How Does the Ketogenic Diet Contribute Towards Seizure Control in Kids with Epilepsy?

Not Every Kid Reaps Benefit from the Ketogenic Diet

Different diets have been implemented for the purpose of weight loss and most of them pass the test of time only as fad diets that don’t last long. But there are some others which have been strongly suggested even by physicians and health experts to resolve various health issues in individuals-such as the DASH or Ketogenic diet. The DASH diet has been approved for lowering hypertension and the Ketogenic diet exists as an effective treatment against epilepsy. Almost 70% of people with epilepsy could have their seizures controlled with anti-epileptic drugs (AEDs) and for those whose seizures are not arrested with AEDs, the Ketogenic diet proves to be an effective treatment plan. Following the diet helps in reducing the number of seizures, severity of each and also evoke other benefits.
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The Ketogenic diet (KD) is a high fat, low carbohydrate, controlled protein diet used since the 1920s as an effective treatment for intractable epilepsy. Though its only a modified nutrient intake plan, physicians suggest taking up KD only after two suitable medications have been tried and have not provided any fruitful results. KD might be used for adults and children with maximum monitoring done on infants who have been suggested for the diet. It works on the principle that our body uses glucose from carbs as a source of energy. Chemicals called ketones are formed when our body uses fat as an energy source and a fatty acid called decanoic acid might be involved in the way the diet works. The KD mimics the body’s response to starvation by using fat as the primary energy source in the absence of sufficient carbohydrate source. Though the exact process by which ketosis control seizures is unknown researchers hypothesize that ketones have an anticonvulsant effect when crossing the blood brain barrier. It’s a known fact that the various options available for treating kids with pharmacoresistant epilepsy is limited and even surgery is not a viable option for most of them. Almost 30% kids with seizures remain unresponsive to pharmacologic treatment or suffer from extreme side effects of AEDs. It was then that the International Ketogenic Diet Study Group consisting of 26 paediatric epilepsy specialists and dietitians came to a conclusion that KD should be the suggested mode of treatment for those children who failed 2 or 3 anticonvulsant therapies, especially in those with symptomatic generalized epilepsies.

A meta-analysis of 19 observational studies in 2006 showed that six months after starting a ketogenic diet almost 60% kids were relieved from seizures by more than 50% and 30% kids had almost 90% reduction in seizures. It was kids aged 1-10 with generalized seizures who were maximum benefitted by the diet. Another study conducted sometime later on 145 kids aged 2-16 years suffering from daily seizures randomly divided into the diet or control group showed that seizure percentage was lower in the diet group compared to the control group; 28 kids in the diet group experienced 50% decrease in seizures compared to only 4 in the control group who benefited and 5 kids in diet group had 90% reduction in seizures while none in the control group benefited in such ways.

Single-Centre Retrospective Analysis
KD is a valuable option for those with drug-resistant epilepsy (DRE) which can be given for a minimum period of 3 months and continued for several years if it proves to be beneficial. But, constant monitoring of the child is required to keep it effective and prevent the onset of any adverse short-term or long-term effects which might include any effect on the child’s growth. There isn’t much data regarding the effects of KD on the affected kid’s growth-A study by Peterson et al. showed that participants with marked ketosis were characterized by decrease in height for age z-scores which was not evident in those with low or moderate ketosis. The same was also shown by Spulber et al. in a study of 22 kids showing negative link between child growth rate and blood beta-hydroxybutyrate (β-OHB) concentration. A retrospective study by Nation et al. showed that a caloric and protein intake <80% of the recommended values and protein/energy ratio ≤1.4g protein/100 kcal was linked to decreased growth percentile.

The study here probed into growth changes in 34 kids suffering from DRE (n=14) or glucose transporter type 1 deficiency syndrome (GLUT1-DS, n=20) all of whom were treated with KD for 12 months. Inclusion criteria was that kids should be 2-17 years of age, there should be a diagnosis for DRE or GLUT1-DS and treatment with KD done for at least 12 months. Kids with severe organ failure, thyroid disorders or needing enteral or parenteral nutrition were excluded from the study. Growth, clinical and body composition of the participants were calculated at baseline and 12 months after follow-up. Weekly food diaries were assessed to understand the weekly food caloric intake, food preferences and intolerances and total energy intake was formulated based on every patient’s need. Kids aged 3 months-10 years were assessed of their energy needs every quarter while adolescents were analysed every 6 months. The research group ensured that every participant was provided 0.8-1.0 gram of protein per kilogram of body weight from animal sources such as meat, fish, poultry, eggs and milk. All participants took multivitamin and mineral supplements as per their age and sex.

What started as a 1:1 ketogenic diet went to 2:1, 3:1 or 4:1 ratios and participants were assessed for fasting blood ketones, supplements use and for presence of any adverse effects. Each of the participant’s height, weight, BMI and other measurements were taken.

Results
Median age of study participants was 7.5 years, kids with GLUT1-DS were diagnosed at an older age than those with DRE and hence, started with dietary treatment immediately after diagnosis. All participants with GLUT1-DS were on ambulation and did not take AEDs and 10 patients with DRE were on multiple anti-epileptic drugs of which 5 were not able to ambulate. At baseline, there was no difference in height or other parameters between both set of patients. Even after 12 months of study the median height scores did not change significantly from baseline. The kids were put into three growth pattern groups after 12 months of KD-increased (Group-I), tracking (Group-T) and decreased (Group-D) linear growth. There were 6 kids in Group-I of whom 3 had GLUT1-DS; Group-T had 21 patients of whom 13 had GLUT1-DS and Group-D had 7 kids of whom 4 had GLUT1-DS. The three groups did not differ in characteristics at baseline. There was different in energy intake in Group-T compared to Group-I. 11 of 34 kids refused food intake or incomplete meal consumption at intervals. Not much difference in fasting β-OHB levels after 12 months were observed between the three groups. There was an inverse association between fasting β-OHB blood levels at 12 months and height.

While there was no significant difference in height, weight or BMI scores between the three groups at baseline after 12 months it was observed that height and growth velocity scores were lower in Group-D than in Group-I, weight scores were impaired in Group-D and T than in Group-I. There was no difference seen in fat mass percentage between the groups at baseline nor after 12 months.

A 10-Year, Single-Centre Study on Ketogenic Diet
The KD has been used at the Children’s Memorial Hospital, Chicago since the year 1963 and researchers focused on the effect of the diet in patients under the age of 3 in a span of ten year (April 2004 to June 2014). All the patients were grouped into two-early withdrawal or adherent group. The reason behind early withdrawal was questioned and this involved three clinical features-very short-term efficiency of KD, adverse events and implementation and practise of KD. Those kids who underwent 3 months of KD treatment were further classified into 4 groups based on percentage of seizure reduction 3 months-complete seizure control, >90% improvement, 50-90% improvement and <50% improvement. Anyone who experienced >50% seizure control was categorized as responders and others as non-responders. Patients were also classified based on their age into three groups-<1-year-old, 1-2-year olds and >2 years old. Each of the participants’ calorie and protein needs were calculated and vitamin and mineral supplementation was provided based on food intake and nutrient requirements.

Results
109 patients aged below 3 were given the Ketogenic diet and included in the analysis. The median age at which seizures started in them was around 4 months of age and each of them had used medications at least 4 times before starting the diet. More than 50% of them had West syndrome and all of the 109 participants’ EEG was abnormal at the start of the diet. The youngest patient was 3 weeks old. KD was initiated at a 1:1 ratio (fat grams: carbs + protein grams) increasing up to 3:1 on day 3. 20 patients were on a 3:1 ratio, 13 were on a 3.5:1 ratio and 59 were on 4:1 ration. 4.75:1 was the maximum observed ratio and every child reached a fat: no fat ratio of 3:1 or higher except one kid (2.75:1). Solids (33%), liquids (32%) and a combination of both (33%) were given to the kids. 8 of the kids fed on expressed breast milk, median duration of the diet was 1.1 years and one patient suffered from positive urine ketosis at some point of the diet. There was no response in seizures for 3 months of KD administration.
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But after 3 months, 39% patients (n=42) experienced more than 50% reduction in seizures. Of the 42, 20 (18%) of them accomplished complete seizure control and another 3(3%) experienced >90% seizure reduction. Age was not a matter in enabling seizure reduction in kids following KD. But what surprised the researchers was the fact that a genetic mutation or a chromosomal abnormality in patients improved their response to seizures after starting on the KD diet. Though no adverse effects were seen but constipation was commonly reported in the adherent group who were on the diet for a longer period of time.

This shows that the KD is an effective and safe intervention for kids suffering from epilepsy. But given the advantages, the KD is not suitable for all kids and neither can be called ‘user friendly’ given the time and energy needed to maintain ketosis. Some kids refuse to follow the diet and even parents are stressed when diet-induced social modifications become essential. While many studies report the benefits of the diet the medical consequences of KD are not well documented. For instance, a study by Balaban-Gil et al. showed a 10% rate of serious complications in 52 kids with refractory epilepsy and we even have anecdotal reports of coma and death often blamed on metabolic diseases. Another study by Kang et al. showed that while kids following the diet reaped benefits in seizure control they also started experiencing dehydration and gastrointestinal complications within 4 weeks of diet onset. There were also cases of hypoglycaemia, aspiration pneumonia, serum lipid abnormalities, infectious diseases, electrolyte imbalance and acidosis, hepatitis and acute pancreatitis. Three patients died within 60 days of starting to follow the diet-all of them due to brain damage. But it was also observed that the dropout rate of study participants in the research conducted by Kang et al. was more than the dropout rate observed at other centres. But researchers feel that most complications of KD are temporary and could be managed with effective treatment. Ketogenic diet is complicated maybe even life threatening but with high levels of expertise, experience and monitoring it is possible to make the best of it as much as possible. The diet should be administered only by an expert dietitian who has potential knowledge and expertise in KD.

References
Impact of the Ketogenic Diet on Linear Growth in Children: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683244/pdf/nutrients-11-01442.pdf

The Ketogenic Diet in Children 3 Years of Age or Younger: https://www.nature.com/articles/s41598-019-45147-6

The Use of Ketogenic Diet in Paediatric Patients with Epilepsy : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3434405/pdf/ISRN.PEDIATRICS2012-263139.pdf
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Food for Thought: The Ketogenic Diet & Adverse Effects in Children: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1198735/pdf/epc_00044.pdf