Gender-Dependent Effect of Maternal Methyl-Enriched Diet on the Expression of Genetic Absence Epilepsy and Comorbid Depression in Adult Offspring of WAG/Rij Rats.

In the present study it has been shown for the first time that maternal methyl-enriched diet (choline, betaine, folic acid, vitamin B12, L-methionine, zinc) during perinatal period reduces the expression of genetic absence epilepsy and comorbid depression in adult offspring of WAG/Rij rats. This beneficial effect was more pronounced in males compared with females. It is assumed that epigenetic modifications induced by maternal methyl-enriched diet in the offspring at the early stages of ontogenesis might be a possible mechanism underlying the correction of genetically-based pathologic phenotype in WAG/Rij rats. Results suggest that methyl-enriched diet during perinatal period can be potentially used for mitigation or prevention epileptogenesis and depression-like comorbid disorders in people genetically predisposed to absence epilepsy.

Glut1 deficiency is a rare but treatable cause of childhood absence epilepsy with atypical features.

Glucose transporter type 1 deficiency syndrome (GLUT1-DS) is a rare genetic disorder caused by pathogenic variants in SLC2A1, resulting in impaired glucose uptake through the blood-brain barrier. Our objective is to analyze the frequency of GLUT1-DS in patients with absences with atypical features. Sequencing analysis and detection of copy number variation of the SLC2A1 gene was carried out in patients with atypical absences including: early-onset absence, intellectual disability, additional seizure types, refractory epilepsy, associated movement disorders, as well as those who have first-degree relatives with absence epilepsy or atypical EEG ictal discharges. Of the 43 patients analyzed, pathogenic variations were found in 2 (4.6%). Six atypical characteristics were found in these 2 patients. The greater the number of atypical characteristics presenting in patients with absence seizures, the more likely they have a SLC2A1 mutation. Although GLUT1-DS is an infrequent cause of absence epilepsy, recognizing this disorder is important, since initiation of a ketogenic diet can reduce the frequency of seizures, the severity of the movement disorder, and also improve the quality of life of the patients and their families.

The glucose transporter type 1 (Glut1) syndromes.

The glucose transporter type 1 (Glut1) is the most important energy carrier of the brain across the blood-brain barrier. In the early nineties, the first genetic defect of Glut1 was described and known as the Glut1 deficiency syndrome (Glut1-DS). It is characterized by early infantile seizures, developmental delay, microcephaly, and ataxia. Recently, milder variants have also been described. The clinical picture of Glut1 defects and the understanding of the pathophysiology of this disease have significantly grown. A special form of transient movement disorders, the paroxysmal exertion-induced dyskinesia (PED), absence epilepsies particularly with an early onset absence epilepsy (EOAE) and childhood absence epilepsy (CAE), myoclonic astatic epilepsy (MAE), episodic choreoathetosis and spasticity (CSE), and focal epilepsy can be based on a Glut1 defect. Despite the rarity of these diseases, the Glut1 syndromes are of high clinical interest since a very effective therapy, the ketogenic diet, can improve or reverse symptoms especially if it is started as early as possible. The present article summarizes the clinical features of Glut1 syndromes and discusses the underlying genetic mutations, including the available data on functional tests as well as the genotype-phenotype correlations. This article is part of the Special Issue "Individualized Epilepsy Management: Medicines, Surgery and Beyond".

Use of the modified Atkins diet for treatment of refractory childhood epilepsy: a randomized controlled trial.

PURPOSE: The aim of this study was to evaluate the efficacy of the modified Atkins diet in a randomized controlled trial in children with refractory epilepsy. METHODS: Children aged 2-14 years who had daily seizures despite the appropriate use of at least three anticonvulsant drugs were enrolled. Children were randomized to receive either the modified Atkins diet or no dietary intervention for a period of 3 months. The ongoing anticonvulsant medications were continued unchanged in both the groups. Seizure control at 3 months was the primary end point. Analysis was intention to treat. Adverse effects of the diet were assessed by parental reports (ClinicalTrials.gov Identifier: NCT00836836). KEY FINDINGS: Among a total of 102 children, 50 were in the diet group and 52 in the control group. Four children discontinued the diet before the study end point, and three children in the control group were lost to follow-up. The mean seizure frequency at 3 months, expressed as a percentage of the baseline, was significantly less in the diet group: 59 ± 54 (95% confidence interval [CI] 44-74.5) versus 95.5 ± 48 (95% CI 82-109), p = 0.003. The proportion of children with >90% seizure reduction (30% vs. 7.7%, p = 0.005) and >50% seizure reduction was significantly higher in the diet group (52% vs. 11.5%, p < 0.001). Constipation was the most common adverse effect among children on the diet (23, 46%). SIGNIFICANCE: The modified Atkins diet was found to be effective and well tolerated in children with drug-refractory epilepsy.

Efficacy of the ketogenic diet in Lennox-Gastaut syndrome: a retrospective review of one institution's experience and summary of the literature.

AIM: To determine the efficacy of the ketogenic diet for children with Lennox-Gastaut syndrome (LGS) at our institution and in the literature. METHOD: The records of children with LGS initiated on the ketogenic diet at our institution from 1994 to 2010 were reviewed. Inclusion criteria included the presence of ≤2.5Hz spike-and-wave complexes on electroencephalogram, multiple seizure types including tonic, atonic, or atypical absence, developmental delay, and age under 1 year. We additionally reviewed the literature for cases of LGS treated with the ketogenic diet and their outcomes. RESULTS: Seventy-one children (41 males, 30 females, median age 3y 6mo, range 18mo-18y), with LGS were initiated on the ketogenic diet. Using an intent-to-treat analysis, after 6 months, 36 (51%) achieved more than 50% seizure reduction, 16 (23%) experienced more than 90% seizure reduction, and 1 (1%) achieved seizure freedom. Results were similar after 12 months. Age, sex, side effects, valproate use, and history of infantile spasms were not predictive of more than 90% seizure reduction. In the literature, 88 of 189 (47%) children with LGS had more than 50% seizure reduction after 3 to 36 months of ketogenic diet treatment. INTERPRETATION: The ketogenic diet is efficacious in the treatment of LGS, with approximately one-half of children responding at 12 months.

Do patients with absence epilepsy respond to ketogenic diets?

Dietary therapies are established as beneficial for symptomatic generalized epilepsies such as Lennox-Gastaut syndrome; however, the outcome for idiopathic generalized epilepsy has never been specifically reported. The efficacy of the ketogenic and modified Atkins diet for childhood and juvenile absence epilepsy was evaluated from both historical literature review and patients treated at Johns Hopkins Hospital. Upon review of 17 published studies in which absence epilepsy was included as a patient subpopulation, approximately 69% of 133 with clear outcomes patients who received the ketogenic diet had a >50% seizure reduction, and 34% of these patients became seizure free. At Johns Hopkins Hospital, the ketogenic diet (n = 8) and modified Atkins diet (n = 13) led to similar outcomes, with 18 (82%) having a >50% seizure reduction, of which 10 (48%) had a >90% seizure reduction and 4 (19%) were seizure free. Neither age at diet onset, number of anticonvulsants used previously, particular diet used, nor gender correlated with success.

Paroxysmal exercise-induced dyskinesia, writer's cramp, migraine with aura and absence epilepsy in twin brothers with a novel SLC2A1 missense mutation.

We report two monochorionic twins that progressively developed, between ages 5 and 10, a combination of episodic neurological disorders including paroxysmal exercise-induced dyskinesia, migraine without or with aura, absence seizures and writer's cramp. CSF/serum glucose ratio was moderately decreased in both patients. Mutational analysis of SLC2A1 gene identified a de novo heterozygous missense mutation in exon 4. This novel mutation has been previously showed to disrupt glucose transport in vitro. Both patients showed immediate and near-complete response to ketogenic diet. This clinical observation suggests that a high index of suspicion for GLUT1 deficiency syndrome is warranted in evaluating patients with multiple neurological paroxysmal events.

Early-onset absence epilepsy caused by mutations in the glucose transporter GLUT1.

Absence epilepsies of childhood are heterogeneous with most cases following complex inheritance. Those cases with onset before 4 years of age represent a poorly studied subset. We screened 34 patients with early-onset absence epilepsy for mutations in SLC2A1, the gene encoding the GLUT1 glucose transporter. Mutations leading to reduced protein function were found in 12% (4/34) of patients. Two mutations arose de novo, and two were familial. These findings suggest GLUT1 deficiency underlies a significant proportion of early-onset absence epilepsy, which has both genetic counseling and treatment implications because the ketogenic diet is effective in GLUT1 deficiency.

The ketogenic diet has no effect on the expression of spike-and-wave discharges and nutrient transporters in genetic absence epilepsy rats from Strasbourg.

The genetic absence epilepsy rat from Strasbourg is considered an isomorphic, predictive, and homologous model of typical childhood absence epilepsy. It is characterized by the expression of spike-and-wave discharges (SWDs) in the thalamus and cortex. The ketogenic diet (KD) is successfully used in humans and animals with various types of seizures, but was not effective in children with intractable atypical absence epilepsy. Here, we studied its potential impact on the occurrence of SWDs in genetic absence epilepsy rat from Strasbourg. Rats were fed the KD for 3 weeks during which they were regularly subjected to the electroencephalographic recording of SWDs. The KD did not influence the number and duration of SWDs despite a 15-22% decrease in plasma glucose levels and a large increase in beta-hydroxybutyrate levels. Likewise, the KD did not affect the level of expression of the blood-brain barrier glucose transporter GLUT1 or of the monocarboxylate transporters, MCT1 and MCT2. This report extends the observation in humans that the KD does not appear to show effectiveness in intractable atypical absence epilepsy to this model of typical childhood absence epilepsy which responds to specific antiepileptic drugs.

Ketogenic diet in Rett syndrome.

Treatment of Rett syndrome with the ketogenic diet has been reported only once and showed positive effects on seizure frequency and behavior. We report a patient with Rett syndrome who was treated with the ketogenic diet for 4 years. The diet was initiated at the age of 8 years owing to the patient's refractory epilepsy and led to a 70% reduction in seizures. Treatment with the ketogenic diet was also associated with improvements in contact and behavior. Diagnosis of Rett syndrome was confirmed by molecular detection of the Ser134Cys mutation in the MECP2 gene, which has previously been described only in classic Rett syndrome. This observation demonstrates that the ketogenic diet has a positive effect on Rett syndrome.

A risk-benefit assessment of therapies for Lennox-Gastaut syndrome.

The treatment of Lennox-Gastaut syndrome has been improved for some patients by the introduction of adjunctive therapy with newer anticonvulsants such as lamotrigine and topiramate and the availability of vagal nerve stimulation and the re-emergence of the use of the ketogenic diet in recent years. The place of standard anticonvulsants and the role of callosotomy needs to be re-evaluated in view of the new developments. Although recommendations for the treatment of patients with Lennox-Gastaut syndrome are difficult to make in the absence of direct head-on comparative trials, the following suggested treatment recommendations are based on the best evidence available. Medical treatment should start with valproic acid (sodium valproate) and be followed by adjunctive therapy with either lamotrigine or topiramate; clobazam can be added if necessary for better seizure control while trying to reduce the dose of the other anticonvulsants. If standard treatment does not achieve sufficient seizure control or proves to be intolerable, vagal nerve stimulation, ketogenic diet, felbamate, benzodiazepines such as clonazepam, and phenobarbital (phenobarbitone) are recommended as third-line choices. Further considerations include ethosuximide, methsuximide, corticotropin (adrenocorticotropic hormone) or corticosteroids, pyridoxine (vitamin B6) and vigabatrin. If adequate drug treatment and vagal nerve stimulation provide insufficient seizure control, partial callosotomy may be an option for the treatment of frequent, intractable and disabling drop attacks. These suggestions are based on the best evidence available and do not in any way exclude the use of other treatments if compelling individual risk-benefit considerations apply.

The medium chain triglyceride diet and intractable epilepsy.

Fifty children with drug resistant epilepsy were treated with the Medium Chain Triglyceride (MCT) Emulsion diet. Eight achieved complete control of seizures (four without anticonvulsant drugs), and with the addition of anticonvulsants four had seizures reduced in frequency by 90% and 10 by 50-90%. The best results were obtained with astatic myoclonic and absence seizures, but control of seizures was improved in four children with tonic-clonic and three with complex partial seizures. Food given at the same time as MCT helped to reduce side effects, and an extra dose of MCT before bedtime improved control of nocturnal seizures.

Early biochemical and EEG correlates of the ketogenic diet in children with atypical absence epilepsy.

Early changes in blood chemistry and the electroencephalogram were monitored during the first three hours after initiating the medium chain triglyceride (MCT) diet in nine children with intractable atypical absence seizures. Serum glucose, insulin, triglycerides, cholesterol, free fatty acids, ketone bodies concentrations, and venous pH were assayed before and at timed intervals after MCT oil was administered orally. The concentration of serum ketones rose progressively over three hours, beta-hydroxybutyrate proportionately higher than acetoacetate. A statistically significant decrease in the group mean number of epileptiform discharges occurred following MCT therapy. Seizure frequency decreased by more than 50 percent in two-thirds of the children during the 10 week treatment period.

[Treatment of lennox syndrome with medium chain triglycerides (author's transl)]. / Tratamiento del síndrome de Lennox con triglicéridos de cadena media.

Twelve cases of Lennox syndrome were treated with a ketogenic diet with medium chain triglycerides during an average period of five months. All the cases were resistant to drug treatment. In five cases seizures disappeared, in five the frequency decreased and two remained without changes. The alertness improved in seven cases. Electroencephalographic records did not show any important improvement. The diet was generally well tolerated and it only had to be discontinued in one case.