The Ketogenic Diet Revisited: Beyond Ketones.

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Epilepsy is a neurological disease characterized by seizures, which affects up to 65 million people worldwide (1). About two-thirds of patients with epilepsy are able to achieve seizure control with current antiseizure medication (ASM) (2), whereas one-third of epilepsy patients are difficult to treat, i.e., patients with drug-resistant epilepsy (DRE). In addition, ASM can induce (serious) adverse events and a significant reduction of the quality of life (QoL), leading to ASM retention rates around 50% (3). DRE can induce neurobiochemical alterations and emotional and physical dysfunctions. The multifaceted status of DRE patients underscores the emphasis on non-pharmacological options, and therapies that target multiple mechanisms are likely to be more effective to treat DRE (4), thereby acting as a “magic shotgun” rather than a “magic bullet.” If epilepsy surgery is not an option in a patient with DRE, vagus nerve stimulation (VNS) (5) or dietary treatments, such as the ketogenic diet (KD), are valuable alternative options (5–7). Initial studies with dietary treatments report on the classical KD, consisting of 80% fat and 20% protein plus carbohydrate (4:1 KD) or 75% fat and 25% protein plus carbohydrate (3:1 KD) (8). A KD using medium-chain triglycerides (MCTs) leads to more ketones/kcal of energy and a more efficient absorption (9). Therefore, the MCT diet is less restrictive since it consists of a lower amount of fat and a higher intake of protein and carbohydrate (10). The modified Atkins diet (MAD) (11) and the low-glycemic index treatment (LGIT) (12) are other dietary therapies mimicking the seizure reduction result of the KD, but they are less restrictive. Clinical studies show that both modalities (VNS and KD) lead to a seizure frequency reduction (SFR) by at least 50% in half of the DRE patients. A recent study proposed a treatment algorithm for pediatric DRE, including non-pharmacological treatment options such as VNS and the KD (13). Interestingly, the KD therapy has some advantages in comparison to VNS: the SFR is slightly higher for patients on the KD (14); the KD is non-invasive, and there are few to no neurotoxic effects when compared to multiple ASM (6). Nevertheless, there are barriers and disadvantages in putting the KD into practice, such as palatability issues, compliance issues, side effects (usually mild), variable response rates, and restrictions to the daily life of the patient (15). Overall, a multidisciplinary team (pediatric neurologist, dietician/nutritionist, and a primary care-giver) is indispensable when dietary treatments are initiated and also during maintenance (16). Currently, we are unable to pinpoint the mechanism(s) of action of the KD, and it is possible that dietary therapies will be classified as “magic shotguns” (17–20). Therefore, our aim was to elaborate on the newest pathways involved, such as the gut microbiome and serine synthesis.