The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet.

The ketogenic diet (KD) is used to treat refractory epilepsy, but the mechanisms underlying its neuroprotective effects remain unclear. Here, we show that the gut microbiota is altered by the KD and required for protection against acute electrically induced seizures and spontaneous tonic-clonic seizures in two mouse models. Mice treated with antibiotics or reared germ free are resistant to KD-mediated seizure protection. Enrichment of, and gnotobiotic co-colonization with, KD-associated Akkermansia and Parabacteroides restores seizure protection. Moreover, transplantation of the KD gut microbiota and treatment with Akkermansia and Parabacteroides each confer seizure protection to mice fed a control diet. Alterations in colonic lumenal, serum, and hippocampal metabolomic profiles correlate with seizure protection, including reductions in systemic gamma-glutamylated amino acids and elevated hippocampal GABA/glutamate levels. Bacterial cross-feeding decreases gamma-glutamyltranspeptidase activity, and inhibiting gamma-glutamylation promotes seizure protection in vivo. Overall, this study reveals that the gut microbiota modulates host metabolism and seizure susceptibility in mice.

Effect of a Ketogenic Diet on Oxidative Posttranslational Protein Modifications and Brain Homogenate Denaturation in the Kindling Model of Epilepsy in Mice.

This study focused on the ketogenic diet (KD) effects on oxidative posttranslational protein modification (PPM) as presumptive factors implicated in epileptogenesis. A 28-day of KD treatment was performed. The corneal kindling model of epileptogenesis was used. Four groups of adult male ICR mice (25-30 g) were randomized in standard rodent chow (SRC) group, KD-treatment group; SRC + kindling group; KD + kindling group (n = 10 each). Advanced oxidation protein products (AOPP) and protein carbonyl contents of brain homogenates together with differential scanning calorimetry (DSC) were evaluated. Two exothermic transitions (Exo1 and Exo2) were explored after deconvolution of the thermograms. Factor analysis was applied. The protective effect of KD in the kindling model was demonstrated with both decreased seizure score and increased seizure latency. KD significantly decreased glucose and increased ketone bodies (KB) in blood. Despite its antiseizure effect, the KD increased the AOPP level and the brain proteome's exothermic transitions, suggestive for qualitative modifications. The ratio of the two exothermic peaks (Exo2/Exo1) of the thermograms from the KD vs. SRC treated group differed more than twice (3.7 vs. 1.6). Kindling introduced the opposite effect, changing this ratio to 2.7 for the KD + kindling group. Kindling significantly increased glucose and KB in the blood whereas decreased the BW under the SRC treatment. Kindling decreased carbonyl proteins in the brain irrespectively of the diet. Further evaluations are needed to assess the nature of correspondence of calorimetric images of the brain homogenates with PPM.

The ketogenic diet raises brain oxygen levels, attenuates postictal hypoxia, and protects against learning impairments.

OBJECTIVES: A prolonged vasoconstriction/hypoperfusion/hypoxic event follows self-terminating focal seizures. The ketogenic diet (KD) has demonstrated efficacy as a metabolic treatment for intractable epilepsy and other disorders but its effect on local brain oxygen levels is completely unknown. This study investigated the effects of the KD on tissue oxygenation in the hippocampus before and after electrically elicited (kindled) seizures and whether it could protect against a seizure-induced learning impairment. We also examined the effects of the ketone ß-hydroxybutyrate (BHB) as a potential underlying mechanism. METHODS: Male and female rats were given access to one of three diet protocols 2 weeks prior to the initiation of seizures: KD, caloric restricted standard chow, and ad libitum standard chow. Dorsal hippocampal oxygen levels were measured prior to initiation of diets as well as before and after a 10-day kindling paradigm. Male rats were then tested on a novel object recognition task to assess postictal learning impairments. In a separate cohort, BHB was administered 30 min prior to seizure elicitation to determine whether it influenced oxygen dynamics. RESULTS: The KD increased dorsal hippocampal oxygen levels, ameliorated postictal hypoxia, and prevented postictal learning impairments. Acute BHB administration did not alter oxygen levels before or after seizures. INTERPRETATION: The ketogenic diet raised brain oxygen levels and attenuated severe postictal hypoxia likely through a mechanism independent of ketosis and shows promise as a non-pharmacological treatment to prevent the postictal state.

The role of ketogenic diet in controlling epileptic seizures.

OBJECTIVES: To study the role of the ketogenic diet (KD) in controlling seizures in children with medically resistant epilepsy in Saudi Arabia. METHODS: This retrospective study was conducted in the Pediatric Neurology Clinic at a tertiary care epilepsy center. Thirty-one patients with medically resistant epilepsy were enrolled from 2013 to 2018. The seizure reduction variables were evaluated at 6, 12, 18 and 24 months after enrollment. RESULTS: Of the 31 patients, 14 (45.2%) were males and 17 (54.8%) were females. The most common types of seizures were myoclonic seizures and mixed seizures, both of which occurred in 9 (29%) of the participants. Of the participants, 15 (48.4%) had seizures one to 5 times per day. Six months after starting a KD, 2 (6.45%) of participants were seizure-free; 6 (19.35%) were seizure-free after 12 months of treatment. CONCLUSION: The present study highlighted the effectiveness of KD in medically resistant epilepsy children to local population. A larger cohort is warrant to confirm these findings.

Magnesium Supplementation did not affect the Antiseizure Property of Ketogenic Diet but Reduced Lipid Dysmetabolism.

BACKGROUND: Ketogenic diets (KD) have been used globally in epilepsy management. Similarly, supplementation of diets with magnesium has been associated with disease prevention and improvement. However, the effect of magnesium (Mg) supplementation in conjunction with KD on epilepsy has not yet been investigated. We hypothesized that magnesium supplementation in KD would improve the effectiveness of the diet. METHODS: Forty-eight male Wistar rats were used for the study. The animals were fed on 4 diet types: I-normal rat chow (ND), II-ND with Mg supplement (ND+Mg), III-medium chain ketogenic diet (KD) and IV-KD with Mg supplement (KD+Mg). Animals in each group were divided into 3: experimental, control and observatory. The experimental drug was intraperitoneal Pentylenetetrazole (PTZ) administered at 25 mg/kg. The rats were observed for 2 hours after the drug administration and induced seizures noted. The levels of serum electrolytes and plasma lipid levels were determined using standard methods. RESULTS: The seizure latency was significantly prolonged 60.8±0.5mins in group III compared with 8.7±2.1mins in group I (p<0.05). The seizure duration was 42.5±2.5mins in group III and 142.3±4.7 in group I (p<0.05). With Mg supplementation, seizure latency was 62.6±1.5mins in group IV and 7.9±0.7mins in group I (p<0.05). The seizure duration was 45.5±4.5min in group IV and 139.3±3.9mins in group II (p< 0.05). The KD-fed rats showed a tendency to develop dyslipidemia as evidenced by elevated Total Cholesterol /HDL and LDL/HDL (2.32±0.32 and 1.19±0.08) in group III, which was reversed in the KD+Mg fed group IV (1.96±0.32 and 1.08±0.09) with p<0.05. CONCLUSION: Mg supplementation of KD did not affect its antiseizure property and does not confer antiseizure effect on ND. Mg supplement showed a tendency to reduce derangement in lipid metabolism associated with KD.

Ketogenic and anaplerotic dietary modifications ameliorate seizure activity in Drosophila models of mitochondrial encephalomyopathy and glycolytic enzymopathy.

Seizures are a feature not only of the many forms of epilepsy, but also of global metabolic diseases such as mitochondrial encephalomyopathy (ME) and glycolytic enzymopathy (GE). Modern anti-epileptic drugs (AEDs) are successful in many cases, but some patients are refractory to existing AEDs, which has led to a surge in interest in clinically managed dietary therapy such as the ketogenic diet (KD). This high-fat, low-carbohydrate diet causes a cellular switch from glycolysis to fatty acid oxidation and ketone body generation, with a wide array of downstream effects at the genetic, protein, and metabolite level that may mediate seizure protection. We have recently shown that a Drosophila model of human ME (ATP61) responds robustly to the KD; here, we have investigated the mechanistic importance of the major metabolic consequences of the KD in the context of this bioenergetics disease: ketogenesis, reduction of glycolysis, and anaplerosis. We have found that reduction of glycolysis does not confer seizure protection, but that dietary supplementation with ketone bodies or the anaplerotic lipid triheptanoin, which directly replenishes the citric acid cycle, can mimic the success of the ketogenic diet even in the presence of standard carbohydrate levels. We have also shown that the proper functioning of the citric acid cycle is crucial to the success of the KD in the context of ME. Furthermore, our data reveal that multiple seizure models, in addition to ATP61, are treatable with the ketogenic diet. Importantly, one of these mutants is TPIsugarkill, which models human glycolytic enzymopathy, an incurable metabolic disorder with severe neurological consequences. Overall, these studies reveal widespread success of the KD in Drosophila, further cementing its status as an excellent model for studies of KD treatment and mechanism, and reveal key insights into the therapeutic potential of dietary therapy against neuronal hyperexcitability in epilepsy and metabolic disease.

Outcome of Nonketotic Hyperglycinemia in Lebanon: 14-Year Retrospective Review.

Nonketotic hyperglycinemia is a rare inborn error of glycine metabolism characterized by a severe metabolic encephalopathy with drug-resistant seizures. Here, we report the outcome of nonketotic hyperglycinemia in a cohort of patients diagnosed and followed-up at a tertiary care reference center in Lebanon, between 2000 and 2014.Eight out of 12 patients with nonketotic hyperglycinemia were retrospectively reviewed. The remainders were excluded for incomplete data. The majority of cases presented with seizures and hypsarrhythmia or burst suppression patterns. Half of the patients died. Survival varied between 7 days and 18 years. Seizures remained unresponsive with poor outcome, despite standard supportive care and antiepileptic therapy; however, two patients were responsive to ketogenic diet and one of them became seizure-free.Scarce data on the outcome of nonketotic hyperglycinemia patients from the Middle East and North Africa region are available. The ketogenic diet, in combination with standard therapies, appears to be effective in controlling the seizures in this devastating disorder. Larger multicenter studies are still needed to establish the role of the ketogenic diet in nonketotic hyperglycinemia.

Optimized mid-long term management of ketogenic diet in children with refractory epilepsy.

This study aims to explore the mid-long term management of ketogenic diet (KD) for the treatment of refractory epilepsy in children, and carry out an efficacy assessment. The data of epileptic children who received KD in our hospital from January 2011 to August 2012 (basic management plan group, n=57) were retrospectively analyzed. On this basis, epileptic children who received KD from September 2012 to April 2014 (optimized management plan group, n=52) were managed according to the mid-long term management plan. The effective rate of KD at the first, third, sixth and ninth month was 90.4%, 73.1%, 65.4% and 38.5%, respectively, in the optimized management plan group, and 63.2%, 45.6%, 38.6% and 21.1%, respectively, in the basic management plan group, and the differences were statistically significant. The compliance rate of KD at the third, sixth and ninth month was 94.2%, 78.8% and 63.5%, respectively, in the optimized management plan group, and 82.5%, 47.4% and 28.1%, respectively, in the basic management plan group, and the differences were statistically significant. Optimized mid-long term management of KD in children can improve the control rate of epileptic seizures, and the compliance of patients.

History of dietary treatment from Wilder's hypothesis to the first open studies in the 1920s.

In the ketogenic diet (KD) history, Wilder is often mentioned as the first author to report on the use of KD for patients with epilepsy. Our article aimed to understand how Wilder formulated the hypothesis of the KD effectiveness for patients with epilepsy, and how the KD was used and spread in the 1920s. In 1921, Wilder published two articles on the effects of ketonemia on epilepsy. He first reported on the interest of fasting for patients with epilepsy, suggesting that the benefits of fasting on seizures might be dependent on ketonemia. He then hypothesized that equally good results could be obtained with a KD, very rich in fat and very low in carbohydrate, which would provoke ketogenesis, and observed the effects of this diet on three patients for the first time. Following the publication of Wilder articles, 9 papers on KD were published during the 1920s, involving more than 400 patients with epilepsy. Ketogenic diet therapies (KDT) are now evidence-based treatments of epilepsy. Available experimental data do not confirm the role of ketosis as the unique mechanism of the KD. The KD is still explored to understand all the underlying mechanisms.

Modified ketogenic diets in adults with refractory epilepsy: Efficacious improvements in seizure frequency, seizure severity, and quality of life.

OBJECTIVE: This study evaluates the efficacy of a modified ketogenic diet (MKD) on seizure frequency, severity, and quality of life (QOL), as well as potential complications of MKD therapy among adults with drug-resistant epilepsy (DRE). METHODS: Changes in seizure frequency, severity, QOL, and side effects were retrospectively examined among adults, ≥17 years of age, with DRE (≥2 antiepileptic drugs [AEDs]), after 3 months of MKD therapy. Attention was paid to medication or vagus nerve stimulator (VNS) changes as well to evaluate potential confounders. RESULTS: A total of 60% (n = 33) of the 55 individuals reported ≥50% seizure frequency improvement, 42 (76%) reported improvement in seizure severity, and 48 (87%) reported improvement in QOL. More patients following a modified ketogenic diet - 15 g net carbohydrate daily (MKD-15) (95%) compared with a MKD-50 (69%) reported improvement in QOL (p = 0.02). Weight among the entire sample declined from 77.5 (20) kg to 73.9 (19.0) kg (p < 0.0001), and total cholesterol (TC), low density lipoprotein (LDL), and total cholesterol:high density lipoprotein (TC:HDL) increased significantly (p = 0.03, p = 0.04, and p = 0.02, respectively). Free carnitine values were available for a select number of patients, 26 (47%) at baseline, and 7 (13%) at follow-up, of which 8 (31%) at baseline, and 2 (29%) at follow-up had carnitine deficiency (<25 nmol/mL). Constipation was noted in 5 patients (9%), and no kidney stones were reported during the study period. There were no statistical differences in number or dose changes for AED or VNS during the study period. SIGNIFICANCE: Modified ketogenic diet therapies reduce seizure frequency and severity and improve QOL among adults with DRE with few side effects outside of weight loss, a desired outcome among many adults with DRE. More restrictive MKDs may offer improved seizure severity and QOL. Modified ketogenic diet therapy increases LDL cholesterol, which may be cardioprotective if related to an increase in LDL particle size with high saturated fat intake; however, more research is needed examining LDL particle size changes among those receiving MKD therapy.

Efficacy of the ketogenic diet in Chinese children with Dravet syndrome: A focus on neuropsychological development.

OBJECTIVES: In this retrospective study, we evaluated the efficacy of the ketogenic diet (KD) treatment in Chinese children with Dravet syndrome (DS) as well as its effect on neuropsychological development. METHODS: Twenty-six children (14 male) living with DS and being treated with KD at our department between July 2014 and December 2017 were enrolled in the study. The efficacy of KD was measured by seizure frequency before and after the diet. Additionally, children's neuropsychological development, as evaluated by the Gesell developmental schedule, was compared between the KD and a non-KD group. RESULTS: After 3, 6, 12, 18, 24, and 30 months, 92.3%, 84.6%, 46.2%, 30.8%, 19.2%, and 19.2% remained on the KD, while 38.4%, 34.6%, 38.4%, 23.0%, 15.4%, and 15.4% showed >50% reduction in seizure. The development age (DA) subscores of 12 children, as measured by the Gesell developmental schedule, increased after commencement of KD. However, children's development quotient (DQ) subscores (age-adjusted) decreased after KD. In the non-KD group (40 participants), an increase of DA subscores and decrease of DQ subscores were also observed. Results found no difference in changes of DQ subscores over time between the two groups. The DQ subscores after the diet in the KD group (20 participants) did not differ significantly when compared to the DQ subscores at same age in the non-KD group (20 patients) (t-test). CONCLUSIONS: The DA subscores of 12 children in KD group increased after KD; when compared with that of the non-KD group, no significant difference was observed in respect to the changes of DQ subscore over time. Effects on cognitive and other neuropsychological development outcomes of KD for children living with DS require further study.

Disturbed phospholipid metabolism in serine biosynthesis defects revealed by metabolomic profiling.

Serine biosynthesis defects are autosomal recessive metabolic disorders resulting from the deficiency of any of the three enzymes involved in de novo serine biosynthesis, specifically phosphoglycerate dehydrogenase (PGDH), phosphoserine aminotransferase (PSAT), and phosphoserine phosphatase (PSP). In this study, we performed metabolomic profiling on 4 children with serine biosynthesis defects; 3 with PGDH deficiency and 1 with PSAT deficiency. The evaluations were performed at baseline and with serine and glycine supplementation. Metabolomic profiling performed at baseline showed low phospholipid species, including glycerophosphocholine, glycerophosphoethanolamine, and sphingomyelin. All children had low serine and glycine as expected. Low glycerophosphocholine compounds were found in 4 children, low glycerophosphoethanolamine compounds in 3 children, and low sphingomyelin species in 2 children. Metabolic profiling with serine and glycine supplementation showed normalization of most of the low phospholipid compounds in the 4 children. Phospholipids are the major component of plasma and intracellular membranes, and phosphatidylcholine is the most abundant phospholipid of all mammalian cell types and subcellular organelles. Phosphatidylcholine is of particular importance for the nervous system, where it is essential for neuronal differentiation. The observed low phosphatidylcholine species in children with serine biosynthesis defects that improved after serine supplementation, supports the role of serine as a significant precursor for phosphatidylcholine. The vital role that phosphatidylcholine has during neuronal differentiation and the pronounced neurological manifestations in serine biosynthesis defects suggest that phosphatidylcholine deficiency occurring secondary to serine deficiency may have a significant contribution to the development of the neurological manifestations in individuals with serine biosynthesis defects.

Control of seizures by ketogenic diet-induced modulation of metabolic pathways.

Epilepsy is too complex to be considered as a disease; it is more of a syndrome, characterized by seizures, which can be caused by a diverse array of afflictions. As such, drug interventions that target a single biological pathway will only help the specific individuals where that drug's mechanism of action is relevant to their disorder. Most likely, this will not alleviate all forms of epilepsy nor the potential biological pathways causing the seizures, such as glucose/amino acid transport, mitochondrial dysfunction, or neuronal myelination. Considering our current inability to test every individual effectively for the true causes of their epilepsy and the alarming number of misdiagnoses observed, we propose the use of the ketogenic diet (KD) as an effective and efficient preliminary/long-term treatment. The KD mimics fasting by altering substrate metabolism from carbohydrates to fatty acids and ketone bodies (KBs). Here, we underscore the need to understand the underlying cellular mechanisms governing the KD's modulation of various forms of epilepsy and how a diverse array of metabolites including soluble fibers, specific fatty acids, and functional amino acids (e.g., leucine, D-serine, glycine, arginine metabolites, and N-acetyl-cysteine) may potentially enhance the KD's ability to treat and reverse, not mask, these neurological disorders that lead to epilepsy.

Synergistic protection against acute flurothyl-induced seizures by adjuvant treatment of the ketogenic diet with the type 2 diabetes drug pioglitazone.

OBJECTIVE: We have previously found that the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) contributes to the mechanism of action of the ketogenic diet (KD), an established treatment for pediatric refractory epilepsy. We have found that the KD increases brain PPARγ and that inhibition or genetic loss of PPARγ prevents the antiseizure effects of the KD on (1) acutely induced seizures in nonepileptic mice and (2) spontaneous recurrent seizures in epileptic mice. Here, we tested the hypothesis that adjuvant treatment of KD-treated mice with a PPARγ agonist, pioglitazone, would result in an additive effect. METHODS: Acute seizures were induced in three groups of C57Bl/6 mice by inhalation exposure to flurothyl gas. In Group 1, mice were weaned onto either a standard diet or KD comprised of a fat:carbohydrate/protein ratio of either 6:1, 3:1, or 1:1 for 2 weeks. In Group 2, vehicle or pioglitazone (0.1, 1, 10, 80 mg/kg) was administered 4 h prior to flurothyl exposure. In Group 3, vehicle or increasing doses of pioglitazone were administered to KD-treated mice 4 h prior to flurothyl exposure. Latency times to clonic seizures and generalized tonic-clonic (GTC) seizures were recorded, and isobolographic analysis was used to determine combinatorial interactions. RESULTS: Neither KD treatment nor pioglitazone alone or in combination affected clonic seizures. However, the latency to GTC seizures was dose-dependently and significantly increased by both KD (~57%, p < 0.05) and pioglitazone (~28%, p < 0.05). Coadministration of an ineffective 1:1 KD and pioglitazone resulted in ~47-55% (p < 0.05) increase in latency to GTC. Isobolographic analysis indicated a synergistic interaction of the KD and pioglitazone. SIGNIFICANCE: These results suggest coadministration may enable reduction of the KD ratio without loss of seizure protection. Such adjuvant treatment could improve quality of life and limit adverse effects of a classic KD or high-dose pioglitazone.

Ketone Bodies as Anti-Seizure Agents.

There is growing evidence that ketone bodies (KB)-derived from fatty acid oxidation and produced during fasting or consumption of high-fat diets-can exert broad neuroprotective effects. With respect to epilepsy, KB (such as ß-hydroxybutyrate or BHB, acetoacetate and acetone) have been shown to block acutely induced and spontaneous recurrent seizures in various animal models. Although the mechanisms underlying the anti-seizure effects of KB have not been fully elucidated, recent experimental studies have invoked ketone-mediated effects on both inhibitory (e.g., GABAergic, purinergic and ATP-sensitive potassium channels) and excitatory (e.g., vesicular glutamate transporters) neurotransmission, as well as mitochondrial targets (e.g., respiratory chain and mitochondrial permeability transition). Moreover, BHB appears to exert both epigenetic (i.e., inhibition of histone deacetylases or HDACs) and anti-inflammatory (i.e., peripheral modulation of hydroxycarboxylic acid receptor and inhibition of the NOD-like receptor protein 3 or NRLP3 inflammasome) activity. While the latter two effects of BHB have yet to be directly linked to ictogenesis and/or epileptogenesis, parallel lines of evidence indicate that HDAC inhibition and a reduction in neuroinflammation alone or collectively can block seizure activity. Nevertheless, the notion that KB are themselves anti-seizure agents requires clinical validation, as prior studies have not revealed a clear correlation between blood ketone levels and seizure control. Notwithstanding this limitation, there is growing evidence that KB are more than just cellular fuels, and can exert profound biochemical, cellular and epigenetic changes favoring an overall attenuation in brain network excitability.

Low glycemic index treatment for seizure control in Angelman syndrome: A case series from the Center for Dietary Therapy of Epilepsy at the Massachusetts General Hospital.

The low glycemic index treatment, a dietary therapy that focuses on glycemic index and reduced carbohydrate intake, has been successful in reducing seizure frequency in the general epilepsy population. Epilepsy is a common feature of Angelman syndrome and seizures are often refractory to multiple medications, especially in those with maternal deletions. Dietary therapy has become a more frequently used option for treating epilepsy, often in combination with other antiepileptic drugs, due to its efficacy and favorable side effect profile. This study aimed to assess the effectiveness of the low glycemic index treatment for seizure control in Angelman syndrome. Through a retrospective medical record review of 23 subjects who utilized the low glycemic index treatment at the Clinic and Center for Dietary Therapy of Epilepsy at the Massachusetts General Hospital, we found that the high level of seizure control and favorable side effect profile make the low glycemic index treatment a viable treatment for seizures in Angelman syndrome. The majority of subjects in our cohort experienced some level of seizure reduction after initiating the diet, 5 (22%) maintained complete seizure freedom, 10 (43%) maintained seizure freedom except in the setting of illness or non-convulsive status epilepticus, 7 (30%) had a decrease in seizure frequency, and only 1 (4%) did not have enough information to determine seizure control post-initiation. The low glycemic index treatment monotherapy was successful for some subjects in our cohort but most subjects used an antiepileptic drug concurrently. Some subjects were able to maintain the same level of seizure control on a liberalized version of the low glycemic index treatment which included a larger amount of low glycemic carbohydrates. No correlation between the level of carbohydrate restriction and level of seizure control was found. Few subjects experienced side effects and those that did found them to be mild and easily treated. The efficacy of the low glycemic index treatment and its favorable side effect profile make it an excellent alternative or supplement to antiepileptic drug therapy for the treatment of seizures in Angelman syndrome.

Dietary therapy for epilepsy. / Diettbehandling av epilepsi.

Children with pharmacoresistant epilepsy should be offered ketogenic dietary therapy. The diet, which is rich in fat and low in carbohydrate, has a beneficial effect in reducing seizures in this patient group. It may also have a beneficial effect in adults, but there is less evidence than in children. Dietary treatment of epilepsy is a specialist therapy, and in order to adhere to the diet, strong motivation of the patient and relatives as well as close follow-up from the specialist health service are necessary.

Six-month efficacy of the Ketogenic diet is predicted after 3 months and is unrelated to clinical variables.

OBJECTIVE: The aim of this study was to evaluate the 6-month efficacy of a Ketogenic diet (KD) in children with drug-resistant epilepsy and to analyze the associated factors that affect the efficacy of a KD. METHODS: Eighty-seven pediatric patients with drug-resistant epilepsy who followed a KD for at least 6 months were included in this study. The efficacy of a KD was assessed based upon the seizure frequency, as recorded by parents and caregivers. The number of cases and the degree of efficacy in different age ranges were also considered. The effects of gender, age, seizure type, etiology, blood glucose and ketone levels, seizure frequency before the diet, and cognition on the length of time on a KD were analyzed. RESULTS: (1) There was no significant correlation between the length of time on a KD and efficacy (χ(2)=2.31, P=0.51). The 3-month efficacy of a KD was 51%, which did not further increase when the course was extended to 6 months. (2) There was a positive correlation between increased cognition and the efficacy of a KD after 3 months (γ=0.31, P=0.003). (3) The efficacy analysis of 3-month treatment with a KD revealed, with respect to seizure types, that there were 37 patients with multiple seizure phenotypes and 50 patients with a single seizure phenotype. The overall efficacy of a KD in the group with multiple seizure phenotypes was 61%. The efficacy of a KD was not statistically associated with a coexisting syndrome or a type of syndrome; however, the efficacy of a KD had a tendency to be increased in certain types of syndromes. The overall efficacy in the group with a single seizure phenotype was 87%, and the efficacy was not associated with seizure type. (4) The 3-month efficacy of a KD was not correlated with age, gender, etiology, blood glucose or ketone levels, or the seizure frequency before treatment. CONCLUSION: An observation time of 3 months is appropriate for assessing the efficacy of a KD in treating children with drug-resistant epilepsy. The factors that likely influence the efficacy of a KD are unclear, but our study suggests that incorporating more patient samples will help determine whether patients with certain syndromes can benefit from a KD.

Rapid chain generation of interpostsynaptic functional LINKs can trigger seizure generation: Evidence for potential interconnections from pathology to behavior.

The experimental finding that a paroxysmal depolarizing shift (PDS), an electrophysiological correlate of seizure activity, is a giant excitatory postsynaptic potential (EPSP) necessitates a mechanism for spatially summating several EPSPs at the level of the postsynaptic terminals (dendritic spines). In this context, we will examine reversible interpostsynaptic functional LINKs (IPLs), a proposed mechanism for inducing first-person virtual internal sensations of higher brain functions concurrent with triggering behavioral motor activity for possible pathological changes that may contribute to seizures. Pathological conditions can trigger a rapid chain generation and propagation of different forms of IPLs leading to seizure generation. A large number of observations made at different levels during both ictal and interictal periods are explained by this mechanism, including the tonic and clonic motor activity, different types of hallucinations, loss of consciousness, gradual worsening of cognitive abilities, a relationship with kindling (which uses an augmented stimulation protocol than that used for inducing long-term potentiation (LTP), which is an electrophysiological correlate of behavioral makers of internal sensation of memory), effect of a ketogenic diet on seizure prevention, dendritic spine loss in seizure disorders, neurodegenerative changes, and associated behavioral changes. The interconnectable nature of these findings is explained as loss of function states of a proposed normal functioning of the nervous system.

The changing face of dietary therapy for epilepsy.

UNLABELLED: Ketogenic diet is an established and effective non-pharmacologic treatment for drug-resistant epilepsy. Ketogenic diet represents the treatment of choice for GLUT-1 deficiency syndrome and pyruvate dehydrogenase complex deficiency. Infantile spasms, Dravet syndrome and myoclonic-astatic epilepsy are epilepsy syndromes for which ketogenic diet should be considered early in the therapeutic pathway. Recently, clinical indications for ketogenic diet have been increasing, as there is emerging evidence regarding safety and effectiveness. Specifically, ketogenic diet response has been investigated in refractory status epilepticus and encephalopathy with status epilepticus during sleep. New targets in neuropharmacology, such as mitochondrial permeability transition, are being studied and might lead to using it effectively in other neurological diseases. But, inefficient connectivity and impaired ketogenic diet proposal limit ideal availability of this therapeutic option. Ketogenic diet in Italy is not yet considered as standard of care, not even as a therapeutic option for many child neurologists and epileptologists. CONCLUSIONS: The aim of this review is to revisit ketogenic diet effectiveness and safety in order to highlight its importance in drug-resistant epilepsy and other neurological disorders. WHAT IS KNOWN: • Ketogenic diet efficacy is now described in large case series, with adequate diet compliance and side effects control. • Ketogenic diet is far from being attempted as a first line therapy. Its availability varies worldwide. What is New: • New pharmacological targets such as mitochondrial permeability transition and new epileptic syndromes and etiologies responding to the diet such as refractory status epilepticus are being pointed out. • Ketogenic diet can function at its best when used as a tailor-made therapy. Fine tuning is crucial.