Drugs, Diets, and DEEs: A Comparative Review of Medical and Dietary Treatments in Developmental and Epileptic Encephalopathies

Abstract

Add-on Ketogenic Diet Versus Antiseizure Medications Alone in Children with Developmental and Epileptic Encephalopathies: A Prospective Comparative Cohort Study

Hu W, Li L, Zhao F, Su S, Zhang H, Li X. Front Neurol. 2025;16:1677046. doi: 10.3389/fneur.2025.1677046

Objective: To compare the effectiveness and safety of ketogenic diet (KD) versus antiseizure medications (ASMs) adjustment in developmental and epileptic encephalopathy (DEE). Methods: In this prospective, single-center cohort study, 268 participants were allocated to either the KD group (n = 128) or the control group (n = 140; ASMs adjustment alone). Outcomes were assessed at 3 and 6 months. The primary outcome was the ≥50% seizure response rate at 6 months. Secondary outcomes included seizure-free rates, electroencephalography (EEG) improvements, and developmental progress. Other outcomes included adverse events, retention rate, and predictors of KD response. Results: At 6-month evaluation, KD group demonstrated significantly better seizure response than in controls (50.78% vs 29.29% RR = 1.73, 95% CI 1.27-2.36, P < .001). The KD group superior in secondary outcomes, including higher seizure-free rates, greater EEG improvement, and better developmental progress. The adverse actions were slight and acceptable. Survival analysis revealed a higher retention rate in KD group than that in control group at any point (HR = 0.68, 95%CI 0.50-0.92, P < .05). No significant predictor of KD effectiveness could be found. Interpretation: The KD demonstrated superior effectiveness and safety over ASMs adjustments in children with DEE, achieving not only reduced seizure frequency and EEG abnormalities but also improved developmental outcome. These findings supported early consideration of KD in DEE management.

Commentary

Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies characterized by seizures, frequent epileptiform discharges on electroencephalogram (EEG), and developmental slowing or regression. Developmental and epileptic encephalopathies can occur at any age but most commonly have an onset in infancy or childhood which is a critical period of the brain development. In DEEs, both the underlying aetiology and the frequent seizures/abnormal EEG patterns are postulated to contribute to developmental plateau or regression. ¹ The aetiologies of DEEs are vast with a genetic aetiology being the most attributed cause, and, to date, more than 900 genes have been associated with DEEs. In the clinical practice, DEEs pose significant treatment challenges due to a high seizure burden, high prevalence of drug-resistant epilepsy, and developmental and cognitive stagnation or regression that may worsen over time.

Developmental and epileptic encephalopathies are not a monolith. They encompass many epilepsy syndromes with a variety of aetiologies and developmental comorbidities. In the recent years, the therapeutic approach to DEEs has been targeting mechanistically/genetically specific therapy, for example, mechanistic target of rapamycin inhibitors in DEE associated with tuberous sclerosis complex, sodium channel blocking agents in gain-of-function SCN2A and SCN8A-DEEs, or antisense oligonucleotides and gene editing therapy in loss-of-function SCN1A Dravet syndrome, which are currently only available through a clinical trial. The pathophysiology of epilepsy and developmental encephalopathy in DEEs is complex and involves a multitude of pathways which are highly heterogenous, depending on the aetiology and often, the genetic underpinning. These may likely contribute to the struggle in finding a targeted treatment or “precision” therapy for all the DEEs resulting in a large majority of DEEs still remain without any targeted or disease-modifying therapies. The treatment of seizures and epilepsy in this group is similar to standard epileptic treatment regimens with selecting antiseizure medications (ASMs) based on the patients’ seizure types, epilepsy syndromes, and potential adverse effects. However, due to a high incidence of drug-resistant epilepsy in these patients, non-pharmacological therapies, such as an epilepsy surgery, dietary therapy, or neurostimulation devices have often been utilized albeit generally after several failed medications.

Ketogenic diet therapy (KDT) is a dietary therapy that has been most extensively used and studied as a treatment of epilepsy associated with DEEs, especially in those who are not candidates for surgery. The ketogenic diet, a metabolism-based therapy, exerts antiseizure and antiepileptogenic properties through multifaceted pathways, including affecting the ion channels, alteration of neurotransmitters, promoting mitochondrial function and biogenesis, which leads to potential long-term neuroprotection, decreasing the inflammasome, altering the gut microbiome, and inducing the epigenetic changes. Thus, KDT may be an attractive treatment option for DEEs that do not yet have a targeted treatment. Multiple studies have shown favourable efficacy of the KDT for seizure control with relatively low and manageable adverse effects. ²

In this study, Hu et al prospectively looked at seizure and developmental outcomes of add-on KDT compared to adjustment or titration of ASMs alone in 268 children with drug-resistant DEEs. The authors found a significantly greater seizure response and seizure-free rates in the add-on KDT group compared to the continued/adjusting ASM group with the seizure response rate of 50.8% versus 29.3% (RR 1.73, P < .001) and seizure-free rate of 20.3% versus 10.7% (RR 1.9, P < .05), respectively. ³ These findings are aligned with several prior studies which demonstrated the efficacy of the KDT in controlling seizures in DEEs with seizure response rates of 49% to 64% at 6 months of treatment.^4-6 Interestingly, DEEs with a genetic aetiology demonstrated remarkable responsiveness to the KDT.^4,5 Moreover, when the authors looked at the response in syndrome-specific DEEs, the KDT showed superior effectiveness in drug-resistant Infantile Epileptic Spasms Syndrome and epilepsy with myoclonic-atonic seizures (EMAtS) when compared to medication treatment alone (48.4% vs 30.3% and 60% vs 22.2%, respectively). These findings are similar to the prior multicenter retrospective study by Nickels et al, which revealed a response rate of 79% with the KDT compared to 26% with ASMs alone in children with EMAtS. ⁷ However, for other syndrome specific DEEs, this study by Hu et al was underpowered preventing a clear conclusion for overall syndrome-specific DEEs.

Another important aspect of the treatment of DEEs is to improve the cognitive and developmental outcomes as developmental stagnation and regression is common in this population and is partially due to the frequent seizures and abnormal EEG patterns. Although ASMs can effectively control seizures in patients with epilepsy, they can sometimes negatively impact the development, cognitive functions, and alertness in patients with epilepsy, especially with polypharmacy. On the other hand, KDT, has shown to improve cognitive and developmental outcomes in both children and adults with epilepsy independent of seizure control or reduction of ASMs, as elucidated by the systematic review by van Berkel et al. ⁸ Similarly, in this study by Hu et al, children with drug-resistant DEEs who were treated with KDT showed a higher developmental improvement than the medication-alone group (36.7% vs 5.7%, P < .001) when evaluated with a formal assessment tool. This could be in part explained by the mechanisms of the KDT which metabolically and efficiently increases a brain energy reserve and promote potential long-term neuroprotection.^9,10

The KDT is versatile with different diet options available to modify based on different patient populations. It is also not a permanent treatment, nor does it require a surgery. The KDT has relatively low and manageable adverse effects and few interactions with other treatment modalities. Most importantly, KDT has shown a greater efficacy in seizure control and promoting cognitive and developmental outcomes in children with DEEs than ASMs alone. Given the favourable benefits, as mentioned above, it may be reasonable to consider the KDT as an early treatment option for patients with DEEs, especially those without a specific or targeted therapy, and not wait until the epilepsy becomes drug-resistant and the developmental decline inevitable.

Future investigators may want to study and look for a biomarker to determine the response to the KDT or certain ASMs in patients with different syndrome or genetic specific DEEs which may help with the selection of the initial therapy. Lastly, a combination of treatment modalities, for example, surgery and diet or diet and different devices in patients with DEEs may also be worth exploring in a large-scale study.