A comparison of the ability of a 4:1 ketogenic diet and a 6.3:1 ketogenic diet to elevate seizure thresholds in adult and young rats

PURPOSE: The pentylenetetrazol (PTZ) infusion test was used to compare seizure thresholds in adult and young rats fed either a 4:1 ketogenic diet (KD) or a 6.3:1 KD. We hypothesized that both KDs would significantly elevate seizure thresholds and that the 4:1 KD would serve as a better model of the KD used clinically. METHODS: Ninety adult rats and 75 young rats were placed on one of five experimental diets: (a) a 4:1 KD, (b) a control diet balanced to the 4:1 KD, (c) a 6.3:1 KD, (d) a standard control diet, or (e) an ad libitum standard control diet. All subjects were seizure tested by using the PTZ infusion test. Blood glucose and beta-hydroxybutyrate (beta-OHB) levels were measured. RESULTS: Neither KD elevated absolute "latencies to seizure" in young or adult rats. Similarly, neither KD elevated "threshold doses" in adult rats. In young rats, the 6.3:1 KD, but not the 4:1 KD, significantly elevated threshold doses. The 6.3:1 KD group showed poorer weight gain than the 4:1 KD group when compared with respective controls. The most dramatic discrepancies were seen in young rats. CONCLUSIONS: "Threshold doses" and "latency to seizure" data provided conflicting measures of seizure threshold. This was likely due to the inflation of threshold doses calculated by using the much smaller body weights found in the 6.3:1 KD group. Ultimately, the PTZ infusion test in rats may not be a good preparation to model the anticonvulsant effects of the KD seen clinically, especially when dietary treatments lead to significantly mismatched body weights between the groups.     

Calorie restriction and ketogenic diet diminish neuronal excitability in rat dentate gyrus in vivo

PURPOSE: The ketogenic diet (KD) is an effective treatment for intractable epilepsy. However, little is known about its underlying mechanisms. METHODS: In this study, in vivo extracellular field responses to angular bundle stimulation were recorded in the dentate gyrus of Sprague-Dawley rats fed one of three diets: ketogenic calorie-restricted (KCR), normal calorie-restricted (NCR), or normal ad libitum (NAL). Input/output curves and paired-pulse relations were used to assess network excitability. A maximal dentate activation (MDA) protocol was used to measure electrographic seizure threshold and duration. RESULTS: Animals fed calorie-restricted (CR) diets exhibited greater paired-pulse inhibition, an elevated MDA threshold, and an absence of spreading depression-like events compared with ad libitum-fed controls. In the MDA model of epileptogenesis, the rate of increase in electrographic seizure duration after repeated stimuli was markedly reduced in KCR-fed animals compared with NCR- and NAL-fed controls. CONCLUSIONS: These data suggest that CR, by itself, can be anticonvulsant, and treatment with a KCR diet may be both anticonvulsant and antiepileptogenic.     

Tonic and atonic seizures: Medical therapy and ketogenic diet

Tonic and atonic seizures are typically seen in what are often referred to as the catastrophic epilepsies. In simply considering what each of the terms signifies (either the complete loss of tone or a marked increase in tone), they would appear to be at the most diverse ends of the spectrum. They would appear to be as opposite as hot and cold or hard and soft. And yet they are often found to occur in the same patient. This article examines the nature of these seizures and discusses some of the syndromes in which they are seen. Although these seizures are often very difficult to control, some of our medications/therapies have been shown to be effective. Recommendations concerning the efficacy of these therapies and a review of the newer therapies are provided. In addition, the ketogenic diet has been particularly successful in treating these seizures; this is discussed in some detail. Finally, although outcomes for these children are generally less than ideal, many can be helped with a persistent approach that balances seizure control against the side effects of medication.     

The anticonvulsant activity of acetone, the major ketone body in the ketogenic diet, is not dependent on its metabolites acetol, 1,2-propanediol, methylglyoxal, or pyruvic acid

BACKGROUND: Acetone, one of the principal ketone bodies elevated during treatment with the ketogenic diet, exhibits anticonvulsant properties that may contribute to the seizure protection conferred by the diet. The anticonvulsant mechanism of acetone is unknown, but it is metabolized to several bioactive substances that could play a role. METHODS: Acetone and its major metabolites-acetol, 1,2-propanediol, methylglyoxal, and pyruvic acid-were assessed for anticonvulsant activity in two mouse seizure models. Various doses of the substances administered intraperitoneally were characterized for their ability to elevate the threshold for clonic seizures induced by intravenous infusion of pentylenetetrazol (PTZ) and for protection against tonic seizures induced by subcutaneous bolus administration of 4-aminopyridine (4-AP). The inverted-screen test was used to assess acute neurological toxicity. RESULTS: Acetone (1-32 mmol/kg, i.p.), in a dose-dependent fashion, elevated the PTZ threshold and conferred protection against 4-AP seizures (ED(50), 26.3 mmol/kg). Effective doses of acetone (10-32 mmol/kg) did not cause motor impairment in the inverted-screen test (TD(50), 45.7 mmol/kg). In doses 10-fold greater than the minimally effective dose of acetone (3.2 mmol/kg), the metabolites acetol, 1,2-propanediol, and pyruvic acid were inactive in the PTZ model. At higher doses that produced motor impairment, acetol and 1,2-propanediol (but not pyruvic acid) did elevate the PTZ threshold. Methylglyoxal had both proconvulsant and anticonvulsant actions, and had substantial toxicity, producing respiratory distress, motor impairment, and death. None of the acetone metabolites protected against 4-AP seizures. CONCLUSIONS: This study confirms the broad-spectrum anticonvulsant properties of acetone and indicates that the seizure protection conferred is unlikely to result from its major metabolic products.     

Efficacy of the ketogenic diet in the 6-Hz seizure test

PURPOSE: Since the ketogenic diet is effective in drug-resistant epilepsies, we sought to determine whether it is active in the 6-Hz seizure test, which identifies agents with a broader spectrum of activity than conventional antiepileptic screening tests. METHODS: Male (3-4 week old) NIH Swiss mice were fed a normal or ketogenic diet ad libitum for 2-21 days. The intensity of the corneal stimulation current required to elicit seizures in the 6-Hz test was measured. Blood glucose and beta-hydroxybutyrate were measured on the day of seizure testing. RESULTS: CC(50) (current intensity producing seizures in 50% of mice tested) was 50.6 mA and 15 mA in mice fed for 12 days with a ketogenic or normal diet, respectively (p < 0.001). CC(50) was elevated in separate experiments after 16, but not 2, 5, and 21 days of ketogenic diet exposure. CC(50) values of growing mice fed the normal diet does not differ, indicating CC(50) does not vary with mouse weight during a rapid growth phase. beta-Hydroxybutyrate was significantly higher, and glucose was significantly lower in mice fed the ketogenic diet than those fed the normal diet. Blood glucose and beta-hydroxybutyrate levels did not correlate with CC(50). DISCUSSION: The ketogenic diet significantly elevates the seizure threshold in the 6-Hz test in a time-specific manner. Protection from seizures in this model was not related to level of ketosis. CC(50) was insensitive to body weight in mice fed the normal diet, demonstrating that the 6-Hz model can assess anticonvulsant regimens where weight is a confounding factor.     

Dietary fat, ketosis, and seizure resistance in rats on the ketogenic diet

PURPOSE: Fat is the major component of the ketogenic diet (KD), yet no studies have examined whether the type of fat used in the diet can be optimized to provide additional benefits. The purpose of the present experiments was to compare the efficiency of different fats in inducing ketosis and affording seizure resistance. METHODS: The effects of KDs that incorporate lard, butter, medium-chain triglycerides (MCT), or flaxseed oil or a mixture of the latter three fats were examined in rats fed KD for up to 98 days. The maximal electroshock (MES) or pentylenetetrazole (PTZ) threshold tests were used to assess seizure susceptibility in two separate experiments. RESULTS: The rank order of induced ketosis was MCT > mixture > or = flaxseed oil > or = lard = butter > or = control. MES failed to reveal anticonvulsant effects, but the PTZ test indicated that up to 50% of rats fed the KD were seizure protected (p < 0.05). The measures of seizure protection, seizure incidence and score, did not correlate, however, with the level of ketosis in the range of 0. 7-5.2 mmol/L for beta-hydroxybutyrate. In the long-term study, flaxseed oil KD maintained stable ketosis throughout 98 days, whereas ketones declined with lard and butter KD to the control level. CONCLUSIONS: Seizure protection with the versions of the KD did not improve with the higher level of ketosis. The focus of the KD improvement, therefore, is not the achievement of higher ketosis per se but rather designing a diet that provides steady ketosis, exploits advantages of certain fats for neurological development or seizure protection via a nonketogenic mechanism, and is nutritionally balanced.     

The ketogenic diet: adolescents can do it,too

PURPOSE: To determine both the efficacy of and compliance with the ketogenic diet in the adolescent population. METHODS: A retrospective study of 45 patients, aged 12-19 years, consecutively enrolled in a ketogenic diet program from 1994 to 2002, was performed. Thirty-seven patients were from The Johns Hopkins Medical Institutions; eight were from The University of Texas at Houston. Charts were reviewed, and patients were contacted by telephone. RESULTS: Six months after diet initiation, 28 (62%) of 45 remained on the ketogenic diet, with six (21%) of 28 having 50-90% seizure reduction, and eight (29%) of 28 having >90%. At 12 months, 20 (44%) of 45 remained on the diet, with seven (35%) of 20 having 50-90% seizure reduction and six (30%) of 20 achieving >90% efficacy. Only 22% discontinued the diet for perceived restrictiveness. The mean diet duration was 1.2 years. Patients with multiple seizure types did best, whereas gender, prior seizure frequency, diet ratio, and age did not influence outcome. Patients dependent on parents for daily care were more likely to remain on the diet at 6 months, but had less efficacy. Weight loss (60%) and menstrual dysfunction (45% of female subjects) were the most commonly reported side effects. CONCLUSIONS: The ketogenic diet is as well tolerated and efficacious for adolescents with epilepsy as for the general childhood population.     

Clinical aspects of the ketogenic diet

The ketogenic diet remains a valuable therapeutic option for patients with intractable epilepsy. Clinical aspects of the diet's success may provide insights into epileptogenesis and anticonvulsant action. The diet's efficacy has been established primarily through large case series. The diet has been used successfully in patients with many different epilepsy syndromes in countries around the world. Potential adverse effects can be avoided with careful attention during the diet's initiation and maintenance phases. In the last decade, variations to the classical ketogenic diet have been utilized. Ketogenic diets now are being used for diseases other than epilepsy. This critical analysis of the diet should provide the impetus for further clinical and basic research into the diet's application and mechanisms of action.     

Long-term follow-up of the ketogenic diet for refractory epilepsy: Multicenter Argentinean experience in 216 pediatric patients

Purpose

In this Argentinean retrospective, collaborative, multicenter study, we examine the efficacy and tolerability of the ketogenic diet (KD) for different epilepsy syndromes.

Materials and methods

we evaluated the clinical records of 216 patients started on the KD between March 1, 1990 and December 31, 2010.

Results

One hundred forty of the initial patients (65%) remained on the diet at the end of the study period. Twenty-nine patients (20.5%) became seizure free and 50 children (36%) had a 75–99% decrease in seizures. Thus, 56.5% of the patients had a seizure control of more than 75%. The best results were found in patients with epilepsy with myoclonic-astatic seizures, Lennox–Gastaut syndrome, and West syndrome. Good results were also found in patients with Dravet syndrome, in those with symptomatic focal epilepsy secondary to malformations of cortical development, and in patients with tuberous sclerosis. Seizures were significantly reduced in four patients with fever-induced refractory epileptic encephalopathy in school-age children and in two patients with epileptic encephalopathy with continuous spikes and waves during slow sleep. The median period of follow-up after discontinuation of the diet was 6 years. Twenty patients who had become seizure free discontinued the diet, but seizures recurred in five (25%). Of 40 patients with a seizure reduction of more than 50% who discontinued the diet, 10 presented with recurrent seizures.

Conclusion

The ketogenic diet is a good option in the treatment of refractory epilepsy. After discontinuing the diet, seizures recurrence occurred in few patients.     

Ketogenic diet exhibits neuroprotective effects in hippocampus but fails to prevent epileptogenesis in the lithium‐pilocarpine model of mesial temporal lobe epilepsy in adult rats

Purpose: Although the number of antiepileptic drugs (AEDs) is increasing, none displays neuroprotective or antiepileptogenic properties that could prevent status epilepticus (SE)–induced drug‐resistant epilepsy. Ketogenic diet (KD) and calorie restriction (CR) are proposed as alternative treatments in epilepsy. Our goal was to assess the neuroprotective or antiepileptogenic effect of these diets in a well‐characterized model of mesial temporal lobe epilepsy following initial SE induced by lithium‐pilocarpine in adult rats. Methods: Seventy‐five P50 male Wistar rats were fed a specific diet: normocalorie carbohydrate (NC), hypocalorie carbohydrate (HC), normocalorie ketogenic (NK), or hypocalorie ketogenic (HK). Rats were subjected to lithium‐pilocarpine SE, except six NC to constitute a control group for histology (C). Four rats per group were implanted with epidural electrodes to record electroencephalography (EEG) during SE and the next six following days. From the seventh day, the animals were video‐recorded 10 h daily to determine latency to epilepsy onset. Neuronal loss in hippocampus and parahippocampal cortices was analyzed 1 month after the first spontaneous seizure. Results: After lithium‐pilocarpine injection, neither KD nor CR modified SE features or latency to epilepsy. In hippocampal layers, KD or CR exhibited a neuroprotective potential without cooperative effect. Parahippocampal cortices were not protected by the diets. Conclusion: The antiepileptic effect of KD and/or CR is overwhelmed by lithium‐pilocarpine injection. The isolated protection of hippocampal layers induced by KD or CR or their association failed to modify the course of epileptogenesis.     

The outcome of children with intractable seizures: a 3- to 6-year follow-up of 67 children who remained on the ketogenic diet less than one year

PURPOSE: To determine the long-term outcome of children with difficult-to-control seizures who remained on the ketogenic diet for <1 year. METHODS: Between 1994 and 1996, 150 children with epilepsy, refractory to at least two medications, initiated the ketogenic diet according to the Hopkins protocol. Three to six years after diet initiation, all the families were contacted by telephone or questionnaire to assess their child's current seizure status, medications, and therapies. RESULTS: Sixty-seven children discontinued the diet within 1 year of initiation. Follow-up data were available for 54 of these children. Ten subsequently had surgery, and three underwent VNS implantation. These operated-on children were significantly more likely to be >50% controlled at follow-up than were those managed with medications alone (p < 0.05). A statistically significant difference in long-term outcome was noted between those who responded while on the diet, even if they discontinued it before 1 year, and those who did not (p < 0.05), but no statistical correlation was found between length of time that they had remained on the diet and long-term prognosis. CONCLUSIONS: Almost half of the children who discontinued the diet during the first year had a decrease in seizures when assessed 3-6 years later. Twenty-two percent of these had become seizure free without surgery. We were unable to ascertain whether this may have been due to new medications. Those who saw some improvement while on the diet were more likely to have a favorable long-term outcome. Resective surgery, in children who were candidates, or vagal nerve stimulation (VNS) implantation, was more likely to result in significant seizure improvement than was management with medications alone. Whether or not the diet was effective, most families did not regret trying it and would recommend it to others.     

生酮饮食治疗癫痫的神经保护作用

近年来抗癫痫药物(AEDs)得到很大的发展和深入研究,但AEDs治疗通常面临着很多显著的副作用,仍有很多类型的癫痫无法控制.19世纪90年代以来,生酮饮食(ketogenic diet,KD)已成为有效治疗癫痫的方法之一,尤其是在难控制的癫痫和减少药物副作用方面。研究表明,对于儿童难治性癫痫的治疗,KD比AEDs更为有效.KD是一种营养均衡的以脂肪为主的饮食,已被FDA认证并列为控制儿童顽固性癫痫的医疗食品.本文就KD用于治疗癫痫的神经保护作用进行综述.     

Anterior thalamic mediation of experimental seizures: selective EEG spectral coherence

PURPOSE: Physiological evidence has shown that the anterior thalamus (AN) and its associated efferents/afferents constitute an important propagation pathway for pentylenetetrazol (PTZ)-mediated generalized seizures in rodents. Previous work demonstrated metabolic, physical, chemical, and electrical stimulation data supporting a role for AN in the expression of PTZ seizures. We now extend these observations through examination of neuroelectric signal indicators during seizure epochs. We show that the EEG recorded from AN is highly coherent with surface cortical (CTX) EEG during the immediate preconvulsant period and during the ictal stateough. METHODS: Awake rats were continuously infused with PTZ until clonic seizures were recorded by using both subcortical AN, posterior thalamus (PT), or hippocampal (HPC) bipolar electrodes and cortical EEG. Through the signal-analysis techniques of ordinary and partial coherence, it was possible to focus selectively on signal correlations between AN and CTX (AN/CTX) by removing the effects of unaffiliated regions such as PT and HPC. RESULTS: Coherence of PT/CTX was observed to be modest, and partial coherence of PT/CTX with the effects of AN/CTX removed did not improve the signal coherence of PT/CTX (PT/CTX-AN). In contrast, AN/CTX coherence was observed to be high, with undiminished correlation when PT/CTX influence was removed (AN/CTX-PT). The most robust band of AN/CTX coherence was centered around the spike-wave clonic frequency of 1-3 Hz. Partial multiple coherence-analysis techniques were used to remove the possible signal contributions from hippocampus in addition to PT. The AN/CTX coherence remained fully preserved in the low-frequency bands. CONCLUSIONS: These data provide electrophysiologic evidence supporting the special role of the anterior thalamus in the propagation of seizure activity between subcortex and cortex.     

Rational treatment options with AEDs and ketogenic diet in Landau-Kleffner syndrome: Still waiting after all these years

Antiepileptic drugs (AEDs) remain a first treatment approach in Landau-Kleffner syndrome (LKS) and related syndromes. In the current literature, only class IV evidence is available. Inclusion criteria and outcome parameters are ill-defined. Most commonly, valproate, ethosuximide, and/or benzodiazepines are used. More recent case series show that sulthiame and especially levetiracetam can be considered as effective drugs. Smaller studies also point to the ketogenic diet as a valuable treatment option in LKS.     

Effect of a ketogenic diet on autism spectrum disorder: A systematic review

Autism spectrum disorder (ASD) is primarily characterized by impaired social interaction and communication, as well as restricted repetitive behaviours and interests. The utilization of the ketogenic diet (KD) in different neurological disorders has become a valid approach over time, and recently, it has also been advocated as a potential therapeutic for ASD. A MEDLINE, Scopus and Cochrane search was performed by two independent reviewers to investigate the relationship between ASD and the KD in humans and experimental studies. Of the eighty-one potentially relevant articles, eight articles met the inclusion criteria: three studies with animals and five studies with humans. The consistency between reviewers was κ = 0.817. In humans, the studies mainly focused on the behavioural outcomes provided by this diet and reported ameliorated behavioural symptoms via an improved score in the Childhood Autism Rating Scale (CARS). The KD in prenatal valproic acid (VPA)-exposed rodents, as well as in BTBR and Mecp2 mice strains, resulted in an attenuation of some autistic-like features. The limited number of reports of improvements after treatment with the KD is insufficient to attest to the practicability of the KD as a treatment for ASD, but it is still a good indicator that this diet is a promising therapeutic option for this disorder.     

Efficacy and tolerability of the ketogenic diet according to lipid:nonlipid ratios--comparison of 3:1 with 4:1 diet

PURPOSE: The ketogenic diet (KD) has been considered a highly potent antiepileptic treatment for intractable childhood epilepsy. In this study, we compared the antiepileptic efficacy and diet tolerability of two different diets with lipid:nonlipid ratios of 3:1 and 4:1. METHODS: Seventy-six patients with refractory childhood epilepsy were randomly placed into two groups and were started on KD diets with nonlipid:lipid ratios of either 3:1 or 4:1. Antiepileptic efficacy and diet tolerability were evaluated 3 months after initiating the diet. Patients showing seizure-free outcome with the 4:1 diet were changed to the 3:1 diet, and those without a seizure-free outcome on the 3:1 diet were changed to the 4:1 diet, for three more months, after which time their progress was monitored. RESULTS: (1) Antiepileptic efficacy was higher for the 4:1 than the 3:1 diet (p < 0.05). Twenty-two (55.0%) of 40 patients on the 4:1 diet and 11 (30.5%) of 36 patients on the 3:1 diet became seizure free. Seizure reduction of over 90% was observed in 2 (5.0%) patients on the 4:1 diet, and 2 (5.6%) on the 3:1 diet. (2) Dietary tolerability was better for the 3:1 than the 4:1 diet. Gastrointestinal symptoms were observed in 5 (13.9%) patients with the 3:1 diet and 14 (35.0%) patients with the 4:1 diet (p < 0.05). (3) For seizure-free patients who started on the 4:1 diet, antiepileptic efficacy was maintained after changing to the 3:1 diet, while 10 (83.3%) of 12 patients who were not seizure free with the 3:1 diet showed increased seizure reduction after changing to the 4:1 diet. (4) Complications from the KD and laboratory data were not significantly different between the two groups. CONCLUSIONS: The 4:1 KD showed greater antiepileptic efficacy than the 3:1 diet with higher seizure-free outcome. In most cases, seizure free outcome was maintained even after changing the ratio to 3:1. Dietary tolerability was better in the 3:1 diet than the 4:1 with less frequent gastrointestinal symptoms.     

The ketogenic diet for intractable epilepsy in adults: preliminary results

PURPOSE: Little is known concerning the efficacy and adverse effects of the ketogenic diet in adults with refractory epilepsy. This review reports preliminary results in 11 adults prospectively treated with the diet who had previously failed to gain seizure control with two or more medications and/or surgery. METHODS: Eleven patients nine women, two men), median age, 32.2 years (range, 19-45 years) were treated with the ketogenic diet with a 4:1 ratio with fluid restriction. Six patients had symptomatic partial epilepsy, and five had symptomatic generalized epilepsy. The diet was administered in addition to antiepileptic medication by a multidisciplinary team geared exclusively to adult patients. Medications were not changed while on the diet. Seizure frequency at 8-month follow-up was compared with frequency during a baseline period. RESULTS: At 8 months of follow-up, three patients had a 90% seizure decrease, three patients had a 50-89% decrease in seizure frequency, one patient had <50% seizure decrease, and four patients discontinued the diet. Of the four patients who discontinued the diet, two had no appreciable change in their seizures despite high ketone levels. Two patients were unable to maintain persistent ketosis at home, despite having done so in the hospital. All seizure types responded to the diet. Common adverse effects included constipation and menstrual irregularities in women. Most patients reported a subjective improvement in concentration. Serum cholesterol and triglycerides increased while on the diet as well as cholesterol high-density lipoprotein (HDL) ratios. CONCLUSIONS: The ketogenic diet shows promise in both adult generalized and partial epilepsy. Persistent ketosis was possible in adults, and the diet was tolerable for most patients. Further study assessing the efficacy of the ketogenic diet, and the cognitive and long-term effects is ongoing.     

The effect of the 'classic' ketogenic diet on animal seizure models

Bough et al. have recently demonstrated anticonvulsant effects of the 'classic' ketogenic diet (KD) in the pentylenetetrazol infusion model in rats. Proconvulsant effects were seen, however, when the 'classic' diet was tested against maximal electroshock (MES) seizures. These differing results may reflect the fact that the two models involve different kinds of epileptogenic stimulus, or, as Bough et al. note that the two tests involve different stimulation paradigms. The pentylenetetrazol infusion paradigm is a threshold test, whereas the MES test employs a stimulus which is well above threshold. The present experiments were designed to test the effects of the 'classic' KD against seizures triggered in rats by both threshold and suprathreshold levels of electricity and pentylenetetrazol. The threshold tests employed were the pentylenetetrazol infusion test, and the threshold electroconvulsive shock (ECS) test. The subcutaneous pentylenetetrazol (scMET) test was also included, since it is sometimes considered to be a 'threshold' test. The suprathreshold tests employed were the maximal pentylenetetrazol test (MMT) and the maximal electroshock test (MES). The KD failed to suppress seizures in either of the tests involving suprathreshold stimulation (MMT and MES), although there was a significant increase in latency in the MMT test. Small but significant threshold elevations (15-20%) were seen, however, in both the pentylenetetrazol infusion test and the ECS threshold test. No seizure suppression was seen in the scMET test, which actually employs a suprasthreshold stimulus. These data indicate that the KD has significant anticonvulsant effects against both chemically and electrically triggered seizures, but that they consist of small elevations in threshold which will be seen only when threshold measures are used.