Intractable Epilepsy In Children Research Articles

Resting-state functional MRI study of conventional MRI-negative intractable epilepsy in children.

The study aimed at investigating functional connectivity strength (FCS) changes in children with MRI-negative intractable epilepsy (ITE) and evaluating correlations between aberrant FCS and both disease duration and intelligence quotient (IQ). Fifteen children with ITE, 24 children with non-intractable epilepsy (nITE) and 25 matched healthy controls (HCs) were subjected to rs-fMRI. IQ was evaluated by neuropsychological assessment. Voxelwise analysis of covariance was conducted in the whole brain, and then pairwise comparisons were made across three groups using Bonferroni corrections. FCS was significantly different among three groups. Relative to HCs, ITE patients exhibited decreased FCS in right temporal pole of the superior temporal gyrus, middle temporal gyrus, bilateral precuneus, etc and increased FCS values in left triangular part of the inferior frontal gyrus, parahippocampal gyrus, supplementary motor area, caudate and right calcarine fissure and surrounding cortex and midbrain. The nITE patients presented decreased FCS in right orbital superior frontal gyrus, precuneus etc and increased FCS in bilateral fusiform gyri, parahippocampal gyri, etc. In comparison to nITE patients, the ITE patients presented decreased FCS in right medial superior frontal gyrus and left inferior temporal gyrus and increased FCS in right middle temporal gyrus, inferior temporal gyrus and calcarine fissure and surrounding cortex. Correlation analysis indicated that FCS in left caudate demonstrated correlation with verbal IQ (VIQ) and disease duration. ITE patients demonstrated changed FCS values in the temporal and prefrontal cortices relative to nITE patients, which may be related to drug resistance in epilepsy. FCS in the left caudate nucleus associated with VIQ, suggesting the caudate may become a key target for improving cognitive impairment and seizures in children with ITE.

Contemporary Insights into Intractable Epilepsy in Children.

While most children with epilepsy find their seizures manageable through medication, some continue to experience seizures despite trying multiple drugs. Failure of medical treatment often becomes apparent early on, and for these cases, it is advisable to seek further treatment options at a specialized epilepsy center. Such centers offer additional treatments like epilepsy surgery, vagus nerve stimulation, and ketogenic diets. There is no universal definition for what constitutes "medically intractable" epilepsy. A proposal by a task force from the International League Against Epilepsy suggests that drug-resistant epilepsy could be defined as the inability to control seizures even after two adequate treatment attempts with well-chosen and tolerated medications, either alone or in combination. In this review, the authors discussed the management of intractable epilepsy in children.

The Effectiveness of Modified Atkins Ketogenic Diet on Children with Intractable Epilepsy: A Pilot Study from Indonesia.

The ketogenic diet has recently been explored as a potential treatment approach for intractable epilepsy in children and has been applied in various parts of the world. The ketogenic diet is also effective for the treatment of mood disorders, especially for adolescent and young adults with epilepsy. The Modified Atkins Diet (MAD) is the less restrictive type of ketogenic diet with similar principles as the classic type. However, no study has been conducted to evaluate the use of MAD in children with severe epilepsy in Indonesia. This study aims to assess the effectiveness, tolerance, compliance, and the adverse effects of MAD in children with intractable epilepsy during a 6-month monitoring period. This is a pilot experimental study involving children aged 2-18 years old with intractable epilepsy at the Pediatric Neurology and the Pediatric Nutrition & Metabolic Diseases Clinics at the Dr. Cipto Mangunkusumo Hospital Jakarta between November 2021 and June 2022. A total of 31 subjects met the inclusion criteria and received the MAD in the first month, followed by 13 (41.9%) subjects in the third month, and 9 (29%) subjects in the sixth month. The MAD reduced the seizure frequency by 50% (p = 0.144), 62% (p = 0.221), and 83.3% (p = 0.028) in the first, third, and sixth months, respectively. The most frequent adverse effects are vomiting and diarrhea. Noncompliance was observed in 18 (58.1%) subjects. A sample of the MAD food menu guidebook was developed to make it easier for parents to adhere to the diet. The MAD reduces the mean seizure frequency in children with intractable epilepsy in the first, third, and sixth months, with a statistical significance in the sixth month. A further randomized, controlled, and multicenter clinical trial with a larger sample size and longer observation period is required. This trial is registered with Protocol ID 20-10-1323.

Surgical treatment of epilepsy in children with focal cortical dysplasia in central gyri

Assessment of the outcome after epilepsy surgery in children with FCD in central lobules. Nine patients, median age 3.7 ys, IQR=5.7 ys (min 1.8- max 15.7 ys) with FCD in central gyri and DR-epilepsy underwent surgery. Standard preoperative evaluation included MRI and video-EEG. Invasive recordings were used in 2 cases, coupled by fMRI in 2. An ECOG and neuronavigation, as well as stimulation and mapping of primary motor cortex were used routinely during the procedure. Gross total resection was achieved in 7 patients according to postoperative MRI. Six patients with new or worsening of already existing hemiparesis recovered within a year after surgery. At the last FU (med 5 ys) favorable outcome (Engel class IA) has been achieved in 6 cases (66.7%), while two patients with persisting seizures reported seizing less frequently (Engel II-III). Three patients were able to discontinue AED-treatment and four children resumed development with improvement in cognition and behavior.

Pathogenesis and Therapeutic Targets of Focal Cortical Dysplasia Based on Bioinformatics Analysis.

Focal cortical dysplasia (FCD), a malformation of cortical development, is the most common cause of intractable epilepsy in children. However, the causes and underlying molecular events of FCD need further investigation. The microarray dataset GSE62019 and GSE97365 were obtained from Gene Expression Omnibus. To examine critical genes and signaling pathways, bioinformatics analysis tools such as protein-protein interaction (PPI) networks, miRNA-mRNA interaction networks, and immune infiltration in FCD samples were used to fully elucidate the pathogenesis of FCD. A total of 534 differentially expressed genes (DEGs) and 71 differentially expressed miRNAs (DEMs) were obtained. The DEGs obtained were enriched in ribosomal, protein targeting, and pathways of neurodegeneration multiple diseases, whereas the target genes of DEMs were enriched in signaling pathways such as transforming growth factor beta, Wnt, PI3K-Akt, etc. Finally, four hub genes (RPL11, FAU, RPS20, RPL27) and five key miRNAs (hsa-let-7b, hsa-miR-185, hsa-miR-23b, hsa-miR-222 and hsa-miR-92b) were obtained by PPI network, miRNA-mRNA network, and ROC analysis. The immune infiltration results showed that the infiltration levels of five immune cells (MDSC, regulatory T cells, activated CD8+ T cells, macrophage and effector memory CD8+ T cells) were slightly higher in FCD samples than in control samples. Moreover, the gene expressions of RPS19, RPL19, and RPS24 were highly correlated with the infiltration levels and immune characteristics of 28 immune cells. It broadens the understanding of the molecular mechanisms underlying the development of FCD and enlightens the identification of molecular targets and diagnostic biomarkers for FCD.

Surgical treatment of pediatric intractable frontal lobe epilepsy due to malformation of cortical development

BackgroundMalformation of cortical development (MCD) is a common cause of intractable epilepsy in children. In this study, the effectiveness of frontal lobe epilepsy (FLE) surgery in children with intractable epilepsy due to MCD was assessed and its prognostic factors were studied.MethodsSeventy-six patients with intractable FLE who received epilepsy surgery between January 2016 and March 2018 in Peking University First Hospital were recruited in this study. All the resected brain tissues were demonstrated to be MCD. All patients were followed up for at least 3 years. The clinical data and prognosis were analyzed retrospectively. Univariate and multivariate analyses were performed to investigate the correlations between clinical variables and prognostic outcome (Engel classification).ResultsSixty (78.9%) patients had Engel class I postoperative outcome. The mean age at surgery was 6.00 ± 4.24 years. Sixty-six patients (86.8%) had daily seizures, 40.2% of the patients had epileptic spasm, and 33% of the patients had extensive interictal EEG abnormalities, which, however, could not provide any helpful information for localizing epileptogenic zones. About 29% of the patients had normal MRI findings even by experienced radiologists, and 26% of the patients had epileptogenic lesion involving adjacent lobes. There was a significant correlation between acute postoperative seizure (APOS) and prognosis (P < 0.05): APOS predicted poor prognosis. There was a significant correlation between pathology and prognosis (P < 0.05): FCD IA and FCD IIB were correlated with a good outcome. Both variables with a significance level of P < 0.05 during univariate analysis, including pathology and APOS, were included in multivariate analysis, which were significant independent predictors of prognosis.ConclusionsThe clinical manifestations of pediatric intractable FLE due to MCD are more complicated than those in adults. Multidisplinary presurgical evaluation in pediatric epilepsy is mandatory. The surgical outcome of pediatric FLE due to MCD could reach a seizure-free rate of 78.9% with the follow-up of at least 3 years. The post-operative pathology and APOS may be related to the prognosis of surgery in this group of pediatric patients.

Current Review in Basic Science: Animal Models of Focal Cortical Dysplasia and Epilepsy.

Focal cortical dysplasia (FCD) is a malformation of cortical development that is a prevalent cause of intractable epilepsy in children. Of the three FCD subtypes, understanding the etiology and pathogenesis of FCD type II has seen the most progress owing to the recent advances in identifying gene mutations along the mTOR signaling pathway as a frequent cause of this disorder. Accordingly, numerous animal models of FCD type II based on genetic manipulation of the mTOR signaling pathway have emerged to investigate the mechanisms of epileptogenesis and novel therapeutics for epilepsy. These include transgenic and in utero electroporation-based animal models. Here, we review the histopathological and electroclinical features of existing FCD type II animal models and discuss the scientific and technical considerations, clinical applications, and limitations of current models. We also highlight other models of FCD based on early life acquired factors.

Histopathological Findings in Brain Tissue of Patients with Pharmacoresistant Focal Epilepsy

Background: Pharmacoresistant epilepsy represents 30-40% of cases with intractable epilepsy in children, and up to 20% of adult cases. Various cerebral lesions can lead to drug-resistant focal epilepsy. They are medically refractory but the complete surgical resection correlates with good outcome.

Current Pharmacologic Strategies for Treatment of Intractable Epilepsy in Children.

Epileptic encephalopathy (EE) is a devastating pediatric disease that features medically resistant seizures, which can contribute to global developmental delays. Despite technological advancements in genetics, the neurobiological mechanisms of EEs are not fully understood, leaving few therapeutic options for affected patients. In this review, we introduce the most common EEs in pediatrics (i.e., Ohtahara syndrome, Dravet syndrome, and Lennox-Gastaut syndrome) and their molecular mechanisms that cause excitation/inhibition imbalances. We then discuss some of the essential molecules that are frequently dysregulated in EEs. Specifically, we explore voltage-gated ion channels, synaptic transmission-related proteins, and ligand-gated ion channels in association with the pathophysiology of Ohtahara syndrome, Dravet syndrome, and Lennox-Gastaut syndrome. Finally, we review currently available antiepileptic drugs used to treat seizures in patients with EEs. Since these patients often fail to achieve seizure relief even with the combination therapy, further extensive research efforts to explore the involved molecular mechanisms will be required to develop new drugs for patients with intractable epilepsy.

Risk Factors of Intractable Epilepsy in Children with Cerebral Palsy.

ObjectivesWe aimed to investigate the risk factors predicting the development of intractable epilepsy in children with cerebral palsy (CP), with an emphasis on perinatal characteristics, seizure semiology, imaging, and EEG findings.Materials & MethodsFollowing a descriptive, retrospective, case-control design, 106 children with CP and epilepsy from 2015 to 2020 were studied (46 children with CP and intractable epilepsy and 60 with CP and controlled epilepsy). Data were retrieved from medical records of participants (i.e., demographics, clinical characteristics, perinatal history, etiology of seizure and CP, seizure semiology, intellectual functions, therapeutic options, brain imaging, and EEG findings).ResultsWe established a model of the most important risk factors that can predict intractable epilepsy in children with CP. The model included the additive effect of a poor Apgar score at 5 minutes, the presence of neonatal seizures, focal epilepsy, and focal slowing on the EEG background (Area under the receiver operating characteristic of 0.810). conclusionThe findings can be used to identify intractable epilepsy in children who suffer from CP with further support by offering early therapeutic interventions intended to reduce the burden of refractory seizures.

Focal cortical dysplasia: etiology, epileptogenesis, classification, clinical presentation, imaging, and management.

Focal cortical dysplasia (FCD) is the most prevalent cause of intractable epilepsy in children. It was first described by Taylor et al. in 1971. In 2011, the International League against Epilepsy described an international consensus of classification for FCD. However, the exact mechanism causing this pathology remains unclear. The diagnosis and recognition of FCD increase with the advances in neuroradiology and electrophysiology. In this paper, we discuss the literature regarding management of FCD with a focus on etiology, pathophysiology, classification, clinical presentation, and imaging modalities. We will also discuss certain variables affecting surgical outcome of patients with FCD. Based on our review findings, it is concluded that surgical management with complete resection of the lesion following preoperative localization of the epileptogenic zone in patients with FCD subtypes can provide a seizure-free outcome.

Pediatric to Adult Transitions of Ketogenic Dietary Therapy for Epilepsy.

Ketogenic therapy is now an accepted treatment forpediatric and adult patients with medically refractory epilepsy.1-3 However, young adults treated with a ketogenic diet face unique challenges when transitioning to adult neurology providers.4 The variable acceptance of dietary therapy, paucity of nutritionists and adult neurology providers educated in dietary therapy, and lack of insurance coverage for dietary education may interfere with transition to adult care. In addition, patients in this life stage may just begin to independently seek medical care, cook meals, and manage medications, making strict dietary limitations difficult.4 In this worldwide study, we surveyed 191 pediatric and adult neurology providers who prescribe ketogenic dietary therapy for epilepsy. Our response rate was 39% with a total of 74 valid surveys received. Our goal was to identify perceived barriers that inhibit effective transition and successful continuation of dietary therapy during transition to adult care. We found that dietary therapy is a more accepted treatment of intractable epilepsy in children (84%) than adults (17%) in all geographic areas. Although half of pediatric neurology providers (50%) transition their young adult patients on dietary therapy to adult providers, only 23% have a documented transition plan or a formal transition protocol. Most (87%) pediatric providers who prescribe the ketogenic diet feel the lack of sufficient adult providers who prescribe dietary therapy as a barrier to transitioning adolescent and young adult patients.

A girl with protein-losing enteropathy during a ketogenic diet: a case report

BackgroundA ketogenic diet (KD) is an effective treatment for intractable epilepsy in children. Protein–losing enteropathy (PLE) is a rarely reported but serious complication of KDs.Case presentationA 3-month-old female patient presented with PLE while following a KD as treatment for intractable epilepsy. She also had genovariation of the STXBP1 gene. The patient suffered from general edema and hypoalbuminemia but no diarrhea. Esophagogastroduodenoscopy (EDG) revealed lymphatic ectasia in the lamina propria. We diagnosed her with intestinal lymphangiectasia, and after decreasing the KD ratio from 4:1 to 1.05:1, we successfully controlled her edema and hypoalbuminemia. As of now, the convulsions and hypsarrhythmia have disappeared, and the seizure-free state has lasted for 20 months.ConclusionsPLE may be managed by decreasing the ketogenic ratio rather than discontinuing a KD since for some patients, a KD is the only effective therapy available at present.

A study of clinical profile of intractable epilepsy in children

Background: This study was undertaken to find out the prevalence and clinical features of intractable epilepsy (IE) in a tertiary referral center.Methods: Study was conducted in a tertiary care hospital on 60 children with intractable epilepsy. Cases includes intractable epilepsy is when seizures continue to occur despite maximally tolerated doses of more than two antiepileptics, occurrence of an average of one seizure per month for 18 months with no more than a 3 month seizure free period during these 18 months. Controls: epileptic children who had good control of seizures for the previous 18 months.Results: The prevalence of intractable seizures was 10% with maximum number of children 25 (41.6%) belonged to the 5-12 years. 15 (50%) children had daily seizures. Myoclonic seizures proved to be an important predictor of intractability. 4 children among the cases had history of family seizures, 6 children in cases had history febrile seizure, whereas, 6 children among the controls had history of family seizures, 8 children in controls had history febrile seizure. 23.3% of children presented with Status epilepticus in the cases and 16.6% of the children in the controls. Remote symptomatic etiology 12(40%) is the commonest cause of seizure. 13 (43.3%) children in cases and 3 (10%) children among the controls had a history suggestive of birth asphyxia. EEG was abnormal in 17 (56.6%) cases when compared to 11 (36.6%) children in the controls. CT scan was abnormal in 14 (46.6%) cases and 10 (33.3%) controls. MRI was abnormal in 16 (53.3%) children of the cases and 8 (26.6%) children of the controls.Conclusions: The commonest cause of intractable epilepsy was perinatal asphyxia. Perinatal asphyxia can be prevented by good nutrition during pregnancy, regular antenatal check ups with detection of high risk pregnancy, promoting hospital deliveries and prompt resuscitation of newborn when required.

A journey through formation and malformations of the neo-cortex.

Malformations of cortical development (MCD) are a heterogeneous group of disorders characterized by abnormal structure of the cerebral cortex. MCDs are an important cause of development delay and intractable epilepsy in children. In this review, we explore the embryological stages of development of neo-cortex, the imageology of various malformations which may occur during the journey of this development, the recent advances in imaging techniques used for diagnosing these malformations, and finally a simplified radiological approach to malformations of cortical development. We discuss the classification of MCD according to the embryologic stage of cerebral cortex at which the abnormality occurred and the unique imaging features of various malformations, including microcephaly, hemimegalencephaly, lissencephaly, focal cortical dysplasia, heterotopias, polymicrogyria, schizencephaly, and neonatal CMV infection. Also, a rare variant of hemimegalencephaly, namely posterior quadrantic dysplasia, is illustrated; the diagnosis of which is crucial for neurosurgeons to decide management. The technological advancement in the imaging of MCD has taken a leap in the recent years. Imaging now also plays an enormous role in mapping of the abnormalities, delineation of proper surgical boundaries, and quantifying risks of visual, language, and sensorimotor dysfunction. With the introduction of various motor-sparing surgeries and disconnection procedures, proper identification and delineation of these malformations have gained utmost significance. Knowledge of the wide imaging spectrum of MCD, familiarity with recent advances in imaging and an optimal radiological approach is essential for the general radiologist to accurately diagnose and prognosticate MCD as well as provide the best surgical approach to the operating surgeon.

Megalencephaly syndromes associated with mutations of core components of the PI3K-AKT-MTOR pathway: PIK3CA, PIK3R2, AKT3, and MTOR.

Megalencephaly (MEG) is a developmental abnormality of brain growth characterized by early onset, often progressive, brain overgrowth. Focal forms of megalencephaly associated with cortical dysplasia, such as hemimegalencephaly and focal cortical dysplasia, are common causes of focal intractable epilepsy in children. The increasing use of high throughput sequencing methods, including high depth sequencing to more accurately detect and quantify mosaic mutations, has allowed us to identify the molecular etiologies of many MEG syndromes, including most notably the PI3K-AKT-MTOR related MEG disorders. Thorough molecular and clinical characterization of affected individuals further allow us to derive preliminary genotype-phenotype correlations depending on the gene, mutation, level of mosaicism, and tissue distribution. Our review of published data on these disorders so far shows that mildly activating variants (that are typically constitutional or germline) are associated with diffuse megalencephaly with intellectual disability and/or autism spectrum disorder; moderately activating variants (that are typically high-level mosaic) are associated with megalencephaly with pigmentary abnormalities of the skin; and strongly activating variants (that are usually very low-level mosaic) are associated with focal brain malformations including hemimegalencephaly and focal cortical dysplasia. Accurate molecular diagnosis of these disorders is undoubtedly crucial to more optimally treat children with these disorders using PI3K-AKT-MTOR pathway inhibitors.

Application of positron emission computed tomography/magnetic resonance imaging coregistration in improving epileptic foci detection rate of structural intractable epilepsy in children

Objective To study the predictive value of magnetic resonance imaging (MRI), positron emission computed tomography (PET) and PET/MRI coregistration in intractable epilepsy of children. Methods A retrospectively analysis was performed based on the surgery data at the Department of Children Epilepsy Center of Peking University First Hospital from September 2015 to March 2016.The clinical data, surgery and follow-up study data, interictal and ictal electroencephalogram, MRI, PET and PET/MRI coregistration data were collected.By comparison with the epileptogenic zone designed by pre-surgical workup, the accuracy of MRI, PET and PET/MRI coregistration in detecting lesion was assessed.In the patients who had no seizure during ≥1 year follow-up, their sensitivity, specificity, positive predictive value, negative predictive value of MRI, PET and PET/MRI coregistration were calculated. Results (1)A total of 62 patients underwent surgery, 30 boys and 32 girls.The average age on epilepsy onset was 2.50 years (2 days-11.70 years), and average age on surgery was 5.10 years old(0.75-15.60 years old). (2)Surgical treatment of 62 cases included the resection of the focal or lobar(32 cases, 51.6%), and the multilobar (16 cases, 25.8%). Hemispherotomy was done in 14 cases (22.6%). During ≥1 year follow-up, seizure outcome was Engel class Ⅰ in 57 cases (91.9%) out of the 62 patients, Engel class Ⅱ to Engel class Ⅳ in 1 case, 3 cases, and 1 case, respectively.(3) Referred to epileptogenic zone designed by presurgical workup, MRI represented 64.5%(40/62 cases) results with accordance, PET and PET/MRI coregistration was 72.5%(45/62 cases) and 85.5%(53/62 cases), respectively, and the difference was significant(χ2=7.25, P=0.03). (4) Based on the patients of Engel class Ⅰ, their sensitivity and specificity were 66.7%, 60.0% in MRI, 75.4%, 60.0% in PET %, and 85.9%, 80.0% in PET/MRI coregistration, respectively.(5)There were 11 non-lesion cases of all focal cortical dysplasia in pathology, and subtle structural abnormalities were de tected in 9 cases by reviewing MRI. Conclusions PET/MRI coregistration can improve lesion detection of intractable epilepsy in children. Key words: Intractable epilepsy; Magnetic resonance imaging; Positron emission computed tomography; Positron emission computed tomography/magnetic resonance imaging coregistration; Epileptogenic zone

Vagus nerve stimulation therapy for post-encephalitic intractable epilepsy in children

Objective To evaluate the effect of vagus nerve stimulation (VNS) on post-encephalitic intractable epilepsy and the improvement of postoperative cognitive function and quality of life. Methods The patients with post-encephalitic epilepsy in Sanbo Brain Hospital, Capital Medical University from January 2008 to December 2016 were selected.A single center and retrospective study method was used to evaluate the cognitive function, social function of preoperative and postoperative and postoperative seizure classification.The follow-up time points included preoperative, posto-perative in 6 months, 1 year after operation and postoperative annual review. Results A total of 43 patients were followed up, including 19 females and 24 males, with an average age of (9.37± 4.18) years old.The time of follow-up was (43.90 ± 33.04) months.According to Engel classification: Grade Ⅰ 3 cases (7.0%), grade Ⅱ 3 cases (7.0%), grade Ⅲ 14 cases (32.6%), grade Ⅳ 21 cases (48.8%). According to McHugh classification: Grade Ⅰ 8 cases (18.6%), grade Ⅱ 12 cases (28%), grade Ⅲ 11 cases (25.5%), grade Ⅳ 6 cases (14.0%), grade Ⅴ 4 cases (9.3%). Speech improvement of postoperative: significant improvement in 3 cases (7.0%), slightly improved in 17 cases (39.6%); interpersonal communication improvement of postoperative: significantly increased 7 cases (16.4%), slightly improved 16 cases(37.2%); learning/working ability improvement of postoperative: significantly improved 6 cases(14.0%), slightly increased 14 cases(32.6%). The postoperative VIQ (6.21±5.02) scores, PIQ (7.28±6.10) scores, FIQ (2.93±3.74) scores and MQ were (4.81±2.98) scores higher than preoperative. Conclusions VNS can effectively improve the seizures of post-encephalitic epilepsy as well as the children′s quality of life, cognition and social function. Key words: Post-encephalitic epilepsy; Vagus nerve stimulation; Cognitive function; Follow-up study

Invasive Neuromodulation for the Treatment of Pediatric Epilepsy.

Neuromodulatory strategies are increasingly adopted for the treatment of intractable epilepsy in children. These encompass a wide range of treatments aimed at externally stimulating neural circuitry in order to decrease seizure frequency. In the current review, the authors discuss the evidence for invasive neuromodulation, namely vagus nerve and deep brain stimulation in affected children. Putative mechanisms of action and biomarkers of treatment success are explored and evidence of the efficacy of invasive neuromodulation is highlighted.

Intractable Epilepsy in Children

A seizure is defined as a paroxysmal and transient occurrence of signs or symptoms resulting from abnormal synchronous or excessive neuronal activity in the brain. About 15 to 40 percent of children who have any type of seizure are resistant to standard anti-seizure drugs, so called intractable epilepsy. Before documenting the seizure attacks as refractory, the selected drugs using for the type of seizure and dose of them should be checked. There are several factors that predict development of refractory seizures. These include age <1 year, multiple seizures before starting the treatment, myoclonic seizures, neurologic defects, neonatal and daily seizures, male gender, and first abnormal electroencephalogram and brain imaging (including computerized tomography scan and / or MRI). Options for the management of refractory epilepsy, after prescribing routine anti-seizure drugs are: Second line drugs (IVIG treatment, Ketogenic diet, Prednisolone treatment or Herbal treatment), Surgery and Stem cell therapy. Because none of these methods can stop all the drug-resistant epilepsies, researches are going on.