4. Ketogenic diet therapies in adults with epilepsy

Few epilepsy centers in the world offer a dedicated adult ketogenic service [3]. Such a service should consist of a neurologist, nurse, dietitian, and ideally a psychologist and social worker [3, 47].

### 4.1 Selecting the right adult for a ketogenic diet

Ketogenic diets in adults are indicated in drug-resistant epilepsy and certain seizure disorders (Table 6); they may be used in adults of all ages [47].

### 4.1.1 Drug-resistant epilepsy in adults

In 2010, the ILAE defined drug-resistant epilepsy as the failure of adequate trials of two appropriately chosen, tolerated, and used anti-epileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom [28]. Since adults may suffer from drug-resistant epilepsy for decades, many adult patients have already failed multiple trials of anti-epileptic drugs over their lifetime.

Further anti-epileptic drug trials and epilepsy surgery may be feasible options in adults with drug-resistant epilepsy [30]. However, subsequent drug trials confer only a slight (about 5%) chance of inducing seizure remission [31]. Surgery should always be considered, but some eligible adults may not be ready to pursue surgery [48], and many others will not be eligible due to a generalized or multifocal epilepsy syndrome, or nonresectable lesion of ictal onset.

When drug trials and surgery are not feasible, a ketogenic diet may be indicated [48]. Many single-arm studies have demonstrated the efficacy and safety of ketogenic diets in treating drug-resistant epilepsy in adults, but to date there are no randomized controlled trials of a ketogenic diet in adults with drug-resistant epilepsy.

Surprisingly, a 1930 study remains the largest retrospective case series to examine a ketogenic diet in adults with epilepsy [49]. In this study, 100 adolescents and adults with epilepsy were treated with a CKD. After 1–46 months, 56% of patients had a greater than 50% seizure reduction.

ILAE = International League Against Epilepsy; GLUT1 DS = GLUT1 deficiency syndrome; PDHD = pyruvate dehydrogenase complex deficiency; JME = juvenile myoclonic epilepsy.

### Table 6.

Epilepsy disorders in adults for which a ketogenic diet may be indicated; this list is not comprehensive.

### Ketogenic Diet Therapies in Children and Adults with Epilepsy DOI: http://dx.doi.org/10.5772/intechopen.83711

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

Few epilepsy centers in the world offer a dedicated adult ketogenic service [3]. Such a service should consist of a neurologist, nurse, dietitian, and ideally a psy-

Ketogenic diets in adults are indicated in drug-resistant epilepsy and certain

In 2010, the ILAE defined drug-resistant epilepsy as the failure of adequate trials

Further anti-epileptic drug trials and epilepsy surgery may be feasible options in adults with drug-resistant epilepsy [30]. However, subsequent drug trials confer only a slight (about 5%) chance of inducing seizure remission [31]. Surgery should always be considered, but some eligible adults may not be ready to pursue surgery [48], and many others will not be eligible due to a generalized or multifocal epilepsy

When drug trials and surgery are not feasible, a ketogenic diet may be indicated [48]. Many single-arm studies have demonstrated the efficacy and safety of ketogenic diets in treating drug-resistant epilepsy in adults, but to date there are no randomized

Surprisingly, a 1930 study remains the largest retrospective case series to examine a ketogenic diet in adults with epilepsy [49]. In this study, 100 adolescents and adults with epilepsy were treated with a CKD. After 1–46 months, 56% of patients

ILAE = International League Against Epilepsy; GLUT1 DS = GLUT1 deficiency syndrome; PDHD = pyruvate

Epilepsy disorders in adults for which a ketogenic diet may be indicated; this list is not comprehensive.

PDHD

Lennox-Gastaut syndrome

Rett syndrome

controlled trials of a ketogenic diet in adults with drug-resistant epilepsy.

General disorder Specific disorder Drug-resistant epilepsy 2010 ILAE definition

Disorders of brain metabolism GLUT1 DS

Specific seizure disorders JME

dehydrogenase complex deficiency; JME = juvenile myoclonic epilepsy.

of two appropriately chosen, tolerated, and used anti-epileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom [28]. Since adults may suffer from drug-resistant epilepsy for decades, many adult patients have already failed multiple trials of anti-epileptic drugs over their

seizure disorders (Table 6); they may be used in adults of all ages [47].

4. Ketogenic diet therapies in adults with epilepsy

4.1 Selecting the right adult for a ketogenic diet

syndrome, or nonresectable lesion of ictal onset.

had a greater than 50% seizure reduction.

chologist and social worker [3, 47].

Epilepsy - Advances in Diagnosis and Therapy

4.1.1 Drug-resistant epilepsy in adults

hospital.

lifetime.

Table 6.

158

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

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.

### 4.1.2 Specific seizure disorders in adults

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

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

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 the diet alongside them.

### 4.2.1 Medical evaluation

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

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

Finally, investigations should be ordered to rule out contraindications to a ketogenic diet (as a rule, it is not necessary to screen for disorders of fat metabolism in adults, unless the history suggests otherwise) [47]. Laboratory investigations include complete blood count, electrolytes, liver and kidney function tests, fasting lipid profile, calcium, vitamin D, and a urinalysis [3]. Given that the effects of a ketogenic diet on pregnancy are not known [3], pregnancy testing may be indicated in women of childbearing age. Baseline anti-epileptic drug levels can be measured, although few concerns for drug-diet interactions exist. A recent EEG and MRI brain should be obtained to identify potential surgical candidates. Given that ketogenic diets and anti-epileptic drugs may predispose adults to osteopenia, a baseline bone density scan may be wise. Further tests, such as ECG and renal ultrasound, are

A nutritional evaluation should be performed by a dietitian experienced in managing ketogenic diets in adults, and ought to include an assessment of baseline physical status, a decision as to which is the most appropriate ketogenic diet option

Baseline weight and body-mass index should be measured and recommended calorie and fluid intake calculated, including the desired ratio of fat to protein to carbohydrate [48]. Food aversions and allergies must be clearly documented. When selecting which conventional ketogenic diet to use, the most important factors to consider in adults are culinary and social restrictions [48, 50]. Since the CKD is the most restrictive of the four, it is rarely a viable long-term option in adults (unless given as a formula). The MCT diet is slightly less restrictive, but still not viable in most adults due to the copious quantities of MCT oil and resulting gastrointestinal side-effects. The MAD and LGIT are less restrictive conventional options in adults, but both are still associated with considerable dropout rates [54]. Thus, although conventional ketogenic diets should be offered, the adult may not be motivated to pursue any of them; this will negatively impact diet implementation. If conventional ketogenic diets do not appeal to the adult, a fifth option, that of a non-conventional ketogenic diet, can be considered. Such a diet might consist of dietitian-verified recipes obtained from trusted ketogenic diet books and websites, a major advantage of which is that it can be specifically tailored towards the adult's food preferences, reducing the perception that their diet is restrictive. It is now possible to prepare a variety of ketogenic diets, including vegetarian and culturallytailored ketogenic diets (theoretically, as long as a ketogenic diet sustains physiological ketosis, it is "ketogenic"). Given that each conventional ketogenic diet is decades old (nearly a century old in the case of the CKD), a newer, less restrictive, patient-tailored ketogenic diet is appealing to many adults, although it must be

for that adult, and education about their chosen ketogenic diet.

Ketogenic Diet Therapies in Children and Adults with Epilepsy

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

emphasized that evidence for such a diet in epilepsy may be lacking.

range as well as readily available at their local food markets.

161

Since many adults with epilepsy are of lower socioeconomic status, the dietitian must strive to minimize any socioeconomic impediments that may disrupt their ketogenic diet. Social activities are to be encouraged, but they can also jeopardize the diet; it is extremely helpful if the dietitian provides a list of appropriate food options relevant to most restaurants and social gatherings that will inform the adult as to what they can and cannot eat, so as not to disrupt the diet. For meals made at home, the dietitian should recommend foods that are both within the adult's budget

Given the limited fruit, vegetable, and calcium content in many ketogenic diets, adults should be commenced on a carbohydrate-free multivitamin [3, 47]. Some

ordered as clinically indicated.

4.2.2 Nutritional evaluation

### Table 7.

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

comorbidities include hypercholesterolemia, underweight body-mass index, kidney stones, osteopenia or osteoporosis, gastrointestinal issues (such as gastroesophageal reflux and constipation), cardiomyopathy, and diabetes [3]. Adults with type 1 diabetes can safely pursue a ketogenic diet, but must be closely monitored as their insulin requirements often decline, putting them at risk of hypoglycemia if they do not adjust their insulin doses accordingly [53]. Adults with type 2 diabetes may also start a ketogenic diet [3]; in fact, such adults may be ideal candidates.

Second, it is critical to identify psychological, socioeconomic, cultural, and religious factors with the potential to disrupt the adult's ketogenic diet [3]. Diet adherence in adults may be endangered by any number of factors, including personality traits, alcohol habits, income, cultural influences, and religious preferences; each must be realistically appraised before the adult and ketogenic service commit to the diet.

Third, the adult's level of commitment to ketogenic diet therapy must be elucidated. Diet modification often involves a major change in lifestyle, therefore anything less than a full commitment is likely to fail. If the adult holds any reservations about commencing the diet, these should be explored; if unsolvable, the adult may not yet be ready for the diet. The neurologist should counsel the adult on how to deal with inevitable "mixed messages" regarding the purported negative aspects of high-fat diets from friends, family, and even other medical professionals. Lastly, it can be helpful to emphasize the additional positive aspects of a ketogenic diet, such as beneficial effects on cognition, energy, and mood [47].

Fourth, the adult's medications should be reviewed. In general, anti-epileptic drug blood levels are not altered by a ketogenic diet, therefore dose adjustments are not usually required. However, for the same reasons as in children, exceptions might be made in the case of valproate, zonisamide, or topiramate [2]. All medications should be reviewed for carbohydrate content, which may necessitate a switch to lower carbohydrate preparations [47].

Fifth, the adult should be provided with a means of self-monitoring their diet, which critically provides feedback as to how effectively they are achieving physiological ketosis. In adults, it is best to prescribe a blood glucose and ketone monitor given that this method is easier, more specific, and more accurate than urine dipstick testing [38]. The adult should be shown how to use the monitor.

Ketogenic Diet Therapies in Children and Adults with Epilepsy DOI: http://dx.doi.org/10.5772/intechopen.83711

Finally, investigations should be ordered to rule out contraindications to a ketogenic diet (as a rule, it is not necessary to screen for disorders of fat metabolism in adults, unless the history suggests otherwise) [47]. Laboratory investigations include complete blood count, electrolytes, liver and kidney function tests, fasting lipid profile, calcium, vitamin D, and a urinalysis [3]. Given that the effects of a ketogenic diet on pregnancy are not known [3], pregnancy testing may be indicated in women of childbearing age. Baseline anti-epileptic drug levels can be measured, although few concerns for drug-diet interactions exist. A recent EEG and MRI brain should be obtained to identify potential surgical candidates. Given that ketogenic diets and anti-epileptic drugs may predispose adults to osteopenia, a baseline bone density scan may be wise. Further tests, such as ECG and renal ultrasound, are ordered as clinically indicated.

### 4.2.2 Nutritional evaluation

comorbidities include hypercholesterolemia, underweight body-mass index, kidney stones, osteopenia or osteoporosis, gastrointestinal issues (such as gastroesophageal

Provide supplements Educate patient

type 1 diabetes can safely pursue a ketogenic diet, but must be closely monitored as their insulin requirements often decline, putting them at risk of hypoglycemia if they do not adjust their insulin doses accordingly [53]. Adults with type 2 diabetes may also start a ketogenic diet [3]; in fact, such adults may be ideal candidates. Second, it is critical to identify psychological, socioeconomic, cultural, and religious factors with the potential to disrupt the adult's ketogenic diet [3]. Diet adherence in adults may be endangered by any number of factors, including personality traits, alcohol habits, income, cultural influences, and religious preferences; each must be realistically appraised before the adult and ketogenic service commit to the diet. Third, the adult's level of commitment to ketogenic diet therapy must be elucidated. Diet modification often involves a major change in lifestyle, therefore anything less than a full commitment is likely to fail. If the adult holds any reservations about commencing the diet, these should be explored; if unsolvable, the adult may not yet be ready for the diet. The neurologist should counsel the adult on how to deal with inevitable "mixed messages" regarding the purported negative aspects of high-fat diets from friends, family, and even other medical professionals. Lastly, it can be helpful to emphasize the additional positive aspects of a ketogenic diet, such

Fourth, the adult's medications should be reviewed. In general, anti-epileptic drug blood levels are not altered by a ketogenic diet, therefore dose adjustments are not usually required. However, for the same reasons as in children, exceptions might be made in the case of valproate, zonisamide, or topiramate [2]. All medications should be reviewed for carbohydrate content, which may necessitate a switch

Fifth, the adult should be provided with a means of self-monitoring their diet, which critically provides feedback as to how effectively they are achieving physiological ketosis. In adults, it is best to prescribe a blood glucose and ketone monitor given that this method is easier, more specific, and more accurate than urine dipstick testing [38]. The adult should be shown how to use the monitor.

reflux and constipation), cardiomyopathy, and diabetes [3]. Adults with

Medical Assess baseline epilepsy state and comorbidities

Nutritional Assess baseline physical parameters

Elucidate level of commitment

Order investigations

Review anti-epileptic drugs and medications

Identify psycho-socioeconomic, cultural, and religious factors

Provide blood glucose and ketone monitor; show how to use

If none appropriate, offer a non-conventional ketogenic diet

Select most appropriate conventional ketogenic diet

Provide list of foods for social settings

as beneficial effects on cognition, energy, and mood [47].

to lower carbohydrate preparations [47].

Evaluation Steps

Epilepsy - Advances in Diagnosis and Therapy

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

Table 7.

160

A nutritional evaluation should be performed by a dietitian experienced in managing ketogenic diets in adults, and ought to include an assessment of baseline physical status, a decision as to which is the most appropriate ketogenic diet option for that adult, and education about their chosen ketogenic diet.

Baseline weight and body-mass index should be measured and recommended calorie and fluid intake calculated, including the desired ratio of fat to protein to carbohydrate [48]. Food aversions and allergies must be clearly documented.

When selecting which conventional ketogenic diet to use, the most important factors to consider in adults are culinary and social restrictions [48, 50]. Since the CKD is the most restrictive of the four, it is rarely a viable long-term option in adults (unless given as a formula). The MCT diet is slightly less restrictive, but still not viable in most adults due to the copious quantities of MCT oil and resulting gastrointestinal side-effects. The MAD and LGIT are less restrictive conventional options in adults, but both are still associated with considerable dropout rates [54]. Thus, although conventional ketogenic diets should be offered, the adult may not be motivated to pursue any of them; this will negatively impact diet implementation.

If conventional ketogenic diets do not appeal to the adult, a fifth option, that of a non-conventional ketogenic diet, can be considered. Such a diet might consist of dietitian-verified recipes obtained from trusted ketogenic diet books and websites, a major advantage of which is that it can be specifically tailored towards the adult's food preferences, reducing the perception that their diet is restrictive. It is now possible to prepare a variety of ketogenic diets, including vegetarian and culturallytailored ketogenic diets (theoretically, as long as a ketogenic diet sustains physiological ketosis, it is "ketogenic"). Given that each conventional ketogenic diet is decades old (nearly a century old in the case of the CKD), a newer, less restrictive, patient-tailored ketogenic diet is appealing to many adults, although it must be emphasized that evidence for such a diet in epilepsy may be lacking.

Since many adults with epilepsy are of lower socioeconomic status, the dietitian must strive to minimize any socioeconomic impediments that may disrupt their ketogenic diet. Social activities are to be encouraged, but they can also jeopardize the diet; it is extremely helpful if the dietitian provides a list of appropriate food options relevant to most restaurants and social gatherings that will inform the adult as to what they can and cannot eat, so as not to disrupt the diet. For meals made at home, the dietitian should recommend foods that are both within the adult's budget range as well as readily available at their local food markets.

Given the limited fruit, vegetable, and calcium content in many ketogenic diets, adults should be commenced on a carbohydrate-free multivitamin [3, 47]. Some

ketogenic services also supplement adults with calcium, vitamin D, and magnesium [3, 47].

4.3.2 Diet maintenance

at every visit, and alter each as required.

osteopenia or osteoporosis, are rare in adults [47].

4.3.3 Diet cessation

163

is the case for all adults.

additional benefits may be significant and should be documented.

ling seizures, it can be switched over to another type of ketogenic diet.

Ketogenic diets often work rapidly, within days [43]. The adult should regularly monitor their blood BHB level daily for the first several weeks, then two or three times a week once readings indicate that constant physiological ketosis has been achieved. There are no firm recommendations regarding optimal blood BHB levels in adults [3], although aiming for at least 2 mmol/L at all times seems reasonable. If seizure control or ketone levels are not responding as expected, a 3-day food diary

The neurologist or dietitian should be in regular phone or email contact during

6 months, and every 6 months thereafter [3]. The neurologist should document the adult's seizure response to the diet; regardless of any improvement, anti-epileptic drugs should not be altered unless necessary, as 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 [47]. If osteopenia is a concern, a bone density scan may be warranted every 5 years or less [47], and bone protection therapy prescribed as needed. The dietitian should monitor weight, nutritional intake, and fluid hydration

Adverse effects may occur in adults on a ketogenic diet, but are generally transient, and rarely serious enough to necessitate stopping the diet [47]. The two most common adverse effects in adults are hyperlipidemia and weight loss [48]. Raised LDL levels are seen in least one-quarter of adults with epilepsy [48]. However, triglyceride levels often decline, and HDL levels usually increase [47]. Moreover, among healthy adults following a low-carbohydrate diet, the LDL increase is due to increased LDL particle size rather than particle number, which may be associated with a lower risk of atherosclerosis [56]. Furthermore, LDL and total cholesterol levels typically normalize within a year of commencing the diet [57], and return to baseline within 3 months of stopping it [50]. Weight loss is also common on a ketogenic diet, seen in at least one-fifth of adult with epilepsy [48], but since many such adults are overweight or obese, this adverse effect is often desired and beneficial [47]. Other adverse effects, such as kidney stones and

Benefits other than seizure control may also occur with a ketogenic diet, including improved arousal, alertness, concentration, energy, and mood [3, 47]. Moreover, adults on a ketogenic diet often report increased quality of life scores [58]. Given that many adults with epilepsy suffer from impaired quality of life, these

Unlike children, the long-term benefits on seizure control in adults with epilepsy may not outlast dietary therapy [59]. Further studies are needed to determine if this

It is customary to maintain a ketogenic diet for at least 3 months before passing judgment on its efficacy in seizure control [3]. 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 the adult experiences a greater than 50% seizure reduction and no serious adverse effects, their ketogenic diet can be maintained indefinitely [3]. If the adult starts to perceive their diet as overly restrictive, yet it remains effective at control-

may be useful to discover potential oversights in diet implementation.

Ketogenic Diet Therapies in Children and Adults with Epilepsy

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

the initial weeks of the diet, with multidisciplinary follow-up visits at 3 and

Lastly, education is essential; the adult needs to understand exactly what is required of them to implement their diet. A classroom-based format, with multiple adult patients present, can be advantageous [26]. The dietitian should demonstrate how to identify sources of fat, protein, and carbohydrate, how to count net carbohydrate (total carbohydrate minus fiber) for those on a MAD or non-conventional ketogenic diet, how to identify foods with a low glycemic index for those on an LGIT diet, and how to navigate potential pitfalls [26]. Helpful additional resources should be provided [55] and any expectations addressed.

### 4.3 Implementing a ketogenic diet in an adult

Once the adult has been prepared, their chosen diet can be implemented (Table 8) [47]. The ketogenic service should provide as much support as the adult needs, but also encourage them to develop a sense of "ownership" over their diet, thus conferring a feeling of empowerment over their epilepsy.