Introduction
A therapeutic diet is used to treat a medical condition, and when prescribed by a Physician and implemented by a Dietitian, it is referred to as Medical Nutrition Therapy (MNT) [1].
Therapeutic ketogenic diets are a form of medical nutrition therapy using a specific ratio of fat to protein plus carbohydrate. These diets are also referred to as ketogenic diet therapy or ketogenic metabolic therapy, and may be used as an adjunct treatment for specific physical health conditions.
Therapeutic ketogenic diets are very high in fat and help the body enter and stay in a state called ketosis. In ketosis, the body burns fat for energy instead of carbohydrates. Nutritional ketosis occurs when the ketone called beta-hydroxybutyrate (BHB) reaches levels between 0.5 and 3.0 mmol/L[2].
In therapeutic ketogenic diets, like those used to treat epilepsy and seizure disorders, BHB levels can go up to 4.0 mmol/L [3], and for conditions such as glioblastoma, where a therapeutic ketogenic diet is used as an adjunct treatment alongside chemotherapy and radiation, BHB levels can reach up to 3.0 mmol/L [4,5,6].
Note: Just because a therapeutic diet may help in glioblastoma does not mean it is suitable for all types of cancer. Most cancers use glucose to grow, while a few use ketone bodies.
Types of Therapeutic Ketogenic Diets
Ketogenic diets are a type of low-carbohydrate diet.
Low-carbohydrate diets are defined as diets in which less than 130 grams of carbohydrates per day, or less than 26% of total energy intake, are consumed [7]. This level of carbohydrate intake is considered too high for therapeutic purposes, such as the treatment of epilepsy or seizure disorders, or when used as an adjunct therapy for glioblastoma. However, they are often used to manage type 2 diabetes.
Moderate-carbohydrate diets are defined as diets in which 130–225 grams of carbohydrates per day, or 26–45% of total energy intake, are consumed [7]. While these diets can be used to help manage type 2 diabetes or obesity, the carbohydrate intake is still too high for the treatment of epilepsy, seizure disorders, or as an adjunct therapy in glioblastoma.
A very low-carbohydrate diet is also referred to as a “ketogenic diet.” In this diet, carbohydrate intake is limited to 20–50 grams per day, or about 10% of total energy intake [7]. It is considered safe and effective for the treatment of type 2 diabetes and obesity [2], and it is also used in the treatment of epilepsy, seizure disorders [3], and as an adjunct therapy in glioblastoma [4,5,6]. Because carbohydrate intake is kept very low, protein and fat intake are increased.
In therapeutic ketogenic diets used for obesity management or to help manage type 2 diabetes, protein intake is set between 15% and 35–40% of total calories. Nutritional ketosis is induced because the diet is very high in fat and very low in carbohydrates, allowing β-hydroxybutyrate (BHB) levels to reach 0.5–3.0 mmol/L [2].
For the treatment of epilepsy, seizure disorders, or as an adjunct therapy in glioblastoma, protein intake is kept as low as 15% of calories to allow BHB levels to rise to between 3.0 and 4.0 mmol/L.
Therapeutic Ketogenic Diets for Epilepsy, Seizure Disorder, and Adjunct Treatment in Glioblastoma
A therapeutic ketogenic diet has been used since the 1920s by Dr. Russell Wilder for the treatment of diabetes and later for the treatment of epilepsy.
In fact, the term “ketogenic diet” is credited to Wilder himself. The precise percentages of carbohydrate, fat, and protein in what is now called the “classic” Ketogenic Diet (KD) were calculated by Dr. M.G. Peterman in 1925 [8], and these same ratios are still used today.
Therapeutic ketogenic diets that are used for epilepsy, seizure disorders, and as adjunct therapy in glioblastoma are very high in fat, low in protein, and low in carbohydrates. Ratios range from 4:1 (4 parts fat for every 1 part protein plus carbohydrate) to 3:1 (3 parts fat for every 1 part protein plus carbohydrate), and for maintenance, ratios as low as 2:1 (2 parts fat for every 1 part protein plus carbohydrate) may be used.
The Diet Prescription
As a Dietitian who designs therapeutic ketogenic diets, the first step is to determine the amount of energy (calories, in kcal) the individual needs. This is calculated based on the person’s weight, height, activity level, nutritional requirements, and whether weight loss is to be avoided, such as in the treatment of glioblastoma.
The second step is to determine the percentage of calories that needs to come from fat, protein, and carbohydrate is calculated based on the specific dietary prescription, whether 4:1 or 3:1. Because of the very high fat and very low carbohydrate content of a 4:1 or 3:1 ketogenic diet, and the small amount of protein, the design of these diets is time-consuming. It is very challenging to create palatable food combinations at each meal to meet the precise macronutrient ratios (protein, fat, and carbohydrate).
To keep ketone production constant over the day, each meal must contain the exact amounts of fat, protein, and carbohydrate specified in the diet prescription. Just as medication has a “dosage,” the specific types and exact amounts of food in the diet prescription are treated as a “food dosage.”
When adults are trialing a 4:1 or 3:1 ketogenic diet for seizure disorders, or during chemotherapy and radiation for glioblastoma, the diet calculations are performed, and a simple breakfast, lunch, and dinner meal plan is designed for use during the first six weeks. Occasionally, an extra dinner meal is included to allow for alternation.
If the diet is found to improve symptoms, those with seizure disorders may choose to remain on the therapeutic diet for an extended period. In such cases, additional lunch and dinner options may be designed, while most people are content to continue eating the same breakfast.
For those with glioblastoma, a 2:1 Modified Atkins Diet is usually requested to be designed for use between rounds of chemotherapy and radiation, and this is done. This diet allows for more protein while keeping carbohydrate intake low and provides a more pleasant “break” for those who have found the restrictive meals of a 4:1 or 3:1 ketogenic diet difficult. Another advantage is that, because it is unknown whether the type of glioblastoma may feed on ketones, alternating between a high-ketone and low-ketone diet in this way reduces the risk of providing high ketone levels when chemotherapy or radiation is not being administered.
For those who are first starting a therapeutic ketogenic diet for epilepsy or as an adjunct treatment in glioblastoma, a challenge is presented by the requirement that the amounts of food on the final meal plan must be weighed precisely and accurately. Even the smallest amount of vegetables, which contain some protein and carbohydrates, can affect the macronutrient ratios and reduce the therapeutic benefit of the diet. Therefore, all foods must be weighed to the gram.
In addition, daily monitoring of blood ketone levels is required at the beginning to determine when the desired therapeutic range has been achieved. For epilepsy and seizure disorders, this range is often defined as β-hydroxybutyrate (BHB) levels between 3.0 and 4.0 mmol/L. Once the desired levels can be maintained by following the diet, less frequent testing can be performed.
Classic Ketogenic Diet (KD) – 4:1
In the classic Ketogenic Diet (KD), the total number of calories is matched to the amount of calories needed by the person. Protein is usually set at 1 gram per kilogram of body weight, carbohydrate is limited to 10–15 grams per day in total, and the remaining calories are provided as fat. For very young children, the diet may be prescribed based on body weight, for example, 75–100 calories for each kilogram (2.2 pounds) of body weight.
Since the 1920s, several other therapeutic ketogenic diets have been developed for the treatment of epilepsy and seizure disorders, including the Modified Ketogenic Diet (MKD) and the Modified Atkins Diet (MAD). All of these diets are very low in carbohydrates and high in fat, which by definition makes them ketogenic, and they differ in the amount of protein that is provided.
In addition to their use in epilepsy and seizure disorders, any of these therapeutic ketogenic diets may be prescribed as adjunct treatment for glioblastoma or as adjunct treatment for Alzheimer’s disease.
The classic Ketogenic Diet (KD) is based on a 4:1 ratio, meaning 4 parts fat for every 1 part protein plus carbohydrates. In other words, for every 5 grams of food, 4 grams are fat and 1 gram is protein and/or carbohydrate.
In the classic Ketogenic Diet, 80% of calories (4 out of 5) are provided from fat, and 20% of calories (1 out of 5) are provided from a combination of protein and carbohydrates. Protein may be set at 15% of calories, with a maximum of 5% of calories coming from carbohydrate, or protein may be set lower at 10%, with carbohydrate as high as 10%.
Modified Ketogenic Diet (MKD) – 3:1 ratio
The Modified Ketogenic Diet (MKD) has a 3:1 ratio, which means 3 parts fat for every 1 part protein and carbohydrate. This diet is 75% of calories from fat, and 25% from a combination of protein and carbohydrate. Protein may be set at 15% of calories, with a maximum of 10% of calories coming from carbohydrate [5].
Modified Atkins Diet (MAD) – 2:1 ratio
In the Modified Atkins Diet (MAD), a 2:1 ratio is used, meaning 2 parts fat for every 1 part protein and carbohydrate. In this diet, carbohydrate intake is restricted to less than 15 grams per day for children and less than 20 grams per day for adults. For adults following a Modified Atkins Diet, 60% of calories are provided from fat, 30% of calories from protein, and 10% of calories from carbohydrate [5].
“Chasing Ketones” – betahydroxybutyrate, the therapeutic goal
While people following the popular “keto diet” for weight loss or type 2 diabetes management are often teased for “chasing ketones” (because their goal is fat loss or improved blood sugar, rather than high ketone production), those following a therapeutic ketogenic diet for epilepsy or seizure disorders, are seeking to maintain ketones between 3.0 mmol/L and 4.0 mmol/L.
The therapeutic goal of a 4:1 or 3:1 therapeutic ketogenic diet is to have the person’s blood ketone level reach 3.0 mmol/L of β-hydroxybutyrate (BHB) as quickly as possible and to maintain it at that level (or, in some cases, increase to up to 4.0 mmol/L). Since the therapeutic benefit is provided by the ketones, nothing that is not part of the diet prescription should be eaten.
It is recommended that for those starting a therapeutic ketogenic diet, a medical-grade Abbott Precision Freestyle Neo meter be obtained from a pharmacy. This meter measures both blood glucose and ketones and is very accurate and reliable, unlike some meters purchased online and used by people following the popular “keto diet” for weight loss. The meter is provided at no cost when 100 glucose strips are purchased (about $1 per strip). It is also recommended that 30 ketone strips be purchased for the same monitor ($3 each), which will last approximately one month when blood glucose is checked three times per day and ketones once per day.
Blood glucose should not fall below 4.0 mmol/L when measured with the meter, and blood ketone levels should ideally measure 3.0 mmol/L, and up to 4.0 mmol/L for epilepsy and seizure disorders—but not higher. If ketone levels exceed 4.0 mmol/L, one’s doctor should be contacted, and if levels rise higher, medical help should be sought immediately.
For people diagnosed with glioblastoma, a 4:1 (or 3:1) therapeutic ketogenic diet is ideally started upon discharge from the hospital so that chemotherapy and radiation treatments are begun while ketone levels are already at 3.0 mmol/L BHB.
For seizure disorders, neurologists who refer patients for dietary management generally seek ketone levels as close to 4.0 mmol/L as possible, because this is where the most benefit is seen. Once seizures have stopped, a gradual transition to a 3:1 or 2:1 diet may be attempted, as long as seizures remain in remission.
To achieve the precise level of ketones required, a certain amount of trial and error in adjusting the diet is involved, but for those seeking to extend life (as in glioblastoma) or improve quality of life (as in epilepsy or seizure disorders), the process may be worthwhile.
NOTE: (April 13, 2021): While some research papers indicate that advanced gliomas do not use ketones as a fuel source, a research paper published in September 2020 has called this into question. According to this paper, different types of glioblastoma cells exist, and some are able to oxidize fatty acids and use ketones for energy. It is suggested that when glucose levels are reduced, some glioblastoma cells may adapt by partially shifting their metabolism to use oxidized fatty acids and ketones. Therefore, seeking lower levels of ketone production may be advantageous.
[Sperry J, Condro MC, Guo L, et al. Glioblastoma Utilizes Fatty Acids and Ketone Bodies for Growth, Allowing Progression during Ketogenic Diet Therapy, iScience, Volume 23, Issue 9, 25 September 2020, 101453].
Many thanks are extended to Cliff Harvey, PhD, for helping to complete this understanding.
More Info?
Under the Services tab, you can learn about the 3:1 and 2:1 therapeutic ketogenic diets that I design for adults with epilepsy or seizure disorder, or those diagnosed with glioblastoma who are seeking to use a therapeutic ketogenic diet as adjunct treatment (along with chemo and radiation).
For those who have received a new diagnosis of glioblastoma and need the earliest available appointment, please reach out through the Contact Form.
To your good health!
Joy
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References
- U.S. Department of Health and Human Services: Final MNT regulations. CMS-1169-FC. Federal Register, 1 November 2001. 42 CFR Parts 405, 410, 411, 414, and 415
- Nasir H. Bhanpuri, Sarah J. Hallberg, Paul T. Williams et al, Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restriction at 1 year: an open-label, non-randomized, controlled study, Cardiovascular Diabetology, 2018, 17(56)
- Meira ID, Romao TT, Pires do Prado HJ, Ketogenic Diet and Epilepsy: What We Know So Far, Front. Neurosci., 29 January 2019, https://doi.org/10.3389/fnins.2019.00005
- van der Louw EJTM, Olieman JF, van den Bemt PMLA, et al. Ketogenic diet treatment as adjuvant to standard treatment of glioblastoma multiforme: a feasibility and safety study. Ther Adv Med Oncol. 2019;11, 2019 Jun 21. doi:10.1177/1758835919853958
- Schwartz KA, Noel M, Nikolai M, Investigating the Ketogenic Diet As Treatment for Primary Aggressive Brain Cancer: Challenges and Lessons Learned, Front. Nutr., 23 February 2018 | https://doi.org/10.3389/fnut.2018.00011
- Klein P, Tyrlikova I, Zuccoli G, Tyrlik A, Maroon JC. Treatment of glioblastoma multiforme with “classic” 4:1 ketogenic diet total meal replacement. Cancer Metab. 2020;8(1):24. Published 2020 Nov 9. doi:10.1186/s40170-020-00230-9
- Feinman RD, Pogozelski WK, Astrup A, Bernstein RK, Fine EJ,Westman EC, et al. Dietary Carbohydrate Restriction as the First Approach in Diabetes Management: a critical review and evidence base. Nutrition. 2015;31(1):1—13
- Peterman MG, The Ketogenic Diet, JAMA. 1928;90(18):1427—1429. doi:10.1001/jama.1928.02690450007003
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