|Ahead of print
Ketogenic diet in children with drug refractory epilepsy: Do we need 4:1 ketogenic ratio?
Purva K Karnavat1, Anaita U Hegde2, Shilpa Kulkarni3, Roshan Kore4, Bhakti Tulaskar5, Suvarna Sawant6, Omkar Hajirnis7
1 Department of Pediatric Neurosciences, Surya Hospital, Mumbai, Maharashtra, India
2 Department of Pediatrics, Jaslok Hospital and Research Centre, Mumbai, Maharashtra, India
3 Department of Pediatrics, Bai Jerbai Wadia Hospital for Children, Mumbai, Maharashtra, India
4 Department of Dietitics, SRCC Children’s Hospital, Mumbai, Maharashtra, India
5 Department of Dietitics, Seth G.S. Medical College and KEMH, Mumbai, Maharashtra, India
6 Department of Dietitics, HCG Cancer Centre, Mumbai, Maharashtra, India
7 Synapse Centre, Mumbai, Maharashtra, India
|Date of Submission||02-Sep-2021|
|Date of Decision||13-Dec-2021|
|Date of Acceptance||27-Dec-2021|
|Date of Web Publication||12-Jul-2022|
Purva K Karnavat,
Department of Pediatric Neurosciences, Surya Hospitals, Santacruz West Mumbai 400054, Maharashtra
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Introduction: Ketogenic diet (KD), well-accepted therapy for drug-resistant epilepsy (DRE), can be tried on an outpatient basis, thereby reducing the need of hospitalization/starvation. Here, we analyze the efficacy and safety profile of outpatient-based KD in children with DRE with particular reference to ratios of the KD. Materials and Methods: Children aged 0–18 years enrolled between 2008 and 2018, under “Keto Kid Project”––an outpatient-based project were included in this study. Demographic and clinical details, investigation profile in terms of epilepsy, and suitability for diet were noted. Diet was initiated at lower ratios and slowly increased on a case-to-case basis. For the purpose of the analysis, subjects were divided into two groups based on their maintenance ratios: higher ratios (>3:1) and lower ratios (≤3:1). Seizure control, other benefits in terms of behavior and side effect profile were reviewed. Results: A total of 117 of 138 children enrolled in program who had completed three months on diet were taken for analysis. A total of 97 of 117 were on lower maintenance ratios and 20 of 117 on higher ratios at the time of analysis. Lennox-Gastaut syndrome was the most common syndromic diagnosis followed by West syndrome in both groups. Retention of diet was higher in children on lower ratios. Although the consistency of ketosis was higher in those on higher ratios, seizure control was similar across both groups. Antiepileptic drugs (AED) reduced significantly after diet (P = .0016) among both groups with no difference between each other. Other beneficial effects included alertness and improved behavior across both groups. The main reasons for withdrawal were frequent infections, lack of benefit, and poor compliance. Both groups had a similar incidence of side effects. Conclusions: Seizure control, reduction of AED burden, and behavioral benefits of the diet using locally available food recipes (vegetarian and nonvegetarian) were noteworthy in this study. Ketosis and seizure control can be effectively maintained on lower ratios.
Keywords: Adverse effects, Indian children, ketogenic diet, lower ratios, refractory epilepsy
| Introduction|| |
The ketogenic diet (KD) has been used for the treatment of epilepsy in children for almost 100 years. The first reports of its beneficial action were seen in individuals with seizures who found betterment from starvation. Subsequently, a diet was proposed which was high in fat content, as a breakdown of fat for energy produces ketones, mimicking starvation.,
There have been over 700 peer-reviewed publications in the past two decades alone. The KD is carried out in different countries keeping in mind the local food customs. Despite the predominantly starch-based Indian diet, the KD has been successfully implemented in India. The few existing studies from India successfully highlight the efficacy of the KD in Indian children using local versions of the classic KD.,, A worldwide survey on use of the KD has shown success with lower ratios.
This report not only analyses 10 years’ clinical data to assess the efficacy and safety of the outpatient-based KD for Indian children, but more importantly assesses the association of ratios of KD with efficacy, safety, and tolerability in children.
The aims and objectives of the study are as follows:
- 1. To understand the difference (if any) between lower and higher ratios of the diet with respect to the efficacy, tolerability, and safety of the KD
- 2. To compare the difference in adverse effects between the ratios
| Materials and Methods|| |
This open, nonblinded, retrospective study was conducted between January 2008–April 2018. Patients enrolled and followed up from January 2008 till April 2018 in the Keto Kid Project as a joint venture of two tertiary care epilepsy centers catering to two different economic strata in the city of Mumbai were included in the study. Ethics approval for publishing the data was taken in 2016.
The KD protocol was different from usual KD protocols as this was primarily an outpatient clinic-based diet program where the doctors and dieticians simultaneously examined, discussed, and planned each patient’s treatment. Diet was initiated at lower ratios and slowly increased on a case-to-case basis in an outpatient setting (unless specifically indicated). Inclusion criteria were (1) children with treatment resistant or intractable epilepsy as per ILAE guidelines, defined as ‘‘failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom” and (2) children who were on the diet for at least 3 months. Exclusion criteria were (1) children with known or suspected inborn errors of metabolism, systemic illnesses, hyperlipidemia, and renal stones. (2) Children who could not complete the initiation process. (3) Children who had not completed 3 months on diet at the time of analysis.
Families or other caregivers who were made to understand the implications of the diet were prepared to bring the child to the center, and were available for regular home monitoring of the child. Before initiation, families were given detailed information explaining the KD. Written informed consent was obtained from the parents or caregivers.
A detailed history and examination was conducted on all children. Details regarding seizure onset, semiology, duration, and frequency were noted along with other relevant history like perinatal details, family history, developmental milestones, and treatment history. Investigations like electroencephalogram (EEG) and 1.5 OR 3 Tesla magnetic resonance imaging (MRI) and relevant metabolic and genetic workup were noted in order to get a syndromic/ etiologic classification of epilepsy. The drug therapy was studied in detail along with a profile of the side effects. Before starting the diet, complete blood count, blood sugar levels, renal and liver function tests, complete lipid profile, serum electrolytes, uric acid, and urine (routine and microscopic) examination along with urinary spot calcium–creatinine ratios were done. These were repeated every three to six months in the first year and every six to twelve months thereafter. Metabolic screening particularly to rule out organic acidemias was performed. CSF examination wherever indicated was performed along with simultaneous blood sugar estimation. Detailed neuropsychological testing with behavioral analysis was also performed wherever possible. EEG was recorded before commencing the diet using the standard 10–20 protocol and was repeated yearly or earlier if indicated. Medications were changed to carbohydrate-free preparations, like sugar-free syrups and tablets.
Ketogenic diet initiation
After an initial unrestricted carbohydrate washout (food with only up to 10 grams carbohydrate) with an aim to achieve significant ketosis, KD was initiated at lower ratios. The KD ratio is defined as the ratio of grams of fat to grams of carbohydrate plus protein. After a carbohydrate washout, a period lasting 7–10 days a rapid initiation of the diet was done by giving full calories from day 1. Water requirement was calculated at approximately 1 mL/calorie and adjusted subjectively to maintain an adequate urine output.
After an extensive dietetic history including the family food habits, taboos, and food preferences, Indian diet recipes both vegetarian and non-vegetarian were given which could be prepared with common locally available foods. Diets were supplemented with vitamins and minerals. Over 10 years, a database of more than 150 recipes catering to different food habits and preferences has been established and is growing by the day.
Ketogenic diet maintenance and follow-up
The parents or caregivers maintained a daily urine ketone level chart, the urine being checked 3–4 times a day using Ketodiastix. A daily seizure diary was maintained. The anticonvulsants were unchanged for the first 3 months of the diet and adjusted according to child’s conditions thereafter.
Patients were initially followed up on outpatient basis at intervals of two weeks for the first two visits. The calorie and ketogenic ratio were fine-tuned to achieve stable urine ketosis of 4+ throughout the day. If urine ketones are less than 4+ (1+,2+ or 3+), the weight is maintained and water intake is as per the individual requirement then the ratio is customized to 2.5, 3, 3.5, or 4:1. In case there is significant weight gain the calories are adjusted to maintain the expected body weight which will help to maintain the ketosis. In case the fluid intake is very high, it is adjusted to get the desired ketones. Thereafter they were periodically reviewed every 3 months and the same protocol is followed at every visit. They were also closely monitored by telephone calls between clinic visits. Those who were lost to follow up after being 3 months on the diet, were called up and asked the exact time and reason for withdrawal and those who could not be reached were regarded as having stopped the diet after the last contact.
At every follow-up, the seizure frequency was recorded by parental reports and seizure diaries. The time to achieve relative seizure control was also assessed. The main measure of efficacy was the decrease in seizure frequency as depicted through parental reports and seizure diaries. The average seizure number in one month before diet initiation was compared to the seizure number (i.e., average seizure number in a month after at least 3 months on the diet), and was expressed as a percentage of reduction. The seizure control was categorized into the following categories: No change or increase in seizure frequency, <25% seizure reduction, 25%–50% seizure reduction, 50%–75% seizure reduction, 75%–99% seizure reduction, and complete seizure freedom. Seizure reduction of ≥50% was considered as benefitted by the diet.
The diet compliance was checked by parental records of daily urine ketones chart and the ketosis control was assessed along with time to achieve ketosis. Patients who were shifted to the Modified Atkins’s diet were also monitored and their reasons for shifting to it were noted.
Anthropometry (weight and height) was stringently checked at each visit. Dietary caloric modifications were done according to the weight on the day of visit. Similarly, the number of antiepileptic drugs before diet initiation was compared to the number of anti-epileptic drugs after at least 3 months on the diet.
Parental complaints and adverse effects were assessed, noted, and addressed. Beneficial effects like improved alertness, behavior control and importantly restarting school as a secondary benefit were noted. Worsening of seizure frequency, other side effects of diet like gastrointestinal upset, drowsiness were noted if any. All investigations as done prior to diet initiation were asked to be repeated either whenever indicated or at yearly intervals.
For the purpose of the analysis, subjects were divided into two groups based on their maintenance ratios: higher ratios (>3:1) and lower ratios (≤3:1). The outcomes were measured with respect to (1) efficacy viz. syndromic diagnosis, etiologic diagnosis, age at onset of diet, source of diet and seizure control, (2) tolerability viz. ketosis achieved, time taken to achieve ketosis and seizure control, duration of diet, and (3) safety viz. side effects profile.
Statistical analysis was done using Prismgraphpad 7. Statistics used were frequency distribution, chi-square test, Fischer exact t test, paired t test, and Pearson correlation.
| Results|| |
138 consecutive children were enrolled of which 21 were excluded based on the exclusion criteria. Thus, a total of 117 patients were included and analyzed in the study. A total of 97 of 117 were on lower maintenance ratios and 20/117 on higher ratios at the time of analysis. 24%, 47%, 25%, and 4% of the cohort on lower maintenance ratios were initiated on the KD at age groups of <2 years, 2–5 years, 5–10 years, and >10 years, respectively. These numbers were 50%, 30%, 20%, and 0% in cohort on higher maintenance ratios, respectively. Approximately 33% and 30% were females in lower and higher maintenance ratios, respectively. Subjects on higher ratios had a higher non-vegetarian preference of meals (80%) as compared to those on lower ratios (55%).
Symptomatic epilepsy due to varied reasons as against idiopathic epilepsy was the predominant etiology in both groups (78% and 65%). Lennox Gastaut syndrome (LGS) was the most common syndromic diagnosis followed by West syndrome. The results of baseline patient characteristics at enrolment are presented in [Table 1].
Efficacy and tolerability
Amongst the lower maintenance ratios, LGS (41%) was the most common syndromic diagnosis with 80% showing ≥50% seizure control [Table 2]. This was followed by West syndrome (28%) where 50% showed >50% seizure control. Approximately 4% of cohort belonged to Dravet syndrome with 100% benefit. Amongst higher maintenance ratios, LGS was the most common syndromic diagnosis (35%) followed by West syndrome (30%). 86% and 100% showed ≥50% seizure control in both groups, respectively. There was no significant difference in the syndromic diagnoses noted between the groups (P = .881). Overall subjects with non-symptomatic epilepsy had better seizure control (P = .012). However, when compared between the ketogenic ratios it showed no statistical significance (P = .25).
|Table 2: Statistical analysis (between lower and higher maintenance ratios)|
Click here to view
60% of cohort on lower ratios achieved ketosis within 6 months, whereas 18% achieved ketosis after 6 months; 22% did not achieve ketosis at all. Among higher maintenance ratios, this number was 50%, 15% and 35%, respectively, with no difference between the groups (P = .588). However, ketosis was more consistent in subjects on higher maintenance ratios (P = .008). Approximately 62% and 55% of cohort achieved ≥50% seizure control on lower and higher ratios, respectively, with no significance (P = .619). 39%, 27%, and 24% achieved seizure control at 0–3 months, 3–6 months, and more than 6 months, respectively, in lower ratios. This was 45%, 25%, and 30%, respectively, in higher ratios. There was no correlation between ratio of diet and time taken for seizure control (P = .870). Retention on the diet was better noted among children on lower ratio (P = .0.03).
Antiepileptic drugs (AED) reduced significantly after diet (P = .0016) overall. 4 patients were off AED and 6 were on single drug at the time of analysis. However, no difference was seen between the groups (P = 1.00).
Approximately 28% and 30% children had absolutely no side effects and did very well on the diet of lower and higher ratios, respectively. Adverse effects noted while on diet along with measures taken to correct those side effects are enumerated in [Table 3].
Approximately 21% and 25% of children on lower and higher maintenance ratios withdrew from the diet as they saw no benefit. The other reasons for withdrawal are completion of treatment, death (unrelated to the diet), non-compliance, loss to follow up or increase rate of infections [Table 4].
| Discussion|| |
The KD includes 80% fat, 15% protein, and 5% carbohydrate; the ratio of fat to carbohydrate plus protein ranges from 2:1 to 4:1, with higher ratios seen as more restrictive but more effective. Most of the fat in the classic, most commonly used KD is provided as long-chain triglycerides.
The ketogenic ratio is defined as the ratio of grams of fat to grams of carbohydrate plus protein. Traditionally, the KD has been calculated based on specific ratios, based on patient age. Infants and teens were generally started on a 3:1 ratio and other children on a 4:1 ratio. Lower ratios gave an advantage of better palatability and more quantity thereby improving the compliance of the diet.
To the best of our knowledge, our study is one of the few studies and probably the first from India comparing the ketogenic ratios across a large cohort of pediatric patients.
We noticed that children maintained on higher ratios had a nonvegetarian-based diet as compared to lower ratios (P = .043).
Approximately 62.4% of children in our study achieved seizure control of >50% including 25.6% who had 100% control, whereas 9.4% did not benefit in terms of seizure control. Recently published studies have reported that at 12 months of the classic KD, 23% to 44% of patients showed a reduction of seizure frequency of >50%, including 7% to 22% who became seizure free.,,, The overall seizure outcomes of the KD in our study were similar to the results of these previous reports.,,, However, when analyzed based on maintenance ratios, lower ratios were as efficacious as higher ratios in seizure control outcomes suggesting that children can be well managed on lower ratios. A recent review in 2020 has mentioned about the efficacy in lower as well higher ratios of classic KD. A previous study by Vykunta Raju et al. too observed that 2.5:1 ratio KD is possibly as effective as 4:1 KD in controlling seizures and has fewer adverse effects.
Approximately 67% of our cohort younger than 5 years of age showed seizure control of more than 50%; though not statistically significant (P = .133). There was no statistical difference between the ketogenic ratios versus age at which KD was initiated and gender, though children younger than 2 years were more frequently maintained on higher ratios.
Retention rate of diet was higher in children who had seen a benefit with seizure outcomes significantly (P = .00). Similar findings were noted in study published earlier. Retention of diet was also noted to be higher in children on lower maintenance ratios as lower ratios give better palatability and higher quantities of food (P = .03). Consistency of ketosis was better with higher ratios.
A survey of worldwide use of the KD has shown that centers in India and Asia use lower ratios with good success. Furthermore, “newer” variations of the diet, such as the modified Atkins diet and the low glycemic index diet have significantly lower ratios, yet similar efficacy to the traditional diet.,,,, Seo et al. observed that the 4:1 KD showed greater antiepileptic efficacy than the 3:1 diet with higher seizure-free outcome.
Tolerability and safety
Majority of children (100/117) in our study were started on KD ratios of 2:1 and 97/117 children were then maintained well on ratios ≤3:1. 5/117, 6/117, and 5/117 were started on ratios 2.5:1, 3:1, and 4:1, respectively. Two of five children started on 4:1 could be weaned to lower ratios with seizure control ≥ 50%.
A study by Nylen et al. has shown that although higher ratios may confer better seizure control, they may also result in poorer tolerability of the diet. A study by Wirrell observed that lower ketogenic ratios are frequently as effective as higher ones at controlling seizures, and result in fewer adverse effects. She further suggested that starting at higher ratios may result in better control, but that ratios can often be weaned over time without deterioration. Seo et al. maintained that seizure-free outcome was maintained even after changing the ratio to 3:1. Dietary tolerability was better in the 3:1 diet than the 4:1 with less frequent gastrointestinal symptoms.
Our experiences in tolerability and safety were comparable to those of previously published reports., The side effect profile was similar across both groups. Children who were transferred to MAD mostly belonged to school-going age group or older, those who would be hungry, with non-compliant parents or who had complete seizure freedom but did not want to stop KD. We had six deaths while on diet though they were unrelated to the diet. Other side effects were closely monitored by doing appropriate investigations. These side effects if seen were then treated by modifying the diet and taking other measures necessary as mentioned in [Table 4]. Recently published meta-analysis has also suggested that KD is a relatively safe dietary therapy.
Benefits of the diet
The mean number of anti-epileptic medications prior to onset of the dietary therapy was 3.1 and while on the diet were 2.7. We intended to taper the AEDs ≥3 months after the KD if the patient showed a consistent ketosis and reduction of seizure frequency. We were able to decrease the number of AEDs in 41 patients, including 5 children who were able to discontinue the drugs. Our results, when compared with number of medications of the prediet period, showed a statistically significant decrease of medication at the time of analysis (P = .001). However, there was no difference between lower and higher ratios. Reports about the efficacy of the KD consistently stated that it was possible to decrease the drugs; sometimes this was statistically significant, and sometimes it was not.,,,
Other benefits were noted in the form of improved behavior and alertness. However, these were parent-reported outcomes and no formal assessment was done. Approximately 18.8% children began with schooling as their alertness and behavior improved. Various research papers have shown cognitive and behavioral benefits with KD.,, Two children with CSWS were initiated on KD only for their cognitive and behavior concerns. Both of them showed significant benefit with the diet with no further decline of cognitive scores after the initiation of the diet.
The limitations of the study include the inability to perform a detailed neuropsychological assessment to understand the behavior and cognitive benefits of the diet and also the parental bias in reporting the seizure control and side effects.
| Conclusion|| |
In conclusion, although used in India where the staple diet is starch and carbohydrate, with substantially less fat than traditional western diets, the KD is a cost-effective therapeutic modality for intractable epilepsies in children. Lower ratios are equally efficacious when compared to higher ratios giving additional benefits in terms of greater quantities, better palatability, and hence better compliance. KD is seen to improve seizure control, reduction of AEDs with associated benefits in behavior, alertness and schooling.
Ethical policy and institutional review board statement
We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Wilder RM. The effects of ketonemia on the course of epilepsy. May Clin Proc 1921;2:307-08.
Peterman MG. The ketogenic diet in epilepsy. JAMA 1925;84:1979-83.
Kessler SK, Neal EG, Camfield CS, Kossoff EH. Dietary therapies for epilepsy: future research. Epilepsy Behav 2011;22:17-22.
Nathan JK, Purandare AS, Parekh ZB, Manohar HV. Ketogenic diet in Indian children with uncontrolled epilepsy. Indian Pediatr 2009;46:669-73.
Sharma S, Gulati S, Kalra V, Agarwala A, Kabra M. Seizure control and biochemical profile on the ketogenic diet in young children with refractory epilepsy: Indian experience. Seizure 2009;18:446-9.
Baby N, Vinayan KP, Pavithran N, Grace Roy A. A pragmatic study on efficacy, tolerability and long term acceptance of ketogenic diet therapy in 74 South Indian children with pharmacoresistant epilepsy. Seizure 2018;58:41-6.
Kossoff EH, McGrogan JR. Worldwide use of the ketogenic diet. Epilepsia 2005;46:280-9.
Nylen K, Likhodii S, Abdelmalik PA, Clarke J, Burnham WM. A comparison of the ability of a 4:1 ketogenic diet and a 6.3:1 ketogenic diet to elevate seizure thresholds in adult and young rats. Epilepsia 2005;46:1198-204.
Wirrell EC. Ketogenic ratio, calories, and fluids: do they matter? Epilepsia 2008;49:17-9.
Freeman JM, Vining EP, Pillas DJ, Pyzik PL, Casey JC, Kelly LM. The efficacy of the ketogenic diet-1998: a prospective evaluation of intervention in 150 children. Pediatrics 1998;102:1358-63.
DiMario FJ Jr, Holland J. The ketogenic diet: a review of the experience at Connecticut children’s medical center. Pediatr Neurol 2002;26:288-92.
Vining EP, Freeman JM, Ballaban-Gil K, Camfield CS, Camfield PR, Holmes GL, et al
. A multicenter study of the efficacy of the ketogenic diet. Arch Neurol 1998;55:1433-7.
Swink TD, Vinning EPG, Freeman JM. The ketogenic diet. In: Barnes LA, editor. Advances in pediatrics. vol. 44. St. Louis, MO: Mosby; 1997. p. 297-329.
Wells J, Swaminathan A, Paseka J, Hanson C. Efficacy and safety of a ketogenic diet in children and adolescents with refractory epilepsy: a review. Nutrients 2020;12:1809.
Vykunta Raju KN, Gulati S, Kabra M, Agarwala A, Sharma S, Pandey RM, et al
. Efficacy of 4:1 (classic) versus 2.5:1 ketogenic ratio diets in refractory epilepsy in young children: a randomized open labeled study. Epilepsy Res. 2011;96:96-100.
Kossoff EH, Krauss GL, McGrogan JR, Freeman JM. Efficacy of the Atkins diet as therapy for intractable epilepsy. Neurology 2003;61:1789-91.
Pfeifer HH, Thiele EA. Low-glycemic-index treatment: a liberalized ketogenic diet for treatment of intractable epilepsy. Neurology 2005;65:1810-2.
D’Andrea Meira I, Romão TT, Pires do Prado HJ, Krüger LT, Pires MEP, da Conceição PO. Ketogenic diet and epilepsy: what we know so far. Front Neurosci 2019;13:5.
Seo JH, Lee YM, Lee JS, Kang HC, Kim HD. Efficacy and tolerability of the ketogenic diet according to lipid:nonlipid ratios: comparison of 3:1 with 4:1 diet. Epilepsia 2007;48: 801-5.
Chul Kang H, Joo Kim Y, Wook Kim D, Dong Kim H. Efficacy and safety of the ketogenic diet for intractable childhood epilepsy: Korean multicentric experience. Epilepsia 2005;46:272-9.
Cai QY, Zhou ZJ, Luo R, Gan J, Li SP, Mu DZ, et al
. Safety and tolerability of the ketogenic diet used for the treatment of refractory childhood epilepsy: a systematic review of published prospective studies. World J Pediatr 2017;13:528-36.
Bjurulf B, Magnus P, Hallböök T, Strømme P. Potassium citrate and metabolic acidosis in children with epilepsy on the ketogenic diet: a prospective controlled study. Dev Med Child Neurol 2020;62:57-61.
Hemingway C, Freeman JM, Pillas DJ, Pyzik PL. The ketogenic diet: a 3- to 6-year follow-up of 150 children enrolled prospectively. Pediatrics 2001;108:898-905.
Gasior M, Rogawski MA, Hartman AL. Neuroprotective and disease-modifying effects of the ketogenic diet. Behav Pharmacol 2006;17:431-9.
van Berkel AA, IJff DM, Verkuyl JM. Cognitive benefits of the ketogenic diet in patients with epilepsy: a systematic overview. Epilepsy Behav 2018;87:69-77.
Dominique M IJff, Postulart D, Lambrechts DAJE, Majoie MHJM, de Kinderen RJA, Hendriksen JGM, et al
. Aldenkamp cognitive and behavioral impact of the ketogenic diet in children and adolescents with refractory epilepsy: a randomized controlled trial. Epilepsy Behav 2016;60:153-7.
[Table 1], [Table 2], [Table 3], [Table 4]