29 Ketogenic Diet and Alternative Therapies

Dana Ekstein¹ and Steven C. Schachter²

¹ Department of Neurology, Epilepsy Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
² Department of Neurology, Center for Integration of Medicine and Innovative Technology, Beth Israel Deaconess Medical Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

Introduction

The ketogenic diets (KDs), including the classic KD, the medium-chain triglycerides (MCT) KD, the modified Atkins diet (MAD), and the low glycemic index treatment (LGIT), are nutritional therapies that increase the serum concentration of ketones and are efficacious for treating children with drug-resistant epilepsy. This chapter provides a practical guide to the implementation of these diets as well as a discussion of currently available complementary and alternative medications for the treatment of epilepsy.

Ketogenic diets

The KD was developed at the Mayo Clinic in Rochester, Minnesota, in the early 1920s, at a time when the only other available drug therapies for epilepsy were bromides and phenobarbital. The KD was designed to mimic the metabolic effects of fasting, which had been commonly recommended for the treatment of epilepsy for centuries. While widely used initially in children and adults, the KD became less popular after the introduction of phenytoin and other antiepileptic drugs (AEDs) in the middle of the 20th century. As a result, its use became restricted almost exclusively to the treatment of very severe cases of epilepsy in children at a limited number of tertiary epilepsy centers. Since the 1990s, renewed interest has led to more frequent, mainstream use of the KD. During the past several years, there have been clinical trials supporting its efficacy, introduction of new modified protocols, and increasing use in the adult population, and surprisingly, extension to nonepileptic medical conditions.

The classic KD requires consumption of 4 g of fat for each gram of combined proteins and carbohydrates (ketone ratio 4:1). Often, although there is a lack of evidence for this practice, an overall calorie and fluid restriction is also implemented as part of the KD protocol. The net effect is that 90% of consumed energy is derived from fats. The fat consists of long-chain triglycerides (LCT) found in standard foods, such as butter and mayonnaise. The efficacy of this regimen has been reliably demonstrated.

EVIDENCE AT A GLANCE

In a recent randomized controlled trial of the KD composed of 145 children, the mean seizure frequency decreased by 38% in subjects treated with the KD for 3 months and increased by 37% in the control group. Overall, published studies have demonstrated seizure freedom in 3–33% of patients; 7–56% have more than a 90% reduction of seizure frequency and 19–38% experience seizure reductions of 50–90%.

There have been attempts to introduce modifications to the classic KD protocol over the years. For example, a reduction of the ketogenic ratio to 3:1 was found to be as effective as the 4:1 ratio at 3 and 6 months; however, the onset of the effect may be faster with the classic protocol. MCT fat, available as coconut milk, oil, and emulsions, produces more ketones per gram than does LCT fat. Therefore, when MCTs are used as a substitute for LCTs, only 60% of energy has to be derived from fat, allowing a higher proportion of protein and carbohydrates to be consumed. The efficacy of this MCT KD variant was shown to be similar to that of the classic KD at 3 months and up to 1 year, although, again, the effect of the classic KD may be initiated more quickly. In practice, KD treatment is individualized by combining various proportions of MCT- and LCT-derived fat to achieve sufficient ketones and the best tolerance.

The MAD and the LGIT have also been adopted for the treatment of epilepsy in the last decade. These regimens do not restrict protein intake, calories, or fluids and are therefore more easily implemented and better tolerated. The MAD restricts carbohydrate consumption to 10 g initially and up to 20 g after 3 months, resulting in a ketogenic ratio of approximately 1:1. The LGIT is based on carbohydrates that produce only a minimal acute increase in blood glucose, allowing for a total of 40–60 g/day of carbohydrates. No randomized controlled trials that directly compare these diets and the KD have been performed. However, the reported efficacy of the MAD and the LGIT is not much lower than that of the classic KD, in particular after 6 months of treatment. Higher fat intake in the first month of the diet and lower carbohydrate consumption in the first 3 months lead to improved seizure control in patients treated with the MAD.

Indications and preparations for treatment with the ketogenic diet

The KD is the first-line treatment of choice for glucose transporter 1 (GLUT1) and pyruvate dehydrogenase deficiency (PDHD) syndromes. In these diseases, characterized by the inability to use glucose as a metabolic substrate, ketones serve as the substitute fuel for the brain. KD should also be used in the treatment of people with epilepsy who are drug resistant, which means they have failed to achieve seizure freedom after two adequately chosen and implemented AED regimens (Chapter 14). Several epilepsy syndromes may respond particularly well to the KD, including Dravet, Doose, and Rett syndromes, as well as infantile spasms and other epileptic encephalopathies including Landau–Kleffner syndrome (conditions described in Chapter 21). In addition, beneficial effects have been reported in Lafora body disease, subacute sclerosing panencephalitis, selected mitochondrial disorders, and focal epilepsy secondary to lissencephaly. In these types of epilepsy, as well as in small children who are fed formula and patients using enteral nutrition, KD may be tried relatively early after diagnosis of AED intractability (see Chapter 14). Although the data on the use of KD in adults are still limited, growing evidence from small trials lasting 3–12 months suggests that 22–55% of this population may have more than 50% seizure reduction.

Another emerging indication for treatment with the KD is super-refractory status epilepticus (SE), defined as SE that continues for more than 24 h despite anesthesia. In the literature, there are 20 cases of patients who benefited from the diet in this setting, nine of them having febrile infection-related epilepsy syndrome (FIRES), a very severe epilepsy syndrome affecting previously healthy children. Further discussion of the initial management and intensive care unit (ICU) management of SE is provided in Chapters 31 and 32.

Patients in whom epileptic foci were identified and who are candidates for epilepsy surgery may have a less favorable response to KD. For them and for patients in whom adequate nutrition cannot be maintained due to their resistance or caregivers’ noncompliance, the KD is relatively contraindicated. The KD is absolutely contraindicated in people with disorders of fat metabolism, although MCT fat–only diets may be given safely to individuals with carnitine deficiency. In search of these disorders, a thorough metabolic evaluation of blood, urine, and CSF should be obtained in patients in whom the precise etiology of epilepsy has not been determined and in individuals with developmental delay, hypotonia, cardiomyopathy, and exercise intolerance.