The impact of the ketogenic diet on arterial morphology and endothelial function in children and young adults with epilepsy: A case–control study

PurposeThe present study aimed to assess the impact of the ketogenic diet on arterial morphology and endothelial function of the big vessels of the neck and on cardiac diastolic function, in a cohort of epileptic children and young adults treated with the ketogenic diet.MethodsPatients were recruited based on the following inclusion criteria: (1) patients who were or had been on the ketogenic diet for a time period of at least six months. Each patient underwent measurement of carotid intima media thickness, carotid artery stiffness, echocardiography, and diastolic function assessment. Patients with drug resistant epilepsy, matched for number, age and sex and never treated with ketogenic diet, were recruited as controls.ResultsThe population study was composed by 43 epilepsy patients (23 males), aged between 19 months and 31 years (mean 11 years). Twenty-three patients were or had been treated with ketogenic diet, and 20 had never been on it (control group). Subjects treated with the ketogenic diet had higher arterial stiffness parameters, including AIx and β-index and higher serum levels of cholesterol or triglycerides compared to those who had never been on the diet (control group) (p < 0.001).ConclusionsArterial stiffness is increased in children and young adults treated with the ketogenic diet, before the increase of the intima media thickness. This supports that arterial stiffness is an early marker of vascular damage.     

Long‐term outcomes of children treated with the ketogenic diet in the past

Purpose: The ketogenic diet has well‐established short‐ and long‐term outcomes for children with intractable epilepsy, but only for those actively receiving it. However, no information exists about its long‐term effects years after it has been discontinued. Methods: Living subjects were identified who were treated at the Johns Hopkins Hospital with the ketogenic diet from November 1993 to December 2008 for ≥1 month, and had discontinued it ≥6 months prior to this study. Of 530 patients who were eligible, 254 were successfully contacted by phone or e‐mail with a survey and request for laboratory studies. Results: Questionnaires were completed by 101 patients, with a median current age of 13 years (range 2–26 years). Median time since discontinuing the ketogenic diet was 6 years (range 0.8–14 years). Few (8%) still preferred to eat high fat foods. In comparison to the 52% responder rate (>50% seizure reduction) at ketogenic diet discontinuation, 79% were now similarly improved (p = 0.0001). Ninety‐six percent would recommend the ketogenic diet to others, yet only 54% would have started it before trying anticonvulsants. Lipids were normal (mean total cholesterol 158 mg/dl), despite most being abnormal while on the ketogenic diet. The mean Z scores for those younger than age 18 years were ?1.28 for height and ?0.79 for weight. In those 18 years of age or older, the mean body mass index (BMI) was 22.2. Discussion: This is the first study to report on the long‐term effects of the ketogenic diet after discontinuation. The majority of subjects are currently doing well with regard to health and seizure control.     

Acute pancreatitis causing death in a child on the ketogenic diet

The ketogenic diet has demonstrated good efficacy in children with pharmacologically resistant seizures. Relatively few serious complications have been reported in the more than 70 years in which the diet has been used. We report a child who developed acute pancreatitis and died. A 9-year-old girl had a seizure disorder with associated developmental delay owing to glucose transport protein deficiency. The ketogenic diet with medium chain triglyceride oil had been initiated shortly after diagnosis in infancy. She was not on anticonvulsants. She presented in coma with decreased respiratory effort and shock, requiring resuscitation. Investigations were consistent with pancreatitis. Despite fluid resuscitation and inotropic support, she had prolonged hypotension and acidosis. She subsequently had a cardiac arrest and died. A postmortem examination confirmed hemorrhagic pancreatitis. Hypertriglyceridemia is a risk factor for developing acute pancreatitis. The high fat content of the ketogenic diet often causes hyperlipidemia. The outcome for this patient raises concern regarding a potential consequence of the ketogenic diet.     

Ketogenic diet: outpatient initiation, without fluid, or caloric restrictions

Although the ketogenic diet has been used for more than 80 years, the optimal methods of initiating the diet and its maintenance have not been clearly defined. This retrospective study was performed to review our experience with initiation of the ketogenic diet in the outpatient and inpatient settings and maintenance of the diet without fluid or caloric restriction. We analyzed 54 patients who had medically intractable epilepsy of whom 44% manifested some degree of mental retardation, 80% had multiple seizure types, and failed on average 4.8 antiepileptic drugs. Forty-four patients underwent induction of the ketogenic diet on an outpatient basis and 21 as inpatients. Three patients in each group were fasted at the initiation of the diet. No significant differences were observed with regard to seizure control in that 62% and 71% had greater than 50% improvement in the outpatient and inpatient groups, respectively. Both groups manifested improvement in alertness and social interaction. The efficacy of a ketogenic diet in the symptomatic epilepsies was confirmed, and benefit for medically refractory childhood absence epilepsy was documented. We conclude that a prospective, randomized trial is necessary to compare outpatient vs inpatient initiation of the ketogenic diet and the utility of fluid and caloric restriction.     

Tuberous sclerosis complex and the ketogenic diet

PURPOSE: Tuberous sclerosis complex (TSC) is a condition that is frequently associated with intractable, early-onset epilepsy, and often is first seen as infantile spasms. If medications fail and no clear epileptogenic tuber is identified, nonpharmacologic therapies are often attempted. The use of the ketogenic diet specifically for children with TSC and epilepsy has not been previously described. METHODS: A chart review was performed of patients with TSC treated with the ketogenic diet over a 5-year period at Johns Hopkins Hospital and Massachusetts General Hospital. RESULTS: Twelve children, ages 8 months to 18 years, were identified. Eleven (92%) children had a >50% reduction in their seizures at 6 months on the diet, and 8 (67%) had a >90% response. Five children had at least a 5-month seizure-free response. Diet duration ranged from 2 months to 5 years (mean, 2 years). CONCLUSIONS: In this limited-duration case series of 12 patients, the ketogenic diet was a generally effective therapeutic modality for the intractable epilepsy occasionally seen in children with TSC.     

Ketogenic diet in Rett syndrome

Treatment of Rett syndrome with the ketogenic diet has been reported only once and showed positive effects on seizure frequency and behavior. We report a patient with Rett syndrome who was treated with the ketogenic diet for 4 years. The diet was initiated at the age of 8 years owing to the patient's refractory epilepsy and led to a 70% reduction in seizures. Treatment with the ketogenic diet was also associated with improvements in contact and behavior. Diagnosis of Rett syndrome was confirmed by molecular detection of the Ser134Cys mutation in the MECP2 gene, which has previously been described only in classic Rett syndrome. This observation demonstrates that the ketogenic diet has a positive effect on Rett syndrome.     

Epilepsy of infancy with migrating focal seizures: three patients treated with the ketogenic diet

Aim. We present three patients with epilepsy of infancy with migrating focal seizures treated with the ketogenic diet. Methods. Between February 1, 2012 and January 31, 2014, three patients who met the diagnostic criteria for migrating focal seizures in infancy at our department were placed on the ketogenic diet and followed for a minimum of seven months. Results. Two of the three children responded well to the ketogenic diet. One of these patients became seizure‐free and his neuropsychological performance also significantly improved. The other child had a seizure reduction of 75% to 99% with only weekly seizures and moderate psychomotor improvement. For these two patients who responded well to the ketogenic diet, hospital admission was not required. The remaining patient had a seizure reduction of less than 50%. Tolerability of the diet was good in all three patients. Conclusion. Early treatment with the ketogenic diet should be considered for epilepsy of infancy with migrating focal seizures to control seizures and status epilepticus, and avoid progressive cognitive impairment.     

The ketogenic diet improves recently worsened focal epilepsy

Aim  We observed a dramatic response to the ketogenic diet in several patients with highly refractory epilepsy whose seizure frequency had recently worsened. This study aimed to identify whether this characteristic was a useful indication for the ketogenic diet.
Method  From the 70 patients who received the ketogenic diet during a 3-year period at our institution, we retrospectively selected patients with focal epilepsy. There were 22 children, 13 females and nine males, aged from 5 months to 18 years 6 months (mean 6y 9mo, SD 5y 11mo). Fifteen had symptomatic and seven had cryptogenic focal epilepsy. Seizure frequency 1 week before initiating the ketogenic diet was compared with that at 1 month and at the last visit on the diet.
Results  Eleven patients were responders (defined as reduction of seizures by more than 50%) at 1 month. Responders were higher ( p =0.046) in the group with a recent worsening of seizures than in those with stable seizure frequency. Seven patients were still seizure-free at 6 months on the diet. Tolerability was excellent in 10 patients. Five patients stopped the diet because of early side effects.
Interpretation  The ketogenic diet may be a valuable therapeutic option for children with pharmacoresistant focal epilepsy, particularly those with a recent deterioration of seizure control and neurological status. Because of its rapid effect, the ketogenic diet may be a useful support to intravenous emergency drugs in such a situation.     

The ketogenic diet and the QT interval

Cardiac complications have been rarely reported associated with the ketogenic diet. Prolonged QT interval in the electrocardiogram and torsades de pointes arrhythmias have been described in a few cases. The effect of the ketogenic diet on QT interval has not been systematically evaluated. We obtained serial electrocardiograms in our patients on the ketogenic diet to look for changes in the mean QT interval. Twenty seven children aged 6 months to 5 years with refractory epilepsy were enrolled. Classic ketogenic diet was introduced using a non-fasting gradual initiation protocol. All patients were supplemented with oral calcium and selenium. Electrocardiograms were obtained at baseline and after 1, 3, 6, and 12 months on the ketogenic diet. There was no statistically significant change in the corrected QT interval over time. There were no ST segment changes or dysrhythmias in any of the electrocardiograms.     

The use of the ketogenic diet in a patient with subacute sclerosing panencephalitis.

OBJECTIVE: To report on the effects of the ketogenic diet on a 9-year-old boy with myoclonic jerks due to subacute sclerosing panencephalitis (SSPE). METHODS: A 9-year-old boy presented with progressively worsening myoclonus unresponsive to valproic acid and clonazepam. He was started on the ketogenic diet maintaining urine ketones at greater than 80 mg x dl(-1). RESULTS: Within 2 weeks of dietary initiation, myoclonic jerks stopped. Four weeks later he developed cognitive slowing. Results of electroencephalogram and cerebrospinal fluid analysis were consistent with SSPE. Three months after ketogenic diet initiation, myoclonic jerks reappeared and were refractory to treatment. CONCLUSION: The ketogenic diet may be useful in controlling, even temporarily, the myoclonic jerks of SSPE.     

The impact of early versus late anticonvulsant reduction after ketogenic diet initiation

The ideal timing of anticonvulsant reduction for a child started on the ketogenic diet is unclear. The records of 81 children started on the ketogenic diet consecutively over a 2-year period were reviewed for a 6-month period after diet initiation. During their first 6 months on the ketogenic diet, medications were tapered in 53 of 81 (65%) patients, with 30 of 53 (57%) considered "early" (tapered during diet initiation or within the first month afterward). No differences were seen between the early and late groups with respect to percentage with > 90% seizure reduction at 3 months (47% vs 48%), diet duration (1.1 vs 0.9 years), percentage remaining on the ketogenic diet to date (73% vs 65%), or improved alertness (63% vs 57%). Nine of fifty-three (17%) had transient seizure increases during medication tapering, with no correlation to the timing in which this occurred; however, five were taking benzodiazepines or barbiturates. All had > 50% seizure reduction at 3 months despite the transient worsening. Early reduction of anticonvulsants in children initiated on the ketogenic diet appears to be safe and well tolerated. However, it offers no specific advantage compared with a later taper.     

Experience in the use of the ketogenic diet as early therapy

The ketogenic diet has traditionally been considered an anticonvulsant therapy of last resort, despite excellent efficacy and limited side effects. We hypothesized that the ketogenic diet would have similar results in patients with new-onset epilepsy. A retrospective study was conducted of patients started on the ketogenic diet since 1994. Thirteen of 460 (2.8%) patients were started on the ketogenic diet as early (zero or one prior anticonvulsant) therapy for seizures. Of those remaining on the diet, 60% (6 of 10) had a > 90% seizure reduction at 6 months and 100% (6 of 6) had a > 90% reduction at 12 months. Patients with infantile spasms were as likely to achieve > 50% seizure reduction at 6 months as patients with other seizure types (75% vs 60%; P = .6). The ketogenic diet can be a valuable therapy before epilepsy becomes intractable. In the 13 patients reported, efficacy without side effects was achieved similarly to that with patients with intractable epilepsy.     

Ketogenic diet in patients with myoclonic-astatic epilepsy.

For more than 80 years, the ketogenic diet has been used as an alternative to antiepileptic drugs for patients with refractory epilepsy. Myoclonic-astatic epilepsy in early childhood is one of the malignant epilepsy syndromes that often proves refractory to antiepileptic drugs treatment. Objective. In this prospective study we assess the efficacy and tolerability of the ketogenic diet in patients with myoclonic-astatic epilepsy. Material and methods. Between March 1, 1990 and August 31, 2004, 30 patients who met diagnostic criteria of myoclonic-astatic epilepsy were seen at our department. Eleven of them were placed on the ketogenic diet using the Hopkins protocol and were followed for a minimum of 18 months. Results. The children had previously received a mean of 5.2 different antiepileptic drugs and were on a mean of 2.2 antiepileptic drugs when the diet was started. Eighteen months after initiating the diet, six of the patients (54.5%) remained on the diet. Two patients (18%) were seizure-free, two (18%) had a 75-99% decrease in seizures, and the remaining two children (18%) had a 50% to 74% decrease in seizures. The first two patients were tapered off the diet after remaining seizure-free, without antiepileptic drugs for several years. In the two patients who had sporadic seizures, antiepileptic drugs were reduced to one, and in the last two the seizure frequency was significantly reduced. No differences in seizure control were found when compared for age, sex, or seizure type. Five of our patients discontinued the ketogenic diet in less than 3 months (four because of lack of effectiveness and one because of persistent vomiting). Conclusion. The ketogenic diet is a promising therapy for patients with myoclonic-astatic epilepsy, with over half the children showing a > 50% reduction in seizures, and seizure-freedom in 18%. In drug resistant cases of myoclonic-astatic epilepsy, the diet should be considered early in the course of this syndrome and not as a last resort.     

The ketogenic diet for the treatment of childhood epilepsy: a randomised controlled trial

BACKGROUND: The ketogenic diet has been widely and successfully used to treat children with drug-resistant epilepsy since the 1920s. The aim of this study was to test the efficacy of the ketogenic diet in a randomised controlled trial. METHODS: 145 children aged between 2 and 16 years who had at least daily seizures (or more than seven seizures per week), had failed to respond to at least two antiepileptic drugs, and had not been treated previously with the ketogenic diet participated in a randomised controlled trial of its efficacy to control seizures. Enrolment for the trial ran between December, 2001, and July, 2006. Children were seen at one of two hospital centres or a residential centre for young people with epilepsy. Children were randomly assigned to receive a ketogenic diet, either immediately or after a 3-month delay, with no other changes to treatment (control group). Neither the family nor investigators were blinded to the group assignment. Early withdrawals were recorded, and seizure frequency on the diet was assessed after 3 months and compared with that of the controls. The primary endpoint was a reduction in seizures; analysis was intention to treat. Tolerability of the diet was assessed by questionnaire at 3 months. The trial is registered with ClinicalTrials.gov, number NCT00564915. FINDINGS: 73 children were assigned to the ketogenic diet and 72 children to the control group. Data from 103 children were available for analysis: 54 on the ketogenic diet and 49 controls. Of those who did not complete the trial, 16 children did not receive their intervention, 16 did not provide adequate data, and ten withdrew from the treatment before the 3-month review, six because of intolerance. After 3 months, the mean percentage of baseline seizures was significantly lower in the diet group than in the controls (62.0%vs 136.9%, 75% decrease, 95% CI 42.4-107.4%; p<0.0001). 28 children (38%) in the diet group had greater than 50% seizure reduction compared with four (6%) controls (p<0.0001), and five children (7%) in the diet group had greater than 90% seizure reduction compared with no controls (p=0.0582). There was no significant difference in the efficacy of the treatment between symptomatic generalised or symptomatic focal syndromes. The most frequent side-effects reported at 3-month review were constipation, vomiting, lack of energy, and hunger. INTERPRETATION: The results from this trial of the ketogenic diet support its use in children with treatment-intractable epilepsy. FUNDING: HSA Charitable Trust; Smiths Charity; Scientific Hospital Supplies; Milk Development Council.     

Ketogenic diet in pediatric epilepsy patients with gastrostomy feeding

Ketogenic diet is effective in the control of intractable seizures. Poor compliance is a major limiting factor. In one study, only 50% of children receiving the oral ketogenic diet remained on the diet after 1 year. Twelve children with static encephalopathy and intractable symptomatic epilepsy were given the ketogenic diet via gastrostomy tube. Mean age was 3 years (range, 7 months to 6.5 years). Mean seizure frequency at baseline was 199/month. Seizure frequency after 12 and 18 months of diet was compared with baseline. After 12 months on the diet, the number of antiepileptic drugs was compared with baseline. Median seizure reduction at 1 year and 18 months was 61% and 66%, respectively (P = 0.02). Individually, six patients had 90% seizure reduction, one had 75% reduction, three had 50% reduction, and two patients did not improve. Mean antiepileptic drugs at baseline was 2.8; at 12 months 1.6 (49% reduction). Three patients had weight loss. Two patients discontinued the diet at 13 months and 21 months, respectively, because of diarrhea and weight loss. Compliance with diet was 100% during treatment. This study suggests that the ketogenic diet via gastrostomy feeding tube is safe and effective in children with intractable seizures and ensures compliance.     

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.     

Long-term follow-up of children treated with the modified Atkins diet

The modified Atkins diet has been studied in mostly short-term clinical trials and case series. No studies have systematically examined the long-term benefits and side effects. The modified Atkins diet was started without prior ketogenic diet use in 87 children at the Johns Hopkins Hospital since 2002, of which 54 continued for more than 6 months. Children who had not been seen within the past 2 years were contacted by phone and email. At their most recent point during the modified Atkins diet (mean 19.9 months), 30 of 54 (55%) children with diet durations of more than 6 months achieved >50% improvement; 19 (35%) were seizure-free. Using an intent-to-treat analysis, at 12 months, 33 of 87 (38%) had >50% seizure reduction; 16 (18%) were seizure-free. These results are similar to published data for short-term modified Atkins diet and long-term ketogenic diet use. Side effects were predominantly elevations in lipid profile and gastrointestinal upset.     

Seizure tests distinguish intermittent fasting from the ketogenic diet

Purpose: Calorie restriction can be anticonvulsant in animal models. The ketogenic diet was designed to mimic calorie restriction and has been assumed to work by the same mechanisms. We challenged this assumption by profiling the effects of these dietary regimens in mice subjected to a battery of acute seizure tests. Methods: Juvenile male NIH Swiss mice received ketogenic diet or a normal diet fed in restricted quantities (continuously or intermittently) for ～12 days, starting at 3–4 weeks of age. Seizures were induced by the 6 Hz test, kainic acid, maximal electroshock, or pentylenetetrazol. Results: The ketogenic and calorie‐restricted diets often had opposite effects depending on the seizure test. The ketogenic diet protected from 6 Hz–induced seizures, whereas calorie restriction (daily and intermittent) increased seizure activity. Conversely, calorie restriction protected juvenile mice against seizures induced by kainic acid, whereas the ketogenic diet failed to protect. Intermittent caloric restriction worsened seizures induced by maximal electroshock but had no effect on those induced by pentylenetetrazol. Discussion: In contrast to a longstanding hypothesis, calorie restriction and the ketogenic diet differ in their acute seizure test profiles, suggesting that they have different underlying anticonvulsant mechanisms. These findings highlight the importance of the 6 Hz test and its ability to reflect the benefits of ketosis and fat consumption.     

Ketogenic diet in adolescents and adults with epilepsy

PurposeThe ketogenic diet is an alternative treatment for patients with refractory epilepsy. Most studies to date report dietary response in children. There are limited data evaluating the efficacy of the ketogenic diet in adults. This is a report of the long-term outcome in a largely adult population of patients treated with the ketogenic diet for epilepsy.MethodTwenty-nine adult and adolescent patients (mean age 32 years, range 11–51) were initiated on the ketogenic diet and followed until diet discontinuation. Clinical response and adverse effects were noted during the duration of the diet.ResultsFifty-two percent of patients had a significant reduction in seizure frequency on the ketogenic diet, including 45% with ≥50% reduction in seizure frequency. Thirty-one percent had no improvement, seven percent were unable to successfully initiate the diet, and 10% had a >50% increase in seizure frequency. The diet was continued for a mean of 9 months (range 0.13–35 months), with five patients completing ≥23 months. There was a trend toward better response and better tolerability/longer duration in patients with symptomatic generalized epilepsy. The diet was generally well-tolerated, but undesired weight loss and constipation were the most frequent adverse effects.ConclusionThe ketogenic diet can be used safely in the adult and adolescent population, with a response rate similar to those seen in children. Patient with symptomatic generalized epilepsy may be particularly good candidates for this type of dietary treatment.     

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.