Ketogenic diet improves seizures

This paper is part of the 2018 Microbiome Special Issue of NMJ. Download the full issue here.

Relation

Wu Q, Wang H, Fan YY, et al. Effects of a ketogenic diet on 52 children with pharmacoresistant epileptic encephalopathy: a clinical prospective study.Behavior of the brain. 2018;8(5):e00973.

Draft

Prospective clinical study

Objective

To measure the effects of a ketogenic diet on children suffering from drug-resistant epileptic seizures

Participant

From an initial group of 62 children, 52 children with pharmacoresistant epileptic encephalopathy completed a 12-week ketogenic diet. Thirty of these 52 were male; Ages ranged from 3 months to 7 years. All participants had been diagnosed with pharmacoresistant epileptic encephalopathy, had taken 2 or more types of antiepileptic drugs, and were still experiencing frequent seizures (>4 seizures per month) despite regular treatment. All participants were Chinese.

Nutritional intervention

Nutritionists prepared ketogenic diets according to the modified Johns Hopkins program for each participant. The fat to nonfat ratio of each diet was gradually increased from 0.5:1.0 to 4.0:1.0 within 1 to 2 months according to each patient's specific circumstances. The ketogenic diet recipes are designed to fit Chinese eating habits. All participants received the ketogenic nutritional intervention.

Study parameters assessed

Participants underwent a battery of laboratory tests that included routine chemistry, urine, lipid, liver, and urinary profiles; ultrasound, electrocardiogram and electroencephalogram studies; and close monitoring of glucose, ketone bodies, seizures, and adverse events during the study period.

Seizures were tracked beginning one month before the dietary intervention to obtain a baseline measure of seizure frequency. During the treatment period, a diary of seizure occurrence was kept by a parent or guardian. Seizure frequency was compared at weeks 4, 12, and 24.

UCLA has already granted licensing rights to a start-up company that is raising funds to develop a probiotic treatment for epilepsy.

Changes in seizure quality were assessed using 4-hour EEGs at weeks 4 and 12. To compare the effects, a 4-hour EEG was performed before treatment and 3 months after completion of treatment. The Gesell Developmental Scale was used to assess cognitive function after the 12 weeks of treatment.

Assessing changes in seizure severity is complicated. Seizures can change in type, frequency and intensity. These researchers used the Engel classification system, which describes response to epilepsy treatments using the following grading system:

Grade 1: complete remission after treatment

Grade II: rare epileptic episodes affecting function (90%-100% remission)

Grade III: Seizures have improved (50% fewer seizures)

Grade IV: no significant improvement

Primary outcome measure

Treatment was considered effective if the patient's seizure activity was reduced by at least 50%.

Key insights

Treatment was considered effective in 29 of the 52 participants (56%) at the end of 12 weeks of treatment. In responders, the effect of treatment was evident in the first 2 weeks. In 15 of the cases, benefits were observed in the first week of treatment. At the end of the study, 14 participants (27%) were seizure-free. A significant reduction in the number of seizures was observed in 9 cases (17%). A reduction in the number of seizures by half or more was observed in 6 cases (11.5%). Treatment was not considered effective in 23 cases (44%). Remember that the benchmark for effectiveness was at least a 50% reduction in the number of seizures from baseline (Engel Classification Grade III or higher).

Practice implications

Why is this study on ketogenic diet and epilepsy included in this special issue that includes articles on the human biome? At first glance, you might think that this article was added accidentally.

The ketogenic diet was proven effective in treating childhood seizures almost a century ago.¹The ketogenic diet is far from new, although this idea of ​​using it as a strategy in drug-resistant cases has been gaining attention recently.²

What is new is that we have learned that the effects of the ketogenic diet on epilepsy may be related to its effect on the gut biome.

The authors of the ketogenic diet study in children discussed here do not mention this in their discussion of results. In their discussion, they weren't sure why the diet worked for nearly half of the participants. They suggested that switching the brain to use ketones as an energy source, or perhaps calorie restriction itself, might have something to do with the benefits.

The latest hypothesis for ketogenic anticonvulsant effects is compelling enough to be presented here, even though the data comes from mouse experiments.

Previous experiments with mice have shown that ketogenic diets prevent the development of epilepsy,³improving symptoms of autism,⁴Improvement of motor symptoms in Alzheimer's disease,⁵and reduce epileptic activity in the brain.⁶

In the issue of May 24, 2018cellChristine Olson and colleagues in Elaine Hsiao's lab at UCLA suggested that the ketogenic diet rapidly alters the gut biome in a specific way so that it provides protection against both electrically induced seizures and spontaneous tonic-clonic seizures in 2 mouse models of epilepsy.⁷

In this mouse study, the authors showed that the ketogenic diet did not provide protection from seizures in ketogenic mice that were either raised in a germ-free environment or heavily treated with antibiotics. But transplanting the mice with populations ofAkkermansiaandParabacteroidesBacteria conferred protection against seizures.

Olson et al. suggest that the high-fat, low-carbohydrate ketogenic diet shifts the gut biome, reducing diversity and increasing populationsAkkermansia muciniphilaandParabacteroides sppBacteria. This shift in bacterial populations then reduces gamma-glutamyl transpeptidase activity, which reduces gamma-glutamyl amino acids in the blood, which in turn increases gamma-aminobutyric acid (GABA) levels in the brain. Increased GABA in the brain provides protection against seizures.

Hsiao's lab has produced a steady stream of interesting research related to the gut biome and its effects on the brains of mice and humans.

In 2013, Hsiao reported that changes in the microbiota and gastrointestinal barrier could be corrected in a mouse model of autismBacteroides fragilis. Hsiao believes such modification of the gut biome could reduce autism-like symptoms.⁸Hsiao's work on autism continues. It is now widely accepted that immune disorders and digestive problems are common conditions in children on the autism spectrum.^9.10

UCLA has already granted licensing rights to a start-up company that is raising funds to develop a probiotic treatment for epilepsy. The idea is that the right formulation of bacteria modulates GABA and provides the neuroprotective effects of a ketogenic diet in pill form. Swallowing a pill would be easier than following a ketogenic diet and carries fewer risks of side effects.¹¹

There may be other strategies to increase gut populations of these bacteria. Metformin, a drug used to treat type 2 diabetes, appears to increase the populations of these two types of bacteria in mice.¹²Yang et al. reported in 2017 that chronic use of metformin in mice had some anticonvulsant effects.¹³Consuming certain “resistant starches” designed to reach the colon can also increase populations of these bacteria.¹⁴

The relationships between different types of bacteria and diseases are far from understood. BothAkkermansia muciniphilaandAcinetobacter calcoaceticuswere found four times more frequently in patients with multiple sclerosis (MS) than in healthy peopleParabacteroides distasonisis four times more common in healthy people than in patients with MS.AkkermansiaandAcinetobacterare associated with inflammatory reactions in MS, duringParabacteroidesappears to have an anti-inflammatory effect.^fifteenThis makes determining how we approach the use of specific probiotics for a particular patient more difficult than it might seem at first glance.

Treatment for epilepsy may be poised to focus on altering the gut biome with a combination of probiotics, a ketogenic diet, and resistant starch supplementation. If this strategy does indeed increase GABA levels in the brain, we now have a long list of other possible therapeutic targets.