Epilepsy in Tibetan-Inhabited Plateau Regions of Western China: A Narrative Review of Epidemiology, Uncertainty About Chronic High-Altitude Effects, and Evidence-Informed Healthcare Priorities.

Epilepsy in Tibetan-Inhabited Plateau Regions of Western China: A Narrative Review of Epidemiology, Uncertainty About Chronic High-Altitude Effects, and Evidence-Informed Healthcare Priorities

Highlights

What are the main findings?Community surveys reported prevalence estimates of 2.5–23.5 per 1000, but methods and case definitions differed; no resident-population study identified in this review reported all four review-defined features used here to assess claims about chronic altitude exposure.

Regional evidence documents selected potentially preventable causes, gaps in treatment quality and continuity, and uneven diagnostic and workforce capacity. In one assessed subgroup, 35.4% screened positive for depressive symptoms and 52.0% for anxiety symptoms.

What are the implications of the main findings?Healthcare priorities can be evaluated prospectively even while the role of chronic altitude exposure remains uncertain.

The four review-defined appraisal features provide a transparent framework for examining claims about altitude-related health risks in remote settings.

Abstract

Background/Objectives: In Tibetan-inhabited plateau regions of western China, remoteness, uneven access to care, and preventable causes complicate epilepsy care. We assessed whether regional evidence supports an independent effect of chronic altitude exposure on epilepsy risk and identified healthcare priorities. Methods: We conducted a targeted narrative review of English-language journal articles published through 12 June 2026 (PubMed/MEDLINE, Web of Science Core Collection, citation tracking). Altitude-related evidence was evaluated against four prespecified, review-defined features; core sources underwent structured qualitative appraisal. Results: Three community surveys with differing case definitions and ascertainment reported prevalence estimates of 2.5–23.5 per 1000; the most recent (Daofu County, 2025) reported 4.4 per 1000 (95% confidence interval 3.7–5.1). No population-based incidence study of long-term residents was identified among the retrieved publications, and no identified resident-population study reported all four features. Regional studies documented parasitic, traumatic, and vascular etiologies, historical treatment gaps of 97–100%, and uneven diagnostic and workforce capacity. Among 127 Daofu participants assessed in detail, 33.1% were classified as receiving nonstandard treatment and 14.2% as untreated; 35.4% and 52.0% screened positive for depressive and anxiety symptoms. Conclusions: Current evidence neither establishes nor excludes an independent effect of chronic altitude exposure. It supports prospective evaluation of prevention, treatment continuity, diagnostic and referral services, workforce development, integrated mental health care, and surveillance.

1. Introduction

Epilepsy imposes substantial health and societal burdens, particularly where acquired causes and gaps in treatment persist [1,2,3]. China has expanded community-based epilepsy management and specialized services over the past two decades [4]. However, access to diagnosis, treatment, and continuing care may remain uneven in remote areas, where workforce distribution and retention can constrain service delivery [5]. In Tibetan-inhabited plateau regions of western China, altitude exposure, remoteness, and healthcare access vary together. These overlapping conditions make it difficult to separate biological effects of altitude from social, diagnostic, and health service influences.

Published surveys and modeled analyses have reported substantially different estimates of epilepsy prevalence in these regions [6,7,8,9]. Geographic and environmental explanations have been proposed for regional variation [6]. However, residence in a plateau region does not establish an individual’s chronic altitude exposure. For descriptive consistency, this review uses high altitude to denote elevations of at least 2500 m when source data permit; this threshold is descriptive and does not imply a biological cutoff for epilepsy risk [10]. Epilepsy is distinguished from an isolated seizure and from an acute symptomatic seizure occurring in close temporal association with an acute insult [11,12].

Healthcare access and effective coverage are also distinct. Access reflects whether people can obtain and use services when needed. Effective coverage reflects receipt of care that is adequate to improve health outcomes, not simply contact with services [13,14,15]. These distinctions are important when interpreting regional variation in recorded prevalence, treatment, and outcomes.

This review addresses three questions: (1) what available studies show about epilepsy prevalence, etiologies, treatment, and outcomes in these regions; (2) whether available evidence supports an independent effect of chronic altitude exposure on epilepsy among long-term residents; and (3) which healthcare and public health priorities warrant evaluation despite this uncertainty. By separating unresolved altitude attribution from more directly supported healthcare needs, the review identifies priorities that can be evaluated without assuming a causal effect of altitude. Four explicitly defined features guide our assessment of evidence for a chronic-altitude effect.

2. Methods

We conducted a narrative review of peer-reviewed evidence relevant to epilepsy in Tibetan-inhabited plateau regions of western China. A narrative approach was appropriate because the evidence spans population surveys, clinical cohorts, modeled estimates, biological studies, and health service research, with substantial differences in populations, exposures, outcomes, and study purposes. Throughout this review, “Tibetan-inhabited plateau regions” is used as a sociogeographic descriptor. We classified studies as directly relevant when participants were sampled from the Tibet Autonomous Region or from Tibetan autonomous prefectures or counties in western China. Studies from neighboring areas or mixed populations were classified as indirect evidence unless results for the target region were reported separately; examples include a physician survey combining Lhasa and Xichang, a rural management cohort from counties outside the target plateau setting, and a military cohort outside the target region. We treated administrative location, ethnicity, place of residence, and individual altitude exposure as distinct concepts.

Targeted searches of PubMed/MEDLINE and Web of Science Core Collection were conducted on 12 June 2026. The searches combined epilepsy- and seizure-related terms with terms describing the Tibetan-inhabited plateau regions or altitude exposure; the database-specific strategies and record flow are reported in Supplementary Table S1. Backward and forward citation tracking supplemented the database searches. Eligible sources were peer-reviewed journal articles published in English through 12 June 2026. Chinese-language publications and non-journal reports were outside the scope of this review. Statements that no study of a particular design was identified are limited to the literature retrieved for this review.

We selected sources that informed epilepsy prevalence or distribution; potentially preventable or modifiable etiologies; status epilepticus; treatment continuity or effective coverage; mortality; diagnostic or workforce capacity; mental health comorbidity; biological plausibility; or seizures after recent or subacute altitude exposure. When sources addressed similar questions, we emphasized those with explicit case definitions, defined denominators, and measures of uncertainty. For core sources, we documented the setting and study period, population and residency criteria, outcome definitions and ascertainment, sample size, major estimates, relevance to chronic altitude exposure, and principal limitations.

We assessed evidence for an effect of chronic altitude exposure using four review-defined features (Table 1): temporally appropriate measurement of chronic altitude exposure; comparable epilepsy ascertainment across populations; an informative contrast in altitude exposure; and appropriate handling of major social, etiologic, diagnostic, and health system factors. The four domains were specified before appraisal, drawing on epidemiologic principles of exposure measurement, outcome ascertainment, exposure contrast, and confounding, as well as established standards for epilepsy epidemiology [16]. Their wording was refined during manuscript preparation, but the domains remained unchanged throughout the appraisal. We synthesized the findings narratively because populations, outcomes, exposure measures, and study objectives differed across sources. We did not pool community prevalence estimates because differences in case definitions, sampling, study periods, and diagnostic ascertainment made it implausible that the surveys estimated a common underlying prevalence. We report confidence or uncertainty intervals when available in the original publications and did not calculate additional intervals.

We conducted a structured qualitative appraisal of the ten sources in Table 2 and the two regional studies of parasitic disease described in Section 3.2 (Supplementary Table S2). For each source, we evaluated sampling and selection, outcome ascertainment, exposure or setting characterization, analysis and contextual factors, precision, and applicability. We also assessed sources relevant to altitude exposure against the four features in Table 1. We assigned no summary scores. The appraisal domains are not a validated risk-of-bias instrument. Yulong Li and Yixiu Lin conducted the appraisal jointly through discussion; they did not perform independent duplicate appraisals.

3. Results

Table 2 summarizes the main evidence and its limitations. Supplementary Table S2 presents the structured appraisal.

3.1. Population Epidemiology and Limits of Inference About Chronic Altitude

Three community surveys reported substantially different prevalence estimates among residents. A 2006 household survey of 14,822 rural residents reported a lifetime prevalence of convulsive epilepsy of 2.5 per 1000 (95% CI 1.8–3.4) and an active prevalence of 2.4 per 1000 (95% CI 1.7–3.3) [7]. A 2008 household survey of 7669 residents across 45 villages in two Zayul County towns reported a lifetime prevalence of convulsive epilepsy of 23.5 per 1000 (95% CI 20.1–26.9) and an active prevalence of 22.8 per 1000 (95% CI 19.5–26.1) [8]. In Daofu County, a 2025 survey of 37,390 permanent residents identified 164 cases using the 2014 International League Against Epilepsy definition. The crude prevalence was 4.4 per 1000 (95% CI 3.7–5.1) [9].

The two earlier surveys assessed convulsive epilepsy without routinely using electroencephalography (EEG) or neuroimaging to ascertain cases. In the Zayul survey, 25 of 180 cases (13.9%) were classified as alcohol-related [8]. Some alcohol-related events may have been acute symptomatic seizures, which alone do not establish a diagnosis of epilepsy [11,12]. This distinction adds uncertainty to comparisons across surveys. Among cases identified in Daofu, 82.9% reported prior computed tomography (CT) or magnetic resonance imaging (MRI), and 78.0% reported prior EEG [9]. The surveys differed in location, study period, sampling, case definition, and ascertainment. Their prevalence estimates are therefore not directly comparable. No population-based incidence study of long-term residents was identified through this review.

Participant-level residential altitude was not reported in any of the three community surveys [7,8,9]. These data cannot support an individual-level altitude–response analysis. Residence in a plateau administrative region is not a direct measure of lifetime altitude exposure.

A national synthesis reported Tibet-specific estimates ranging from 2.42 to 23.47 per 1000. The largest contributing survey reported the lowest estimate, whereas the smallest reported the highest. The high-prevalence corridor described in that synthesis was not defined by measured altitude and lay well below plateau elevations [6]. This synthesis included the two earlier surveys discussed above [7,8] and does not provide independent replication of their findings. International evidence also shows substantial heterogeneity in prevalence estimates according to rurality, study size, case definition, and ascertainment [16,17,18]. GBD 2019 modeled an age-standardized epilepsy prevalence for Tibet of 438.85 per 100,000 (95% uncertainty interval 115.95–740.52), compared with 219.69 per 100,000 nationally [19]. These GBD estimates refer to the modeled idiopathic epilepsy cause category rather than to epilepsy of all etiologies [1,19]. This modeled, province-level age-standardized estimate measures a different quantity from the crude community survey estimates; direct numerical comparison is inappropriate. The wide uncertainty interval indicates substantial imprecision.

Evidence from recent or subacute ascent concerns a different exposure and outcome. A prospective military cohort outside the target region followed 39,213 healthy adult men who had ascended from low altitude and stayed at elevations of at least 2500 m for more than 30 days. During 39,848.6 person-years, 41 new-onset seizures occurred, corresponding to 102.9 per 100,000 person-years (95% CI 75.8–139.7); 12 were associated with cerebral venous thrombosis [20]. Exposure was recorded in broad altitude categories. There was no concurrent low-altitude comparison group, and only two events occurred above 5800 m. The outcome was new-onset seizure, not incident epilepsy. The study therefore does not estimate epilepsy incidence among acclimatized long-term residents.

Hypobaric hypoxia has been proposed to modify seizure susceptibility through oxidative, inflammatory, vascular, and neuronal pathways [21,22]. However, this evidence is experimental or indirect and cannot establish whether chronic altitude exposure changes epilepsy risk among long-term residents. Physiologic and genetic adaptation among Tibetan highlanders further limits extrapolation from recent ascent to lifelong residence [23]. No study of long-term residents identified in this review reported all four review-defined features used here to evaluate causal claims about chronic altitude exposure (Table 1; Supplementary Table S2).

3.2. Potentially Preventable or Modifiable Etiologies

In the Daofu community survey, investigators attributed epilepsy to intracranial parasitic infection in 16.5% of identified cases, traumatic brain injury in 11.0%, and stroke in 7.3%; the cause was classified as unknown in 32.3% [9]. A retrospective comparison included 165 inpatients with epilepsy in Ganzi and 165 age- and sex-matched inpatients in Chengdu. Among patients in Ganzi, reported etiologies included head trauma in 20.6%, stroke in 10.9%, neurocysticercosis in 7.9%, cerebral echinococcosis in 6.7%, and tuberculous infection in 5.5%. Infectious etiologies were more frequent in Ganzi than in Chengdu (24.8% vs. 7.3%; unadjusted odds ratio 4.22, 95% CI 2.12–8.37) [24]. The inpatient groups were matched on age and sex, but the reported odds ratio was not adjusted using a multivariable model. The cohorts differed substantially in residence, education, occupation, ethnic composition, and diagnostic practice. The difference in infectious etiologies cannot be attributed to altitude, and the inpatient proportions should not be interpreted as population estimates.

Two regional studies provide further context on parasitic exposures and associated neurologic disease. In a survey of 661 Tibetan volunteers in one township of Yajiang County, Ganzi, 56 participants (8.5%) were identified as having symptoms suggestive of late-onset epilepsy. Among tested participants classified as having epilepsy, 9 of 55 (16.4%) were seropositive for Taenia solium cysticercosis antibodies, compared with 11 of 445 (2.5%) participants without epilepsy [25]. The site was selected after hospital reports of cysticercosis, and epilepsy was assessed by questionnaire and clinical examination without neuroimaging. Seropositivity alone cannot establish neurocysticercosis as the cause of epilepsy. No T. solium carriers were identified among 21 confirmed tapeworm carriers. These data indicate local exposure to cysticercosis but cannot establish a representative epilepsy prevalence or an etiologic fraction. In a Ganzi hospital cohort of 97 patients with intracranial alveolar echinococcosis, 20 (20.6%) had epilepsy. The investigators reported an association between cortical involvement and epilepsy in multivariable logistic regression, with a wide confidence interval; 13 of the 16 patients receiving antiseizure medication had unsatisfactory seizure control [26].

Evidence of parasitic, traumatic, and vascular etiologies in community and clinical studies suggests potential prevention priorities. Neurocysticercosis is a preventable cause of acquired epilepsy in endemic settings [27]. Clinical and imaging findings are central to diagnostic criteria; serology alone is insufficient [28,29]. Studies in endemic settings also document neurocysticercosis among people with epilepsy [30]. Control of Taenia solium transmission depends on the local enabling environment as well as on the technical intervention itself [31]. Echinococcosis has imposed a substantial burden in parts of the Tibetan Plateau [32] and requires species- and setting-specific control [33]. Central nervous system infection can produce acute symptomatic seizures and, after a latent interval, acquired epilepsy through inflammatory and structural injury [34]. These findings support evaluating prevention strategies but do not establish the population-attributable burden of any specific cause.

3.3. Treatment Continuity, Effective Coverage, and Severe Outcomes

The two historical surveys reported large treatment gaps. Both defined the treatment gap by the absence of optimal, regular antiseizure medication during the week before the survey among people with active convulsive epilepsy. By this definition, the gap was 97% (34 of 35) in the 2006 survey [7]. This does not mean that 97% received no treatment of any kind. In the Zayul survey, the gap was 100%, and none of the 175 people with active epilepsy reported taking either antiseizure medication or traditional Tibetan medicine during that week [8]. In Zayul, the surveyed health facilities, including the county hospital, did not provide conventional antiseizure medication, and no local health worker had received formal training in epilepsy care [8]. Both estimates reflect historical definitions and local service conditions, not current treatment coverage. The International League Against Epilepsy (ILAE) Epidemiology Commission has highlighted variation in treatment-gap definitions and proposed separate diagnostic and therapeutic components [35]. By contrast, the Daofu study reported treatment-status categories rather than a comparable treatment-gap estimate [9].

The more recent Daofu study documents medication use and contact with specialist care, but these measures do not establish effective coverage. In Daofu, 83.5% of all 164 identified cases were using at least one antiseizure medication, and 87.8% had sought tertiary care. Among 127 participants assessed in detail, investigators classified 33.1% as receiving nonstandard treatment and 14.2% as untreated [9]. Medication receipt alone does not establish appropriate, continuous, or effective care. Measures of effective coverage should include treatment appropriateness, retention, seizure control, adverse effects, and quality of life [14,15].

In a two-center study of status epilepticus, 223 of 318 patients admitted in Tibet (70.1%) had previously diagnosed epilepsy with inadequate seizure control. Of these, 111 had never received an antiseizure medication, and 52 (23.3%) had received treatment that the investigators judged inappropriate; 40 had used traditional Tibetan medicine alone [36]. These categories reflect the investigators’ definitions and do not establish patient nonadherence or treatment preferences. No nonconvulsive status epilepticus was recorded in Tibet, and EEG and lumbar puncture were used less often [36]. Unadjusted outcome comparisons cannot establish differences in hospital performance. These findings motivate evaluation of whether continuity of epilepsy care, rescue planning, and timely referral can prevent some episodes of status epilepticus. Historical treatment-gap estimates should not be compared directly with contemporary medication use because definitions of active, untreated, and traditionally treated epilepsy differ across studies [37,38,39].

Evidence on mortality in the target population remains indirect. GBD 2019 modeled an age-standardized mortality rate for idiopathic epilepsy in Tibet of 4.26 per 100,000 (95% uncertainty interval 1.43–5.66) [19]. This model-based population mortality rate is distinct from the mortality rate among people with epilepsy. A management cohort in 10 rural counties of Sichuan recorded 44 probable cases of sudden unexpected death in epilepsy (SUDEP) during 31,347 person-years among 10,128 people with convulsive epilepsy. The reported SUDEP incidence was lower during follow-up years 6–8 than during years 1–5 (incidence rate ratio 0.4, 95% CI 0.2–0.8) [40]. The cohort was uncontrolled and not plateau-specific, so it cannot estimate plateau SUDEP. The study nevertheless demonstrates that follow-up, medication supply, and death ascertainment can be organized in a rural management program [40]. Future regional mortality surveillance could include structured ascertainment of SUDEP [41]. More generally, effective coverage should be assessed by outcomes such as seizure control rather than medication receipt alone [14,15].

3.4. Diagnostic and Referral Capacity, Workforce, and Mental Health

Available studies suggest variation in diagnostic and workforce capacity but are not representative of the entire region. In the Ganzi inpatient comparison, EEG had been used in 30.9% of patients, compared with 91.5% in Chengdu [24]. A 2026 convenience survey of 325 physicians attending epilepsy training found that 73.97% of the Chengdu participants were neurologists, compared with 12.85% of the investigators’ combined plateau group [42]. The investigators reported no statistically significant differences in neurologist knowledge scores between groups. However, the plateau subgroup included only 23 neurologists, and the convenience sample cannot estimate workforce density or clinical competence. The plateau group combined Lhasa and Xichang. Because Xichang lies outside this review’s target region, the combined results provide only indirect evidence for the plateau population.

China has developed a tiered network of epilepsy centers [43]. This network could support referrals and specialist consultation, but its reach, quality, and equity in plateau counties have not been evaluated. Remote review of EEG, imaging, and clinical information and locally adapted community health worker or mobile health models are potential service approaches [44,45]. Their effectiveness in the target region remains untested.

Mental health care is an important consideration in designing epilepsy services. Among the 127 participants assessed in Daofu, 45 (35.4%; 95% CI 27.1–43.8) screened positive for depressive symptoms and 66 (52.0%; 95% CI 43.3–60.7) screened positive for anxiety symptoms [9]. These symptoms were assessed using Tibetan-language translations of the Chinese Neurological Disorders Depression Inventory for Epilepsy and the Generalized Anxiety Disorder-7 scale, respectively. Psychiatric comorbidity is more common in people with epilepsy than in the general population and can add substantially to disability and impaired quality of life [46,47]. These proportions come from one subgroup and should not be generalized to the entire regional epilepsy population. They support evaluating mental health screening and referral as part of epilepsy care.

healthcare-14-03511-t002_Table 2Table 2Selected Evidence Informing the Review.

Study and Design Population and Outcome Main Findings Principal Inferential Limitation

Zhao et al., 2008 [7]; door-to-door survey, 2006 14,822 rural residents in the Lhasa and Chamdo areas; lifetime convulsive epilepsy Crude prevalence 2.5/1000 (95% CI 1.8–3.4); active 2.4/1000 (95% CI 1.7–3.3); 34 of 35 active cases had not received optimal, regular ASM in the preceding week No participant-level altitude data; few cases; EEG and imaging not routinely used to ascertain epilepsy; historical survey

Zhao et al., 2010 [8]; door-to-door survey, 2008 7669 residents across 45 villages in two Zayul County towns; convulsive epilepsy Crude lifetime prevalence 23.5/1000 (95% CI 20.1–26.9); active 22.8/1000 (95% CI 19.5–26.1); 100% treatment gap; neither antiseizure medication nor traditional Tibetan medicine reported in the preceding week No participant-level altitude data; no EEG or neuroimaging for case ascertainment; 13.9% classified as alcohol-related

Wang et al., 2026 [9]; community survey, 2025 37,390 permanent residents in Daofu County; ILAE-defined epilepsy (164 cases); 127 assessed in detail Crude prevalence 4.4/1000 (95% CI 3.7–5.1); parasitic 16.5%, traumatic 11.0%, stroke 7.3%, unknown 32.3% a; medication use 83.5% a; nonstandard treatment 33.1% and untreated 14.2% b Single county; no altitude contrast; potential underascertainment of subtle or nonconvulsive seizures

Wu et al., 2022 [6]; national synthesis Published prevalence surveys across China; five Tibet-specific surveys Tibet-specific estimates 2.42–23.47/1000; the largest survey produced the lowest estimate; the proposed high-prevalence belt was not altitude-defined Ecological synthesis; heterogeneous study periods, designs, and case definitions

Liu et al., 2023 [19]; GBD 2019 modeling Province-level estimates for China Modeled, age-standardized prevalence of idiopathic epilepsy in Tibet 438.85/100,000 (95% UI 115.95–740.52); age-standardized mortality rate 4.26/100,000 (95% UI 1.43–5.66) Modeled province-level estimates; sparse regional inputs; altitude not measured as an exposure; not comparable with crude survey estimates

Chen et al., 2018 [24]; retrospective inpatient comparison 165 Ganzi and 165 age- and sex-matched Chengdu inpatients with epilepsy Infectious etiologies 24.8% vs. 7.3% (unadjusted OR 4.22, 95% CI 2.12–8.37); EEG use 30.9% vs. 91.5% Hospital-based selection; socioeconomic and diagnostic differences; altitude not measured

Peng et al., 2025 [36]; two-center status epilepticus study, 2015–2020 318 patients in Tibet and 301 in Chengdu with status epilepticus 223 (70.1%) had inadequately controlled preexisting epilepsy; 111 had never received antiseizure medication, and 52 (23.3%) had received treatment judged inappropriate Different diagnostic ascertainment; no nonconvulsive status epilepticus recorded; crude outcomes do not measure comparative hospital quality

Wang et al., 2021 [40]; rural management cohort 10,128 people with convulsive epilepsy; 31,347 person-years 44 probable SUDEP cases; incidence lower in years 6–8 than in the first 5 years (IRR 0.4, 95% CI 0.2–0.8) Not specific to the target plateau region; uncontrolled; program effects cannot be inferred

Xiao et al., 2026 [42]; physician training survey 325 physicians recruited in Chengdu, Lhasa, and Xichang Neurologists comprised 73.97% of the Chengdu group and 12.85% of the combined plateau group; no statistically significant difference in neurologist knowledge scores reported (23 in the plateau subgroup) Convenience sample; Xichang and Lhasa grouped; cannot estimate workforce density or competence

Srinath et al., 2022 [20]; prospective military cohort 39,213 healthy adult men after ascent to at least 2500 m; 39,848.6 person-years 41 new-onset seizures; 102.9/100,000 person-years (95% CI 75.8–139.7); 12 associated with cerebral venous thrombosis Recent ascent rather than lifelong residence; broad exposure categories; no low-altitude comparator; new-onset seizures, not incident epilepsy

Prevalence estimates from community surveys are crude; GBD estimates are modeled, age-standardized, and refer to the idiopathic epilepsy cause category. a Denominator, 164 identified cases. b Denominator, 127 participants assessed in detail; the Daofu prevalence refers to 37,390 residents. No study of a resident population identified in this review reported all four review-defined features relevant to causal interpretation of chronic altitude exposure (Table 1; Supplementary Table S2). ASM, antiseizure medication; CI, confidence interval; EEG, electroencephalography; GBD, Global Burden of Disease; ILAE, International League Against Epilepsy; IRR, incidence rate ratio; OR, odds ratio; SUDEP, sudden unexpected death in epilepsy; UI, uncertainty interval.

4. Discussion

Regional studies provide stronger evidence of unmet healthcare needs and potentially modifiable causes than of an independent effect of chronic altitude exposure. Community estimates of epilepsy frequency are highly heterogeneous. Available population studies identified in this review do not combine direct, temporally appropriate exposure measurement with comparable epilepsy ascertainment, an informative altitude contrast, and adequate handling of major contextual factors. Whether chronic altitude exposure independently affects epilepsy risk remains unresolved. The evidence neither establishes nor excludes such an effect. This uncertainty does not preclude identification of healthcare priorities supported by more direct regional evidence.

Altitude, remoteness, and access to care may influence observed epilepsy patterns through distinct mechanisms. Experimental and indirect evidence suggests that chronic hypobaric hypoxia could affect seizure susceptibility [21,22]. Whether this alters epilepsy risk among long-term residents remains unknown. Terrain, travel time, clinician availability, household resources, and diagnostic capacity may also affect case detection, treatment continuity, and survival. Differences in measurement further complicate interpretation. Incomplete case finding may reduce recorded prevalence without changing disease incidence. Differences in access to EEG and imaging can affect diagnostic confirmation and etiologic classification, and therefore the comparability of recorded prevalence. Prevalence also depends on incidence, remission, and mortality [16,17,18]. Regional differences therefore cannot be attributed to altitude without an explicit causal framework and comparable measurement across populations. The same distinction matters for healthcare planning because service access, diagnostic intensity, and treatment continuity are measurable domains that can be evaluated without assuming an altitude effect. Recent-ascent cohorts, experimental studies, non-plateau cohorts, and convenience samples can inform biological hypotheses or service planning. They cannot directly estimate population-level effects among long-term residents of the target region.

The causal role of a contextual factor depends on the question being asked and when that factor occurs. Remoteness, socioeconomic conditions, and occupational or household exposure to parasites may confound an altitude–epilepsy association if they are associated with both residential altitude and epilepsy risk and are not themselves consequences of altitude. If residence at higher altitude increases travel barriers and limits access to care, healthcare access may mediate effects on subsequent epilepsy outcomes. Hypoxia-related vascular or neuronal changes are other possible mediating pathways [21,22], but their contribution to epilepsy risk among long-term residents has not been established. Genetic or physiologic adaptation, duration of residence, and age at exposure may modify any effect of hypobaric hypoxia [23]. Diagnostic capacity chiefly affects measurement: EEG and imaging availability can influence case ascertainment, etiologic classification, and recorded prevalence without necessarily changing underlying epilepsy risk [16,17,18]. Lower case detection in remote settings could reduce recorded prevalence, whereas differences in etiologic exposures could produce apparent altitude-related associations; the net direction of bias cannot be determined from the available data. Future studies should specify the hypothesized causal relationships in advance rather than adjust indiscriminately for all contextual variables.

These findings illustrate a broader challenge in remote settings: environmental exposure, remoteness, diagnostic intensity, and access to continuing care may vary together. Without separate measurement of these factors, geographic differences may be incorrectly attributed to altitude alone. The four review-defined features in Table 1 make explicit the limitations of causal claims based on geographic exposure proxies.

The available evidence provides a clearer basis for setting healthcare and public health research priorities. Prevention research can prioritize locally documented acquired causes [9,24]. Evaluation of setting-specific measures to control Taenia solium and Echinococcus transmission is warranted by locally documented parasitic etiologies [9,24,25,26], the echinococcosis burden reported for parts of the Tibetan Plateau [32], and established prevention frameworks [31,33]. Injury prevention, vascular risk reduction, and stroke care are additional priorities suggested by the traumatic and vascular etiologies reported in the local community and inpatient studies [9,24]. Epilepsy care should be assessed by effective coverage, not medication receipt alone: appropriate treatment, continuity, retention, seizure control, adverse effects, and quality of life [14,15]. Diagnostic and referral services can be evaluated using interpretable EEG availability, reporting times, completion of indicated CT or MRI, access to neuroradiology review, referral completion, and the time and cost required to reach care. Remote specialist support could expand access to expertise but should complement local services and be evaluated for accountability, data governance, and equitable access [44].

Workforce planning requires representative data on clinician distribution, training, and retention; convenience samples cannot provide these estimates [5,42]. Regional surveillance should use standardized case definitions, structured death ascertainment, and repeated measurement of prevalence, incidence when feasible, treatment gaps, and effective coverage [16,41]. Mental health assessment should be evaluated as an integral part of epilepsy services [46,47]. Figure 1 summarizes the distinction between evidence-supported healthcare priorities and the unresolved chronic-altitude question. Table 3 presents measurable domains for prospective evaluation. These domains warrant prospective evaluation; the effectiveness of specific interventions in this setting has not been established.

Evaluating healthcare interventions and testing the chronic-altitude hypothesis require different study designs. Service interventions should be evaluated using designs capable of estimating their effects. For phased implementation, stepped-wedge trials or difference-in-differences designs may be appropriate when their assumptions are satisfied. More informative evidence on chronic altitude exposure would come from multisite incidence cohorts or repeated surveys with harmonized International League Against Epilepsy case definitions and epidemiologic methods [11,12,16,48]. Such studies should measure altitude directly, record lifetime residential history and migration, and prespecify potential confounders, mediators, and effect modifiers. Informative altitude contrasts would also require comparable case ascertainment and measurement of diagnostic intensity and relevant social and health system factors.

Several limitations should be considered. The searches were targeted rather than exhaustive and were restricted to PubMed/MEDLINE, Web of Science, and English-language peer-reviewed literature; relevant studies indexed elsewhere or published in other languages may therefore have been missed. Restriction to published English-language articles introduces potential publication and language bias, particularly because some regional surveys and service reports are published only in Chinese. Statements that no qualifying study was identified should be interpreted as the yield of this review rather than proof of absence. Evidence available only in reports, policy documents, theses, websites, or conference proceedings was excluded. The included community studies used different epilepsy and treatment definitions. Clinical cohorts were subject to referral and admission selection; workforce data came from a convenience sample; and modeled estimates relied on limited regional inputs. Some studies shared investigators or institutions, and patient populations may overlap across hospital-based reports. We did not access unpublished or participant-level data. The heterogeneity of the available studies precluded a meaningful pooled prevalence estimate, and the evidence did not permit estimation of population-attributable fractions. Affordability, travel burden, stigma, language access, and cultural acceptability were not directly assessed in the included studies and warrant evaluation in the target population.

5. Conclusions

The studies identified in this review cannot establish whether chronic altitude exposure independently affects epilepsy incidence or prevalence among long-term residents of Tibetan-inhabited plateau regions of western China. Lack of sufficient evidence should not be interpreted as evidence of no effect. Regional studies more directly document selected infectious, traumatic, and vascular etiologies, historical treatment gaps, challenges in treatment continuity, and uneven diagnostic capacity. In one assessed community subgroup, 35.4% screened positive for depressive symptoms and 52.0% for anxiety symptoms.

Priorities for prospective evaluation include prevention of locally relevant acquired causes, treatment continuity and effective coverage, diagnostic and referral services, workforce development, mental health integration, and region-specific surveillance. These priorities can be studied without first resolving the chronic-altitude question. Studies addressing the altitude hypothesis should measure exposure directly, compare informative altitude ranges, harmonize epilepsy ascertainment, and prespecify causal models that account for remoteness, social conditions, diagnostic practices, and healthcare access. The review-defined features may also guide appraisal of future studies using geographic proxies for environmental exposure.

References

1.GBD 2021 Epilepsy CollaboratorsGlobal, regional, and national burden of epilepsy, 1990–2021: A systematic analysis for the Global Burden of Disease Study 2021 Lancet Public Health 2025 10 e203 e227 10.1016/s2468-2667(24)00302-5 40015291 PMC11876103

2.Meyer A.C. Dua T. Ma J. Saxena S. Birbeck G. Global disparities in the epilepsy treatment gap: A systematic review Bull. World Health Organ. 2010 88 260 266 10.2471/blt.09.064147 20431789 PMC2855595

3.Newton C.R. Garcia H.H. Epilepsy in poor regions of the world Lancet 2012 380 1193 1201 10.1016/s0140-6736(12)61381-6 23021288

4.Ding D. Zhou D. Sander J.W. Wang W. Li S. Hong Z. Epilepsy in China: Major progress in the past two decades Lancet Neurol. 2021 20 316 326 10.1016/s1474-4422(21)00023-5 33743240

5.Dolea C. Stormont L. Braichet J.M. Evaluated strategies to increase attraction and retention of health workers in remote and rural areas Bull. World Health Organ. 2010 88 379 385 10.2471/blt.09.070607 20461133 PMC2865654

6.Wu L. Ye Z. Li Y. Luo M. Li S. Mi H. Qiu Z. Jiang Y. Is there an epilepsy belt of high prevalence rate in China? Front. Neurol. 2022 13 99430510.3389/fneur.2022.994305 36341118 PMC9626959

7.Zhao Y. Zhang Q. Tsering T. Sangwan Hu X. Liu L. Shang H. Chen Q. Liu Y. Yang X. Prevalence of convulsive epilepsy and health-related quality of life of the population with convulsive epilepsy in rural areas of Tibet Autonomous Region in China: An initial survey Epilepsy Behav. 2008 12 373 381 10.1016/j.yebeh.2007.10.012 18180204

8.Zhao Y.H. Zhang Q. Long N. Yang C. Hong J. Mu L. Zhou D. Prevalence of epilepsy and alcohol-related risk in Zayul County, Tibet Autonomous Region in China: An initial survey Epilepsy Behav. 2010 19 635 638 10.1016/j.yebeh.2010.09.025 20961814

9.Wang C. Chen D. Zhao L. Liu F. Zhang L. Liu X. Liu L. Clinical characteristics and factors associated with psychiatric comorbidity among people with epilepsy in Ganzi Tibetan autonomous prefecture of China: A cross-sectional study Acta Epileptol. 2026 8 16 10.1186/s42494-026-00256-4 41943067 PMC13054977

10.Bärtsch P. Swenson E.R. Acute high-altitude illnesses N. Engl. J. Med. 2013 368 2294 2302 10.1056/nejmcp1214870 23758234

11.Fisher R.S. Acevedo C. Arzimanoglou A. Bogacz A. Cross J.H. Elger C.E. Engel J. Jr.Forsgren L. French J.A. Glynn M. ILAE official report: A practical clinical definition of epilepsy Epilepsia 2014 55 475 482 10.1111/epi.12550 24730690

12.Beghi E. Carpio A. Forsgren L. Hesdorffer D.C. Malmgren K. Sander J.W. Tomson T. Recommendation for a definition of acute symptomatic seizure Epilepsia 2010 51 671 675 10.1111/j.1528-1167.2009.02285.x 19732133

13.Levesque J.F. Harris M.F. Russell G. Patient-centred access to health care: Conceptualising access at the interface of health systems and populations Int. J. Equity Health 2013 12 18 10.1186/1475-9276-12-18 23496984 PMC3610159

14.Kruk M.E. Gage A.D. Arsenault C. Jordan K. Leslie H.H. Roder-DeWan S. Adeyi O. Barker P. Daelmans B. Doubova S.V. High-quality health systems in the Sustainable Development Goals era: Time for a revolution Lancet Glob. Health 2018 6 e1196 e1252 10.1016/s2214-109x(18)30386-3 30196093 PMC7734391

15.Ng M. Fullman N. Dieleman J.L. Flaxman A.D. Murray C.J. Lim S.S. Effective coverage: A metric for monitoring Universal Health Coverage PLoS Med. 2014 11 e100173010.1371/journal.pmed.1001730 25243780 PMC4171091

16.Thurman D.J. Beghi E. Begley C.E. Berg A.T. Buchhalter J.R. Ding D. Hesdorffer D.C. Hauser W.A. Kazis L. Kobau R. Standards for epidemiologic studies and surveillance of epilepsy Epilepsia 2011 52 2 26 10.1111/j.1528-1167.2011.03121.x 21899536

17.Ngugi A.K. Bottomley C. Kleinschmidt I. Sander J.W. Newton C.R. Estimation of the burden of active and life-time epilepsy: A meta-analytic approach Epilepsia 2010 51 883 890 10.1111/j.1528-1167.2009.02481.x 20067507 PMC3410521

18.Fiest K.M. Sauro K.M. Wiebe S. Patten S.B. Kwon C.S. Dykeman J. Pringsheim T. Lorenzetti D.L. Jetté N. Prevalence and incidence of epilepsy: A systematic review and meta-analysis of international studies Neurology 2017 88 296 303 27986877 10.1212/WNL.0000000000003509 PMC5272794

19.Liu W. Xu Y. Lin Y. Wang L. Zhou M. Yin P. Zhao G. Burden of epilepsy in China and its provinces, 1990 to 2019: Findings from the Global Burden of Disease Study 2019 Chin. Med. J. 2023 136 305 312 10.1097/cm9.0000000000002526 36752807 PMC10106145

20.Srinath R. Ahmad F. Asturkar V. Mathur A. Sondhi V. Nanda S.K. New-onset seizure at high altitude among healthy males Seizure 2022 97 82 87 10.1016/j.seizure.2022.03.006 35364357

21.Wilson M.H. Newman S. Imray C.H. The cerebral effects of ascent to high altitudes Lancet Neurol. 2009 8 175 191 10.1016/s1474-4422(09)70014-6 19161909

22.Xu Y. Fan Q. Relationship between chronic hypoxia and seizure susceptibility CNS Neurosci. Ther. 2022 28 1689 1705 10.1111/cns.13942 35983626 PMC9532927

23.Petousi N. Robbins P.A. Human adaptation to the hypoxia of high altitude: The Tibetan paradigm from the pregenomic to the postgenomic era J. Appl. Physiol. 2014 116 875 884 10.1152/japplphysiol.00605.2013 24201705 PMC3972749

24.Chen J. Wu X. He Y. Li S. Deng Y. Chen J. Fang W. Zeren Z. Peng J. Li Y. A retrospective analysis of the clinical features of inpatients with epilepsy in the Ganzi Tibetan Autonomous Prefecture Front. Neurol. 2018 9 89110.3389/fneur.2018.00891 30425677 PMC6218953

25.Li T. Craig P.S. Ito A. Chen X. Qiu D. Qiu J. Sato M.O. Wandra T. Bradshaw H. Li L. Taeniasis/cysticercosis in a Tibetan population in Sichuan Province, China Acta Trop. 2006 100 223 231 10.1016/j.actatropica.2006.11.003 17166477

26.Li S. Chen J. He Y. Chen J. Liao S. Deng Y. Fang W. Zeren Z. Lin M. Yan B. Incidence and risk factors associated with the development of epilepsy in patients with intracranial alveolar echinococcosis Epilepsy Res. 2021 174 106643 10.1016/j.eplepsyres.2021.106643 33964794

27.Ndimubanzi P.C. Carabin H. Budke C.M. Nguyen H. Qian Y.J. Rainwater E. Dickey M. Reynolds S. Stoner J.A. A systematic review of the frequency of neurocyticercosis with a focus on people with epilepsy PLoS Negl. Trop. Dis. 2010 4 e87010.1371/journal.pntd.0000870 21072231 PMC2970544

28.White A.C. Jr.Coyle C.M. Rajshekhar V. Singh G. Hauser W.A. Mohanty A. Garcia H.H. Nash T.E. Diagnosis and treatment of neurocysticercosis: 2017 clinical practice guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH) Clin. Infect. Dis. 2018 66 1159 1163 10.1093/cid/ciy157 29617787 PMC5889044

29.Del Brutto O.H. Nash T.E. White A.C. Jr.Rajshekhar V. Wilkins P.P. Singh G. Vasquez C.M. Salgado P. Gilman R.H. Garcia H.H. Revised diagnostic criteria for neurocysticercosis J. Neurol. Sci. 2017 372 202 210 10.1016/j.jns.2016.11.045 28017213

30.Stelzle D. Schmidt V. Keller L. Ngowi B.J. Matuja W. Escheu G. Hauke P. Richter V. Ovuga E. Pfausler B. Characteristics of people with epilepsy and neurocysticercosis in three eastern African countries—A pooled analysis PLoS Negl. Trop. Dis. 2022 16 e001087010.1371/journal.pntd.0010870 36342903 PMC9639810

31.Ngwili N. Johnson N. Wahome R. Githigia S. Roesel K. Thomas L. A qualitative assessment of the context and enabling environment for the control of Taenia solium infections in endemic settings PLoS Negl. Trop. Dis. 2021 15 e000947010.1371/journal.pntd.0009470 34115758 PMC8221787

32.Budke C.M. Qiu J. Zinsstag J. Wang Q. Torgerson P.R. Use of disability adjusted life years in the estimation of the disease burden of echinococcosis for a high endemic region of the Tibetan plateau Am. J. Trop. Med. Hyg. 2004 71 56 64 10.4269/ajtmh.2004.71.56 15238690

33.Craig P.S. McManus D.P. Lightowlers M.W. Chabalgoity J.A. Garcia H.H. Gavidia C.M. Gilman R.H. Gonzalez A.E. Lorca M. Naquira C. Prevention and control of cystic echinococcosis Lancet Infect. Dis. 2007 7 385 394 10.1016/s1473-3099(07)70134-2 17521591

34.Vezzani A. Fujinami R.S. White H.S. Preux P.M. Blümcke I. Sander J.W. Löscher W. Infections, inflammation and epilepsy Acta Neuropathol. 2016 131 211 234 10.1007/s00401-015-1481-5 26423537 PMC4867498

35.Kwon C.S. Wagner R.G. Carpio A. Jetté N. Newton C.R. Thurman D.J. The worldwide epilepsy treatment gap: A systematic review and recommendations for revised definitions—A report from the ILAE Epidemiology Commission Epilepsia 2022 63 551 564 10.1111/epi.17112 35001365

36.Peng W. Lu L. Hao Y. Xiong W. Abdulaziz A.T. Lian Y. Chen L. Wu X. Zhao Y. Zhou D. Etiological features of status epilepticus of the in-patient cohort in Tibet: A retrospective comparative study Seizure 2025 125 179 185 10.1016/j.seizure.2025.01.001 39862626

37.Singh B. Mahajan N. Singh G. Sander J.W. Temporal trends in the epilepsy treatment gap in low- and low-middle-income countries: A meta-analysis J. Neurol. Sci. 2022 434 120174 10.1016/j.jns.2022.120174 35144236

38.Mbuba C.K. Ngugi A.K. Newton C.R. Carter J.A. The epilepsy treatment gap in developing countries: A systematic review of the magnitude, causes, and intervention strategies Epilepsia 2008 49 1491 1503 10.1111/j.1528-1167.2008.01693.x 18557778 PMC3573323

39.Meyer A.C. Dua T. Boscardin W.J. Escarce J.J. Saxena S. Birbeck G.L. Critical determinants of the epilepsy treatment gap: A cross-national analysis in resource-limited settings Epilepsia 2012 53 2178 2185 10.1111/epi.12002 23106784 PMC3809906

40.Wang H. Chen D. He J. He Y. Liu L. Zhou D. Trend of sudden unexpected death in epilepsy incidence rate in rural West China Front. Neurol. 2021 12 73520110.3389/fneur.2021.735201 34630306 PMC8498108

41.Harden C. Tomson T. Gloss D. Buchhalter J. Cross J.H. Donner E. French J.A. Gil-Nagel A. Hesdorffer D.C. Smithson W.H. Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society Neurology 2017 88 1674 1680 28438841 10.1212/WNL.0000000000003685

42.Xiao X. Xiao J. Zhou C. Pan C. Hao Y. Jin M. Han M. Jiang S. Liu J. Tang Y. Epilepsy awareness among physicians in plains and plateau regions of western China: A cross-sectional study Acta Epileptol. 2026 8 11 10.1186/s42494-026-00251-9 41814440 PMC12977748

43.Lin Y. Hu S. Hao X. Duan L. Wang W. Zhou D. Wang X. Xiao B. Liu X. Wang Y. Epilepsy centers in China: Current status and ways forward Epilepsia 2021 62 2640 2650 10.1111/epi.17058 34510417

44.Dorsey E.R. Glidden A.M. Holloway M.R. Birbeck G.L. Schwamm L.H. Teleneurology and mobile technologies: The future of neurological care Nat. Rev. Neurol. 2018 14 285 297 10.1038/nrneurol.2018.31 29623949

45.Dolo H. Kamaforo M. Konipo F.D.N. Sangho O. Daou M. Camara B. Konate A. Sininta M. Sangare M. Toure D.M. Utilizing an mHealth platform and community health workers to enhance epilepsy screening and treatment in a rural setting in Mali: A closed cohort study J. Epidemiol. Glob. Health 2025 15 109 10.1007/s44197-025-00454-2 40847217 PMC12373575

46.Fiest K.M. Dykeman J. Patten S.B. Wiebe S. Kaplan G.G. Maxwell C.J. Bulloch A.G.M. Jetté N. Depression in epilepsy: A systematic review and meta-analysis Neurology 2013 80 590 599 23175727 10.1212/WNL.0b013e31827b1ae0 PMC3589287

47.Keezer M.R. Sisodiya S.M. Sander J.W. Comorbidities of epilepsy: Current concepts and future perspectives Lancet Neurol. 2016 15 106 115 10.1016/s1474-4422(15)00225-2 26549780

48.Scheffer I.E. Berkovic S. Capovilla G. Connolly M.B. French J. Guilhoto L. Hirsch E. Jain S. Mathern G.W. Moshé S.L. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology Epilepsia 2017 58 512 521 10.1111/epi.13709 28276062 PMC5386840