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Pediatric and Adult Nutrition in Chronic Diseases, Developmental Disabilities, and Hereditary Metabolic DisordersPrevention, Assessment, and Treatment$

Shirley W. Ekvall and Valli K. Ekvall

Print publication date: 2017

Print ISBN-13: 9780199398911

Published to Oxford Scholarship Online: April 2017

DOI: 10.1093/acprof:oso/9780199398911.001.0001

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Seizures and Epilepsy

Seizures and Epilepsy

(p.91) 10 Seizures and Epilepsy
Pediatric and Adult Nutrition in Chronic Diseases, Developmental Disabilities, and Hereditary Metabolic Disorders

Yael Shiloh-Malawsky

Leslie Huffman

Tuomas Westermarck

Shirley W. Ekvall

Oxford University Press

Abstract and Keywords

This chapter discusses seizures and epilepsy, including biochemical abnormalities, factors to be considered in nutritional evaluation, nutritional considerations with the use of antiepileptic drugs, and dietary management (e.g., ketogenic diets).

Keywords:   seizures, epilepsy, ketogenic diets, antiepileptic drugs, dietary management

Seizures occur in approximately 10% of all people at some time during their lives. An epileptic seizure is a transient occurrence of signs and/or symptoms caused by abnormal excessive or synchronous neuronal activity in the brain.1 An acute provoked seizure is a seizure that occurs in the context of an acute brain insult or systemic disorder; examples are acute stroke, hypoglycemia, and alcohol withdrawal. Seizures are classified as generalized, when they rapidly engage both hemispheres, or as focal (previously partial), when they originate within an area in one hemisphere.2 Commonly recognized generalized seizure types include generalized tonic-clonic seizures (formerly called grand mal) and absence seizures (formerly called petit mal). Other types of generalized seizures are tonic, clonic, atonic, and myoclonic seizures. Some seizures are not clearly define as generalized or focal; an example is infantile spasms.2 Anyone can have a seizure if the appropriate metabolic conditions are present. Relevant conditions include numerous metabolic and nutritional abnormalities.

About 0.5% to 1% of people have epilepsy, a disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. The definition of epilepsy requires the occurrence of at least one unprovoked epileptic seizure.1,3 Epilepsy is a family of disorders; it comprises many different diseases and conditions. The 2010 revised classification of seizures and epilepsy2 defines the cause of epilepsy as either genetic, when epilepsy is the direct result of known genetic defects, or structural/metabolic (previously symptomatic), when there is a known underlying brain abnormality (e.g., remote stroke, brain tumor) or a metabolic disorder known to be associated with epilepsy. At times, the etiology is described as unknown (previously cryptogenic).

Epilepsy most commonly develops during the first year of life, and more than half of epilepsy cases manifest before age 21. Another peak in epilepsy onset occurs in older age, related to the accumulation of brain insults from such conditions as remote stroke, trauma, or tumors.4 Potential causes of epilepsy in infants and children include acute brain-injuring insults such as perinatal asphyxia, sepsis, and hypoglycemia and chronic causes such as brain malformations and genetic disorders.

Biochemical Abnormalities

Common metabolic causes of acute provoked seizures are hypoxia, hypoglycemia, and electrolyte abnormalities. Hypoglycemia is more likely than hyperglycemia to cause seizures. Typical causes of hypoglycemia include hyperinsulinemic states such as insulinomas, nesideoblastosis, and excess insulin administration. It is important to recognize hypoglycemia early because antiepileptic drugs (AEDs) are unlikely to abort an ongoing seizure if the hypoglycemia is not corrected. Hypoglycemia is particularly important to recognize because there is an increased risk of permanent brain injury if this condition is prolonged.

As with hypoglycemia, seizures due to electrolyte imbalances need to be treated with appropriate correction of the underlying abnormalities; mere administration of AEDs is ineffective. The electrolyte abnormalities most commonly associated with seizures are hyponatremia and hypocalcemia.5,6 Less frequently seen in clinical practice are hypomagnesemia, hypophosphatemia, and hypokalemia.7,8,9 A common cause of hyponatremia is diarrhea when the fluid loss is replaced by a hypotonic solution. Another cause is hyponatremia due to use of the medication desmopressin, which is often administered to children with nocturnal enuresis. Hypocalcemia may be seen in vitamin D deficiency, renal disease, parathyroid disease, and pseudohypoparathyroidism (target organ resistance to parathyroid hormone).

Factors To Be Considered in Nutritional Evaluation

Nutritional deficiencies and genetic/metabolic disorders can cause or contribute to seizures, and some epilepsy syndromes respond to specific treatments based on diet or supplementation of cofactors (vitamin-responsive epilepsies). These include, among others, disorders of pyridoxine (vitamin B6), folinic acid, and glucose transporter 1 (GLUT1) deficiency.10

Abnormalities of pyridoxine metabolism due to genetic/metabolic disorders or decreased intake (pyridoxine deficiency) result in inadequate levels in the brain of pyridoxal phosphate (PLP), the active form of vitamin B6, leading to an hyperexcitable state that provokes seizures. Two genetic epilepsies cause PLP deficiency: pyridoxine-dependent seizures and PLP-dependent epilepsy.

Pyridoxine-dependent seizures result from an autosomal recessive disorder caused by mutations in the ALDH7A1 gene, which encodes the protein antiquitin.11 Seizures usually manifest in neonates but can appear later in infancy. These seizures are refractory to antiseizure medications, and the electroencephalogram (EEG) activity is very abnormal. Treatment with intravenous bolus of pyridoxine (50–100 mg) has a dramatic effect. In typical cases, the seizures stop within minutes and the EEG normalizes. There is a small risk of respiratory arrest associated with acute pyridoxine administration. Lifelong therapy with a daily dose of 50 to 200 mg of pyridoxine is effective in preventing seizures in most patients. PLP-dependent epilepsy is an autosomal recessive disorder caused by mutation in the PNPO gene, which is involved in the conversion of vitamin B6 derived from food to PLP. It is characterized by neonatal seizures that are refractory both to conventional AEDs and pyridoxine administration.12 Seizures are responsive to large daily doses of pyridoxal 5′-phosphate, 10 to 80 mg/kg/day in three or four divided doses enterally.

Dietary deficiency of pyridoxine is fairly uncommon. Isoniazid can interfere with pyridoxine metabolism and cause seizures.13 High intake of gingko has also been reported to cause seizures because it acts as an antagonist of pyridoxine.14

Another group of vitamin B–responsive epileptic disorders are the cerebral folate deficiency seizures and folinic acid–responsive seizures. Cerebral folate deficiency is characterized by low folates in the cerebrospinal fluid. The syndrome has been associated with both genetic and acquired conditions; the underlying etiology is not always well understood. In some cases, cerebral folate deficiency has been shown to be related to blocking of folate receptors by autoantibodies. It has also been shown to be associated with specific genetic mutations, such as ALDH7A1 and folate receptor 1 (FOLR1) gene mutations, as well as diverse metabolic and genetic disorders. Folinic acid–responsive seizures are characterized by cessation of seizures after oral administration of folinic acid (3–5 mg/kg/day).15,16

(p.92) The GLUT1 deficiency syndrome causes low glucose concentration in the cerebrospinal fluid; it is a genetic disorder caused by mutation of SLC2A1, the gene that encodes GLUT1.17 The classic patient with GLUT1 deficiency syndrome has drug-resistant seizures beginning in the first year of life; however, the phenotype is highly variable. Lumbar puncture should be performed with the patient in a fasting state to establish the diagnosis. Ketogenic diet (KD) is the treatment of choice of patients with GLUT1 deficiency; it has been shown to be highly effective in controlling the seizures and improving developmental outcome, although neurobehavioral and motor deficits persist in most cases.18

Other metabolic abnormalities are associated with seizures or epilepsy and respond to specific diets or nutritional supplementation. Among these are biotin deficiency, biotinidase deficiency (an enzyme abnormality), creatine deficiency, aminoacidopathies (e.g., maple syrup urine disease, phenylketonuria [PKU]), urea cycle defects (associated with hyperammonemia), Menke disease (associated with decreased serum copper and ceruloplasmin), galactosemia, hyperglycinemia, and porphyria.10

Nutritional Considerations and Antiepileptic Drugs

There are a few anecdotal reports suggesting that some foods and dietary contents might influence the occurrence of seizures, but there is little evidence that avoidance of certain foods will decrease seizure occurrence in children with epilepsy.19 Caffeine is a psychostimulant, but despite theoretical concerns, there is insufficient evidence to support pro-seizure effects of caffeine in animals or humans.20 Anecdotal reports have suggested that the high-intensity sweetener aspartame can cause seizures in some vulnerable individuals, but systematic investigations of this possibility have not supported these reports.21 Grapefruit juice can cause an increase in the serum concentration of carbamazepine (and therefore toxicity) as a result of inhibition of enzymes in the liver and gut wall.22

Women treated with AEDs are at increased risk for fetal malformations.23 There are numerous possible mechanisms for the teratogenicity, including folate deficiency. Carbamazepine, phenobarbital, and phenytoin interfere with folate absorption and may induce a folate deficiency. Supplementation with at least 0.4 mg/day folate (as recommended for all women of child-bearing potential), and up to 4 mg/day (recommended for women with a previously affected child), is recommended for women of child-bearing age with epilepsy who are at risk of becoming pregnant.24

Virtually all AEDs are excreted in breast milk. The concentration of these drugs is usually small enough that the effect on the nursing infant is negligible, although sedation has been reported with some AEDs (e.g., phenobarbital, primidone, ethosuximide). Although the data are limited, it has been shown that valproic acid, phenobarbital, phenytoin, and carbamazepine do not penetrate into breast milk in amounts that might be clinically important.24 Overall, the benefits of breast-feeding outweigh the risk of infant exposure to the low concentration of AEDs in breast milk, and breast-feeding should be encouraged unless symptoms emerge.25

The effect of AEDs on bone health and vitamin D metabolism raises important nutritional considerations. The risk for skeletal fractures in patients with epilepsy is two to five times greater than in the general population. Multiple factors contribute to this risk, including seizures, falls, and comorbidities. In addition, the use of AEDs alone is associated with an increased risk of fractures.26 AEDs were shown to have clinical effects on bone health by multiple mechanisms, including effect on vitamin D metabolism. Optimization of calcium and vitamin D intake and routine screening for calcium and vitamin D metabolites are recommended for all persons with epilepsy treated with AEDs.19,27

Dietary Management

Ketogenic Diet

For centuries, it has been observed that fasting and starvation are associated with a reduction in seizures. The KD, initially described by Wilder in 1921, was formulated to mimic the biochemical effects of starvation—that is, to induce ketosis.28 The KD was used extensively in the early to middle 20th century as a treatment for epilepsy. Its use waned as a greater variety of more conveniently administered AEDs became available. However, despite an ever-increasing number of AEDs, a significant proportion of patients remain refractory to drug treatment. In 1992, neurologists at the Johns Hopkins School of Medicine reported surprisingly high efficacy using the KD to treat medically refractory epilepsy in children, and it has remained an important option for epilepsy treatment. It is usually considered for children who have multiple seizures every week and for whom at least two (and usually more) AEDs have proved ineffective. It is also considered if surgical intervention has either failed or is not an option.29,30 When considering the KD, it is important to evaluate for metabolic conditions that may contraindicate a very-high-fat diet. Such conditions include carnitine deficiencies, beta-oxidation defects, porphyria, and pyruvate carboxylase deficiency.31

The underlying biochemical mechanism of the KD antiseizure effect is still unclear. Achieving a state of ketosis seems critical, and caloric restriction alone may have some antiseizure effect.31,32 There is experimental evidence for four distinct molecular mechanisms that could contribute to the antiseizure effect of these diets. These mechanisms include carbohydrate reduction, activation of adenosine triphosphate (ATP)–sensitive potassium channels by mitochondrial metabolism, inhibition of the mammalian target of rapamycin (mTOR) pathway, and inhibition of glutamatergic excitatory synaptic transmission.33

To achieve a state of ketosis, the KD comprises a strictly monitored number of calories, a high proportion of fat, and a combination of low-protein and low-carbohydrate foods. In the past, fluid was restricted in these patients. This is no longer practiced according to Wirrell, who stated that there is little evidence that fluid restriction is needed or beneficial.31,32 In addition, there are some reports that fluid restriction as part of the KD increases the incidence of constipation and kidney stones. The “dose” of the KD is expressed as a ratio of fat to combined protein and carbohydrate (by weight) and most commonly ranges from 3:1 to 4:1. Meal size, calories, and timing are strictly controlled. Patients started on the KD become ketotic, and parents monitor urine ketones daily with the use of urine chemsticks. Serum ketones are also elevated and can be monitored by measuring the serum concentration of beta-hydroxybutyrate. With these metabolic changes, a patient’s breath may smell sweet or may smell of acetone.

Over the past few decades, multiple versions of the KD have been established. These include the classic KD, the modified Atkins diet (MAD), the medium-chain triglyceride (MCT) oil diet, and low glycemic index diet.

The classic KD maintains a 3:1 or 4:1 ratio of fat to combined protein and carbohydrate, with 80% to 90% of calories in the diet from fat. In the past, the diet had to be calculated by hand, and foods were labeled as ketogenic or antiketogenic:

KetogenicAntiketogenic=0.90 fat+0.46 protein+0.0 carbohydrate0.10 fat+0.58 protein+1.0 carbohydrate

Today, the classic KD meals are calculated with the use of a computerized nutrient database program such as KetoDietCalculator (ketodietcalculator.org), with all food weighed on a digital gram scale. Many creative ketogenic recipes are now widely available through the efforts of dedicated dietitians and parent networks, and the increased variety has made the classic KD more palatable. There are also commercially available products that permit easier administration of the KD via gastrostomy tube feedings. In several studies, the classic KD resulted in a greater than 50% decrease in seizures in about half of treated children and complete seizure control in 10% to 15%.34 Table 10–1 shows a sample paradigm for calculating the initial KD composition.

The MAD has become popular as an alternative to the KD. It is a less restrictive option because it limits carbohydrate intake without requiring protein and calorie restriction, weighing of foods, or hospitalization when starting the diet.35 This version is most often used for adult patients who do not respond to medication and are not candidates (p.93) for surgical intervention, but it is becoming more common for pediatric patients as well. The average adult patient begins the MAD by restricting carbohydrates to 15 to 20 g/day, and pediatric patients begin at 10 to 15 g/day.36 MAD outcomes are comparable to those of the KD. In a retrospective review, about 48% of patients (adults and children combined) had a greater than 50% reduction, 26% had a greater than 90% reduction, and 13% became seizure free over a period of 3 to 6 months when MAD was used before the KD.36

The last two alternatives to the KD most used in the United States are the MCT oil diet and the Low Glycemic Index Treatment (LGIT). The MCT oil variation was traditionally considered more palatable than the classic KD. MCT oil is used as the primary source of fat calories, thereby decreasing the “volume” of fat the patient receives (Table 10–2). As improvements have been made to the classic KD, the MCT oil diet is less readily used. The LGIT limits the amount of carbohydrate, similar to MAD, but emphasizes carbohydrates that are lower on the glycemic index. Table 48–1 in Chapter 48 provides a glycemic index list. For additional information, visit the website of the Charlie Foundation for Ketogenic Therapies (www.charliefoundation.org).

The average duration of therapy with the KD and its alternatives ranges from 2 to 3 years. In some reported cases, the KD has been continued as long as 20 years.31 Supplementation with a multivitamin, calcium, and vitamin D are very important while on the KD or a KD alternative. Both medications and supplements should be taken in tablet form (i.e., a nonchewable, non-orodispersible tablet) or compounded in a sugar-free solution because of the carbohydrate content in these products.

Table 10–1. Calculation of a Typical Ketogenic Diet (KD) Composition

Steps in Calculation

Example Calculation

1. Determine caloric recommendation based on RDA; the KD should supply 75% and 100% of this amount, depending on activity level.

Assume a 6-year-old child with an ideal weight of 20 kg; the KD should supply 68 kcal/kg.

2. Calculate total calories per day.

20 kg × 68 kcal/kg = 1360 kcal/day

3. Choose the starting ratio, usually 3:1 or 4:1.

4:1 ratio = 36 kcal F for every 4 kcal combined (P + C); 36 kcal + 4 kcal = 40 kcal per “unit” of food

4. Calculate total “units” of food per day.

1360 kcal/day ÷ 40 kcal/unit = 34 units/day

5. Calculate F using the determined ratio.

4 × 34 units = 136 g F per day

6. Total of P + C will usually be 1 × units/day.

1 × 34 units = 34 g (P + C)

7. Calculate P requirement using RDA.

At 1 g P per 1 kg body weight, 1 g/kg × 20 kg = 20 g P

8. The allotment of C is the (P + C) total from step 6 minus the P requirement from step 7.

34 g − 20 g = 14 g C

9. The total daily diet is divided equally into three or four meals.

Intake of 136 g F, 20 g P, and 14 g C in three meals daily = 45 g F, 7 g P, and 5 g C per meal

10. Fluids should be calculated at 0.7–1.0 of the daily maintenance requirements and divided throughout day.

For a 20-kg child, 1050–1500 mL/day should be consumed, or 70–100 mL/hr over 15 waking hours

C = carbohydrate; F = fat; P = protein; RDA = recommended daily allowance.

Table 10–2. Calculation of the Medium-Chain Triglyceride (MCT) Diet

Steps in Calculation

Example Calculation

1. Establish caloric needs according to the RDA.

Assume a value of 1900 kcal/day.

2. Determine the amount of MCT oil to be given (50–70% of total kcal); 1 g MCT = 8.3 kcal, and 1 tbsp (15 mL) MCT = 14 g

  • 60% × 1900 kcal = 1140 kcal from MCT

  • 1140 kcal ÷ 8.3 kcal/g= 137 g MCT

  • 137 g ÷ 14 g/tbsp = 9.8 tbsp (147 mL) MCT

3. Determine the calories to be provided by foods exclusive of MCT.

1900 − 1140 = 760 kcal

4. Establish P intake according to RDA (at least 36 g of P for a 5- to 7-year-old child weighing 28 kg)

  • Assume 41 g of protein is needed.

  • 41 g × 4 kcal/g = at least 164 kcal P

5. Estimate maximum calories (19% of total) to be given in form of C.

  • 19% × 1900 = no more than 361 kcal from C

  • 361 kcal ÷ 4 kcal/g = no more than 90 g of C

6. Estimate maximum calories for P + C (29% of total)

29% × 1900 = no more than 551 kcal from (P + C)

7. Estimate minimum calories to be given in the form of F exclusive of MCT (11% of total)

  • 11% × 1900 = at least 209 kcal from other F

  • 209 kcal ÷ 9 kcal/g = 23 g F other than MCT

8. After determining all of these dietary requirements, calculate the dietary pattern using exchange lists.

The dietary requirements can be met by consumption of 9.8 tbsp MCT, 23 g other F, 41 g P, and 90 g C, plus 26 additional kcal to total 1900 kcal/day

* See Chapter 48.

C = carbohydrate; F = fat; P = protein; RDA = recommended daily allowance; tbsp = tablespoon.

Selecting those patients most likely to benefit from the KD remains a challenge. Because starting the KD involves hospitalization (in most cases), extensive education, and a commitment of at least 3 months, it is desirable to be able to predict with greater precision which patients are most likely to sustain a reduction in seizures.34 Age is a frequently cited component: The average patient ranges from 1 to 12 years of age, although there are reports of effective treatment in adults, adolescents, and infants.34,35,36

The type of seizure and epilepsy syndrome should be considered when screening candidates for a trial of the KD. Multiple published case series have shown the KD and its alternatives to be an effective antiseizure treatment.31,32,36,37,38,39 Success has also been reported for children with infantile spasms, Lennox-Gastaut syndrome, Rett syndrome, and Landau-Kleffner syndrome. KD is the recommended treatment for GLUT1 deficiency.18,40,41,42

Like other epilepsy treatments, the KD involves some risks. Common adverse effects can be short or long term. Short-term side effects may include lethargy, constipation, dehydration, hypoglycemia, emesis, weight change, increased hypercholesterolemia, and dyslipidemia. Long-term effects may include growth retardation, gastrointestinal disturbances, changes in bone metabolism, pancreatitis, increased bruising, and renal stones.31,43 To improve initial tolerance of the diet, the meals are often started at one-third of the target size (calories), given as a liquid (shake) or as regular food. Input from a dietitian is essential in implementing and fine-tuning the diet. Detrimental effects of the KD have been reported; these include heart disease and death, although they occur very rarely.31


Children prescribed the KD need to be followed closely by their physician and dietitian. Monitoring of weight and height is important for adjusting the calorie intake and ensuring that adequate growth continues. Parents should check urine ketones daily; a review of their values (p.94) will help determine whether the KD ratio needs to be increased or calories adjusted. Poor ketosis and excessive weight gain can indicate too many calories, too low a ketogenic ratio, or compliance problems. Careful assessment of the child for hair loss, lethargy, poor wound healing, abnormal bruising or bleeding, and behavior changes is also important. Laboratory values commonly checked at clinic visits are electrolytes (including calcium and phosphorus), glucose, complete blood count, total protein, albumin, amylase, blood urea nitrogen, beta-hydroxybutyrate, and creatinine. Urine is checked for blood and crystals, which could be early signs of renal stones. Also, follow-up visits are a good time to determine whether to decrease or discontinue concomitant AEDs if seizure control has improved since the introduction of the KD.


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