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[New antiepileptic drugs].
Vidaurre, J, Herbst, J
Medicina. 2019;:48-53
Abstract
Antiepileptic drugs are the first treatment option in patients with epilepsy. Drugs developed after 2000 are known as third generation antiepileptic drugs. These medications offer new mechanisms of action and favorable pharmacokinetics, decreasing the occurrence of side effects and drug-drug interactions. Broad spectrum antiepileptic drugs, such as brivaracetam and clobazam are good choices for generalized tonic colonic seizures and are well tolerated.New sodium channel blockers such as lacosamide and eslicarbazepine, have a more "benign" side effect profile than the first or second generation of sodium channel blockers. These new drugs are useful therapies in patients with epilepsy of difficult control. Cannabidiol and fenfluramine are useful in the treatment of Dravet or Lennox Gastaut syndrome. Allopregnenolona and ganaxolone showed good efficacy in status epilepticus and could play an important future role in this clinical scenario.
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Valproate decreases vitamin D levels in pediatric patients with epilepsy.
Xu, Z, Jing, X, Li, G, Sun, J, Guo, H, Hu, Y, Sun, F, Wen, X, Chen, F, Wang, T, et al
Seizure. 2019;:60-65
Abstract
PURPOSE To compare Vitamin D (Vit D) levels in children with epilepsy on valproate monotherapy with healthy controls. METHODS A meta-analysis performed on articles identified from PubMed and Web of Science online databases evaluated using National Institute of Health National Heart, Lung, and Blood Institute Study Quality Assessment Tools. Subgroup analyses and publication bias assessments were also performed. RESULTS Eleven publications were eligible based on inclusion/exclusion criteria for the meta-analysis. Results noted a decrease in the mean Vit D level in children with epilepsy on valproate monotherapy compared with healthy children with a Standard Mean Difference = -0.313 [-0.457, -0.169]. Cumulative meta-analysis showed progressive negative effect of valproate therapy on Vit D levels across time. Other antiepileptic medications caused a similar effect on Vit D status. There was no evidence of publication bias in the analyses. Type of study design and country of origin introduced heterogeneities into the meta-analyses. CONCLUSION This meta-analysis provides evidence that long-term therapy with valproate causes a decrease in Vit D levels in children. Therefore, in children with a seizure disorder on long-term valproate therapy, 25-OH-Vit D levels should be monitored and appropriate supplementation implemented if levels are deficient.
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The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: A common epileptic encephalopathy.
Coughlin, CR, Swanson, MA, Spector, E, Meeks, NJL, Kronquist, KE, Aslamy, M, Wempe, MF, van Karnebeek, CDM, Gospe, SM, Aziz, VG, et al
Journal of inherited metabolic disease. 2019;(2):353-361
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Abstract
Pyridoxine dependent epilepsy (PDE) is a treatable epileptic encephalopathy characterized by a positive response to pharmacologic doses of pyridoxine. Despite seizure control, at least 75% of individuals have intellectual disability and developmental delay. Current treatment paradigms have resulted in improved cognitive outcomes emphasizing the importance of an early diagnosis. As genetic testing is increasingly accepted as first tier testing for epileptic encephalopathies, we aimed to provide a comprehensive overview of ALDH7A1 mutations that cause PDE. The genotypes, ethnic origin and reported gender was collected from 185 subjects with a diagnosis of PDE. The population frequency for the variants in this report and the existing literature were reviewed in the Genome Aggregation Database (gnomAD). Novel variants identified in population databases were also evaluated through in silico prediction software and select variants were over-expressed in an E.coli-based expression system to measure α-aminoadipic semialdehyde dehydrogenase activity and production of α-aminoadipic acid. This study adds 47 novel variants to the literature resulting in a total of 165 reported pathogenic variants. Based on this report, in silico predictions, and general population data, we estimate an incidence of approximately 1:64,352 live births. This report provides a comprehensive overview of known ALDH7A1 mutations that cause PDE, and suggests that PDE may be more common than initially estimated. Due to the relative high frequency of the disease, the likelihood of under-diagnosis given the wide clinical spectrum and limited awareness among clinicians as well as the cognitive improvement noted with early treatment, newborn screening for PDE may be warranted.
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Update on the treatment of vitamin B6 dependent epilepsies.
Mastrangelo, M, Cesario, S
Expert review of neurotherapeutics. 2019;(11):1135-1147
Abstract
Introduction: Vitamin B6 dependent epilepsies are a group of treatable diseases (ALDH7A1 deficiency, PNPO deficiency, PLP binding protein deficiency, hyperprolinaemia type II and hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects) responding to pyridoxine or pyridoxal-5I-phosphate. Areas covered: A critical review was conducted on the therapeutic management of all the reported patients with genetically confirmed diagnoses of diseases affecting vitamin B6 metabolism and presenting with pyridoxine or pyridoxal-5I-phosphate dependent-seizures. Data about safety and efficacy were analyzed as well as the management of supplementation with pyridoxine or pyridoxal-5I-phosphate both in the acute phases and in the maintenance therapies. The authors also analyzed alternative therapeutic strategies for ALDH7A1 deficiency (lysine-restricted diet, arginine supplementation, oligonucleotide antisense therapy, upstream inhibition of aminoadipic semialdehyde synthase). Expert opinion: The administration of pyridoxine or pyridoxal-5I-phosphate should be considered in all intractable seizures also beyond the first year of life. Lysine restricted diet and arginine supplementation should be introduced in all the confirmed ALDH7A1 deficient patients. Pre or post-natal supplementation with pyridoxine should be given in familial cases until an eventual molecular genetic disconfirmation. Minor data about alternative therapies are available for other disorders of vitamin B6 metabolism.
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Ketogenic dietary therapies for epilepsy and beyond.
deCampo, DM, Kossoff, EH
Current opinion in clinical nutrition and metabolic care. 2019;(4):264-268
Abstract
PURPOSE OF REVIEW The ketogenic diet, a high-fat, low-carbohydrate therapy, has become an established treatment for pediatric epilepsy since 1921. There has recently been an increase in important studies on the ketogenic diet, and this review will highlight the most recent in order to provide a synthesis of where this field stands today. RECENT FINDINGS Clinical studies continue to support the use of ketogenic diets in epilepsy, with more recent trials supporting its use in adults. Clinical recommendations published in 2018 based on a decade of practice and research, guide implementation and management of the ketogenic diet in epilepsy. One of the most rapidly growing 'indications' includes the role of ketogenic diets in status epilepticus. An exciting new potential mechanism for how the ketogenic diet exerts its antiseizure effects is through changing the composition of the gut microbiome. Lastly, ketogenic diets are being applied to a range of neurological conditions from autism to Alzheimer's disease. SUMMARY The ketogenic diet is a versatile therapy, with growing clinical evidence and guidelines, widely used for the treatment of epilepsy. New indications include status epilepticus and neurological conditions other than epilepsy.
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Comparison of the relapse rates in seizure-free patients in whom antiepileptic therapy was discontinued and those in whom the therapy was continued: A meta-analysis.
Wang, J, Huang, P, Song, Z
Epilepsy & behavior : E&B. 2019;(Pt A):106577
Abstract
About 70% of patients with epilepsy can be seizure-free with an appropriate treatment. When the seizures are under control, discontinuation of the antiepileptic drugs (AEDs) can help avoid their side effects; however, it may increase the risk of relapse. Some studies have compared the relapse rates between patients in whom AEDs have been continued and those in whom AEDs have been discontinued. However, it is not clear whether AED discontinuation causes a higher seizure recurrence rate. This meta-analysis aimed mainly to determine whether the seizure recurrence rate was different between seizure-free patients in whom AEDs were continued and those in whom AEDs were discontinued. The I2 value was used for assessing the heterogeneity; the Mantel-Haenszel test was used to calculate the odds ratios (ORs) with 95% confidence intervals (CIs). Seven cohort studies and randomized controlled trials (RCTs) met the inclusion criteria. The study quality evaluation was performed respectively using the Newcastle-Ottawa Scale and the Jadad scale. A total of 1253 patients were included. The relapse rate was higher in patients in whom AEDs were discontinued than in those in whom the AED treatment was continued. Furthermore, we also compared the epilepsy recurrence rates after AED discontinuation between seizure-free patients who were on monotherapy with different AEDs (carbamazepine, phenytoin, sodium valproate, and phenobarbitone/primidone). Four studies and 625 patients were included in this analysis. The epilepsy recurrence rates did not significantly differ between the patients on different AED treatment.
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History of dietary treatment from Wilder's hypothesis to the first open studies in the 1920s.
Höhn, S, Dozières-Puyravel, B, Auvin, S
Epilepsy & behavior : E&B. 2019;(Pt A):106588
Abstract
In the ketogenic diet (KD) history, Wilder is often mentioned as the first author to report on the use of KD for patients with epilepsy. Our article aimed to understand how Wilder formulated the hypothesis of the KD effectiveness for patients with epilepsy, and how the KD was used and spread in the 1920s. In 1921, Wilder published two articles on the effects of ketonemia on epilepsy. He first reported on the interest of fasting for patients with epilepsy, suggesting that the benefits of fasting on seizures might be dependent on ketonemia. He then hypothesized that equally good results could be obtained with a KD, very rich in fat and very low in carbohydrate, which would provoke ketogenesis, and observed the effects of this diet on three patients for the first time. Following the publication of Wilder articles, 9 papers on KD were published during the 1920s, involving more than 400 patients with epilepsy. Ketogenic diet therapies (KDT) are now evidence-based treatments of epilepsy. Available experimental data do not confirm the role of ketosis as the unique mechanism of the KD. The KD is still explored to understand all the underlying mechanisms.
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Anticonvulsant Essential Oils and Their Relationship with Oxidative Stress in Epilepsy.
da Fonsêca, DV, da Silva Maia Bezerra Filho, C, Lima, TC, de Almeida, RN, de Sousa, DP
Biomolecules. 2019;(12)
Abstract
Epilepsy is a most disabling neurological disorder affecting all age groups. Among the various mechanisms that may result in epilepsy, neuronal hyperexcitability and oxidative injury produced by an excessive formation of free radicals may play a role in the development of this pathology. Therefore, new treatment approaches are needed to address resistant conditions that do not respond fully to current antiepileptic drugs. This paper reviews studies on the anticonvulsant activities of essential oils and their chemical constituents. Data from studies published from January 2011 to December 2018 was selected from the PubMed database for examination. The bioactivity of 19 essential oils and 16 constituents is described. Apiaceae and Lamiaceae were the most promising botanical families due to the largest number of reports about plant species from these families that produce anticonvulsant essential oils. Among the evaluated compounds, β-caryophyllene, borneol, eugenol and nerolidol were the constituents that presented antioxidant properties related to anticonvulsant action. These data show the potential of these natural products as health promoting agents and use against various types of seizure disorders. Their properties on oxidative stress may contribute to the control of this neurological condition. However, further studies on the toxicological profile and mechanism of action of essential oils are needed.
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Antiepileptic Drug Treatment of Epilepsy in Children.
Moosa, ANV
Continuum (Minneapolis, Minn.). 2019;(2):381-407
Abstract
PURPOSE OF REVIEW The treatment of epilepsy in children is highly individualized at each and every major step in the management. This review examines various factors that modify the treatment from the point of initiation of therapy to the decision to stop an antiepileptic drug (AED). RECENT FINDINGS AED therapy leads to seizure freedom in about 70% of all children with epilepsy. AED initiation could be delayed until a second seizure in most children and may be avoided altogether in many children with self-limited childhood focal epilepsies. Three key factors influence the choice of AED: seizure type(s), efficacy of the drug for the seizure type, and the side effect profile of the drug(s). For epileptic spasms, steroids and vigabatrin are the most effective treatment options. For absence seizures, ethosuximide and valproic acid are superior to lamotrigine. For focal seizures, many newer AEDs have favorable side effect profiles with efficacy comparable to older-generation drugs. For generalized epilepsies, valproic acid remains the most effective drug for a broad range of seizure types. Genetic and metabolic etiologies may guide unique treatment choices in some children. After 2 years or more of seizure freedom, if the recurrence risk after AED withdrawal is acceptable, slow weaning of AEDs should be done over the span of 6 weeks or longer. After discontinuation, about 70% of patients remain seizure free, and of those with recurrence, the majority achieve seizure control with restarting an AED. When treatment with two or more AEDs fails, other treatment opportunities for drug-resistant epilepsy, including epilepsy surgery, vagal nerve stimulation, and dietary therapies should be considered. SUMMARY Carefully selected medical therapy guided by seizure type and AED characteristics is effective in more than two-thirds of children with epilepsy.
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The current and emerging therapeutic approaches in drug-resistant epilepsy management.
Mehdizadeh, A, Barzegar, M, Negargar, S, Yahyavi, A, Raeisi, S
Acta neurologica Belgica. 2019;(2):155-162
Abstract
Epilepsy is a neurologic disorder consisting of recurrent spontaneous seizures. Antiepileptic drugs administration is the most commonly used therapeutic strategy in the management of epilepsy. However, 20-30% of epilepsy patients have seizure episodes that are not controlled by these medicines (drug-resistant epilepsy). The management of drug-resistant epilepsy, especially in the children, is challenging and can cause economic and social problems, and lower the patients' quality of life, cognition, and mood. Several therapeutic approaches for drug-resistant epilepsy are available including surgical methods, neurostimulation treatments, and diet therapies which lead to diminishing the epileptic seizures. An increasing number of novel and potential therapeutic approaches such as gene therapy, gene editing, cell therapy, exosome therapy, and molecular network targeting have also been explored. The present study is aimed to review these current and emerging therapeutic approaches for drug-resistant epilepsy.