Ann M. Bergin
Most children with epilepsy in childhood achieve seizure freedom with anticonvulsant medication. However, up to one third of patients can have intractable epilepsy continuing to have debilitating seizures despite medications. Dietary manipulation and new techniques of neurostimulation offer approaches that may improve or even achieve seizure control.
DIETARY TREATMENTS FOR EPILEPSY
THE KETOGENIC DIET (KD)
The ketogenic diet simulates the biochemical changes of fasting by providing the majority of calories in the diet from fat. The dietary fat is metabolized to ketone bodies (acetoacetate 3-hydroxybutyrate and acetone) and fatty acids.1which the body utilizes for energy production. A ketogenic diet is high in fat, low in carbohydrate, and provides adequate protein for health and growth; typically it involves a 3:1 to 4:1 ratio of fat (grams) to carbohydrate and protein (grams).2 In order to maintain ketosis, the components of each meal, snack, or beverage must preserve this ratio. The carbohydrate content of medications must be considered and minimized, usually by eliminating sugary liquid or chewable tablets in favor of standard tablet formulations. The diet can be provided using formula preparations for young infants and for patients using feeding tubes. Medical supervision, a specifically trained and knowledgeable nutritionist for diet design, surveillance of growth and nutritional status and parent education are essential to diet success and safety.
Observational studies of the KD report up to 27% of patients having ≽ 90% reduction in seizures at 12 months, and 43% have at least a 50% reduction in seizures.6 A recent randomized, controlled, though not blinded study comparing immediate diet initiation to a control group who were not started on the diet for 3 months showed 38% with a > 50% seizure reduction at 3 months on the diet compared to 6% of controls.8 These results support the efficacy of the diet but suggest that the likelihood of success may not be as high as reported in earlier studies.
The KD is effective treatment for most seizure types, though it is least likely to be effective in complex partial seizures.9,10 Generally, there is a complete cessation or reduction in seizures within 2 weeks in children that will benefit from the KD.11 If there is less than a 50% reduction In seizures, the dietary restriction for the child and burden of producing ketogenic meals is such that the diet is withdrawn. In addition to Lennox-Gastaut syndrome, small series have described efficacy in children with highly refractory epilepsies such as myoclonic astatic epilepsy (Doose syndrome),12 severe myoclonic epilepsy of infancy (Dravet syndrome),13 infantile spasms,14,15 and tuberous sclerosis.16 The diet can be effective across age groups from infancy to adulthood.
Prior to starting the KD, patients are screened for metabolic disorders of fatty acid oxidation which could be associated with a serious risk of deterioration. Acute complications of diet initiation include hypoglycemia, acute acidosis, and vomiting, and suppression of thirst leading to dehydration. Management of these acute complications is the primary reason for initiation of the diet in a hospital setting. The most common long-term complication is constipation; the most common serious complication is nephrolithiasis (6.7%).2,18 Growth failure is frequent, especially if the diet is used for many years.19-21 Other complications include increased bruising, increased infection rate, pancreatitis, and reduced GI motility.
The mechanisms by which the ketogenic diet reduces seizure frequency is unknown. Hypotheses include (1) a direct or indirect anticonvulsant effect of ketone bodies, (2) anticonvulsant effect of elevated levels of polyunsaturated fatty acids (PUFAs), or an indirect effect on mitochondrial energy metabolism, (3) inhibition of glycolysis or an effect on potassium-sensitive ATP channels due to reduced glucose levels and (4) effects on neurotransmitters, (γ-aminobutyric acid (GABA) and norepinephrine) all of which could act to decrease cortical excitability.23
MODIFIED ATKINS DIET
This diet reduces carbohydrate intake to 10 to 15 grams per day, and increases dietary fat and approximates a 2:1 ketogenic diet (KD) ratio. Many patients become ketotic.24 A prospective open-label study of 30 adults reported 33% with a > 50% reduction in seizures at 6 months.25 The diet has been offered on an outpatient basis. Medical supervision is required to monitor for and prevent acidosis, nephrolithiasis, and growth failure, all of which may occur in ketotic patients.
LOW GLYCEMIC INDEX DIET TREATMENT
Total carbohydrate intake is gradually reduced to 40 to 60 grams/day and “allowed” carbohydrates are chosen for their low glycemic index. The proportion of calories from fat is increased. This diet approximates a 1:1 ketogenic ratio. Patients are not generally ketotic. This diet is initiated in the outpatient setting. A pilot study reported efficacy similar to the KD in initial follow-up.26
NEUROSTIMULATION
In the context of the treatment of epilepsy, neurostimulation describes the chronic intermittent electrical or magnetic stimulation of sites in the central or peripheral nervous system with the goal of raising the seizure threshold and reducing the frequency of seizures. These relatively new techniques are used adjunctively in patients with intractable epilepsy. Overall efficacy of neurostimulation strategies has been modest to date, with very few patients achieving freedom from seizures by this means. Neurostimulation is rarely associated with cognitive or behavioral adverse effects.
VAGUS NERVE STIMULATION (VNS)
The VNS device was approved for use in adults and children older than 12 years of age with refractory focal-onset seizures in 1997.29 Stimulation of the vagus nerve results in desynchronization of cortical electrical activity that is associated with reduced seizure.30,31 The left vagus nerve is chosen because it carries fewer cardioactive fibers. The stimulator battery is usually implanted in the infraclavicular area, and the lead to the vagus nerve is threaded subcutaneously into the neck. The stimulator provides a repeated stimulus of 0.5 to 3 milliamps, lasting up to 30 seconds every 1 to 5 minutes. On-demand stimulation, can be delivered by the patient/caretaker by passing a handheld magnet over the battery location. This may abort or decrease the duration of a seizure.
The efficacy of vagal nerve stimulation was demonstrated in 2 pivotal studies in adults and children greater than 12 years of age.32,33 A study of sixty children, aged 3 to 18 years at implantation, showed a median seizure reduction of 31% at 6 months. To date, no consistent clinical predictors of a positive outcome have been identified.
A retrospective, uncontrolled, multicenter study of 125 pediatric patients followed for up to 1 year revealed that the mean reduction in seizures was 45% at 6 months. Medication changes were allowed during the study. The proportion experiencing a 50% or greater reduction in seizure number was 57% at 6 months. Age at implantation did not affect efficacy. Assessment of change in quality of life indicated improvement in many patients, which was independent of seizure response. This finding reflects similar observations in adult studies. Longer-term follow-up reported an incremental response over time,37similar to reports in adults.
A multicenter retrospective study of 50 patients with Lennox-Gastaut syndrome showed that 40% achieved a 50% or greater reduction in seizures at 6 months following VNS placement.38 “Drop” seizures and atypical absence seizures were particularly improved. Eleven of 24 patients with generalized seizures (by clinical and EEG criteria), had a > 50% reduction in seizures at 3 months,39 and in 14 patients with idiopathic generalized epilepsy, 8 (57%) had > 50% reduction in seizures.40 Two small studies have suggested reasonable efficacy (approximately 50% of patients with a 50% reduction in seizure frequency) of VNS therapy in tuberous sclerosis. 41,42
Surgical complications are relatively rare in children (0% to 3.5%) and mainly include wound/deep pocket infection.43,44 Stimulus-related adverse effects of cough, dysesthesia, voice alteration/hoarseness, and hypersalivation are relatively common (up to 39%)44 but are often transient. Obstructive sleep apnea is worsened by VNS treatment in some adult patients,45 and similar findings are postulated in children but are not as yet well documented.46,47 Caution is recommended in using this treatment in children with preexisting obstructive sleep apnea. Other vulnerable groups requiring careful assessment may be those with swallowing dysfunction, with the risk of increased aspiration, and those with cardiovascular disease.