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Anticonvulsants are the primary treatment for epilepsy and are effective in controlling seizures in most patients. However, in about one third of patients, relapses do not resolve with medication and require non-pharmacological treatment. One of the traditional diets that allows you to implement this approach, since the beginning of the 20th century, is considered ketogenic. However, alternative options gradually appeared with approximately comparable effect.

Anticonvulsants are the primary treatment for epilepsy and are effective in controlling seizures in most patients. However, in about one third of patients, relapses do not resolve with medication and require non-pharmacological treatment. One of the traditional diets that allows you to implement this approach, since the beginning of the 20th century, is considered ketogenic. However, alternative options gradually appeared with approximately comparable effect.

The mechanism of action of the ketogenic diet

Published reports of the ketogenic diet as an effective treatment for epilepsy date back to the early 1920s. The mechanism by which the ketogenic diet suppresses seizures is still unknown, but is likely multifactorial.

The ketogenic diet uses a diet that is high in fat, adequate in protein (1 g/kg), and low in carbohydrates, which induces metabolic changes often associated with a fasting state. Changes in plasma levels of ketones, insulin, glucose, glucagon, and free fatty acids, which often begin with a short period of fasting, can occur within hours of the start of the diet and can be quite profound].

Which of these metabolic changes are primarily responsible for the reduction in seizure frequency is not known. The ketogenic diet was so named based on the theory that ketone bodies (acetoacetate, acetone, and beta-hydroxybutyrate), formed in the liver from long and medium chain fatty acids, have a direct anticonvulsant effect when crossing the blood-brain barrier. In patients on a ketogenic diet, urine and sometimes serum ketone levels are usually checked to ensure that the diet is being followed correctly, similar to monitoring anticonvulsant drug levels.

However, the importance of ketosis in the mechanism of action of the ketogenic diet is increasingly being questioned. Patients on a ketogenic diet have been shown to have increased mitochondrial biogenesis, oxidative phosphorylation, increased gamma-aminobutyric acid (GABA), decreased neuronal excitability and activation, and stabilized synaptic function. Although they may be caused by ketosis, alternative mechanisms proposed include increased plasma free fatty acids (including polyunsaturated fatty acids), reduced glucose fluctuations, increased activation of ATP-sensitive potassium channels, calorie restriction, and increased brain amino acid levels. It is also possible to inhibit the target of the rapamycin pathway and reduce glutamatergic synaptic transmission. It is likely that the ketogenic diet has several undetermined mechanisms of action, some more important than others for different forms or etiologies of epilepsy.

Indications for the ketogenic diet

Indications for the ketogenic diet

The ketogenic diet is an effective treatment for patients with epilepsy, regardless of age or type of seizure. A meta-analysis of 19 observational studies (1084 patients) found that after six months, approximately 60 percent of children who started the ketogenic diet experienced a reduction in seizures of more than 50 percent, and 30 percent had a reduction of more than 90 percent. Other meta-analyses and reviews have come to similar conclusions. Although treatment for epilepsy is more often considered in children than in adults, growing available (non-randomized) evidence suggests that adults may also benefit from such a diet, although they are more often offered the modified Atkins diet due to ease of use.

Based on the available evidence, a majority (21 out of 26) of the 2009 expert consensus group felt that a ketogenic diet should be considered in children with intractable epilepsy after two or three anticonvulsant treatments have failed. One question remains unanswered: Is the ketogenic diet better than a third or fourth drug? Although evidence suggests that the diet is more likely to be beneficial (50-60% chance of reducing seizures compared to about 30% chance with additional medications), this has never been formally studied in a randomized trial.

For patients with special conditions who appear to be particularly sensitive to the ketogenic diet, it is wise to consider this treatment as early as possible. The expert consensus group has identified conditions with strong evidence for the benefit of the ketogenic diet:

  • infantile spasms
  • epilepsy with myoclonic-atonic seizures (Duz syndrome)
  • Rett syndrome
  • tuberous sclerosis complex
  • severe myoclonic epilepsy of infancy (Drave’s syndrome)
  • pyruvate dehydrogenase deficiency
  • children with a gastrostomy tube or artificial feeding

Lower-quality or newer data support the use of dietary therapy for other conditions:

  • Landau-Kleffner syndrome
  • Lennox-Gastaut syndrome
  • absence epilepsy
  • subacute sclerotic panencephalitis
  • juvenile myoclonic epilepsy
  • refractory status epilepticus
  • focal and generalized epilepsy

Contraindications to the ketogenic diet

Contraindications to the ketogenic diet

Fasting or the use of a ketogenic diet in individuals with inborn metabolic disorders that affect the transport or oxidation of long-chain fatty acids can lead to a devastating catabolic crisis. The ketogenic diet can also aggravate acute intermittent porphyria.

Absolute contraindications to the ketogenic diet include:

  • primary carnitine deficiency
  • carnitine palmitoyltransferase I or II deficiency
  • carnitine translocase deficiency
  • porphyria
  • fatty acid oxidation defects
  • pyruvate carboxylase deficiency

Patients with clinical signs suggestive of one of these diagnoses (cardiomyopathy, hypotension, exercise intolerance, myoglobinuria, mild fatigue) should be evaluated to rule out one of these conditions. In contrast, patients with defects in the mitochondrial respiratory chain complex and epilepsy were safely and effectively treated with the ketogenic diet.

A number of other conditions can make dieting difficult, interfere with dieting, increase the risk of side effects, or suggest that alternative treatments may be more effective:

  • candidates for epilepsy surgery
  • failure to provide adequate nutritional status
  • special dietary requirements or preferences
  • lack of understanding from parents or guardians
  • medical conditions that may be exacerbated by diet, including kidney stones, dyslipidaemia, liver disease, gastroesophageal reflux disease, constipation, cardiomyopathy, and chronic metabolic acidosis

Composition of the ketogenic diet

Composition of the ketogenic diet

The traditional ketogenic diet consists of four parts fat to one part protein and carbohydrates (that is, the ratio of lipids to non-lipids is 4:1). Total calories are limited to 80 to 90 percent of age-appropriate recommended values, but dietitians typically match calories against pre-ketogenic diet baseline levels. Changing the diet to a slightly lower fat content (3:1 lipid/non-lipid ratio versus the traditional 4:1 ratio) improves diet tolerance but may reduce its effectiveness during the first three months.

Alternatively, the diet may be given as a liquid based formula for formula-fed infants and enterally fed patients. There are a number of commercially available products. Since the diet is easy to administer in this form, adherence and efficacy in this population is usually extremely high.

All children are started on a regular carbohydrate-free multivitamin, calcium, and vitamin D. Based on evidence for a reduced risk of kidney stones, daily potassium citrate supplements (2 mg/kg per day) are also recommended for all children.

Switching to a ketogenic diet

It is best to begin the transition to this diet under the supervision of a qualified dietitian and neurologist in a specialized center in which they are familiar with the ketogenic diet and successfully use it to control epilepsy.

The traditional ketogenic diet is started in the hospital after a 24-hour fast. The daily caloric intake and/or ratio of the ketogenic diet is then gradually increased until full ketogenicity for home use is achieved. After an average hospital stay of three to four days, the child is discharged home.

During hospitalization, serum glucose is often monitored every six to eight hours, and urinary ketones are monitored daily. If serum glucose falls below 30 mg/dl, a small amount of orange juice is given. Medications usually remain unchanged during the first month of the diet, although they are replaced with carbohydrate-free preparations.

One of the most important reasons for admission is the education of parents and guardians. Most hospitals schedule lectures and study sessions during appointments.

Following a ketogenic diet

Following a ketogenic diet

Once children transition to a ketogenic diet, they should be seen at the clinic for follow-up every three months during the first year of treatment, with more frequent (sometimes monthly) visits for infants and those at higher nutritional risk. Calorie intake, height and body weight are monitored at each visit. Caloric intake should be adjusted for excessive weight loss or gain. Contact by email and phone between clinic appointments is also recommended.

Laboratory studies, including complete blood count, comprehensive metabolic profile, fasting lipid profile, carnitine profile, urinalysis, urinary calcium and urinary creatinine, are recommended every three months. Parents are advised to measure urine ketones several times a week using test strips. The value of monitoring serum ketones is unclear.

Some children may also need laxatives if they become constipated and/or additional doses of selenium, salt, or carnitine if they have appropriate laboratory abnormalities. The ketogenic ratio can be adjusted if there is loss of seizure control or decreased ketosis.

The clinical response to the diet is rapid, usually within a few weeks. Its efficacy can usually be established in individual patients within two to three months of starting treatment.

Additional studies include serum levels of selenium, zinc, beta-hydroxybutyrate, as well as renal ultrasound and densitometry.

Anticonvulsants and the ketogenic diet

Factors to consider when prescribing anticonvulsants to patients starting diet therapy:

  • although the combination of carbonic anhydrase inhibitors (topiramate, zonisamide) and a ketogenic diet would be expected to increase the risk of kidney stones, this is not the case. In one case series of 221 children on the keto diet, kidney stones were no more common in those taking these anticonvulsants than in any other diet. However, metabolic acidosis may worsen with this combination (especially with zonisamide) and should be monitored, especially in the first weeks/months after starting the keto diet.
  • the use of valproate in the setting of a ketogenic diet may increase the risk of secondary carnitine deficiency and there are rare reports of hepatotoxicity. In children taking this therapeutic combination, enhanced monitoring of liver function tests and carnitine levels may be appropriate. In at least one report of liver dysfunction occurring in a child taking valproate, liver enzymes returned to normal after discontinuation of the drug and resumption of the keto diet. Several cases of pancreatitis have been reported in children on a ketogenic diet who were also taking valproate.
  • in one report of 115 patients on a ketogenic diet, a reduction in seizure frequency of more than 50 percent was more common in patients taking zonisamide, while this was less likely to be achieved in patients taking phenobarbital
  • one study showed lower efficacy with combined use of lamotrigine

The introduction of the ketogenic diet was not associated with a change in plasma concentrations of anticonvulsants in one case series of 51 children, suggesting that no dose adjustments or additional monitoring of drug levels is required in patients on the ketogenic diet beyond what is otherwise required.

If seizure control is achieved on a ketogenic diet, then the dose of anticonvulsants can be gradually reduced and stopped. The results of one series of clinical cases suggest that this may occur as early as the first month. In about 20 percent of patients, anticonvulsants were successfully discontinued. Temporary deterioration was more likely when the drug being reduced was phenobarbital or a benzodiazepine. Most patients on a ketogenic diet continue to take at least one anticonvulsant drug.

Alternatives to the ketogenic diet

MST diet. In the classic ketogenic diet, fat comes primarily from long-chain triglycerides derived from standard foods; protein intake is based on what is required for growth and carbohydrates are limited. An alternative form of the ketogenic diet uses medium chain triglycerides (MCTs) found in an oil supplement as the main source of fat. MCTs produce more ketones, are absorbed more efficiently, and are transported directly to the liver. As a result, less total fat is required in the diet and more protein and carbohydrates can be allowed.

A randomized controlled trial found no difference in efficacy or tolerability between the traditional ketogenic diet and the MCT diet, however there may be individual differences. Initially, 60 percent of the energy source came from MCTs. In some children, this rate needs to be reduced to 30 to 50 percent to minimize gastrointestinal symptoms. MCTs should be given with every meal, or even divided into several smaller meals, to improve tolerance.

Modified Atkins Diet. An alternative diet designed to mimic some aspects of the ketogenic diet, but allows more protein, fluids, and calories without restriction. The diet begins on an outpatient basis without fasting. Carbohydrates are initially limited to 10 grams per day (15 to 20 grams per day for teens and adults), and patients are encouraged to increase their intake of high-fat foods (at the expense of protein). At implementation, most parents will provide their child with a ketogenic diet of approximately 1:1–2:1 (although weighing and measuring foods is not recommended in this regimen). For the first month, a ketogenic liquid supplement (KetoCal shake) can be used to increase the ketogenic ratio. All children are started on multivitamins and calcium, and laboratory tests are performed identically to the traditional ketogenic diet. After one to three months of carbohydrate restriction, the dose of anticonvulsants may be reduced as clinically indicated.

The effectiveness of the diet has been reported in more than 25 studies, including one randomized trial in children. Overall, 175 of the 390 patients enrolled (45%) had at least more than a 50% reduction in seizures at six months, and 96 (25%) had more than 90% fewer seizures. When this cohort was specifically analyzed for adults, the results were less reliable, with 26 of 90 (29 percent) having more than a 50 percent reduction in seizure frequency, and 10 (11 percent) having more than a 90 percent reduction in seizure frequency.

Diet with a low glycemic index. An even less restrictive low-glycemic diet restricts carbohydrate intake to 40–60 grams per day, does not restrict fluid or protein, and has little control over fat and calories. It is started on an outpatient basis without a fasting period. As with other diets, most children on this diet consume significantly more fat than before. Unlike the modified Atkins diet, the type of carbohydrates is important in this diet, only low glycemic index carbohydrates (<50) are allowed. These carbs include strawberries and whole grain bread, as opposed to potatoes, white bread, and most citrus fruits. Serum ketosis is almost non-existent in patients on this diet.

Results from one center demonstrated early benefit of this diet in 74 patients, with 32 percent of participants reporting more than a 50 percent reduction in seizure frequency three to three months after implementation.

Side effects of epilepsy diets

It should be understood that dietary treatment for epilepsy is neither a healthy diet nor a non-drug method free of potential side effects. A significant proportion of patients in whom the diet has significantly reduced the frequency of seizures stop the diet early because of poor tolerability.

Parents and caregivers should be informed of the common, occasional, and rare side effects that may occur in the short term when using dietary treatment, especially the ketogenic diet. Fortunately, most side effects are predictable, often preventable, and only rarely lead to diet discontinuation on their own.

Relative common side effects:

  • Gastrointestinal symptoms. Diarrhea, constipation, nausea, vomiting, and exacerbation of gastroesophageal reflux are some of the most common side effects, occurring in more than half of children on a ketogenic diet. They are usually treated symptomatically with proton pump inhibitors, laxatives, and other agents as needed.
  • Dyslipidemia. While abnormal lipid parameters are common, severe hypercholesterolemia and hypertriglyceridemia are less common. Most changes normalize spontaneously, even without dietary or other intervention, and only a minority of patients require specialized medications. The atherogenic effects of the ketogenic diet, if any, are unknown, but do not appear to occur in children who have been observed years after it has been discontinued.
  • Hypoglycemia. One or more episodes of hypoglycemia occur in about 25% of patients during the first week. Fasting before a diet may increase the risk of hypoglycemia and lethargy, especially in young children (under 2 years of age).
  • Other laboratory abnormalities. Hyperuricemia, hypoproteinemia, hypomagnesemia, hyponatremia, metabolic acidosis are sometimes observed, which should be monitored, but usually the deviations are insignificant. Significant metabolic acidosis requiring treatment may be more common in children who are also taking topiramate or zonisamide. Rare cases of severe hypercalcemia have been reported.
  • Growth retardation. Most children on a ketogenic diet fall into the lower percentiles for height and body weight. Younger children who are on a diet for a longer period of time are most at risk. In one small series of clinical cases, stunting was most pronounced in people with the most severe ketosis. The higher protein content of the MCT diet does not seem to improve the situation.
  • Carnitine deficiency. Carnitine levels usually decrease during the first months of a ketogenic diet, but severe deficiency is rare (<20%). Indicators usually stabilize or improve spontaneously, without the use of nutritional supplements. They are recommended mainly for those who have symptoms of fatigue and lethargy associated with low carnitine levels.
  • Bone diseases. Osteopenia, osteoporosis, and bone fractures are a concern in children on a ketogenic diet, as well as in children on chronic anticonvulsants. Prophylactic calcium and vitamin D supplementation is mandatory for all children on such a diet, but sometimes cannot prevent further bone loss. There is as yet no well-defined role for the use of bone scanning and/or other therapies in these conditions to reduce the risk of bone loss and fractures.
  • Nephrolithiasis. Kidney stones can occur in 7% of children. If fluid intake is normal, the incidence is likely lower, and in one study it was reduced to less than 1 percent with potassium citrate supplementation. The risk of kidney stones is highest in individuals with underlying urologic abnormalities or a personal or family history of nephrolithiasis.
  • Selenium deficiency. Selenium deficiency has been found in 20 percent of children on the ketogenic diet and has caused irreversible cardiomyopathy and sudden death in several reports of children on the ketogenic diet. Cardiomyopathy and QT interval prolongation have also been described in patients on a ketogenic diet who were not deficient in selenium. Although selenium levels can be checked, not all experts believe that this should be done regularly.

More rare complications:

  • Pancreatitis. Pancreatitis has been reported in several children on the ketogenic diet. In most cases, but not all, there was another risk factor for pancreatitis, usually valproate.
  • Increased frequency of seizures. Occurs in about five percent of children, as with any anticonvulsant drug.
  • Iron deficiency. Iron deficiency anemia has been observed in a small number of patients on a ketogenic diet.
  • Hemorrhagic diathesis. An increase in bruising and light bleeding has been reported in patients on the ketogenic diet, suggesting an effect of the diet on platelet function. As a rule, this does not require any special intervention.
  • Vascular changes. Several studies have documented a transient decrease in carotid distensibility in children on a ketogenic diet. The clinical significance of this is currently unclear.

Once the diet is stopped, most of these side effects disappear. In a study of 101 children who had stopped the diet an average of six years prior, height, body weight, cholesterol levels, and eating habits were normal. There was no increased risk of late cardiovascular disease, bone fractures, or kidney stones. Most patients ate normal food years after the keto diet without problems.

Conclusions

Dietary therapy is an effective, safe, non-pharmacological treatment for intractable childhood epilepsy. Reductions in seizure frequency of more than 50 percent occur in 38 to 60 percent of patients, and in 30 percent, more than 90 percent.

Most experts believe that the ketogenic diet is an appropriate treatment option for patients who have not been helped by at least two anticonvulsant medications. There are certain conditions for which the ketogenic diet is particularly effective and may be suggested earlier.

It is important to note that patients with intractable focal epilepsy who are candidates for epilepsy surgery are likely to respond better to epilepsy surgery than to a ketogenic diet.

Before starting a ketogenic diet, patients should be evaluated for potential contraindications and/or factors that may complicate its use.

The ketogenic diet should be supervised by a qualified nutritionist at an epilepsy center.
Alternative diets include the medium chain triglyceride diet, which is similar in efficacy to the traditional diet. The modified Atkins diet and the low glycemic index diet also seem to be effective and may be beneficial for children and adults.

Side effects are usually mild, predictable, preventable, and rarely lead to discontinuation of the diet. The most significant of these are constipation, acidosis, growth retardation, dyslipidemia, kidney stones and bone fractures.

The ketogenic diet is generally recommended for a minimum of three months and a maximum of two years; however, longer periods of effective use have been described. In the absence of severe adverse effects, a slow dose reduction is recommended, but if necessary, the diet can be abandoned more quickly.
Small case series have reported the use of ketogenic diets for indications other than epilepsy (eg, autism, brain tumors, and Alzheimer’s disease). However, before they can be recommended, further study of the relationship between efficacy and safety is required.

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