In this study, we evaluated the effect and tolerability of KD which began with full calories with gradual increases of KD ratio, in 55 children with drug-resistant epilepsy in Northwest China. We found that 58.2% of the patients achieved seizure reduction of over 50%, while 27.3% of the patients became seizure-free on KD at the last contact. This is consistent with the studies of Baby et al. which reported a responder rate of 59.4% on KD in children in South India [6], and of Lambrechts et al. that reported 50% in a randomized clinical trial (RCT) in the Netherlands [14]. A systemic review on 11 studies has reported seizure freedom in 16% of children, and a greater than 50% reduction in 56% of children [15]. Another RCT from the United Kingdom reported that 38% participants had seizure reduction of more than 50% at 3 months [16]. A chinese prospective multicenter study reported that 37.4, 26.1, and 20.4% of participants responded to the diet at 3, 6 and 12 months after the initiation, including 21.7, 10.7 and 11.0% who achieved complete cessation of seizures [17]. The results of our study are comparable to previously published studies, with responder rates of 36.4% (20/55), 30.9% (17/55) and 27.3% (15/55) at 3, 6 and 12 months, respectively.
A single-center study [8] enrolling 389 patients in Turkey reported a retention rate of 69 and 64% at 6 and 12 months, respectively, while a Chinese prospective multicenter study [17] reported a lower retention rate of 44.8 and 26.4% at 6 and 12 months, respectively. Here, we reported retention rate of 70.9 and 43.6% at 6 and 12 months, respectively, which was similar to previous reports [6, 7].
According to the ILAE’s updated recommendation, KD therapies should be offered to patients who had failed to respond to an average of 2.6 (standard deviation 0.9) AEDs [18]. However, the specific time of KD initiation has not been recommended. In the present study, a significant association was found between the duration of epilepsy and the efficacy of the diet, which is inconsistent with a previous study of Chinese children in 2013 [13]. The discrepancy may be due to the difference in the defined time limits of epilepsy duration (6 months or 1 year in our study versus 5 years in that study) [13]. Another reason may be that the KD therapy is most effective in children who have experienced seizures for shortest period of time according to previous literature [19]. Therefore, early and successful introduction of KD therapy may be an important factor for the efficacy of KD.
In our study, we also found that the continuation of the diet for > 6 months was associated with the seizure outcome, which consistent with the previous Indian study [6]. We also found that 71.9% (23 cases) of the responders started to respond to the KD within 6 months; however, 7 cases (21.9%) became responders between 6 months and 1 year. Similarly, a study in Turkey reported that 26 cases (8.2%) who did not respond to KD at 3 months became responders at 12 months [8]. This may be because that children on a traditional carbohydrate-rich diet might need more time to adapt to KD and maintain a stable blood ketone level. The most important factor that affects the continuation of KD is parental effort and patience. In this study, lack of compliance and ineffectiveness of the diet were major reasons for the discontinuation of KD, which was similar to other studies [6, 10, 13, 14]. A lot of parents discontinued the diet earlier, because the efficacy did not reach their expectation and the restrictions of the diet were difficult to adhere to.
The diet imposes strict restriction on content of carbohydrate, which conflicts with the carbohydrate-based diet in Northwest China, resulting in poor acceptability and maintenance. By gradually increasing the diet ratio, all of the 55 patients completed the initiation stage without any severe side effects. In the study of Baby et al., KD was initiated following a fasting protocol, 4 children did not complete the initiation process due to intolerance or side effects [6]. In addition, the responder rate of our study was 58.2% at the last follow-up, which was comparable to the study of Baby et al. [6]. These results indicated that the gradual initiation protocols might be advantageous in improving the patients’ compliance and tolerance during the initiation phase and providing the same efficacy during the maintenance phase.
Similar to previous studies [6, 7, 13,14,15], there was no significant association of age, sex, number of seizure types, number of AEDs at the initiation of KD, or epilepsy syndrome with seizure outcome in our study.
In the present study, the diet appeared to be safe, tolerable, albeit with a few adverse events. Similar to previous reports [7, 13, 16, 17, 20], 3 patients (5.5%) experienced vomiting and slight refusal to eat during KD initiation. Without prior fasting, 1 patient (1.8%) who was younger than 1 year developed hypoglycemia, a much lower rate than that in patients with prior fasting before initiating the diet [11]. During the maintenance phase of KD, gastrointestinal disorders such as vomiting, diarrhea, refusal to eat and constipation occurred in 14 patients (25.5%), most of these symptoms could be easily corrected by adjusting the fatty ratio and changing the consistency of meals. The updated recommendations of ILAE report that gastrointestinal dysfunction may occur in a higher rate in up to 50% of patients [21,22,23]. One patient died during the diet therapy, but no KD-related side-effects were reported during the therapy before the patient’s death, which we already reported in another study [12].
There were some limitations in our study. First, as the numbers in each category were too small to make any meaningful comparison, we did not analyze the seizure outcome based on different etiologies or epileptic syndromes. Second, we did not evaluate the effect of KD on EEG and cognitive development. Third, the results of the present study might be affected by the retrospective nature of data extraction.
