Interventieonderzoek (trials en cohort)
Study reference Study characteristics Patient characteristics Intervention (I) Comparison / control (C) Follow-up Outcome measures and effect size Comments

Kang, 2004

Type of study:

Prospective observational study


Setting: Epilepsy center at Inje University Hospital



South Korea


Source of funding: NR

Inclusion criteria: Treated for intractable childhood epilepsy with KD from July 1995 – October 2001


Exclusion criteria:

No exclusion criteria


N= 129


Mean age ± SD:

64.9 (SD 59.3)


Sex: 53.5% M (n=69) /46.5% F (n=60)

Classic KD with lipid to non-lipid ratio of 4:1



John Hopkins protocol (87), starting with 2 days fasting with fluid intake 75% of maintenance intake.


Introduction to KD directly (n=42) with one third of daily calories on first day, two third on second day and full calories on third day, without fluid restriction.

 No control

Endpoint of follow-up:

Initial tolerability of and complications associated with KD.


Duration of follow-up:

Mean 12 months (SD 10.1)


For how many participants were no complete outcome data available?: 0

Seizure free: 36/129 (27.9%)

Seizure reduction >50%: 57/129 (44.2%)

Seizure reduction <50%: 36/129 (27.9%)


Of 93 patients who were seizure free or had reduction >50%, 41 could not maintain the diet. Reasons:

-    Various complications (n=20)

-    Intolerance (n=18)

-    Dropout (n=3)


In total 67 patients stopped KD within 6.1 (SD 4.7) month (26 because of complications).


Most common complications during first 4 weeks: dehydration (mainly in patients with John Hopkins protocol) and gastrointestinal disturbances.


Most common complications after first 4 weeks: osteopenia and renal stones.


Most complications improved with conservative management and did not require cessation of KD.


46 patients showed hypertriglyceridemia, 41 showed hypercholesterolemia. These complications improved spontaneously in 33 respectively 30 patients.

Sharma, 2013

Type of study:

paediatric department of a tertiary care hospital


Source of funding:
Indian government

Inclusion criteria: Children aged 2–14 years who had daily seizures (or more than seven seizures per week) despite the appropriate use of at least three anticonvulsant drugs

Exclusion criteria: Children with known or suspected inborn errors of metabolism, systemic illness, or motivational issues in the family that would preclude compliance


Diet group N=50

Mean age ± SD: 4.7 ± 2.8 yrs

Sex:82 % M (n=41) /18% F (n=9)

Seizure types: Myoclonic 23 (46%)

Atonic 14 (28%) 

Absence 13 (26%)

Tonic–clonic 7 (14%)

Partial 10 (20%)

Epileptic Spasms 9 (18%)

Control group N=52

Mean age ± SD: 5.2 ± 3.3 yrs

Sex:71 % M (n=37) /29% F (n=15)

Seizure types
Tonic 23 (44.2%)

Myoclonic 24 (51%)
Atonic 13 (25%)
Absence 7 (13.5%)
Tonic–clonic 9 (17.3%)
Partial 9 (17.3%)
Epileptic Spasms 10 (19.2%)

Modified Atkins diet
Carbohydrate intake was restricted to 10 g/day. The intake of fat (e.g., cream, butter, oils, ghee) was actively encouraged. Protein intake was not restricted. There was no calorie restriction

The ongoing anticonvulsant medications were continued unchanged.

Each child also received a sugar-free, fatsoluble vitamin supplement and calcium supplementation.


Normal diet with no additional dietary input, and remained on the same ongoing anticonvulsant medication for the 3 months.

Endpoint of follow-up:
Seizure control at 3 months

Duration of follow-up:

3 months

For how many participants were no complete outcome data available?:

Diet group: N=4 discontinued the diet

Control group: n=3 loss to follow up


Endpoint of follow-up:
Seizure control at 3 months

Duration of follow-up:
3 months

For how many participants were no complete outcome data available?:
Diet group: N=4 discontinued the diet

Control group: n=3 loss to follow up


Kim et al., 2016

Type of study: Randomized Clinical Trial


Setting: From March 2011 to March 2014, 104 patients aged 1–18 years who had refractory epilepsy were randomly assignedie tanh diet group


Country: South Korea


Source of funding: This research was supported by National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2013R1A2A2A01014108).

Inclusion criteria: patient age in the range of 1–18 years, seizure frequency >4 seizures per month, and treatment failure of ≥2 prescribed antiepileptic drugs

Exclusion criteria: history of previous dietary therapy, a history of hyperlipidemia, renal calculi, or any other medical conditions incompatible with dietary therapy

N= 104

I: 51

C: 53

Mean age ± SD:

I: 1 to <2 years: 17 (33)

2 to <6 years 16 (31)

6–18 years: 18 (35)


1 to <2 years: 20 (38)

2 to <6 years:17 (32)

6–18 years: 16 (30)


I: 32 M (63%)/19 F (37%)

C: 26  M (49%)/2F (51%)

Mean age at seizure onset:

I: 2.1 (±2.5)

C: 2.4 (±3.1)

Mean age at the beginning of dietary therapy:

I: 4.9 (±4.0)

C: 4.84 (±4.0)

Classic ketogenic diet (KD)

All patients in the KD group received dietary therapy with a 4:1 lipid to nonlipid ratio and nonfasting initiation protocol

Modified Atkins Diet (MAD

MAD group patients followed the Johns Hopkins protocol

Endpoint of follow-up: seizure control

Mean seizure number

Duration of follow-up: All enrolled patients were assessed during the 4-week baseline period, and at 1, 3, and 6 months after discharge. 

For how many participants were no complete outcome data available?: 86 patients (39 from the KD group and 47 from the MAD group) at the 3-month follow-up. Complete data from 70 patients (34 from KD group, 36 from MAD group) were available at the 6-month follow-up. A total of 34 patients dropped out during the study (17 from KD group, 17 from MAD group)  

>50% redcution in seizures (patients(%):

3 months:

C: 22 (43) 22; I: (42) 0.527

P= 0.527

6 months:

C: 20 (39); I: 19 (36)



>90% reduction in seizures (patients(%):

3 months:

C: 19 (37); I: 17 (32)

P= 0.314

6 months:

C: 19 (37); I: 16 (30)

P= 0.474


Seizure freedom (patients(%):

3 months:

C: 13(25); I: 17(33)

P= 0.374

 (p = 0.374)

-6 months:

C: 16 (31); I: 12 (23)

P= 0.461

Lambrechts et al., 2017

Type of study: Randomized controlled trial

Setting: This study was carried out within a tertiary referral center for epilepsy (Kempenhaeghe, Heeze, the Netherlands). Patients were included during the period of July 2010 until August 2014

Country: the Netherlands

Source of funding: This study was funded by the Netherlands Organization for Health Research and Development (ZonMw), grant application number 171002204.

Inclusion criteria: children and adolescents with refractory epilepsy not eligible for epilepsy surgery aged 1-18 years

Exclusion criteria: medicalcontra-indications or the expectation that compliance with the diet was not possible because of severe behavioral or motivational problems

N= 57 randomized, 48 analyzed (9 discontinued/dropout)

I: n=26; C: n=22

Mean age:

I: 7;8 years (2;1-16;5); C: 8;1 years (1;1–15;7)


I: 18 M (69,2%);C: 9 M (40,9%)

Ketogenic Diet, accordingie tae Dutch guideline during a 5-day hospitalization at the epilepsy center. The start of the diet was defined as the first change madeie tae patien’’s daily nutrition and the end of the diet as the first step in down-titration to a regular diet.

Care as usual (CAU) defined as the child continuing to take his or her anti-epileptic drugs (AEDs).

Endpoint of follow-up: 50% reduction in seizure frequency at 4 months.

Duration of follow-up: 17 months in total for KD-group; 4 months fort he CAU-group

For how many participants were no complete outcome data available?: 3 in CAU-group and 3 in KD-group

≥50% reduction in seizure frequency:

1 month (n(%)):

I: 7 (26.9)

C: 3 (13.7)

4 months (n(%)):

I: 7 (27.0)

C: 1 (4.5)


Seizure free:

1 month (n(%)):

I: 2 (7.7)

C: 1 (4.5)

4 months (n(%)):

I: 3 (11.5)

C: 2 (9.2)


Mean percentage of baseline seizures after 4 months (95%CI):

I: 56%(36-76%)

C: 99%(65-133%)



Seizure severity: NHS3-score at 4 months:



I: 15 (65.2%)

C: 7 (36.8%)

No improvement:

I: 8 (34.8%)

C: 12 (63.2%)



Side effects

Total SIDEAD-scores showed no statistically significant differences between groups at 6 weeks nor at 4 months. There was, however, a statistically significant difference in gastrointestinal symptoms, where patients treated with the KD having a higher score at 6 weeks (P = 0.015) and at 4 months (P = 0.021). The mean value of gastrointestinal symptoms in the KD group increased from 3.08 at baseline, to 4.08 after 6 weeks, and declined to 3.14 after 4 months of treatment.

Zare, et al., 2017

Type of study: Randomized controlled trial

Setting: Adult Neurology Clinic of Kashani Hospital, inclusion from February 2010 up tot December 2012

Country: Iran

Source of funding: This work was supported by the Plastic Surgery Research Center, Isfahan University of Medical Sciences, Isfahan.

Inclusion criteria: age of ≥ 18 years and refractory epilepsy (two or more seizures attacks every month in spite of treatment with at least two appropriate antiepileptic drugs).

Exclusion criteria: previous use of the AD or mAD for > 1 week, previous use of the ketogenic diet within the past year, patients with kidney, heart, renal disease or hypercholesterolemia, patients with history of coronary heart disease, cerebrovascular disease, peripheral vascular disease, atherosclerosis, previous myocardial infarctions, or renal dysfunction, pregnant individuals, body mass index (BMI) below 18.5, status epilepticus within the past 6 months, 2 week seizure-free period within the past 6 months.

N= 66; I: N= 34; C: N= 32


Mean age: I: 29.4 years (+/- 8.8); C: 27.2 years (+/- 7.3);

Sex: I: 24 M (70.6%); C: 21 M (65.6%)


Type of seizure:

Complex partial: I: 18 (52.9%); C: 18 (56.35)

Generalized tonic clonic: I: 16 (47.1%); C: 14 (43.7%)

Antiepileptic drugs and modified Atkins Diet

Antiepileptic drugs only

Endpoint of follow-up: 50% reduction in seizure frequency at 2 months.

Duration of follow-up: 2 months

For how many participants were no complete outcome data available? None

≥ 50% reduction in seizure frequency after 2 months (n(%)):

I: 12 (35.3%)

C: 0 (0%)


Seizure free after 2 months (n(%)):

I: 0 (0%)

C: 0 (0%)

Side effects: Not reported

The mAD may be effective as a cotherapy treatment for adults with refractory epilepsy and decrease 2.19 times seizure frequency in comparison with control groups. Trials with the more tolerant dietary regime, with larger sample size and longer duration, should be performed in future.

AED was continued unchanged for at leat the 2 months, but when necessary, the drugs were changed in both groups.

Small number of patients, difference between groups in medication use.