Heung Dong Kim

Early‐ and Late‐onset Complications of the Ketogenic Diet for Intractable Epilepsy

Summary:  Purpose: This study was undertaken to evaluate the exact limitations of the ketogenic diet (KD) and to collect data on the prevention and management of its risks.

Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy

Focal cortical dysplasia type II (FCDII) is a sporadic developmental malformation of the cerebral cortex characterized by dysmorphic neurons, dyslamination and medically refractory epilepsy. It has been hypothesized that FCD is caused by somatic mutations in affected regions. Here, we used deep whole-exome sequencing (read depth, 412–668×) validated by site-specific amplicon sequencing (100–347,499×) in paired brain-blood DNA from four subjects with FCDII and uncovered a de novo brain somatic mutation, mechanistic target of rapamycin (MTOR) c.7280T>C (p.Leu2427Pro) in two subjects. Deep sequencing of the MTOR gene in an additional 73 subjects with FCDII using hybrid capture and PCR amplicon sequencing identified eight different somatic missense mutations found in multiple brain tissue samples of ten subjects. The identified mutations accounted for 15.6% of all subjects with FCDII studied (12 of 77). The identified mutations induced the hyperactivation of mTOR kinase. Focal cortical expression of mutant MTOR by in utero electroporation in mice was sufficient to disrupt neuronal migration and cause spontaneous seizures and cytomegalic neurons. Inhibition of mTOR with rapamycin suppressed cytomegalic neurons and epileptic seizures. This study provides, to our knowledge, the first evidence that brain somatic activating mutations in MTOR cause FCD and identifies mTOR as a treatment target for intractable epilepsy in FCD.

Safe and Effective Use of the Ketogenic Diet in Children with Epilepsy and Mitochondrial Respiratory Chain Complex Defects

Summary:  Purpose: To evaluate the clinical efficacy and safety of the ketogenic diet (KD) for patients with intractable childhood epilepsy and mitochondrial respiratory chain (RC) complex defects.

Efficacy and safety of the ketogenic diet for intractable childhood epilepsy: Korean multicentric experience

Summary:  Purpose: We wished to evaluate the efficacy and safety of the ketogenic diet (KD), and we also evaluated the prognosis of the patients after successful discontinuation of the diet in infants, children, and adolescents with refractory epilepsy.

Mitochondrial respiratory chain defects: underlying etiology in various epileptic conditions.

Purpose: To determine if defects in mitochondrial respiratory chain enzyme complexes (MRCs) contribute to the etiology of childhood epilepsy.

Benefits of the nonfasting ketogenic diet compared with the initial fasting ketogenic diet.

Objective. The ketogenic diet (KD) is traditionally introduced with an initial period of fasting and fluid restriction that is difficult and sometimes complicated by moderate dehydration. This investigation compares the efficacy and tolerability of the nonfasting ketogenic diet (NFKD) and the conventional initial-fasting ketogenic diet (IFKD). Methods. Forty-one children with intractable epilepsy were treated with the NFKD, beginning with a gradual increase in calories with no initial fasting or fluid restriction. This NFKD population was compared retrospectively with 83 recent historical control subjects who were treated with the IFKD. Efficacy, tolerability, time until strong ketosis, and occurrence of complications were compared. Results. Fourteen (34.1%) patients became seizure-free for at least 3 months after the NFKD, compared with 29 (34.9%) after the IFKD. There was no significant difference in days until strong urinary ketosis between the 2 groups. The incidence of hypoglycemia was also not significantly different between the groups as most other laboratory findings, although the blood urea nitrogen was elevated in 24.1% of the IFKD group and in only 12.2% of the NFKD patients without statistical significance. Conversely, moderate dehydration was significantly less frequent in the NFKD group (12.2%) than in the IFKD group (62.7%). Finally, these results were reflected to the shortening of the hospitalization period in the NFKD group. Conclusions. These observations suggest that initial fasting and fluid restriction are not essential for the KD and that the tolerability of this treatment may be improved. These data support our intention to conduct a formal, prospective, randomized trial comparing 2 forms of the KD.

Use of a Modified Atkins Diet in Intractable Childhood Epilepsy

Summary:  Purpose: To evaluate the efficacy, safety and tolerability of a modified Atkins diet in intractable childhood epilepsy.

Efficacy and Tolerability of the Ketogenic Diet According to Lipid:Nonlipid Ratios—Comparison of 3:1 with 4:1 Diet

Summary:  Purpose: The ketogenic diet (KD) has been considered a highly potent antiepileptic treatment for intractable childhood epilepsy. In this study, we compared the antiepileptic efficacy and diet tolerability of two different diets with lipid:nonlipid ratios of 3:1 and 4:1.

Diffusion tensor MRI visualizes decreased subcortical fiber connectivity in focal cortical dysplasia

Diffusion tensor imaging (DTI) was applied to 12 patients with focal cortical dysplasia (FCD) in frontal or occipital cortex. Fiber tractography was obtained from seeding points in superior longitudinal fasciculus or posterior corona radiata. Mean fractional anisotropy of fiber bundles around the affected cortex was decreased in comparison to the contralateral hemisphere with statistical significance (paired t test, P = 0.0274). On visual analysis, tractography depicted decreased volume of fiber bundles connected to the dysplastic cortex invariably even in those with a normal T2 signal intensity of underlying white matter adjacent to FCD. DTI has high potential to be applied to localize the FCD and to provide a better understanding of the pathological changes in the white matter.

Ketogenic diet for treatment of infantile spasms

This study sought to evaluate the efficacy, tolerability, and safety of a ketogenic diet (KD) in the treatment of infantile spasms (IS), incorporating a revised protocol based on our previous experience with KD. We undertook a retrospective analysis of 43 children who suffered from catastrophic IS and tried KD from June 1995 to May 2004 in two Korean epilepsy centers. Outcome measures included seizure frequency, electroencephalograms (EEGs), adverse reactions, and neurological development. Overall, the diet achieved the seizure-free state in 53.5% (23/43) of patients and a greater than 90% reduction of seizure frequency in 62.8% (27/43) of patients. The seizure outcomes were highly concordant with improvements in EEG findings and development. In addition, KD could be maintained more safely and more comfortably because of our revised protocol that included an initial non-fasting diet, a short-term trial of 8 months, a more protein-rich diet with a lipid to non-lipid ratio of 3:1, and liquid ketogenic milk. Most complications were transient and KD was well tolerated in most cases. KD can be an effective alternative therapy for catastrophic IS, and additional benefits may be derived from constant revision of the diet in the future.