The Modified Atkins Diet for Epilepsy: Two Decades of an "Alternative" Ketogenic Diet Therapy.

In 2003, the first case series of six patients treated with an Atkins diet for epilepsy was published in the journal Neurology. The concept was a simple, outpatient-initiated diet in which ketosis could be maintained by eating high-fat foods while tracking and limiting daily carbohydrate counts based on food ingredient labels. Twenty years later, after dozens of studies encompassing hundreds of patients, including several randomized controlled trials, the Modified Atkins Diet is a proven method of providing ketogenic dietary therapy for epilepsy. It is a diet therapy of choice for adolescents and adults, is being investigated for new-onset epilepsy, and is researched for neurological conditions other than epilepsy. Adverse effects do exist but may be less common than the classic ketogenic diet. This review will cover the history, clinical trials, implementation, current utilization, and future directions of this "alternative" ketogenic diet therapy on its 20-year anniversary.

Association between ketosis and metabolic adaptation at the level of resting metabolic rate.

BACKGROUND: The ketone body ß-hydroxybutyrate (ßHB) has been shown to act as a signaling molecule that regulates metabolism and energy homeostasis during starvation in animal models. A potential association between ßHB and metabolic adaptation (a reduction in energy expenditure below predicted levels) in humans has never been explored. OBJECTIVE: To determine if metabolic adaptation at the level of resting metabolic rate (RMR) was associated with the magnitude of ketosis induced by a very-low energy diet (VLED). A secondary aim was to investigate if the association was modulated by sex. METHODS: Sixty-four individuals with obesity (BMI: 34.5 ± 3.4 kg/m2; age: 45.7 ± 8.0 years; 31 males) enrolled in a 1000 kcal/day diet for 8 weeks. Body weight/composition, RMR and ßHB (as a measure of ketosis) were determined at baseline and week 9 (W9). Metabolic adaptation was defined as a significantly lower measured versus predicted RMR (from own regression model). RESULTS: Participants lost on average 14.0 ± 3.9 kg and were ketotic (ßHB: 0.76 ± 0.51 mM) at W9. A significant metabolic adaptation was seen (-84 ± 106 kcal/day, P < 0.001), with no significant differences between sexes. [ßHB] was positively correlated with the magnitude of metabolic adaptation in females (r = 0.432, P = 0.012, n = 33), but not in males (r = 0.089, P = 0.634, n = 31). CONCLUSION: In females with obesity, but not males, the larger the [ßHB] under VLED, the greater the metabolic adaptation at the level of RMR. More studies are needed to confirm these findings and to explore the mechanisms behind the sex difference in the association between ketosis and metabolic adaptation. TRIAL REGISTRATION NAME: Clinicaltrials.gov. STUDY REGISTRATION ID: NCT02944253. URL: https://clinicaltrials.gov/ct2/show/NCT02944253.

Families' Perception of Classic Ketogenic Diet Management in Acute Medical Conditions: A Web-Based Survey.

Objective: To describe families' experiences in managing epileptic patients undergoing ketogenic dietary therapies (KDTs) in acute medical settings. Methods: We conducted a short online survey addressed to the families of patients undergoing a classic ketogenic diet (cKD) for at least three months. The survey was composed of 18 questions exploring the following issues: demographic characteristics, epilepsy diagnosis, ketogenic-diet treatment history, the reason for emergency-ward admission and patient management, surgery-procedure management, and outcomes. Results: A sample of 50 families agreed to participate. Out of 50 patients, 33 (66%) had been undergoing a cKD for more than two years. Fifteen (30%) patients had been admitted at least once to the Emergency Room (ER), and 8.2% had undergone surgical procedures during cKD treatment. The causes of ER admission were the following: seizures, infection, trauma, and gastrointestinal or respiratory problems. In 75% of cases, blood ketonemia was not monitored during ER admission, and according to 46% of responders, the medical staff intervening did not have a basic knowledge of KDTs. Conclusions: According to both our experience and caregivers' reports, it might be useful to search for standardized specific approaches to patients undergoing KDTs in the emergency setting.

Modulation of Cellular Biochemistry, Epigenetics and Metabolomics by Ketone Bodies. Implications of the Ketogenic Diet in the Physiology of the Organism and Pathological States.

Ketone bodies (KBs), comprising ß-hydroxybutyrate, acetoacetate and acetone, are a set of fuel molecules serving as an alternative energy source to glucose. KBs are mainly produced by the liver from fatty acids during periods of fasting, and prolonged or intense physical activity. In diabetes, mainly type-1, ketoacidosis is the pathological response to glucose malabsorption. Endogenous production of ketone bodies is promoted by consumption of a ketogenic diet (KD), a diet virtually devoid of carbohydrates. Despite its recently widespread use, the systemic impact of KD is only partially understood, and ranges from physiologically beneficial outcomes in particular circumstances to potentially harmful effects. Here, we firstly review ketone body metabolism and molecular signaling, to then link the understanding of ketone bodies' biochemistry to controversies regarding their putative or proven medical benefits. We overview the physiological consequences of ketone bodies' consumption, focusing on (i) KB-induced histone post-translational modifications, particularly ß-hydroxybutyrylation and acetylation, which appears to be the core epigenetic mechanisms of activity of ß-hydroxybutyrate to modulate inflammation; (ii) inflammatory responses to a KD; (iii) proven benefits of the KD in the context of neuronal disease and cancer; and (iv) consequences of the KD's application on cardiovascular health and on physical performance.

Accidental ketosis-induced polyuria in a toddler: a case report.

BACKGROUND: In the pediatric population, parental concern of recent onset frequent or large volume urination in young children is common. CASE PRESENTATION: A 2-year-old male with no significant past medical history and unremarkable family history was brought to his pediatrician by his mother who reports that the child had been "soaking through his diapers" for the previous two to 3 days. Mother states that patient has not had an appreciable change in the number of wet diapers per day, just the perceived weight/volume of each diaper. The patient's mother denied any recent illness, apparent abdominal pain, dysuria, or recent changes in his bowel movements. She similarly denied polydipsia, polyphagia, or gross hematuria in the patient. Patient's diet consists of eating a low carbohydrate with mostly high protein and fat diet that was similar to the paleo-type diet consumed by her and her husband. Meals over the recent days were even lower in carbohydrates than usual as the family was actively trying to consume healthier food options. On physical exam the child was found to be afebrile with a normal physical exam. A urine dipstick was performed and was positive for 2+ ketones and 1+ protein. Urine leukocytes and nitrites were negative, as was urinary glucose. A fingerstick blood glucose sample was 83 mg/dL. Based on the patient's physical examination, laboratory findings, and the history which revealed a very-low carbohydrate diet, a preliminary diagnosis of ketosis-induced polyuria was made. The patient's mother was advised to incorporate a greater portion of carbohydrates into her son's diet, with a follow-up scheduled for the following week. At the follow-up appointment the mother reports that she had continued the patient's carbohydrate intake and the excessive urine amount per wet diaper has not returned. Repeat urine dipstick confirmed the resolution of the ketonuria and proteinuria. CONCLUSION: This case illustrates the inadvertent consequences that can occur when parents impose new fad diets on their young children. The recent increase in the popularity of fad diets makes the consideration of alternative diets important to review in the patient history and subsequently include in the differential diagnosis of polyuria.

Cetoacidosis como complicación de una dieta baja en hidratos de carbono / Ketoacidosis as a complication of a low carbohydrate diet

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Initiating the ketogenic diet in infants with treatment refractory epilepsy while maintaining a breast milk diet.

PURPOSE: The ketogenic diet has been found to be safe and effective in the treatment of drug resistant epilepsy in childhood. The age range of children undergoing this treatment has steadily been going down. There is strong evidence that it is a safe alternative in infants with drug resistant seizures. The American Academy of Pediatrics strongly supports continuing a breast milk diet until infants are at least six months of age. The purpose of this study is to evaluate the safety and efficacy of the ketogenic diet in infants while maintaining a breast milk diet. METHOD: This is a cohort study of 9 infants between the ages of 1 and 13 months with drug resistant epilepsy treated with the ketogenic diet while maintained on breast milk. The data from the first two patients was gathered retrospectively while the other seven were studied prospectively. RESULTS: We show that all nine infants achieved and maintained ketosis effectively. While one infant had no change in seizure frequency, three were seizure free at the first follow-up visit and four had a burden of seizure reduction greater than 50%. The diet was overall well tolerated, although one child required a hospital stay for dehydration and metabolic acidosis. CONCLUSION: The ketogenic diet can be safely and effectively initiated in infants while continuing human breast milk feedings.

Breastfeeding ketoacidosis: A rare but important diagnosis for emergency physicians to recognize.

We report a case of lactation ketoacidosis in a 22-year-old female who was breastfeeding two infants while dieting. She appeared non-toxic, but had a serum bicarbonate of 7meq/L, a pH of 7.07, and moderate serum ketones. She responded well to simple carbohydrate replenishment and brief cessation of breastfeeding. Emergency Physicians should be aware of this entity so as to avoid unnecessary morbidity and to begin prompt treatment.

Lactation Ketoacidosis: A case series.

Lactation ketoacidosis is an extremely rare type of high anion gap metabolic acidosis. We report two lactating women who were diagnosed with lactation ketoacidosis. The first patient presented to the Emergency Department at Royal Darwin Hospital, Darwin, Australia, in 2018 with lethargy, nausea and abdominal pain after she commenced a new diet regimen based on three meals of protein per day and free of glucose, gluten and dairy products. The second patient presented to the Emergency Department at Sultan Qaboos University Hospital, Muscat, Oman, in 2018 with headache, severe malaise, epigastric pain and worsening of gastroesophageal symptoms. Blood investigation results showed that both patients had high anion gap metabolic acidosis, ketosis and hypoglycaemia. The patients responded well to intravenous dextrose and resumption of a balanced diet. Both patients were able to continue breastfeeding and remained well on follow-up.

Improving compliance in adults with epilepsy on a modified Atkins diet: A randomized trial.

PURPOSE: To determine whether use of a ketogenic formula during the first month of the modified Atkins diet (MAD) in adults with drug-resistant epilepsy (DRE) improves seizure reduction and compliance compared to MAD alone. METHODS: Eighty adults (age ≥18 years) with DRE and ≥4 reliably quantifiable seizures/month were enrolled. All participants were trained to follow a 20 g/day net carbohydrate limit MAD. Patients were randomized to receive one 8-ounce (237 mL) tetrapak of KetoCal®, a 4:1 ketogenic ratio formula, daily in combination with MAD during the first month (treatment arm) or second month (control/cross-over arm). Patients recorded urine ketones, weight, and seizure frequency and followed up at 1 and 2 months. RESULTS: By 1 month, 84% of patients achieved ketosis (median of 4-4.5 days). At 1 month, the treatment arm had a significantly higher ketogenic ratio and more patients with a ≥1:1 ketogenic ratio compared to the control arm. There was no difference in median seizure frequency, proportion of responders (≥50% seizure reduction), or median seizure reduction from baseline between groups. However, patients treated with KetoCal® during the first month were significantly more likely to continue MAD for 6 months or more. CONCLUSION: Although supplementing MAD with a ketogenic formula in the first month did not increase the likelihood of reducing seizures compared to MAD alone, significantly more adults remained on MAD long-term with this approach. This suggests a potential strategy for encouraging compliance with MAD in adults with DRE.

3-hydroxy-3-methylglutaryl-CoA lyase deficiency: a case report and literature review / Deficiencia de la 3-hidroxi-3-metilglutaril-CoA liasa: un caso clínico y revisión de la literatura

Introduction: 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency is an autosomal recessive disorder that usually presents in the neonatal period with vomiting, metabolic acidosis, hypoglycemia and absent ketonuria. Few cases are reported in the literature, and optimal dietary management and long term outcome are not fully understood. Case report: We report a 2 year old girl with HMG-CoA-lyase deficiency who had limited fasting tolerance on a low protein diet, with several recurrent hospital admissions with severe hypoketotic hypoglycaemia and metabolic acidosis. We also review the dietary management and outcome of other reported cases in the literature. Discussion: In order to define optimal dietary treatment, it is important to collect higher numbers of case studies with detailed dietary management, fasting times and outcome (AU)

Introducción: la deficiencia de la 3-hidroxi-3-metilglutaril-CoA (HMG-CoA) liasa es un desorden autosómico recesivo que normalmente se presenta en la infancia con vómitos, acidosis metabólica, hipoglicemia y sin cetonuria. Se han publicado pocos casos en la literatura científica sobre el mejor tratamiento dietético para el adecuado desarrollo de los pacientes a largo plazo, por lo que esta deficiencia no es bien conocida. Caso clínico: presentamos una niña de 2 años con deficiencia de la 3-hidroxi-3-metilglutaril-CoA (HMG-CoA) liasa. Recibiendo una dieta baja en proteína con una tolerancia de ayuno limitada con episodios recurrentes de admisión hospitalaria con hipoglicemia hipoketotica y acidosis metabólica. También hemos revisado el tratamiento dietético y el desarrollo de otros casos publicados en la literatura científica. Discusión: es importante recoger más casos clínicos describiendo el tratamiento dietético seguido, el tiempo máximo de ayuno y el desarrollo de los pacientes con el objetivo de definir el mejor tratamiento (AU)

Ketogenic diet in pyruvate dehydrogenase complex deficiency: short- and long-term outcomes.

OBJECTIVES: Our aime was to study the short- and long-term effects of ketogenic diet on the disease course and disease-related outcomes in patients with pyruvate dehydrogenase complex deficiency, the metabolic factors implicated in treatment outcomes, and potential safety and compliance issues. METHODS: Pediatric patients diagnosed with pyruvate dehydrogenase complex deficiency in Sweden and treated with ketogenic diet were evaluated. Study assessments at specific time points included developmental and neurocognitive testing, patient log books, and investigator and parental questionnaires. A systematic literature review was also performed. RESULTS: Nineteen patients were assessed, the majority having prenatal disease onset. Patients were treated with ketogenic diet for a median of 2.9 years. All patients alive at the time of data registration at a median age of 6 years. The treatment had a positive effect mainly in the areas of epilepsy, ataxia, sleep disturbance, speech/language development, social functioning, and frequency of hospitalizations. It was also safe-except in one patient who discontinued because of acute pancreatitis. The median plasma concentration of ketone bodies (3-hydroxybutyric acid) was 3.3 mmol/l. Poor dietary compliance was associated with relapsing ataxia and stagnation of motor and neurocognitive development. Results of neurocognitive testing are reported for 12 of 19 patients. CONCLUSION: Ketogenic diet was an effective and safe treatment for the majority of patients. Treatment effect was mainly determined by disease phenotype and attainment and maintenance of ketosis.

Valproate effect on ketosis in children under ketogenic diet.

INTRODUCTION: Although ketogenic diet has been proven useful in the management of intractable seizures, interactions with other medicines have been reported. This study reports two patients on co-administration with ketogenic diet and valproate appearing undesirable side effects after increase or decrease of valproate pharmaceutical levels. METHODS: Totally 75 patients suffering from drug-resistant epilepsy were treated with ketogenic diet in our departments. Their age varied from 6 months to 9 years. All patients were followed for at least 12 months and up to five years. Clinical and laboratory variables have been regularly assessed. RESULTS: In 75 patients treated with ketogenic diet and valproate at the same time treatment was well tolerated. Two patients presented mild to moderate undesirable effects. In these patients the removal of valproate treatment resulted in an increase of ketosis with respective clinical signs. The conversion of the diet from 4:1 to 1:1 and 2,5:1 respectively resulted in reduction of ketosis and clinical improvement. CONCLUSION: In the majority of cases co-administration of valproate and ketogenic diet seems to be safe. In two cases, valproate appeared to have a negative effect on ketosis (and weaning it led to over-ketosis). This interaction is worthy of future study.

Recurrent hypoglycemia in a toddler.

Idiopathic ketotic hypoglycemia is the most common cause of hypoglycemia in toddlers. This diagnosis should be considered in any hypoglycemic toddler with no prior history of abnormal growth who is developmentally normal when toxic ingestions and sepsis are inconsistent with the clinical picture. Diagnosis is important in preventing serious long-term sequelae and is made in the setting of hypoglycemia, ketonuria, and ketonemia. Therefore, checking urine and blood ketones is an essential part of the evaluation in any hypoglycemic toddler. We report the case of a 3-year-old girl with recurrent hypoglycemia secondary to idiopathic ketotic hypoglycemia.

Dry period plane of energy: Effects on feed intake, energy balance, milk production, and composition in transition dairy cows.

The objective was to investigate the effect of different dry cow feeding strategies on the degree of ketonemia postpartum. Epidemiologic studies provide evidence of an association between elevated ß-hydroxybutyrate (BHBA) concentrations in postpartum dairy cows and a decreased risk for reproductive success as well as increased risk for several diseases in early lactation, such as displacement of the abomasum and metritis. The plane of energy fed to cows in the prepartum period has been shown to influence ketogenesis and the degree of negative energy balance postpartum. Our hypothesis was that a high-fiber, controlled-energy diet (C) fed during the dry period would lead to a lower degree of hyperketonemia in the first weeks postpartum compared with either a high-energy diet (H), or a diet where an intermediate level of energy would only be fed in the close-up period (starting at 28d before expected parturition), following the same controlled-energy diet in the far-off period. Hyperketonemia in this study was defined as a blood BHBA concentration of ≥1.2mmol/L. Holstein cows (n=84) entering parity 2 or greater were enrolled using a randomized block design and housed in individual tiestalls. All treatment diets were fed for ad libitum intake and contained monensin. Cows received the same fresh cow ration after calving. Blood samples were obtained 3 times weekly before and after calving and analyzed for BHBA and nonesterified fatty acids (NEFA). Milk components, production, and dry matter intake were recorded and energy balance was calculated. Repeated measures ANOVA was conducted for the outcomes dry matter intake, energy balance, BHBA and NEFA concentrations, milk and energy-corrected milk yield, as well as milk composition. Predicted energy balance tended to be less negative postpartum in group C and cows in this group had fewer episodes of hyperketonemia compared with both the intermediate group and group H in the first 3 wk after calving. Postpartum BHBA and NEFA concentrations over time were highest in group H and lowest in group C, whereas milk production was not affected by prepartum plane of energy. Analysis of milk fatty acid composition showed a higher yield of preformed fatty acids in group H compared with group C, suggesting higher lipid mobilization for cows fed H. In this study, a 1-group, controlled-energy dry period approach decreased the degree of negative energy balance as well as the number of episodes and degree of hyperketonemia postpartum.

Movement disorders in GLUT1 deficiency syndrome respond to the modified Atkins diet.

BACKGROUND: Movement disorders are a prominent feature of glucose transporter-1 (GLUT1) deficiency syndrome (GLUT1DS). First-choice treatment is a ketogenic diet, but compliance is poor. We have investigated the effect of the modified Atkins diet as an alternative treatment for movement disorders in GLUT1DS. METHODS: Four patients with GLUT1DS ages 15 to 30 years who had movement disorders as the most prominent feature were prospectively evaluated after initiation of the modified Atkins diet. Movement disorders included dystonia, ataxia, myoclonus, and spasticity, either continuous or paroxysmal, triggered by action or exercise. Duration of treatment ranged from 3 months to 16 months. RESULTS: All patients reached mild to moderate ketosis and experienced remarkable improvement in the frequency and severity of paroxysmal movement disorders. Cognitive function also improved subjectively. CONCLUSIONS: The modified Atkins diet is an effective and feasible alternative to the ketogenic diet for the treatment of GLUT1DS-related paroxysmal movement disorders in adolescence and adulthood.

A pilot study of the modified Atkins diet for Sturge-Weber syndrome.

The modified Atkins diet (MAD) is a dietary treatment for epilepsy which does not restrict fluids or calories. This theoretically makes the MAD safer than the ketogenic diet for children with Sturge-Weber syndrome (SWS). Five children aged 4-18 years with SWS and at least monthly intractable seizures were started prospectively on the MAD for 6 months. All children had urinary ketosis and seizure improvement, including 3 with > 50% seizure reduction.

Reduced pain and inflammation in juvenile and adult rats fed a ketogenic diet.

The ketogenic diet is a high-fat, low-carbohydrate regimen that forces ketone-based rather than glucose-based cellular metabolism. Clinically, maintenance on a ketogenic diet has been proven effective in treating pediatric epilepsy and type II diabetes, and recent basic research provides evidence that ketogenic strategies offer promise in reducing brain injury. Cellular mechanisms hypothesized to be mobilized by ketone metabolism and underlying the success of ketogenic diet therapy, such as reduced reactive oxygen species and increased central adenosine, suggest that the ketolytic metabolism induced by the diet could reduce pain and inflammation. To test the effects of a ketone-based metabolism on pain and inflammation directly, we fed juvenile and adult rats a control diet (standard rodent chow) or ketogenic diet (79% fat) ad libitum for 3-4 weeks. We then quantified hindpaw thermal nociception as a pain measure and complete Freund's adjuvant-induced local hindpaw swelling and plasma extravasation (fluid movement from the vasculature) as inflammation measures. Independent of age, maintenance on a ketogenic diet reduced the peripheral inflammatory response significantly as measured by paw swelling and plasma extravasation. The ketogenic diet also induced significant thermal hypoalgesia independent of age, shown by increased hindpaw withdrawal latency in the hotplate nociception test. Anti-inflammatory and hypoalgesic diet effects were generally more robust in juveniles. The ketogenic diet elevated plasma ketones similarly in both age groups, but caused slowed body growth only in juveniles. These data suggest that applying a ketogenic diet or exploiting cellular mechanisms associated with ketone-based metabolism offers new therapeutic opportunities for controlling pain and peripheral inflammation, and that such a metabolic strategy may offer significant benefits for children and adults.