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The present study was performed at the Neuropediatric Department, Astrid Lindgren Children’s Hospital, Karolinska Hospital. The patients were enrolled consecutively as they attended the Neuropediatric Outpatient Clinic and a decision was made to start KD. The inclusion criteria were: age 2-17 years; therapy-resistant inoperable epilepsy or a diagnosis of a neurometabolic disorder in which KD is recommended, no medical contraindications to a trial with KD, and consent for fecal sampling. Exclusion criteria were antibiotics taken within 3 months before starting KD. The cohort included 12 children starting KD. Eleven suffered from therapy-resistant epilepsy and one had a neurometabolic disorder, pyruvate dehydrogenase deficiency. The latter patient also had epilepsy but seizures were infrequent. For demographics, see Table 1. Four were males and eight females. Their age at diet start were 7.7 ± 4.5 (mean ± SD) years. The mean age at seizure start was 2.1 ± 2.1 (mean ± SD) years, (range 0.1-5.8). The types of seizures were classified according to the revised terminology of the International League Against Epilepsy classifications.60 The majority of children had more than one seizure type.

Etiology could be determined in eight cases. In four patients, Supraketo Official genetic mutations had been verified. The cohort had previously been on treatment with a mean of 5.7 ± 2.3 (mean ± SD) anti-epileptic drugs (AEDs), range 1-9. At the time of KD start, the children were all on daily AED treatment. They were treated with mean 1.8 ± 0.8 (±SD), range 1-3 AEDs at diet start. At 3 months on KD, when follow-up of efficacy and second sampling of fecal microbiota was made, all had the same AEDs and dosing as before diet start except for two patients. One had tapered lacosamid soon after diet start (a non-responder) and the other had a slight increase in clobazam dose (a non-responder). Eleven children had been investigated with neuropsychological formal testing methods concerning intellectual ability. Nine patients were diagnosed with intellectual disability (ID) ranging from mild to severe. One child was found to have learning disability and attention problems but no diagnosis was made, one child was late in development and not yet tested, and one child was clinically not found to have any deficits.

Other comorbidities as autism spectrum disorder, attention- deficit hyperactivity disorder, and cerebral palsy were also common. Nine patients were fed orally and three patients had a gastrostomy. Parents of the children included in the cohort acted as controls (one parent per child). The controls had a normal dietary intake with a western diet and no one had any specific diets. They did not make any substantial changes in their diet during the study period. Seizure frequency was determined from seizure calendars in which parents and other caregivers made daily notes of the number and type(s) of seizures. They made notes during the month before KD and during KD. Calculations of these notes were used to define seizure response. Mean seizure frequency the month before starting KD was compared with mean seizure frequency the month before follow-up. Children with 50% seizure reduction as responders. Evaluation of cognitive and motor function was based on observations made by the parents and caregivers. They answered a questionnaire before diet start and at 3-month follow-up concerning the level of their child’s alertness, social interest and interaction, verbal responsiveness, ability to communicate, and motor function.

Cognitive and motor function was considered improved if clear positive changes were experienced. We followed a standardized protocol for Keto by Supraketo the classic KD, which is a slightly modified version of the protocol of the Johns Hopkins Hospital.61 A dietitian specially trained to carry out KD treatment calculated total calorie level per day and composition of meals and supplements for each individual. These calculations were based on a 2-day diary kept by the parents before admission in which they recorded all food consumed by the child as well as discussions with the parents on the child’s food preferences. We did not use fasting or calorie restriction. A minimum of 1 g/kg body weight per day of protein was used. The children were supplemented with multivitamins and minerals, including potassium, calcium, magnesium, zinc, selenium, and carnitine. Potassium citrate was used to reduce the risk of kidney stones. KD was started on a ratio of 2:1. This ratio was increased weekly in half steps, i.e., after 1 week of 2:1, it was increased to 2.5:1. Usually an optimal ratio for the individual was reached in 3-6 weeks.

This ratio was kept unchanged until 3 months after start when KD was evaluated concerning efficacy and the second fecal sample was taken. To initiate the treatment, the child was hospitalized for 4 days. Before starting KD, a venous blood sample was obtained in the first morning before breakfast for analyses of glucose and the ketone β-hydroxybutyric acid. Fecal samples were obtained by a swab from the diaper or toilet paper. During the stay, KD was introduced and controlled by clinical examinations and daily blood levels of glucose, β-OHB, and acid-base balance. Keto diet school to teach parents, relatives, and caregivers on various aspects of the diet was carried out. After discharge, blood was sampled to monitor blood ketones, glucose, and acid-base balance at every increase in ratio and at 3 months on KD. This study was approved by the Ethics Committee of the Karolinska Hospital ("Regionala etikprövningsnämden i Stockholm", Dnr 2014/1177-32). Written informed consent was obtained from the legal guardians of the children and, when possible, the children themselves.