Cost-Effectiveness of Epilepsy Surgery in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis

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Medline, PubMed, Scopus, and Cochrane Library were searched without restrictions. Studies from World Bank-classified LMICs reporting original cost and/o cost-effectiveness data for epilepsy surgery were included. Two reviewers independently screened records, extracted data, and assessed risk of bias. Pooled seizure freedom (Engel Class I ≥ 12 months) and cost differences were analysed using random-effects Hartung-Knapp models in RevMan app. PRISMA 2020 guidelines were followed. From 20,948 records, 11 studies (2,684 patients) from seven LMICs were included. Direct surgical costs ranged from US $ 500 to US $ 14,894 (2025 USD). The pooled mean cost difference (surgery vs. medical management) was US $ 1,290 (p = 0.07; I²=100%). Surgery showed markedly superior efficacy, with pooled odds ratio for Engel Class I seizure freedom (≥ 12 months) of 22.51 (p < 0.00001; I²=9%), corresponding to 52–79.4% freedom rates in surgical groups versus 7.7–16% in medical groups. Two studies reported ICERs of approximately US $ 1,236 and US $ 26,564 per QALY gained. Epilepsy surgery in LMICs offers over 20-fold higher odds of seizure freedom at modest costs and cost-effective, supporting expansion of accessible surgical programs to reduce the treatment gap in resource-limited settings. Health sciences/Diseases Health sciences/Health care Health sciences/Medical research Health sciences/Neurology Biological sciences/Neuroscience Cost-effectiveness Epilepsy surgery Drug-resistant epilepsy Low and middle-income countries Incremental cost-effectiveness ratio Seizure freedom Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Epilepsy constitutes a major global health burden, affecting approximately 50 million individuals, of whom nearly 80% reside in low- and middle-income countries (LMICs). 1 – 3 Drug-resistant epilepsy (DRE), defined as failure of adequate trials of two tolerated and appropriately chosen antiepileptic drugs, develops in 25–40% of patients. 4 , 5 Randomised controlled trials conducted in high-income countries have demonstrated that epilepsy surgery offers seizure freedom in 60–80% of selected patients with temporal lobe epilepsy and is cost-effective when compared with continued medical management. 6 – 8 In LMICs, however, fewer than 10% of potential surgical candidates ever undergo surgery. 9 Key barriers include absence of comprehensive epilepsy centres, limited access to video-EEG monitoring, shortage of trained epileptologists and neurosurgeons, and perceived unaffordability of surgical treatment. 10 Despite these constraints, individual centres in India, Thailand and Colombia have reported successful surgery and disconnective procedures at direct up to US $ 14,894. 11 – 14 These reports suggest that curative epilepsy surgery can be delivered at a fraction of high-income country costs, yet no study has systematically pooled clinical efficacy and cost-effectiveness data exclusively from LMICs while restricting inclusion to epilepsy surgery and disconnective techniques. Previous systematic reviews have either combined high-income and low-income settings or included neuromodulation procedures such as vagus nerve stimulation, rendering their findings inapplicable to resource-constrained health systems. 15 , 16 Moreover, none have performed meta-regression to explore whether World Bank income classification, surgical volume, or use of invasive monitoring explains heterogeneity in either seizure outcome or cost. The present systematic review and meta-analysis therefore aimed to synthesise the evidence on epilepsy surgery performed exclusively in low- and middle-income countries (LMICs). The specific objectives were to demonstrate that curative surgery is already being successfully implemented across diverse LMIC settings, to estimate pooled direct surgical costs (expressed in 2025 international dollars), to determine pooled cost-effectiveness (incremental cost-effectiveness ratios where reported), and to quantify long-term clinical outcomes, specifically the pooled proportion of patients achieving seizure freedom at ≥ 12-month follow-up. This review provides the first LMIC-specific, pooled evidence base to guide national epilepsy programmes, health-technology assessment agencies, and international funding bodies in scaling up affordable surgical services, thereby reducing the treatment gap and long-term societal costs in regions carrying 80% of the global burden of drug-resistant epilepsy. Results The systematic literature search across Medline, PubMed, Scopus, and the Cochrane Library, without date restrictions, initially retrieved 20 948 records. 11 studies meeting inclusion criteria for quantitative and qualitative synthesis, with 4 additional studies included in qualitative synthesis only. The PRISMA 2020 flow diagram is shown in Fig. 1 . Characteristics of Included Studies Characteristics are summarize in Table 1 . The 11 studies were conducted in seven low- and middle-income countries. Interventions comprised resective epilepsy surgery (temporal lobectomy or extratemporal resection) or disconnective procedures in surgical arms, with comparators consisting of continued medical management using antiepileptic drugs. Participants were adults and children with drug-resistant epilepsy. The included studies reported outcomes from consecutive patients with drug-resistant epilepsy who underwent resective or disconnective surgery. Pooled seizure-freedom rates were consistent across studies (52–79.4%) with very low heterogeneity (I² = 9%), indicating comparable surgical efficacy among studies. Follow-up periods ranged from 12 to 60 months. Outcomes included direct surgical costs, seizure freedom (Engel Class I), incremental cost-effectiveness ratios, and adverse events. Risk of bias assessment using Cochrane RoB-2. Table 1 11 Qualitative Studies No Author (Year) Center Subject (Number of Patients, Condition) Treatment Result parameter Other Parameter Complication/AE Cost Surgery Engel Scale 1 Rao MB, Radhakrishnan K (2000) 18 SCTIMST, India n = 190 (119 ATL, 71 refractory TLE non-ATL; Refractory TLE medically intractable; MTLE common) ATL (anterior temporal lobectomy with amygdalohippocampectomy): Pre-surgical: Noninvasive (clinical, scalp EEG, MRI, VEEG) Costs (USD, 2000; out-of-pocket; GNI/capita $ 310): - ATL (incl. eval): INR 47,000 ( $ 1,200) - Lifetime medical: INR 200,000 ( $ 5,000; ages 26–60 yrs) Seizure-free (Engel I): 70% post-ATL; AED-free: 30% at 3 yrs Complications: Transient 5–10% (memory/language); permanent rare 2 Fandiño-Franky et al. (2000) 21 Hospital Neurologico of the Liga Colornbiana, Colombia 97 patients (62 children, 35 adults) Mean age children 7.9 yrs, adults 25.8 yrs Medically intractable secondarily generalized epilepsy Anterior two-thirds corpus callosotomy (CCS) 5 cases + frontal excision Cost: US $ 3,137-3,995 (year 2000) Clinical (mean FU 35 mo): 66% seizure-free or only non-disabling seizures AED slightly reduced Morbidity: Transient mutism/disconnection syndrome (common, resolved < 3 weeks); Wound infection (2); Hydrocephalus (1 requiring shunt); No mortality Permanent: None reported 3 Wu et al. (2011) 23 West China Hospital, China 143 patients Refractory epilepsy ATL (105) + FLE (38) Selective use MRI/VEEG/PET/IEEG Cost: $ 2550–4230, Operation :2250–3750; US $ 2550 to US $ 4230, for the entire cost of surgery Engel I: ATL 63.8%, FLE 61.1% 4 Dash et al. (2012) 19 SCTIMST, India 285 patients AED-resistant extratemporal epilepsy Extratemporal resective surgery (71/285) 9 invasive EEG Cost: Noninvasive + surgery INR 60,000 (US $ 1,500, 2012) Seizure-free(Engel 1): Surgical 73.2% vs. non-surgical 7.7% (P < 0.0005) Temporary: 4/71 (5.6%, resolved < 3 mo) Permanent non-disabling: 3/71 (4.2%, hemiparesis, all ambulant at 1 year) Anticipated: Hemianopia 9/71 (12.7%) Mortality: 0 5 Tahir et al. (2012) 24 Aga Khan University Hospital, Pakistan 16 patients (first series) Medically refractory (TLE + catastrophic childhood) HS 6, ATL 6, keyhole SAH 4 (neuronavigation-guided) Cost: US $ 1644, direct total cost for regular care US $ 3044, for private care. but “limited resources” Engel I: SAH 100% (12 mo), ATL 83% (24 mo), HS 66% (48 mo) the average blood loss was 200cc in SAH, 350 cc in ATL, 600 cc inHS Morbidity: Minimal in ATL/SAH groups; HS group higher (expected in catastrophic cases) Specific: 2 patients; both patients had undergone functional HS hemispherectomy 6 Kitwitee P, et al. (2017) 27 Prasat Neurological Institute, Thailand n = 70 surgery patients (15 yrs epilepsy, Drug-resistant focal epilepsy) VEEG + surgery: • Pre-surgical: VEEG (4 days median), MRI, PET/SPECT (50%/27%), fMRI/intracranial EEG (7%) Surgery: Resective (ATL 68%, selective AH 6%, lesionectomy 24%) Costs (THB, 2015; societal; 35 THB/USD; GNI/capita 160,000 THB Seizure-free rates (Engel I)at years 1 and 2 after sur- gery were 79.4% and 77.8%. (TLE 80%/92.5%; ETLE 76.9%/90%) ICER: 43,251 THB/QALY (~ $ 1,236 USD; 84% prob CE at threshold). QALY gain: +1.50 - Complications: Transient 20%, permanent 1.4%; mortality 2% 7 Asadi-Pooya et al. (2017) 25 Shiraz University, Iran 22 patients (12 F, 10 M) Age ≥ 18 years Refractory MTLE with MTS Standard temporal lobectomy (ATL) Presurgical: 2-hour video-EEG, 1.5T MRI Cost: US $ 500 total Engel I: 15/22 (68.2%) Good outcome (II): 3/22 (13.6%), III: 4,5%. Mean FU 24.8 mo Complications: None reported (no neurological deficit, infection, or mortality) 8 Kuzniecky R, et al. (2018) 14 Hospital del Niño Dr. José Renán Esquivel, Panama n = 27 (children; intractable epilepsy, upper-middle LMIC) • Condition: Drug-resistant epilepsy (surgically treatable; no prior local program) Hybrid epilepsy surgery program (US-Panama collaboration; 6 missions): • Resective surgeries (with intraoperative ECoG); subdural/depth electrodes + extra-operative monitoring • Multidisciplinary: US neurologists/neurosurgeons/EEG tech + local team general, Average surgery cost per patient: $ 9,850; total direct cost of the program was $ 205 000 for the 27 patients treated, with an average cost of $ 7592 per patient for the overall group Seizure-free (Engel I): 55.6% (15/27) - Engel II: 40.7% (11/27); Engel III: 3.7% (1/27) no major complication, Complications: 3.7% (1 infection; no major morbidity/mortality) 9 Jukkarwala A, et al. (2019) 20 Sumandeep Vidyapeeth, India n = 125 ( HS 51%, gliosis 18%, Drug-resistant remediable epilepsy Low-cost surgery: • Temporal resection 65%, extratemporal 21%, hemispherectomy 10% • Pre-surgical: VEEG (3 days median), 1.5T MRI, ECoG Surgery $ 1,121; Total: $ 1,324 (eval $ 296, surgery $ 1,121; 73% GNI) (quantitative eligible) Engel IA: 92.5%. Engel II; 3,2%. Engel III; 2,1% Complications: 5.6% (7/125; meningitis n = 3, hydrocephalus n = 1, thrombosis n = 1, hemiparesis n = 2 [1 resolved]) 10 Anurat K, et al. (2020) 26 Ramathibodi Hospital, Thailand n = 36 (17 surgery, 19 medical, Drug-resistant focal epilepsy ) Surgery (n = 30; lobectomy/resection): • Pre-surgical: VEEG, 3T MRI, PET; ECoG Costs Surgery vs control :44,450 vs 21,274 Seizure Free: 91.60% vs 67.00% ICER per outcome: 58,891. ICER: $ 117 USD per 1% seizure reduction. QALYs gained:0.87 vs 0.79 ICUR: $ 26 564 USD per QALY gained - Complications: 6.7% (2/30; transient hemiparesis n = 1, infection n = 1) 11 Alegría-Muñoz M, et al. (2025) 22 Ramathibodi Hospital, Thailand 573 pasien (260 + 313); Condition: Epilepsy (focal/generalized); includes SE, drug-resistant for surgery Management incl. surgery: Pharma (mono/dual ASMs, e.g., levetiracetam 40%) Diagnostics/follow-up, SE (ER/ICU) • Surgery: Resective (lesionectomy 46%), VNS Resective: $ 14,894, Costs (USD, 2023; GNI/capita $ 6,590)- Annual w/o SE: $ 2,416 (range $ 1,032- $ 3,847) - With ICU (8 days SE): $ 61,568 (ICU/day $ 7,314) - Resective: $ 14,894; VNS cost: $ 26,566 Meta-analyses were conducted using RevMan Web with random-effects Hartung-Knapp models. We used random-effects models with the Hartung-Knapp-Sidik-Jonkman variance estimator because the included studies were conducted in markedly different LMIC health systems, with expected clinical and methodological heterogeneity. This approach provides more conservative confidence intervals and better accounts for between-study variability than fixed-effect models. Surgical Costs and Seizure Freedom (Engel Class I at ≥ 12 Months) All 11 studies reported direct surgical costs. Figure 2 presents direct medical cost of epilepsy surgery in LMIC expressed as a percentage of national GDP per capita (US dollars ) for the relevant country and year. Four studies provided continuous data for mean cost comparison between surgery and non-surgery groups. The forest plot of mean differences is shown in Fig. 3 a. The pooled mean difference was 1.29 (95% CI -0.13 to 2.70; I² = 100%). Heterogeneity was extreme (p < 0.00001). The funnel plot for surgical cost (mean difference) revealed asymmetric distribution with studies clustered toward positive mean differences and absent points in the lower-left quadrant, suggesting potential publication bias favoring higher reported costs (Fig. 4 a). Four studies contributed dichotomous data (199 of 277 patients in surgery arms versus 12 of 127 in medical arms). The forest plot comparing seizure freedom outcomes between surgery and non-surgery groups is displayed in Fig. 3 b. The pooled odds ratio favoring surgery was 22.51 (95% CI 11.17 to 45.38; p < 0.00001; I² = 9%). Heterogeneity was low (p = 0.28). The funnel plot for seizure freedom (log odds ratio) indicated minor asymmetry, with one study positioned distant from the others on the right side, but no clear evidence of small-study effects given the limited number of included studies (Fig. 4 b). Cost-Effectiveness Two studies reported incremental cost-effectiveness ratios (ICERs) and incremental cost-utility ratios (ICURs). One study reported an ICER of 43,251 THB per QALY gained (approximately US $ 1,236, adjusted to 2025 international dollars), with a QALY gain of 1.50 and an 84% probability of cost-effectiveness at the country-specific threshold. The second study reported an ICER of 58,891 per outcome, US $ 117 per 1% seizure reduction, and an ICUR of US $ 26,564 per QALY gained (QALYs gained: 0.87 in surgery versus 0.79 in medical management). Both studies indicated cost-effectiveness below the World Health Organization threshold for the respective countries. Meta-analysis was not performed due to the limited number of studies, differences in outcome metrics, time horizons, and discount rates. Heterogeneity was extreme for surgical costs and low for seizure freedom, attributable to differences in cost components, follow-up duration, and health system contexts. Complication rates were low across studies. Assessment of publication bias will be finalized following completion of risk of bias evaluation. Discussion Cost of Surgery The analysis of surgical costs across low- and middle-income countries (LMICs) reveals substantial variability in direct costs for epilepsy surgery, as depicted in Fig. 2 , underscoring the influence of economic context, healthcare infrastructure, and procedural optimization strategies on affordability. These costs, encompassing preoperative evaluation, intraoperative procedures, hospitalization, and postoperative care, consistently demonstrate that epilepsy surgery remains viable at a fraction of high-income country equivalents, thereby supporting its scalability in resource-constrained settings. The pooled mean difference in costs between surgical and medical management arms (1.29 US $ thousands; 95% CI -0.13 to 2.70) highlights an initial upfront investment that yields long-term savings through reduced seizure recurrence and associated healthcare utilization. In India, Rao et al. (2000) reported direct costs of approximately US $ 1,200 (GDP per capita $ 442.8) for anterior temporal lobectomy (ATL), primarily comprising noninvasive presurgical evaluations such as scalp EEG and MRI, alongside out-of-pocket expenses for surgery and basic hospitalization. 17 This low figure reflects the program's emphasis on streamlined, noninvasive protocols to minimize diagnostic overheads, with lifetime medical management costs estimated at US $ 5,000, exceeding surgical expenses over time due to ongoing antiepileptic drug (AED) requirements. Similarly, Dash et al. (2012) documented costs of US $ 1,500 (GDP per capita $ 980)for extratemporal resective surgery, including noninvasive evaluations and invasive EEG in select cases (9% of patients), where the bulk of expenses arose from surgical fees and short-term inpatient stays, demonstrating cost containment through targeted patient selection in a resource-poor environment. 18 Jukkarwala et al. (2019) further exemplified efficiency with total costs of US $ 1,324 (evaluation: US $ 296; surgery: US $ 1,121) (GDP per capita $ 2041), achieved via abbreviated video-EEG (median 3 days) and 1.5T MRI without advanced imaging modalities, highlighting how tiered referral systems and epileptologist-led interpretations reduce personnel and equipment demands. 19 In Colombia, Fandiño-Franky et al. (2000) estimated direct costs for corpus callosotomy at US $ 3,137-3,995 (GDP per capita $ 6398.3), dominated by operative and perioperative components, including basic monitoring and wound management, with limited presurgical diagnostics due to the palliative nature of the procedure. 20 This contrasts with Alegría-Muñoz et al. (2025), who reported higher resective surgery costs of US $ 14,894 (GDP per capita $ 7195.1), driven by comprehensive diagnostics (MRI, EEG test) and potential intensive care unit admissions for status epilepticus (escalating annual costs to US $ 61,568), though payer-perspective adjustments via bootstrapping revealed variability tied to pharmaceutical and emergency interventions. 21 China's experience, as outlined by Wu et al. (2011), yielded total costs of US $ 2,550-4,230 (GDP per capita $ 5703.8) for ATL and frontal lobe excisions, with operative expenses (US $ 2,250-3,750) forming the largest share, supplemented by selective use of MRI, video-EEG, PET, and intracranial EEG to constrain presurgical outlays in low-income cohorts. 22 In Pakistan, Tahir et al. (2012) achieved costs of US $ 1,644 (public care) to US $ 3,044 (private) (GDP per capita $ 1204.4) for procedures like hemispherotomy and ATL, where direct components included neuronavigation-guided resections and basic follow-up, offset by collaborative teleconferences that minimized on-site expertise expenses. 23 Thailand's studies illustrate moderate costs reflective of upper-middle-income infrastructure: Kitwitee et al. (2017) detailed US $ 6,194 (GDP per capita $ 6412.1) for video-EEG-monitored resections (societal perspective, including lifetime AEDs), with presurgical evaluation (US $ 1,036 for VEEG/MRI/PET) and year-one surgery/hospitalization comprising 80% of initial outlays. Anurat et al. (2020) reported US $ 1,236 (GDP per capita $ 6985.6) equivalent for pediatric ATL, encompassing advanced presurgical tools (3T MRI, PET, electrocorticography) and transient complication management (e.g., infection), where costs were further moderated by universal coverage schemes. In Iran, Asadi-Pooya et al. (2017) achieved exceptionally low totals under US $ 500 (GDP per capita $ 5753.1) for temporal lobectomy, limited to 2-hour video-EEG and 1.5T MRI, underscoring the feasibility of basic protocols in resource-limited public systems. 24 Finally, Kuzniecky et al. (2018) in Panama documented US $ 7,592-9,850 per patient (GDP per capita $ 1615.1) in a hybrid model, incorporating international missions for electrocorticography and monitoring, with program-wide costs (US $ 205,000 for 27 patients) driven by multidisciplinary training and postoperative surveillance. 14 Comparison of surgery cost The meta-analysis of surgical costs, encompassing four studies with continuous data on mean differences between surgery and non-surgery groups, yielded a pooled estimate of 1.29 US $ thousands (95% CI -0.13 to 2.70; Z = 1.79, p = 0.07), indicating no statistically significant incremental cost for epilepsy surgery over medical management in the short term. As illustrated in the forest plot (Fig. 3 ), individual study estimates exhibited marked dispersion, with three studies demonstrating positive mean differences favoring higher surgical costs (ranging from 0.50 to 3.50 US $ thousands) and one outlier showing a negative value, contributing to the non-significant overall effect. This finding aligns with the extreme heterogeneity observed (I² = 100%; Chi² = 471.38, p < 0.00001), attributable to variations in cost components ( PET/SPECT test in Thailand studies) versus minimalist noninvasive protocols in Indian centers, and differences in follow-up durations (12–60 months) and health system financing models across the seven LMICs. The funnel plot for surgical cost mean differences (Fig. 4 a) revealed notable asymmetry, characterized by clustering of studies toward positive mean differences and an absence of points in the lower-left quadrant, which suggests potential publication bias favoring reports of elevated surgical costs. We visually inspected the funnel plot and formally tested for small-study effects. Egger’s weighted regression test did not show significant funnel plot asymmetry for cost outcomes (intercept µ = 0.94, t(2) = − 0.05, p = 0.97), and the meta-regression test for asymmetry was likewise non-significant (z = 1.89, p = 0.06). We also attempted to apply Duval and Tweedie’s trim-and-fill procedure; however, given the very small number of studies (total study = 4) and the between-study heterogeneity (I² = 100%), the method was unstable and could not be reliably implemented. Accordingly, we present the funnel plot primarily for visual inspection and interpret the risk of publication bias with caution. This asymmetry may reflect selective reporting of higher-cost scenarios in resource-constrained settings, where comprehensive evaluations inflate estimates, or the underrepresentation of low-cost models from tiered centers. 19 Despite the non-significant pooled mean difference, the wide confidence interval encompassing zero underscores that upfront surgical investments are often offset by long-term reductions in AED expenditures and emergency care, as evidenced in lifetime projections from Kitwitee et al. (2017) and Anurat et al. (2020). 25 , 26 This surgery cost pattern aligns with detailed breakdowns in key studies: presurgical diagnostics (video-EEG and MRI) accounted for 15–22% in Indian centers like Jukkarwala et al. (2019) through minimized protocols, rising to 42.8% in Thailand (Kitwitee et al., 2017) due to advanced imaging (PET/SPECT in 27–50% cases), while operative and hospitalization phases dominated at 57–85%. Such variability, as visualized in Fig. 2 , underscores opportunities for cost optimization via non-invasive strategies in lower-middle-income settings. Collectively, these findings indicate that direct costs in LMICs (range: US $ 500 − 14,894) are predominantly influenced by presurgical diagnostics (20–40% of total) and operative/hospitalization phases (50–70%), with indirect factors such as out-of-pocket payments and lost productivity amplifying burdens in lower-middle-income settings like India and Pakistan. Optimization through noninvasive protocols and international collaborations not only curtails expenses but also enhances equity, aligning with global calls for LMIC-specific epilepsy programs to bridge the treatment gap. The establishment of low-cost epilepsy surgery programs in resource-poor settings demonstrates a replicable model that significantly reduces the surgical treatment gap in LMICs. This approach, implemented across three Tier 2 and Tier 3 cities in India, relied on abbreviated presurgical evaluations (median 3-day video-EEG and 1.5T MRI without PET/SPECT or invasive EEG), epileptologist-led interpretations, and an initial phase of invited epilepsy surgeons transitioning to local neurosurgeons, yielding 92.5% Engel Class IA outcomes at an average total cost of US $ 1,324 per patient. By subsidizing expenses for deserving patients and focusing on ideal candidates identified through clinical history and noninvasive data, the model achieved 125 surgeries since 2012 while maintaining minor complication rates of 5.6%, illustrating how decentralized, cost-conscious frameworks can expand access without compromising efficacy. Clinical superiority is further evidenced in pediatric cohorts, where surgery achieved 52% seizure freedom compared to 16% with medical management alone, though short-term cost-effectiveness remains limited (ICER 743,040 THB per QALY at three years exceeding the national threshold). Temporal resections, however, proved highly viable at 36,569 THB per QALY, with projections indicating overall cost-effectiveness beyond three years, reinforcing the need for extended evaluation horizons and policy integration to sustain such transformative models in LMICs. Comparison between surgical intervention and medical management in the meta-analysis of Engel Class I seizure freedom at 12 months or longer demonstrates a pooled odds ratio of 22.51 (95% CI 11.17 to 45.38; p < 0.00001), reflecting substantially greater efficacy with surgery. 17 , 18 , 25 , 26 The forest plot (Fig. 3 b) illustrates uniform positive effects across the four studies, with seizure freedom rates in surgical groups spanning 52% to 79.4% compared to 7.7% to 16% in medical groups, encompassing pediatric and adult populations in Thailand and India. Low heterogeneity (I² = 9%; p = 0.28) arises from consistent outcome definitions and follow-up durations of 12 to 60 months, reinforcing the dependability of surgical advantages despite differences in presurgical imaging and patient selection protocols. 17,18,25,26 Beyond Engel Class I, additional outcomes reveal meaningful clinical improvements: one Indian low-cost program reported Engel Class II in 3.2% and Class III in 2.1% of cases, with no Class IV failures, indicating that over 95% of patients achieved worthwhile improvement or better. 19 Quality of life gains further support surgical value, with lifetime modeling showing an incremental 1.50 QALYs in adults and 0.87 versus 0.79 QALYs in pediatric cohorts, translating to enhanced daily functioning and reduced disability burden. 25 The funnel plot for log odds ratios (Fig. 4 b) displays minor asymmetry, with one study situated farther to the right and no points in the lower-left quadrant, indicating no substantial small-study effects given the small number of included studies. 17,25,26 This configuration implies limited publication bias, bolstering confidence in the pooled estimate. Seizure freedom data from both the forest and funnel plots, combined with Engel Class II-III outcomes and QALY gains, collectively emphasize surgery's pivotal role in LMICs, conferring over 20-fold increased odds of sustained remission alongside quality-of-life benefits outcomes that validate initial expenditures and endorse wider adoption through streamlined, noninvasive diagnostic pathways to maximize clinical value in resource-limited environments. 17,25,26 Seven additional studies enrich the evidence base by exploring procedural diversity and outcomes in varied LMIC contexts. 14 , 19 – 24 Resective approaches dominated, with anterior temporal lobectomy (ATL) applied in Iranian cohorts for mesial temporal lobe epilepsy (MTLE), yielding Engel Class I rates of 68.2% alongside 13.6% Class II. 24 Extratemporal resections (ETLE) and disconnective procedures, including selective amygdalohippocampectomy (SAH) and hemispherectomy (HS) in Pakistani catastrophic childhood cases, achieved Engel Class I outcomes of 83–100% for SAH and 66% for HS. 23 Non-resective strategies broadened applicability: corpus callosotomy in Colombia produced 66% seizure-free or non-disabling seizures in secondarily generalized epilepsy, while a Panamanian hybrid program reported Engel Class I in 55.6%, Class II in 40.7%, and Class III in 3.7% using intraoperative electrocorticography. 14 Low-cost Indian tiered centers optimized resections, 65% temporal lobe epilepsy (TLE) and 21% ETLE, with 92.5% Engel Class IA, 3.2% Class II, and 2.1% Class III. 19 Chinese series demonstrated balanced efficacy in TLE (ATL, 63.8%) and ETLE (frontal lobe excision, 61.1%), and Colombian payer analyses highlighted resective lesionectomy (46%) without Engel reporting to emphasize economic feasibility. 21 , 22 Emerging programs in Indonesia, Vietnam, Malaysia, and Brazil have further expanded the evidence, demonstrating that structured epilepsy surgery initiatives in middle-income settings can achieve Engel Class I rates of 58–78% even with limited access to invasive EEG or magnetoencephalography. 27 – 31 The implementation of epilepsy surgery in low- and middle-income countries (LMICs) is constrained by interconnected challenges across infrastructure, workforce, and financial domains, as depicted in Fig. 5 and synthesized from the 11 included studies. Infrastructure challenges feature the scarcity of comprehensive epilepsy centers and significant heterogeneity in national income, health funding, and financing models. Fewer than 15 comprehensive Level-4 epilepsy centers exist across all of Asia and Latin America combined, serving populations exceeding 4.5 billion, resulting in surgical volumes of < 1 procedure per million inhabitants annually in most LMICs. 18 , 30 , 32 In lower-middle-income settings like India, decentralized tier-2 and tier-3 facilities adopt abbreviated noninvasive protocols (3-day video-EEG, 1.5T MRI), attaining costs of US $ 1,324 per patient. 19 Conversely, upper-middle-income Thailand employs PET/SPECT in 27–50% of cases, raising presurgical diagnostics to 42.8% of total costs within a national universal coverage framework. 25 , 26 Workforce challenges involve insufficient training initiatives, limited epileptology specialization, and high turnover, with general neurosurgeons often conducting procedures in Pakistan and Iran; the Indian transitional approach from international to local surgeons enabled 125 operations since 2012 with 92.5% Engel Class IA outcomes, yet underscores ongoing external dependency. 19 International twinning and telemedicine-supported training models, successfully piloted in Uganda and Indonesia, have increased local surgical capacity by 200–400% within 3–5 years, highlighting scalable pathways for workforce development. 27 , 33 – 35 Financial challenges, notwithstanding direct costs of US $ 500 − 14,894, stem from prevalent out-of-pocket payments and partial insurance coverage, prompting diagnostic delays in Colombia and Panama, while Thailand's system facilitates long-term cost-effectiveness (ICER 36,569 THB per QALY for temporal resections) but excludes select pediatric palliative procedures. 25 The Thai studies most thoroughly exemplify these interrelations, infrastructure hindering workforce capacity and intensifying financial pressures, whereas Jukkarwala et al. (2019) presents a replicable model for resource optimization. 19 , 25 , 26 Despite these disparities, LMIC outcomes remain competitive with high-income countries (HICs): pooled Engel Class I seizure freedom (52-79.4%) closely aligns with HIC benchmarks (60–80%) from randomized trials in the United Kingdom and United States. 6 , 15 , 16 , 36 – 38 LMICs have substantially lower costs of surgery (LMICs: US $ 500 − 14,894 vs. HICs: US $ 20,000-100,000), with similar complication rates (< 6% in LMICs vs. 5–10% in HICs). 6 , 8 , 15 , 39 , 40 Recent multicenter cohorts from Asia and Latin America further confirm that quality-of-life gains (measured by QOLIE-31 and EQ-5D) and reduction in antiepileptic drug polytherapy after successful surgery are equivalent to those reported in high-income settings, underscoring the high value-for-money of epilepsy surgery in LMICs. 28 , 29 , 31 , 41 , 42 Targeted strategies, including regional infrastructure enhancements, standardized training programs, and expanded universal coverage, alongside prospective multicenter trials, are critical to overcoming the treatment gap surpassing 90% in LMICs. This systematic review summary shows (Fig. 6 ) that epilepsy surgery in low- and middle-income countries dominates continued medical management: it requires higher upfront investment but delivers markedly superior seizure-freedom rates (52–92.5%), frequently achieves cure, and generates lower lifetime costs. In Fig. 7 presents the risk-of-bias assessment for the 11 included studies. Most studies showed moderate risk of bias in random sequence generation, allocation concealment, blinding of outcome assessment, and selective reporting with low risk of bias mostly showed in Blinding of participant and Incomplete outcome data. Overall, the methodological quality of the evidence was moderate. This review exhibits several limitations that warrant consideration. The inclusion of only 11 studies, with four contributing to the Engel Class I meta-analysis, constrained statistical power and generalizability, particularly for extratemporal and palliative procedures. Heterogeneity in cost reporting, encompassing direct medical expenses, societal perspectives, and varying currency conversions, precluded a robust pooled cost estimate, while the absence of standardized indirect cost assessments (productivity losses) limited comprehensive economic evaluations. Furthermore, the design of included studies primarily comprised observational cohorts with follow-up durations ranging from 12 to 60 months, which may introduce selection bias toward surgically amenable candidates. Publication bias, though funnel plots and meta-regression Egger's test, cannot be entirely excluded given the small study count. Another limitation of this study is the variation in treatment costs due to the technological advancements that occurred between the years 2000 and 2025. While efforts were made to adjust for changes in economic conditions using the Gross Domestic Product (GDP) per capita for each country and year as reported in the studies, the exact impact of new technologies on treatment costs was not fully accounted. Finally, although both pediatric and adult patients were included across studies and pooled seizure-freedom outcomes showed low heterogeneity (I² = 9%) with comparable efficacy, the limited number of studies precluded formal subgroup analysis by age group. Therefore, potential subtle differences in long-term outcomes or cost-effectiveness between children and adults could not be fully explored. Future focus should aim to include a larger number of studies with longer follow-up durations, indirect costs reporting, and subgroup analysis by age group to better assess long-term outcomes and cost-effectiveness. Additionally, more detailed information on technological advancements and their impact on treatment costs should be incorporated to refine cost estimates. Methods This systematic review was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO) on November 17th 2025 under the title “Cost-Effectiveness of Epilepsy Surgery in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis”. The protocol under registration number CRD420251182159. The protocol is publicly available at: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251182159 . All methods, including literature search strategy, eligibility criteria, data extraction, risk of bias assessment (Cochrane RoB-2), and meta-analytic techniques (RevMan Web), were predefined in the registered protocol to minimize reporting bias and ensure methodological transparency. Any deviations from the protocol will be clearly documented in the final publication. Literature Search Strategy A systematic literature search was conducted across four major online databases: Medline, PubMed, Scopus, and the Cochrane Library. The search was limited to these four as these databases provide the broadest coverage and highest indexing quality for biomedical and health-economic literature worldwide. Together they include > 95% of relevant epilepsy surgery and cost-effectiveness publications, while additional databases predominantly yield duplicate records or studies already captured through manual reference checking and backward citation searching for additional relevant studies. The search utilized a combination of primary keywords and synonyms, specifically "(Cost OR costs OR cost-effectiveness OR cost-utility OR cost-benefit) AND (Epilepsy Surgery OR Temporal epileptic surgery OR temporal lobectomy) AND (low income OR middle income OR LMIC OR low and middle income countries OR developing countries)". No date restrictions were applied.. The review will be published in English and Indonesian language. Inclusion and Exclusion Criteria Articles were included if they met the following criteria: first, they focused on the cost-effectiveness of epilepsy surgery; second, they were conducted in low- and middle-income countries; third, they involved patients with drug-resistant epilepsy undergoing surgery procedures and reported at least one economic outcome (total cost, ICER, cost per QALY, cost per DALY averted, or cost per seizure-free patient). Comparators will comprise standard treatment or controls selected by the study authors. Both randomized and non-randomized study designs will be included. Articles not meeting these criteria will be excluded. Screening and Selection Process The initial search will yield a broad range of articles, which will be filtered based on publication year, relevancy and study type. Two reviewers independently screened the titles and abstracts of all records identified through the systematic search and manual reference checking. Full-text reports of any record considered potentially relevant by at least one reviewer were retrieved and independently evaluated for inclusion by the same two reviewers. Any discrepancies between reviewers during title/abstract screening or full-text assessment were first resolved by discussion. Persistent disagreements were adjudicated by a third reviewer. Exclusions at the full-text stage were categorized and recorded. A PRISMA flow diagram will illustrate the study selection process. Data Extraction and Synthesis Selected articles with key data were systematically extracted, including the article’s title and authors, publication year, study objectives and methodology, sample size and study population, intervention details (epilepsy surgery), comparators (medical management), and key findings related to cost and effectiveness outcomes. Data extraction was performed independently by at least two individuals (or a person/machine combination) with a process to resolve differences. Authors were contacted to provide any required data not available in published reports. Data synthesis was conducted using RevMan Web, aggregating quantitative data for meta-analysis where applicable. For each study, the reported costs in local currencies were converted into US dollars using the average exchange rate of the corresponding study year. When the year of data collection was not explicitly stated, the year of publication was used as a proxy. All monetary values were then inflated to 2025 US dollars according to the US Consumer Price Index (CPI). Country-specific gross domestic product (GDP) per capita for 2025 was obtained from the World Bank database, and direct medical costs were expressed as a percentage of the respective country’s GDP per capita. 43 Analysis and Interpretation Extracted data were analyzed to identify recurring themes, cost-effectiveness thresholds, and research gaps. Similarities and differences across studies were evaluated to assess the economic value of epilepsy surgery in low- and middle-income settings. Meta-analytic techniques included the calculation of cost-effectiveness in epilepsy surgery with 95% confidence intervals for continuous outcomes, with heterogeneity assessed using the I² statistic. Subgroup analyses based on income level, surgical procedure, and time horizon, along with funnel plot assessments for publication bias, were conducted to strengthen the validity of conclusions. The certainty of findings will be assessed using the Cochrane Risk of Bias Tools 2.0 checklist, integrated into the systematic review and meta-analysis process, which adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocols and The Cochrane Handbook for Systematic Reviews of Interventions, with evaluations performed independently by at least two individuals (or a person/machine combination) and a process to resolve differences. Conclusion This systematic review and meta-analysis confirms epilepsy surgery as highly effective and cost-effective for drug-resistant epilepsy in LMICs. Surgery yielded over 20-fold higher odds of Engel Class I seizure freedom (pooled OR 22.51; 95% CI 11.17–45.38) versus medical management, with consistent benefits across ages and low heterogeneity. Procedures like temporal lobectomy, hemispherectomy, and callosotomy improved seizures in > 90% of cases. Costs (US $ 500–14,894) were affordable, driven by presurgical workup and surgery, with noninvasive options suitable for resource-limited settings. Lifetime projections show strong QALY gains, supporting integration into universal health coverage. Urgent expansion of decentralized, low-cost programs is needed to close the treatment gap, with calls for standardized reporting and multicenter trials. Declarations Data availability The datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request. All data extracted from included studies are presented in the manuscript and supplementary materials. No additional datasets were generated or analysed beyond those reported. Author contributions statement M.T.A. conceptualized the study, developed the methodology and protocol, performed the literature search, study selection, data extraction, conducted the formal analysis (including meta-analysis), wrote the original draft, reviewed and edited the manuscript, provided supervision, and managed project administration. F.P. contributed to methodology, performed study selection, data extraction, validation of data, reviewed and edited the manuscript, and prepared visualizations. N.Ö. contributed to methodology, performed formal analysis, validated results, interpreted the health-economics data, and reviewed and edited the manuscript. All authors have read and approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Acknowledgements We sincerely thank to the clinical and research staff, librarians, administrative personnel, and colleagues from epilepsy surgery programs across various centres for their invaluable collaboration, dedication, and critical contributions throughout this research and all patients and families whose experiences continue to inspire the urgent need for accessible surgical care. This review would not have been possible without their collective support. Financial Support And Sponsorship This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Ethical issues Ethical approval was not required for this study because it is a review of previously published literature and does not involve human participants or animals. Competing interests Statement None to declare. ORCID Muhammad Thohar Arifin: https://orcid.org/0000-0003-2363-8026. Firman Pribadi: https://orcid.org/0000-0003-4325-6738. Nurettin Öner: https://orcid.org/0000-0002-4761-7863. References World Health Organization. Global burden of epilepsy. Epilepsy: public. health imperative ;: 9–17. (2019). Newton, C. R. & Garcia, H. H. Epilepsy in poor regions of the world. Lancet 380 , 1193–1201 (2012). World Health Organization. Epilepsy: a public health imperative. https://www.who.int/publications/i/item/epilepsy-a-public-health-imperative (accessed 17 Nov2025). Kim, D. W. et al. Epilepsy with dual pathology: Surgical treatment of cortical dysplasia accompanied by hippocampal sclerosis. Epilepsia 51 , 1429–1435 (2010). Chen, Z., Brodie, M. J., Liew, D. & Kwan, P. Treatment Outcomes in Patients With Newly Diagnosed Epilepsy Treated With Established and New Antiepileptic Drugs. JAMA Neurol. 75 , 279 (2018). Wiebe, S., Blume, W. T., Girvin, J. P., Eliasziw, M. A. & Randomized Controlled Trial of Surgery for Temporal-Lobe Epilepsy. N. Engl. J. Med. 345 , 311–318 (2001). Engel, J. et al. Practice parameter: Temporal lobe and localized neocortical resections for epilepsy. Neurology 60 , 538–547 (2003). Picot, M-C. et al. Cost-effectiveness of epilepsy surgery in a cohort of patients with medically intractable partial epilepsy–preliminary results]. Rev. Neurol. (Paris) . 1 , 5S354–5S367 (2004). 160 Spec No. Beghi, E. et al. Global, regional, and national burden of epilepsy, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 18 , 357–375 (2019). Singh, A. & Trevick, S. The Epidemiology of Global Epilepsy. Neurol. Clin. 34 , 837–847 (2016). Radhakrishnan, K. Epilepsy surgery in India. Neurol. India . 57 , 4 (2009). Nabangchang, C., Sakoolnamarka, S., Paueksakon, P. & Chinvarun, Y. Epilepsy surgery in children and adolescence; Phramongkutklao College of Medicine’s experience. J. Med. Assoc. Thai . 88 (Suppl 3), S263–S270 (2005). Bahou, Y. G. Epilepsy at a university hospital in amman, jordan. Neurosciences (Riyadh) . 9 , 190–195 (2004). Kuzniecky, R. et al. Epilepsy surgery in Panama: Establishment of a successful hybrid program as a model for small middle-income countries. Epilepsia 59 , 2137–2144 (2018). Téllez-Zenteno, J. F., Dhar, R. & Wiebe, S. Long-term seizure outcomes following epilepsy surgery: a systematic review and meta-analysis. Brain 128 , 1188–1198 (2005). Engel, J. Early Surgical Therapy for Drug-Resistant Temporal Lobe Epilepsy. JAMA 307 , 922 (2012). Rao, M. B. & Radhakrishnan, K. Is Epilepsy Surgery Possible in Countries with Limited Resources’. Epilepsia 41 10.1111/j.1528-1157.2000.tb01543.x (2000). Dash, G. K. et al. An audit of the presurgical evaluation and patient selection for extratemporal resective epilepsy surgery in a resource-poor country. Seizure 21 , 361–366 (2012). Jukkarwala, A. et al. Establishment of low cost epilepsy surgery centers in resource poor setting. Seizure 69 , 245–250 (2019). Fandiño-Franky, J., Torres, M., Nariño, D. & Fandiño, J. Corpus Callosotomy in Colombia and Some Reflections on Care and Research Among the Poor in Developing Countries. Epilepsia 41 10.1111/j.1528-1157.2000.tb01541.x (2000). Alegría-Muñoz, M. et al. Cost Analysis of Epilepsy Healthcare in Adults: A Direct Cost Estimate From a Colombian Perspective. Value Health Reg. Issues . 47 , 101074 (2025). Wu, X-T. et al. How to effectively constraint the cost of presurgical evaluation for resective surgery in low-income population: Clinically oriented opinions. Seizure 20 , 425–427 (2011). Tahir, M. Z. et al. Establishment of a Comprehensive Epilepsy Center in Pakistan: Initial Experiences, Results, and Reflections. Epilepsy Res Treat ; 2012: 1–6. (2012). Asadi-Pooya, A. A. et al. Outcome after temporal lobectomy in patients with medically-refractory mesial temporal epilepsy in Iran. J. Neurosurg. Sci. 61. 10.23736/S0390-5616.16.02843-5 (2017). Anurat, K. et al. Cost-effectiveness analysis of epilepsy surgery in children and adolescents with drug resistant focal epilepsy at three years in a tertiary care epilepsy center in Thailand. J. Clin. Neurosci. 79 , 163–168 (2020). Kitwitee, P., Unnwongse, K., Srikijvilaikul, T., Yadee, T. & Limwattananon, C. Cost-Utility of Video-Electroencephalography Monitoring Followed by Surgery in Adults with Drug-Resistant Focal Epilepsy in Thailand. World Neurosurg. 98 , 750–760e3 (2017). Muttaqin, Z. Epilepsy surgery in Indonesia: Achieving better result with limited resources. Med. Hospitalia: J. Clin. Med. 1 , 1–6 (2019). Singh, V. Epilepsy surgery in India. J. Pediatr. Neurosci. 6 , 130 (2011). Akdag, G. Epilepsy due to Intracranial Surgery: 15 Years of Experience. J. Turkish Epilepsi Soc. 10.14744/epilepsi.2016.32559 (2016). Rocque, B. G. et al. Surgical treatment of epilepsy in Vietnam: program development and international collaboration. Neurosurg. Focus . 45 , E3 (2018). Pereira Dalio, M. T. R. et al. Long-Term Outcome of Temporal Lobe Epilepsy Surgery in 621 Patients With Hippocampal Sclerosis: Clinical and Surgical Prognostic Factors. Front. Neurol. 13. 10.3389/fneur.2022.833293 (2022). Mbuba, C. K. & Newton, C. R. Packages of Care for Epilepsy in Low- and Middle-Income Countries. PLoS Med. 6 , e1000162 (2009). Thohar Arifin, M. et al. Initiating an epilepsy surgery program with limited resources in Indonesia. Sci. Rep. 11 , 5066 (2021). Wegoye, E. et al. Bridging the gaps in the setup of a functional epilepsy monitoring unit in Uganda to support epilepsy surgery. Neurosurg. Focus . 58 , E7 (2025). Sen, A., Newton, C. R. & Ngwende, G. Epilepsy in low- to middle-income countries. Curr. Opin. Neurol. 38 , 121–127 (2025). Oldham, M. S., Horn, P. S., Tsevat, J. & Standridge, S. Costs and Clinical Outcomes of Epilepsy Surgery in Children With Drug-Resistant Epilepsy. Pediatr. Neurol. 53 , 216–220 (2015). Radhakrishnan, K. Challenges in the management of epilepsy in resource-poor countries. Nat. Rev. Neurol. 5 , 323–330 (2009). Dwivedi, R. et al. Surgery for Drug-Resistant Epilepsy in Children. N. Engl. J. Med. 377 , 1639–1647 (2017). Hader, W. J. et al. Complications of epilepsy surgery—A systematic review of focal surgical resections and invasive EEG monitoring. Epilepsia 54 , 840–847 (2013). Begley, C. E. & Durgin, T. L. The direct cost of epilepsy in the United States: A systematic review of estimates. Epilepsia 56 , 1376–1387 (2015). Pacheco-Barrios, K. et al. Burden of epilepsy in Latin America and The Caribbean: a trend analysis of the Global Burden of Disease Study 1990–2019. Lancet Reg. Health - Americas . 8 , 100140 (2022). 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. 88 , 260–266 (2010). GDP per capita. (current US $ ) | Data. https://data.worldbank.org/indicator/NY.GDP.PCAP.CD (accessed 4 Dec2025). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Revision requested 05 May, 2026 Reviews received at journal 04 May, 2026 Reviewers agreed at journal 13 Apr, 2026 Reviews received at journal 12 Apr, 2026 Reviewers agreed at journal 21 Mar, 2026 Reviewers invited by journal 19 Mar, 2026 Editor assigned by journal 19 Mar, 2026 Editor invited by journal 06 Mar, 2026 Submission checks completed at journal 04 Mar, 2026 First submitted to journal 04 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8962993","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":610009024,"identity":"5d6fe6ba-9044-4a46-9c4e-f8e3d83b2968","order_by":0,"name":"Muhamad Thohar Arifin","email":"","orcid":"","institution":"Muhammadiyah University of Yogyakarta","correspondingAuthor":false,"prefix":"","firstName":"Muhamad","middleName":"Thohar","lastName":"Arifin","suffix":""},{"id":610009025,"identity":"7076e720-516c-438c-aa98-0b085f5d7912","order_by":1,"name":"Firman 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04:23:53","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8962993/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8962993/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105564919,"identity":"8d472472-16d5-4eb2-a53d-8946b435787b","added_by":"auto","created_at":"2026-03-27 12:51:18","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":562230,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow diagram\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8962993/v1/20966c5bc817017ffba60603.jpg"},{"id":105564682,"identity":"1aa9f30d-fe54-414d-a04b-7bfeccfbe8c6","added_by":"auto","created_at":"2026-03-27 12:50:30","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":344887,"visible":true,"origin":"","legend":"\u003cp\u003eDirect medical cost of epilepsy surgery in LMIC expressed as a percentage of national GDP per capita (in US$) for the relevant country and year each study conducted.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8962993/v1/eddd20ac3673524ace0e63fd.jpg"},{"id":105565544,"identity":"9b26cc43-ce3e-433d-bbfa-9b5ecaffc4df","added_by":"auto","created_at":"2026-03-27 12:53:32","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":649088,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot between Surgery vs Non-surgery of: (A) cost (in US$1000); (B) Engel 1 Scale (Seizure Free) outcome\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8962993/v1/4194209dd115c5b6df86e288.jpg"},{"id":105565053,"identity":"5fd914a8-d886-4272-8655-988a11929a1b","added_by":"auto","created_at":"2026-03-27 12:51:42","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":96605,"visible":true,"origin":"","legend":"\u003cp\u003eFunnel plot of between Surgery vs Non-surgery for (A) Cost (in US$1000); (B) Engel 1 (Seizure Free) outcome\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8962993/v1/9e8ecefbb347bb8e4bab76d8.jpg"},{"id":105565071,"identity":"6300117d-3efd-4d42-acb6-49fbf64fa6dd","added_by":"auto","created_at":"2026-03-27 12:51:47","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":151535,"visible":true,"origin":"","legend":"\u003cp\u003eChallenge of surgery in LMIC\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8962993/v1/6cd1cbc5167b6d23b5e4cb49.jpg"},{"id":105565044,"identity":"08c8e2a0-4eac-4554-96cf-14cf72bf6b78","added_by":"auto","created_at":"2026-03-27 12:51:39","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":227810,"visible":true,"origin":"","legend":"\u003cp\u003eGraphical abstract of drug therapy and surgery\u003c/p\u003e","description":"","filename":"6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8962993/v1/1feb00d31adf6d7176ff41ae.jpg"},{"id":105565021,"identity":"db0d280b-7a9b-4f2c-9320-7f953ca96ffc","added_by":"auto","created_at":"2026-03-27 12:51:37","extension":"jpg","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":497320,"visible":true,"origin":"","legend":"\u003cp\u003eResult Risk of Bias Cochrane RoB-2 of 11 Studies.\u003c/p\u003e","description":"","filename":"7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8962993/v1/1de5366401ebbb1b75b2e648.jpg"},{"id":106959584,"identity":"102ba5e2-dbd2-4f9a-9335-cbe568c8d883","added_by":"auto","created_at":"2026-04-15 09:11:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3449891,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8962993/v1/5f16aecb-cdef-4def-ad4e-13eed064352b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Cost-Effectiveness of Epilepsy Surgery in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEpilepsy constitutes a major global health burden, affecting approximately 50\u0026nbsp;million individuals, of whom nearly 80% reside in low- and middle-income countries (LMICs).\u003csup\u003e\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Drug-resistant epilepsy (DRE), defined as failure of adequate trials of two tolerated and appropriately chosen antiepileptic drugs, develops in 25\u0026ndash;40% of patients.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Randomised controlled trials conducted in high-income countries have demonstrated that epilepsy surgery offers seizure freedom in 60\u0026ndash;80% of selected patients with temporal lobe epilepsy and is cost-effective when compared with continued medical management.\u003csup\u003e\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn LMICs, however, fewer than 10% of potential surgical candidates ever undergo surgery.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Key barriers include absence of comprehensive epilepsy centres, limited access to video-EEG monitoring, shortage of trained epileptologists and neurosurgeons, and perceived unaffordability of surgical treatment.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Despite these constraints, individual centres in India, Thailand and Colombia have reported successful surgery and disconnective procedures at direct up to US\u003cspan\u003e$\u003c/span\u003e14,894.\u003csup\u003e\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e These reports suggest that curative epilepsy surgery can be delivered at a fraction of high-income country costs, yet no study has systematically pooled clinical efficacy and cost-effectiveness data exclusively from LMICs while restricting inclusion to epilepsy surgery and disconnective techniques.\u003c/p\u003e \u003cp\u003ePrevious systematic reviews have either combined high-income and low-income settings or included neuromodulation procedures such as vagus nerve stimulation, rendering their findings inapplicable to resource-constrained health systems.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Moreover, none have performed meta-regression to explore whether World Bank income classification, surgical volume, or use of invasive monitoring explains heterogeneity in either seizure outcome or cost.\u003c/p\u003e \u003cp\u003eThe present systematic review and meta-analysis therefore aimed to synthesise the evidence on epilepsy surgery performed exclusively in low- and middle-income countries (LMICs). The specific objectives were to demonstrate that curative surgery is already being successfully implemented across diverse LMIC settings, to estimate pooled direct surgical costs (expressed in 2025 international dollars), to determine pooled cost-effectiveness (incremental cost-effectiveness ratios where reported), and to quantify long-term clinical outcomes, specifically the pooled proportion of patients achieving seizure freedom at \u0026ge;\u0026thinsp;12-month follow-up. This review provides the first LMIC-specific, pooled evidence base to guide national epilepsy programmes, health-technology assessment agencies, and international funding bodies in scaling up affordable surgical services, thereby reducing the treatment gap and long-term societal costs in regions carrying 80% of the global burden of drug-resistant epilepsy.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e \u003c/p\u003e \u003cp\u003eThe systematic literature search across Medline, PubMed, Scopus, and the Cochrane Library, without date restrictions, initially retrieved 20 948 records. 11 studies meeting inclusion criteria for quantitative and qualitative synthesis, with 4 additional studies included in qualitative synthesis only. The PRISMA 2020 flow diagram is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eCharacteristics of Included Studies\u003c/h2\u003e \u003cp\u003eCharacteristics are summarize in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The 11 studies were conducted in seven low- and middle-income countries. Interventions comprised resective epilepsy surgery (temporal lobectomy or extratemporal resection) or disconnective procedures in surgical arms, with comparators consisting of continued medical management using antiepileptic drugs. Participants were adults and children with drug-resistant epilepsy. The included studies reported outcomes from consecutive patients with drug-resistant epilepsy who underwent resective or disconnective surgery. Pooled seizure-freedom rates were consistent across studies (52\u0026ndash;79.4%) with very low heterogeneity (I\u0026sup2; = 9%), indicating comparable surgical efficacy among studies. Follow-up periods ranged from 12 to 60 months. Outcomes included direct surgical costs, seizure freedom (Engel Class I), incremental cost-effectiveness ratios, and adverse events. Risk of bias assessment using Cochrane RoB-2.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e11 Qualitative Studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAuthor (Year)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCenter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSubject (Number of Patients, Condition)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eResult parameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eOther Parameter\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eComplication/AE\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCost Surgery\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eEngel Scale\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRao MB, Radhakrishnan K (2000)\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSCTIMST, India\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;190 (119 ATL, 71 refractory TLE non-ATL; Refractory TLE medically intractable; MTLE common)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eATL (anterior temporal lobectomy with amygdalohippocampectomy):\u003c/p\u003e \u003cp\u003ePre-surgical: Noninvasive (clinical, scalp EEG, MRI, VEEG)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCosts (USD, 2000; out-of-pocket; GNI/capita \u003cspan\u003e$\u003c/span\u003e310): - ATL (incl. eval): INR 47,000 (\u003cspan\u003e$\u003c/span\u003e1,200) - Lifetime medical: INR 200,000 (\u003cspan\u003e$\u003c/span\u003e5,000; ages 26\u0026ndash;60 yrs)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeizure-free (Engel I): 70% post-ATL; AED-free: 30% at 3 yrs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eComplications: Transient 5\u0026ndash;10% (memory/language); permanent rare\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFandi\u0026ntilde;o-Franky et al. (2000)\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHospital Neurologico of the Liga Colornbiana, Colombia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e97 patients (62 children, 35 adults) Mean age children 7.9 yrs, adults 25.8 yrs Medically intractable secondarily generalized epilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAnterior two-thirds corpus callosotomy (CCS) 5 cases\u0026thinsp;+\u0026thinsp;frontal excision\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCost: US\u003cspan\u003e$\u003c/span\u003e 3,137-3,995 (year 2000)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eClinical (mean FU 35 mo): 66% seizure-free or only non-disabling seizures AED slightly reduced\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMorbidity: Transient mutism/disconnection syndrome (common, resolved\u0026thinsp;\u0026lt;\u0026thinsp;3 weeks); Wound infection (2); Hydrocephalus (1 requiring shunt);\u003c/p\u003e \u003cp\u003eNo mortality Permanent: None reported\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWu et al. (2011)\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWest China Hospital, China\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e143 patients Refractory epilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eATL (105)\u0026thinsp;+\u0026thinsp;FLE (38) Selective use MRI/VEEG/PET/IEEG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCost: \u003cspan\u003e$\u003c/span\u003e2550\u0026ndash;4230, Operation :2250\u0026ndash;3750; US\u003cspan\u003e$\u003c/span\u003e 2550 to US\u003cspan\u003e$\u003c/span\u003e 4230, for the entire cost of surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eEngel I: ATL 63.8%, FLE 61.1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDash et al. (2012) \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSCTIMST, India\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e285 patients AED-resistant extratemporal epilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eExtratemporal resective surgery (71/285) 9 invasive EEG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCost: Noninvasive\u0026thinsp;+\u0026thinsp;surgery INR 60,000 (US\u003cspan\u003e$\u003c/span\u003e1,500, 2012)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeizure-free(Engel 1): Surgical 73.2% vs. non-surgical 7.7% (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0005)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eTemporary: 4/71 (5.6%, resolved\u0026thinsp;\u0026lt;\u0026thinsp;3 mo) Permanent non-disabling: 3/71 (4.2%, hemiparesis, all ambulant at 1\u0026nbsp;year) Anticipated: Hemianopia 9/71 (12.7%) Mortality: 0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTahir et al. (2012)\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAga Khan University Hospital, Pakistan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 patients (first series) Medically refractory (TLE\u0026thinsp;+\u0026thinsp;catastrophic childhood)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHS 6, ATL 6, keyhole SAH 4 (neuronavigation-guided)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCost: US\u003cspan\u003e$\u003c/span\u003e 1644, direct total cost for regular care\u003c/p\u003e \u003cp\u003eUS\u003cspan\u003e$\u003c/span\u003e 3044, for private care. but \u0026ldquo;limited resources\u0026rdquo;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eEngel I: SAH 100% (12 mo), ATL 83% (24 mo), HS 66% (48 mo)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003ethe average blood loss was 200cc in SAH, 350 cc in ATL, 600 cc inHS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eMorbidity: Minimal in ATL/SAH groups; HS group higher (expected in catastrophic cases) Specific: 2 patients; both patients had undergone functional HS hemispherectomy\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKitwitee P, et al. (2017)\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePrasat Neurological Institute, Thailand\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;70 surgery patients (15 yrs epilepsy, Drug-resistant focal epilepsy)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVEEG\u0026thinsp;+\u0026thinsp;surgery: \u0026bull; Pre-surgical: VEEG (4 days median), MRI, PET/SPECT (50%/27%), fMRI/intracranial EEG (7%) Surgery: Resective (ATL 68%, selective AH 6%, lesionectomy 24%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCosts (THB, 2015; societal; 35 THB/USD; GNI/capita 160,000 THB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeizure-free rates (Engel I)at years 1 and 2 after sur- gery were 79.4% and 77.8%. (TLE 80%/92.5%; ETLE 76.9%/90%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eICER: 43,251 THB/QALY (~\u003cspan\u003e$\u003c/span\u003e1,236 USD; 84% prob CE at threshold). QALY gain: +1.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e- Complications: Transient 20%, permanent 1.4%; mortality 2%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAsadi-Pooya et al. (2017)\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eShiraz University, Iran\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 patients (12 F, 10 M) Age\u0026thinsp;\u0026ge;\u0026thinsp;18 years Refractory MTLE with MTS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eStandard temporal lobectomy (ATL) Presurgical: 2-hour video-EEG, 1.5T MRI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCost: US\u003cspan\u003e$\u003c/span\u003e 500 total\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eEngel I: 15/22 (68.2%) Good outcome (II): 3/22 (13.6%), III: 4,5%. Mean FU 24.8 mo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eComplications: None reported (no neurological deficit, infection, or mortality)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKuzniecky R, et al. (2018)\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHospital del Ni\u0026ntilde;o Dr. Jos\u0026eacute; Ren\u0026aacute;n Esquivel, Panama\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;27 (children; intractable epilepsy, upper-middle LMIC) \u0026bull; Condition: Drug-resistant epilepsy (surgically treatable; no prior local program)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHybrid epilepsy surgery program (US-Panama collaboration; 6 missions):\u003c/p\u003e \u003cp\u003e\u0026bull; Resective surgeries (with intraoperative ECoG); subdural/depth electrodes\u0026thinsp;+\u0026thinsp;extra-operative monitoring\u003c/p\u003e \u003cp\u003e\u0026bull; Multidisciplinary: US neurologists/neurosurgeons/EEG tech\u0026thinsp;+\u0026thinsp;local team\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003egeneral, Average surgery cost per patient: \u003cspan\u003e$\u003c/span\u003e9,850; total direct cost of the program was \u003cspan\u003e$\u003c/span\u003e205 000 for the 27 patients treated, with an average cost of \u003cspan\u003e$\u003c/span\u003e7592 per patient for the overall group\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeizure-free (Engel I): 55.6% (15/27) - Engel II: 40.7% (11/27); Engel III: 3.7% (1/27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eno major complication, Complications: 3.7% (1 infection; no major morbidity/mortality)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eJukkarwala A, et al. (2019)\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSumandeep Vidyapeeth, India\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;125 ( HS 51%, gliosis 18%, Drug-resistant remediable epilepsy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLow-cost surgery:\u003c/p\u003e \u003cp\u003e\u0026bull; Temporal resection 65%, extratemporal 21%, hemispherectomy 10%\u003c/p\u003e \u003cp\u003e\u0026bull; Pre-surgical: VEEG (3 days median), 1.5T MRI, ECoG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSurgery \u003cspan\u003e$\u003c/span\u003e1,121; Total: \u003cspan\u003e$\u003c/span\u003e1,324 (eval \u003cspan\u003e$\u003c/span\u003e296, surgery \u003cspan\u003e$\u003c/span\u003e1,121; 73% GNI) (quantitative eligible)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eEngel IA: 92.5%. Engel II; 3,2%. Engel III; 2,1%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eComplications: 5.6% (7/125; meningitis n\u0026thinsp;=\u0026thinsp;3, hydrocephalus n\u0026thinsp;=\u0026thinsp;1, thrombosis n\u0026thinsp;=\u0026thinsp;1, hemiparesis n\u0026thinsp;=\u0026thinsp;2 [1 resolved])\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAnurat K, et al. (2020)\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRamathibodi Hospital, Thailand\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;36 (17 surgery, 19 medical, Drug-resistant focal epilepsy )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSurgery (n\u0026thinsp;=\u0026thinsp;30; lobectomy/resection):\u003c/p\u003e \u003cp\u003e\u0026bull; Pre-surgical: VEEG, 3T MRI, PET; ECoG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCosts Surgery vs control :44,450 vs 21,274\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSeizure Free: 91.60% vs 67.00%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eICER per outcome: 58,891. ICER: \u003cspan\u003e$\u003c/span\u003e117 USD per 1% seizure reduction. QALYs gained:0.87 vs 0.79\u003c/p\u003e \u003cp\u003eICUR: \u003cspan\u003e$\u003c/span\u003e26\u0026thinsp;564 USD per QALY gained\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e- Complications: 6.7% (2/30; transient hemiparesis n\u0026thinsp;=\u0026thinsp;1, infection n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlegr\u0026iacute;a-Mu\u0026ntilde;oz M, et al. (2025)\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRamathibodi Hospital, Thailand\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e573 pasien (260\u0026thinsp;+\u0026thinsp;313); Condition: Epilepsy (focal/generalized); includes SE, drug-resistant for surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eManagement incl. surgery:\u003c/p\u003e \u003cp\u003ePharma (mono/dual ASMs, e.g., levetiracetam 40%)\u003c/p\u003e \u003cp\u003eDiagnostics/follow-up, SE (ER/ICU) \u0026bull; Surgery: Resective (lesionectomy 46%), VNS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eResective: \u003cspan\u003e$\u003c/span\u003e14,894, Costs (USD, 2023; GNI/capita \u003cspan\u003e$\u003c/span\u003e6,590)- Annual w/o SE: \u003cspan\u003e$\u003c/span\u003e2,416 (range \u003cspan\u003e$\u003c/span\u003e1,032-\u003cspan\u003e$\u003c/span\u003e3,847) - With ICU (8 days SE): \u003cspan\u003e$\u003c/span\u003e61,568 (ICU/day \u003cspan\u003e$\u003c/span\u003e7,314) - Resective: \u003cspan\u003e$\u003c/span\u003e14,894;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVNS cost: \u003cspan\u003e$\u003c/span\u003e26,566\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eMeta-analyses were conducted using RevMan Web with random-effects Hartung-Knapp models. We used random-effects models with the Hartung-Knapp-Sidik-Jonkman variance estimator because the included studies were conducted in markedly different LMIC health systems, with expected clinical and methodological heterogeneity. This approach provides more conservative confidence intervals and better accounts for between-study variability than fixed-effect models.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eSurgical Costs and Seizure Freedom (Engel Class I at ≥ 12 Months)\u003c/h3\u003e\n\u003cp\u003eAll 11 studies reported direct surgical costs. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e presents direct medical cost of epilepsy surgery in LMIC expressed as a percentage of national GDP per capita (US dollars ) for the relevant country and year. Four studies provided continuous data for mean cost comparison between surgery and non-surgery groups. The forest plot of mean differences is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe pooled mean difference was 1.29 (95% CI -0.13 to 2.70; I\u0026sup2; = 100%). Heterogeneity was extreme (p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001). The funnel plot for surgical cost (mean difference) revealed asymmetric distribution with studies clustered toward positive mean differences and absent points in the lower-left quadrant, suggesting potential publication bias favoring higher reported costs (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea). Four studies contributed dichotomous data (199 of 277 patients in surgery arms versus 12 of 127 in medical arms). The forest plot comparing seizure freedom outcomes between surgery and non-surgery groups is displayed in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb. The pooled odds ratio favoring surgery was 22.51 (95% CI 11.17 to 45.38; p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001; I\u0026sup2; = 9%). Heterogeneity was low (p\u0026thinsp;=\u0026thinsp;0.28). The funnel plot for seizure freedom (log odds ratio) indicated minor asymmetry, with one study positioned distant from the others on the right side, but no clear evidence of small-study effects given the limited number of included studies (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eCost-Effectiveness\u003c/h3\u003e\n\u003cp\u003eTwo studies reported incremental cost-effectiveness ratios (ICERs) and incremental cost-utility ratios (ICURs). One study reported an ICER of 43,251 THB per QALY gained (approximately US\u003cspan\u003e$\u003c/span\u003e1,236, adjusted to 2025 international dollars), with a QALY gain of 1.50 and an 84% probability of cost-effectiveness at the country-specific threshold. The second study reported an ICER of 58,891 per outcome, US\u003cspan\u003e$\u003c/span\u003e117 per 1% seizure reduction, and an ICUR of US\u003cspan\u003e$\u003c/span\u003e26,564 per QALY gained (QALYs gained: 0.87 in surgery versus 0.79 in medical management). Both studies indicated cost-effectiveness below the World Health Organization threshold for the respective countries. Meta-analysis was not performed due to the limited number of studies, differences in outcome metrics, time horizons, and discount rates.\u003c/p\u003e \u003cp\u003eHeterogeneity was extreme for surgical costs and low for seizure freedom, attributable to differences in cost components, follow-up duration, and health system contexts. Complication rates were low across studies. Assessment of publication bias will be finalized following completion of risk of bias evaluation.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eCost of Surgery\u003c/h2\u003e \u003cp\u003eThe analysis of surgical costs across low- and middle-income countries (LMICs) reveals substantial variability in direct costs for epilepsy surgery, as depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, underscoring the influence of economic context, healthcare infrastructure, and procedural optimization strategies on affordability. These costs, encompassing preoperative evaluation, intraoperative procedures, hospitalization, and postoperative care, consistently demonstrate that epilepsy surgery remains viable at a fraction of high-income country equivalents, thereby supporting its scalability in resource-constrained settings. The pooled mean difference in costs between surgical and medical management arms (1.29 US\u003cspan\u003e$\u003c/span\u003e thousands; 95% CI -0.13 to 2.70) highlights an initial upfront investment that yields long-term savings through reduced seizure recurrence and associated healthcare utilization.\u003c/p\u003e \u003cp\u003eIn India, Rao et al. (2000) reported direct costs of approximately US\u003cspan\u003e$\u003c/span\u003e1,200 (GDP per capita \u003cspan\u003e$\u003c/span\u003e442.8) for anterior temporal lobectomy (ATL), primarily comprising noninvasive presurgical evaluations such as scalp EEG and MRI, alongside out-of-pocket expenses for surgery and basic hospitalization.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e This low figure reflects the program's emphasis on streamlined, noninvasive protocols to minimize diagnostic overheads, with lifetime medical management costs estimated at US\u003cspan\u003e$\u003c/span\u003e5,000, exceeding surgical expenses over time due to ongoing antiepileptic drug (AED) requirements. Similarly, Dash et al. (2012) documented costs of US\u003cspan\u003e$\u003c/span\u003e1,500 (GDP per capita \u003cspan\u003e$\u003c/span\u003e980)for extratemporal resective surgery, including noninvasive evaluations and invasive EEG in select cases (9% of patients), where the bulk of expenses arose from surgical fees and short-term inpatient stays, demonstrating cost containment through targeted patient selection in a resource-poor environment.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e Jukkarwala et al. (2019) further exemplified efficiency with total costs of US\u003cspan\u003e$\u003c/span\u003e1,324 (evaluation: US\u003cspan\u003e$\u003c/span\u003e296; surgery: US\u003cspan\u003e$\u003c/span\u003e1,121) (GDP per capita \u003cspan\u003e$\u003c/span\u003e2041), achieved via abbreviated video-EEG (median 3 days) and 1.5T MRI without advanced imaging modalities, highlighting how tiered referral systems and epileptologist-led interpretations reduce personnel and equipment demands.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn Colombia, Fandi\u0026ntilde;o-Franky et al. (2000) estimated direct costs for corpus callosotomy at US\u003cspan\u003e$\u003c/span\u003e3,137-3,995 (GDP per capita \u003cspan\u003e$\u003c/span\u003e6398.3), dominated by operative and perioperative components, including basic monitoring and wound management, with limited presurgical diagnostics due to the palliative nature of the procedure.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e This contrasts with Alegr\u0026iacute;a-Mu\u0026ntilde;oz et al. (2025), who reported higher resective surgery costs of US\u003cspan\u003e$\u003c/span\u003e14,894 (GDP per capita \u003cspan\u003e$\u003c/span\u003e7195.1), driven by comprehensive diagnostics (MRI, EEG test) and potential intensive care unit admissions for status epilepticus (escalating annual costs to US\u003cspan\u003e$\u003c/span\u003e61,568), though payer-perspective adjustments via bootstrapping revealed variability tied to pharmaceutical and emergency interventions.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eChina's experience, as outlined by Wu et al. (2011), yielded total costs of US\u003cspan\u003e$\u003c/span\u003e2,550-4,230 (GDP per capita \u003cspan\u003e$\u003c/span\u003e5703.8) for ATL and frontal lobe excisions, with operative expenses (US\u003cspan\u003e$\u003c/span\u003e2,250-3,750) forming the largest share, supplemented by selective use of MRI, video-EEG, PET, and intracranial EEG to constrain presurgical outlays in low-income cohorts.\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e In Pakistan, Tahir et al. (2012) achieved costs of US\u003cspan\u003e$\u003c/span\u003e1,644 (public care) to US\u003cspan\u003e$\u003c/span\u003e3,044 (private) (GDP per capita \u003cspan\u003e$\u003c/span\u003e1204.4) for procedures like hemispherotomy and ATL, where direct components included neuronavigation-guided resections and basic follow-up, offset by collaborative teleconferences that minimized on-site expertise expenses.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThailand's studies illustrate moderate costs reflective of upper-middle-income infrastructure: Kitwitee et al. (2017) detailed US\u003cspan\u003e$\u003c/span\u003e6,194 (GDP per capita \u003cspan\u003e$\u003c/span\u003e6412.1) for video-EEG-monitored resections (societal perspective, including lifetime AEDs), with presurgical evaluation (US\u003cspan\u003e$\u003c/span\u003e1,036 for VEEG/MRI/PET) and year-one surgery/hospitalization comprising 80% of initial outlays. Anurat et al. (2020) reported US\u003cspan\u003e$\u003c/span\u003e1,236 (GDP per capita \u003cspan\u003e$\u003c/span\u003e6985.6) equivalent for pediatric ATL, encompassing advanced presurgical tools (3T MRI, PET, electrocorticography) and transient complication management (e.g., infection), where costs were further moderated by universal coverage schemes.\u003c/p\u003e \u003cp\u003eIn Iran, Asadi-Pooya et al. (2017) achieved exceptionally low totals under US\u003cspan\u003e$\u003c/span\u003e500 (GDP per capita \u003cspan\u003e$\u003c/span\u003e5753.1) for temporal lobectomy, limited to 2-hour video-EEG and 1.5T MRI, underscoring the feasibility of basic protocols in resource-limited public systems.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Finally, Kuzniecky et al. (2018) in Panama documented US\u003cspan\u003e$\u003c/span\u003e7,592-9,850 per patient (GDP per capita \u003cspan\u003e$\u003c/span\u003e1615.1) in a hybrid model, incorporating international missions for electrocorticography and monitoring, with program-wide costs (US\u003cspan\u003e$\u003c/span\u003e205,000 for 27 patients) driven by multidisciplinary training and postoperative surveillance.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eComparison of surgery cost\u003c/h2\u003e \u003cp\u003eThe meta-analysis of surgical costs, encompassing four studies with continuous data on mean differences between surgery and non-surgery groups, yielded a pooled estimate of 1.29 US\u003cspan\u003e$\u003c/span\u003e thousands (95% CI -0.13 to 2.70; Z\u0026thinsp;=\u0026thinsp;1.79, p\u0026thinsp;=\u0026thinsp;0.07), indicating no statistically significant incremental cost for epilepsy surgery over medical management in the short term. As illustrated in the forest plot (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), individual study estimates exhibited marked dispersion, with three studies demonstrating positive mean differences favoring higher surgical costs (ranging from 0.50 to 3.50 US\u003cspan\u003e$\u003c/span\u003e thousands) and one outlier showing a negative value, contributing to the non-significant overall effect. This finding aligns with the extreme heterogeneity observed (I\u0026sup2; = 100%; Chi\u0026sup2; = 471.38, p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001), attributable to variations in cost components ( PET/SPECT test in Thailand studies) versus minimalist noninvasive protocols in Indian centers, and differences in follow-up durations (12\u0026ndash;60 months) and health system financing models across the seven LMICs.\u003c/p\u003e \u003cp\u003eThe funnel plot for surgical cost mean differences (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea) revealed notable asymmetry, characterized by clustering of studies toward positive mean differences and an absence of points in the lower-left quadrant, which suggests potential publication bias favoring reports of elevated surgical costs. We visually inspected the funnel plot and formally tested for small-study effects. Egger\u0026rsquo;s weighted regression test did not show significant funnel plot asymmetry for cost outcomes (intercept \u0026micro;\u0026thinsp;=\u0026thinsp;0.94, t(2) = \u0026minus;\u0026thinsp;0.05, p\u0026thinsp;=\u0026thinsp;0.97), and the meta-regression test for asymmetry was likewise non-significant (z\u0026thinsp;=\u0026thinsp;1.89, p\u0026thinsp;=\u0026thinsp;0.06). We also attempted to apply Duval and Tweedie\u0026rsquo;s trim-and-fill procedure; however, given the very small number of studies (total study\u0026thinsp;=\u0026thinsp;4) and the between-study heterogeneity (I\u0026sup2; = 100%), the method was unstable and could not be reliably implemented. Accordingly, we present the funnel plot primarily for visual inspection and interpret the risk of publication bias with caution. This asymmetry may reflect selective reporting of higher-cost scenarios in resource-constrained settings, where comprehensive evaluations inflate estimates, or the underrepresentation of low-cost models from tiered centers.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Despite the non-significant pooled mean difference, the wide confidence interval encompassing zero underscores that upfront surgical investments are often offset by long-term reductions in AED expenditures and emergency care, as evidenced in lifetime projections from Kitwitee et al. (2017) and Anurat et al. (2020).\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis surgery cost pattern aligns with detailed breakdowns in key studies: presurgical diagnostics (video-EEG and MRI) accounted for 15\u0026ndash;22% in Indian centers like Jukkarwala et al. (2019) through minimized protocols, rising to 42.8% in Thailand (Kitwitee et al., 2017) due to advanced imaging (PET/SPECT in 27\u0026ndash;50% cases), while operative and hospitalization phases dominated at 57\u0026ndash;85%. Such variability, as visualized in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, underscores opportunities for cost optimization via non-invasive strategies in lower-middle-income settings. Collectively, these findings indicate that direct costs in LMICs (range: US\u003cspan\u003e$\u003c/span\u003e500\u0026thinsp;\u0026minus;\u0026thinsp;14,894) are predominantly influenced by presurgical diagnostics (20\u0026ndash;40% of total) and operative/hospitalization phases (50\u0026ndash;70%), with indirect factors such as out-of-pocket payments and lost productivity amplifying burdens in lower-middle-income settings like India and Pakistan. Optimization through noninvasive protocols and international collaborations not only curtails expenses but also enhances equity, aligning with global calls for LMIC-specific epilepsy programs to bridge the treatment gap.\u003c/p\u003e \u003cp\u003eThe establishment of low-cost epilepsy surgery programs in resource-poor settings demonstrates a replicable model that significantly reduces the surgical treatment gap in LMICs. This approach, implemented across three Tier 2 and Tier 3 cities in India, relied on abbreviated presurgical evaluations (median 3-day video-EEG and 1.5T MRI without PET/SPECT or invasive EEG), epileptologist-led interpretations, and an initial phase of invited epilepsy surgeons transitioning to local neurosurgeons, yielding 92.5% Engel Class IA outcomes at an average total cost of US\u003cspan\u003e$\u003c/span\u003e1,324 per patient. By subsidizing expenses for deserving patients and focusing on ideal candidates identified through clinical history and noninvasive data, the model achieved 125 surgeries since 2012 while maintaining minor complication rates of 5.6%, illustrating how decentralized, cost-conscious frameworks can expand access without compromising efficacy. Clinical superiority is further evidenced in pediatric cohorts, where surgery achieved 52% seizure freedom compared to 16% with medical management alone, though short-term cost-effectiveness remains limited (ICER 743,040 THB per QALY at three years exceeding the national threshold). Temporal resections, however, proved highly viable at 36,569 THB per QALY, with projections indicating overall cost-effectiveness beyond three years, reinforcing the need for extended evaluation horizons and policy integration to sustain such transformative models in LMICs.\u003c/p\u003e \u003cp\u003eComparison between surgical intervention and medical management in the meta-analysis of Engel Class I seizure freedom at 12 months or longer demonstrates a pooled odds ratio of 22.51 (95% CI 11.17 to 45.38; p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001), reflecting substantially greater efficacy with surgery.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e The forest plot (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb) illustrates uniform positive effects across the four studies, with seizure freedom rates in surgical groups spanning 52% to 79.4% compared to 7.7% to 16% in medical groups, encompassing pediatric and adult populations in Thailand and India. Low heterogeneity (I\u0026sup2; = 9%; p\u0026thinsp;=\u0026thinsp;0.28) arises from consistent outcome definitions and follow-up durations of 12 to 60 months, reinforcing the dependability of surgical advantages despite differences in presurgical imaging and patient selection protocols. \u003csup\u003e17,18,25,26\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eBeyond Engel Class I, additional outcomes reveal meaningful clinical improvements: one Indian low-cost program reported Engel Class II in 3.2% and Class III in 2.1% of cases, with no Class IV failures, indicating that over 95% of patients achieved worthwhile improvement or better.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Quality of life gains further support surgical value, with lifetime modeling showing an incremental 1.50 QALYs in adults and 0.87 versus 0.79 QALYs in pediatric cohorts, translating to enhanced daily functioning and reduced disability burden.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e The funnel plot for log odds ratios (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb) displays minor asymmetry, with one study situated farther to the right and no points in the lower-left quadrant, indicating no substantial small-study effects given the small number of included studies. \u003csup\u003e17,25,26\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThis configuration implies limited publication bias, bolstering confidence in the pooled estimate. Seizure freedom data from both the forest and funnel plots, combined with Engel Class II-III outcomes and QALY gains, collectively emphasize surgery's pivotal role in LMICs, conferring over 20-fold increased odds of sustained remission alongside quality-of-life benefits outcomes that validate initial expenditures and endorse wider adoption through streamlined, noninvasive diagnostic pathways to maximize clinical value in resource-limited environments. \u003csup\u003e17,25,26\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eSeven additional studies enrich the evidence base by exploring procedural diversity and outcomes in varied LMIC contexts.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan additionalcitationids=\"CR20 CR21 CR22 CR23\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e Resective approaches dominated, with anterior temporal lobectomy (ATL) applied in Iranian cohorts for mesial temporal lobe epilepsy (MTLE), yielding Engel Class I rates of 68.2% alongside 13.6% Class II.\u003csup\u003e24\u003c/sup\u003e Extratemporal resections (ETLE) and disconnective procedures, including selective amygdalohippocampectomy (SAH) and hemispherectomy (HS) in Pakistani catastrophic childhood cases, achieved Engel Class I outcomes of 83\u0026ndash;100% for SAH and 66% for HS.\u003csup\u003e23\u003c/sup\u003e Non-resective strategies broadened applicability: corpus callosotomy in Colombia produced 66% seizure-free or non-disabling seizures in secondarily generalized epilepsy, while a Panamanian hybrid program reported Engel Class I in 55.6%, Class II in 40.7%, and Class III in 3.7% using intraoperative electrocorticography.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e Low-cost Indian tiered centers optimized resections, 65% temporal lobe epilepsy (TLE) and 21% ETLE, with 92.5% Engel Class IA, 3.2% Class II, and 2.1% Class III.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Chinese series demonstrated balanced efficacy in TLE (ATL, 63.8%) and ETLE (frontal lobe excision, 61.1%), and Colombian payer analyses highlighted resective lesionectomy (46%) without Engel reporting to emphasize economic feasibility.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Emerging programs in Indonesia, Vietnam, Malaysia, and Brazil have further expanded the evidence, demonstrating that structured epilepsy surgery initiatives in middle-income settings can achieve Engel Class I rates of 58\u0026ndash;78% even with limited access to invasive EEG or magnetoencephalography.\u003csup\u003e\u003cspan additionalcitationids=\"CR28 CR29 CR30\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe implementation of epilepsy surgery in low- and middle-income countries (LMICs) is constrained by interconnected challenges across infrastructure, workforce, and financial domains, as depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e and synthesized from the 11 included studies. Infrastructure challenges feature the scarcity of comprehensive epilepsy centers and significant heterogeneity in national income, health funding, and financing models. Fewer than 15 comprehensive Level-4 epilepsy centers exist across all of Asia and Latin America combined, serving populations exceeding 4.5\u0026nbsp;billion, resulting in surgical volumes of \u0026lt;\u0026thinsp;1 procedure per million inhabitants annually in most LMICs.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn lower-middle-income settings like India, decentralized tier-2 and tier-3 facilities adopt abbreviated noninvasive protocols (3-day video-EEG, 1.5T MRI), attaining costs of US\u003cspan\u003e$\u003c/span\u003e1,324 per patient.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Conversely, upper-middle-income Thailand employs PET/SPECT in 27\u0026ndash;50% of cases, raising presurgical diagnostics to 42.8% of total costs within a national universal coverage framework.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e Workforce challenges involve insufficient training initiatives, limited epileptology specialization, and high turnover, with general neurosurgeons often conducting procedures in Pakistan and Iran; the Indian transitional approach from international to local surgeons enabled 125 operations since 2012 with 92.5% Engel Class IA outcomes, yet underscores ongoing external dependency. \u003csup\u003e19\u003c/sup\u003e International twinning and telemedicine-supported training models, successfully piloted in Uganda and Indonesia, have increased local surgical capacity by 200\u0026ndash;400% within 3\u0026ndash;5 years, highlighting scalable pathways for workforce development.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e,\u003cspan additionalcitationids=\"CR34\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eFinancial challenges, notwithstanding direct costs of US\u003cspan\u003e$\u003c/span\u003e500\u0026thinsp;\u0026minus;\u0026thinsp;14,894, stem from prevalent out-of-pocket payments and partial insurance coverage, prompting diagnostic delays in Colombia and Panama, while Thailand's system facilitates long-term cost-effectiveness (ICER 36,569 THB per QALY for temporal resections) but excludes select pediatric palliative procedures.\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e The Thai studies most thoroughly exemplify these interrelations, infrastructure hindering workforce capacity and intensifying financial pressures, whereas Jukkarwala et al. (2019) presents a replicable model for resource optimization.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e,\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e Despite these disparities, LMIC outcomes remain competitive with high-income countries (HICs): pooled Engel Class I seizure freedom (52-79.4%) closely aligns with HIC benchmarks (60\u0026ndash;80%) from randomized trials in the United Kingdom and United States.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e LMICs have substantially lower costs of surgery (LMICs: US\u003cspan\u003e$\u003c/span\u003e500\u0026thinsp;\u0026minus;\u0026thinsp;14,894 vs. HICs: US\u003cspan\u003e$\u003c/span\u003e20,000-100,000), with similar complication rates (\u0026lt;\u0026thinsp;6% in LMICs vs. 5\u0026ndash;10% in HICs).\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e Recent multicenter cohorts from Asia and Latin America further confirm that quality-of-life gains (measured by QOLIE-31 and EQ-5D) and reduction in antiepileptic drug polytherapy after successful surgery are equivalent to those reported in high-income settings, underscoring the high value-for-money of epilepsy surgery in LMICs.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e,\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e Targeted strategies, including regional infrastructure enhancements, standardized training programs, and expanded universal coverage, alongside prospective multicenter trials, are critical to overcoming the treatment gap surpassing 90% in LMICs.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThis systematic review summary shows (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e) that epilepsy surgery in low- and middle-income countries dominates continued medical management: it requires higher upfront investment but delivers markedly superior seizure-freedom rates (52\u0026ndash;92.5%), frequently achieves cure, and generates lower lifetime costs. In Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e presents the risk-of-bias assessment for the 11 included studies. Most studies showed moderate risk of bias in random sequence generation, allocation concealment, blinding of outcome assessment, and selective reporting with low risk of bias mostly showed in Blinding of participant and Incomplete outcome data. Overall, the methodological quality of the evidence was moderate.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThis review exhibits several limitations that warrant consideration. The inclusion of only 11 studies, with four contributing to the Engel Class I meta-analysis, constrained statistical power and generalizability, particularly for extratemporal and palliative procedures. Heterogeneity in cost reporting, encompassing direct medical expenses, societal perspectives, and varying currency conversions, precluded a robust pooled cost estimate, while the absence of standardized indirect cost assessments (productivity losses) limited comprehensive economic evaluations. Furthermore, the design of included studies primarily comprised observational cohorts with follow-up durations ranging from 12 to 60 months, which may introduce selection bias toward surgically amenable candidates. Publication bias, though funnel plots and meta-regression Egger's test, cannot be entirely excluded given the small study count. Another limitation of this study is the variation in treatment costs due to the technological advancements that occurred between the years 2000 and 2025. While efforts were made to adjust for changes in economic conditions using the Gross Domestic Product (GDP) per capita for each country and year as reported in the studies, the exact impact of new technologies on treatment costs was not fully accounted. Finally, although both pediatric and adult patients were included across studies and pooled seizure-freedom outcomes showed low heterogeneity (I\u0026sup2; = 9%) with comparable efficacy, the limited number of studies precluded formal subgroup analysis by age group. Therefore, potential subtle differences in long-term outcomes or cost-effectiveness between children and adults could not be fully explored.\u003c/p\u003e \u003cp\u003eFuture focus should aim to include a larger number of studies with longer follow-up durations, indirect costs reporting, and subgroup analysis by age group to better assess long-term outcomes and cost-effectiveness. Additionally, more detailed information on technological advancements and their impact on treatment costs should be incorporated to refine cost estimates.\u003c/p\u003e \u003c/div\u003e"},{"header":"Methods","content":"\u003cp\u003eThis systematic review was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO) on November 17th 2025 under the title \u0026ldquo;Cost-Effectiveness of Epilepsy Surgery in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis\u0026rdquo;. The protocol under registration number CRD420251182159. The protocol is publicly available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.crd.york.ac.uk/PROSPERO/view/CRD420251182159\u003c/span\u003e\u003cspan address=\"https://www.crd.york.ac.uk/PROSPERO/view/CRD420251182159\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. All methods, including literature search strategy, eligibility criteria, data extraction, risk of bias assessment (Cochrane RoB-2), and meta-analytic techniques (RevMan Web), were predefined in the registered protocol to minimize reporting bias and ensure methodological transparency. Any deviations from the protocol will be clearly documented in the final publication.\u003c/p\u003e\n\u003ch3\u003eLiterature Search Strategy\u003c/h3\u003e\n\u003cp\u003eA systematic literature search was conducted across four major online databases: Medline, PubMed, Scopus, and the Cochrane Library. The search was limited to these four as these databases provide the broadest coverage and highest indexing quality for biomedical and health-economic literature worldwide. Together they include\u0026thinsp;\u0026gt;\u0026thinsp;95% of relevant epilepsy surgery and cost-effectiveness publications, while additional databases predominantly yield duplicate records or studies already captured through manual reference checking and backward citation searching for additional relevant studies. The search utilized a combination of primary keywords and synonyms, specifically \"(Cost OR costs OR cost-effectiveness OR cost-utility OR cost-benefit) AND (Epilepsy Surgery OR Temporal epileptic surgery OR temporal lobectomy) AND (low income OR middle income OR LMIC OR low and middle income countries OR developing countries)\". No date restrictions were applied.. The review will be published in English and Indonesian language.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eInclusion and Exclusion Criteria\u003c/h2\u003e \u003cp\u003eArticles were included if they met the following criteria: first, they focused on the cost-effectiveness of epilepsy surgery; second, they were conducted in low- and middle-income countries; third, they involved patients with drug-resistant epilepsy undergoing surgery procedures and reported at least one economic outcome (total cost, ICER, cost per QALY, cost per DALY averted, or cost per seizure-free patient). Comparators will comprise standard treatment or controls selected by the study authors. Both randomized and non-randomized study designs will be included. Articles not meeting these criteria will be excluded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eScreening and Selection Process\u003c/h2\u003e \u003cp\u003eThe initial search will yield a broad range of articles, which will be filtered based on publication year, relevancy and study type. Two reviewers independently screened the titles and abstracts of all records identified through the systematic search and manual reference checking. Full-text reports of any record considered potentially relevant by at least one reviewer were retrieved and independently evaluated for inclusion by the same two reviewers.\u003c/p\u003e \u003cp\u003eAny discrepancies between reviewers during title/abstract screening or full-text assessment were first resolved by discussion. Persistent disagreements were adjudicated by a third reviewer. Exclusions at the full-text stage were categorized and recorded. A PRISMA flow diagram will illustrate the study selection process.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eData Extraction and Synthesis\u003c/h2\u003e \u003cp\u003eSelected articles with key data were systematically extracted, including the article\u0026rsquo;s title and authors, publication year, study objectives and methodology, sample size and study population, intervention details (epilepsy surgery), comparators (medical management), and key findings related to cost and effectiveness outcomes. Data extraction was performed independently by at least two individuals (or a person/machine combination) with a process to resolve differences. Authors were contacted to provide any required data not available in published reports. Data synthesis was conducted using RevMan Web, aggregating quantitative data for meta-analysis where applicable. For each study, the reported costs in local currencies were converted into US dollars using the average exchange rate of the corresponding study year. When the year of data collection was not explicitly stated, the year of publication was used as a proxy. All monetary values were then inflated to 2025 US dollars according to the US Consumer Price Index (CPI). Country-specific gross domestic product (GDP) per capita for 2025 was obtained from the World Bank database, and direct medical costs were expressed as a percentage of the respective country\u0026rsquo;s GDP per capita.\u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eAnalysis and Interpretation\u003c/h2\u003e \u003cp\u003eExtracted data were analyzed to identify recurring themes, cost-effectiveness thresholds, and research gaps. Similarities and differences across studies were evaluated to assess the economic value of epilepsy surgery in low- and middle-income settings. Meta-analytic techniques included the calculation of cost-effectiveness in epilepsy surgery with 95% confidence intervals for continuous outcomes, with heterogeneity assessed using the I\u0026sup2; statistic. Subgroup analyses based on income level, surgical procedure, and time horizon, along with funnel plot assessments for publication bias, were conducted to strengthen the validity of conclusions. The certainty of findings will be assessed using the Cochrane Risk of Bias Tools 2.0 checklist, integrated into the systematic review and meta-analysis process, which adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocols and The Cochrane Handbook for Systematic Reviews of Interventions, with evaluations performed independently by at least two individuals (or a person/machine combination) and a process to resolve differences.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis systematic review and meta-analysis confirms epilepsy surgery as highly effective and cost-effective for drug-resistant epilepsy in LMICs. Surgery yielded over 20-fold higher odds of Engel Class I seizure freedom (pooled OR 22.51; 95% CI 11.17\u0026ndash;45.38) versus medical management, with consistent benefits across ages and low heterogeneity. Procedures like temporal lobectomy, hemispherectomy, and callosotomy improved seizures in \u0026gt;\u0026thinsp;90% of cases. Costs (US\u003cspan\u003e$\u003c/span\u003e500\u0026ndash;14,894) were affordable, driven by presurgical workup and surgery, with noninvasive options suitable for resource-limited settings. Lifetime projections show strong QALY gains, supporting integration into universal health coverage. Urgent expansion of decentralized, low-cost programs is needed to close the treatment gap, with calls for standardized reporting and multicenter trials.\u003c/p\u003e "},{"header":"Declarations","content":"\u003ch3\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are available from the corresponding author on reasonable request. All data extracted from included studies are presented in the manuscript and supplementary materials. No additional datasets were generated or analysed beyond those reported.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eAuthor contributions statement\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eM.T.A. conceptualized the study, developed the methodology and protocol, performed the literature search, study selection, data extraction, conducted the formal analysis (including meta-analysis), wrote the original draft, reviewed and edited the manuscript, provided supervision, and managed project administration. F.P. contributed to methodology, performed study selection, data extraction, validation of data, reviewed and edited the manuscript, and prepared visualizations. N.\u0026Ouml;. contributed to methodology, performed formal analysis, validated results, interpreted the health-economics data, and reviewed and edited the manuscript. All authors have read and approved the final version of the manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe sincerely thank to the clinical and research staff, librarians, administrative personnel, and colleagues from epilepsy surgery programs across various centres for their invaluable collaboration, dedication, and critical contributions throughout this research \u0026nbsp;and all patients and families whose experiences continue to inspire the urgent need for accessible surgical care. This review would not have been possible without their collective support.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial Support And Sponsorship\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical issues\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval was not required for this study because it is a review of previously published literature and does not involve human participants or animals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eORCID\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMuhammad Thohar Arifin: https://orcid.org/0000-0003-2363-8026.\u003c/p\u003e\n\u003cp\u003eFirman Pribadi: https://orcid.org/0000-0003-4325-6738.\u003c/p\u003e\n\u003cp\u003eNurettin \u0026Ouml;ner: https://orcid.org/0000-0002-4761-7863.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWorld Health Organization. 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Burden of epilepsy in Latin America and The Caribbean: a trend analysis of the Global Burden of Disease Study 1990\u0026ndash;2019. \u003cem\u003eLancet Reg. Health - Americas\u003c/em\u003e. \u003cb\u003e8\u003c/b\u003e, 100140 (2022).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMeyer, A-C., Dua, T., Ma, J., Saxena, S. \u0026amp; Birbeck, G. Global disparities in the epilepsy treatment gap: a systematic review. \u003cem\u003eBull. World Health Organ.\u003c/em\u003e \u003cb\u003e88\u003c/b\u003e, 260\u0026ndash;266 (2010).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGDP per capita. (current US\u003cspan\u003e$\u003c/span\u003e) | Data. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://data.worldbank.org/indicator/NY.GDP.PCAP.CD\u003c/span\u003e\u003cspan address=\"https://data.worldbank.org/indicator/NY.GDP.PCAP.CD\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (accessed 4 Dec2025).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Cost-effectiveness, Epilepsy surgery, Drug-resistant epilepsy, Low and middle-income countries, Incremental cost-effectiveness ratio, Seizure freedom","lastPublishedDoi":"10.21203/rs.3.rs-8962993/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8962993/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis review aim to analyse the cost-effectiveness of epilepsy surgery for drug-resistant epilepsy in low- and middle-income countries (LMICs). Medline, PubMed, Scopus, and Cochrane Library were searched without restrictions. Studies from World Bank-classified LMICs reporting original cost and/o cost-effectiveness data for epilepsy surgery were included. Two reviewers independently screened records, extracted data, and assessed risk of bias. Pooled seizure freedom (Engel Class I\u0026thinsp;\u0026ge;\u0026thinsp;12 months) and cost differences were analysed using random-effects Hartung-Knapp models in RevMan app. PRISMA 2020 guidelines were followed. From 20,948 records, 11 studies (2,684 patients) from seven LMICs were included. Direct surgical costs ranged from US\u003cspan\u003e$\u003c/span\u003e500 to US\u003cspan\u003e$\u003c/span\u003e14,894 (2025 USD). The pooled mean cost difference (surgery vs. medical management) was US\u003cspan\u003e$\u003c/span\u003e1,290 (p\u0026thinsp;=\u0026thinsp;0.07; I\u0026sup2;=100%). Surgery showed markedly superior efficacy, with pooled odds ratio for Engel Class I seizure freedom (\u0026ge;\u0026thinsp;12 months) of 22.51 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.00001; I\u0026sup2;=9%), corresponding to 52\u0026ndash;79.4% freedom rates in surgical groups versus 7.7\u0026ndash;16% in medical groups. Two studies reported ICERs of approximately US\u003cspan\u003e$\u003c/span\u003e1,236 and US\u003cspan\u003e$\u003c/span\u003e26,564 per QALY gained. Epilepsy surgery in LMICs offers over 20-fold higher odds of seizure freedom at modest costs and cost-effective, supporting expansion of accessible surgical programs to reduce the treatment gap in resource-limited settings.\u003c/p\u003e","manuscriptTitle":"Cost-Effectiveness of Epilepsy Surgery in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-24 17:16:58","doi":"10.21203/rs.3.rs-8962993/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-05-05T06:01:48+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-04T12:15:25+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"148028393038151446670382332923540065674","date":"2026-04-13T09:10:26+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-12T04:34:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"18705109840600636680040098124229340062","date":"2026-03-22T01:21:44+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-19T22:27:56+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-19T22:24:59+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-06T08:51:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-04T10:55:49+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2026-03-04T07:58:08+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"03b61380-ce08-4858-bef5-fb65dee2c55d","owner":[],"postedDate":"March 24th, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Revision requested","date":"2026-05-05T06:01:48+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-05-04T12:15:25+00:00","index":48,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[{"id":64909313,"name":"Health sciences/Diseases"},{"id":64909314,"name":"Health sciences/Health care"},{"id":64909315,"name":"Health sciences/Medical research"},{"id":64909316,"name":"Health sciences/Neurology"},{"id":64909317,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2026-05-05T06:10:56+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-24 17:16:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8962993","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8962993","identity":"rs-8962993","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}