3.3.1 Diet initiation

Currently, it is recommended that the CKD be initiated with the child in hospital [2]. The advantages of an inpatient admission include the ability to closely observe


expected, a 3-day food diary may be useful to discover potential oversights in diet

Ketogenic Diet Therapies in Children and Adults with Epilepsy

DOI: http://dx.doi.org/10.5772/intechopen.83711

The pediatric neurologist and dietitian should be in frequent phone or email contact with the caregiver during the initial weeks of the diet, with additional follow-up visits occurring at 1, 3, 6, 9, and 12 months, and every 6 months thereafter [2]. The pediatric neurologist should document the child's seizure response, and regardless of any improvement, resist altering their anti-epileptic drugs unless necessary; alterations may make it difficult to gauge diet efficacy on seizure control. Recommended follow-up tests include complete blood count, electrolytes, liver and kidney function tests, fasting lipid profile, calcium, and vitamin D [2]. Since ketogenic diets and anti-epileptic drugs may predispose a child to osteopenia, some pediatric ketogenic services perform a bone density scan after 2 years on the diet [2]. The dietitian should monitor the child's physical parameters and nutritional intake at every visit. Ketogenic diets have a diuretic effect and fluid content in the food may be lessened, therefore fluid hydration must be monitored, and increased if

Both the caregiver and the pediatric ketogenic service must monitor the child for adverse effects. Gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and constipation appear in up to 50% of children on the CKD, but are easily remedied by increasing fluid, salt, and fiber intake [2]. Hyperlipidemia is common, with raised triglyceride and low-density lipoprotein (LDL) levels seen in up to 60% of children on the CKD, but the increase is usually transient and normalizes within 1 year; if desired, the LDL can be lowered by altering the types of fats ingested (for example, by increasing olive oil and decreasing saturated fats) [2]. Moreover, ketogenic diets may slightly inhibit a child's growth; adjustments in calorie intake may compensate. Kidney stones may occur in 3–7% of children on the CKD, but can be prevented with oral citrates [2]. Ultimately, such common adverse effects are rarely sufficient reasons to discontinue the CKD, but rarer adverse effects such as cardiomyopathy, prolonged

Upon ceasing a ketogenic diet, the long-term benefits on seizure control often outlast the diet itself. In children who become seizure-free on a ketogenic diet, 80% will remain so after diet cessation [45], an effect that can persist for many years. The child's ketogenic diet should be maintained for at least 3 months before passing judgment on its efficacy in seizure control [2]. The exception to this rule is if the seizures worsen for longer than 1–2 weeks after commencing the diet, or if a serious adverse effect occurs—in either case, it may be wise to discontinue the diet

If a child experiences the "usual" greater than 50% seizure reduction, the ketogenic diet is usually discontinued after 2 years [2]. In new-onset infantile spasms, the diet can be ceased at 6 months [46]. In drug-resistant epilepsy in which seizure control is virtually complete (over 90% seizure reduction) and GLUT1 DS, the diet can be carried into adulthood [2]. Older children may start to see their diet as overly restrictive; if it effectively controls the seizures, it may be switched over to another type of ketogenic diet (for example, from a CKD or MCT diet to a MAD or LGIT diet). A child's ketogenic diet should be ceased gradually (over several months) [2]. In

the case of the CKD, the ratio can be reduced by decreasing the ratio of fat to protein plus carbohydrate monthly, from 4:1 to 3:1 to 2:1 to 1:1, allowing the child to gradually adapt to the decreasing fat intake, followed by the reintroduction of regular foods. However, it is usually still possible to cease the diet more rapidly (over several weeks) without negative consequences, although some children may

QT interval, and pancreatitis may provide sufficient reason to do so.

implementation.

necessary [26].

3.3.3 Diet cessation

sooner.

157

### Table 5.

Implementing a ketogenic diet in a child with epilepsy.

the child, medically intervene if necessary, and provide more time to educate the caregiver on how to maintain the diet upon returning home.

Traditionally, a 12–24 hours fast has been used to commence the diet in an inpatient setting [2]. Fasting may lead to a quicker onset of seizure reduction, which may be useful in refractory status epilepticus [2]. However, induction fasts do not improve ketosis or seizure control at 3 months, and fasted children experience weight loss, hypoglycemia, and acidosis more frequently, which may increase the length of hospital stay [42]. Thus, although an induction fast should be considered, most pediatric ketogenic services no longer routinely fast children, and none recommend fasting infants under 2 years of age [2].

Regardless of whether an induction fast is utilized, several approaches may be used to introduce the CKD in hospital [2]. One approach involves starting the diet at one-third or one-half of the final calorie level, increasing the calories by one-third or one-half over several days until full calorie intake is achieved, keeping the fat to protein to carbohydrate ratio constant. Another approach is to start with full calorie intake, but increase the ratio of fat to protein plus carbohydrate daily, from 1:1 to 2:1 to 3:1 to 4:1, allowing the child to gradually adapt to the increasing fat intake. Yet another approach is to simply commence the CKD at full calories and a 4:1 ratio on the first day, which does not appear to prolong hospital stay, increase adverse effects, or decrease diet efficacy at 3 months.

In older children, the CKD may be initiated as an outpatient, the advantages of which include reduced family stress and fewer hospital-associated costs [2]. Most pediatric ketogenic services also routinely initiate the less-restrictive MAD and LGIT diet in the outpatient setting. If a graded introduction is required at home, clear instructions must be given to the caregiver on how to do so.

### 3.3.2 Diet maintenance

Once initiated, ketogenic diets tend to work rapidly and effectively, with 75% of children responding within 14 days [43]. Complete seizure freedom often occurs within several months of initiation, although it may take up to 18 months [44]. The caregiver should monitor the child's ketone levels (ideally, the blood BHB level) daily for the first several weeks, then two or three times a week once readings consistently show the child to be in physiological ketosis. Most pediatric ketogenic services recommend a blood BHB level of 4–6 mmol/L, although this is not based on clinical evidence [3]. If seizure control or ketone levels are not responding as

expected, a 3-day food diary may be useful to discover potential oversights in diet implementation.

The pediatric neurologist and dietitian should be in frequent phone or email contact with the caregiver during the initial weeks of the diet, with additional follow-up visits occurring at 1, 3, 6, 9, and 12 months, and every 6 months thereafter [2]. The pediatric neurologist should document the child's seizure response, and regardless of any improvement, resist altering their anti-epileptic drugs unless necessary; alterations may make it difficult to gauge diet efficacy on seizure control. Recommended follow-up tests include complete blood count, electrolytes, liver and kidney function tests, fasting lipid profile, calcium, and vitamin D [2]. Since ketogenic diets and anti-epileptic drugs may predispose a child to osteopenia, some pediatric ketogenic services perform a bone density scan after 2 years on the diet [2]. The dietitian should monitor the child's physical parameters and nutritional intake at every visit. Ketogenic diets have a diuretic effect and fluid content in the food may be lessened, therefore fluid hydration must be monitored, and increased if necessary [26].

Both the caregiver and the pediatric ketogenic service must monitor the child for adverse effects. Gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and constipation appear in up to 50% of children on the CKD, but are easily remedied by increasing fluid, salt, and fiber intake [2]. Hyperlipidemia is common, with raised triglyceride and low-density lipoprotein (LDL) levels seen in up to 60% of children on the CKD, but the increase is usually transient and normalizes within 1 year; if desired, the LDL can be lowered by altering the types of fats ingested (for example, by increasing olive oil and decreasing saturated fats) [2]. Moreover, ketogenic diets may slightly inhibit a child's growth; adjustments in calorie intake may compensate. Kidney stones may occur in 3–7% of children on the CKD, but can be prevented with oral citrates [2]. Ultimately, such common adverse effects are rarely sufficient reasons to discontinue the CKD, but rarer adverse effects such as cardiomyopathy, prolonged QT interval, and pancreatitis may provide sufficient reason to do so.

### 3.3.3 Diet cessation

the child, medically intervene if necessary, and provide more time to educate the

Initiation Decide whether to initiate as inpatient or outpatient

Maintenance Caregiver monitors seizure control and ketone levels

Cessation Identify when diet should be ceased (if ever)

Monitor for adverse effects

If inpatient, decide on induction fast and diet introduction If outpatient, provide clear instructions to caregiver

If to be ceased, consider switching to another ketogenic diet

Review at 1, 3, 6, 9, 12 months, and 6-monthly after

If to be ceased, decide on rate of diet cessation

Traditionally, a 12–24 hours fast has been used to commence the diet in an inpatient setting [2]. Fasting may lead to a quicker onset of seizure reduction, which may be useful in refractory status epilepticus [2]. However, induction fasts do not improve ketosis or seizure control at 3 months, and fasted children experience weight loss, hypoglycemia, and acidosis more frequently, which may increase the length of hospital stay [42]. Thus, although an induction fast should be considered, most pediatric ketogenic services no longer routinely fast children, and none rec-

Regardless of whether an induction fast is utilized, several approaches may be used to introduce the CKD in hospital [2]. One approach involves starting the diet at one-third or one-half of the final calorie level, increasing the calories by one-third or one-half over several days until full calorie intake is achieved, keeping the fat to protein to carbohydrate ratio constant. Another approach is to start with full calorie intake, but increase the ratio of fat to protein plus carbohydrate daily, from 1:1 to 2:1 to 3:1 to 4:1, allowing the child to gradually adapt to the increasing fat intake. Yet another approach is to simply commence the CKD at full calories and a 4:1 ratio on the first day, which does not appear to prolong hospital stay, increase adverse

In older children, the CKD may be initiated as an outpatient, the advantages of which include reduced family stress and fewer hospital-associated costs [2]. Most pediatric ketogenic services also routinely initiate the less-restrictive MAD and LGIT diet in the outpatient setting. If a graded introduction is required at home,

Once initiated, ketogenic diets tend to work rapidly and effectively, with 75% of children responding within 14 days [43]. Complete seizure freedom often occurs within several months of initiation, although it may take up to 18 months [44]. The caregiver should monitor the child's ketone levels (ideally, the blood BHB level) daily for the first several weeks, then two or three times a week once readings consistently show the child to be in physiological ketosis. Most pediatric ketogenic services recommend a blood BHB level of 4–6 mmol/L, although this is not based on clinical evidence [3]. If seizure control or ketone levels are not responding as

clear instructions must be given to the caregiver on how to do so.

caregiver on how to maintain the diet upon returning home.

ommend fasting infants under 2 years of age [2].

Stage Steps

Epilepsy - Advances in Diagnosis and Therapy

Implementing a ketogenic diet in a child with epilepsy.

effects, or decrease diet efficacy at 3 months.

3.3.2 Diet maintenance

156

Table 5.

Upon ceasing a ketogenic diet, the long-term benefits on seizure control often outlast the diet itself. In children who become seizure-free on a ketogenic diet, 80% will remain so after diet cessation [45], an effect that can persist for many years.

The child's ketogenic diet should be maintained for at least 3 months before passing judgment on its efficacy in seizure control [2]. The exception to this rule is if the seizures worsen for longer than 1–2 weeks after commencing the diet, or if a serious adverse effect occurs—in either case, it may be wise to discontinue the diet sooner.

If a child experiences the "usual" greater than 50% seizure reduction, the ketogenic diet is usually discontinued after 2 years [2]. In new-onset infantile spasms, the diet can be ceased at 6 months [46]. In drug-resistant epilepsy in which seizure control is virtually complete (over 90% seizure reduction) and GLUT1 DS, the diet can be carried into adulthood [2]. Older children may start to see their diet as overly restrictive; if it effectively controls the seizures, it may be switched over to another type of ketogenic diet (for example, from a CKD or MCT diet to a MAD or LGIT diet).

A child's ketogenic diet should be ceased gradually (over several months) [2]. In the case of the CKD, the ratio can be reduced by decreasing the ratio of fat to protein plus carbohydrate monthly, from 4:1 to 3:1 to 2:1 to 1:1, allowing the child to gradually adapt to the decreasing fat intake, followed by the reintroduction of regular foods. However, it is usually still possible to cease the diet more rapidly (over several weeks) without negative consequences, although some children may

experience a higher risk of increased seizures during the tapering-down period. If medically necessary, ketogenic diets can be stopped abruptly; this is best done in hospital.

In 2014, a review of all subsequently published ketogenic diet studies in adults with drug-resistant epilepsy was published [50]. Five studies examined the use of a CKD to treat a combined total of 47 adults with drug-resistant epilepsy. After 3–26 months, 15 patients (32%) had a greater than 50% seizure reduction, with 24 patients (51%) stopping the diet before study completion. Another five studies examined the use of a MAD to treat a combined total of 85 adults with drugresistant epilepsy. After 3–12 months, 24 patients (28%) had a greater than 50% seizure reduction, with 36 patients (42%) stopping the diet before completion. For

In 2016, the largest observational study of a ketogenic diet in adults with drugresistant epilepsy was published, in which 106 patients were treated with a MAD [48]. After 3 months, 38 patients (36%) had a greater than 50% seizure reduction, with 47 patients (44%) not completing the study, largely due to diet restrictiveness. Pooling the results from these single-arm studies suggests that 30–40% of adults with drug-resistant epilepsy experience a greater than 50% seizure reduction after 3 or more months on a ketogenic diet. While these results are encouraging, they emanate from single-arm studies; moreover, 40–50% of adults stopped their diet before study completion. Clearly, randomized controlled trials involving less restrictive ketogenic diets are needed in adults with drug-resistant epilepsy.

Ketogenic diets remain standard treatments for disorders of impaired brain glucose metabolism in adults [47]. In GLUT1 DS, ketogenic diets have been shown to confer seizure freedom in up to 90% of patients, including adults [47]. The prognosis in more severe forms of PDHD may be poor, but less severely affected individuals may benefit from a ketogenic diet as they transition to adulthood.

In addition to GLUT1 DS and PDHD, ketogenic diet therapy may be warranted in several seizure disorders often seen in adults, including juvenile myoclonic epilepsy (JME), Lennox-Gastaut syndrome, and Rett syndrome [48]. JME is particularly common, representing 5–10% of all epilepsy cases, and typically manifests in adolescence or early adulthood with a combination of myoclonic jerks or seizures, absence seizures, and generalized tonic-clonic seizures. In two separate case series, 60–70% of adolescents and adults with JME experienced a 50% seizure reduction

Once the adult has been selected for the diet, a medical and nutritional evaluation is advised (Table 7) [3, 47]. If possible, a cohabiting partner (spouse or family member) should accompany the adult to the evaluations, and ideally participate in

A brief medical evaluation should be performed by a neurologist with experience managing ketogenic diets in adults, and should include a history of the epilepsy, comorbidities, psychological and socioeconomic factors, level of commitment

First, the neurologist must ascertain the adult's baseline epilepsy state and any comorbidities that may complicate their ketogenic diet. The symptomatology and frequency of the various types of seizures should be documented in sufficient detail

so as to later gauge diet efficacy on seizure control. Potentially complicating

both diets, most patients withdrew due to culinary and social restrictions.

Ketogenic Diet Therapies in Children and Adults with Epilepsy

DOI: http://dx.doi.org/10.5772/intechopen.83711

4.1.2 Specific seizure disorders in adults

after 3 months of MAD therapy [51, 52].

to the diet, medications, and investigations [47].

the diet alongside them.

4.2.1 Medical evaluation

159

4.2 Preparing an adult (and partner) for a ketogenic diet
