Metabolic Treatments for Intractable Epilepsy

Metabolic Treatments for Intractable Epilepsy Sarah A. Kelley, MD, and Adam L. Hartman, MD When a child on anticonvulsant medications continues to have seizures, what other options should be considered? Over the past 100 years, dietary therapies for the treatment of intractable epilepsy have become more widely recognized, and their use has continued to expand throughout the world. An increasing number of studies has shown efficacy of these metabolic treatments in improving seizure control. Currently, 4 types of dietary therapy are available in the clinic: the classic long chain fatty acid “ketogenic” diet, the medium chain triglyceride diet, the modified Atkins diet, and the low glycemic index treatment. These therapies should be considered earlier in the treatment of intractable epilepsy because they offer a different approach to treatment that has proven efficacious, tolerable, and cost-effective. Semin Pediatr Neurol 18:179-185 © 2011 Elsevier Inc. All rights reserved.

According to the Epilepsy Foundation, 326,000 children in the United States under the age of 16 have been diagnosed with epilepsy.1 Nearly 20% are medically intractable (ie, not adequately treated by at least 2 medications).2 These children, as well as hundreds of thousands adults, need alternative treatments to anticonvulsant medications. In the absence of a surgically resectable lesion, 1 underused but highly effective option is metabolism-based therapy.

What Is the History of Metabolism-Based Therapy? Centuries ago, Hippocrates noted that fasting treated convulsions.3 One hundred years ago, Guelpa and Marie4 rediscovered and published this fact. Ten years later, a systematic approach to using this knowledge began when, while starting with an incorrect hypothesis that one should rid the gut of toxins to treat epilepsy, Dr Hugh Conklin successfully treated seizures using gut rest. Geyelin5 followed this work and showed improved seizure control in fasted patients. Others, including Wilder, began investigating a high-fat low-carbohydrate diet to mimic the effects of fasting. This “ketogenic” diet, although successful, was not as popular initially as the available anticonvulsants, such as phenobarbital and bromides.6 It was often used for intractable cases and for some time was the only treatment that was effective for “petit mal” seizures.7 A significant study of the diet was undertaken during its early days, and by the early 1940s it was regularly

From Johns Hopkins Hospital, Baltimore, MD. Address reprint requests to Adam L. Hartman, MD, Johns Hopkins Hospital, 600 N Wolfe Street, Meyer 2-147, Baltimore, MD 21287. E-mail: [email protected]

1071-9091/11/$-see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.spen.2011.06.004

taught as one of the few epilepsy treatments available. However, as new anticonvulsants were developed, attention was drawn away from the diets.3 A resurgence of interest in a ketogenic diet came with its ability to control Charlie Abrahams’ seizures in the 1990s. His father, Hollywood producer Jim Abrahams, started the Charlie Foundation and worked to educate the public on a ketogenic diet’s effectiveness. Today, a ketogenic diet is widely available throughout the United States and in many countries around the world.8 It continues to be used for intractable seizures, certain seizure syndromes, status epilepticus, and even neurologic diseases other than epilepsy.

What Is Metabolism-Based Therapy? Today there are 4 main types of metabolism-based therapy that are used with the goal of reducing seizures. These include the classic ketogenic diet, medium chain triglyceride diet, the modified Atkins diet (MAD), and the low glycemic index treatment. The first 3 have higher than typical fat content and low-carbohydrate content; the last controls quality of carbohydrates. All are effective in treating seizures. The classic ketogenic diet uses long chain fatty acids (LCFAs) as its primary fat source. This diet is high fat, low carbohydrate, with adequate protein for growth (usually at least 1 g/kg/d). The most commonly used ratios are 4:1 or 3:1 (ratio of grams of fat to grams of carbohydrate ⫹ protein). In these diets, 90% and 86% of calories are from fat, respectively. In the past, fluid was restricted with this diet. This is not done anymore because there is no evidence that fluid restriction is necessary for diet efficacy (although it probably elevated ketone concentration in the blood and urine because of dehydration). Previously, calories had been restricted to 179

S.A. Kelley and A.L. Hartman

180 80% to 90%. However, most children are not calorie restricted on the diet as it is prescribed today. The only children whose calories are restricted include those who are obese or tube fed and, thus, less active and requiring fewer calories. The medium chain triglyceride (MCT) diet first was introduced in the 1970s and has more ketones per calorie than the LCFA-based diet. In the MCT diet, ketones are absorbed more efficiently than in the LCFA-based diet, and MCTs are transported directly to the liver. MCTs, unlike LCFAs, do not require additional energy to be used or stored. As a result, 10% to 20% less calories are required from fat, and, therefore, more carbohydrates and proteins can be added to the diet. In a randomized trial comparing MCT with LCFA diet, there was no difference in efficacy found at 3, 6, or 12 months.9 Some have combined the MCT and LCFA diet in an attempt to optimize seizure control and minimize side effects (see later). The MAD was first reported in 2003 by Kossoff et al.10 This diet restricts carbohydrates while encouraging consumption of high-fat foods with no limit on the amount of protein or total calories allowed. Generally, a 1:1 ratio is used (the typical North American diet is 0.3:1). Starting out with a higher ratio, by combining it with a ketogenic diet, may be beneficial, as shown in 1 study in which a liquid ketogenic diet preparation supplement was added to the patient’s diet for the first month.11 The MAD has the advantage of being less restrictive than the prior 2 and more widely available. The low glycemic index treatment is based on the concept that fewer fluctuations in glucose lead to effective seizure control. Unlike the others, this is not a high-fat diet. In this diet, patients limit their carbohydrates to 40 to 60 g/d, and these carbohydrates are restricted to those with a glycemic index of less than 50. This prevents a large postprandial increase in glucose. In a retrospective review, the low glycemic index treatment had an efficacy comparable to the classic ketogenic diet.12 There was no correlation between seizure control and ketosis. Advantages with this diet are that the food the patient is eating looks similar to everyone else’s food in comparison with the LCFA and MCT diets. This diet has not been studied as extensively as the others.

When Is MetabolismBased Therapy Used? Metabolism-based therapy for epilepsy is used most often in the setting of intractable seizures. The recent definition of drug-resistant epilepsy put forth by the ILAE task force is the failure of 2 appropriate anticonvulsants after adequate and tolerated trials.13 This definition does not incorporate other nonmedication interventions, such as diets and surgery. Metabolism-based therapy may be considered after the failure of 2 medications; however, in practice, a median of 5 anticonvulsants typically is used before starting a ketogenic diet,14 which is similar to the number of anticonvulsants tried before surgery is considered.2 A ketogenic diet has an efficacy in controlling seizures that is similar to new anticonvulsants, including severe forms of epilepsy, such as Lennox-Gastaut syndrome, although patient retention on the diet probably is lower than typically seen in medication trials (Table 1). There are some epilepsy syndromes in which a ketogenic diet has been used successfully as a first-line agent, such as in infantile spasms.15 One of the common questions in clinical studies is whether a ketogenic diet is more effective in certain seizure types. One recent randomized controlled trial showed that there was no significant difference in efficacy between generalized and focal epilepsy.16,17 Focal seizures appear to be less likely to have a ⬎90% response to a ketogenic diet than generalized seizures.18 However, a ketogenic diet still may offer significantly improved seizure control even if seizure remission is not obtained. In select cases, it also might reduce surgical morbidity by allowing the postponement of an operation until the patient is older or more medically stable. A ketogenic diet may be highly effective in myoclonic atonic epilepsy (MAE or Doose syndrome), infantile spasms (West syndrome), and severe myoclonic epilepsy of infancy (Dravet syndrome).19 Some symptomatic epilepsies, such as tuberous sclerosis complex and Landau-Kleffner syndrome, also may benefit from a ketogenic diet. The study by Neal et al16 showed the greatest efficacy in unspecified symptomatic generalized epilepsy, continuous spike and slow wave of sleep, MAE, and multifocal epilepsy. Studies also have shown

Table 1 Comparison of the Ketogenic Diet to Medicines in Lennox-Gastaut Syndrome >50% Improvement in Seizure Type Treatment

All Seizures

Atonic*

Generalized Tonic*

Ketogenic diet

40%

44%

50%

Topiramate Lamotrigine Clobazam

21% 33%† NA

26%† 37%† (LD) 38%; HD: 83%

43%† NA

Rufinamide

31%†

43%†

NA

GTC* 37%

Completed Experimental Arm

Trial Duration

Trial Type

44% (33/75)

12 mo

98% (47/48) 91% (72/79) LD.83% (30/36) HD: 88% (28/32) 86% (64/74)

11 wk 16 wk 7 wk

Open label RCT RCT RCT

65 66 67

12 wk

RCT

68

Reference 41

LD, low dose (target ⴝ 0.25 mg/kg/d); HD, high dose (target ⴝ 1 mg/kg/d); NA, not statistically analyzed; RCT, randomized clinical trial. *Some studies combined these seizures types. †Statistically significant versus placebo.

Metabolic treatments for intractable epilepsy efficacy in childhood and juvenile absence epilepsy. Approximately 70% of those with absence epilepsy have ⬎50% seizure reduction, and as many as 34% become seizure free.20 Patients who are incapable of using glucose for fuel in the brain require a ketogenic diet for seizure control. These include glucose transporter defects (eg, moderate to severe GLUT1 deficiency) and pyruvate dehydrogenase deficiency.21,22 In these disorders, a ketogenic diet provides ketone bodies, which bypass a metabolic block and provide an alternative fuel source. By contrast, a ketogenic diet is contraindicated in those who are unable to use ketone bodies for fuel or are dependent on glucose, including pyruvate decarboxylase deficiency, fatty acid oxidation defects, primary carnitine deficiency, porphyria, and some mitochondrial disorders.8 A ketogenic diet also may have a synergistic effect when combined with other treatments, such as concurrent use with zonisamide or the vagus nerve stimulator.23 Phenobarbital might have a negative effect23,24 although phenobarbital use may be an indicator of patients with more intractable epilepsy before starting the diet. Metabolism-based therapy has been used in status epilepticus in a variety of cases.25,26 In children with refractory epileptic encephalopathy in school-aged children, a diet successfully stopped the status epilepticus; however, all the children went on to develop epilepsy.25 Most recently, investigative uses of a diet in other neurologic disorders, such as Parkinson disease and Alzheimer disease, are being explored.27,28

181 Table 2 Selection of a Metabolism-Based Therapy Diet/Treatment

Best Candidates

Ketogenic (LCFA) formula Ketogenic food

Infants (formula fed) G/J-tube fed primarily Young children whose diet is managed by a parent Patients with disorders requiring dietary intervention (eg, moderate to severe GLUT-1 deficiency) Patients with incomplete response to modified Atkins diet Patients with significant constipation on LCFA diet Can be used in combination with LCFA Adolescents/adults Unable to comply with a more restrictive diet Patients who would like food similar to peers Countries where carbohydrate content of diet is higher Patients who find a high-fat diet unpalatable Unable to comply with more restrictive diet Patients who would like food similar to peers

Ketogenic (MCT)

Modified Atkins

Low glycemic index

G/J, gastro/jejunal; GLUT-1, glucose transporter type 1; MCT, medium chain triglyceride.

Which Form of MetabolismBased Therapy Should I Use? The selection of a specific diet to choose for a particular patient depends on a variety of factors, including tolerability, ability to adhere to a dietary regimen, side effect profile, age of the patient, and cost of the diet (Table 2). Infants who take formula as their main source of nutrition and children fed via a gastrostomy tube can be more easily maintained on a diet by using a ketogenic formula as their source of nutrition for a ketogenic diet. Experience at our center suggests that adolescents and adults are more likely to adhere to a less restrictive diet although studies show similar efficacy between children and adults with all diets.17,29 Patients with failure to thrive, severe reflux, and poor feeding also may have increased difficulty with the more restrictive diets. It is prudent to investigate and treat these problems before starting the diet so resources can be used most effectively on those with a high probability of tolerating the diet. Side effect profiles will be discussed later.

How Do I Initiate A Ketogenic Diet? Laboratory studies typically obtained before initiating a ketogenic diet include fasting lipids (to serve as a baseline and to screen for disorders of lipid metabolism), complete metabolic panel (ie, serum electrolytes, liver function, and kidney tests), and urine calcium and creatinine levels (to screen for risk of nephrolithiasis). In our center, the diet is initiated in

an inpatient setting where the patient may be monitored for side effects during the acute fast and where a nutritionist can be intimately involved with educating the family regarding the diet. Some centers initiate the diet in the outpatient setting but do not use an initial fast in this context. Is a fast necessary before initiating a ketogenic diet? Children who are fasted at the start of the diet may achieve faster onset of seizure control, but their ultimate seizure control on the diet does not appear to be affected.30 Side effects of weight loss, hypoglycemia, and acidosis are less frequent in those who are not fasted.30 At our institution, the introduction of ketogenic foods occurs over 3 days with a gradual increase in calories. Blood glucose levels are followed for the first day (during the fast and initiation of the diet) but are discontinued once the patient is consuming adequate calories. Urine ketones also are followed during the first few days, largely to educate parents for home care. Classes on practical aspects of the diet’s implementation (ie, computer programs for menus and sick day management) occur during the hospitalization as well. After this initiation stage, calories can be adjusted as needed for adequate patient growth and development. Nutritionists and neurologists stay involved in the patient’s care throughout this process. Anticonvulsants are not changed during the diet initiation process and, typically, not for at least a few months afterward (exceptions may be made if a patient has significant medication toxicity or an outstanding

182 and rapid response to the diet). Anticonvulsant formulations, however, may need to be changed if the formulation the patient is taking has significant carbohydrate content. The MAD is initiated in the outpatient setting with limited guidance from a nutritionist. Laboratory studies are completed as with the ketogenic diets. Ketones are monitored weekly. The initial counseling takes less than an hour and involves teaching patients how to count carbohydrates and encouraging them to eat high-fat foods. At our center, we provide the families with a packet that includes information on recommended low-carbohydrate foods, where to get them, and supportive web sites. Carbohydrates are restricted further at the start of the diet, to 10 g/d for children, and then slowly increased after 1 month. Anticonvulsants are left unchanged for a minimum of 1 month. The low glycemic index treatment (LGIT) is initiated in the outpatient setting. A nutritionist and neurologist are involved in the care and education of these patients. Nutritionists teach families about the glycemic index, and patients are instructed to limit carbohydrate intake to foods with a glycemic index of less than 50. Carbohydrate intake may be increased over time to increase tolerability of the diet. Recommendations for adequate calorie intake are made. Specific meal plans are generally not implemented. Portion sizes are based on diabetic exchanges and not weighed as they are in the LCFA and MCT diets.31

When Do I Stop the Diet? The Consensus Report from 2009 recommends giving the diet at least 3 and a half months to assess for efficacy.8 Most often, however, improvement in seizure control will be seen in 2 weeks if it is going to be effective, with a median time for seizure remission of 5 days.32 When used as first line for infantile spasms, we discontinue the ketogenic diet after 2 weeks if spasms are still present in attempts to obtain seizure control as quickly as possible. If the diet is effective, patients often will continue it for 2 years before tapering off over a course of weeks to a couple of months (infantile spasms typically are treated for 6 months or less). This 2-year timeframe is adopted from recommendations for the length of anticonvulsant medication treatment. The diet may be stopped abruptly at any time in the case of medical emergency where glucose is required and can be reinitiated afterward. Those who have ⬎90% control of seizures often stay on the diet much longer.33 The longest treatment at our center has been 25 years.34 It is unclear whether long-term efficacy is the result or the cause of longer diet use. Those who are seizure free on the diet often remain so after it is discontinued. This may be because of the natural history of the seizure disorder, but an alternative explanation is that it could be caused by long-term effects (possibly disease-modifying effects) of the diet. The risk of recurrence in 1 study after stopping the diet was about 20%. If seizures recurred, approximately 58% regained control, and 6% became intractable.35 This is in comparison with the rate of recurrence after stopping anticonvulsants of approximately 30% to 50% with an intractability rate from 1% to 25% depending on the

S.A. Kelley and A.L. Hartman study.36-38 One caveat is that the ketogenic diet has not been compared directly with medicines in this regard. There have yet to be studies looking at seizure outcomes after stopping the MAD or LGIT. Similarly, there is no evidence as to when these treatments should be stopped in the event of good seizure control. Practically speaking, current guidelines for cessation of the ketogenic diets and anticonvulsant medications are used.

Are There Side Effects or A Need for Supplementation? Many families inquire about metabolism-based therapy because they believe it is a “natural” seizure treatment. However, just like any medical intervention, there can be side effects. The most common side effects are constipation, acidosis, hypercholesterolemia (approximately 20% increase that resolves over time),14 kidney stones (now mostly preventable with potassium citrate supplementation), and hunger (which often can be fixed with diet modifications). Cardiac abnormalities, bruising, hair thinning, and bone fractures may be caused by vitamin deficiencies and also may be attributable to anticonvulsant medications.39 Growth restriction is quite common especially in younger children.39 Death has been noted as an adverse event in a small number of patients while on a ketogenic diet.40 Causes of death have included infection, status epilepticus, cardiac and respiratory arrest, and lipoid pneumonia among others.17,41,42 In 1 case series, 2 children with selenium deficiency showed prolongation of the QT interval and subsequently died.43 Children with refractory seizures have an increased incidence of death.44 Therefore, the observed deaths may not have been as a direct consequence of a diet. When on the diet, there are also lifestyle restrictions, especially on the more restrictive diets, because of being unable to eat the same food as peers. Food must be specially ordered when ketogenic formulas are used, and a dietician should continue to oversee the patient’s meals. Daily vitamin supplementation also is necessary as the diet is deficient in some nutrients. Multivitamin and mineral supplements are required. Potassium citrate reduces the incidence of kidney stones. Some have proposed carnitine supplementation if the patient is fatigued, but there is no clear evidence to support its use. The MCT diet often causes diarrhea if high amounts of MCT oils are used. Abdominal discomfort also is a common side effect. MCT oil, because of its bowel effects, may be added to the LCFA diets if patients have severe constipation. MCT oils, however, are more expensive and may not be reimbursable by insurance in the United States. The MAD in general has fewer side effects than a traditional ketogenic diet. Some will still experience nausea, vomiting, and loss of appetite with this diet. Cholesterol has been shown to modestly increase by 25 to 50 mg/dL.45 The long-term effects, for the most part, however, have not yet been studied. The MAD has the potential for some side effects seen in a ketogenic diet because it too has high amounts of fat

Metabolic treatments for intractable epilepsy and protein. Although this diet may be less restrictive than the LCFA and MCT diets, it still requires motivation to adhere to it. The LGIT also requires a motivated patient because the diet is restrictive and being able to choose food might make it even more difficult to adhere to the diet. Reports of nausea and vomiting at diet initiation have been noted as well as fatigue. Further studies to elucidate possible side effects of this treatment have yet to be completed.

Does MetabolismBased Therapy Work? Until 2008, there were no randomized trials of the diet. One recent trial looked at children aged 2 to 16 years with intractable generalized or focal-onset epilepsy. Children were randomized to either immediate initiation of a ketogenic diet or continuation of their normal diet for 3 months followed by the initiation of a ketogenic diet. After 3 months, 38% of children on the ketogenic diet had ⬎50% seizure reduction compared with only 6% of controls (P ⬍ .0001).16 A follow-up study randomized children to the classic LCFA diet or the MCT diet. After 3, 6, and 12 months, there was no statistically significantly difference between diets in terms of seizure frequency. Although the sample size was not large enough to show that the 2 diets were equally efficacious, the data suggest there is no increased benefit to seizure control in one over the other.9 In the initial study, there was no intervention in the control arm subjects, however, making it difficult to know if another treatment would have been just as effective as the addition of a ketogenic diet. These studies did not include patients under the age of 2 for whom a ketogenic diet may also be effective. A subsequent randomized blinded crossover study was performed in patients with Lennox-Gastaut syndrome by using a glucose versus saccharin supplement. These children were fasted initially for 36 hours and then, once started on a ketogenic diet, received either 60 g of glucose or the same amount of a saccharin solution with the expectation that glucose would break the ketosis, thus providing the ability to study the ketosis-related effects of a ketogenic diet. Ketosis, however, was not eliminated in the control group. There were fewer (not statistically significant) seizures observed in the saccharin group, and there was no change in electroencephalographic findings.46 Although this study did not achieve the intended outcome in the control group, it showed that it is possible to complete a randomized double-blinded study of a ketogenic diet. Recent discussions at the Global Symposium on the Dietary Treatments for Epilepsy and Other Neurological Disorders in Scotland in 2010 focused on the necessity of designing a prospective randomized controlled trial to provide higher levels of evidence for the efficacy of the diets. MAE was chosen because of the diet’s demonstrated effectiveness in previous studies.47,48 The proposed study would randomize children to a medication or diet after 1 medication failure.49

183 Other retrospective and prospective observational studies have shown a range of diet efficacy results.50 One meta-analysis in 2000 showed 15.8% of patients achieved seizure freedom and 55.8% of patients had a ⬎50% reduction in seizures, whereas another meta-analysis in 2006 showed 15.6% of patients achieved seizure freedom and 33% of patients had a ⬎50% reduction.40,51 The meta-analysis in 2006 showed increased efficacy in generalized seizures and in those who adhered to the diet over a longer period.52 A recent study in catastrophic epileptic encephalopathies looked at younger children (3 months to 5 years) and found almost three quarters of patients had significant improvement in seizures initially with about 50% at 1 year maintaining this good control.53 The MAD has been studied in observational prospective and retrospective studies in both children and adults. In these studies, observed efficacy was similar to that seen in the ketogenic diets; 45% of patients had a 50% to 90% reduction in seizure, and 28% had a ⬎90% reduction.45 More recent small studies in Japan, Islamic Republic of Iran, and Denmark showed comparable results.54-56 Two retrospective studies of the LGIT showed similar to slightly greater efficacy in seizure reduction of ⬎50%.31,57 These studies were small and allowed for changes in anticonvulsants in some patients during the diet treatment. Additionally, an intent-to-treat analysis was not performed. The MAD and the LGIT have not been studied prospectively or in a randomized or controlled setting.

When Should MetabolismBased Therapy Be Implemented? Over the past 20 years, there has been further acceptance of metabolism-based therapies in the treatment of intractable epilepsy. It is still, however, rarely used as first-line therapy and typically only after 5 or more anticonvulsants have been tried and/or other treatments, such as vagus nerve stimulation, have failed. In England, the National Institute for Health and Clinical Excellence Guidelines (2004) suggested that a ketogenic diet be used as adjunctive therapy in children with drug resistant epilepsy.58 One survey in 2008 showed that child neurologists disagreed on when to implement a ketogenic diet. Sixty percent of child neurologists typically used it as a last resort.59 This article did point out that there are no studies evaluating when the therapy should be used in the course of treatment. Should we be using the diet more frequently? Should we be using it sooner or for a wider range of seizure types and conditions?

Other Benefits Many parents report that their child is more alert after starting a ketogenic diet.60 Motor development and behavior may improve in some children.17 Whether this is because of the diet itself, better seizure control, or fewer anticonvulsants is unclear. Pulsifer et al60 showed that in those who stayed on the diet there was a significant improvement in developmen-

S.A. Kelley and A.L. Hartman

184 tal functioning, physical functioning, attention, social issues, and self-help skills. This study also showed that parental stress did not significantly increase as might be predicted when introducing a family to a restrictive diet. In this study, improved function occurred even without reduction in the amount of anticonvulsants the child was taking or a decrease in seizure frequency.60 If a ketogenic diet works to reduce the child’s seizures, then the child also might be able to discontinue some of their anticonvulsants and reduce the side effects from these medications, particularly sedation and drug-drug interactions. The side effect profile of a ketogenic diet is usually manageable. A ketogenic diet also can have positive effects, such as weight loss, whereas some anticonvulsants (eg, valproate, which is used commonly in patients with intractable epilepsy) have the opposite effect. The ability to wean medications on the MAD or LGIT needs further study. Weight loss has been shown in adults on the MAD61; however, the effect on weight is not known in children. Those on the LGIT had stable body mass indexes during up to 12 months of treatment.12 Patients may see a reduction in seizures within days (especially with a fast) and most of the time within 2 to 4 weeks. Medications may take this long or longer if they need to be titrated to see a good effect. Other treatments, such as vagus nerve stimulation, often can take months or years before an optimal effect is seen.62 Although a large effect is seen immediately after the initiation of a ketogenic diet, its efficacy may increase over time.33 Whether this is because of a direct anticonvulsant effect, the nature of epilepsy itself, the diet fundamentally changing function within the central nervous system, or a neuroprotective quality of the diet is unclear. Another important benefit is that the diet can be costeffective. People with epilepsy use significantly more health care resources especially when admitted to the hospital.63 Those in the younger age groups, who would be the most likely candidates for the diet, incur the greatest costs. Mandel et al showed a significant reduction in the total cost of care for a child after the initiation of a ketogenic diet (even with the cost of the initial hospital stay).64 The initiation of the diet on an outpatient basis may even be more cost-effective. Children using metabolism-based therapy may have fewer seizures and ultimately be on fewer medications. With the seizure control that the diet affords, parents are less likely to need to miss multiple days of work, leading in turn to less stress. Additionally, the cost of diet foods (formulas may be covered by insurance) is less than many anticonvulsants. In Maryland, the ketogenic diet formula Ketocal is covered for those with gastrostomy tubes and in babies who are using it as their primary formula. Otherwise, these formulas can be bought relatively inexpensively (approximately $20-$25 a day, depending on amount of calories needed, for those exclusively formula fed) over the Internet. One calculation found the cost for 1 day of solid ketogenic diet food to cost $2.94, whereas the minimum cost for regular food in 1 day was $4.20 and being on lamotrigine would cost an additional $5.33 a day or levetiracetam $2.20 per day (EP Vining, personal communication, November 2010).

Conclusions Metabolism-based therapy offers an alternative, safe, effective, proven, and potentially cost-saving treatment for patients with intractable epilepsy. Diets require a greater time investment than medication but should be considered early in therapy for those whose seizures are resistant to medication and continue to have poor seizure control. A number of diet options and variations are now available to make the diets more palatable and easier to administer with the help of a neurologist and a nutritionist. Future randomized controlled studies will help to better define the utility and timing of implementation for these therapies.

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