Efficacy of the ketogenic diet as the treatment for epilepsy

Literature Review Report
Efficacy of Ketogenic Diet as a Treatment for Epilepsy
Name of the Student
University
Efficacy of Ketogenic Diet as a Treatment for Epilepsy
1. Literature Review
1.1. Background
Anticonvulsant medications do not provide adequate cure in many patients with epilepsy. This is because either these drugs are not effective in controlling seizures or might lead to poor toleration profiles. One form of nutritional therapy called the “ketogenic diet,” has been associated with management of such epileptic cases1. The diet is used as an adjunct to the pharmacological interventions for controlling the episodes of seizure. The ketogenic diet is a high fat-low carbohydrate/protein diet and has been implicated for the control of seizures across various age groups of patients2. The ketogenic diet regime has to be complied strictly, to get benefit for control of seizures. However, the diet is not preferred by pediatric patients, due to its unpalatable nature2. The ketogenic ratio is described by the weight of fat divided by the combined weight of carbohydrate and protein in the diet. The ideal ratio is 4:1 for children below the age of eighteen months, or is older than 12 years. Individuals who are obese should be ideally planned at 3:1 ratio21.
1.2. Mechanisms of Action
The mechanisms that make ketogenic diet an important adjunct in control of seizures has been elucidated through various studies3. The ketogenic diet has been associated with a reduction of glutamic acid in the brain.

This amino acid is excitatory in nature and stimulates various post synaptic membranes in transmission of action potentials4. The ketogenic diet is speculated to limit the availability of oxaloacetate (an important intermediate of the TCA cycle), to the aspartate aminotransferase reaction4.
Due to the unavailability of oxaloacetate, glutamate is available for the glutamate decarboxylase reaction. This situation leads to the formation of GABA (Gamma Amino Butyric Acid), which is the inhibitory amino acid in the Central Nervous System4. Thus excess availability of GABA reduces the firing of the mossy fibers in the cerebellum. The mossy fiber output is excitatory and is the basis of seizures associated with epilepsy. Hence, inhibition of Mossy fiber output reduces the prevalence of seizures associated with epilepsy5.
It has been also shown, that ketogenic diet leads to the formation of glutamine. Glutamine is the precursor of GABA. The philosophy behind ketogenic diet is increased production of ketone bodies (which are acetoacetate, beta-hydroxybutyrate and acetone). The ketone body carbon gets metabolized to glutamine. Due to increased ketosis, acetate is readily available to the astrocytes (a form of glial cells) in the brain where it gets converted to glutamine. Hence, ketogenic diet helps to increase the pool of glutamine in the brain. This leads to increased production of GABA, which is necessary for the control of seizures5.
Recent studies have also documented that the low carbohydrate feature of ketogenic diet is responsible for the anticonvulsant activities. Such speculations stemmed from inhibition of glycolysis (reduced metabolism of carbohydrates) with iodoacetate or 2-deoxyglucose. The epileptic form electrical activities were reduced in brain slices, and it was anticipated that iodoacetate or 2-deoxyglucose, raised the threshold of seizures, in rats6,7. Studies have shown that high fat –low carbohydrate is also instrumental in modulating the enzymatic activity of Phosphoenolpyruvate carboxykinase (PEPCK)6,.
Phsophoenolpyruvate (PEP) is an essential intermediate of the glycolytic pathway. The decrease in cellular concentrations of PEP will lead to increased conversion of oxaloacetate to PEP. Thus increased activity of PEPCK will help in the conversion of GTP to GDP and reduce GTP/GDP ratio in the brain. Lowering of GTP will lead to decreased excitation of synaptic terminals and thus reducing the mossy fiber output. On the other hand, unavailability of oxaloacetate (through PEPCK reaction) to the aspartate aminotransferase reaction will cause glutamate, to be available for the glutamate decarboxylase reaction. Hence, increased GABA will be available for the control of seizures6.
A recent study indicated that the ketogenic diet component decanoic acid increases mitochondrial density and the enzymes citrate synthase and complex I of the electron transport chain. Such finding was correlated to the increase in seizure threshold. Decanoic acid was speculated to act as an agonist of peroxisome-proliferator-activated receptor alpha (PPARα)14.
1.3. Evidences of Anticonvulsant Efficacy
A randomized controlled trial was conducted with 145 children (aged 2 to 6 years), who had daily seizures and were non-respondent to two antiepileptic drugs for three months. Individuals were supplemented with ketogenic diet and the other arm was not given such diet (control). It was observed that the group of individuals who received ketogenic diet, had lower baseline seizures, compared to controls (62% versus 137% with p< 0.0001). In fact 28 children (38% of experimental) who received ketogenic diet had greater than 50% reduction in seizures compared to control group (6%). 7% individuals who received ketogenic diet had >90% seizure control. This study established the role of ketogenic diets in controlling the episodes of seizure compared to controls7.
There have been debates, as to the form in which ketogenic diet must be supplemented. It was believed that medium chain triglycerides are more potent sources of ketone bodies. However, a study conducted on 149 children with intractable epilepsy indicated that both classical and medium-chain triglyceride protocols are equally effective and safe in controlling the episodes of seizures in children13.
In a study on 26 children (mean age 6.1 years), the CSF levels of excitatory and inhibitory amino acids were assessed with ketogenic diet. The prevalence of seizures was also quantified. There was a significant increase in GABA, taurine, serine and glycine. On the other hand, ketogenic diet reduced the levels of asparagines, alanine, tyrosine and phenylalanine. The levels of arginine, threonine, citrulline, leucine, isoleucine and valine were unchanged. Threonine levels were significantly positively correlated (p= 0.016) with episodes of seizures. Individuals, who had a 50% reduction in their seizure episodes exhibited increased levels of GABA compared to non-responders with ketogenic diet (p =0.041)8.
In a study done on nine adult patients with refractory epilepsy, it was indicated that ketogenic diet did not significantly improve their seizure control. 6 out of 8 patients did not have significant control of seizures. However, the study concluded that since 2/8 patients had improved seizure controls with ketogenic diet, some patients might benefit from such regimes17.
A study was conducted with medium straight chain triglycerides (MCTs) compared to established epilepsy treatment with valproate. The study was carried out in pediatric patients who had intractable epileptic seizures. Histone deacetylase activity with valproate treatment was considered a teratogen. Therefore, the study also evaluated the safety profile of medium chain triglycerides compared to valproate. The diet comprised of medium chain triglycerides, which are commonly prescribed and also the scientists made certain combinations. The study indicated that medium chain triglycerides were more potent than valproate, caused less sedation than valproate and ensured enhanced neuroprotection. However, the exact mechanism of action of epilepsy control was not elucidated, but it was speculated that MCTs were carried by the hepatic portal system and provided ketone bodies to the brain19.
A recent study has also demonstrated that Branched Chain Amino Acids (BCAA) helps as an adjunct to ketogenic diet, in controlling seizures. 17 children, in the age range of 2 to 7 years, who had recurrent episodes of seizures even with ketogenic diet, were supplemented with BCAA. The addition of BCAA reduced the prevalence of seizures completely in 3 patients while most patients had a seizure reduction of 50% to 90%. Although the fat to protein ratio got changed (4:1 to 2.5:1), there was no reduction in ketosis. It was concluded that BCAA potentiated the effects of ketogenic amino acids9.
Molecular sensors have been implicated in programming of cellular metabolism in response to administered ketogenic diet. The sensors that were evaluated were peroxisome-proliferator-activated receptor alpha (PPARα). The ketogenic diet caused a switch to ketogenesis, with various modulations in cellular lipid, carbohydrate, amino acids and inflammatory pathways. Such modulations were implicated for the seizure control efficacy of ketogenic diet, and also for the activity of anti-epileptic drug, valproic acid10.
The ketogenic diet is considered an effective treatment option in refractory epilepsies in pediatric patients. The CA3 hippocampal regions of epileptic Kv1.1aknockout mice generated sharp pathologic waves and high-frequency oscillations (a model of epileptic seizures). These waves were prolonged and produced faster ripples and frequency compared to the general epileptic waves. The synaptic activity of the hyper excitable mossy fibers (in knockout mice model) significantly reduced the cell spike-timing activity in the CA3 cells (The basis of the epileptic model). Earlier studies demonstrated that there was a 75% reduction in episodes of seizures, in knockout mice, that were fed with ketogenic diet. It was observed that ketogenic diet caused significant attenuation of the spike –wave activity and reduced the episodes of fast ripples. The diet also improved the spike-timing reliability of the CA3 cells. The mossy fiber excitability was reduced and there was a significant reduction in coupling of postsynaptic potentials (trigger factor for seizures) and amount of spikes in the CA3 regions. Hence, KD diet was implicated to modify the CA3 generated oscillations by abatement of hyperactive mossy fiber synapses11. The KD diet was speculated to improve mitochondrial functions in the hippocampus region, which might be responsible for alleviation of seizures12,18.
In a recent study, a retrospective observational analysis was carried out with 60 patients, who had initiated ketogenic diet for refractory epilepsy. 24 individuals were assessed for the levels of neurotransmitters, pterins and amino acids in their cerebrospinal fluid. The mean age of the subjects were 24 months and 83.3% had focal epilepsies while in the rest the etiology was unknown. After six months of initiating ketogenic diet therapy, seizures were reduced (> 50% reduction in episodes of seizure) in 31.6% of patients. The levels of arginine and lysine were significantly correlated to ketogenic diet while the concentrations of pterins and biogenic amines were not altered significantly20.
1.4. Pros and Cons of Ketogenic Diet Therapy
Ketogenic diet does reduce the rate of glutamate transamination to aspartate (due to reduced availability of oxaloacetate), cause increased conversion of glutamate to GABA and also increases uptake of neutral amino acids, which are the possible mechanisms that reduce the episodes of seizures, in epileptic patients. The therapy is safe, but might be unpalatable to pediatric patients. However, in certain instances, the ketogenic diet was not sufficient for seizure reduction and had to be supplemented with BCAAs. Ketogenic amino acids reduced the mossy fiber outputs and this lead to a functional reduction of hyperactivity15,16. The diet has been evidenced through various studies to significantly reduce episodes of tremor15,16.
The ketogenic diet has been established as a safe regime and effective in epileptic seizures. However, the side effects and toleration profile were only related to high consumption of fat diets as in normal individuals, and also the common effects of high metabolism of fats compared to proteins or carbohydrates. No additional risk was noted in the short term modules. However long-term effects of such diets, have not been established in terms of safety profile22.
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