Treatment Of Refractory Childhood Epilepsy Research Articles

The efficacy and safety of a ketogenic diet for children with refractory epilepsy in China: a retrospective single-center cohort study.

BackgroundThe ketogenic diet (KD) has been implemented in many different counties. However, in China, study concerning the efficacy of the KD is still at an early-stage of evaluation. Furthermore, the KD is thought to be incompatible with Chinese children because of its lack of palatability, especially for the Asian population. In addition, its substantial antiepileptic effect remains to be confirmed.MethodsTo evaluate the efficacy and safety of the KD treatment of refractory childhood epilepsy in China, we prospectively enrolled 147 children with refractory epilepsy for KD treatment in Guangdong 999 Brain Hospital and followed up the children for 6 months. Outcome was measured by seizure frequencies before and after the KD diet and adverse effects. We also evaluated influences of different variables (starting age, duration of epilepsy, and others) on the outcome.ResultsWe found after 1 month, 3 months, and 6 months of KD treatment, 28.0%, 55%, and 67.9% of the subjects remained on diet with a >50% seizure reduction and seizure-free rates of 6.5%, 13.2%, and 23.3%, respectively. Gender, starting age, duration, etiology, classification, and seizure type of epilepsy showed no significant influence on efficacy. Anorexia, diarrhea, and gravel were the main side-effects of the KD treatment.ConclusionsIn conclusion, the KD is a safe and efficacious method for childhood refractory epilepsy treatment.

Non-Pharmacological and Non-Surgical Treatment of Refractory Childhood Epilepsy.

Nearly 20-40% of patients with epilepsy are likely to have drug resistant epilepsy (DRE). Add-on antiseizure drugs do not produce optimal seizure control in these patients. Among the non-pharmacological options, only resective surgery is curative. However, a large majority of patients are not candidates for resective epilepsy surgery. For these children with DRE, non-pharmacological non-surgery "palliative" options should be considered early than late. These include dietary therapies and neuromodulation. While there are numerous clinical trials supporting the efficacy of dietary therapies (viz ketogenic diet, modified Atkins diet and low glycemic index therapy), the evidence for neuromodulation is still evolving. Neuromodulation techniques include vagal nerve stimulation, deep brain stimulation, and transcranial magnetic stimulation. Each of the options, whether diet or neuromodulation, has its own advantages, disadvantages and adverse events profile. These have to be considered and discussed with the family before deciding the modality being chosen.

The ketogenic diet is effective for refractory epilepsy associated with acquired structural epileptic encephalopathy.

Ketogenic diet therapies have proven efficacy for refractory epilepsy. There are many reports of their use in the genetic developmental and epileptic encephalopathies; however, little attention has been paid as to whether the diet is also effective in individuals with an acquired structural aetiology. We observed remarkable efficacy of the diet in two patients with hypoxic-ischaemic encephalopathy. We then analysed our cases with refractory structural epilepsies of acquired origin to characterize their response to the ketogenic diet. The classical ketogenic diet was implemented with dietary ratios of 3:1 to 4.4:1. Seizure frequency at 1month, 3months, 6months, 1year, and 2years was ascertained. A responder was defined as greater than 50% seizure reduction compared to baseline. Seven of the nine patients were responders at 3months. Somewhat surprisingly we found that the ketogenic diet was effective in patients with a developmental and epileptic encephalopathy due to an acquired structural aetiology. This cohort may not be routinely considered for the ketogenic diet because of their structural and acquired, rather than genetic, basis. The ketogenic diet should be considered early in the management of patients with acquired structural encephalopathies as it can improve seizure control with the potential to improve developmental outcome. The ketogenic diet was effective in children with epilepsy associated with an acquired structural aetiology.

Advance of mechanism of ketogenic diet in refractory childhood epilepsy

Ketogenic diet(KD)has an auxiliary treatment for refractory epilepsy.It is recently demonstrated by clinical practice and researches that KD is effective in some children with refractory epilepsy.Despite much progress has been made on the anticonvulsant mechanisms of KD, no biological target related to clinical efficacy has been found so far.The biochemical characteristics of KD and its metabolic changes are discussed(including the roles of neuronal γ-aminobutyric acid, glutamate, ATP sensitive potassium channels and purine metabolism, and so on). The mechanism and recent progress of KD in the treatment of refractory childhood epilepsy are reviewed. Key words: Ketogenic diet; Metabolism; Epilepsy; Child

Safety and tolerability of the ketogenic diet used for the treatment of refractory childhood epilepsy: a systematic review of published prospective studies.

To review the available evidence from prospective studies on the safety and tolerability of the ketogenic diet (KD) for the treatment of refractory childhood epilepsy. A comprehensive bibliographic search was performed with the aim of retrieving prospective studies that monitored adverse effects (AEs) in children after receiving the classic or medium-chain triglyceride KD therapy for refractory epilepsy. A total of 45 studies were retrieved, including 7 randomized controlled trials. More than 40 categories of AEs were reported. The most common AEs included gastrointestinal disturbances (40.6%), hyperlipidemia (12.8%), hyperuricemia (4.4%), lethargy (4.1%), infectious diseases (3.8%) and hypoproteinemia (3.8%). Severe AEs, such as respiratory failure and pancreatitis, occurred in no more than 0.5% of children. Specifically, patients receiving KD therapy should be monitored for osteopenia, urological stones, right ventricular diastolic dysfunction, and growth disturbance. The total retention rates of the diet for 1 year and 2 years were 45.7% and 29.2%, respectively. Nearly half of the patients discontinued the diet because of lack of efficacy. AEs were not the main reason for the KD discontinuation. None of the 24 deaths reported after initiation of the diet was attributed to the KD. KD is a relatively safe dietary therapy. However, because the KD can cause various AEs, it should be implemented under careful medical supervision. Continuous follow-up is needed to address the long-term impact of the diet on the overall health of children.

Distinct capability of some fats on unsaturated fatty acid and antioxidant enrichment of foods for ketogenic diet purpose

Ketogenic diet is a dietetic approach for the treatment of refractory childhood epilepsy. In this experiment we aimed to assess the total lipid content enrichment capability of different however, less studied fats, as well as the possibilities to transfer unsaturated fatty acids and antioxidants into different foods, as these substances proved to be relevant in the mechanism of the ketogenic diet. We also determined the stability of different fats during food preparation and short-term storage. French fries, meatloaf and fried zucchini were prepared with sunflower oil, olive oil, coconut oil, rape oil and lard. The total lipid contents, iodine values, rancidities and antioxidant-activities of the samples were ascertained immediately after the preparation and after 3-day-storage on 4°C. Our results indicate that the different foods are distinct in their lipid uptake capabilities, while the fats cannot be distinguished by their penetrance abilities into the foods. Sunflower and rape oils proved to be the best for unsaturated fatty acid enrichment but as rape oil proved to be sensitive to both heat and storage time, sunflower oil seems to be the best option. Anitoxidant-acitvity did not show any tendencies.

Cannabidiol Limits T Cell-Mediated Chronic Autoimmune Myocarditis: Implications to Autoimmune Disorders and Organ Transplantation.

Myocarditis is a major cause of heart failure and sudden cardiac death in young adults and adolescents. Many cases of myocarditis are associated with autoimmune processes in which cardiac myosin is a major autoantigen. Conventional immunosuppressive therapies often provide unsatisfactory results and are associated with adverse toxicities during the treatment of autoimmune myocarditis. Cannabidiol (CBD) is a nonpsychoactive constituent of marijuana that exerts antiinflammatory effects independent of classical cannabinoid receptors. Recently, 80 clinical trials have investigated the effects of CBD in various diseases from inflammatory bowel disease to graft versus host disease. CBD-based formulations are used for the management of multiple sclerosis in numerous countries, and CBD also received U.S. Food and Drug Administration approval for the treatment of refractory childhood epilepsy and glioblastoma multiforme. Herein, using a well-established mouse model of experimental autoimmune myocarditis (EAM) induced by immunization with cardiac myosin emmulsified in adjuvant resulting in T cell-mediated inflammation, cardiomyocyte cell death, fibrosis and myocardial dysfunction, we studied the potential beneficial effects of CBD. EAM was characterized by marked myocardial T-cell infiltration, profound inflammatory response and fibrosis (measured by quantitative real-time polymerase chain reaction, histology and immunohistochemistry analyses) accompanied by marked attenuation of both systolic and diastolic cardiac functions measured with a pressure-volume conductance catheter technique. Chronic treatment with CBD largely attenuated the CD3+ and CD4+ T cell-mediated inflammatory response and injury, myocardial fibrosis and cardiac dysfunction in mice. In conclusion, CBD may represent a promising novel treatment for managing autoimmune myocarditis and possibly other autoimmune disorders and organ transplantation.

Efficacy of the Ketogenic Diet for the Treatment of Refractory Childhood Epilepsy: Cerebrospinal Fluid Neurotransmitters and Amino Acid Levels

ObjectiveThe mechanisms of the ketogenic diet remain unclear, but several predictors of response have been proposed. We aimed is to study the relationship between the etiology of epilepsy, cerebrospinal fluid neurotransmitters, pterins, and amino acids, and response to a ketogenic diet. MethodsWe studied 60 patients who began classic ketogenic diet treatment for refractory epilepsy. In 24 of 60 individuals, we analyzed cerebrospinal fluid neurotransmitters, pterins, and amino acids in baseline conditions. Mean age at epilepsy onset was 24 months, 83.3% were focal epilepsies, and in 51.7% the etiology of the epilepsy was unknown. ResultsSix months after initiating the ketogenic diet, it was effective (greater than a 50% reduction in seizure frequency) in 31.6% of patients. We did not find a link between rate of efficacy for the ketogenic diet and etiologies of epilepsy, nor did we find a link between the rate of efficacy for the ketogenic diet and cerebrospinal fluid pterins and biogenic amines concentrations. However, we found statistically significant differences for lysine and arginine values in the cerebrospinal fluid between ketogenic diet responders and nonresponders, but not for the other amino acids analyzed. SignificanceThe values of some amino acids were significantly different in relationship with the ketogenic diet efficacy; however, the epilepsy etiology and the cerebrospinal fluid biogenic amine and pterin values were not.

Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox–Gastaut syndrome

There is a great need for safe and effective therapies for treatment of infantile spasms (IS) and Lennox–Gastaut syndrome (LGS). Based on anecdotal reports and limited experience in an open-label trial, cannabidiol (CBD) has received tremendous attention as a potential treatment for pediatric epilepsy, especially Dravet syndrome. However, there is scant evidence of specific utility for treatment of IS and LGS. We sought to document the experiences of children with IS and/or LGS who have been treated with CBD-enriched cannabis preparations. We conducted a brief online survey of parents who administered CBD-enriched cannabis preparations for the treatment of their children's epilepsy. We specifically recruited parents of children with IS and LGS and focused on perceived efficacy, dosage, and tolerability. Survey respondents included 117 parents of children with epilepsy (including 53 with IS or LGS) who had administered CBD products to their children. Perceived efficacy and tolerability were similar across etiologic subgroups. Eighty-five percent of all parents reported a reduction in seizure frequency, and 14% reported complete seizure freedom. Epilepsy was characterized as highly refractory with median latency from epilepsy onset to CBD initiation of five years, during which the patient's seizures failed to improve after a median of eight antiseizure medication trials. The median duration and the median dosage of CBD exposure were 6.8months and 4.3mg/kg/day, respectively. Reported side effects were far less common during CBD exposure, with the exception of increased appetite (30%). A high proportion of respondents reported improvement in sleep (53%), alertness (71%), and mood (63%) during CBD therapy. Although this study suggests a potential role for CBD in the treatment of refractory childhood epilepsy including IS and LGS, it does not represent compelling evidence of efficacy or safety. From a methodological standpoint, this study is extraordinarily vulnerable to participation bias and limited by lack of blinded outcome ascertainment. Appropriately controlled clinical trials are essential to establish efficacy and safety.

The Therapeutic Options in Childhood Epilepsy: From Pharmaceuticals to Nutraceuticals

Epilepsy is one of the most common neurological disorders of childhood. Treatment of epileptic seizures is governed by weighing the benefit- risk of using anti-epileptic drugs. An important limitation of their use is that, in at least one third of patients, seizures are resistant to the available older and new-generation anti-epileptic drugs. This challenge makes the non-pharmacologic mode of treatment an attractive option. With the global demonstration of the therapeutic benefits of the ketogenic diet signaling a possible paradigm shift, evaluating its risk profile will help to establish its benefit-risk ratio. Multifaceted side effects of the diet have been reported in several studies but have not precluded its use. To promote its world-wide acceptability, its components should be modified to include locallyavailable food stuffs. The present review aims to highlight and compare the benefit-risk ratio of using anti-epileptic drugs and the ketogenic diet in the treatment of refractory childhood epilepsy.

Use of the modified Atkins diet for treatment of refractory childhood epilepsy: A randomized controlled trial

The aim of this study was to evaluate the efficacy of the modified Atkins diet in a randomized controlled trial in children with refractory epilepsy. Children aged 2-14 years who had daily seizures despite the appropriate use of at least three anticonvulsant drugs were enrolled. Children were randomized to receive either the modified Atkins diet or no dietary intervention for a period of 3 months. The ongoing anticonvulsant medications were continued unchanged in both the groups. Seizure control at 3 months was the primary end point. Analysis was intention to treat. Adverse effects of the diet were assessed by parental reports (ClinicalTrials.gov Identifier: NCT00836836). Among a total of 102 children, 50 were in the diet group and 52 in the control group. Four children discontinued the diet before the study end point, and three children in the control group were lost to follow-up. The mean seizure frequency at 3 months, expressed as a percentage of the baseline, was significantly less in the diet group: 59 ± 54 (95% confidence interval [CI] 44-74.5) versus 95.5 ± 48 (95% CI 82-109), p = 0.003. The proportion of children with >90% seizure reduction (30% vs. 7.7%, p = 0.005) and >50% seizure reduction was significantly higher in the diet group (52% vs. 11.5%, p < 0.001). Constipation was the most common adverse effect among children on the diet (23, 46%). The modified Atkins diet was found to be effective and well tolerated in children with drug-refractory epilepsy.

Efficacy and safety of the ketogenic diet in Chinese children

ObjectiveTo evaluate the efficacy and safety of the ketogenic diet (KD) treatment of refractory childhood epilepsy in China and determine which children are more likely to respond. MethodsBetween 2004 and 2011, we prospectively enrolled 317 children with refractory epilepsy for the KD treatment in Shenzhen Children's Hospital and followed up for at least a year. Outcome was measured by seizure frequencies before and after the diet, change in anticonvulsant use and adverse effects. We also evaluated influences of different variables (starting age, duration of epilepsy and underlying conditions) on the outcome. ResultsIntent-to-treat analysis showed that after 3, 6 and 12 months, 62.8%, 42.0% and 24.3% remained on the diet, 35.0%, 26.2% and 18.6% showed >50% seizure reduction, including 20.8%, 13.6% and 10.7% seizure free, respectively. Starting age may influence efficacy. The ≥10 age group showed worse response than the <10 age group, though the difference was statistically significant (p=0.039) at 3 month only. Other variables such as duration of epilepsy at the start of the diet, seizure types and aetiologies showed no significant influence on efficacy. Frequently reported complications included GI disturbance, food refusal and hypoproteinaemia. ConclusionsThe KD is a safe and efficacious therapy for intractable childhood epilepsy in Chinese children. The influence of age on efficacy is worth further investigation.

Pregabalin: Preliminary Experience in Intractable Childhood Epilepsy

Pregabalin is a new antiepileptic drug that acts at presynaptic calcium channels, modulating neurotransmitter release. We report on treating consecutive children with severe drug-resistant epilepsy in a prospective, open-label, add-on trial. Nineteen children (63% male) aged 4-15 years (mean, 9.7; S.D., 2.9) were included. Most (74%) had daily seizures that failed multiple drugs (mean, 5). Epilepsy was symptomatic in 58%, and 74% exhibited associated cognitive deficits. Seizures were mixed in nine (47%), and four (21%) manifested Lennox-Gastaut syndrome. Pregabalin was maintained at 150-300 mg/day. On pregabalin, one (6%) child became seizure-free, and seven (37%) had >50% seizure reduction. The percentage of children with daily seizures was reduced from 74% before pregabalin to 37% afterward (P < 0.002). Side effects were evident in six (32%) with somnolence, weight gain, dizziness, or behavioral change. The drug was withdrawn in five (26%) children for lack of efficacy, and in two (11%) for worsening of myoclonic epilepsy. We conclude that pregabalin is a useful addition in the treatment of refractory childhood epilepsy. The drug should be used with caution in myoclonic epilepsy. Controlled studies are needed to establish long-term efficacy and tolerability.

Ketogenic diet increases glutathione peroxidase activity in rat hippocampus.

Ketogenic diets have been used in the treatment of refractory childhood epilepsy for almost 80 years; however, we know little about the underlying biochemical basis of their action. In this study, we evaluate oxidative stress in different brain regions from Wistar rats fed a ketogenic diet. Cerebral cortex appears to have not been affected by this diet, and cerebellum presented a decrease in antioxidant capacity measured by a luminol oxidation assay without changes in antioxidant enzyme activities--glutathione peroxidase, catalase, and superoxide dismutase. In the hippocampus, however, we observed an increase in antioxidant activity accompanied by an increase of glutathione peroxidase (about 4 times) and no changes in lipoperoxidation levels. We suggest that the higher activity of this enzyme induced by ketogenic diet in hippocampus might contribute to protect this structure from neurodegenerative sequelae of convulsive disorders.

Surgical Treatment of Refractory Childhood Epilepsy with Special Reference to the Role of Pediatric Neurologists: Introductory R e m a r k s

Surgical Treatment of Refractory Childhood Epilepsy with Special Reference to the Role of Pediatric Neurologists: Introductory R e m a r k s

Clobazam as an Add-on Drug in the Treatment of Refractory Epilepsy of Childhood

We report the results of a double-blind cross-over study comparing clobazam and placebo in the treatment of refractory childhood epilepsy. Fifty-two percent of patients had greater than 50% reduction in their seizure frequency when taking the clobazam. During the placebo phase no patient recorded a greater than 50% reduction in seizure frequency. Sex, age, seizure type, intellect did not appear to differentiate clobazam responsive from nonresponsive patients. Only 2/21 patients had behavioral changes on the drug sufficiently severe to require the patient to drop out of the study prematurely. Drug interactions between clobazam and the other anticonvulsant medicines did not occur.