To assess patients with super-refractory status epilepticus and treated with the ketogenic diet in the pediatric intensive care unit.
Six patients with super-refractory status epilepticus in the pediatric intensive care unit of Cengiz GÖkçek Children's Hospital were evaluated retrospectively. Demographic characteristics, antiepileptics used, time of start and duration of ketogenic diet, and the efficacy of the diet and its side-effects were evaluated.
Four of the six patients (66.6%) were female. Patients' mean age was 2.8 years (min: 1, max: 9 years). Four epileptic encephalopathies were determined, two Lennox-Gastaut, one WWOX encephalopathy, and one undiagnosed epileptic encephalopathy. Mean time from the start of status epilepticus to start of ketogenic diet was 13.1 days (min: 8, max: 20) and mean duration of the ketogenic diet was 4.1 months (min: 1, max: 8). One patient's seizures ceased, and the seizures of two other patients decreased by more than 50%. One patient died from complications not associated with the ketogenic diet.
In this retrospective study of the efficacy of the ketogenic diet in the treatment of super-refractory epilepticus, decreases in seizure numbers of at least 50% were achieved in 50% of patients. No life-threatening complications occurred. Multi-centered, prospective studies with larger patient number will shed further light on this subject.
Childhood, Epilepsy, Ketogenic diet, Status epilepticus
Super-refractory status epilepticus (SRSE) is defined as persistence of seizures 24 h after administration of general anesthetics or as recurrence of seizures following withdrawal of general anesthetics . SRSE may have a range of etiological causes and has high morbidity and mortality .
The ketogenic diet (KD) is a high-fat, low-carbohydrate, adequate-protein diet. It has been used in the treatment of drug-resistant epilepsy in adults and children for many years . The few studies of its use in childhood status epilepticus (SE) and SRSE have involved low patient numbers [4-6]. This study focuses on whether KD is a safe and effective therapeutic method in SRSE. The efficacy and safety of KD was evaluated in six patients meeting SRSE criteria in our center.
Six patients aged 1-18 months admitted to the Gaziantep Cengiz GÖkçek Children's Hospital pediatric intensive care unit with a diagnosis of SRSE were evaluated retrospectively. KD was initiated at a 4:1 ratio to all patients with persisting seizures despite conventional antiepileptic therapy and general anesthetics. Before starting KD, all patients underwent basic tests to eliminate the contraindications for KD contraindications (Table 1). KD was administered to all patients in four total doses via nasogastric tube. In contrast to the KD protocol applied in refractory epilepsy, KD was planned in the form of four KD meals from the first day, rather than increasing the number of KD meals by one each day. No patient was fasted before the diet. The seizure burden of the patients and the decrease in the number of seizures were calculated starting from the first day of hospitalization with the diagnosis of status epilepticus until discharge, regardless of whether the patients had previous epilepsy or not. In addition to patients' demographic characteristics, we also evaluated on which day of SE the diet was started, when ketosis began, antiepileptic drugs used before KD, side-effects, time to end of SE, and neurological status at discharge. Since beta hydroxybutyrate could not studied in our health center laboratory, the ketosis status of the patients was evaluated with urine ketone three times a day. Antiepileptics were modified from suspension to tablet form, all intravenous therapies were administered with non-glucose-containing fluid, and all exogenous glucose sources were eliminated. All patients were started on oral multivitamins, and children with selenium and carnitine deficiency received appropriate support. All data were obtained from patient records. Due to the lack of a long-term electroencephalography (EEG) monitoring unit in our hospital, daily conventional 30 minute electroencephalography findings were evaluated by a pediatric neurologist.
Table 1: Pre-KD basal laboratory tests. View Table 1
Six patients were included in the study. Patients' demographic characteristics are summarized in (Table 2). Patients' ages ranged between one and nine years, with a mean age of 2.8 years. Focal SE was present in two patients, and five had a previous history of seizure. The patients constituted a heterogeneous etiological group. Lennox-Gastaut syndrome was determined in two patients, drug-resistant epilepsy with cerebral palsy in one, herpes simplex virus encephalopathy in one, and previously diagnosed epileptic encephalopathy with WWOX gene positivity in one. Non-lesional epileptic encephalopathy (unclassified) not diagnosed genetically was present in one patient. Mean time from onset of SE to initiation of KD diet was 13.1 days (min: 8, max: 20), and mean duration of KD was 4.1 months (min: 1, max: 8). Since inflammatory processes could not be excluded before KD, three patients had received intravenous immunoglobulin, and two received pulse methylprednisolone or adrenocorticopic hormone (ACTH). A conventional SE protocol was applied to all patients, who received at least four antiepileptic drugs before start of KD. Four patients tolerated KD at a 4:1 ratio, while the ratio was reduced to 3:1 in two cases due to side-effects. No life-threatening complication was observed in any patient (Table 3). Side-effects included hyperlipidemia in one patient, gastro-esophageal reflux in two, weight loss and vomiting in two, and increased seizure numbers in one. One patient's seizures resolved entirely and seizure free until fourth day of the KD. Seizure burden of two other patients decreased by more than 50%. Seizure numbers decreased by less than 50% or else increased in the other three patients. One patient died due to infection, while the other subjects were enrolled in rehabilitation programs and discharged.
Table 2: Patient characteristics and treatments received before initiation of ketogenic diet. View Table 2
Table 3: Patients' ketogenic diet responses and side-effects. View Table 3
With our experience from this small patient series, we concluded that KD is an effective and safe therapeutic option in SRSE. KD is recommended in SRSE by several centers, although previous studies in SRSE have involved low patient numbers [7,8]. One study of the efficacy of KD in febrile illness-related epileptic encephalopathy (FIRES) observed that seizures ceased on the fourth day of KD therapy in seven out of 10 patients . FIRES was not present in any of our patients. One review study involving children and adults reported that 25 out of 32 patients started on KD due to SE were completely seizure-free . In our study, the figure was significantly lower, at 1/6 (16.6%). We attribute this to our study group consisting entirely of children. The total prevalence of seizures in previous studies of SRSE ranges between 40% and 100%, but is lower in the pediatric age group [4,7,9-11].
The youngest patient receiving KD in the literature was a nine-week-old subject with malignant migratory partial epilepsy, in whom a decrease in seizures of more than 50% was reported with KD . The youngest child in our study was a one-year-old patient with WWOX encephalopathy. The manifestation of SE ceased in this patient on Day 4 of KD, while daily seizure burden decreased by less than 50% compared to baseline.
Prolongation of SE has been proved to increase morbidity and mortality in experimental studies . While early seizure control was established with early administration of phenytoin and diazepam in one animal study, these had no effect when applied later. This is due to functional and structural changes in GABA-A receptors [14-16]. Since these changes also reduce the effect of antiepileptic drugs in the central nervous system, antiepileptics have a limited effect in SRSE. In the light of these findings, prompt initiation of KD in SRSE should be considered since this will reduce morbidity and mortality. The antiepileptic function of KD is thought to be potentially associated with its anti-inflammatory effect and neurotransmitter modulation .
Due to the difficulty in administering a high fat ratio intravenously, and since it can cause alterations in the metabolism of most antiepileptic drugs metabolized in the liver, we elected to administer KD to all patients by enteral nasogastric tube, rather than parenterally. As also applied in the previous literature, patients were started on oral nutrition after extubation, a ketogenic menu also began being prepared after discharge, and nutrition was continued in this manner .
Limitations of this study include its retrospective nature, the small patient group, and that other antiepileptics continued to be administered during application of the KD. The effect of antiepileptic drugs, intravenous immunoglobulins and steroids could not therefore be excluded in the decrease in or cessation of seizures. Although, no antiepileptic drugs or immunological agents added after initiation of KD.
However, due to the low number of studies showing the efficacy of KD in childhood SRSE worldwide and the fact that we encountered no such publication from Turkey, we think that our study will make a significant contribution to the literature.
In this retrospective study of the efficacy of KD in SRSE, seizure burden decreased by more than 50% in 50% of patients. This shows that KD is an effective therapeutic method in SRSE. No life-threatening complications were observed. Multi-centered, prospective studies with larger patient number will shed further light on effectiveness of KD in SRSE in childhood.