This paper is part of NMJ's 2018 Microbiome Special Issue. Download the full issue here.
Wu Q, Wang H, Fan YY, et al. Ketogenic diet effects on 52 children with pharmacoresistant epileptic encephalopathy: a clinical prospective study. Brain Behav. 2018;8(5):e00973.
Prospective clinical trial
To measure the impact of a ketogenic diet on children suffering from drug-resistant epileptic seizures
Out of an initial group of 62 children, 52 children with pharmacoresistant epileptic encephalopathy completed 12 weeks of a 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 kinds of antiepileptic drugs, and still had frequent seizures despite regular treatment (>4 seizures per month). All of the participants were Chinese.
Nutritionists prepared ketogenic diets for each participant in accordance with the modified Johns Hopkins program. The fat to nonfat ratio in each diet was incrementally increased from 0.5:1.0 to 4.0:1.0 within 1 to 2 months according to the specific circumstances of each patient. The ketogenic diet recipes were designed to fit Chinese eating habits. All participants received the ketogenic diet intervention.
Study Parameters Assessed
Participants underwent a full battery of lab testing, which included routine chemistries, urine, lipid, liver, and urinary profiles; ultrasound, electrocardiogram, and electroencephalogram studies; and close monitoring of glucose, ketones, seizures, and adverse reactions during the study period.
Seizures were tracked starting a month before the dietary intervention to get a baseline measure of seizure frequency. A journal of seizure occurrence was kept by a parent or guardian during the treatment phase. 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 the quality of seizures was determined using 4-hour–long EEGs at weeks 4 and 12. To compare effects, a 4-hour EEG was done before treatment and at 3 months after treatment concluded. Gesell Development Scale was used to evaluate cognitive function after the 12 weeks of treatment.
Evaluating changes in seizure severity is complicated. Seizures can change in type, frequency, and intensity. These researchers used the Engel classification system that describes response to epilepsy treatments using the following grading system:
Grade 1: complete remission after treatment
Grade II: rare epileptic episodes that affect function (90%-100% remission)
Grade III: seizures have improved (50% reduction in seizures)
Grade IV: no significant improvement
Primary Outcome Measure
Treatment was considered effective if the patient had a 50% or greater reduction in seizure activity.
The 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 apparent in the first 2 weeks. Benefits were seen in 15 of the cases in the first week of treatment. At the end of the study 14 participants (27%) were seizure-free. A marked reduction in the number of seizures was seen in 9 cases (17%). A reduction by half or more of the number of seizures was seen in 6 cases (11.5%). The treatment was deemed not effective in 23 cases (44%). Keep in mind the bar for being effective was at least a 50% reduction in the number of seizures from baseline (Engel classification Grade III or above).
Why is this study on ketogenic diets and epilepsy included in this special issue that features articles on the human biome? At first glance you may think this article was inserted inadvertently.
The ketogenic diet was proven effective in treating childhood seizures nearly a hundred years ago.1 The ketogenic diet is far from new even if this idea of employing it as a strategy in drug-refractory cases is receiving recent attention.2
What is new is that we have learned that the ketogenic diet’s impact on epilepsy may be related to its effect on the gut biome.
The authors of the ketogenic diet study in children reviewed here do not mention this in their discussion of results. In their discussion, they were unsure why the diet works for nearly half of the participants. They suggested that shifting the brain to using ketones as an energy source or perhaps the caloric restriction itself might have something to do with the benefits.
The newest hypothesis for the ketogenic antiseizure effect is compelling enough to feature here, even if the data is derived from mice experiments.
Earlier mice experiments have demonstrated that ketogenic diets prevent development of epilepsy,3 improve symptoms of autism,4 improve motor symptoms in Alzheimer’s disease,5 and reduce epileptic activity in the brain.6
In the May 24, 2018 issue of Cell, Christine Olson and colleagues at Elaine Hsiao’s lab at UCLA suggested that the ketogenic diet quickly 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 demonstrated that the ketogenic diet did not provide seizure protection to germ-free mice, who were either raised in a germ-free environment or were heavily treated with antibiotics. But transplanting the mice with populations of Akkermansia and Parabacteroides bacteria conferred protection against seizures.
Olson et al propose that the high-fat, low-carbohydrate ketogenic diet shifts the gut biome, decreasing diversity and increasing populations of Akkermansia muciniphila and Parabacteroides spp bacteria. This shift in populations of bacteria then decreases gamma-glutamyltranspeptidase activity, decreasing gamma-glutamyl amino acids in the blood, which in turn increases gamma-aminobutyric acid (GABA) levels in the brain. Increased GABA in the brain offers the protection against seizures.
Hsiao’s lab has been producing a steady stream of interesting research related to the gut biome and its impact on the brains of mice and humans.
In 2013 Hsiao reported that in a mouse model of autism, alterations in microbiota and the gastrointestinal barrier could be corrected using Bacteroides fragilis. Hsiao believes modifying the gut biome in this way could reduce autism-like symptoms.8 Hsiao’s work on autism continues. It is now well-accepted that immune dysfunction and digestive issues are common conditions among 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 will modulate GABA, providing the neuroprotective effects of a ketogenic diet in pill form. Swallowing a pill would be easier than following a ketogenic diet and pose 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, apparently increases populations of both these bacterial species in mice.12 Yang et al reported in 2017 that chronic use of metformin does have some antiseizure effect in mice.13 Consumption of certain “resistant starches” designed to reach the large intestine may also increase populations of these bacteria.14
The relationships between various bacteria species and disease is far from understood. Both Akkermansia muciniphila and Acinetobacter calcoaceticus were found to be 4 times more abundant in patients with multiple sclerosis (MS) than in healthy people, while Parabacteroides distasonis is 4 times more abundant in healthy people than in patients with MS. Akkermansia and Acinetobacter are associated with inflammatory responses in MS, while Parabacteroides appears to have an anti-inflammatory action.15 This makes determining how we approach the use of specific probiotics for any given patient trickier than it may seem at first glance.
Treatment of epilepsy may be on the verge of shifting to a focus on altering the gut biome using a combination of probiotics, a ketogenic diet, and supplementation with resistant starches. If this strategy does indeed increase GABA levels in the brain, a long list of other possible therapeutic targets is now in front of us.
- Peterman MG. The ketogenic diet in epilepsy. JAMA. 1925;84(26):1979-1983.
- Holtkamp M. Pharmacotherapy for refractory and super-refractory status epilepticus in adults. Drugs. 2018;78(3):307-326.
- Lusardi TA, Akula KK, Coffman SQ, et al. Ketogenic diet prevents epileptogenesis and disease progression in adult mice and rats. Neuropharmacology. 2015;99:500-509.
- Ruskin DN, Svedova J, Cote JL, et al. Ketogenic diet improves core symptoms of autism in BTBR mice. PLoS One. 2013;8(6):e65021.
- Brownlow ML, Benner L, D'Agostino D, Gordon MN, Morgan D. Ketogenic diet improves motor performance but not cognition in two mouse models of Alzheimer's pathology. PLoS One. 2013;8(9):e75713.
- Forero-Quintero LS, Deitmer JW, Becker HM. Reduction of epileptiform activity in ketogenic mice: the role of monocarboxylate transporters. Sci Rep. 2017;7(1):4900.
- Olson CA, Vuong HE, Yano JM, et al. The gut microbiota mediates the anti-seizure effects of the ketogenic diet [published online ahead of print May 24, 2018]. Cell.
- Hsiao EY, McBride SW, Hsien S, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013;155(7):1451-1463.
- Hsiao EY. Gastrointestinal issues in autism spectrum disorder. Harv Rev Psychiatry. 2014;22(2):104-111.
- Vuong HE, Hsiao EY. Emerging roles for the gut microbiome in autism spectrum disorder. Biol Psychiatry. 2017;81(5):411-423.
- Taylor NP. Bloom bags cash, UCLA tech to treat epilepsy via the microbiome. https://www.fiercebiotech.com/biotech/bloom-bags-cash-ucla-tech-to-treat-epilepsy-via-microbiome. Published May 24, 2018. Accessed June 18, 2018.
- Lee H, Lee Y, Kim J, et al. Modulation of the gut microbiota by metformin improves metabolic profiles in aged obese mice. Gut Microbes. 2017:1-11.
- Yang Y, Zhu B, Zheng F, et al. Chronic metformin treatment facilitates seizure termination. Biochem Biophys Res Commun. 2017;484(2):450-455.
- Graf D, Di Cagno R, Fåk F, et al. Contribution of diet to the composition of the human gut microbiota. Microb Ecol Health Dis. 2015;26:10.3402/mehd.v26.26164.
- Cekanaviciute E, Yoo BB, Runia TF, et al. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proc Natl Acad Sci. 2017;114 (40):10713-10718.