What do Kourtney Kardashian, body-builders, and many kids with epilepsy have in common? They may all be utilizing the ketogenic diet. This article delves into the specifics of the ketogenic diet as a nonpharmacologic treatment strategy to control refractory epilepsy in children, exploring its history, mechanisms, variations, implementation, and the crucial role of healthcare providers in ensuring its success.
Introduction to the Ketogenic Diet
The ketogenic diet (KD) is a dietary approach used to treat intractable epilepsy, a condition where seizures are not well-controlled by medicines. Although this diet has been used successfully to reduce seizures since the 1920s, the anticonvulsant mechanism of ketosis remains unknown. The KD can be traced back to the texts of Hippocrates at the 5th century BC. In 1921, Wilder reported the significant seizure control effect of the KD at first. Following the introduction of phenytoin (Dilantin) in 1938, dietary treatment for seizures took the back stage as medication use surged. Fortunately, the KD gained popularity after receiving national attention on NBC’s “Dateline” when the story of Charlie, a 2-year-old boy with epilepsy, became seizure-free after trying the KD.
The diet is very high in fat, and very low in carbohydrates, including enough protein to help your child grow. The human body prefers to get energy from carbohydrates like those found in starchy, sugary foods, but if deprived of carbs, our bodies will burn fat for energy instead. The ketogenic diet, developed almost a century ago, essentially leaves the body in full-time fat-burning mode. As a result, the body’s chemistry changes in complex ways that help inhibit seizures.
Understanding Epilepsy and the Brain's Energy Needs
Our brains operate incredibly, almost like a circuit board. In the brain, billions of nerve cells arranged in intricate patterns interact with each other through electrical circuits, resulting in all of our cognitive function. If a disruption hits any of these electrical circuits, a seizure could occur, presenting an uncontrollable disturbance in behavior, sensation, or movement with (or without) altered states of alertness and comprehension.
Epilepsy is a common neurological disorder that can affect anyone and stems from a variety of causes, including genetic makeup, structural brain changes, tumors, prior infections, and inflammation. "The definition of epilepsy is two or more seizures, unprovoked," says Oliver. The diagnosis, then, starts with ruling out all the other possible causes. Since epilepsy disrupts brain activity, it can also affect a child’s ability to learn and function appropriately.
Read also: Epilepsy medication and its impact on weight
Just like the body, the brain functions on energy. Normally, carbs are the fuel your body's cells use to do what they do, from firing muscles to zapping signals across the surface of the brain. "When you break down carbs you get glucose," adds Stephanie Criteser, RD, a dietitian with the Epilepsy Program. If it's getting enough of them, your body typically saves protein and fat for other purposes. Protein repairs and builds muscle and other tissues, while fat constructs everything from hormones to the protective coating of brain cells.
How the Ketogenic Diet Works
The KD is a high-fat, low-carb and adequate protein diet that forces the body into a state of ketosis, meaning the body is primarily utilizing fat instead of carbohydrates for metabolic energy. "Basically, the body thinks it's starving," says Jennifer Oliver, a pediatric nurse practitioner specializing in ketogenic diet within Children's Hospital Colorado's Epilepsy Program. Ketosis, then, is the state of burning ketones to get energy.
When the body is in ketosis, the liver uses fatty acids to make ketone bodies, which can cross the blood-brain barrier and substitute for glucose as an energy source. While the exact mechanism of how ketosis controls seizures is unknown, one theory is that ketones have an anticonvulsant effect when crossing the blood-brain barrier. Ketones raise production of a substance called GABBA, which reduces electrical activity in the brain. Free radicals are chemicals that cause inflammation in the brain - they're part of the damaging mechanisms in Alzheimer's and stroke. Chronic acidosis is one of the downsides of keto, but for kids with epilepsy, it could be a benefit.
Indications and Efficacy of the Ketogenic Diet
The primary indication for a ketogenic diet is intractable childhood epilepsy. The treatment is typically recommended when traditional antiepileptic drugs (AEDs) have failed or AED therapy causes unacceptable side effects. Approximately 30% of children who develop epilepsy will develop refractory seizures unresponsive to pharmacologic treatment or experience intolerable side effects from antiseizure medications. If there are 1-3 trials of the appropriately chosen medication, nearly 70 percent of children with epilepsy can gain control of their seizures. However, for the 30 percent of children who can’t control their seizures with medication, the ketogenic diet (KD) might be an option. This low-carb, high-fat diet is effective in significantly reducing seizures by as much as 50 percent in many patients, and can call for decreased dosage in medications.
A 2006 meta-analysis of 19 observational studies (1084 patients) found that after six months of initiating a ketogenic diet, approximately 60 percent of children had a greater than 50 percent seizure reduction and 30 percent had greater than 90 percent seizure reduction. The results of the meta-analysis also suggest that children maintained on a ketogenic diet may also be able to reduce their AED with better seizure control.
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More recently, a randomized controlled trial was performed to test the efficacy of a ketogenic diet on drug-resistant childhood epilepsy. The study included 145 children between 2 and 16 years of age who had at least daily seizures and had failed to respond to at least two antiepileptic drugs. At 3 months, the mean percentage of baseline seizures was significantly lower in the diet group than in the control group who had experienced an increase in seizures from baseline (62% versus 137%; P < 0.0001). In addition, 28 children in the diet group versus 4 children in the control group experienced a greater than 50% seizure reduction (P < 0.0001), and five children in the diet group had greater than 90% seizure reduction compared to zero children in the control group (P = 0.0582).
Variations of the Ketogenic Diet
Multiple variations of ketogenic diets exist, but the most commonly prescribed are the classic ketogenic diet, the modified Atkins diet, the low-glycemic index treatment diet, the medium-chain triglyceride (MCT) diet, and the modified MCT diet.
Classic Ketogenic Diet
The classic ketogenic diet is the oldest of the diets and is one of the strictest. A gram scale is required to weigh food portions because no estimations are permitted. The diet restricts daily calories calculated by the patient's dietitian with a distribution of 85-90% long-chain fatty acid, 6-8% protein, and 2-4% carbohydrates. The most frequently used ratios of fat to non-fat (carbohydrate+protein) in the KD diet 4:1 and 3:1. To maintain a strong ketosis state, a 4:1 ratio is used, and a 3:1 ratio is used for children under 1 year or older children to improve compliance with the KD.
Modified Atkins Diet
Unlike the standard Atkins diet, the modified Atkins diet does not restrict calories, allowing unlimited protein and fat intake, and is more lenient with the use of estimations of portion sizes. The modified Atkins dietary requirements are comprised of 60-70% long-chain fatty acid, 25-30% protein, and 5% carbohydrate. The percentages of calories are 75-80% from fat, 17% from protein, and the remainder from carbohydrate. The ratio of fat and non-fat in the MAD is almost 1.5-2:1.
Low-Glycemic Index Treatment Diet
The low-glycemic index (low-GI) treatment diet restricts the patient's carbohydrate intake to low-GI carbohydrates, allowing for a larger daily allowance of carbohydrates. The glycemic index scores individual carbohydrates based on each food item's effect on raising blood glucose within two hours of consumption. For the LGIT, carbohydrates need to be limited to 40-60 g per day and percentages of calories are 60% from fat, 30% from protein, and 10% from carbohydrate and the ratio of fat and non-fat in the diet is almost 0.66:1.
Read also: Ketogenic Recipes for Epilepsy
Medium-Chain Triglyceride (MCT) Diet
Normal dietary fat contains mostly long-chain triglycerides. Medium-chain triglycerides (MCTs), such as decanoic acid and octanoic acid, are absorbed more effectively and are more ketogenic than LCTs because they generate more ketones per unit of energy when metabolized. Patients on the MCT diet are able to introduce more carbohydrates and proteins into their diet compared to the classic ketogenic diet. The MCT diet is comprised of 71% medium-chain fatty acid, 10% protein, and 19% carbohydrate.
Modified MCT Diet
Alternatively, the modified MCT diet combines the use of both long-chain and medium-chain fatty acids. The modified MCT diet distributes the calories as 30% MCT oil, 40-50% conventional or long-chain fatty acids, 10-20% protein, and 5-10% carbohydrates. The classical and modified MCT ketogenic diets are equally effective, and differences in tolerability are not statistically significant. Despite its flexibility, the MCT diet is disfavored since MCT oil is more expensive than other fats and is not covered by insurance companies.
Implementing the Ketogenic Diet
The initiation of the diet requires an average four-day hospitalization to achieve ketosis in the patient as well as to provide thorough education on diet maintenance for both the patient and the caregivers. Initiation of a ketogenic diet most often occurs in an inpatient setting at an epilepsy center in order to safely monitor glucose levels and urine ketone levels. Traditionally, the diet is initiated after a 24-48-hour fasting period, and it is slowly introduced until the patient successfully achieves the full ketogenic diet to be discharged home with. The average hospital stay is four days, during which the family and the patient are educated on the diet.
During the diet, the physician evaluates and manages complications of KD. Right after the physician, the head of the team, decides to start the KD program, the dietitian provides nutritional management to maintain the KD, and the nurse examines the child for tolerance toward the KD diet and educates caregivers how to care for the child with the KD at home.
Dietary Management and Meal Planning
Our KD program starts without initial fasting. Total fat contents in a patient's meal is gradually increased within 3 days. On the first day the meals provide an 1/3 of energy of daily requirement with a desired ratio of major nutrients. For the meal planning, the dietitian has to decide nutritional requirement of energy and nutrient distribution. In general case, calories for the KD are allowed up to 85~95% of daily requirement. Total 90% of calories are from fat, 6~8% of calories are from protein and remaining calories are from carbohydrate.
The carbohydrate-rich foods such as rice, bread, grain and simple sugars are eliminated. One food is selected from each food group which is categorized to either meat, fish, vegetables, milk or fat sources. The amounts of each food are calculated in grams and the content of nutrients are analyzed to achieve a desired ratio based on the individual nutrient requirement. It is not easy for caregivers to calculate the amounts of each food in grams by themselves. For their convenience, the KD team provides them a computer program to calculate accurate amounts of foods and nutrients contents to minimize human errors.
In order to achieve the ideal ratio, more fat from vegetable oils is needed not only from foods but also from others. Olive oil is usually supplied as a main fat source. In order to improve the composition of fatty acids, olive oil is combined with sesame oil, perilla seed oil, canola oil and others.
Types of Formulation
There are three basic types of formulation; all-in-one, separated, and semi-separated types. All-in-one type is a blended or pureed form for the children at the initial stage of the KD, and also for children who have difficulties in chewing and swallowing. All-in-one type has an advantage of maintaining the desired ratio of the meal and does not affect feeding time which can be extended by meal tolerance of a child. Separated type is for children who have enough abilities to chew and swallow. It is generally recommended to finish the meal completely within 30 minutes. But when the child has difficulties in eating oils, it can be mixed with nuts and milk. Maintaining the desired ratio of fat and non-fat is the most important thing in the KD.
Monitoring and Follow-Up
After returning home, follow-up monitoring for the KD is needed at 1, 3, 6, 12, 18, and 24 month intervals to control seizure and metabolic complications. The compliance of the patients with the diet mainly depends on the types of diet and the patient population. Children who are fed enterally usually demonstrate very high compliance rates, whereas a diet having a fat : nonfat ratio of more than 4.5 : 1 usually leads to poor compliance. Older children and adolescents usually have difficulty adhering to strict diet ratio. Thus, a lower fat : nonfat ratio is often used in this population.
Duration and Discontinuation
The duration of the ketogenic diet varies among patients. The expected length of therapy should be discussed with the patient and/or the family prior to starting the diet, but most patients should expect a minimum of a 3-month trial period. In regards to monitoring the effects of the diet, the anticonvulsant activity gradually increases over time but usually requires several days to weeks to see a noticeable effect. A six week treatment period is usually sufficient to determine success or failure.
The dietary treatment continues 2-3 years in order to achieve seizure control. The ratio of fat and non-fat decreases slowly from 4:1, 3:1, 2:1 to normal diet over 2-3 months. If seizure control is optimized after a few months, AED therapy may be tapered or discontinued. The weaning process is done over several months to avoid triggering seizures. Some people stay on a keto diet for years.
Risks and Side Effects
Ketogenic diets, like any other treatment, are not without risk and require monitoring of complications. Short-term adverse effects include dehydration, mild metabolic acidosis, and hypoglycemia during fasting. Long-term adverse effects include nephrolithiasis, constipation, vitamin and mineral deficiencies, increased cholesterol, retarded growth in young children, and decreased bone mineral density. Various laboratory values should be monitored initially and routinely (usually every 3 months for the 1st year) when patients are started on a ketogenic diet.
The most common complications in the KD are gastrointestinal discomforts including nausea, vomiting, constipation, and diarrhea. High fat diet can affect on serum levels of lipid profile and can result in dyslipidemia such as hypertriglyceridemia and hypercholesterolemia.
Drug Interactions
The addition of a ketogenic diet to a patient's current antiepileptic drug regimen is generally well tolerated and safe. There is some evidence demonstrating that the combination of a ketogenic diet with zonisamide is beneficial in reducing seizures. Alternatively, children on phenobarbital have less success in managing seizures when a ketogenic diet was added.
There are a few drug interactions with ketogenic diets that prompt careful monitoring if the interaction cannot be avoided. In particular, monitor bicarbonate levels in patients on concomitant AED therapy consisting of a carbonic anhydrase inhibitor, such as acetazolamide or methazolamide. The reduction in bicarbonate levels in addition to the increased acid caused by ketones may cause metabolic acidosis.
The Role of Pharmacists
Since ketogenic diets have been proven effective for patients with intractable epilepsy, it becomes essential for healthcare providers to help maintain ketosis to prevent relapse of seizures. A ketogenic diet, consisting of low carbohydrate and high fat intake, leaves little room for additional carbohydrates supplied by medications. Patients on ketogenic diets who exceed their daily carbohydrate limit have the risk of seizure relapse, necessitating hospital readmission to repeat the diet initiation process. These patients are at a high risk for diversion from the diet.
Pharmacists can play an important role in restricting the use of medications with high carbohydrate content. A general rule of thumb is that carbohydrate content is the highest in suspensions and solutions, lower in chewable and disintegrating tablets, and lowest in tablets and capsules that are meant to be swallowed whole. Also, labels reading “sugar-free” can be misleading and often contain carbohydrates, such as sorbitol.
Pharmacists have the resources and the expertise to help identify and prevent the initiation of medications with high carbohydrate content in patients on ketogenic diets. In the inpatient setting, one solution to help avoid the prescribing of high carbohydrate-content medications is to add “sugar” as an allergy to the patient's profile or medical record. For institutions utilizing electronic medical records, a pop-up screen alerting the clinician that the patient is “on a ketogenic diet” is another practical option.
Maintaining Ketosis and Preventing Relapse
Since patients on ketogenic diets may be admitted for nonseizure related issues, the diet may be overlooked during the treatment of the primary condition. Providing pharmacists with a system to catch high carbohydrate-content medications during order entry or via a software alert system can protect the patient from seizure recurrence and the reinitiation of a ketogenic diet.
Pharmacists can utilize their resources to recommend medications with low-carbohydrate preparations for patients on a ketogenic diet. The general rule is that there is a greater carbohydrate content in liquid formulations than chewable and disintegrating tablets, with the least carbohydrate content found in tablets and capsules.
The Importance of a Keto Team
Close monitoring is required when someone starts the diet, so patients are admitted to the hospital for keto diet initiation. Kids on the diet need to be followed closely by their keto team, who will make sure that kids follow the diet, get the nutrients they need, and monitor their seizures.
A child suffering with epilepsy is usually to initiate the KD. In our hospital, a KD team is composed of a physician, a registered nurse, and a registered dietitian. During the diet, the physician evaluates and manages complications of KD. Right after the physician, the head of the team, decides to start the KD program, the dietitian provides nutritional management to maintain the KD, and the nurse examines the child for tolerance toward the KD diet and educates caregivers how to care for the child with the KD at home.