Managing Refractory Epilepsy in a Resource-Limited Setting

Abstract

Drug-resistant epilepsy (DRE) disproportionately affects individuals in low- and middle-income countries (LMIC), where access to affordable and effective care remains a significant challenge. Patients with DRE face high healthcare costs, inadequate access to epilepsy surgery, and limited availability of trained professionals. This review explores a multifaceted approach to managing DRE in resource-constrained settings. Key strategies include rational polypharmacy with cost-effective antiseizure medications (ASM), implementation of dietary therapies like the ketogenic diet, and cost-conscious presurgical evaluations. Enhancing emergency care systems, particularly for conditions like status epilepticus, is critical, as is the development of standardized diagnostic and treatment protocols and training programs for healthcare providers. By addressing these gaps, LMIC can improve outcomes for individuals with DRE and reduce the burden of untreated seizures on patients and healthcare systems.

Keywords

epilepsy surgery low- and middle-income countries refractory epilepsy low resources ketogenic diet polypharmacy

Introduction

Epilepsy affects 65 million people worldwide, with at least one-third of patients remaining refractory to medications, if available and appropriately used.^1,2 This refractory group experiences a disproportionate burden of frequent medical visits, polypharmacy, hospitalizations, and extensive presurgical evaluations, all of which contribute to heightened healthcare costs and significant morbidity, mortality, and disability. Notably, 80% of patients with drug-resistant epilepsy (DRE) reside in low- and middle-income countries (LMIC), where affordability and access to care compound these challenges.^3,4

In LMIC, the financial burden of epilepsy care is overwhelming. A recent study in Asia revealed that patients often spend half their monthly income on antiseizure medications, with costs escalating due to polypharmacy required for DRE.⁵ This financial strain frequently leads to medication nonadherence that worsens seizure control. Similarly, epilepsy surgery, though considered cost-effective, may require approximately a year's income, making it prohibitively expensive.^6,7 While underutilization of epilepsy surgery is a global issue, these deficits are particularly pronounced in resource-constrained settings.

Access barriers further exacerbate the problem. Specialized care is scarce, physician-to-patient ratios are low, and medication shortages create vast epilepsy-care deserts. Emergency medical systems are often underdeveloped, and limited awareness and guidelines for managing epilepsy emergencies, such as status epilepticus, frequently result in inadequate prehospital treatment.⁸

Moreover, the recent expansion of epilepsy treatments into minimally invasive surgery and gene therapies threatens to widen the access gap further in developing countries.

This review examines the multifaceted challenges of managing medically refractory epilepsy in the setting of resource-limited environments. It explores strategic polypharmacy as a multidimensional concept for optimizing treatment combinations and minimizing adverse effects to achieve better patient outcomes while reducing the substantial personal and national economic burden of untreated epilepsy. It also proposes strategies to adopt cost-effective diagnostic and therapeutic approaches to expand the reach of epilepsy surgery and ketogenic diets alongside provider training, and robust emergency care guidelines.

Strategic Polypharmacy in Refractory Epilepsy

Patients with DRE fail monotherapy and, to the degree available, many are not surgical candidates. Global studies highlight the economic strain of epilepsy in LMIC⁹ including direct (eg, antiseizure medications, ASM) and indirect (eg underemployment) costs as well as intangible impacts through social stigmatization.¹⁰ In China, ASM represented most of the direct costs,¹¹ while, in Ethiopia, increased costs were related to increased numbers of ASM with catastrophic economic consequences for one-third of persons with epilepsy (PWE).¹²

Combining ASM introduces challenges such as an increased risk of adverse drug reactions, especially with first-generation medications.¹³ Treatment failure can occur from incorrect diagnosis (not epilepsy¹⁴); inadequate dosing, suboptimal drug choices, and nonadherence related to tolerability or cost, especially among children and the elderly. Substitution is more likely if the new ASM is enzyme-inducing, or when using high number polypharmacy, while add-on strategies are more likely if the new ASM is a GABA agonist or previously treated with several ASM.¹⁵ These complexities prompt the need for strategic polypharmacy.

Strategic Combinations

For focal epilepsy, combinations with different mechanisms of action such as valproate (VPA) with lamotrigine (LTG), levetiracetam (LEV) with topiramate (TPM), and carbamazepine (CBZ) with clobazam (CLB) are particularly efficacious. National and regional guidelines are needed to standardize safe and effective ASM combinations.

Increasing ASM Range

ASM costs are disproportionately borne by patients in poorer countries (Table 1). Affordable, first-line ASMs should be prioritized based on seizure types and patient needs. Introducing newer ASMs, including Cenobamate, may potentially lessen polypharmacy and defer capital-intensive scarce surgical treatments.¹⁶

Table 1.

Affordability Comparisons for a Basic ASM (VPA) (Several Current Online Sources).

Country	Valproic Acid (Annual Cost, USD)	Per Capita GDP (USD)	Valproic Acid Cost as % of Per Capita GDP
United States (USA)	$540	$70,000	0.77%
Brazil	$300	$9000	3.33%
South Africa	$200	$6000	3.33%
Nigeria	$150	$2200	6.82%
Kenya	$80	$1700	4.71%
India	$50	$2200	2.27%
Thailand	$200	$6000	3.33%
Bangladesh	$30	$2000	1.50%
Indonesia	$100	$4500	2.22%
China	$400	$12,000	3.33%

Cost Management and Expanding Access

Treating epilepsy is cheaper than leaving it untreated¹⁷ and sourcing high-quality generics can be a critical component. National strategies must consider volume-based discounts, long-term contracts, price-locking, group purchasing, direct shipping, and careful inventory management. If possible, white labeling reduces marketing costs.

Comorbidity-Associated Polypharmacy

Comorbidities, particularly cardiovascular disease or mental health issues require a carefully balanced approach¹⁸ including thoughtful medication selection to avoid exacerbating epilepsy symptoms. Examples of such selections would be the use of nonenzyme-inducing, weight loss, or weight-neutral second-generation ASMs, rather than first-generation agents, in case of obesity. Additionally, medications for comorbidities may compromise ASM efficacy. Yet relatively inexpensive ASMs such as LTG, CBZ, and VPA may have therapeutically beneficial mental health benefits. Therefore, a thorough assessment of all comorbidities may minimize side effects and maximize benefits.

Education and Best Practices

Training healthcare professionals in rational polypharmacy is critical. Educating patients and addressing cultural beliefs can enhance adherence and reduce stigma. While consideration for polypharmacy should warrant early specialist referral for potential DRE, generalists should be educated on rational basic polypharmacy, considering local availabilities.¹⁹ Additionally, community health workers or mobile clinics can enhance follow-up care in remote areas.

Strategic polypharmacy plays a key role in worsening resource constraints. Despite this, high-number polypharmacy is difficult because of cost, side effects, and adherence, and all jurisdictions should periodically reevaluate their ASM formularies.

Future Directions

Newer ASM polypharmacy may offer the potential for seizure freedom or a meaningful reduction in seizures, which is of particularly great significance in areas of high stigmatization and unemployment. Artificial intelligence (AI) may identify appropriate ASMs within a cost-effective strategy and help overburdened physicians make quicker, better treatment decisions if integrated into EHRs or on mobile devices. The use of mobile health apps for medication reminders and seizure tracking can ensure compliance. Implementation of telemedicine for expert consultations in areas with limited access to specialists can bridge issues of access to care.²⁰ Local studies are necessary to evaluate the long-term outcomes of polypharmacy in diverse LMIC settings. Finally, the focus must be on holistically improving quality of life rather than just seizure control.

Effective Implementation of Dietary Therapies in Low-Middle-Income Countries

The ketogenic diet (KD), a nonpharmacologic treatment indicated in DRE, reduces seizures by over 50% in one-third of children who try it.²¹ In a survey conducted by the ILAE in August 2024, physicians in 78 countries reported providing ketogenic therapy as a treatment for their patients with epilepsy (“International Ketogenic Diet Centers”).²² However, only 26% of the LMIC were reported in this list (Figure 1). Despite the growing number of countries adopting this treatment over the past decade, large gaps in access to ketogenic therapy persist throughout the world. Guidelines for optimal management of children receiving KD include extensive laboratory monitoring and nutritional supplementation²³; however, medical providers in resource-limited communities do not have access to these resources, creating potential barriers to dietary therapy. Additional barriers include a lack of provider training. However, if patients have access to higher-fat foods, it is possible to overcome all other barriers.

Figure 1.

Low-middle-income countries reporting epilepsy surgery, presence of ketogenic diet (KD) centers,both epilepsy surgery and KD centers,and those that report neither epilepsy surgery nor KD centers. List of low-income and low-middle-income countries sourced from world bank (49), list of countries offering epilepsy surgery obtained from publication by Watila et al (29), and list of countries with KD centers from International League Against Epilepsy International Ketogenic Diet Centers List(22).

To make dietary therapy more obtainable in resource-limited communities, an ILAE task force compiled minimal requirements that should be available at a ketogenic therapy center.²⁴ The guidelines allow a medical provider familiar with epilepsy and metabolic conditions to identify and refer patients, start, stop therapy, and wean ASMs. A trained medical provider can manage the modified Atkins diet (MAD) and low glycemic index treatment (LGIT) without the need for a dietitian, but a trained dietitian is still mandatory for a classic ketogenic diet or a medium-chain triglyceride diet.

Initial evaluation should include weight and height measurements, diet history, and baseline laboratory studies. In areas with limited monitoring or access to emergent medical care, it is important that high-risk patients such as infants and those with comorbidities must be transitioned to a ketogenic therapy in a hospital setting so that they can be closely monitored for side effects.²⁴ With reliable communication and good patient education, diet initiation can be completed in the outpatient setting, particularly for patients treated with MAD or LGIT. In either an inpatient or outpatient setting, initiation can be more gradual to allow for monitoring of untoward effects when laboratory studies are more limited. Local nutritionists can collaborate with a specialist ketogenic dietitian to identify accessible and affordable foods and integrate cultural aspects of dietary staples while planning the meals. For families unable to afford or use digital scales, standardized tools like tablespoons and cups can be used to design recipes, replacing weight-based measurements.^25,26

Follow-up monitoring is recommended every 3-6 months but more frequently in infants or medically complex patients.²⁴ While in-person appointments are preferred, telehealth, phone, or written communication can work well if the patients or their caregivers can provide accurate weight and height measurements. Supplementation with multivitamins and calcium is recommended, as are routine laboratory studies. Management of side effects typically involves managing constipation, electrolyte loss, or acidosis. Baking soda is an affordable treatment for acidosis and provides additional sodium, which is often needed in the diet. Due to the diet's diuretic effect, it is essential to ensure that patients are meeting or exceeding daily fluid requirements. Adequate fluid intake also helps reduce the risk of side effects of constipation, acidosis, and renal stones.

Future Directions

While minimal guidelines have been created for ketogenic diet centers in LMIC²⁴ they continue to be unobtainable for many communities. Studies have shown that variations of ketogenic therapy have comparable efficacy to a classic ketogenic diet,²⁷ have less risk for side effects, require less medical monitoring, and can be done without a dietitian. Continued efforts should be made to explore safely minimizing laboratory studies focusing on implementing variations of a classic ketogenic diet to minimize risks.

Epilepsy Surgery Evaluations on a Budget

The success of epilepsy surgery is dictated by accurate localization of the epileptogenic zone and aberrant networks, and their demarcation from functional cortical areas. This can be achieved with a thorough presurgical evaluation.²⁸ Depending on the complexity of the anatomo-electro-clinical hypothesis, the investigative strategies to select ideal candidates for epilepsy surgery may vary from basic (MRI, VEEG, and neuropsychological assessment) to more advanced and expensive noninvasive and invasive investigations (such as PET, SPECT, MSI, ESI, and stereo-EEG).²⁸

Although greater than three-fourths of PWE reside in LMIC,^1,4 only 12% of these countries conduct epilepsy surgery²⁹ (Figure 1). Large patient numbers, difficulty in identifying them, limited facilities and expertise to investigate and select surgical candidates, and affordability pose serious challenges in the management of DRE in LMIC.³ For example, India with over 10 million PWE has 2000 neurologists (1 neurologist for 5000 PWE).^3,30 While two-thirds of PWE live in rural areas, nearly all the neurologists practice close to cities. Hence, the majority of PWE is managed by primary and secondary care physicians with little experience in identifying patients with DRE and in referring them to comprehensive epilepsy centers where they can undergo presurgical evaluation^3,30 A recent survey on the prevalence of epilepsy monitoring units (EMU) in India identified 52 EMUs (1 EMU per 25 million people), which is equivalent to 3 EMUs and 15 EMUs to the entire populations of UK and USA, respectively.³¹ When compared to EMUs in governmental sectors, the EMUs in nongovernmental (corporate) sectors had a 10-fold shorter waiting period for long-term VEM but were 5-fold more expensive and, hence, were beyond the affordability of the majority.³¹

The epilepsy surgery outcomes in patients from LMIC generally do not differ from those of high-income countries.^32,33 Moreover, the cost of presurgical evaluation and surgery in LMIC is only a fraction of the cost incurred in high-income countries. In India, the average cost for patients selected by noninvasive basic presurgical evaluation and subjected to standard anterior temporal lobectomy is US$ 1500, while the cost increases 5-fold in those selected after invasive EEG evaluation.³⁴ Without insurance, the patient and the family typically bear the cost of presurgical evaluation and surgery. Additionally, because of the adverse effects and stigma associated with ASM therapy, females in particular, of marriageable and childbearing age, aspire not only to be seizure-free but also ASM-free after surgery, which is difficult to guarantee preoperatively. For these reasons, epilepsy surgery centers in LMIC should adopt a stepwise approach by focusing on good-outcome patients who can be selected by cost-effective noninvasive presurgical evaluation and refer patients who require complex expensive evaluations to advanced centers. In India with the present rate of nearly 1000 epilepsy surgery per year, only 2 per 1000 (0.2%) eligible patients undergo epilepsy surgery.³⁴ To close this enormous surgical treatment gap, attempts are being made to educate physicians in identifying patients with DRE, developing more epilepsy surgery centers across the country, guiding the selection of ideal surgical candidates by cost-effective presurgical evaluations, and evolving national epilepsy surgery programs.³⁰

Future Directions

The use of AI to automate personnel-intensive processes such as EEG analysis or imaging review may make presurgical evaluations more affordable and accessible in LMIC.³⁵ Simultaneously, machine learning models that analyze and consolidate clinical, genetic, and imaging data are improving in their prediction accuracy and could be used to prioritize patients who are likely to have greater chances of a successful surgical outcome.³⁶

Treating Emergencies in Epilepsy in Resource-Constrained Environments

Status epilepticus (SE) is the most common emergency in epilepsy, with an accepted operational definition of either an unremitting generalized convulsive seizure lasting longer than 5 min or multiple bilateral convulsive seizures without an interictal return to the baseline level of consciousness within 5 min.^37,38 The reported annual incidence of status epilepticus ranges from 1.3 to 74 cases per 100,000 population however, epidemiological studies calculate this using a duration of 30 min^39–41 underestimating the true burden. SE occurs more commonly in the setting of DRE. As seizure duration is considered the most important modifiable outcome predictor, there is a need for rapid evaluation and intervention to avoid cardiovascular morbidity and refractory status.⁴²

The treatment of status epilepticus in resource-constrained areas has been described as inadequate in various studies and the lack of quantification of this treatment gap compounds the problem.⁴³ Various factors contribute to poor outcomes and inadequate treatment of SE in low resource areas, including inadequate prehospital care, lack of advanced diagnostic and treatment facilities, significant delay in patients’ presentation at the hospital, delays in transfer to better-equipped facilities capable of providing critical care support, shortage of essential antiseizure medications (ASMs), poor levels of knowledge regarding SE among healthcare workers and lack of local guidelines for the management of SE.^44–46

Poor outcomes for patients presenting with SE in LMIC have been widely reported. It is estimated that people with epilepsy have a 2.6-fold higher (range 1.3-7.2) mortality risk compared to the general populations of LMIC, with the main causes of death being complications of SE, SUDEP, and injuries.⁴⁷

Going forward, policymakers and advocates in low-resource regions need to invest in the education of healthcare workers, patients, and the public regarding epilepsy and the impact of SE in particular.^44–46 The provision of essential medications such as benzodiazepines which, when given at the earliest opportunity, hold the potential to terminate SE, should be made a priority. Indeed, the availability of cheap, safe, and effective ASMs such as phenobarbitone could reduce the time to termination of SE in both children and adults.⁴⁸

Time is of the essence in the management of SE. A recent systematic review identified the lack of protocols that are adapted to local contexts to guide effective and timely interventions for SE as a major contributor to poor outcomes.⁴⁴ Operationalization of prehospital emergency services remains a significant challenge in many low resource areas.⁴⁶ Investments into effective emergency-response systems and standardized protocols would go a long way in providing life-saving prehospital care for patients with SE and facilitate transfer to centers that are well staffed and equipped to handle these cases.⁴⁶ Finally, prolonged nonepileptic seizures may mimic SE and an accurate diagnosis requires educating healthcare personnel and easy access to appropriate diagnostic tools to identify and save such individuals from inappropriate, invasive treatments.

Future Directions

To further improve care, we need to expand access to basic diagnostic tools like EEG and imaging at district-level hospitals and utilize telemedicine for remote consultation and guidance from specialists. Mobile apps for seizure tracking, medication reminders, and management protocols can prove beneficial in preventing status epilepticus. Finally, a structured referral system for timely escalation of care in refractory cases is critical.

Conclusion

Affordable management of DRE in LMIC requires a multifaceted approach encompassing protocol-driven strategic polypharmacy, optimized use of nonpharmacologic therapies, prioritization of well-localized surgical cases, and development of prehospital emergency service lines with clear algorithms. The evolving technological landscape, particularly AI-driven healthcare solutions, holds promise for mitigating the shortage of expert personnel and addressing the epilepsy-care gap in these resource-constrained settings.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Ruta Yardi

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Managing Refractory Epilepsy in a Resource-Limited Setting—Doing More With Less

Abstract

Keywords

Introduction

Strategic Polypharmacy in Refractory Epilepsy

Strategic Combinations

Increasing ASM Range

Cost Management and Expanding Access

Comorbidity-Associated Polypharmacy

Education and Best Practices

Future Directions

Effective Implementation of Dietary Therapies in Low-Middle-Income Countries

Future Directions

Epilepsy Surgery Evaluations on a Budget

Future Directions

Treating Emergencies in Epilepsy in Resource-Constrained Environments

Future Directions

Conclusion

Footnotes

Declaration of Conflicting Interests

Funding

ORCID iD

References