SEARCH

SEARCH BY CITATION

Keywords:

  • Glycemic index;
  • Low glycemic index treatment;
  • Refractory epilepsy;
  • Dietary therapy

Summary

  1. Top of page
  2. Efficacy of LGIT
  3. Implementation of the LGIT
  4. Tolerability of LGIT
  5. Possible Mechanisms of Action
  6. Acknowledgment
  7. References

Despite the substantial efficacy of the ketogenic diet (KD) in treating refractory epilepsy, use of the KD remains limited because of difficulties in implementation and tolerability. An effective alternative dietary approach is a low glycemic index treatment (LGIT), which liberalizes the extreme carbohydrate restriction of the KD but restricts the type of carbohydrate-containing foods to those that produce relatively small changes in blood glucose. Foods with a “glycemic index” of less than 50 produce less than half the area-under-the-curve elevation of blood glucose compared to a reference food. The LGIT approach produces comparable efficacy to the classic KD, but tolerability is improved and implementation is much simpler. The LGIT appears to be a viable first-line dietary therapy for epilepsy.

Developed in the 1920s, the classic ketogenic diet (KD) is arguably the most effective treatment available for medically refractory epilepsy. Over the past 80 years, numerous case series of the classic KD, performed largely in children, have shown that up to one-third of patients who initiate the KD experience a dramatic decrease in seizure frequency (Bailey et al., 2005). However, there are several limitations to the availability, implementation, and maintenance of the KD.

Traditional implementation of the KD required an initial fast of 24–48 h followed by gradual introduction of the KD over several days during an inpatient hospitalization. Ideally, calculation of the KD is performed by a skilled KD dietitian who educates the child and family in how to implement and maintain the KD, and who also prepares numerous individualized meal plans to meet the child's protein, fat, and carbohydrate goals to 0.1 g precision. Due to several factors, including a relatively limited number of experienced dietitians, difficulty with reimbursement, and the intensity of labor in initiating and maintaining patients on a classic KD, access to this diet remains limited. Even when the KD is available, its restrictiveness often makes it difficult for a child and family to adhere to, and being on the KD can become socially isolating both for the child and family.

Although the KD is highly effective in treating epilepsy, its implementation is often limited and its tolerability less than ideal. Therefore, there is a need for the development of alternative dietary therapies. Over the past few years, two such diets have been introduced: the modified Atkins diet (MAD) and the low glycemic index treatment (LGIT). The MAD was developed based on the popular Atkins diet (Kossoff et al., 2006).

The use of LGIT in treating epilepsy was initially reported in 2005 (Pfeifer & Thiele, 2005). The hypothesis that a LGIT might be effective in the treatment of epilepsy was suggested to us by clinical observations of children on the KD. In particular, children on the KD can be very sensitive to exposure to extra carbohydrates, with immediate adverse effects on seizure control (Huttenlocher 1976). In addition, while on the KD, children have remarkably stable blood glucose levels, even during prolonged fasting (Valencia et al., 2002). These observations led to the hypothesis that one of the mechanisms of the KD may be stabilization of blood glucose levels, which would then also result in modulation of insulin secretion and numerous other metabolic effects.

The index cases for LGIT were two adolescent boys, both with medically refractory generalized epilepsies with greater than 40 seizures per day. After initiation of classic KD, both experienced a greater than 90% reduction in seizure frequency. Unfortunately, neither boy was able to tolerate the restrictiveness of the KD. After discontinuing KD therapy, the parents of one of the boys noted a fluctuation in seizure frequency based on dietary intake, that is, significantly more seizures when high carbohydrate foods were consumed. Following this observation, both boys were initiated on a diet that permitted higher total carbohydrate intake than the classic KD (Fig. 1), but with the carbohydrates limited to low glycemic index foods that produce relatively little elevation in blood glucose; both experienced >90% seizure reduction. Subsequently, the LGIT was found to be effective at providing seizure control with both focal and generalized epilepsies of various etiologies, and was generally well tolerated (Pfeifer & Thiele, 2005).

image

Figure 1. Percentage of carbohydrate, fat, and protein intake on the typical (Western) diet, KD, and LGIT.

Download figure to PowerPoint

The glycemic index (GI) is a measure of a food's tendency to elevate blood glucose (Jenkins et al., 1981). The GI of a particular food is determined by measuring the incremental area under the blood glucose curve after feeding a test carbohydrate, compared to equivalent amount of ingested reference food, such as glucose. Foods with high GI such as watermelon, bagels, and potatoes produce substantial increases in blood glucose following ingestion, whereas foods with low GI such as apples, cucumbers, and some whole grain breads result in lower postprandial blood glucose and insulin profiles (Bell & Sears, 2003).

Many factors affect a food's GI. These include particle size (finer particles are more easily digested and therefore have a higher GI), type of starch (straight chains of amylase are harder to digest and therefore have a lower GI compared to branched chain amylopectin which is easier to break down and therefore has a higher GI), starch gelatinization, as the less gelatinized a starch the slower the digestion rate, presence of fat (e.g., buttered bread has lower GI than bread alone), and acidity (the higher the acidity of a food, the lower its GI).

The fiber content of a food also affects its GI. Fiber remains undigested until it reaches the large intestine, where bacteria cause the fiber to ferment and break down. The products of bacterial fermentation are short-chain fatty acids, including butyrate, which may be further converted into beta-hydroxybutyrate. Therefore, even though fiber is typically classified as a carbohydrate, it is not absorbed in the form of carbohydrate. In addition, the presence of fiber can also affect the absorption rate (and therefore the GI) of other carbohydrates.

Efficacy of LGIT

  1. Top of page
  2. Efficacy of LGIT
  3. Implementation of the LGIT
  4. Tolerability of LGIT
  5. Possible Mechanisms of Action
  6. Acknowledgment
  7. References

The initial report of the use of LGIT in epilepsy described 20 patients, nine of whom were started on LGIT after some treatment with a classic KD, and 11 of whom were started on LGIT prior to a trial of the classic KD (Pfeifer & Thiele, 2005). Patients ranged in age from 5–34 years. They had been treated with an average of seven previous antiepileptic drugs (AEDs) without achieving ideal seizure control, and had seizure frequencies ranging from over 100 seizures per day to a seizure every 6 weeks. After an average of 20 weeks on LGIT, ten patients experienced a >90% reduction in seizure frequency, including six of 11 with no previous dietary therapy. Subsequently, the LGIT has been offered as an alternative to the classic KD through the MGH Center for Dietary Therapy of Epilepsy. Preliminary analysis of 60 patients who have subsequently initiated LGIT with no prior history of dietary therapy show a >50% reduction in seizures in 38% of patients after 1 month, and 24% of the total experienced >90% seizure reduction. Twenty-three patients continued on LGIT 6 months following initiation; of these, 60% had a >50% reduction in seizures and 38% had a >90% reduction in seizures. This patient cohort included patients with generalized and partial onset seizures.

Implementation of the LGIT

  1. Top of page
  2. Efficacy of LGIT
  3. Implementation of the LGIT
  4. Tolerability of LGIT
  5. Possible Mechanisms of Action
  6. Acknowledgment
  7. References

We believe that the LGIT should be considered as a potential treatment when two appropriate AEDs have not effectively controlled seizures, while an AED is being titrated to a therapeutic dose, and as an alternative to the classic KD. Patients that receive 100% of their nutrition through tube feedings are not considered for LGIT as ketogenic formulas as readily available.

Initiation of LGIT is performed on an outpatient basis with education and dietary recommendations provided by an experienced dietitian. Calorie goals for each patient are based on that individual's current intake to maintain adequate growth and nutrition. These goals are based on 3-day food records that are completed by the patient and family as well as dietary reference intakes and recommended daily allowances for the patient's age and size. Based on calorie needs, goals are individualized for grams of protein, fat, and carbohydrate. Protein contributes 20–30% of calories, while fat contributes 60%. Carbohydrate intake is limited to 40–60 g per day, and these are restricted to carbohydrate-containing foods with a GI <50. Carbohydrate intake is sometimes tapered from the individual patient's baseline carbohydrate intake, to improve tolerability. The LGIT diet is similar to a 1:1 KD ratio. The dietitian reviews formulated individual patient goals, including recommended daily calorie intake and breakdown by protein, fats, and carbohydrates as well as recommended daily fluid intake. Specific meal plans are not typically provided, but recommendations are made depending on food preferences and individual goals. Menu planning is discussed, and a sample day's menu is provided along with instructions on how to balance each meal with a protein source, a fat source and a carbohydrate source. Foods need not be weighed; intake is based on portion sizes, which are based on diabetic exchanges. For example, one small apple is equal to 15 g carbohydrates, 1 oz of chicken has 7 g protein, and 1 tsp butter contains 5 g of fat. Fluid intake is encouraged, and vitamins and minerals are supplemented to meet individual needs.

LGIT education includes background on the concepts of the GI and its potential role in epilepsy treatment. Instruction is provided on how to read and interpret food labels, focusing on total carbohydrates per serving and determining the sources of carbohydrates from the list of ingredients. Information is also provided regarding recipe, snack, and brand name recommendations. Possible side effects of the diet and methods of minimizing them are discussed, including constipation, acidosis, and weight loss. If patients are on a carbonic anhydrase inhibitor, they are started on potassium citrate to minimize risk of acidosis.

Since the LGIT has thus far been utilized primarily in children, close clinical follow-up is recommended to ensure that growth and nutritional status are adequate. Children are seen after initial month of LGIT and then every 3 months. At follow-up visits, efficacy and tolerability of LGIT are assessed, anthropometrics and blood chemistries are obtained, and recommendations are made to “fine tune” the diet or adjust AEDs.

Tolerability of LGIT

  1. Top of page
  2. Efficacy of LGIT
  3. Implementation of the LGIT
  4. Tolerability of LGIT
  5. Possible Mechanisms of Action
  6. Acknowledgment
  7. References

In our experience, the LGIT is better tolerated and more palatable than the KD. The KD, although efficacious, continues to be difficult for most patients and families in terms of compliance and tolerability. In addition to rigid, complicated meal plans, the food is often viewed as unpalatable. Furthermore, the dietary restrictions of the KD may be accompanied by psychosocial issues: some patients experience social isolation because they eat obviously distinct foods from their peers. Anecdotal evidence suggests that the LGIT is easier to tolerate for several reasons. First, meals are easier to prepare; detailed meal plans are not required and portions need not be weighed with a gram scale. Second, the LGIT is more palatable due to the liberalized carbohydrate content and decreased fat content. Third, there are fewer psychosocial issues because the food is viewed as more “normal” and patients are able to eat outside the home without having to prepare special meals in advance. Finally, the LGIT, unlike the KD, can be initiated in an outpatient setting. However, despite the relative ease of management compared with the KD, the LGIT remains too restrictive for some families.

Possible Mechanisms of Action

  1. Top of page
  2. Efficacy of LGIT
  3. Implementation of the LGIT
  4. Tolerability of LGIT
  5. Possible Mechanisms of Action
  6. Acknowledgment
  7. References

Although the exact therapeutic mechanisms of the fasting state and the KD remain unknown, many of the metabolic changes that accompany such diets have been investigated. The most obvious change is the elevation of serum ketone bodies and their partial substitution for glucose as a major metabolic substrate of the brain (Owen et al., 1967; Appleton & DeVivo, 1974; DeVivo et al., 1978; Schwartzkroin 1999). Although many have proposed that ketosis is the primary mediator of the antiepileptic effects of the KD, a correlation between the degree of ketosis and the level of seizure control has not been demonstrated consistently (Appleton & DeVivo, 1974; Bough et al., 1999). Furthermore, animal studies have shown that ketone bodies do not directly alter excitatory or inhibitory synaptic transmission in hippocampal slices (Thio et al., 2000). These findings suggest that ketosis alone may not account for the anticonvulsant effects of the KD (Greene et al., 2003).

Fasting and the KD also have significant effects on glucose levels (Schwartzkroin 1999; Greene et al., 2001). Glucose production and utilization are significantly decreased in the fasting state or while on the KD, resulting in a net decrease in blood glucose levels (Haymond et al., 1983). Blood glucose levels also stabilize when additional energy substrates are not provided, even for prolonged periods of time (Valencia et al., 2002). More recent studies of flurothyl-induced seizures in rats have shown circulating glucose levels to be positively correlated with seizure susceptibility (Schwechter et al., 2003). Furthermore, with food or glucose intake, seizures can be induced rapidly in association with rising blood glucose and falling ketone levels (Huttenlocher 1976; Greene et al., 2003). These findings suggest that glucose and perhaps related metabolic factors play a significant role in seizure control.

The LGIT is designed to prevent dramatic fluctuations in blood glucose. Although not extensively studied in epilepsy, low-GI diets are known to lower postprandial plasma glucose and insulin profiles among diabetics and patients with cardiovascular disease (Brand et al., 1991; Rizkalla et al., 2004). In a recent study on the metabolic effects of a low-GI diet in a healthy population, investigators used the MiniMed continuous glucose monitor, which measures blood glucose every 5 min over a 24-h period; they found that the individuals on a low-GI diet for 1 week had improved glucose profiles (Brynes et al., 2005). It is possible that the seizure protection afforded by the LGIT may be due to stable blood glucose and insulin levels. Further study of the mechanism of action of LGIT is needed.

Acknowledgment

  1. Top of page
  2. Efficacy of LGIT
  3. Implementation of the LGIT
  4. Tolerability of LGIT
  5. Possible Mechanisms of Action
  6. Acknowledgment
  7. References

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Disclosure: Heidi Pfeifer serves as a consultant to Nutrica; the other authors of this article disclose that there are no conflicts of interest.

References

  1. Top of page
  2. Efficacy of LGIT
  3. Implementation of the LGIT
  4. Tolerability of LGIT
  5. Possible Mechanisms of Action
  6. Acknowledgment
  7. References