3.1.1 Drug-resistant epilepsy in children

In 2010, the International League Against Epilepsy (ILAE) defined drug-resistant epilepsy as the failure of adequate trials of two appropriately chosen, tolerated, and used anti-epileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom [28]. The drugs must have been appropriate for the seizure type, tolerated at therapeutic doses, and given a reasonable period of time to work (at least 6 months) [29] before declaring drug resistance.

When drug-resistant epilepsy is declared, further anti-epileptic drug trials or epilepsy surgery may be helpful [30]. However, even after carefully excluding confounding factors and optimizing the drug approach, subsequent trials have only a slight (about 5%) chance of inducing seizure remission [31]. Surgery should always be considered in children with drug-resistant epilepsy, especially when a lesion concordant to the epilepsy is detected on imaging [30], but many children are not surgical candidates due to a generalized or multifocal epilepsy syndrome, or nonresectable location of ictal onset.

When drug trials and surgery are no longer feasible, a ketogenic diet is indicated [2]. Numerous studies have demonstrated the efficacy and safety of using ketogenic diets to treat drug-resistant epilepsy in children, but until the previous decade there were no randomized controlled trials. Since 2008, four published randomized controlled trials have compared the efficacy of a ketogenic diet with continued medications or a placebo arm in children with drug-resistant epilepsy [32–35].


dietary intervention. Given these encouraging results, many epilepsy specialists advocate that ketogenic diets be used earlier in the management of children with

Since ketogenic diets induce a shift away from glycolytic energy production towards mitochondrial oxidative phosphorylation, they are the treatment of choice in two childhood disorders of impaired brain glucose metabolism: glucose transporter type 1 deficiency syndrome (GLUT1 DS) and pyruvate dehydrogenase complex deficiency (PDHD) [2]. In both cases, the ketones produced by the diet bypass

GLUT1 DS results from impaired glucose transport across the blood-brain barrier due to mutations in the SLC2A1 gene, which encodes the glucose transporter, GLUT1 [36]. Clinically, GLUT1 DS is characterized by cognitive impairment, mixed seizure types, and a complex movement disorder. The vast majority of children with GLUT1 DS achieve seizure freedom with a CKD, which should be introduced as early as possible and continued through to adulthood [36]. The CKD may be difficult to tolerate in older children and adolescents, in which case the MAD is also effective [2]. In GLUT1 DS, ketogenic diets may also enhance the child's alertness,

In PDHD, pyruvate is unable to be metabolized into acetyl-CoA, resulting in abnormal mitochondrial metabolism and lactic acidosis [37]. Clinically, PDHD is characterized by seizures, severe encephalopathy, and—usually—death during childhood. The CKD is effective and safe in PDHD, and appears to increase longevity and improve mental development [37]. However, severe forms of PDHD may

Ketogenic diets should be considered early in the management of children with seizure disorders that consistently demonstrate a 60–70% improvement in seizure control, well above the "usual" 40–50% improvement [2]. These disorders include Angelman syndrome, complex I mitochondrial disorders, Doose syndrome, Dravet syndrome, febrile infection-related epilepsy syndrome (FIRES), formula-fed infants or children, infantile spasms, Ohtahara syndrome, super-refractory status

Once the child is selected for a ketogenic diet, a medical and nutritional evaluation is both strongly advised (Table 4) [2, 26]. In addition to the caregiver (usually

A medical evaluation should be performed by a pediatric neurologist experienced in managing ketogenic diets in children, and include an assessment of the child's epilepsy, comorbidities, psychological and socioeconomic factors, medica-

First, the pediatric neurologist must assess the child's baseline epilepsy state and any comorbidities that may complicate a ketogenic diet. Seizure symptomatology and frequency should be documented in sufficient detail so as to later gauge diet

a parent), anyone else who will be helping institute the diet should attend.

the metabolic defects, serving as an alternative energy source for the brain.

and they frequently improve the movement disorder [36].

3.1.3 Specific seizure disorders in children

epilepticus, and tuberous sclerosis complex [2].

3.2.1 Medical evaluation

tions, and investigations [2].

153

3.2 Preparing a child (and caregiver) for a ketogenic diet

not be appropriate for the diet if quality of life is not improved [2].

drug-resistant epilepsy [2].

3.1.2 Disorders of brain metabolism in children

DOI: http://dx.doi.org/10.5772/intechopen.83711

Ketogenic Diet Therapies in Children and Adults with Epilepsy

ILAE = International League Against Epilepsy; GLUT1 DS = glucose transporter type 1 deficiency syndrome; PDHD = pyruvate dehydrogenase complex deficiency; FIRES = febrile infection-related epilepsy syndrome.

### Table 3.

Epilepsy disorders in children for which a ketogenic diet may be strongly indicated.

The first randomized controlled trial compared the efficacy of a CKD versus no diet intervention in 145 children with drug-resistant epilepsy [32]. After 3 months, 28 children (38%) in the CKD group had a greater than 50% seizure reduction compared to four children (6%) in the control group. One weakness of the study was its unblinded design, with both patients and assessors aware of the group allocations.

The following year, a randomized controlled trial was published in 20 children with drug-resistant Lennox-Gastaut syndrome [33]. All patients were fasted 36 hours and then randomized to receive either a CKD plus a daily solution containing 60 g glucose per day or a solution containing saccharin (an artificial sweetener); the aim of the design was to ensure that both patients and assessors remained blinded to treatment. To the surprise of the investigators, both groups had positive blood BHB levels after 6 days, indicating that the glucose solution did not suppress physiological ketosis. Perhaps as a result of this, the study demonstrated only a borderline, nonstatistically significant reduction in seizures in the saccharin arm.

The next randomized controlled trial compared the efficacy of a MAD versus no diet intervention in 102 children with drug-resistant epilepsy [34]. Surgical candidates were not excluded. After 3 months, 52% of children in the MAD group had a greater than 50% seizure reduction compared to 11.5% of those in the control group. A weakness of the study was its unblinded design, with both patients and assessors aware of the group allocations.

The most recent randomized controlled trial compared the efficacy of a ketogenic diet (CKD or MCT diet) versus no diet intervention in 57 children and adolescents with drug-resistant epilepsy [35]. None of the patients were eligible for surgery. After 4 months, 13 children (50%) in the ketogenic diet group had a greater than 50% seizure reduction compared to 4 children (18.2%) in the control group.

Pooling the results from these randomized controlled trials suggests that 40–50% of children experience a greater than 50% seizure reduction after 3–4 months on a ketogenic diet, compared to 10–15% of children receiving no dietary intervention. Given these encouraging results, many epilepsy specialists advocate that ketogenic diets be used earlier in the management of children with drug-resistant epilepsy [2].
