Epilepsy is a chronic neurological disorder characterized by recurrent seizures. These seizures manifest as short episodes of involuntary movement that can affect part or all of the body, sometimes accompanied by loss of consciousness and control of bladder or bowel function. Epilepsy is defined as the occurrence of two or more unprovoked seizures. A common type of epilepsy affecting 6 in 10 people is idiopathic epilepsy, which means that in over 50% of global cases, the cause of the disease is not identified. When the cause of epilepsy is known, it is called secondary or symptomatic epilepsy. Causes of secondary or symptomatic epilepsy include brain tumors, stroke, brain infection and severe head injury, congenital abnormalities associated with brain defects, brain damage as a result of prenatal or perinatal injuries, and certain genetic syndromes.
Approximately 50-70 million people worldwide suffer from epilepsy, with an estimated 2.4-4.6 million people diagnosed each year. The global burden of epilepsy disproportionately affects low- and middle-income countries, where the annual incidence is much higher (139 per 100,000 people) than in high-income countries (49 per 100,000 people). Regardless of a country's income, epilepsy poses a high risk of disability, economic loss, social isolation, and premature death. It is a serious and costly health problem worldwide, including estimated indirect and direct costs annually of around EUR 15.5 billion in Europe and USD 15.5 billion in the United States.
Currently available pharmacological treatment of epilepsy has limited effectiveness. In epileptic patients, pharmacological treatment with available anticonvulsants leads to seizure control in <70% of cases. Surgical intervention can lead to control in a selected subset of patients, but still leaves a significant number of patients with uncontrolled seizures. Recent studies in low-, middle-, and high-income countries have shown that up to 70% of adults and children with epilepsy can be successfully treated with antiepileptic drugs. After 2 to 5 years of successful therapy and no seizures, medications can be withdrawn in approximately 70% of children and 60% of adults without recurrence.
When pharmacological and/or surgical treatment is not effective, the ketogenic diet proves to be useful. The ketogenic diet has been used in patients with difficult-to-treat epilepsy since 1921, with minor changes in recent years. It is a last resort treatment for many children, adolescents, and adults with epilepsy resistant to routine medications.
The Ketogenic Diet: A Metabolic Approach to Epilepsy Management
The ketogenic diet (KD) is a specialized dietary approach characterized by a very high-fat and low-carbohydrate intake, reducing carbohydrate to less as 10% of used energy. This restriction triggers a systemic shift from glucose metabolism toward the metabolism of fatty acids yielding ketone bodies, such as acetoacetate and β-hydroxybutyrate as substrates for energy. The ketogenic diet provides sufficient protein for growth and development. Energy is mostly derived from fat delivered in the diet and by the utilization of body fat. The ketogenic diet is a biochemical model of fasting, which shifts organs to utilize ketone bodies as the source to replace glucose for the brain. The ketogenic diet allows about 90% of the total caloric income from fat and 6% from protein and 4% from carbohydrates.
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For many refractory epileptic patients, dietary treatment promises to improve the quality of life with a significant decrease in seizure frequency. For this reason, an increase in the global use of the ketogenic diet is currently observed. Successful implementation of this diet depends on the active support of the health care team, the social and educational system, and finally the family. The ketogenic diet requires strict dietary and medical control due to its restrictiveness and side effects.
Types of Ketogenic Diets
The classic ketogenic diet (CKD) consists of a high-fat and low-protein and carbohydrate diet, with restricted calories and fluids. The CKD is rich in lipids (90%) and low in carbohydrates and protein, in order to produce ketosis, and simulates a starvation state. It is a rigid diet, mathematically and individually calculated, and medically monitored. It must also provide adequate vitamins and minerals.
In the last 20 years, new variants of the KD diet have emerged, including the Modified Atkins diet (MAD), a low-glycemic-index diet, which although it has a high fat content, allows more protein and does not restrict calories and fluids. Several studies have shown that the new variants of the KD have a similar efficacy to the CKD.
The modified Atkins diet (MAD) aims to provide increased flexibility and palatability, with a 1:1 ratio of fat to carbohydrates and protein, and contains around 65% fat, 25% protein, and 10% carbohydrate. Fat is encouraged and the carbohydrate intake is limited to 10-20 g/day in children and 15-20 g/day in adults. Because of carbohydrate restriction, the MAD can also produce urinary ketones. The MAD does not require weighing food on a gram scale, or restricting fluids.
Clinical Evidence Supporting Ketogenic Diet Therapy
In 1998, a multicenter study was conducted in 51 children with drug-resistant epilepsy. Forty-seven percent of children remained on a diet for a year. Forty-three percent of them were seizure-free, 39% controlled 50-90% of seizures, and 17% did not respond. In the same year, a group from Johns Hopkins published a study conducted on 150 children aged 1-16 years. One year after starting the ketogenic diet, 7% were without seizures, 27% of children had a decrease in seizure frequency >90% and 50% a seizure frequency reduction >50%.
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Seventy children with drug resistant epilepsy were qualified for a retrospective long-term study at the University of São Paulo to assess the effectiveness and tolerability of the ketogenic diet. Within one year, in 55% of those who remained on the ketogenic diet, 70% had seizure control >75%, 25% had seizure control in the range of 50-75%, and 2.5% had seizure control <50%. The effectiveness of the ketogenic diet was significantly higher in cases of generalized epilepsy than partial epilepsy.
The Neal’s group in 2008 conducted the first randomized clinical controlled trial to assess the effectiveness of a ketogenic diet in drug-resistant epilepsy. They observed 145 children with epilepsy who did not respond to two antiepileptic drugs. The children were randomly divided into two groups: one received a ketogenic diet immediately, and the other after three months with a combination of two antiepileptic drugs. After three months, the ketogenic dietary group had a 75% reduction in seizure frequency compared to the control group. In addition, 38% of children in the ketogenic diet group had a >50% reduction in seizures, and 7% had a >90% decrease in seizure frequency. The data showed that the ketogenic diet has advantages over no change in treatment.
The published meta-analysis evaluated 270 patients, of whom 168 were given a ketogenic diet. The rates of effectiveness of a ketogenic diet in difficult-to-treat epilepsy for adults ranged from 13 to 70%. The meta-analysis showed a combined ketogenic diet efficiency rate of 42%, with significant heterogeneity in all studies. In addition, the data indicated that the ketogenic diet can be a promising complement to incurable epilepsy therapy in adults and is best started with a modified Atkins diet and then consider switching to the classic ketogenic diet if greater seizure control is required.
Recently several randomized clinical trials have been published that support the use of a ketogenic diet in the treatment of drug-resistant epilepsy, but these studies have a weak point associated with small sample sizes. For example, a randomized controlled study of a ketogenic diet in refractory pediatric epilepsy was studied for 4 months in 48 children (26 ketogenic diet, 22 care as usual) aged 1-18 years. The average seizure frequency after 4 months compared to baseline was significantly lower in the ketogenic diet group (56%) than in the care as usual group (99%). Twice as many patients in the dietary ketogenic group had a significant decrease in seizure frequency.
Martin-McGill et al. published an updated Cochrane review on the evidence for ketogenic diet anti-seizure activity from randomized clinical trials. In randomized clinical trials, 778 patients participated in 11 trials; 712 children and adolescents and 66 adults. Reported seizure freedom rates ranged from 0 to 55% after three months, and reported seizure reduction rates reached up to 85%.
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Implementation and Monitoring
A ketogenic diet should be considered for patients who have not responded adequately to therapy with two well-selected and well-dosed antiepileptic drugs. Therefore, neurologists often recommend other therapies, such as diet, including ketogenic diet, to provide patients with better antiepileptic control.
To obtain the optimum engagement of the family and the patients, providing information and training is essential because the diet is difficult to maintain. Counselors should talk with the family about their expectations and make clear the efficacy rate and adverse events (AE), to reduce the abandonment of the diet. It is also important to review the medications and change from oral solutions (carbohydrate content) to tablets. The KD counseling, evaluation and follow-up should be done by a multidisciplinary team.
Before starting the diet, the patient should maintain a seizure diary to establish a frequency parameter. Also needed are a laboratory evaluation including selenium and carnitine levels, electroencephalogram (EEG), and a magnetic resonance image (MRI) of the brain. A renal ultrasound should be done in case of kidney stones; an electrocardiogram and carotid ultrasound are considered optional. The nutritional evaluation includes a nutritional anamnesis including a 3-day food report, food habits, allergies, aversions, and intolerances. Baseline weight, height, and the ideal weight for stature and body mass index (BMI) are needed to calculate the ketogenic ratio, calories, and fluid intake.
The goal is to reach a ratio of four portion of fat to one portion of protein plus carbohydrate, described as “4:1.” To achieve this level, one of two approaches, with or without fasting, may be used. In the former approach, the patient must be hospitalized for 12-48 h, or when ketones are present in the urine, to prevent the development of hypoglycemia and dehydration. This method tends to accelerate the development of ketosis although it can generate more stress on the patient. When ketosis is reached, the meals are calculated to maintain a constant KD ratio, while calories are added until full-calorie meals are tolerated. The latter approach requires no hospitalization and the KD ratio increases weekly, from 1:1, 2:1 and 3:1 to 4:1.
Taking into account that the KD provides only small amounts of fruits, vegetables, grains, milk and cheese, supplementation is essential. Patients on the KD should be seen regularly every 3 months, and the family should be able to easily contact the diet team to resolve possible doubts and discuss adverse effects. In each evaluation, the seizure dairy and the child’s cognitive development and behavior should be observed. It has been noted that it is possible to improve the cognitive development and behavior even without a change in the seizure frequency.
Potential Mechanisms of Action
The precise mechanism of action of the ketogenic diet is not fully understood, although many possible explanations have been proposed. There are many changes that occur in the body and brain as a result of the diet, but it is unclear which of these alterations is responsible for the anticonvulsant effect. The key aspect of the ketogenic diet involves the restriction of carbohydrates, which are no longer able to be converted to glucose and provide for the body’s metabolic and energy needs.
In the absence of glucose due to lack of carbohydrates in the diet, the ketone bodies β-hydroxybutyrate, acetoacetate and acetone are synthesized and are able to cross the blood-brain barrier to provide an alternative source of energy for the brain. Neither pharmacological anticonvulsants nor the ketogenic diet is able to cure epilepsy but work due to their ability to suppress epileptic seizures.
The shift in the energy metabolism from glycolytic energy production to energy generation through oxidative phosphorylation (fatty acid b-oxidation and ketone-body production) is part of the anticonvulsant mechanism of the KD.
Several mechanisms have been proposed to explain the anticonvulsant effects of the KD, including:
- Neurotransmitter Modulation: The KD may influence the levels and activity of neurotransmitters, particularly GABA and glutamate, which play critical roles in neuronal excitability. Increased GABA levels can lead to neuronal hyperpolarization, reducing the likelihood of seizures.
- Energy Metabolism and Mitochondrial Function: The KD alters brain energy metabolism, shifting from glucose to ketone bodies as the primary fuel source. This metabolic shift may enhance mitochondrial function and energy reserve, stabilizing neuronal activity.
- Gut Microbiota Modulation: The KD can modify the gut microbiota composition, potentially influencing the production of neurotransmitters and other metabolites that affect brain function and seizure susceptibility.
- Anti-inflammatory Effects: The KD may reduce inflammation in the brain, which can contribute to seizure control.
- Epigenetic Modifications: The KD may induce epigenetic changes, such as histone deacetylation, that alter gene expression and influence neuronal function.
Production of ketone bodies and potential primary anticonvulsant mechanisms: 1 GABA neurotransmitter (neuronal hyperpolarization and membrane channels; (2) inactivation of VGLUT and inhibition of glutamate neurotransmitter; 3 modified concentrations of biogenic monoamines; and 4 antioxidant mechanism of diminishing reactive oxygen species.
Adverse Effects
Because KD is not a physiological diet, it is necessary to recognize and closely manage AE. Acute AE include dehydration, hypoglycemia, lethargy, metabolic acidosis, and gastrointestinal symptoms. However, most of the side effects involve weight loss, high levels of low-density lipoprotein, and elevated total cholesterol. The family should also be informed about how to recognize the symptoms of hypoglycemia and be advised to administer a small amount of juice or other forms of dextrose.
Adverse reactions associated with the administration of a ketogenic diet were severe dehydration or acidosis, lethargy, somnolence, severe infections, mood swings, vomiting, and constipation.
Reported seizure freedom rates ranged from 0 to 55% after three months, and reported seizure reduction rates reached up to 85%. All studies had adverse effects of dietary interventions. The most commonly reported adverse reactions were gastrointestinal syndromes. Side effects were the most common reason for participants dropping out of research. Other reasons for giving up were lack of effectiveness and lack of diet acceptance.
Contraindications
In contrast, some pathologies are considered contra-indicated for KD. Absolute contraindications have been described and summarized by Kossoff et al. (2018) (Table 3).
The Role of Gut Microbiota
The role of gut microbiota has recently been studied for its effect on several diseases, especially those with some inflammatory involvement. Several metabolic pathways are known to be modulated by the gut microbiota. Olson et al. (2018) demonstrated the impact of gut microbiota on the anti-seizure effect of KD. She found that KD modifies the gut microbiota, with a decrease in alpha-diversity and increases in the putatively beneficial bacteria Akkermansia muciniphila and Parabacteroides spp. This microbiota transformation leads to changes in the colonic luminal metabolome, with a decrease in gamma-glutamyl amino acids. This increases the GABA/glutamate content in the brain by decreasing gamma-glutamyl amino acids in the blood.
Future Directions
Considering the aforementioned studies, we have verified that the mechanisms of action of KBs, which are involved in the reduction of epileptic seizures, are distinct and complex. In addition, the major mechanisms proposed to date are based on experimental models and few clinical studies, which have small sample sizes and uncontrolled designs. Furthermore, the multiple etiologies of epilepsy represent an important limitation to the understanding of the relationships between the KD, KBs and neuronal mechanisms in the control of seizures.
Thus, we propose the following:
I - that physical or chemical mechanisms employed to induce seizures should follow standardized protocols;
II - that the physiological levels of KBs should be more frequently considered in experimental treatments;
III - that the etiologies of epilepsy are better characterized in future clinical trials;
IV - that biomarkers of treatment efficacies (levels of KBs, GABA and monoamines) are evaluated;
V - that the potential side effects of treatments are systematically monitored; and
VI - that novel mechanisms of action of KBs are evaluated.
In consideration of these proposals, positive clinical responses to the KD remain the principal goal of this treatment.
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