Ketogenic Diet in Pediatric N-Methyl-D-Aspartate Receptor Encephalitis Presenting with Refractory Epilepsy: A Novel Case Report

INTRODUCTION

N-methyl-D-aspartate receptor (NMDAR) encephalitis is a rare but increasingly recognized form of autoimmune encephalopathy, characterized by the production of autoantibodies targeting the NR1 subunit of the NMDAR, a glutamate receptor and ion channel expressed abundantly in the central nervous system. This antibody-mediated neuroinflammatory disorder predominantly affects children and young adults and presents with a constellation of symptoms including acute-onset behavioral and psychiatric disturbances, cognitive impairment, central hypoventilation, seizures, movement abnormalities (such as orofacial dyskinesias and choreoathetosis), and dysautonomia.^[1] In pediatric populations, seizures are a prominent feature and are frequently refractory to conventional anti-seizure medications (ASMs), highlighting the urgent need for alternative therapeutic strategies.^[2] The ketogenic diet (KD), a high-fat, adequate-protein, low-carbohydrate nutritional therapy initially introduced in the 1920s as a treatment for intractable epilepsy, has garnered renewed clinical interest for its efficacy in pharmacoresistant epilepsies.

KD induces a metabolic shift from glucose to ketone bodies (β-hydroxybutyrate and acetoacetate) as the primary cerebral energy substrate, thereby modulating neuronal excitability and seizure threshold.^[3] Emerging evidence further supports its immunomodulatory, antioxidant, and neuroprotective properties, which may be beneficial in autoimmune-mediated neurological disorders such as NMDAR encephalitis.^[4,5] Proposed mechanisms include the inhibition of pro-inflammatory cytokine production, modulation of the mammalian target of rapamycin pathway, and attenuation of glutamate excitotoxicity. While traditional KD initiation protocols involve hospitalization and fasting to induce ketosis rapidly, non-fasting, outpatient-initiated protocols are now increasingly preferred, especially in pediatric populations, due to enhanced tolerability, reduced risk of hypoglycemia, and improved feasibility in resource-limited settings.^[6] Furthermore, customizing the diet to align with regional and cultural dietary practices has been shown to improve caregiver compliance and long-term adherence, particularly in low- and middle-income countries.^[7] In this context, we report the first documented case from India of a non-fasting, home-initiated, culturally adapted KD implemented in a young child diagnosed with NMDAR encephalitis and drug-resistant seizures. The intervention resulted in significant clinical improvement, including sustained seizure freedom and favorable nutritional outcomes, underscoring the potential role of KD as a safe and effective adjunctive therapy in autoimmune epileptic encephalopathies.

CASE REPORT

A toddler aged 2 years with a prior diagnosis of NMDAR receptor autoimmune encephalitis presented with persistent epileptic spasms characterized by head drop seizures. These episodes lasted 4–5 s and occurred 2–3 times weekly despite being on multiple ASMs, including sodium valproate (20 mg/kg/day), brivaracetam (2.5 mg/kg/day), and zonisamide (5 mg/kg/day). Birth history revealed late preterm delivery through lower segment cesarean section in view of maternal pregnancy-induced hypertension and gestational diabetes mellitus, with a neonatal intensive care unit (ICU) stay postpartum due to maternal ICU admission. Developmentally, the child exhibited mild global delays: Running was achieved, but fine motor grasp remained immature; language skills were limited to babbling, and social responsiveness was delayed.

On examination, anthropometry showed a weight of 12.5 kg and height of 81 cm, corresponding to World Health Organization Z-scores of −2 and below −3, respectively. Neurological examination indicated generalized hypotonia (tone 4/5 in all limbs). Electroencephalogram revealed bilateral fronto-centro-parietal interictal epileptiform discharges, more prominent on the left side, with no electrographic seizures recorded.

Positron emission tomography and computed tomography brain scan revealed a large confluent area of significant hypometabolism in the posterior aspect of the left occipital lobe, accompanied by a few small patchy regions of hypometabolism in its medial aspect. In addition, mild diffuse relative hypometabolism was noted throughout the remainder of the left cerebral hemisphere, with the exception of scattered regions within the left frontal lobe. Mild relative hypometabolism was also observed in the left thalamus and the left caudate nucleus, suggesting widespread, yet regionally varied, cortical and subcortical metabolic dysfunction within the left hemisphere [Figure 1].

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Figure 1:

Positron emission tomography and computed tomography brain.

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No overt signs or symptoms of nutritional deficiencies were observed during the clinical evaluation. Dietary recall and parental interview confirmed reduced food intake according to age. No food allergies or intolerances were reported. Nutritional risk was evaluated using the screening tool for risk on nutritional status and growth (STRONGkids) screening tool, classifying the patient at medium risk for malnutrition due to neurological disorder and ongoing pharmacologic therapy [Table 1].

Medical nutrition therapy was initiated using the nutrition care process model, beginning with a non-fasting ketogenic protocol customized to local dietary preferences. The initial ketogenic macronutrient distribution was 5% carbohydrate, 31% protein, and 64% fat. South Indian dietary staples such as coconut oil, ghee, paneer, and egg were used to meet fat and protein goals. On the 3^rd day, urinary ketone levels reached 4+ (80–160 mg/dL), indicating successful ketosis induction. Consequently, the plan was transitioned to a 2:1 ketogenic ratio on day 4, targeting 9% carbohydrates, 9% protein, and 82% fat. Parents received intensive counseling and hands-on training on weighing ingredients, meal preparation, and ketone monitoring. They were instructed to maintain a seizure diary and provide weekly teleconsultation updates. Adjustments to calorie and fat content were made to sustain consistent ketone levels without compromising weight or growth.

Within 1 month of diet initiation, the child exhibited a 70% reduction in seizure frequency. By the 2^nd month, seizure reduction reached 90%, and by the 4^th month, the child became seizure free. At the time of this report, the patient has completed 10 months of the 2:1 KD, remains seizure free, and continues to tolerate the diet well [Figure 2].

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Figure 2:

Percentage reduction in seizure following ketogenic diet.

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Growth parameters improved with age-appropriate gain in weight and height, and no biochemical abnormalities or signs of nutrient deficiencies were observed. Developmental gains were noted in the form of improved social interaction, play behavior, and attention span. The family reported enhanced quality of life, reduced caregiver stress, and high compliance with the dietary regimen.

DISCUSSION

Refractory epilepsy associated with autoimmune encephalitis constitutes a complex and therapeutically challenging condition, particularly in the pediatric population. Despite aggressive immunotherapy and polypharmacy with ASMs, a significant proportion of patients fail to achieve adequate seizure control, necessitating the integration of adjunctive nonpharmacological interventions. The KD, a high-fat, low-carbohydrate, normocaloric dietary therapy, has demonstrated robust efficacy in managing pharmacoresistant epilepsy across multiple childhood epileptic encephalopathies, including Lennox–Gastaut syndrome, Dravet syndrome, and glucose transporter type 1 deficiency syndrome.^[8] Although clinical data are still limited, growing evidence suggests that KD may confer therapeutic benefits in autoimmune encephalitides, including anti-NMDAR encephalitis, where immune-mediated pathophysiology plays a central role in disease progression and seizure generation.^[5,9] The mechanism of action of KD is hypothesized to extend beyond the induction of cerebral ketosis and resultant modulation of neuronal excitability. KD has been shown to exert anti-inflammatory and immunoregulatory effects, potentially through mechanisms such as alteration of gut microbiota composition, enhancement of mitochondrial bioenergetics, reduction in oxidative stress, and suppression of systemic and central nervous system pro-inflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha.^[10,11] These pleiotropic effects may be particularly relevant in autoimmune conditions characterized by cytokine dysregulation and neuroinflammation. In the present case, a non-fasting, culturally tailored KD was initiated at home using locally available, economically viable food ingredients, thereby enhancing feasibility and adherence in a resource-constrained setting. More importantly, the patient’s clinical response was both rapid and sustained, despite ongoing polytherapy with multiple ASMs. This suggests a potential synergistic effect of KD when combined with conventional pharmacologic and immunotherapeutic modalities. To address nutritional concerns, particularly in the context of prolonged illness and dietary restrictions, the STRONGkids scoring system was employed at baseline to identify malnutrition risk. This facilitated early initiation of nutritional intervention and monitoring, ensuring that dietary therapy remained both efficacious and safe.

The success of this approach is consistent with contemporary global consensus guidelines, which advocate for non-fasting initiation protocols and individualized dietary plans adapted to cultural and regional dietary patterns to optimize long-term adherence and clinical outcomes.^[6,7] Furthermore, continued longitudinal follow-up through telehealth consultations played a critical role in reinforcing dietary compliance, troubleshooting challenges, and sustaining therapeutic momentum, especially in geographically underserved regions.

CONCLUSION

This case exemplifies the feasibility, safety, and therapeutic success of a non-fasting, home-based KD in a toddler with NMDAR autoimmune encephalitis and drug-resistant epilepsy. The approach underscores the importance of individualized nutrition therapy, culturally tailored diet plans, and robust family education for optimizing outcomes in resource-constrained settings.