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Management of Epilepsy With The Ketogenic Diet
Epilepsy in TSC patients can be treated with anticonvulsants, antiepileptics, surgery, a vagus nerve stimulator, or the ketogenic diet. The ketogenic diet is another effective treatment for epilepsy that has anticonvulsant effects, as well as possesses antiepileptic and disease-modifying properties in both animal and human models although the mechanisms of action are not thoroughly understood. It has been discovered that the diet itself inhibits the mammalian target of rapamycin (mTOR) pathway, which has shown to have anticonvulsant effects and possible antiepileptogensis. The ketogenic diet has shown to be most beneficial in children with infantile spasms who are unresponsive to standard anticonvulsants, and do not qualify to undergo surgery, or implementation of a vagus nerve stimulator. Although the diet is mostly used in children with TSC, many adults who started the diet as children have successfully maintained the diet, with only slight modifications. There is also no know documented number as to the exact number of patients with TSC who are currently using the diet for epilepsy treatment or those who are not.

History
When it was first proposed at the Mayo Clinic in 1924, the diet was designed to imitate starvation. This diet entailed the child with epilepsy consuming 10-15g of carbohydrate per day, 1g protein per kilogram of body weight, and the rest of the calories were consumed as fat. Reports of the same diet being used to treat childhood epilepsy were conducted at the University of Rochester and Harvard University during the same year. During the early 1900’s the diet was considered to be changing epilepsy treatment, but was viewed as difficult, expensive, and rigid. For this reasoning, drug therapy was considered the most effective treatment around the 1960’s.

Implementation
In 1927, the ketogenic diet evolved into the strict diet used today when scientists at Harvard University developed the protocol that is still used for initiating and calculating the diet. These steps include: 36-48 hours of fasting to accelerate the production of ketosis and slowly increasing the amounts of fats introduced to the diet over the course of several hospitalized days. Maintaining the diet has proven to be the biggest challenge due to the strict guidelines the individuals need to follow including limiting their calorie restriction to 75%, limiting fluid consumption to 80%, and following specific meals that require all foods be weighed to the correct amounts. Unlike the typical American diet that is high in carbohydrates, and moderate in fats and protein, the ketogenic diet is very high in fats, and very low in both carbohydrates and protein. The formulation of the calories the individuals must consume is based on age, current intake, and ideal body weight. Many patients will lose weight while on the diet, but often times the individual will gain quite a bit of weight. While on the diet the four food groups that the patient must adhere to include protein, fruit or vegetable, fat, and cream. The individual needs to closely monitor their extra carbohydrate intake from sweetener, medications, or even toothpaste. The exact implementation of the diet in patients with TSC is the same as described in the ketogenic diet page. In children this diet has shown to have more than a 90% reduction in seizures, although it is especially hard for children and parents to follow the strict regulations of the die. The individual also must have a comprehensive medical team consisting of a dietician, epilepsy nurse specialist, and pediatric neurologist. The side effects of the ketogenic diet include, but are not limited to, renal stones (5-8%), growth inhibition, deficiencies in calcium and water soluble vitamins, and constipation related to fluid restriction and decrease in food intake.

The Diet as an mTOR Inhibitor
The ability of the mTOR pathway to integrate energy and nutrient signals makes it a logical candidate for use by the ketogenic diet. As the mTOR pathway is responsible for metabolic processes, The ketogenic diet can inhibit the pathway in epileptic patients by decreasing signaling in the liver and brain. The mTOR pathway is also responsible for anabolic processes and cellular growth, which the ketogenic diet impairs, showing that it inhibits the mTOR pathway.

Efficacy
Recent studies have shown through collaborations between Massachusetts General Hospital and Johns Hopkins Hospital that 92% of children with TSC between the ages of 8 months and 18 years who had treated their seizures with the ketogenic diet had greater than a 50% seizure reduction, and 67% had greater than a 90% reduction. The duration of the diet had varied for each patient, but lasted between 2 months and 5 years with an average duration of 2 years. In another study conducted in 2010 at The Johns Hopkins hospital, the ketogenic diet was determined to be an effective treatment for infantile spasms because over two-thirds of the patients treated showed significantly reduced seizures. Noted through this study was the idea that the diet should be highly considered after failure of drug therapy.

Discontinuation
In regards to stopping the ketogenic diet, most children have discontinued the diet after approximately 2 years, and in a recent study, 92% of those who ceased treatment with the diet were still seizure and medication free. 20% of patients had seizures returning at an average of 2.4 years after treatment, and 58% of those studied were able to be classified as seizure free after a second treatment. Finally, 6% of the patients studied still continue to have daily seizures regardless of dietary therapies such as the ketogenic diet and medication. Many children are able to stop treatment, but some have successfully remained on the diet well into adulthood. It has also been shown through MRI and EEG results in patients that severe TSC, and lower initial seizure frequency, had increased a patient’s probability of seizure recurrence.