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.     

Vitamin D status in children with intractable epilepsy, and impact of the ketogenic diet

PURPOSE: The aim of this study was to describe vitamin D status in children with intractable epilepsy prescribed newer antiepileptic drugs (AEDs) before initiation of and during 15-month treatment with the ketogenic diet (KD). METHODS: Serum vitamin D (25-OHD and 1,25-OHD) and parathyroid hormone (PTH) were assessed in prepubertal children with intractable epilepsy before initiation of and during KD therapy. Three-day weighed dietary records including KD and vitamin and mineral supplementation were obtained at baseline and at 1 month. RESULTS: Forty-five children (aged 5.1 +/- 2.7 years) were enrolled. Before KD therapy, 4% had deficient and 51% had insufficient serum 25-OHD levels. Vitamin D intake was less than recommended in 47%. Adequate vitamin D intake, fewer AEDs, and generalized seizures were associated with higher serum 25-OHD levels (p < 0.01). After 3 months on the KD, 25-OHD levels increased (p < 0.001), and PTH declined (p < 0.001). Over the next 12-month period, 25-OHD levels steadily declined (p < 0.001), and PTH did not significantly change. CONCLUSIONS: Children with intractable epilepsy treated with newer AEDs had poor vitamin D status. Their status improved over the first 3 months of KD therapy with vitamin D supplementation and slowly declined thereafter.     

Early- and late-onset complications of the ketogenic diet for intractable epilepsy

PURPOSE: This study was undertaken to evaluate the exact limitations of the ketogenic diet (KD) and to collect data on the prevention and management of its risks. METHODS: Patients (129) who were on the KD from July 1995 to October 2001 at our epilepsy center were assessed in the study. Early-onset (within 4 weeks of the commencement of the KD until stabilization) and late-onset complications (occurring after 4 weeks) were reviewed. RESULTS: The most common early-onset complication was dehydration, especially in patients who started the KD with initial fasting. Gastrointestinal (GI) disturbances, such as nausea/vomiting, diarrhea, and constipation, also were frequently noted, sometimes associated with gastritis and fat intolerance. Other early-onset complications, in order of frequency, were hypertriglyceridemia, transient hyperuricemia, hypercholesterolemia, various infectious diseases, symptomatic hypoglycemia, hypoproteinemia, hypomagnesemia, repetitive hyponatremia, low concentrations of high-density lipoprotein, lipoid pneumonia due to aspiration, hepatitis, acute pancreatitis, and persistent metabolic acidosis. Late-onset complications also included osteopenia, renal stones, cardiomyopathy, secondary hypocarnitinemia, and iron-deficiency anemia. Most early- and late-onset complications were transient and successfully managed by careful follow-up and conservative strategies. However, 22 (17.1%) patients ceased the KD because of various kinds of serious complications, and four (3.1%) patients died during the KD, two of sepsis, one of cardiomyopathy, and one of lipoid pneumonia. CONCLUSIONS: Most complications of the KD are transient and can be managed easily with various conservative treatments. However, life-threatening complications should be monitored closely during follow-up.     

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.     

Efficacy and safety of the ketogenic diet for intractable childhood epilepsy: Korean multicentric experience

PURPOSE: We wished to evaluate the efficacy and safety of the ketogenic diet (KD), and we also evaluated the prognosis of the patients after successful discontinuation of the diet in infants, children, and adolescents with refractory epilepsy. METHODS: This was a retrospective study of epilepsy patients treated with the KD during 1995 through 2003 at the Korean multicenters. Outcome measures included seizure frequency, electroencephalography (EEG), adverse reactions, and antiepileptic drug (AED) number. The variables related to the efficacy and prognosis also were analyzed. RESULTS: The outcomes of the 199 patients enrolled in this study at 6 and 12 months after the diet were revealed; 68% and 46% of patients remained on the diet, 58% and 41% showed a reduction of seizure frequency of >50%, including 33% and 25% who became seizure free, respectively. Finally, 66 (34%) of 199 patients successfully completed or maintained the diet. EEGs showed an improvement in background in 40 (72.7%) of 55 patients and a reduction in generalized and focal discharges in 41 (57.7%) of 71 and 15 (33.3%) of 45 patients. Most complications were mild, but five patients died during the KD. No significant variables were related to the efficacy, but those with symptomatic (p=0.047) and partial epilepsies (p=0.073) showed more frequent relapse after completion of the diet. CONCLUSIONS: The KD is a safe and effective alternative therapy for intractable childhood epilepsy in Korea, although the customary diet contains substantially less fat than traditional Western diets, but life-threatening complications should be monitored closely during follow-up.     

Worldwide use of the ketogenic diet

PURPOSE: Over the past decade, the use of the ketogenic diet internationally has increased dramatically. The purpose of this survey was to evaluate the use of the diet worldwide. METHODS: With the use of the Internet, e-mail requests for information about international ketogenic diet centers (outside the United States) were made over a 9-month period. Assistance also was obtained from the Child Neurology Society and International League Against Epilepsy. Questions included patient enrollment (total and annually), year the diet was first offered, unique cultural and religious issues in the country, community opinion, and research interests. RESULTS: Successful communication was made with 73 academic centers in 41 countries outside the United States. Sixteen (39%) countries provided information from multiple centers. The median duration offering the diet was 8 years (range, 1-45 years). The average number of patients enrolled to date was 71.6 per country, with 5.4 new patients annually. Common difficulties included avoiding rice intake, tolerating higher fat-to-protein and carbohydrate ratios (e.g., 4:1), finding specific nutritional labels on foods, and handling the growing interest from large populations with limited resources. Nevertheless, cultural and religious issues were generally not limiting; physician and patient acceptance of the diet as an option is high; and most meals were similar among countries. Centers often had great pride in their programs, and international collaborative groups are forming rapidly. A website is now available with updated center information at http://www.neuro.jhmi.edu/Epilepsy/Peds/ketoworldwide.htm CONCLUSIONS: Despite occasional difficulties, the ketogenic diet is being used worldwide.     

Concomitant treatment with topiramate and ketogenic diet in pediatric epilepsy

PURPOSE: Topiramate (TPM) is widely used as add-on therapy for epilepsy. TPM inhibits carbonic anhydrase, which may result in metabolic acidosis from decreased serum bicarbonate. The ketogenic diet (KGD) predisposes patients to metabolic acidosis, especially during induction. In children with refractory epilepsy, cotreatment with TPM and KGD may be considered, but special attention should be paid to the combined risks for metabolic acidosis and nephrolithiasis. We report our experience in 14 children cotreated with TPM and the KGD. METHODS: Medical records of 14 children cotreated with the KGD and TPM for medically refractory epilepsy were reviewed retrospectively. Bicarbonate levels were analyzed and correlated with clinical profiles, including duration of cotreatment, TPM dose, KGD ratio, and seizure control. RESULTS: Nine children had a <20% decrease in bicarbonate levels, from 5.3 to 12.3 mEq/L (mean, 7.6 mEq/L). Cotreatment was continued in all patients for duration of 33 to 544 days (seven had remained on cotreatment at the end of the study period), although two children required bicarbonate supplements to continue the KGD. No patient had nephrolithiasis. CONCLUSIONS: Although a large decrease in bicarbonate level occurred in the majority of children, the decrease appeared mostly at the time of KGD induction when added to prior TPM therapy. Bicarbonate levels should be monitored carefully with TPM and KGD cotreatment, and bicarbonate supplements given when symptomatic.     

A case of Ohtahara syndrome with mitochondrial respiratory chain complex I deficiency

Ohtahara syndrome (OS) is known as an intractable epileptic syndrome in neonatal and early infantile period, differentiated from early myoclonic encephalopathy (EME) in its etiology. We report a patient with OS associated with mitochondrial respiratory chain complex (MRC) I defect. With ketogenic diet and mitochondrial cocktail therapy, seizures were completely controlled and suppression-burst patterns disappeared 3 months after starting treatment. It is suggested that OS could be caused by specific metabolic disorder such as MRC defect and the intensive therapies including ketogenic diet, vitamin and coenzyme therapy and antioxidant treatment might be helpful for some patients.     

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.     

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.     

Successful treatment of intractable epilepsy with ketogenic diet therapy in twins with ALG3-CDG

BackgroundCongenital disorders of glycosylation (CDG) is a heterogeneous group of congenital metabolic diseases with multisystem clinical involvement. ALG3-CDG is a very rare subtype with only 24 cases reported so far.CaseHere, we report two siblings with dysmorphic features, growth retardation, microcephaly, intractable epilepsy, and hemangioma in the frontal, occipital and lumbosacral regions.ResultsWe studied two siblings by whole exome sequencing. A pathogenic variant in ALG3 (NM_005787.6: c.165C > T; p.Gly55=) that had been previously associated with congenital glycolysis defect type 1d was identified. Their intractable seizures were controlled by ketogenic diet.ConclusionAlthough prominent findings of growth retardation and microcephaly seen in our patients have been extensively reported before, presence of hemangioma is a novel finding that may be used as an indication for ALG3-CDG diagnosis. Our patients are the first reported cases whose intractable seizures were controlled with ketogenic diet. This report adds ketogenic diet as an option for treatment of intractable epilepsy in ALG3-CDG.     

The ketogenic diet and other dietary treatments for refractory epilepsy in children

The ketogenic diet is a high-fat, low-carbohydrate, and restricted protein diet that is useful in patients with refractory epilepsy. The efficacy of the ketogenic diet is better than most of the new antiepileptic drugs. Other modifications of the diet are also beneficial, such as the modified Atkins diet and the low glycemic index treatment. There is a lack of awareness of the ketogenic diet as a treatment modality for epilepsy amongst pediatricians and neurologists. In this review, the use of the ketogenic diet and other dietary treatments in refractory epilepsy is discussed. The Indian experience with the use of these dietary treatments is also briefly reviewed.     

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.     

Tumor growth in patients with tuberous sclerosis complex on the ketogenic diet

Purpose

New evidence is emerging that the availability of nutrients plays a key role in regulating the mammalian target of rapamycin complex-1 (mTORC1) signaling pathway in human cancers. Tuberous sclerosis complex (TSC) is a genetic disorder which results in the growth of hamartomatous lesions in multiple organs due to insufficient suppression of the mTORC1 pathway. A minority of patients with TSC who develop epilepsy which is intractable to standard anticonvulsant medical and/or surgical treatments are treated with the ketogenic diet. To provide insight into the effects of nutrient manipulation on tumor growth in this condition, we describe our experience in a unique group of patients with known tuberous sclerosis complex who are on the ketogenic diet for seizure control. Methods: A retrospective chart review was performed of patients with TSC treated with the ketogenic diet between January 2002 and May 2007 at Massachusetts General Hospital. Results: Five patients with definite TSC underwent serial imaging for tumor growth while on the ketogenic diet or had unchanged imaging prior to the onset of the diet and after termination. Three out of five patients, all children, had progression of a known tumor or tumors or the development of a new tumor while on the ketogenic diet. Conclusion: In this limited case series of five TSC patients, the ketogenic diet did not induce tumor regression or suppress the growth of TSC-related tumors.     

Growth dependence on insulin-like growth factor-1 during the ketogenic diet

Purpose:   To examine the influence of the ketogenic diet (KD) on linear growth and insulin-like growth factor I (IGF-I) levels in children with pharmacotherapy-resistant epilepsy.
Methods:   A prospective study was designed to evaluate growth, serum IGF-I levels, blood β-hydroxybutyric acid (β-OHB), and seizure frequency before and during KD in 22 children (median age 5.5 years). Growth was assessed by measurements of weight, height, body mass index (BMI), and height velocity. Standard deviation scores (SDS) were calculated for all measured parameters as well as for serum IGF-I to eliminate the influence of age- and sex-related differences among patients.
Results:   Fourteen of the 22 patients responded to the KD. Weight, height, BMI, and height velocity decreased significantly during the KD. We found that the KD had profound influence on growth and IGF-I levels. No correlation was found between seizure response and growth alterations. Height velocity correlated negatively with β-OHB during the KD. The slope of the regression of height velocity against IGF-I decreased significantly during the KD.
Conclusions:   Height velocity was most affected in those with pronounced ketosis, which implies that, in clinical practice, the level of ketosis should be related to outcomes in seizure response and growth. Our data indicate that growth disturbances and the decreased sensitivity of growth to similar IGF-I levels during KD are independent of seizure reduction. The metabolic status induced by KD may be the mechanism underlying both alterations of linear growth and seizure reduction.     

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.     

Ketogenic diet using a Japanese ketogenic milk for patients with epilepsy: A multi-institutional study

Background

In Japan, Meiji 817-B (M817-B), a powdered ketogenic milk, has been available since the ketogenic diet was introduced to infants and tube-fed children with medication-resistant epilepsy in the 1980s.