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Abstract Up to 65 million people worldwide are affected by epilepsy. Approximately one third of epileptic patients still have difficulty being treated, even though two-thirds of them can control their seizures with current Anti-Seizure Medication (ASM). The International League Against Epilepsy (ILAE) defines Drug-Resistant Epilepsy (DRE) as the failure of adequate trials of two tolerated, properly selected and utilized antiepileptic drug schedules to achieve sustained relief of seizures. Therefore, one should initially attempt surgical therapies, if a patient is eligible and if surgery is not a possibility for a patient with DRE, Dietary therapy like the Ketogenic Diet (KD) is an alternative. KD (a high-fat, adequate-protein, and low carbohydrate diet) is an effective, non-invasive, and non-pharmacologic treatment for refractory childhood epilepsy used since 1920s with few to no neurotoxic effects when compared to multiple ASM. Despite the KD’s effectiveness, most patients discontinue the diet because of its unpalatable and restrictive features. So, new variants of KD have emerged, including the Modified Atkins Diet (MAD) and the low-glycemic-index diet. MAD provides a more palatable and less restrictive dietary treatment option. However, since KD is not a physiological diet, it is important to identify and carefully monitor any AEs. AEs can happen at the start of the diet as well as months after KD initiation. Dehydration, altered electrolytes, hypoglycemia, tiredness, abdominal pain, nausea/vomiting, diarrhea, and constipation are short-term AE, while hypoproteinemia, hypocalcemia, hypercalciuria, urolithiasis, Summary 122 alterations in lipid profiles, an increase in transaminases or cardiomyopathy are possible long-term AE. Electroencephalographic (EEG) features are improved by KD in addition to significantly reducing clinical seizures in epileptic patients. The aim of this study: This study aimed to assess short and long-term efficacy, safety, and tolerability of KD (classic KD and MAD) in childhood DRE and to investigate the effect of KD on EEG features of children with DRE. Patients and Methods: We initially enrolled forty patients with DRE attending Pediatric KD outpatient clinic at Menoufia University Hospital and an informed (written) consent was obtained from each parent or caregiver. Our inclusion criteria were patients who had received two or more types of regular antiepileptic drugs, but frequent seizures continued regardless their age. Patients with chronic diseases, congenital metabolic disorders, liver diseases, and systemic diseases were excluded from the study. Patients were randomly assigned to two groups, group 1 (classic KD group): 20 patients received classic KD and group 2 (MAD group): 20 patients kept on MAD. Before starting KD, we collected demographic and clinical data of studied patients including age, sex, age of start of seizures, anthropometric measurements (weight, length/height, weight for length/height, and BMI) according to Egyptian Z score growth references for Egyptian children, etiology, type of seizures, , seizure Summary 123 frequency, and seizure severity. Number of antiepileptic drugs used, and baseline EEG were also documented. Morning blood samples were taken after 8–12 hours fasting. Triglycerides (TG), total cholesterol, low-density lipoprotein (LDL-C) and high-density lipoprotein (HDL-C) were measured. Parents or caregivers were educated about diet preparation at home with close monitoring of blood glucose and urinary ketones. Multivitamins, calcium, and vitamin D were given as supplements Patients were requested to attend their regular monthly outpatient visits for six months, then every three months for 24 months. After one month of KD initiation, two patients of classic KD group and one patient of MAD group were excluded from the study due to non-compliance of their caregivers. At 3 months follow up visit, six patients were excluded from the study as they did not tolerate the MAD and the ketogenic liquid formula. Also, one patient of MAD group died secondary to infection in COVID19 epidemic, so only 30 patients completed the study for two years, 15 in each group. The clinical efficacy of KD was evaluated regarding seizures frequency and severity prior to and 3 and 6 months after the KD treatment were analyzed. By comparing EEG before and 3 and 6 months after the KD therapy regarding the background rhythm and variations of inter-ictal epileptiform activity, the effect of KD on EEG features was assessed. Anthropometric measurements, lipid profile, and the development of AE were monitored at 3 months intervals up to 24 months. In addition, we assessed the possibility of antiepileptic drugs withdrawal in seizure free patients after the first 6 months. Summary 124 Results: Out of 40 patients enrolled initially in our study, 30 patients with median age 3 years (36 months) in classic KD group versus 6 years (72 months) in MAD group tolerated this study for 24 months, 11 patients (36.67%) were under weight, 3 patients (10%) were overweight, and 7 patients (23.33%) were wasted with non-significant difference between the two groups. According to ILAE 2017, epilepsy of unknown etiology was the commonest etiology among the participants [12 patients (40%)] and Myoclonic seizures was the most prevalent type [10 cases (33.33%)]. The median of seizures severity scale and seizures frequency per day of 165 and 10 respectively. There was statistically significant decrease in seizure severity by -100 % percent change after 3 and 6 months of KD compared to baseline with non-significant difference between both groups. Six months after initiation of KD, 60 % of patients in classic KD group and 46.67% of patients in MAD group became seizure free and the other 40 % and 53.33% had ≥ 50% seizure reduction with median percent decrease of -83.33% and -75% after 3 months in classic KD and MAD respectively and -100% after 6 months in both groups. The best seizures control was observed in genetic epilepsy. On the other hand, the efficacy of KD for epilepsy of unknown etiology was poor. The better EEG before treatment, the better seizures control as there was a statistically significant difference regarding seizures control between patients with initially normal EEG and patients with abnormal EEG after 3 and 6 months of KD and normal EEG before treatment was associated with better seizures control. Summary 125 As the length of the KD treatment was increased, significant changes in the background rhythms of the children were observed. Our results did not find any correlation between the level of urinary ketones and seizure control 3 and 6 months after KD. Our results revealed that gastrointestinal (GI) complications were frequent in our studied cases and constipation was the commonest with the same occurrence in the two groups (33.33%). We didn‘t document renal/genitourinary complications in our study. In our study, median level of HDL decrease did not reach the low level till the end of the study for 24 months. Also, median level of LDL, total cholesterol, and triglycerides increase did not reach high level (remained in the acceptable level) throughout the study period, without significant difference between classic KD group and MAD group. Upon regular follow up visits every 3 months after the first 6 months, it was possible to withdraw one AEDs in 3 patients (20%) of classic KD group and 5 patients (33.33%) of MAD groups, in addition to withdrawal of two AEDs in 3 patients (20%) in classic KD group and 2 patients (13.33%) in MAD group leading to less AEDs side effects and better quality of life while on adequate seizure control by KD. The current study found a positive impact of KD on growth of studied cases (weight loss and BMI reduction were minimal) except in patients who were significantly overweight at diet initiation. Conclusion: 1. Both common types of KD (classic KD and MAD) are effective for treatment of DRE. Summary 126 2. MAD was more palatable for children with less restrictive options than classic KD with no significant difference regarding efficacy and safety. 3. High serum lipid profile (cardiovascular AE) is often suspected in children following a high fat diet, but lipid profile remained in the acceptable level up to 24 months. Therefore, KD constitutes a safe treatment. 4. KD had a positive impact on growth despite, inconsistent results of the KD‘s effect on growth. 5. In addition to showing strong clinical effectiveness, KD also showed significant improvement in EEG by decreasing the frequency of interictal epileptic discharges and enhancement of the background rhythm. Recommendation: 1. Although no serious complications were recorded, long-term follow-up and larger scale studies are recommended to further ensure the safety of KD in childhood period. 2. The role of KD as a single line of therapy, whether from the beginning or after withdrawal of all other medications once full control is established, is also recommended to be clarified by more research. 3. More research on evaluation of efficacy, tolerability and safety of other types of KD like low glycemic index treatment (LGIT) and medium- chain triglycerides diet (MCTD) is recommended. 4. Lastly, further studies are needed to identify predictors of KD efficacy, studies to find any correlation between type of seizures, etiology of epilepsy, EEG findings and favorable seizure outcomes to assess if the KD can be considered as a first line of treatment of epilepsy in specific situations. |