Ketogenic Diet: an Alternative Treatment for Refractory Epilepsy
Diets

Author: Simona Dagatti
Date: 08/02/2014

Description

INTRODUCTION

Ketogenic diet is a high fat, adequate (for growth) protein, low carbohydrate diet used as a therapy for epileptic children. This regimen aims to produce a controlled ketonaemia to manipulate metabolism principles and brain energetic.
This diet can be an alternative treatment for intractable epilepsy. Refractory epilepsy is defined by inadequate control of seizures despite optimal treatment with conventional medications.

NATURE OF KETOGENIC DIET (KD)

The existence of the KD dates back to old times. The idea that epilepsy could be cured by diet was first proposed as a ‘water diet’ – initially described by Rawlle Geyelin (1921) based on the work of Michigan paediatrician Hugh Conklic (1922) in which children would be fasted for as long as 3 weeks. Dr Wilder (1921) first described the use of a maintained diet to mimic this starvation (high fat and low carbohydrates). It is essentially the same KD that is in use now, as it was observed that starvation-produced ketosis could have an impact on brain disorders. Another researcher (Peterman, 1925) gave the first report about its application and efficacy, with 60% of his patients being seizure-free and another 35% having more than 50% improvement. Until then, the only efficacious drugs were phenobarbital and bromides. Modern pharmaceutical practice has displaced the diet for a while, because it was less convenient for patients and their families who had to adhere in a strict regimen and show compliance with its rules. The diet experienced its resurgence at the beginning of the 1990s. Although many children responded well to conventional anti-epileptic drugs, still a substantial number was experiencing intractable epileptic seizures due to ineffectiveness, whilst potential toxicity from multiple AED was another reason for this resurgence.
The classic KD starts with an initial period of fasting and fluid restriction until ketone bodies appear in the urine, followed by the introduction usually of high-fat (80%), adequate-protein (15%), low-carbohydrate foods (5%).

The diet is inadequate in trace elements, minerals and certain vitamins and thus supplementation is necessary in order to avoid nutritional deficiencies.
Most of the studies show that the diet should be maintained for 2 years and then slowly withdrawn over a 6–9-month period. After this period, consumption of a regular diet is less likely to reinitiate seizure activity, but knowing that only approximately 10% of the children on the diet become seizure-free it is difficult to adapt to such a decision.

The ketogenic diet in children with epilepsy. 2006

MECHANISMS OF ACTION

The mechanism of effect of ketosis on seizures is not understood. Various theories have postulated that:
1) there is a direct stabilizing effect of ketone bodies on the central nervous system;
2) resulting acidosis accompanying ketosis modifies the seizure threshold;
3) changes in fluid and electrolyte balance result in reduced seizures;
4) change in lipid concentration induced by the diet has an anti-seizure effect.

Ketogenic Diet for the Treatment of Refractory Epilepsy in Children: A Systematic Review of Efficacy. 2000

One of the possible mechanisms of action is the increase of brain glutamic acid decarboxylase-65 and -67 expression induced by calorie-restricted ketogenic diet. In fact glutamic acid decarboxylase (GAD) is the rate-limiting enzyme in γ-aminobutyric acid synthesis , which levels are decreased in animal models of epilepsy.
In a recent study brain GAD levels were evaluated in a well-established, seizure-suppressing, rodent model of the ketogenic diet. Because the diet is most effective when administered with a modest (approximately 10%) calorie restriction, it has been studied three groups of animals: rats fed ad libitum standard rat chow (Ad lib-Std); calorie-restricted standard chow (CR-Std); and an isocaloric, calorie-restricted ketogenic diet (CR-Ket). It has been found that GAD67 mRNA was significantly increased in the inferior and superior colliculi and cerebellar cortex in both CR diet groups compared with control (e.g., by 45% in the superior colliculus and by 71% in the cerebellar cortex; P <.001). GAD65 mRNA was selectively increased in the superior colliculus and temporal cortex in both CR-Std and CR-Ket diet groups compared with ad lib controls. The only apparent CR-Ket-specific effect was a 30% increase in GAD67 mRNA in the striatum (P =.03). Enhanced GAD immunoreactivity was detected in parallel with the mRNA changes. These data clearly show that calorie restriction increases brain GAD65 and -67 expression in several brain regions, independent of ketogenic effects. These observations may explain why caloric restriction improves the efficacy of the ketogenic diet in treating epilepsy and suggest that diet modification might be useful in treatment of a number of brain disorders characterized by impaired GAD or GABA activity.

Caloric restriction augments brain glutamic acid decarboxylase-65 and -67 expression. 2004

Other studies point out the role of BAD protein, a protein involved in apoptosis and glucose metabolism.
BAD imparts reciprocal effects on metabolism of glucose and ketone bodies in brain cells. These effects involve phosphoregulation of BAD and are independent of its apoptotic function. BAD modifications that reduce glucose metabolism produce a marked increase in the activity of metabolically sensitive K(ATP) channels in neurons, as well as resistance to behavioral and electrographic seizures in vivo. Seizure resistance is reversed by genetic ablation of the K(ATP) channel, implicating the BAD-K(ATP) axis in metabolic control of neuronal excitation and seizure responses.

BAD-dependent regulation of fuel metabolism and K(ATP) channel activity confers resistance to epileptic seizures. 2012

KETOGENIC DIET CONTRAINDICATIONS AND PATIENT SELECTION

Ketogenic diet is a dietary therapy that is mainly considered in patients that can't be cured with surgery and has been unsuccessfully treated with three or more anticonvulsant medications.
The best candidates are children, but there are evidences of efficacy of the diet also in adolescents and adults.
Patients that are initiating the ketogenic diet must be screened for disorders of fatty acid transport and oxidation. In fact, fatty acid metabolism disorders are the main contraindications for the tretment.
Absolute contraindications are:
1) Carnitine deficiency (primary)
2) Carnitine palmitoyltransferase (CPT) I or II deficiency
3) Carnitine translocase deficiency
4) β-oxidation defects
1) Medium-chain acyl dehydrogenase deficiency (MCAD)
2) Long-chain acyl dehydrogenase deficiency (LCAD)
3) Short-chain acyl dehydrogenase deficiency (SCAD)
4) Long-chain 3-hydroxyacyl-CoA deficiency
5) Medium-chain 3-hydroxyacyl-CoA deficiency.
5) Pyruvate carboxylase deficiency
6) Porphyria
Relative contraindications are:
1) Inability to maintain adequate nutrition
2) Surgical focus identified by neuroimaging and video EEG monitoring
3) Parent or caregiver noncompliance

Optimal clinical management of children receiving the ketogenic diet: Recommendations of the International Ketogenic Diet Study Group. 2009

EFFICACY OF KETOGENIC DIET

There are many studies proving the efficacy of the treatment, although they are only prospective uncontrolled and retrospective studies.
Authors from Johns Hopkins (where this treatment was first developed) reported the outcomes of 150 consecutive children 3, 6, and 12 months after initiating the diet, as well as their 3- to 6-year follow-up. With an intention-to-treat methodology, these 150 children (who had averaged 410 seizures per month and whose seizures had failed to adequately improve on a mean of 6.2 medications) had a dramatic outcome. Twelve months after initiating the diet, 7% of the children were seizure free, and another 20% had a 90% decrease in seizures. Three to 6 years later, 27% of these same children had few or no seizures. Most of them were now off the diet and on fewer or even no medications.
Since the 1920s, reports of efficacy have been remarkably consistent across all age groups, seizure frequencies, and international locations. In general, 10%–15% of children who initiated the diet were seizure free 1 year later, 30% had a >90% reduction in seizures, and 40% to 50% found that the diet was either too difficult to continue or insufficiently effective and therefore discontinued it during the first 6 months.

The Ketogenic Diet: One Decade Later. 2007

Systematic reviews support the efficacy of ketogenic diet. The studies indicated that some children report reduction in seizure frequency. The estimated rate for obtaining complete seizure control was 15.6% (95% confidence interval 10.4-20.8%) with 33% (95% confidence interval 24.3-41.8%) reporting greater than 50% reduction in seizures.

A Systematic Review of the Use of the Ketogenic Diet in Childhood Epilepsy. 2006

Ketogenic diet seems to be efficacious in reducing the frequency of seizures in childhood epilepsy. Moreover, the reduction in seizures is unlikely to be attributable to a placebo effect or to spontaneous improvement.

ADVERSE EFFECTS

Adverse effects of the KD only infrequently require the diet to be discontinued but are important for neurologists and pediatricians to recognize. Early-onset adverse effects associated with diet initiation include acidosis, hypoglycemia, gastrointestinal distress, dehydration, and lethargy. They are typically transient and easily managed and are minimized if patients are not fasted. Later adverse effects include dyslipidemia, kidney stones, and slowing of growth.
Deaths have been reported in patients on the diet, although it is unclear that any of the deaths have been a result of the diet.
It is clear that the success and safety of the diet are best achieved by the close supervision of the patient by an experienced team that includes the physician, the dietician, and, often, a nurse.

The Ketogenic Diet: One Decade Later, 2007

CONCLUSIONS

In summary, ketogenic diet is a safe and efficacious alternative treatment for children with refractory epilepsy. However, further studies, in particular prospective controlled studies, should be done to validate the efficacy of the treatment and to inquire the mechanisms of action of ketone bodies produced by the diet.

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