Food For Thought: The Ketogenic Diet As Epilepsy Treatment

While ketogenic diets have been used to treat epilepsy for the last 100 years, they are now finding a resurgence of interest. The diets shift the body’s energy source from glucose to ketones, mimicking the physiological effects of fasting; Hippocrates noted that fasting could reduce seizure frequency (see timeline below).

A boy named Charlie and a sea change

The classic ketogenic diet gained popularity in the 1920s and 1930s, but its presence faded with the availability of more anti-seizure medications, which had fewer lifestyle restrictions. As recently as 25 years ago, the ketogenic diet was rarely used as a treatment for epilepsy.

At that time, Johns Hopkins (USA) was one of the few institutions offering the classic ketogenic diet (90% of calories from fat, 7% from protein and only 3% from carbohydrates) as treatment for pediatric epilepsy. They met with families from many areas of the country—and around the world—who could not find a local physician to offer the diet.

"There were many doctors who told families they didn’t believe in it and that it was too hard," said Eric Kossoff, professor of neurology and pediatrics at the Johns Hopkins University School of Medicine.

But families had started to seek treatments for refractory epilepsy that might improve seizure control, and perhaps with fewer adverse effects than medications. Neurologists began to gradually accept the ketogenic diet as a valid treatment option in those situations. Much of the shift hinged on the publicity surrounding a single patient: Charlie Abrahams, a 2-year-old boy with drug-resistant epilepsy and cognitive decline.

Charlie was treated with the ketogenic diet in 1994. He became seizure free within a month, spent several years on the diet and never had another seizure. (He is now 28.) Charlie’s father, Jim Abrahams, formed The Charlie Foundation to increase awareness of the ketogenic diet, and in 1994 Charlie’s story was featured on a US television program called NBC Dateline, which resulted in thousands of phone calls to the Charlie Foundation from parents seeking more information for their children with drug-resistant epilepsy.

Abrahams also directed a film depicting the family’s experience, First Do No Harm (1997), and the Charlie Foundation supported the first prospective trial of the classic ketogenic diet, which was published in 1998.

Since then, ketogenic diets have become increasingly studied and accepted as a pillar of epilepsy treatment. “The ketogenic is mainstream, it is everywhere,” said Eric Kossoff, professor of neurology at Johns Hopkins. "It’s one of the four major ways we treat epilepsy, along with medication, surgery and nerve stimulation."

Some skepticism remains, however, said Kossoff. "There are some neurologists who are not as familiar with it, or who are not willing to prescribe it."

Types of ketogenic diets

Due to its very high fat requirement, the classical KD can be difficult to maintain. Less restrictive alternatives appear to be nearly as effective while providing more food choice. These alternatives include the modified Atkins diet (MAD; also called the modified ketogenic diet), the medium-chain triglyceride (MCT) diet, and low glycemic index therapy (LGIT).

Do the diets work?

Published in 1998, the first KD trial included 51 children who were enrolled at 7 sites. Eighty-eight percent of the children remained on the diet after 3 months, 69% remained on it at 6 months, and 47% remained on it at 1 year. Three months after initiating the diet, 54% of children had at least a 50% decrease in seizure frequency. At 1 year, 10% of patients were seizure free.

Another 1998 study followed 150 children between age 1 and 16. Collectively, they averaged 410 seizures per month. Three months after starting the diet, 32% of the children had at least a 90% decrease in seizures. After a year, 55% of children were still on the diet; of those, 27 % had at least a 90% decrease in seizures.

Since then, other studies have collectively shown that up to 55% of children achieve seizure freedom with classical KD after 3 months, and 85% achieve seizure reduction. The first randomized clinical trial, published in 2008, included 145 children randomized to dietary treatment or usual care . After three months, 38% of the diet group had greater than a 50% seizure reduction, compared with 6% in the usual-care group, and 7% of the diet group had a 90% or greater reduction in seizures, compared with 0% in the control group. “This study justifies consideration of the KD alongside any other anti-epileptic drug (AED) in the treatment of drug resistant epilepsy,” wrote the authors.

Though few studies have compared the various diet types, a recent randomized trial found that in 158 children, median seizure reductions were 66% on classical KD, 45% on Modified Atkins diet (MAD) and 54% on low-glycemic-index treatment (LGIT) after 24 weeks. Similar numbers of children across the three treatments experienced at least a 50% reduction in seizures.

The trial also showed that changes in seizure burden were more gradual with LGIT than with the other two diets, but the rate of adverse effects was lowest in the LGIT group. LGIT is considered the least restrictive diet of the three, which may make long-term adherence more likely.

"There is increasing evidence that the ketogenic diet, in whatever form may be most practical for the individual, may be effective where drugs have failed across the age range," said Helen Cross, The Prince of Wales's Chair of Childhood Epilepsy and Head of Programme in Clinical Neurosciences at the Great Ormond Street Institute of Child Health at University College London, and senior author of the 2008 randomized trial.

Who is a candidate for a ketogenic diet?

Ketogenic diets have been shown effective in children as young as 6 weeks, on up through adulthood. In general, anyone who can tolerate the diet safely is a candidate to try it.

Certain groups may benefit more than others, however. For certain conditions, evidence shows that a ketogenic diet is highly beneficial and should be used early in patient management. These conditions are:

• Angelman syndrome
• Complex 1 mitochondrial disorders
• Tuberous sclerosis complex
• Dravet syndrome
• Doose syndrome
• GLUT-1 deficiency syndrome*
• Infantile spasms
• Febrile infection-related epilepsy syndrome (FIRES, now considered a subset of NORSE)
• Solely formula-fed infants or children with drug-resistant seizures
• Ohtahara syndrome
• Pyruvate dehydrogenase deficiency*
• Super refractory status epilepticus (SRSE)

*A ketogenic diet is the treatment of choice for this condition.

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For other conditions—including childhood absence epilepsy, cortical malformation, juvenile myoclonic epilepsy, Lennox-Gastaut syndrome, and Rett syndrome—a KD has been reported as moderately beneficial. For more detail, see the recommendations from the International Ketogenic Diet Study Group.

Starting the diet

Traditionally, initiating the ketogenic diet required a short hospital stay, during which the diet was safely started, ketones are monitored, and the person is tested for hypoglycemia or other metabolic issues. The Johns Hopkins program admits patients for three days, provides education and recipe/meal planning to families, and then schedules follow-up visits every one to three months.

Common adverse effects of the ketogenic diets include constipation, vomiting and diarrhea. Constipation is the most common side effect, but usually tapers off over time or can be managed with medication, said Natasha Schoeler, research dietitian in Clinical Neurosciences at the Great Ormond Street Institute of Child Health at University College London.

"Generally, side effects seem to be consistent across the various types of diet,” said Schoeler. “We do sometimes see higher rates in individuals on the classic KD compared with the other forms of diet, but the differences are not striking."

Other short-term side effects can include lethargy, irritability, hunger, loss of appetite, exacerbation of reflux, and increased susceptibility to respiratory tract infections. Schoeler noted that many of these side effects are common in the general population and are also seen in control groups of KD trials.

If the diet is effective, tapering of AEDs can occur, said Schoeler. "Usually if someone is experiencing a very good response to the KD, at least at the three-month mark, or even before, we can start tapering off medications," she said. "Many people do come off medication completely, but others don’t, so it has to be what works best for each person."

What are the drawbacks?

Besides the diet’s potential side effects, ketogenic diets can be expensive. "Medications can be expensive, but insurance will cover them," said Kossoff. "On the diet, families buy more meat, dairy, eggs—and insurance companies don’t pay for groceries. There are ways to make it less expensive, but it’s definitely a cost issue for some families."

These diets also infiltrate all aspects of daily life and can be difficult for families to maintain. Meals for social events, schooldays and holidays must be carefully planned. Such planning requires consistent time and effort, as well as buy-in from extended family members, friends and school administrators and teachers. A meta-analysis of 12 studies including 270 adults on the ketogenic diet found the compliance rate for the classical KD was 38%, and for the modified Atkins diet it was 56%. The authors cited possible side effects, psychosocial factors and the restrictiveness of the diets as possible reasons for the low compliance.

"Even if you’re doing the low-glycemic-index treatment or the modified Atkins diet, you’re still radically changing the way someone eats," said Kossoff. "It’s pretty easy for a month or so, and then it gets old."

Is it a lifelong therapy?

For children with conditions for which a KD is the treatment of choice, and for most adults with epilepsy who find success with a KD, the diet is generally a lifelong commitment. But for others, after two years on the diet it is possible to return to a less restrictive way of eating.

"Around the 2-year mark, we have a discussion with each family as to whether it’s the right time to discontinue the diet," said Schoeler. "There are data showing that 75% to 80% of people who are seizure free on the diet will maintain it off the diet."

Less clear is what happens to those who have reduced seizures but not seizure freedom, she said. "We don’t know if they maintain that response after going off the diet. And of course, there is a risk in anyone that seizures will return."

How does it work?

We really don’t understand how the diet may benefit some people and some conditions. A recent review listed at least 12 mechanisms at play, including effects on neurotransmitters, mitochondria, gut microbiota, DNA methylation, ion channels, inflammation, and G-protein coupled receptors.

"It’s extremely complex," said Kossoff. "I don’t think there will ever be a pill that could completely replicate what the diet does."

But some groups are trying to tease out the key mechanisms of the KD in hopes of providing at least a partial “ketogenic diet in a pill.” Several compounds are in development, including 2-deoxyglucose (2-DG), a glucose analogue that can be taken up by cells, but not used for energy. Instead, it partially blocks cell metabolism activity. 2-DG has been used (as fluorodeoxyglucose) in PET scans to identify areas of glucose uptake, such as in tumor cells. Some studies have shown that 2-DG has anti-seizure activity, while others show the opposite.

A 2018 animal study showed that the ketogenic diet’s effects are dependent upon the gut microbiome, and identified two types of bacteria that proliferated in the guts of mice given KD. Changes in the gut bacteria led to changes in the biochemistry of the gut, which affected neurotransmitters in the brain. Ketogenic diets also inhibit adenosine kinase, resulting in increased levels of adenosine. “Abnormally low levels of adenosine are a hallmark of the epileptic brain,” said Detlev Boison, who spoke about metabolic therapies for epilepsy at the 2020 North American Virtual Epilepsy Congress. Boison, professor of neurosurgery at Rutgers University’s Robert Wood Johnson Medical School, said that inhibiting adenosine kinase may not only reduce seizures, but also prevent epileptogenesis. Work by his group has shown that systemic treatment with an adenosine kinase inhibitor (5-iodotubercidin) stops the development of epilepsy in a mouse model.

The ketogenic diet for status epilepticus

Based on existing evidence, the International Ketogenic Diet Study Group already recommends the ketogenic diet for treating super refractory status epilepticus (SRSE) and febrile infectious refractory epilepsy syndrome (FIRES), a subset of new-onset refractory status epilepticus (see list of conditions in which the KD is highly beneficial, above).

The KD also may be effective for status epilepticus (SE). A 2019 systematic review of 17 articles (4 observational studies, 10 case reports, and 3 case series) found that KD led to the cessation of SE in 82% of adult patients. And a recent study of pediatric patients on a KD seen in the emergency department found significantly lower rates of status epilepticus in children who had been on the diet for at least six months, compared with those following it for less time.

Because the ketogenic diet is currently one of the last options tried in SE—if it is tried at all—there is a risk of the diet being administered too quickly and interacting with other therapies, said Schoeler. Care must be taken to avoid starting the diet in patients on propofol, as propofol infusion syndrome is a rare but often fatal consequence.

The ketogenic diet for other conditions

The ketogenic diet is being recognized in a wide variety of other conditions, such as dementia, brain tumors and some metabolic diseases, said Cross.

Indeed, in the first 10 months of 2020, more than 300 studies were published on the ketogenic diet for other diseases and conditions, including weight loss, cancer, type 2 diabetes, cognitive impairment, heart failure, autism, bipolar disorder, athletic performance, Alzheimer’s disease, and COVID-19.

The ketogenic diet in 2020

Today, several factors make ketogenic diets easier to follow in high-resource regions. Besides the less restrictive alternatives to the classical KD, there also are ketogenic formulas, snacks, shakes, and ready-to-eat meals available. Much of the product explosion stems from the increased popularity of “going keto” as a strategy for weight loss or insulin control.

There also is more professional support for the diet than in the past. "There’s still some cynicism, but very few doctors don’t believe it works, though they may not recommend it high on their list of options," said Kossoff. But going on a ketogenic diet is still an undertaking.

"The diet still requires a hospital admission most of the time, and weighing and measuring," he said. "It’s still easier to take a pill. We need to find ways to make the diets easier and more accessible."

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