A Concise Review of Ketogenic Dietary Interventions in the Management of Rare Diseases

Table 1

Randomized control trials describing efficacy and safety of ketogenic diet compared with other \treatment modalities.

	Author	Year	Country	Study population	Type of KD	Interventions	Sample size	Results	Adverse effects	Cost effectiveness
1	Dressler et al.	2019	Austria	Infants with West syndrome	Without fasting and fluid restriction, 1 : 1 fat : nonfat, and individually increased to 3 : 1(ratio was limited when beta‐hydroxybutyrate levels reached >5 mmol L).	Group 1: ketogenic diet (KD); Group 2: standard ACTH treatment	Group 1: n = 16; Group 2: n = 16	Electroclinical remission at 28 days was nonsignificant (62% (KD) vs. 69% (ACTH)); Without prior vigabatrin treatment, remission at day 28 was 47% (KD) and 80% (ACTH, ); Relapse rate 16% (KD) and 43% (ACTH) (); Age‐appropriate psychomotor development and adaptive behaviour were similar.	Adverse effects needing acute medical intervention: 30% (KD) vs. 94% (ACTH) ()	N/A
2	Wijnen et al.	2017	Netherlands	Children and adolescents with intractable epilepsy	Classical ketogenic diet, the medium-chain triglyceride (MCT) diet, or a mixture of both diets.	Group 1: ketogenic diet; Group 2: care as usual (CAU) with AEDs	Group 1: n = 26; Group 2: n = 22	At 16 months, 35% of the KD participants had a seizure reduction ≥ 50% from baseline, compared with 18% of the CAU participants; 46.2% of the KD group reported a decrease in the severity of their worst seizure compared to 32% of the CAU group.	At 4-month follow-up, the KD group showed significantly more gastrointestinal problems compared to the CAU group (). At 16 months, the KD group reported fewer problems compared to CAU ().	Mean costs per patient in the CAU group were 53,367 euros compared to 61,019 euros per patient in the KD group
3	Lambrechts et al.	2016	Netherlands	Refractory epilepsy patients aged 1–18 years	Most frequent was the MCT diet. When only tube feeding was given, a liquid form of the classical KD was used.	Group 1: ketogenic diet; Group 2: care as usual (continued taking usual AEDs)	Group 1: n = 26; Group 2: n = 22	13 patients (50%) treated with the KD and four patients (18.2%) of the CAU group were responders. Mean seizure frequency at 4 months compared to baseline was significantly lower () in the KD group (56%) (95% CI: 36–76) than in the CAU group (99%) (95% CI: 65–133%). Twice as many patients in the KD group had a relevant decrease in the seizure severity score ().	Patients treated with the KD had a significantly higher score for gastrointestinal symptoms () without an increase in the total score of side effects.	N/A
4	Ijff et al.	2016	Netherlands	Refractory epilepsy patients aged 1–18 years	N/A	Group 1: KD with AEDs; Group 2: only AED (CAU)	Group 1: n = 28; Group 2: n = 22	The KD group showed lower levels of anxious and mood-disturbed behaviour and was rated as more productive. Cognitive test results showed an improvement of activation in the KD group.	N/A	N/A
5	Kim et al.	2015	Korea	Intractable childhood epilepsy	4 : 1 lipid to nonlipid ratio and nonfasting initiation protocol.	Group 1: KD; Group 2: modified Atkins diet (MAD)	Group 1: n = 51; Group 2: n = 53	KD group had a lower mean percentage of baseline seizures compared with the MAD group at 3 months (38.6% for KD; 47.9% for MAD) and 6 months (33.8% for KD; 44.6% for MAD), but the differences were not statistically significant (95% confidence interval (CI): 24.1–50.8; for 3 months; 95% CI: 17.8–46.1; for 6 months). The rate of seizure freedom at 3 months after diet therapy initiation was significantly higher (53% for KD; 20% for MAD;) in patients aged 1-2 years.	The MAD had advantages with respect to better tolerability and fewer serious side effects.	N/A
6	Neal et al.	2008	United Kingdom	Drug-resistant epilepsy children aged between 2 and 16 years	Classical diets were started at a 2 : 1 ratio (fat : protein and carbohydrate) and gradually increased to a 3 : 1 or 4 : 1 ratio over 1-2 weeks, as tolerated.	Group 1: KD; Group 2: control group—care as usual (with AEDs)	Group 1: n = 54; Group 2: n = 49	After 3 months, the mean percentage of baseline seizures was significantly lower in the KD group than in the controls (62.0% vs. 136.9%, 75% decrease; 95% CI: 42.4–107.4; ). 28 children (38%) in the KD group had greater than 50% seizure reduction compared with four (6%) controls (), and five children (7%) in the diet group had greater than 90% seizure reduction compared with no controls (). No significant difference in the efficacy of the treatment between symptomatic generalised or symptomatic focal syndromes.	The most frequent side effects reported at a 3-month review were constipation, vomiting, lack of energy, and hunger.	N/A

KD: ketogenic diet; ACTH: adrenocorticotropin hormone; MCT: medium-chain triglyceride; CAU: care as usual; AEDs: antiepileptic drugs; N/A: not available.