Efficacy and safety of ketogenic dietary infancy age 2021

Seizure: European Journal of Epilepsy 92 (2021) 106–111
Contents lists available at ScienceDirect
Seizure: European Journal of Epilepsy

journal homepage: www.elsevier.com/locate/seizure
Efficacy and safety of ketogenic dietary theraphies in infancy. A

single-center experience in 42 infants less than two years of age
Jana Ruiz-Herrero a, *, Elvira Cañedo-Villarroya b, Isabel Pérez-Sebastián c,
Beatriz Bernardino-Cuesta d, Consuelo Pedrón-Giner b
a
Department of Pediatric Gastroenterology, Pediatric Service, San Rafael Hospital, Madrid, Spain
b
Department of Gastroenterology and Nutrition, University Children´s Hospital Niño Jesús, Madrid, Spain
c
Department of Pediatric Neurology, Pediatric Service, University Hospital La Moraleja, Madrid, Spain
d
Department of Neurology, University Children´s Hospital Niño Jesús, Madrid, Spain
A R T I C L E I N F O A B S T R A C T
Keywords: Purpose: Ketogenic dietary therapies (KDT) are high-fat and low-carbohydrate diets that may achieve seizure
Ketogenic dietary therapies control and improve cognitive state. We describe our KDT experience in infants (children less than two years of
Classic ketogenic diet age).
Infancy
Research methods & procedures: We conducted a retrospective, descriptive and observational study of 42 infants
Epilepsy
Drug resistant epilepsy
treated with KDT between 2000-2018.
Results: The types of KDT started were: classic ketogenic diet ratio 3:1 (40), ratio 4:1 (1) and modified ketogenic
diet with medium-chain triglycerides (1). Four patients switched to a modified Atkins diet. During follow-up,
79%, 57%, 38% and 17% of infants remained on KDT at 3, 6, 12 and 24 months, respectively. Seizure reduc
tion ≥50% compared to baseline was achieved in 50%, 45%, 38% and 17% at 3, 6, 12 and 24 months,
respectively. Seizure control was excellent (reduction >90%) in 33%, 31%, 26% and 12%, and seizure-free in
fants were 9, 9, 10 and 4, at different follow-up intervals, respectively. Sixty-three percent of infants with West
syndrome were responders to KDT. Mean length of KDT was 390 days (16 days-4.9 years). Ineffectiveness was the
reason for withdrawal in 50% of patients. Early adverse effects (during first month) occurred in 40% of infants.
The most frequent early side effects were asymptomatic hypoglycemia and gastrointestinal disturbances. Late-
onset side effects occurred in 55-14% of infants during therapy, and most frequent were hypercalciuria and
dyslipidaemia.
Conclusion: KDT are useful and effective treatments in infancy. Side effects are frequent but mild and easy to
manage.
1. Introduction The ketogenic dietary therapies (KDT) are effective treatments for
drug resistant epilepsy in childhood [3–7]. Most KDT are high-fat,
Epilepsy is one of the major neurological disorders in childhood, and low-carbohydrate diets. KDT are unbalanced diets that may lead to
its incidence is higher during the first two years of life [1]. Seizure in nutritional deficiencies and growth retardation. Infancy is a critical
infants may lead to severe cognitive problems and may seriously affect period for feeding, growth and cognitive development, so in the past,
psychomotor development [2]. In addition, some severe epileptic en KDT were not recommended for infants. However, recent papers have
cephalopathies typically appear in the first months of life. Pharmaco described the effectiveness and safety of KDT in these ages [8–10], and
logical treatment of epilepsy in infancy is often ineffective, and up to one guidelines for the management of KDT in infants have been published
third of infants may have drug resistant epilepsy. In this group of pa [11].
tients, the use of multiple ineffective antiseizure medicines (ASMs) may Classic ketogenic diet (CKD) 3:1 ratio (3 g of fat to 1 g of carbohy
lead to progressive deterioration and the appearance of side effects that drates plus protein) is the most used KDT in infants because it allows
may worsen the patient’s condition. sufficient protein intake [11]. Other ratios may be used based on ketosis,
* Corresponding author at: San Rafael Hospital, Serrano Street, 199, 2016, Madrid, Spain.
E-mail addresses: jana.ruizherrero@hotmail.com (J. Ruiz-Herrero), consuelocarmen.pedron@salud.madrid.org (C. Pedrón-Giner).
https://doi.org/10.1016/j.seizure.2021.08.018
Received 10 February 2021; Received in revised form 24 June 2021; Accepted 25 August 2021
Available online 29 August 2021
1059-1311/© 2021 The Author(s). Published by Elsevier Ltd on behalf of British Epilepsy Association. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Downloaded for Anonymous User (n/a) at United Arab Emirates Ministry of Health & Prevention from ClinicalKey.com by Elsevier on
October 30, 2024. For personal use only. No other uses without permission. Copyright ©2024. Elsevier Inc. All rights reserved.
J. Ruiz-Herrero et al. Seizure: European Journal of Epilepsy 92 (2021) 106–111
side effects, and growth [11]. In the ketogenic diet with medium-chain 3. Results
triglycerides (MCT, KD-MCT), 71% of the total caloric intake comes
from fat sources, 11% as natural food fat and 60% as MCT [12]. The Forty-two infants (21 males) started on a KDT. All of them had drug
modified KD-MCT allows higher natural food fat (41%). The modified resistant epilepsy except one patient. She was suspected to have a
Atkins diet (MAD) is a less restricted type of KDT that only restricts glucose transporter type 1 deficiency syndrome (GLUT1DS) without
carbohydrates intake to 10 grams per day [13]. seizure who had not been treated with ASMs. Mean number of ASMs
We describe our experience in infants (<2 years-old) with epilepsy. tested prior KDT was 4.6 (± 2.3, range 0-10). Fourteen patients (33%)
Our aim is to assess effectiveness, side effects, growth development and were treated with >5 ASMs, and 43% of children suffered side-effects
impact on nutritional status in infants on a KDT. from ASMs. Other treatments tested prior to KDT were: epilepsy sur
gery (1), gamma globulin (1), corticosteroids (6), adrenocorticotropic
2. Methods hormone (ACTH) (9), and other such as vitamin B6 and cofactors (31).
The specific etiology was unknown in 10 infants. Genetic disorders
Medical patient’s records of all the children who were on a KDT at were the most frequent diagnosis (Table 1). Before the onset of KDT, two
the Niño Jesús Pediatric Hospital of Madrid (Spain) between January infants were in status epilepticus, and in five it could not be possible to
2000 and December 2018 were reviewed. All infants (<2 year-old) were count the number of daily seizure, so frequent they were. The median
recruited for this retrospective observational descriptive study. Data number of seizures among children who could count them was 7 per day
were collected anonymously, the Committee for Ethics in Clinical (IQR 3-15). All patients with epilepsy had daily seizure. Most frequently
Research approved the investigation (R-0002/15), and the relatives type of seizures reported were tonic (33.3%), focal onset seizure (26.2%)
were informed and signed an informed consent. and various type (14.3%). Generalized tonic-clonic seizures (4),
Demographic data and information about the etiology of epilepsy, myoclonic seizures (3), and clonic seizures (2) were less frequent. Only
treatments used, KDT implemented, efficiency of KDT, adverse effects, the patient with Angelmal syndrome had typical absences. Eleven in
laboratory blood and urine analyses, and anthropometry were collected. fants had West syndrome and two met the criteria of migrating focal
Anthropometric parameters were adjusted by sex and age according to epilepsy.
the growth charts of the World Health Organization (WHO). Median age at the beginning of symptoms was 3.9 months (IQR 53-
Patients underwent a thorough examination prior to KDT and then
after the 1st, 3rd, 6th, 12th and 24th month, or before being weaned off
the diet or being discharged. The effectiveness of KDT was measured by Table 1
a reduction in ASMs and seizures. The reduction in seizures was grad Etiological diagnosis of infants on a ketogenic dietary therapy.
uated comparing to baseline as follows: 100% (seizure-freedom), 90%– Etiology Frequency Percent Specific Etiology
100% improvement, 50%–90%, <50%, 0% (no improvement), or in
Unknown 10 24
crease of the amount of seizures. Metabolic 6 14 3 GLUT1DS (1 confirmed SLC2A1 gene
The diet started before 2009 was implemented following the John mutation)
Radcliffe Hospital protocol [14]. Between 2009 and 2014, the recom 2 mitochondrial diseases
mendations of the International Ketogenic Diet Study Group [15] were 1 neuronal ceroid lipofuscinoses
Structural 10 24
followed to implement KDT. Since 2015, a protocol developed in our
6 malformations of cortical
nutrition department was used, with similar recommendations to those development (5 cortical dysplasia, 1
published in recent guidelines [11,16]. The WHO energy requirements, lissencephaly)
on the basis of age and weight, were used. Energy requirements were 2 cortical tuber (tuberous sclerosis
calculated also in the basis of a food diary. Protein intake was calculated complex)
1 leptomeningeal angioma (Sturge
according to daily recommendations (1 g/kg/day in children > 1 year,
Weber)
and 1.5 in children ≤ 1 year). Needs of liquids were calculated according 1 hypoxic-ischemic encephalopathy
to Holliday–Segar method. All KDT were started in an inpatient setting. (sepsis related)
Most of the diets (40/42) were introduced increasing the ketogenic ratio
Genetic 14 33 10 gene mutation disorders
progressively, without fasting or liquid restriction. Caloric restriction to
disorders 3 CDKL5
80% of basal energy needs was used in the introduction of the modified 1 KCNQ2
KD-MCT. KDT were administered orally in 29 patients (69%). Naso 1 STXBP1
gastric tube was used in 12 (29%) and gastrostomy tube in 1 (2%). The 1 SCN2A
type of diet or the route was modified in 9 children. Two patients needed 1 CHRNA4
1 RBFOX1
a reduction in the ketogenic ratio. Four patients on a CKD switched to a
1 CNTNAP2 (associated with dysplasia and
MAD 4-35 months after the onset of KDT, all of them were ≥ 21 Pitt Hopkins like syndrome)
months-old and were on a KDT 16-60 months. Two patients needed a 1 PHOX2B (Ondine syndrome))
gastrostomy tube, and one infant who started KDT by nasogastric tube 4 chromosomal disorders
1 trisomy 21 (Down syndrome)
could continue orally 15 days after the onset. Only 15 patients were
1 chromosome 15 duplication
exclusively breastfed before treatment, and only two for at least six 1 chromosome 1p deletion
months. In all cases, breastfeeding was replaced by the ketogenic 1 chromosome 15q deletion (Angelman
formula. syndrome)
Variables were registered in an Excel program table and statistical Infection 2 5
1 Herpes simplex virus
analyses were carried out with SPSS version 16.0. Quantitative data
meningoencephalitis
were presented as mean and standard deviation for normal distributions, 1 Streptococcus pneumoniae meningitis
and median and interquartile range (IQR, 25th percentile 75th percen
GLUT1DS: glucose transporter type 1 deficiency syndrome; SLC2A1: solute
tile) for data that do not follow normal distribution. Qualitative data
carrier family 2 member 1. CDKL5: cyclin dependent kinase-like 5; KCNQ2:
were expressed as a percentage. Data were analysed on an intention-to-
potassium voltage-gated channel subfamily Q member 2; STXBP1: syntaxin
treat basis. Missing data were addressed by a complete case analysis. binding protein 1; SCN2A: sodium voltage-gated channel alpha subunit 2;
Loss to follow-up was addressed as missing data. CHRNA4: cholinergic receptor nicotinic alpha 4 subunit; RBFOX1: RNA binding
fox-1 homolog 1; CNTNAP2: contactin associated protein like 2; PHOX2B: paired
like homeobox 2B.
107
181 days). Debut occurred within the first month of life in 21%, and in Before KDT, some disturbances in micronutrients and nutritional
76% within the first six months. markers in blood were found. There were observed low levels of: pre
Median age at the onset of KDT was 7.7 months (IQR 4.5-16.7 albumin (<15 mg/dl) in 6 patients, retinol binding protein (RBP) (<2.5
months). Sixty-four patients started KDT <12 months-old, and 38% mg/dl) in 4, selenium (<70 mcg/L) in 15, zinc (<70 mcg/dl) and
<6 months-old. Median time from debut to the onset of the diet was 114 phosphorus (<4.5 mg/dl) in 5, and vitamin B12 (<250 pg/ml), carnitine
days (IQR 64-281). Five patients started the diet within the first month (<33 µmol/L), 25-hydroxyvitamin D (<20 ng/ml), and vitamin A (<0.2
of symptoms, 43% within three months from debut, and 79% within mg/L) in 1. The only patient with a baseline vitamin D deficiency had
twelve months. also a vitamin B12 deficit. All patients with baseline zinc deficiency also
Only one infant was on a KDT between 2005 and 2010. Since 2010, had baseline selenium deficiency.
2-8 infants per year started a KDT. CKD 3:1 ratio was used in 40 patients. Throughout the follow-up, vitamin A, E and D were deficient in one
A modified KD-MCT was used only in a 21 months-old girl with struc child each. At 6 months, one child had zinc deficiency and two selenium
tural epilepsy in 2005. A CKD 4:1 ratio was started in an 18 months-old deficit. At 12 months, 2, 4 and 2 children had deficits in zinc, selenium
boy with structural epilepsy in 2013. Both were withdrawn before 2 and phosphorus, respectively. At 24 months, deficiencies in phosphorus
months of treatment due to ineffectiveness. and selenium were observed in one child each. All these nutrient de
KDT was effective (seizure reduction ≥50% compared to baseline) in ficiencies were observed in patients other than those who were deficient
a half of patients in the first six months. Seizure control was excellent at baseline, except for one child with baseline selenium deficiency who
(seizure reduction >90%) in more than a quarter of our patients during was also deficient at 12 months. Prealbumin and RBP was below normal
the first year, and some patients were completely seizure-free (Table 2). values in 7 and 5 patients each at 6 and 12 months, and in 2 and 3
Fig. 1 represents effectiveness according to type of seizure. According to children, respectively, at 24 months. One of these patients had low levels
the three main causes of epilepsy in our cohort, KDT was effective, of RBP from baseline and in all time slices. Only two children with
throughout the follow-up, in 83-33% of children with metabolic disease, baseline prealbumin below normal values had low levels at 6 and 12
43-14% of patients with a genetic disorder, and 30-10% of children with months and only at 12 months, respectively.
structural epilepsy. Patients with monogenic epilepsies and a seizure Mild alteration of height (z score <-2) was observed in 14% of
reduction ≥50% had mutations in CDKL5, KCNQ2 and STBP1. Within children baseline. Only one of the 6 patients with baseline height
the patients with chromosomal disorders, KDT was effective only in the impairment continued with a height z score <-2 at 3 and 6 months. Two
patient with Down syndrome, who was seizure-free. Among infants with other patients with normal baseline z score of height had a decrease
West syndrome, were responders to KDT 63% of patients at 3 and 6 below -2 at 3 months and 12 months, respectively. Both children had a
months, and only one of the patients with migrating focal epilepsy had a mild alteration of height al 24 months (Table 5 and Fig. S1). Only one
good response. The number of ASMs was reduced throughout the follow- child had a severe alteration of growth (z score of height <-3) at 6
up, specially in the first months from the onset of KDT (Table 3). months. Weight was normal in most patients baseline and after KDT. The
Median levels of betahydroxybutyrate were 4-4.4 mmol/L z-score of body mass index (BMI) and head circumference were altered
throughout the follow-up. Four patients at 3 months, and 2 at 6, 12 and in some infants, especially at baseline (Table 5).
24 months, had low levels of ketones (<2.4 mmol/L) in blood
monitoring. 4. Discussion
Mean length of KDT was 390 days (16 days-4.9 years). Two patients
withdrew within first month of therapy, 9 (21%) within 3 months, and KDT were not recommended for infancy in the past because they
18 (43%) within 6 months. Seventeen infants (40%) were on a KDT for ≥ were considered inappropriate and unsafe at this stage of life. In our
1 year. Ineffectiveness was the reason for withdrawal in 50% of patients. hospital, KDT has been onset in childhood since 2000. However, it was
Only 4 children stopped KDT due to side effects or poor tolerability not until 10 years later when we began to prescribe them routinely in
(vomiting 16 days after the onset of KDT, hypertransaminasemia 4.5 children younger than 2 years old. Our study confirms that KDT are
months after, severe acidosis and dehydration 5 months after, and useful and safety treatments for infants. At 6 months, 45-50% of infants
hypercalciuria and bone fracture due to poor liquid intake and parental in our cohort had a good response, and a quarter had an excellent
refusal to nasogastric tube 21 months after). Three boys died during response o were seizure-free. Nordli and coauthors [17] first described
treatment from underlaying disease. Six infants were on a KDT for more the use of KDT in 32 infants and their results were similar. Twenty
than two years. Of these, 3 continued with the diet when their medical percent of their patients were seizure-free, and an additional 35% had a
record was reviewed, and the other three withdrew for prolonged good response. More recent studies confirmed the good results of KDT in
treatment, without relapses after withdrawal. the treatment of infantile spasms [18–21], the most common seizure
Early adverse effects (during the first month) occurred in 40% of type in infants. Some studies have even shown that KDT are as effective
infants. The most frequent early side effects were asymptomatic hypo as ACTH and have lower rates of side effects and relapse [22]. In our
glycemia (9/42) and gastrointestinal disturbances (4/42), such us cohort, more than half of the infants with spasms and West syndrome
vomiting, constipation and diarrhea. At 3 and 6 months from the onset were diet responders. Another epileptic syndrome in infants in which
of KDT, 55% and 40% of infants suffered from late-onset side effects. KDT has been described to be effective is the migrating focal epilepsy
Those percentages were reduced to 29% and 14% at 12 and 24 months. [23,24]. In our series, there were only two patients with this syndrome,
Most frequent late-onset adverse effects were hypercalciuria and dysli and KDT was effective in only one of them. The patients with a metabolic
pidaemia (Table 4). disease were the most frequently responders in our cohort, probably
because a half of our patients in this group suffered from GLUT1DS, and
KDT is the gold standard treatment for the disorders in which brain
Table 2 metabolism is compromised, due to KDT provides an alternative sub
Effectiveness of ketogenic dietary therapies on seizure reduction. strate. Two recent reviews concluded that KDT are safe and effective for
Seizure reduction compared to baseline* ≥50% ≥90% 100% the treatment of drug resistant epilepsy, GLUT1DS and pyruvate dehy
3 months (n=33, 79%) 21 (50%) 14 (33%) 9 (21%) drogenase deficiency in children ≤2 years [25,26]. Comparing effec
6 months (n=24, 57%) 19 (45%) 13 (31%) 9 (21%) tiveness of KDT in infants versus older children, seizure freedom is more
12 months (n=16, 38%) 16 (38%) 11 (26%) 10 (24%) often achieved and maintained in infants, and acceptance is better [27].
24 months (n=7, 17%) 7 (17%) 5 (12%) 4 (9.5%) The onset of epilepsy in the first years of life is usually associated
*
The percentage of patients in the boxes has been calculated by intention to with poor prognosis, intractability, and even increased death risk [2]. In
treat. our study, three patients (7%) died from underlaying disease, and 30%
108
Fig. 1. Effectiveness of ketogenic dietary therapies according to type of seizures. KDT: ketogenic dietary theraphies. m: months. GTC: generalized tonic clonic.
Table 3 Table 4
Effectiveness of ketogenic dietary therapies (KDT) on the number of antiseizure Early and late-onset secondary effects of ketogenic dietary therapies in infants.
medicines (ASMs) prescribed. Side effects* ≤1 1-3 3-6 6-12 ≥ 24
A month 3 6 12 24 month months months months months
prior to months* months* months months
GI disturbance 4 1 2 1 1
KDT
Hypoglycemia 9 1 1 0 0
Number of ASMs Hypercalciuria 2 6 7 2 1
prescribed 3 (7%) 5 (12%) 5 (12%) 4 3 (7%) Acidosis 0 0 2 6 1
≤ One ASM 13 (31%) 14 7 (17%) (9.5%) 1 Hypertriglyceridemia 1 19 12 3 0
Two ASMs 13 (31%) (33%) 8 (19%) 6 (14%) (2.4%) Hypercholesterolemia 1 5 8 7 3
Three ASMs 13 (31%) 11 3 (7%) 5 (12%) 2 Hyperuricemia 1 6 7 3 2
≥ Four ASMs (26%) 1 (4.8%) Increased liver 0 8 3 4 1
1 (2.4%) (2.4%) 1 enzymes
(2.4%) Dehydration 0 1 1 1 1
Patients in whom Anorexia 0 1 0 0 0
the number of - 16 4 (9.5%) 2 2 *
Hypoglycemia: glucose <50 mg/dL. Hypercalciuria: urine calcium/creatine
ASMs was (35%) (4.8%) (4.8%)
reduced ratio >0.50. Acidosis: pH <7.30. Hypertrigliceridemia: tryglicerides >115 mg/
Mean of ASMs dL. Hypercholesterolemia: cholesterol >200 mg/dL. Hyperuricemia: uric acid
prescribed (SD) 3 (1.4) 2.3 (0.8) 2.4 (1.1) 2.2 2.1 >6 mg/dL. Increased liver enzymes: aspartate aminotransferase (AST) >50 IU/L
(0.9) (1.2) and/or alanine aminotransferase (ALT) >50 IU/L and/or gamma glutamyl
transpeptidase (GGT) >35 IU/L.
SD: standard deviation. *Number of ASMs was not registered in two patients at 3
months and in one at 6 months.
commercialized formulas facilitates compliance and its management by
of infants were tube-fed. The need for a feed tube was indicative of how caregivers. Most of the infants in our cohort were formula-fed before
severe the patients were, but it was also an opportunity to start the diet, KDT, as their neurological status probably made breastfeeding difficult.
since the tube facilitated the management of KDT. Although the age at We replaced breastfeeding for the ketogenic formula in all cases, but
the onset of KDT was not related to seizure outcome in a recent paper there are even studies in infants on a CKD maintaining breastfeeding
[28], the control of seizures should be achieved as soon as possible, in [31]. However, with the beginning of solid food, problems of adherence
order to avoid a progressive neurological deterioration, and ineffective may appear. In these cases, the diet must be individualized, and it is even
and potentially harmful pharmacological treatments. In our cohort, the possible to switch CKD to a less restrictive KDT such as MAD, as we did
delay in the onset of KDT from the onset of symptoms was 4 months, and in four patients with good outcome and prolongued duration of therapy.
the mean ASMs tested before the diet was four. The International League Side effects were frequent in our cohort, but only four infants with
Against Epilepsy defined drug resistant epilepsy as failure of adequate drew due to adverse effects or poor tolerability. Our data are similar to
trials of two tolerated and appropriately chosen and used ASMs sched those published by Dressler in a recent review [30]. Most frequent side
ules [29]. Maybe an earlier use of the diet would have improved the effects were hypoglycemia and gastrointestinal disturbances in a
results of our patients. short-term, and dyslipidemia and hypercalciuria in a long-term. Side
The most frequent used and recommended type of KDT in infancy is effects were mild and were alleviated with dietary modifications or
CKD ratio 3:1[11,30] because it meets protein requirements for a proper commonly used drugs. A recent randomized controlled trial showed that
growth. The ratio can be adjusted based on acceptance, adverse effects, KDT had fewer and less severe side effects than ACTH for infantile
ketosis, or intercurrent situations. In younger infants, the use of spasms [32], so KDT should be considered safe therapies in infancy.
109
Table 5
Z-score of body mass index (BMI), height, weight, and head circumference, and number of patients with alterations in those z-score, baseline and throughout the
follow-up.
Time on the Diet Baseline 3 Months 6 Months 12 Months 24 Months
BMI z <-2 4 2 1 1 0
z >+2 1 0 1 2 1
Mean z-score (SD) -0.2 (1.24) -0.32 (1.14) -0.04 0.65 (1.8) 0.49 (1.7)
(1.26)
z <-2 6 2 2 1 2
Height Mean z-score (SD) -0.15 (1.5) 0.22 (1.55) -0.43 (1.38) -0.77 (0.98) -1.09 (1.5)
Weight z <-2 1 1 1 0 1
z >+2 0 0 0 0 1
Mean z-score (SD) -0.29 (1.09) -0.1 (1.06) -0.31 (0.91) -0.03 (1.10) -0.44 (1.8)
Head circumference z <-2 6 5 3 2 2
z >+2 1 2 1 1 0
Mean z-score (SD) -0.86 (1.77) -0.44 (1.92) -0.8 (1.52) -0.72 (2.4) -1.2 (1.5)
SD: standard deviation
Nutritional deficiencies have been reported in children on KDT. Se [4] Freeman JM, Vining EP, Pillas DJ, Pyzik PL, Casey JC, Kelly LM. Efficacy of the
ketogenic diet-1998: a prospective evaluation of intervention in 150 children.
lenium, carnitine, magnesium and other nutrients have been described
Pediatrics 1998;102(6):1358–63. https://doi.org/10.1542/peds.102.6.1358.
to be deficient in these diets [33,34]. In addition, children with drug [5] Henderson CB, Filloux FM, Alder SC, Lyon JL, Caplin DA. Efficacy of the ketogenic
resistant epilepsy are at risk of vitamin D deficiency [35], and taking diet as a treatment option for epilepsy: meta-analysis. J Child Neurol 2006;21(3):
anticonvulsant medication may be associated with other deficiencies 193–8. https://doi.org/10.2310/7010.2006.00044.
[6] Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G,
[34]. In our study, the most frequent deficiencies observed before KDT Whitney A, Cross JH. The ketogenic diet for the treatment of childhood epilepsy: a
were zinc, selenium, and phosphorous. These deficits improved after the randomized controlled trial. Lancet Neurol 2008;7(6):500–6. https://doi.org/
onset of KDT. Only one patient had vitamin D deficiency baseline, 10.1016/S1474-4422(08)70092-9.
[7] Kim JA, Yoon JR, Lee EJ, Lee JS, Kim JT, Kim HD, Kang HC. Efficacy of the classic
probably because all infants younger than 1 year are supplemented with ketogenic and the modified Atkins diets in refractory childhood epilepsy. Epilepsia
the recommended daily requirements of vitamin D in Spain. 2016;57:51–8. https://doi.org/10.1111/epi.13256.
Growth retardation in children on a KDT has been reported [36,37] [8] Wirrell E, Eckert S, Wong-Kisiel L, Payne E, Nickels K. Ketogenic diet therapy in
infants: efficacy and tolerability. Pediatr Neurol 2018;82:13–8. https://doi.org/
as we have shown in our cohort, and younger children may be at greater 10.1016/j.pediatrneurol.2017.10.018.
risk [38], especially after prolonged treatment [39]. In a study on in [9] Ismayilova N, Leung MA, Kumar R, Smith M, Williams RE. Ketogenic diet therapy
fantile spasms, no differences in the rate of seizure relapse were found in infants less than two years of age for medically refractory epilepsy. Seizure 2018;
57:5–7. https://doi.org/10.1016/j.seizure.2018.02.014.
between seizure-free patients who discontinued the diet at 8 months or 2 [10] Riantarini I, Kim HD, Ko A, Kim SH, Kang HC, Lee JS, et al. Short- and long-term
years [40], so a shorter length of KDT should be considered in these seizure-free outcomes of dietary treatment in infants according to etiology. Seizure
cases [11]. 2019;71:100–4. https://doi.org/10.1016/j.seizure.2019.06.002.
[11] Van der Louw E, van den Hurk D, Neal E, Leiendecker B, Fitzsimmon G, Dority L,
Although the number of patients in our study is small, it is higher
et al. Ketogenic diet guidelines for infants with refractory epilepsy. Eur J Paediatr
than some other previously published cohorts. Despite our sample size Neurol 2016;20(6):798–809. https://doi.org/10.1016/j.ejpn.2016.07.009.
and the retrospective design, the present paper adds evidence to support [12] Huttenlocher PR, Wilbourn AJ, Signore JM. Medium-chain triglycerides as a
the effectiveness and safety of KDT in infants. therapy for intractable childhood epilepsy. Neurology 1971;21:1097–103. https://
doi.org/10.1212/wnl.21.11.1097.
[13] Kossoff EH, Dorward JL. The modified Atkins diet. Epilepsia 2008;49(Suppl 8):
5. Conclusion 37–41. https://doi.org/10.1111/j.1528-1167.2008.01831.x.
[14] Schwartz RH, Eaton J, Bower BD. Aynsley-Green A. Ketogenic diets in the
treatment of epilepsy: short term clinical effects. Dev Med Child Neurol 1989;31:
KDT are effective and safety treatments for epilepsy in infancy. The 145–51.
most accepted type of KDT is CKD ratio 3:1. Adverse effects, although [15] Kossoff EH, Zupec-Kania BA, Amark PE, Ballaban-Gil KR, Bergqvist AGC,
common, are usually mild and easy to treat. Close monitoring is Blackford R, et al. Optimal clinical management of children receiving the ketogenic
diet: recommendations of the international ketogenic diet study group. Epilepsia
important to detect side effects, nutritional deficiencies, and anthropo 2009;50(2):304–17. https://doi.org/10.1111/j.1528-1167.2008.01765.x.
metric disturbances. Growth should be closely controlled in this crucial [16] Kossoff EH, Zupec-Kania BA, Auvin S, Ballaban-Gil KR, BergqvistAGC BR,
stage of life, and modifications in protein or calories intake should be Buchhalter JR, Caraballo RH, Cross JH, Dahlin MG, et al. Optimal clinical
management of children receiving dietary therapies for epilepsy: updated
done if height or weight are affected. recommendations of the International ketogenic diet study group. Epilepsia Open
2018;3:175–92. https://doi.org/10.1002/epi4.12225.
Supplementary materials [17] Nordli DR, Kuroda MM, Carroll J, Koenigsberger DY, Hirsch LJ, Bruner HJ, et al.
Experience with the ketogenic diet in infants. Pediatrics 2001;108(1):129–33.
https://doi.org/10.1542/peds.108.1.129.
Supplementary material associated with this article can be found, in [18] Eun SH, Kang HC, Kim DW, Kim HD. Ketogenic diet for treatment of infantile
the online version, at doi:10.1016/j.seizure.2021.08.018. spasms. Brain Dev 2006;28(9):566–71. https://doi.org/10.1016/j.
braindev.2006.03.011. Brain Dev. 2006;28(9):566-71.
[19] Pires ME, Ilea A, Bourel E, Bellavoine V, Merdariu D, Berquin P, et al. Ketogenic
References diet for infantile spasms refractory to first-line treatments: an open prospective
study. Epilepsy Res 2013;105(1-2):189–94. https://doi.org/10.1016/j.
[1] Wirrell EC, Grossardt BR, Wong-Kisiel LC, Nickels KC. Incidence and classification eplepsyres.2012.11.009.
of new-onset epilepsy and epilepsy syndromes in children in Olmsted County, [20] Kayyali HR, Gustafson M, Myers T, Thompson L, Williams M, Abdelmoity A.
Minnesota from 1980–2004: a population-based study. Epilepsy Res 2011;95(1-2): Ketogenic diet efficacy in the treatment of intractable epileptic spasms. Pediatr
110–8. https://doi.org/10.1016/j.eplepsyres.2011.03.009. Neurol 2014;50(3):224–7. https://doi.org/10.1016/j.pediatrneurol.2013.11.021.
[2] Wirrell E, Wong-Kisiel L, Mandrekar J, Nickels KC. Predictors and course of [21] Hong AM, Turner Z, Hamdy RF, Kossoff EH. Infantile spasms treated with the
medically intractable epilepsy in young children presenting before 36 months of ketogenic diet: prospective single-center experience in 104 consecutive infants.
age: a retrospective, population-based study. Epilepsia 2012;53(9):1563–9. Epilepsia 2010;51(8):1403–7. https://doi.org/10.1111/j.1528-1167.2010.02586.
https://doi.org/10.1111/j.1528-1167.2012.03562.x. x.
[3] Vining EP, Freeman JM, Ballaban-Gil K, Camfield CS, Camfield PR, Holmes GL, [22] Kossoff EH, Hedderick EF, Turner Z, Freeman JM. A case-control evaluation of the
et al. A multicenter study of the efficacy of the ketogenic diet. Arch Neurol 1998;55 ketogenic diet versus ACTH for new-onset infantile spasms. Epilepsia 2008;49(9):
(11):1433–7. https://doi.org/10.1001/archneur.55.11.1433. 1504–9. https://doi.org/10.1111/j.1528-1167.2008.01606.x.
110
[23] Caraballo R, Noli D, Cachia P. Epilepsy of infancy with migrating focal seizures: hormone for infantile spasms: a single-center parallel-cohort randomized
three patients treated with the ketogenic diet. Epileptic Disord 2015;17(2):194–7. controlled trial. Epilepsia 2019;60(3):441–51. https://doi.org/10.1111/epi.14679.
https://doi.org/10.1684/epd.2015.0741. [33] Christodoulides SS, Neal EG, Fitzsimmons G, et al. The effect of the classical and
[24] Armeno M, Verini A, Araujo MB, Reyes G, Caraballo RH. Ketogenic parenteral medium chain triglyceride ketogenic diet on vitamin and mineral levels. J Hum
nutrition in three paediatric patients with epilepsy with migrating focal seizures. Nutr Diet 2012;25:16–26. https://doi.org/10.1111/j.1365-277X.2011.01172.x.
Epileptic Disord 2019;21(5):443–8. https://doi.org/10.1684/epd.2019.1095. [34] Coppola G, Epifanio G, Auricchio G, et al. Plasma free carnitine in epilepsy
[25] Falsaperla R, D’Angelo G, Praticò AD, Mauceri L, Barbagallo M, Pavone P, et al. children, adolescents and young adults treated with old and new antiepileptic
Ketogenic diet for infants with epilepsy: a literature review. Epilepsy Behav 2020; drugs with or without ketogenic diet. Brain Dev 2006;28:358–65. https://doi.org/
112:107361. https://doi.org/10.1016/j.yebeh.2020.107361. 10.1016/j.braindev.2005.11.005.
[26] Lyons L, Schoeler NE, Langan D, Cross JH. Use of ketogenic diet therapy in infants [35] Bergqvist AG, Schall JI, Stallings VA. Vitamin D status in children with intractable
with epilepsy: a systematic review and meta-analysis. Epilepsia 2020;61:1261–81. epilepsy, and impact of the ketogenic diet. Epilepsia 2007;48:66–71. https://doi.
https://doi.org/10.1111/epi.16543. org/10.1111/j.1528-1167.2006.00803.x.
[27] Dressler A, Trimmel-Schwahofer P, Reithofer E, Gröppel G, Mühlebner A, [36] Groleau V, Schall JI, Stallings VA, Bergqvist CA. Long-term impact of the ketogenic
Samueli S, et al. The ketogenic diet in infants - advantages of early use. Epilepsy diet on growth and resting energy expenditure in children with intractable
Res 2015;116:53–8. https://doi.org/10.1016/j.eplepsyres.2015.06.015. epilepsy. Dev Med Child Neurol 2014;56:898–904. https://doi.org/10.1111/
[28] Kim SH, Shaw A, Blackford R, Lowman W, Laux LC, Millichap JJ, et al. The dmcn.12462.
ketogenic diet in children 3 years of age or younger: a 10-year single-center [37] Ferraris C, Guglielmetti M, Pasca L, De Giorgis V, Ferraro OE, Brambilla I, et al.
experience. Sci Rep 2019;9(1):8736. https://doi.org/10.1038/s41598-019-45147- Impact of the ketogenic diet on linear growth in children: a single-center
6. retrospective analysis of 34 cases. Nutrients 2019;11(7):1442. https://doi.org/
[29] Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Hauser WA, Mathern G, Moshé SL, 10.3390/nu11071442.
Perucca E, Wiebe S, French J. Definition of drug resistant epilepsy. Consensus [38] Vining EP, Pyzik P, McGrogan J, Hladky H, Anand A, Kriegler S, et al. Growth of
proposal by the ad hoc task force of the ILAE Commission on Therapeutic children on the ketogenic diet. Dev Med Child Neurol 2002;44(12):796–802.
Strategies. Epilepsia 2010;51(6):1069–77. https://doi.org/10.1111/j.1528- https://doi.org/10.1017/s0012162201002961.
1167.2009.02397.x. Jun. [39] Ruiz Herrero J, Cañedo Villarroya E, García Peñas JJ, García Alcolea B, Gómez
[30] Dressler A, Trimmel-Schwahofer P. The ketogenic diet for infants: how long can Fernández B, Puerta Macfarland LA, et al. Safety and effectiveness of the prolonged
you go? Epilepsy Res 2020;164:106339. https://doi.org/10.1016/j. treatment of children with a ketogenic diet. Nutrients 2020;12(2):306. https://doi.
eplepsyres.2020.106339. org/10.3390/nu12020306.
[31] Le Pichon JB, Thompson L, Gustafson M, Abdelmoity A. Initiating the ketogenic [40] Kang HC, Lee YJ, Lee JS, Lee EJ, Eom S, You SJ, et al. Comparison of short- versus
diet in infants with treatment refractory epilepsy while maintaining a breast milk long-term ketogenic diet for intractable infantile spasms. Epilepsia 2011;52(4):
diet. Seizure 2019;69:41–3. https://doi.org/10.1016/j.seizure.2019.03.017. 781–7. https://doi.org/10.1111/j.1528-1167.2010.02940.x.
[32] Dressler A, Benninger F, Trimmel-Schwahofer P, Gröppel G, Porsche B, Abraham K.
Efficacy and tolerability of the ketogenic diet versus high-dose adrenocorticotropic
111

Efficacy and safety of ketogenic dietary infancy age 2021

Uploaded by

Copyright:

Available Formats

Efficacy and safety of ketogenic dietary infancy age 2021

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Efficacy and safety of ketogenic dietary infancy age 2021

Uploaded by

Copyright:

Available Formats

Seizure: European Journal of Epilepsy 92 (2021) 106–111

Contents lists available at ScienceDirect

Seizure: European Journal of Epilepsy

Efficacy and safety of ketogenic dietary theraphies in infancy. A

SD: standard deviation

You might also like