KD Treatment for Super-refractory Status Epilepticus

This is a multicenter, prospective, randomized, controlled, open-label clinical study to evaluate the efficacy and safety of ketogenic diet (KD) as an adjunctive therapy in patients with Super Refractory Status Epilepticus (SRSE).

The study plans to enroll eligible SRSE patients. Participants will be randomly assigned in a 1:1 ratio to one of two groups:

1. Control Group: Receives standard medical therapy according to current guideline recommendations for SRSE management.
2. Intervention Group: Receives standard medical therapy plus a ketogenic diet intervention.

The KD intervention will be administered via a nasogastric tube using a ketogenic formula. The nutritional goal is 25-30 kcal/kg, initiated at half-strength and advanced to the full caloric target within 72 hours. If no clinical improvement is observed within 2 weeks of initiating the KD, it will be discontinued. For responders, continuation is recommended. All patients in the KD group will receive concomitant daily nutritional supplements.

The primary outcome measure is the efficacy of controlling SRSE within 2 weeks after randomization. Efficacy is defined as the cessation of both clinical and electrographic status epilepticus, as confirmed by continuous EEG monitoring.

Key secondary outcomes include:

* Safety evaluation, including all KD-related adverse events and in-hospital mortality.
* Feasibility of KD (time to achieve ketosis, defined as blood beta-hydroxybutyrate level ≥1.2 mmol/L or urine ketones 1+).
* Neurological and functional outcomes assessed by the modified Rankin Scale (mRS), Glasgow Outcome Scale-Extended (GOS-E), and quality of life (QOLIE-31) at discharge, 3 months, and 6 months.
* Cognitive function (MMSE, MoCA) at 3 and 6 months. Statistical analysis will be performed on both the Full Analysis Set (FAS) and the Per-Protocol Set (PPS).

• the ketogenic diet (Other): First, ketogenic formulation was initiated continuously via naso-enteric tube at 50% of goal and increase to goal (25-30 kcal/kg/day) within 72h. The KD regimen was continued according to seizure control and tolerance before discharge. If the patient was receiving oral nutrition, the modified MAD-KD regimen (carbohydrate 10-20 g/d) was initiated. In addition, if weaning off the diet after discharge, the reduction was 0.5:1 per week.
• Standard Medical Therapy (Drug): Standard Medical Therapy include continuous intravenous infusion of an anesthetic agent, such as midazolam (starting regimen: 0.2 mg/kg IV bolus followed by continuous infusion of 0.1-0.6 mg/kg/h), titrated to seizure termination

Primary outcomes

• Time to cessation of SRSE [2 weeks]: Calculation Method: Based on electroencephalogram (EEG) and clinical seizure activity, the therapeutic efficacy is categorized into three levels: Grade I (Seizure-free): Electrographic and clinical status epilepticus is completely controlled, and follow-up EEG shows resolution of electrographic status epilepticus; record the number of days required to achieve this. Grade II (Partially effective): Epileptiform discharges are reduced by more than 50%; record the number of days required to achieve this. Grade III (Ineffective): Epileptiform discharges are reduced by less than 50%; the recorded number of days required is 14 days.

Sex: All, ages: 14 Years to 80 Years

Inclusion Criteria:

* Patients diagnosed with super-refractory status epilepticus (SRSE), in whom status epilepticus (SE) persists or recurs after the initial treatment for SE-including intravenous benzodiazepines, an anti-seizure medication (ASM, such as valproate, levetiracetam, or phenobarbital), and an anesthetic (e.g., propofol) administered continuously for 24 hours-fails to terminate the episode, or when SE recurs upon reduction of the anesthetic.
* Age between 14 and 80 years, regardless of gender.
* The patient's legal guardian has provided signed informed consent.

Exclusion Criteria:

* Patients with lipid metabolism disorders, including defects in fatty acid transport and beta-oxidation, such as carnitine deficiency (primary) and carnitine-related enzyme deficiencies (including carnitine palmitoyltransferase \[CPT\] I and II deficiency, carnitine translocase deficiency), fatty acid oxidation disorders (including beta-oxidation defects), short-chain acyl-CoA dehydrogenase deficiency (SCAD), medium-chain acyl-CoA dehydrogenase deficiency (MCAD), long-chain acyl-CoA dehydrogenase deficiency (LCAD), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, medium-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, pyruvate carboxylase deficiency, and porphyria.
* Intolerance to enteral feeding (e.g., intestinal obstruction).
* Receipt of propofol infusion within 24 hours.
* Hemodynamic instability (systolic blood pressure <90 mmHg or diastolic blood pressure <60 mmHg, requiring high-dose vasopressors for maintenance).
* Liver failure (aspartate aminotransferase \[AST\], alanine aminotransferase \[ALT\], blood ammonia >5 times the upper limit of normal; total bilirubin >10 mg/dL \[171 μmol/L\]).
* Pancreatitis.
* Pregnancy.
* Metabolic instability (blood glucose <3.1 mmol/L, arterial blood pH <7.2, serum sodium <120 or >160 mmol/L).
* Septic shock.
* Complicated by diabetes insipidus.
* Status epilepticus caused by hypoxic-ischemic brain injury.

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