SUMMARYThe ketogenic diet (KD) is an established, effective nonpharmacologic treatment for intractable childhood epilepsy. The KD is provided differently throughout the world, with occasionally significant variations in its administration. There exists a need for more standardized protocols and management recommendations for clinical and research use. In December 2006, The Charlie Foundation commissioned a panel comprised of 26 pediatric epileptologists and dietitians from nine countries with particular expertise using the KD. This group was created in order to create a consensus statement regarding the clinical management of the KD. Subsequently endorsed by the Practice Committee of the Child Neurology Society, this resultant manuscript addresses issues such as patient selection, pre-KD counseling and evaluation, specific dietary therapy selection, implementation, supplementation, follow-up management, adverse event monitoring, and eventual KD discontinuation. This paper highlights recommendations based on best evidence, including areas of agreement and controversy, unanswered questions, and future research.

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.

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.Methods: Patients (129) who were on the KD from July 1995 to October 2001 at our epilepsy center were assessed in the study. Early-onset (within 4 weeks of the commencement of the KD until stabilization) and late-onset complications (occurring after 4 weeks) were reviewed.Results: The most common early-onset complication was dehydration, especially in patients who started the KD with initial fasting. Gastrointestinal (GI) disturbances, such as nausea/vomiting, diarrhea, and constipation, also were frequently noted, sometimes associated with gastritis and fat intolerance. Other early-onset complications, in order of frequency, were hypertriglyceridemia, transient hyperuricemia, hypercholesterolemia, various infectious diseases, symptomatic hypoglycemia, hypoproteinemia, hypomagnesemia, repetitive hyponatremia, low concentrations of high-density lipoprotein, lipoid pneumonia due to aspiration, hepatitis, acute pancreatitis, and persistent metabolic acidosis. Late-onset complications also included osteopenia, renal stones, cardiomyopathy, secondary hypocarnitinemia, and iron-deficiency anemia. Most early-and late-onset complications were transient and successfully managed by careful follow-up and conservative strategies. However, 22 (17.1%) patients ceased the KD because of various kinds of serious complications, and four (3.1%) patients died during the KD, two of sepsis, one of cardiomyopathy, and one of lipoid pneumonia.Conclusions: Most complications of the KD are transient and can be managed easily with various conservative treatments. However, life-threatening complications should be monitored closely during follow-up. Key Words: Early onset-Late onset-Complications-Ketogenic diet-Intractable epilepsy.The ketogenic diet (KD) is accepted as a potent antiepileptic treatment for intractable childhood epilepsy (1-5) but is still used only in limited patients because of concerns for its poor tolerability and a significant number of different complications associated with it (6-10). Since the active application of KD after the mid 1990s (1-5), many kinds of complications have been reported in several studies, some of which had not been described previously (6-13).Our study provides a detailed description of the earlyand late-onset complications of the KD and data on their exact extent, severity, outcomes, and management. METHODSThe subjects of this study were 129 patients of the Epilepsy Center at Inje University Sanggye Paik Hospital, Accepted May 9, 2004. Address correspondence and reprint requests to Dr. H.D. Kim at Department of Pediatrics, Yonsei University College of Medicine, Severance Hospital, 134, Shinchon Dong, Seodaemun Gu, Seoul, 120-749, Korea. E-mail: hdkimmd@yumc.yonsei.ac.kr who were treated for intractable childhood epilepsy with the KD from July 1995 to October 2001. These patients were followed up for >12 months.Eighty-seven pati...