs rate for older adults with LOE, with an AAPC of 2.41% (S5 Table) (Fig 4). In 2021, Equatorial Guinea had the highest ASPR of LOE among older people (1,364.46 per 100,000 population), and Germany had the highest ASIR of LOE (97.31 per 100,000 population) (S5 Table). However, Zambia had the highest age standardized DALYs rate for LOE (1,059.20 per 100,000 population) and the highest ASMR (46.76 per 100,000 population) (S5 Table).

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Fig 1. Map showing ASPR of LOE in individuals aged ≥65 years in 2021.

Abbreviations: ASPR, age-standardized prevalence rate; LOE, late-onset epilepsy. Note: Base map from Natural Earth (public domain). Map created by the authors in R.

https://doi.org/10.1371/journal.pone.0336588.g001

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Fig 2. Map showing ASIR of LOE in individuals aged ≥65 years in 2021.

Abbreviations: ASIR, age-standardized incidence rate; LOE, late-onset epilepsy. Note: Base map from Natural Earth (public domain). Map created by the authors in R.

https://doi.org/10.1371/journal.pone.0336588.g002

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Fig 3. Map showing ASMR of LOE in individuals aged ≥65 years in 2021.

Abbreviations: ASMR, age-standardized mortality rate; LOE, late-onset epilepsy. Note: Base map from Natural Earth (public domain). Map created by the authors in R.

https://doi.org/10.1371/journal.pone.0336588.g003

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Fig 4. Map showing age-standardized DALYs rate of LOE in individuals aged ≥65 years in 2021.

Abbreviations: DALYs, disability-adjusted life-years; LOE, late-onset epilepsy. Note: Base map from Natural Earth (public domain). Map created by the authors in R.

https://doi.org/10.1371/journal.pone.0336588.g004

Discussion

Globally, the past three decades have seen a substantial rise in the ASPR, ASIR, ASMR, and age-standardized DALYs rates of LOE among individuals aged 65 and over. LOE’s increasing medical and societal costs have turned it into a more significant public health problem. Our study investigates the global burden of LOE, with a special emphasis on trends among seniors (65 years and older) across all GBD regions and countries from 1990 to 2021. Our findings shed light on the changing burden of LOE over the last 30 years, focusing on regions and countries with diverse income levels. These results highlight an upward trend in LOE burden across certain regions and countries. A comprehensive understanding of these epidemiological patterns is essential for policymakers and healthcare practitioners to design and implement effective prevention and management strategies.

Between 1990 and 2021, the global ASPR and ASIR of LOE increased by 21.82% and 30.71%, respectively. In contrast, trends in ASMR and age-standardized DALYs rate associated with LOE in individuals aged 65 and older were less pronounced than those for ASPR and ASIR over the same period. With few exceptions, both the ASPR and ASIR of LOE have shown consistent increases across countries and regions with varying SDI levels. However, the ASMR and age-standardized DALY rate displayed more variable patterns, revealing notable disparities between countries and regions with differing sociodemographic profiles. The growing ASPR and ASIR of LOE among older adults are largely driven by potentially modifiable midlife risk factors [24]. Regionally, the highest ASPR, ASIR, ASMR, and age-standardized DALY rate were observed in high-SDI regions, followed by low-SDI regions, with the lowest rates recorded in high-middle SDI regions. This pattern highlights the persistent socioeconomic disparities in the global burden of LOE [25,26]. The highest ASIR among older adults was noted in Western Europe, Southern Sub-Saharan Africa, and Western Sub-Saharan Africa, where in Africa, this disparity is primarily attributed to the elevated incidence of HIV/AIDS and the overwhelming strain on fragile healthcare systems [27]. In wealthier nations, the incidence of epilepsy increases sharply after age 60 or 65, a trend not consistently observed in populations with lower socioeconomic status [28]. Factors such as high smoking rates, excessive alcohol consumption, and poor cardiovascular risk management may contribute to the high incidence rates in Western Europe.

Global disparities were evident among individuals aged 65 and older, with significant variations observed across different age groups. From 1990 to 2021, the ASIR of LOE exhibited a consistent upward trajectory across all age categories, with the most pronounced increase seen in those aged 80–89 years, particularly among women. Although new-onset idiopathic or unexplained (genetic) generalized epilepsy remains rare in older adults, factors such as chronic sleep deprivation can unmask an underlying lifelong predisposition to epilepsy [29]. As life expectancy increases, individuals with a history of idiopathic or unexplained generalized epilepsy, previously in long-term remission, may experience a relapse in later life. Additionally, physiological disturbances common in older adults can precipitate acute symptomatic seizures, which are defined as seizures occurring in close temporal association with a brain insult [30]. Compared to younger populations, research on epilepsy in older adults remains relatively underdeveloped. Key areas, such as drug trials, psychosocial assessments, and the evaluation of relevant comorbidities, require more comprehensive investigation in individuals aged 65 and older, who represent the largest cohort of epilepsy patients in both resource-rich and increasingly resource-poor regions.

When considering sex, women showed a more significant rise in the ASPR and ASIR of LOE than men. Throughout the study period, the disease burden, measured by DALYs, remained consistently higher in men, despite the contrasting trends. Men are generally more prone to episodes of excitability and epileptic seizures [31–33]. Nevertheless, social dynamics may affect this trend. In some places where epilepsy is heavily stigmatized, women might be more likely than men to conceal their epilepsy diagnosis. Sexual differences are apparent in numerous epilepsy and seizure disorders. The existing evidence indicates that differences in brain steroid hormones or neurosteroid levels between males and females may contribute to the sex differences in controlling seizures and experiencing epileptic seizures [31]. Due to the sex-specific disparities in LOE, there is a need for prevention strategies that are specifically designed for elderly women and men.

Evaluating cross-country differences in the LOE burden along the SDI gradient can provide crucial insights into the distribution of disease burden and identify nations where prevention and control strategies need to be improved. High-SDI countries usually offer their populations better healthcare access and more efficient health systems, which might contribute to a lower overall disease burden. In contrast, countries at lower levels of sociodemographic development exhibited a disproportionate concentration of LOE burden. This observation is consistent with prior research, which has shown that nations with lower SDI levels shoulder a disproportionately higher burden of LOE [15]. A study highlighted that older adults in Sub-Saharan Africa bear a greater disease burden and experience higher mortality rates compared to the global population [34]. The disproportionate burden of LOE in high SDI countries can largely be attributed to two primary factors. First, high SDI nations are characterized by aging populations and higher alcohol consumption, both of which are well-established risk factors for LOE, contributing to its rising incidence. Second, despite advancements in healthcare, no cure for LOE exists, even in developed countries, leading to a persistently elevated prevalence. The disproportionate burden of LOE in low SDI countries can be explained by three key factors. First, weaker healthcare systems and a high prevalence of infections that may precipitate epilepsy exacerbate this inequality. Second, there is a critical shortage of healthcare professionals trained to treat epilepsy, and those with adequate training are often unavailable in rural areas. Furthermore, individuals with epilepsy and their families frequently encounter stigma and discrimination, delaying the initiation of effective anti-seizure therapies. The WHO and the United Nations have increasingly emphasized the need for enhanced healthcare support and the development of medical guidelines in these countries, as part of a broader global call to action. Importantly, notable reductions in these disparities have been observed over time.

Cross-country variations in defining LOE could lead to differences in incidence and prevalence estimates. First, the age threshold defining “late onset” is not standardized across health systems: while some studies adopt 60 years, others use 65 or 70 years, which mechanically alters the denominators and shifts the age distribution of identified cases [28]. Second, there is variation in how faithfully ILAE criteria are implemented across different settings and whether acute symptomatic seizures are excluded; misclassification of these seizures can lead to exaggerated burden estimates [28]. Third, unequal access to diagnostic assessments like EEG and neuroimaging, as well as variations in coding standards and clinical evaluation, may additionally affect the identification of cases. These origins of diagnostic diversity have been recorded in numerous populations and could account for ongoing international discrepancies even after GBD unification. This study aims to characterize late-onset epilepsy in older adults; accordingly, we adopted a ≥ 65-year onset threshold, consistent with the clinically informed, data-driven definition proposed by Josephson et al. (2016) [4], which was derived using rigorous statistical methods. We also acknowledge that some studies have used alternative, and at times ambiguously defined, age cutoffs that are often guided by clinical convention or by national and global definitions of old age. Future research should focus on integrating harmonized multicenter registries with standardized ILAE protocols to mitigate these definitional inconsistencies and improve international comparability.

Acute symptomatic seizures and potential misclassification. In older adults, acute symptomatic seizures (ASyS) account for a large share of first-ever seizures and often occur in the context of acute brain insults such as stroke, metabolic derangements, or systemic illness [28,35,36]. Mistakenly categorizing ASyS as new epilepsy cases would cause an increase in the reported rates of LOE. Recent reports indicate that ASyS can account for up to 50% of new-onset seizures in older adults, with some patients progressing to epilepsy, complicating attribution in surveillance data [28,35,37]. These challenges persist even with harmonization efforts, and they underscore the need to adhere strictly to ILAE distinctions between unprovoked epileptic seizures and ASyS when defining LOE. This principle was followed in our study during the definition stage; nonetheless, we recognize the residual risk of misclassification due to variability in coding, diagnostic procedures, and data sources.

The study is also restricted by its lack of consideration for access to newer-generation antiseizure medications (ASMs). The GBD framework does not provide country-level information on ASM utilization, regulatory approval, or affordability. In regions with significant treatment gaps, such as low- and middle-income countries, these factors may greatly shape outcomes for older adults with LOE. Recent real-world studies have highlighted a rise in the use and effectiveness of third-generation ASMs, including lacosamide, brivaracetam, eslicarbazepine acetate, and perampanel, but access is still inconsistent across various health systems [38–40]. Reports from resource-limited areas repeatedly show that barriers in availability and affordability restrict adherence and clinical benefits [14,41]. Thus, part of the variation in LOE burden between countries may be explained by differences in drug availability rather than only by disease biology. Further studies should blend population-level modeling with registry or survey data on ASM access to more directly evaluate its effect on LOE outcomes.

This study faces limitations that are inherent to the GBD modeling framework. GBD incorporates a variety of sources, such as surveys, hospital records, and claims data, yet it does not provide direct clinical validation through multicenter epilepsy registries. Thus, our estimates should be viewed as indicators modeled at the population level, rather than outcomes confirmed by clinical assessment. The lack of direct validation may introduce risk of bias and constrain the applicability of our findings in specific clinical settings. To enhance diagnostic accuracy, validate case ascertainment, and strengthen the external validity of these estimates, future efforts must integrate multicenter clinical registries with GBD-based models.

An additional limitation involves the likelihood of epilepsy being underreported in regions with limited access to neurological care. The accurate diagnosis and monitoring in many low- and middle-income countries are hampered by a shortage of neurologists, restricted access to EEG and neuroimaging, and deficient health information systems. The underestimation of LOE in our study is probably influenced by these limitations. Despite the GBD framework’s use of modeling strategies to adjust for incomplete data, there may still be some residual diagnostic under-ascertainment. Recent evidence suggests that in resource-limited areas, there are still major gaps in epilepsy treatment and diagnosis, with as many as three-quarters of epilepsy sufferers possibly not receiving appropriate care or timely diagnosis [42,43]. Understanding this context helps explain some of the regional discrepancies we found and points to the need for strengthening health system capacity and registry infrastructure to secure more reliable burden estimates.

These sources of variation as a whole demonstrate the broader methodological constraints inherent to the GBD estimation framework. First, the analysis was exclusively based on modeled data from the GBD database, which gathers information from diverse sources but lacks direct clinical validation. Hence, our findings are modeled estimates for the population, rather than outcomes verified through assessments at the patient level. Second, the large 95% uncertainty intervals around some estimates highlight substantial statistical imprecision, which may impede the detection of significant cross-country differences, particularly in stable DALY trends. Third, the comorbidity adjustments used in the GBD framework assume independence between diseases and sequelae, whereas epilepsy frequently coexists with both somatic and psychiatric conditions [11,44] and is intertwined with social determinants such as stigma and poverty [13]. By simplifying, this assumption could lead to an underestimation of the real interactive effects of comorbidities. Fourth, dependence on administrative and claims data could lead to a bias in identifying cases, favoring treated populations and possibly overlooking those without formal healthcare or health insurance. These considerations highlight the necessity of integrating GBD modeling with clinical registries and health system data to boost diagnostic accuracy, refine comorbidity adjustments, and strengthen the external validity of future estimates.

Conclusion

From 1990 to 2021, the global burden of LOE has shown a continuous upward trend, largely due to the increase in population and its aging. While countries with elevated SDI values continue to experience a disproportionate burden, the differences between nations have slowly reduced. These trends point to the dual challenge of overseeing a rising senior population and addressing continuous disparities in diagnostic and treatment capacities. Strengthening surveillance systems, improving access to antiseizure medications, and integrating epilepsy care into broader ageing and non-communicable disease frameworks will be essential for mitigating the future burden of LOE and promoting equity in neurological health worldwide.

Supporting information

Acknowledgments

We acknowledge with gratitude the participants and investigators of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 collaborators.