Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the International Ketogenic Diet Study Group.

Ketogenic dietary therapies (KDTs) are established, effective nonpharmacologic treatments for intractable childhood epilepsy. For many years KDTs were implemented differently throughout the world due to lack of consistent protocols. In 2009, an expert consensus guideline for the management of children on KDT was published, focusing on topics of patient selection, pre-KDT counseling and evaluation, diet choice and attributes, implementation, supplementation, follow-up, side events, and KDT discontinuation. It has been helpful in outlining a state-of-the-art protocol, standardizing KDT for multicenter clinical trials, and identifying areas of controversy and uncertainty for future research. Now one decade later, the organizers and authors of this guideline present a revised version with additional authors, in order to include recent research, especially regarding other dietary treatments, clarifying indications for use, side effects during initiation and ongoing use, value of supplements, and methods of KDT discontinuation. In addition, authors completed a survey of their institution's practices, which was compared to responses from the original consensus survey, to show trends in management over the last 10 years.

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.

Low glycemic index treatment for seizures in Angelman syndrome.

PURPOSE: The low glycemic index treatment (LGIT) is a high fat, limited carbohydrate diet used in the treatment of epilepsy. The purpose of this study was to assess the efficacy and tolerability of the LGIT for the treatment of refractory seizures in pediatric patients with Angelman syndrome. METHODS: A pediatric Angelman syndrome cohort with refractory epilepsy was treated with the LGIT and followed prospectively over 4 months. Parents recorded a daily seizure log for a minimum of 1 month prior to the start of treatment as well as throughout the LGIT trial. Electroencephalography (EEG) and neuropsychological assessments (Scales of Independent Behavior-Revised and the Vineland Adaptive Behavior Scales-2nd Edition were obtained for each subject at both baseline and 4-month follow-up time points. Clinical evaluations of subjects were completed by a neurologist and dietitian at the time of enrollment, as well as following both the first and fourth months of dietary therapy. At each time point, blood for laboratory chemistries was drawn and anthropometric measures were obtained. KEY FINDINGS: Six children (mean age 3.3 years, range 1.1-4.8) with genetically confirmed Angelman syndrome initiated the LGIT, and completed the trial with no significant adverse events. Cohort averages for indices of seizure severity were as follows: age of 1.6 years at seizure onset, 3 lifetime antiepileptic drugs tried (range 1-6), and baseline seizure frequency of 10.1 events/week (range: 0.4-30.9). All subjects had a decrease in seizure frequency on the LGIT, with five of six exhibiting >80% seizure frequency reduction. All posttrial EEG studies showed improvement and three of four children with epileptiform activity on his or her baseline EEG had no discharges present on follow-up EEG. Developmental gains were noted by parents in all cases, although few of these neurocognitive gains were statistically significant on neuropsychological assessment. SIGNIFICANCE: This is the first prospective study assessing the LGIT for epilepsy. Our results indicate that this dietary therapy is highly effective in treating Angelman syndrome-related seizures. The diet was well tolerated by subjects as evidenced by five of six subjects remaining on the LGIT after completion of the trial. Beyond the prospective trial window, all five subjects who remained on the diet had >90% seizure reduction after 1 year of LGIT therapy. Despite the small sample size in this prospective study, the results indicate a potentially higher degree of efficacy of the LGIT for the Angelman syndrome population than that observed in the general epilepsy population. Although this study is too small to make definitive recommendations, these results suggest that the LGIT is a promising treatment option for Angelman syndrome-related epilepsy.

Low glycemic index treatment for epilepsy in tuberous sclerosis complex.

Retrospective chart review of 15 patients with tuberous sclerosis complex (TSC) who initiated the low glycemic index treatment (LGIT) for epilepsy management at Massachusetts General Hospital over a five-year period. Prior to dietary therapy, this cohort (average age: 8.5 years) had tried an average of 5.8 anti-epileptic drugs with incomplete seizure control. At 6 months on the LGIT, 7/15 (47%) patients experienced >50% reduction in seizure frequency.

The relationship of ketosis and growth to the efficacy of the ketogenic diet in infantile spasms.

The ketogenic diet (KD) is a treatment of infantile spasms (IS). Here, we examine the efficacy of KD in medically refractory IS, examine its impact on growth in infants, and explore its mechanism of action. At 1-3 months after the initiation of the KD, 46% of twenty-six patients had a greater than 90% reduction in IS. No significant relationships between reduction in IS and serum ß-hydroxybutyrate, or glucose levels were identified. Also, the KD had not significantly altered patient's growth parameters. Thus, in corroborating with prior studies, we demonstrate the KD is a well-tolerated and efficacious treatment of IS.

Urolithiasis on the ketogenic diet with concurrent topiramate or zonisamide therapy.

Children with refractory epilepsy who are co-treated with the ketogenic diet (KD) and carbonic anhydrase inhibitor (CA-I) anti-epileptic medications including topiramate (TPM) and zonisamide (ZNS) are at risk for urolithiasis. Retrospective chart review of all children treated with ketogenic therapy at our institution was performed in order to estimate the minimal risk of developing signs or symptoms of stone disease. Children (N=93) were classified into groups according to KD+/-CA-I co-therapy. Fourteen patients had occult hematuria or worse, including 6 with radiologically confirmed stones. Three of 6 calculi developed in the KD+ZNS group of 17 patients who were co-treated for a cumulative total of 97 months (3.1 stones per 100 patient months). One confirmed stone was in the KD+TPM group of 22 children who were co-treated for a cumulative total of 263 months (0.4 stones per 100 patient months). All six patients had at least three of five biochemical risk factors including metabolic acidosis, concentrated urine, acid urine, hypercalciuria and hypocitraturia. Standard of care interventions to minimize hypercalciuria, crystalluria and stone formation used routinely by pediatric nephrologists should also be prescribed by neurologists treating patients with combination anti-epileptic therapy. Non-fasting KD initiation, fluid liberalization, potassium citrate prophylaxis as well as regular laboratory surveillance are indicated in this high risk population.

Efficacy, safety, and tolerability of the low glycemic index treatment in pediatric epilepsy.

PURPOSE: To report the efficacy, safety, and tolerability of the low glycemic index treatment (LGIT) in pediatric epilepsy. METHODS: A retrospective chart review was performed on patients initiating the LGIT at the Massachusetts General Hospital between January 2002 and June 2008. Demographic and clinical information including seizure type, baseline seizure frequency, medications, blood chemistries, side effects, and anthropometrics were collected. Initiation of the LGIT was done in an outpatient setting. Patients were educated by a dietitian to restrict foods with high glycemic index and to limit total daily carbohydrates to 40-60 g. Change in seizure frequency was assessed at 1-, 3-, 6-, 9-, and 12-month follow-up intervals. RESULTS: Seventy-six children were included in the study. Eighty-nine percent had intractable epilepsy (>or=3 antiepileptic drugs). A greater than 50% reduction from baseline seizure frequency was observed in 42%, 50%, 54%, 64%, and 66% of the population with follow-up available at 1, 3, 6, 9, and 12 months, respectively. Increased efficacy was correlated with lower serum glucose levels at some time points, but not with beta-hydroxybutyrate (BOHB) changes or ketosis status at any time point. Only three patients reported side effects (transient lethargy). Blood urea nitrogen (BUN) was elevated in approximately one-third of follow-up laboratory studies. No significant changes were seen in body mass index (BMI) or BMI z-score at any follow-up interval. The most cited reason for treatment discontinuation was the restrictiveness of the diet, in 18 patients (24%). CONCLUSION: The LGIT was associated with reduced seizure frequency in a large fraction of patients, with limited side effects.

Optimal clinical management of children receiving the ketogenic diet: recommendations of the International Ketogenic Diet Study Group.

The ketogenic diet (KD) is an established, effective nonpharmacologic treatment for intractable childhood epilepsy. The KD is provided differently throughout the world, with occasionally significant variations in its administration. There exists a need for more standardized protocols and management recommendations for clinical and research use. In December 2006, The Charlie Foundation commissioned a panel comprised of 26 pediatric epileptologists and dietitians from nine countries with particular expertise using the KD. This group was created in order to create a consensus statement regarding the clinical management of the KD. Subsequently endorsed by the Practice Committee of the Child Neurology Society, this resultant manuscript addresses issues such as patient selection, pre-KD counseling and evaluation, specific dietary therapy selection, implementation, supplementation, follow-up management, adverse event monitoring, and eventual KD discontinuation. This paper highlights recommendations based on best evidence, including areas of agreement and controversy, unanswered questions, and future research.

Low glycemic index treatment: implementation and new insights into efficacy.

Despite the substantial efficacy of the ketogenic diet (KD) in treating refractory epilepsy, use of the KD remains limited because of difficulties in implementation and tolerability. An effective alternative dietary approach is a low glycemic index treatment (LGIT), which liberalizes the extreme carbohydrate restriction of the KD but restricts the type of carbohydrate-containing foods to those that produce relatively small changes in blood glucose. Foods with a "glycemic index" of less than 50 produce less than half the area-under-the-curve elevation of blood glucose compared to a reference food. The LGIT approach produces comparable efficacy to the classic KD, but tolerability is improved and implementation is much simpler. The LGIT appears to be a viable first-line dietary therapy for epilepsy.

Atypical GLUT1 deficiency with prominent movement disorder responsive to ketogenic diet.

Glucose transport protein deficiency due to mutation in the GLUT1 gene is characterized by infantile onset and chronic seizure disorder, microcephaly, global developmental delays, and hypoglycorrhachia. We describe a 10-year-old normocephalic male with prominent ataxia, dystonia, choreoathetosis, and GLUT1 deficiency whose motor abnormalities improved with a ketogenic diet. We illustrate the motor abnormalities, at baseline and after ketogenic diet, that characterize this unusual case. This case broadens the phenotype of GLUT1 deficiency and illustrates the importance of cerebrospinal fluid (CSF) evaluation in detecting potentially treatable conditions in children with undiagnosed movement disorders.

Low-glycemic-index treatment: a liberalized ketogenic diet for treatment of intractable epilepsy.

The ketogenic diet is often effective for intractable epilepsy, but many patients have trouble complying with the strict regimen. The authors tested an alternative diet regimen, a low-glycemic-index treatment, with more liberal total carbohydrate intake but restricted to foods that produce relatively little increase in blood glucose (glycemic index < 50). Ten of 20 patients treated with this regimen experienced a greater than 90% reduction in seizure frequency.

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.

Safety and tolerability of the ketogenic diet in pediatric epilepsy: effects of valproate combination therapy.

PURPOSE: To evaluate safety and tolerability of ketogenic diet (KGD) and valproate (VPA) cotherapy in the treatment of intractable seizures. METHODS: The patient records of children who underwent KGD initiation at the Massachusetts General Hospital for Children from February 2002 to September 2004 were retrospectively assessed. Efficacy was measured by comparing reported seizure frequency at baseline and at 3-month intervals thereafter. Adverse events and reasons for terminating the diet were tabulated. RESULTS: Of 71 patients who underwent KGD initiation, 24 were concomitantly using VPA at the time of initiation. The most serious adverse events were two cases of acute pancreatitis (2.8%), both of which occurred in patients not taking VPA. The most common complications in both groups were acidosis (39.4%), nausea and vomiting (23.9%), hypertriglyceridemia (21.1%), lethargy (18.3%), and behavioral changes and irritability (15.5%). No significant difference in adverse-event profiles was found between the VPA group and the non-VPA group. At 1 year, 32 patients remained on the diet, including 11 in the VPA group. Efficacy was nearly identical in these two groups. CONCLUSIONS: KGD and VPA combination therapy is relatively safe and effective in refractory pediatric epilepsy. Adverse-event profiles of patients on KGD and VPA cotherapy are similar to those of patients on the KGD without VPA. In considering possible treatment options for intractable seizures, cotherapy with these two modalities should not be excluded for safety or tolerability concerns. In some patients, this combination may provide optimal seizure control.

The use of diet in the treatment of epilepsy.

Fasting and other dietary regimens have been used to treat epilepsy since biblical times. The ketogenic diet, which mimics the metabolism of fasting, was used by modern physicians to treat intractable epilepsy beginning in the 1920s. With the rising popularity of drug treatments however, the ketogenic diet lost its previous status and was used in only a handful of clinics for most of the 20th century. The diet regained widespread recognition as a viable treatment option beginning in 1992 due to the efforts of parent advocate groups. Despite challenges to implementation of the treatment, the ketogenic diet has significant potential as a powerful tool for fighting epilepsy.