The exact mechanisms by which the ketogenic diet (KD) exerts its anti-seizure effects have not been elucidated. A number of different mechanisms (1) may contribute to the efficacy. These mechanisms include the role of ketone bodies, fatty acids, and limited glucose. Ketosis can modify the tricarboxylic acid cycle (Kreb’s cycle) to increase the production of the inhibitory neurotransmitter GABA, limit the production of reactive oxygen species, and increase brain energy production. The increase in polyunsaturated fatty acids following KD leads to an increase in uncoupling proteins and associated up-regulation of all the mitochondrial genes and mitochondrial biogenesis. As a result of limited glucose, enhanced oxidative phosphorylation, and reduced glycolytic flux, metabolic K(ATP) channels may be activated leading to hyperpolarized neurons. Studies have not established a correlation between ketone levels and efficacy (1) (Gilbert et al., 2000). It is thought that it is the adaptation to ketosis, rather than the ketosis itself, which is relevant to the antiepileptic effects of KD.



A number of gastrointestinal symptoms, particularly nausea and vomiting, are thought to be associated with ketosis, especially during the initiation phase. KD may also lead to cardiac complications. A study in 20 patients on KD found a significant correlation between prolonged QTc intervals and low bicarbonate and high beta-hydroxybutyrate levels (2). The ketone bodies, acetone, acetoacetate and beta-hydroxybutyrate, are highly acidic, and are probably the main contributory factors to the metabolic acidosis seen in many patients on KD. Renal stones, loss of bone mineral density and fractures are seen in patients on long term KD (3). Metabolic acidosis is probably the main cause of these adverse events (4, 5).



In a study, rats fed on KD had increased cerebral ATP/ADP ratio indicative of raised cerebral energy. It was proposed that this increase in energy may have produced neuronal stability required for seizure control (6). This increase in cerebral energy probably results from the effect of KD on mitochondrial biogenesis. A study in rats showed that those on KD had significantly greater mitochondrial density, and the mitochondria appeared to be metabolically more efficient (7). In support of this observation, another study in rats showed that KD resulted in an up-regulation of all (n = 34) transcripts encoding energy metabolism enzymes and 39 of 42 transcripts encoding mitochondrial proteins. This suggests that KD leads to mitochondrial biogenesis and enhanced energy stores (8). It is possible that the up-regulation of mitochondrial genes caused by KD can be long lasting and, although there is no experimental evidence, this may be the explanation for the observation that some people rendered seizure free on KDs remain seizure free even when the diet is withdrawn.



Caregiver issues and patients’ unwillingness to follow KD are reasons for discontinuation that are as common as the medical reasons of lack of efficacy or complications (9). One review suggests that between 7–15% of children with intractable epilepsy become seizure free, 25–40% have a 90% seizure reduction, and 55% have a >50% seizure reduction (10). It is possible that efficacy may be further improved by modifying KD to minimize features that are not necessary for efficacy and to focus attention on factors that may be critical for efficacy. On the basis that high levels of ketosis are not needed for efficacy and that ketosis and acidosis have potential negative effects, ASEK diet is formulated to control ketosis and acidosis. On the basis of the importance of mitochondrial beta-oxidation in KD, specific substrate is supportive of mitochondria; and attention should be paid to avoid inhibitors of mitochondrial function.




ASEK diet is formulated to achieve a fatty acid profile similar to that of human milk, limit ketosis, limit acidosis, and maximize mitochondrial function


Fatty acid profile of human milk

This is achieved by using butterfat (ghee) and full cream from the milk of pasture-fed cows, with additional fatty acids from eggs, meats, fish, nuts, seeds, and greens. The proportions of saturated, monounsaturated and polyunsaturated fatty acids (PUFAs); the proportions of pre-formed fatty acids: long- chain , medium- chain and short- chain; ratio of omega-6 to omega-3 fatty acids, all affect neuronal membrane homeostasis, structural elements in cells, and production of signaling compounds (11). Different lipids signal into a remarkable range of biological processes. Saturated and monounsaturated fatty acids are signal molecules. Potential synergies of the hundreds of fatty acids in human milk suggest that ASEK diet, by targeting  similar fatty acid composition, may be more therapeutic than KDs based on randomly selected fats (12).

Limit ketosis: a number of features help to limit ketosis

1) Ensure efficient beta-oxidation and adequate carnitine levels.
2) Avoid ketogenic effects of severe caloric restriction.
3) Limit higher proportion of medium-chain fatty acids and PUFAs, which are more ketogenic.
4) Maintain low normal glucose levels to support efficient transport of ketones into cells.

Limit acidosis: this is closely interdependent on limiting ketosis

1) Control degree of ketosis.
2) Avoid excessive amino acids.
3) Avoid acid products of peroxidation from excess PUFAs and highly unsaturated fatty acids (HUFAs).
4) Assure high intake of alkaline-ash producing green vegetables and citrate.

Ensure efficient mitochondrial function

1) Assure nutritional substrate for the various mitochondrial enzymes from specific balances of nutrient-dense whole foods.
2) Avoid, to the fullest extent possible, drugs, toxins, and pesticides that inhibit mitochondrial function.
3) Encourage regular exercise and stress management.



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