INTRODUCTION

Drug-resistant epilepsy (DRE) represents one of the most severe and challenging forms of epilepsy, defined as the failure to achieve sustained seizure freedom despite treatment with at least two appropriate antiseizure medication (ASM) regimens, as recommended by the International League Against Epilepsy (ILAE) guidelines.[1] Pediatric DRE is particularly concerning, especially in children under 5 years of age, due to its profound implications for neurodevelopment, growth, and overall quality of life.[2] In this vulnerable population, seizures not only contribute to immediate health risks but also disrupt critical developmental milestones, compounding the burden of the disease. Understanding the clinical, demographic, and nutritional factors associated with pediatric DRE is crucial for improving early diagnosis, tailoring treatment strategies, and optimizing long-term outcomes. Key factors such as age at onset, gender, seizure type, and nutritional status have been hypothesized to influence disease progression and response to therapy.[3] This study aims to retrospectively analyze these variables in a cohort of pediatric patients diagnosed with DRE over a 5-year period. By identifying significant correlations between these factors and disease outcomes, the study seeks to provide actionable insights for clinicians managing pediatric epilepsy.

MATERIAL AND METHODS Study design and population

A retrospective study was conducted at the Department of Neurology, Sri Ramachandra Hospital, Chennai, Tamil Nadu, India. Medical records of fifty children aged 0–5 years diagnosed with DRE between January 2020, and December 2024 were reviewed.

Type of sampling and reasons for selection

Purposive sampling was used to specifically select pediatric patients aged 0–5 years diagnosed with DRE from medical records between January 2020 and December 2024. This method was chosen to ensure the inclusion of a targeted population meeting predefined clinical criteria, facilitating the study of factors influencing DRE progression and outcomes in this high-risk group.

Patient consent statement

Written informed consent was obtained from the parents or legal guardians of all pediatric patients included in this study. The consent process ensured that participants’ confidentiality and privacy were maintained in accordance with ethical guidelines.

Inclusion criteria

Children aged 0–5 years with a confirmed diagnosis of DRE were included in the study. Eligibility was determined based on the failure to achieve seizure control despite adequate trials of at least two appropriately chosen and tolerated ASMs. In addition, participants were required to have complete medical and nutritional records to ensure comprehensive data analysis.

Exclusion criteria

Children were excluded if they were above 5 years of age or if they had incomplete medical or nutritional records, which could compromise data reliability. Those diagnosed with secondary epilepsy due to progressive metabolic or structural brain disorders were also excluded to maintain a homogenous study population and minimize confounding variables affecting seizure outcomes.

Data collection method

Data extraction was conducted through a systematic review of medical records, capturing demographic details (age and gender), clinical diagnosis, seizure classification, ASMs used, and nutritional status assessments. Nutritional status was assessed using weight-for-age z-scores categorized per the World Health Organization standards into normal, moderate malnutrition, or severe malnutrition. Data accuracy was ensured through cross-verification with hospital records and consultation with treating neurologists and dietitians.

Statistical analysis

Statistical analyses were performed using the Statistical Package for the Social Sciences software (version 24). Descriptive statistics, including mean and standard deviation, were used to summarize continuous variables, while categorical variables were presented as frequencies and percentages. The Chi-square test was applied to assess associations between categorical variables. Paired t-tests were conducted to compare the data. A P < 0.05 was considered statistically significant, indicating meaningful differences in the analyzed parameters.

RESULTS

This retrospective study included fifty pediatric patients with DRE, all under the age of five. The mean age at diagnosis was 3.1 ± 1.2 years, with 32 (64%) patients representing the majority diagnosed between 2 and 4 years of age. Males constituted 29 (57%) patients of the cohort, while females accounted for 21 (43%) patients, resulting in a male-to-female ratio of 1.3:1.

Seizure frequency varied widely, with a median monthly frequency of 12 seizures (range: 4–40). Patients with higher seizure frequencies (≥20/month) were predominantly younger and demonstrated a significant correlation with severe malnutrition (P < 0.01). Focal seizures were the most common type with 27 (54%) cases, followed by generalized seizures with 15 (30%) cases and mixed seizure types with 8 (16%) cases [Table 1].

Table 1: Demographic and clinical characteristics of study cohort.

Variable Number of patients (n) Percentage Age distribution   0–2 years 10 20   2–4 years 32 64   4–5 years 8 16 Sex distribution   Male 29 57   Female 21 43 Seizure type   Focal seizures 27 54   Generalized seizures 15 30   Mixed seizure types 8 16 Anti-seizure medications used   Levetiracetam 40 80   Valproate 38 76   Carbamazepine 21 42 Nutritional status   Normal 18 36   Moderate malnutrition 13 26   Severe malnutrition 19 38 Etiology   Genetic (whole exome sequencing) 14 28   non-genetic 36 72 Biochemical abnormalities   Hypocalcemia 6 12   Hypoglycemia 4 8   Elevated lactate levels 11 22 EEG findings   Generalized slowing 25 50   Multifocal spikes 15 30   Hypsarrhythmia 4 8

Patients had been treated with an average of 3.8 ± 0.9 ASMs, with levetiracetam 40 (80%), valproate 38 (76%), and carbamazepine 21 (42%) being the most frequently used. Despite polytherapy, none achieved sustained seizure freedom [Figure 1]. Nutritional assessment revealed that 19 (38%) patients were severely malnourished, 13 (26%) had moderate malnutrition, and 18 (36%) had normal nutritional status. Severe malnutrition was significantly associated with increased seizure frequency and developmental delays [Table 2].

Figure 1: Potential mechanisms of drug resistance in epilepsy.

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Table 2: Comparison analysis of seizure severity, developmental delay, and severe malnutrition status.

Comparison Chi-square value Degrees of freedom P-value Significance Seizure severity versus developmental delay 10.24 1 <0.01 Significant Seizure severity versus severe malnutrition 12.36 1 <0.01 Significant Severe malnutrition versus developmental delay 14.58 1 <0.01 Significant

Etiology was categorized as genetic in 14 (28%) of the cases, based on whole exome sequencing, and non-genetic in 36 (72%) cases, attributed to perinatal insults in 20 (40%) of the cases, structural anomalies in 10 (20%) cases, or unknown causes in 6 (12%) cases. Genetic etiologies were more common in children with generalized seizure types.

Biochemical parameters revealed abnormalities in 21 (42%) of patients, including hypocalcemia in 6 (12%), hypoglycemia in 4 (8%), and elevated lactate levels in 11 (22%), often associated with metabolic or mitochondrial disorders. These findings were more prevalent in the malnourished subgroup.

Developmental milestones, as assessed by a pediatric epileptologist, were delayed in 32 (64%) patients of the cohort, with severe delays in 20 (40%). Developmental delays were significantly associated with younger age at onset, higher seizure frequency, and malnutrition (P < 0.01). EEG findings were abnormal in 44 (88%) of the patients, predominantly showing generalized slowing 25 (50%), multifocal spikes 15 (30%), and hypsarrhythmia in 4 (8%) of the patients, indicative of underlying epileptic encephalopathies.

DISCUSSION

This study highlights the multifaceted challenges associated with managing DRE in children under 5 years of age, emphasizing the interplay between demographic, clinical, and nutritional factors. The predominance of focal seizures and the high male-to-female ratio observed align with existing literature on pediatric epilepsy patterns. In addition, the correlation between younger age at diagnosis, increased seizure frequency, and severe malnutrition underscores the need for early nutritional and medical interventions.

The high prevalence of severe and moderate malnutrition, 19 (38%) and 13 (26%) of the patients, respectively, in this cohort is particularly concerning, given its significant association with increased seizure frequency and developmental delays. Furthermore, the association between developmental delays and higher seizure frequencies, particularly in younger children, highlights the compounding effects of early-onset epilepsy on neurodevelopment. The study also underscores the limitations of current pharmacological approaches in this population, with patients failing to achieve sustained seizure freedom despite polytherapy. The frequent use of levetiracetam, valproate, and carbamazepine reflects standard practice but highlights the urgent need for alternative treatment strategies, such as dietary therapies, surgical interventions, or novel ASMs.

Biochemical abnormalities, including hypocalcemia, hypoglycemia, and elevated lactate levels, were notably more prevalent in malnourished children, suggesting potential underlying metabolic or mitochondrial dysfunctions that warrant further investigation. These findings support the role of comprehensive metabolic assessments in the diagnostic workup of pediatric DRE.[4]

The high prevalence of abnormal EEG findings, particularly generalized slowing and multifocal spikes, provides valuable insights into the underlying epileptic encephalopathies driving DRE in this cohort. The presence of hypsarrhythmia in a subset of patients aligns with the diagnosis of epileptic syndromes such as infantile spasms, further emphasizing the heterogeneity of DRE.[5]

Moreover, these findings highlight the pressing need for a multidisciplinary approach to the management of pediatric DRE, integrating neurology, nutrition, and metabolic medicine. Given the strong association between malnutrition and increased seizure burden, targeted nutritional interventions, including ketogenic and modified Atkins diets, should be explored as adjunctive therapies. Studies have demonstrated the efficacy of ketogenic dietary therapies in reducing seizure frequency and improving overall neurological outcomes, particularly in drug-resistant cases.[6] Early screening for malnutrition and metabolic derangements, followed by individualized dietary support, may significantly enhance treatment responses and quality of life for affected children.[7]

According to the definition provided by the ILAE, a diagnosis of DRE is made when there is a failure of adequate trials of two or more appropriately chosen and tolerated ASMs, administered at the maximally tolerated doses, to achieve sustained seizure freedom. In line with this definition, all participants in our study had undergone trials with at least two different ASMs at their upper tolerable doses, yet seizures could not be adequately controlled. Therefore, these patients were diagnosed as having DRE.[1] Furthermore, the diagnosis of DRE serves as an indication to initiate dietary therapy, such as the ketogenic diet. According to established guidelines, dietary therapy should only be considered once there has been documented failure of appropriately selected and tolerated ASMs. In the present study, the participants had not received any form of dietary therapy; they were managed solely with standard pharmacological treatment. Upon analysis, they fulfilled the criteria for DRE, and therefore, dietary therapy should be recommended as the next line of management.

In addition, the role of emerging therapeutic strategies, such as gene therapy, neuromodulation, and precision medicine, warrants further exploration. Advances in genetic testing have revealed monogenic epilepsy syndromes that may respond to specific treatments, underscoring the importance of genetic screening in refractory epilepsy cases.[8] Moreover, modalities such as vagus nerve stimulation and responsive neurostimulation have shown promise in reducing seizure burden in selected patients, offering potential alternatives when pharmacological treatments fail.

Another critical aspect is caregiver burden and psychosocial implications. Families of children with DRE often face significant emotional, financial, and logistical challenges, which can impact adherence to treatment regimens and overall patient care. Strengthening family support systems, providing mental health resources, and ensuring access to affordable treatment options are essential components of a comprehensive epilepsy care model.

Future research should focus on longitudinal studies assessing the long-term impact of malnutrition on epilepsy progression, as well as interventional trials evaluating the efficacy of dietary and metabolic therapies in this population.[9] In addition, expanding access to epilepsy care in resource-limited settings remains a priority, as delayed diagnosis and inadequate treatment options disproportionately affect children in low-income communities.[10] By addressing these multifactorial challenges, a more holistic and effective approach to managing pediatric DRE can be achieved.

CONCLUSION

This study underscores the complexity of managing DRE in pediatric patients under 5 years of age, highlighting significant associations between clinical, demographic, and nutritional factors. Severe malnutrition was found to correlate with increased seizure frequency and developmental delays, emphasizing the need for comprehensive nutritional support in the management of pediatric DRE. The failure to achieve sustained seizure freedom despite polytherapy underscores the necessity for alternative therapeutic strategies, including dietary interventions, surgical options, and novel ASMs. Furthermore, the high prevalence of biochemical abnormalities and abnormal EEG findings, particularly in patients with genetic and metabolic etiologies, points to the importance of a thorough diagnostic workup to identify underlying metabolic or mitochondrial disorders. The findings of this study suggest that a multidisciplinary approach, integrating nutritional, metabolic, and pharmacological interventions, is essential for optimizing outcomes in pediatric DRE. This work also aligns with the United Nations Sustainable Development Goal 3, which emphasizes ensuring healthy lives and promoting well-being for all regardless of age. Future research should aim to further investigate the long-term effects of malnutrition on seizure control and neurodevelopment and explore novel treatment options tailored to the unique needs of this vulnerable population.