Participants were 65 children (36 males, 29 females) with intractable seizures, ages 18 months to 14 years 6 months, enrolled in a prospective study at the Johns Hopkins Hospital, Baltimore, MD, USA, to study the diet's efficacy. Children were assessed before diet initiation and at 1-year follow-up.

Stewart , MD, PhD, FRCPC , Kevin Gordon , MD, MS, FRCPC , and Peter Camfield , MD, FRCPC Abstract The ketogenic diet has demonstrated good efficacy in children with pharmacologically resistant seizures. References Freeman JM, Vining EP, Pillas DJ, et al: The efficacy of the ketogenic diet-1998: A prospective evaluation of treatment in 150 children.

In the resting state, adult brain can consume up to 25% of the total body glucose supply; in infants and children, the glucose demand can be up to 80% of whole-body glucose utilization (Cremer, 1982 ; Clarke & Sokoloff, 1994 ). The diffusion of this essential fuel across the blood–brain barrier is exclusively facilitated by the glucose transporter type 1 (GLUT1). This membrane-bound protein is encoded by the SLC2A1 gene (1p35-31.3) and contains 12 membrane-spanning domains with intracellularly-located amino- and carboxy-termini (Mueckler et al., 1985 ). In brain, GLUT1 interacts with a network of other specific GLUT1 isoforms mediating glucose transport into astrocytes and neurons. To date, in practically all patients with GLUT1DS the classical LCT diet with ratios of 4:1 and 3:1 has been used (Coman et al., 2006 ). There are two reports from Japan about the use of alternative KDs in GLUT1DS: a MCT diet (2:1 ratio) was successfully introduced in an 11 y/o patient (Yasushi et al., 2005 ), and Ito et al describe a 7 y/o boy responding to a modified Atkins diet (Ito et al., 2008 ). In the vast majority of GLUT1DS patients, seizure control by the KD is imminent and efficient and anticonvulsant medication can be withdrawn (Klepper, 2007 ). Compliance is much better than in any other indication of the KD.

In intractable childhood epilepsy, the diet's effectiveness for seizure control in children with difficult-to-treat epilepsy has been confirmed in several independent studies [1], [2], [3]. Hypotheses on the anticonvulsive mechanisms of the KD include changes in (a) cerebral energy metabolism, (b) cell properties decreasing excitability, (c) neurotransmitter function and transmission, (d) circulating factors acting as neuromodulators, and (e) brain extracellular milieu (for review see [4]). In addition, ketones appear to have direct anticonvulsant effects in vivo [5], and polyunsaturated fatty acids have recently been discussed as potential mechanisms of seizure protection achieved with the KD [6]. The KD has now emerged as the treatment of choice for the only currently known transport defect at the blood–brain barrier, the glucose transporter 1 deficiency syndrome (GLUT1-DS, OMIM 606777). In this entity, glucose transport across the blood–brain barrier and into brain cells is significantly impaired. As a result of brain energy failure, the patients usually present in early childhood with seizures unresponsive to anticonvulsants, followed by developmental delay and a complex motor disorder with spastic, ataxic, and dystonic elements (for reviews, see [7], [8]). Severe cases develop secondary microcephaly without structural brain abnormalities, but recently characteristic local changes of brain metabolism in the mesial temporal regions, thalami, and basal ganglia have been reported in this entity [9]. Heterozygous autosomal dominant and de novo mutations in the GLUT1 gene have been identified as the cause of the disease in the majority of patients [10], [11], [12]. The anticonvulsive mechanism of the KD in GLUT1 DS is compelling: in hypoglycorrhachia the KD maintains an anabolic state providing ketones that serve as an alternative fuel to the brain (Fig. 1) [13]. The vast majority of patients become seizure-free within days on the KD and show general clinical improvement.

Since its development, the ketogenic diet has become widely used in a variety of epilepsy syndromes including myoclonic–astatic epilepsy, Dravet syndrome, and infantile spasms.1,2 Since its introduction 90 years ago, one of the most common epilepsy syndromes for which the ketogenic diet is used in clinical practice is Lennox–Gastaut syndrome (LGS). LGS was first reported in 1950, though the electroclinical features were first described by the Marseille School in France in 1966.3,4 The criteria for the syndrome have been modified on several occasions; however, the International League Against Epilepsy Classification Commission adopted a formal definition in 1989.5 Most clinicians agree that patients with LGS have an age at onset of less than 8 years (peak 3–5y), multiple seizure types that include tonic seizures (with often atypical absence, atonic, and other seizure types), intellectual disability, and the presence of diffuse, slow spike-wave complexes on electroencephalogram (EEG).5–7 While many large ketogenic diet trials have included children with LGS, outcome data were primarily reported by seizure type rather than any specific epilepsy syndrome.8 As a result, when the International Ketogenic Diet Consensus Guideline was published in 2009, LGS was not included as either a clear or possible ‘indication’ for the ketogenic diet primarily owing to insufficient data.1 This study sought to determine the efficacy of the ketogenic diet for children with LGS at our institution and in the literature. Studies performed at The Johns Hopkins Hospital since 1994 were not included in this historical review because these children are included in the combined analysis of our center’s results (previous section), with the exception of the LGS crossover study of 20 children, which had a separate database.10 When results were reported at multiple time points, we chose to include only the longest diet duration reported.

Access through your institution Abstract The aim of this study was to investigate the effects of ketogenic diet (KD) on cognitive function in patients with glucose transporter protein 1 deficiency syndrome (GLUT1-DS). Six patients with GLUT1-DS who were referred to the National Centre for Epilepsy in Norway during the period of November 2011–September 2013 were included. Subsequently, a large variety of mutations in the SLC2A1 gene have been found to give rise to different degrees of brain glucose deficiency, and the wide clinical spectrum seen in patients with GLUT1-DS is probably partly due to this variety of mutations and their different effects on the function of the protein [3], [4]. It should be noted, however, that cases with GLUT1-DS without SLC2A1 mutations are also reported [5]. It has been claimed that GLUT1-DS is not a degenerative condition [6]. However, lack of energy to the immature brain has been found to disturb normal development throughout childhood [7], [8], [9]. Studies also indicate that sufficient brain glucose is of vital importance to the developing brain in children, while deficiency of brain glucose appears to be of less importance in adolescence [9], [10]. Thus, it is important to identify GLUT1-DS as early as possible and start treatment with ketogenic diet (KD). When treated with KD, ketones will provide an alternative fuel for the neurons [11]. Cognitive deficits are common in patients with classical GLUT1-DS and may be severe [12], [13], [14], [15]. Recently, patients with milder forms of the disease have been reported, including patients without epilepsy [16], [17], [18]. In the milder forms, cognitive development may be less affected and, sometimes, even normal.

Other options, including pyridoxine, sulthiame, valproate, and zonisamide, have only limited reported benefits for IS (Tsao, 2009 ). Topiramate specifically, which is often anecdotally used as a third-line agent after corticosteroids and vigabatrin are unsuccessful, has published benefits of only 47–53% having a >50% spasm reduction (Hosain et al., 2006 ; Korinthenberg & Schreiner, 2007 ). The ketogenic diet (KD) has emerged as an efficacious nonpharmacologic therapy for intractable IS (Nordli et al., 2001 ; Kossoff et al., 2002 ; Eun et al., 2006 ). The widespread availability of several ketogenic formulas has also led to increased use for infants (Kossoff et al., 2004 ; Hosain et al., 2005 ; Eun et al., 2006 ). In 2002 we reported preliminary results using the KD for 23 patients with refractory IS (Kossoff et al., 2002 ). Since that time we have seen a significant increase in referrals for the KD for intractable IS. Approximately two-thirds of patients had >50% spasm improvement after 6 months, which is similar to reports from other institutions of a 71–81% response rate (Nordli et al., 2001 ; Eun et al., 2006 ). It is possible that some of the spasm-free results with the KD over time could be due to spontaneous remission, although our results are higher than the 9–14% described from 6–9 months (Hrachovy et al., 1991 ). Perhaps equally important were the other positive effects of the KD, with significant improvements in development and EEG, as well as reduction in the number of concurrent anticonvulsants.

Access through your institution Abstract There has been renewed interest in the ketogenic diet in the treatment of medically refractory seizure disorders in childhood. This article reports the results of a retrospective chart review of 52 patients who were treated with the ketogenic diet.