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Medicina 2019Antiepileptic drugs are the first treatment option in patients with epilepsy. Drugs developed after 2000 are known as third generation antiepileptic drugs. These... (Review)
Review
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.
Topics: Anticonvulsants; Drug Interactions; Epilepsy; Humans; Status Epilepticus
PubMed: 31603844
DOI: No ID Found -
Revista de Neurologia Oct 2022Status epilepticus is defined as the situation resulting from the failure of the mechanisms responsible for terminating an epileptic seizure. In 2015, an operational... (Review)
Review
INTRODUCTION
Status epilepticus is defined as the situation resulting from the failure of the mechanisms responsible for terminating an epileptic seizure. In 2015, an operational concept was adopted internationally in which two times are identified: a first time, at which treatment must begin (five minutes for convulsive status, 10-15 minutes for focal and non-convulsive status); and a second time, after which there is considered to be a high risk of subsequent sequelae (30 minutes in the case of the convulsive). It occurs in 3-42/100,000 children per year, who are refractory or super-refractory in 10-40% of cases.
DEVELOPMENT
This article will review the different therapeutic options for status, from early treatment at home to the different first-line (benzodiazepines), second-line (phenobarbital, valproic acid, phenytoin, levetiracetam and lacosamide) or third-line treatments, which include both pharmacological (anaesthetics, propofol, ketamine, lidocaine, topiramate, brivaracetam or perampanel) and non-pharmacological (ketogenic diet, immunomodulatory treatments or epilepsy surgery) therapies.
CONCLUSIONS
Early identification and treatment of a prolonged crisis are essential to prevent progression to status. Although with fewer sequelae than in adults, status epilepticus in children represents a cause of mortality of up to 3-5%, while 25% of them will develop subsequent epilepsy, as well as a considerable percentage of neurological sequelae.
Topics: Adult; Anesthetics; Anticonvulsants; Benzodiazepines; Child; Epilepsy; Humans; Ketamine; Lacosamide; Levetiracetam; Lidocaine; Phenobarbital; Phenytoin; Propofol; Seizures; Status Epilepticus; Topiramate; Valproic Acid
PubMed: 36218253
DOI: 10.33588/rn.7508.2022196 -
Journal of Epilepsy Research Dec 2020The definition of status epilepticus (SE) was revised recently in accordance with the various evidences of neuronal injury and changes in clinical settings. Currently,... (Review)
Review
The definition of status epilepticus (SE) was revised recently in accordance with the various evidences of neuronal injury and changes in clinical settings. Currently, the most acceptable duration of continuous seizure activity is 5 minutes. In 2015, the International League Against Epilepsy Task Force, which was convened to develop a definition and classification of SE, presented a new classification based on four axes: 1) semiology, 2) etiology, 3) electroencephalogram (EEG) correlates, and 4) age. The essential element of nonconvulsive SE (NCSE) is the presence of neurological abnormalities induced by a prolonged epileptic process. The definition of refractory SE involves either clinical or electrographic seizures that persist after adequate doses of an initial benzodiazepine and acceptable second-line antiseizure drugs. The use of EEG is critical in the diagnosis and treatment of NCSE. However, there are a wide range of EEG abnormalities in NCSE. Both the Neurocritical Care Society and the American Epilepsy Society have suggested a paradigm for treating convulsive SE (CSE). The first-line treatment of CSE with benzodiazepine is well-established. The second-line treatment comprises intravenous (IV) doses of fosphenytoin (phenytoin), valproate, phenobarbital, levetiracetam, or midazolam. Although fosphenytoin (phenytoin) and valproate are commonly used in NCSE, the effectiveness of antiepileptic drugs (AEDs) on NCSE has not been well studied. New AEDs such as IV levetiracetam and lacosamide can also be used to treat NCSE with fewer side effects and drug-drug interactions. For refractory SE, general anesthesia with IV midazolam, propofol, pentobarbital, or thiopental could be applied. Use of ketamine, megadose phenobarbital therapy, and multiple combinations of various AEDs including high doses of oral AEDs can also be considered. New-onset refractory status epilepticus (NORSE) and its subcategory, febrile infection-related epilepsy syndrome, involve autoimmune processes. AEDs alone are poorly effective in the treatment of SE in autoimmune encephalitis. Immunotherapy such as steroids, immunoglobulin, rituximab, or tocilizumab can be effective.
PubMed: 33659195
DOI: 10.14581/jer.20008 -
CNS Drugs Oct 2022The developmental and epileptic encephalopathies encompass a group of rare syndromes characterised by severe drug-resistant epilepsy with onset in childhood and... (Review)
Review
The developmental and epileptic encephalopathies encompass a group of rare syndromes characterised by severe drug-resistant epilepsy with onset in childhood and significant neurodevelopmental comorbidities. The latter include intellectual disability, developmental delay, behavioural problems including attention-deficit hyperactivity disorder and autism spectrum disorder, psychiatric problems including anxiety and depression, speech impairment and sleep problems. Classical examples of developmental and epileptic encephalopathies include Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex. The mainstay of treatment is with multiple anti-seizure medications (ASMs); however, the ASMs themselves can be associated with psychobehavioural adverse events, and effects (negative or positive) on cognition and sleep. We have performed a targeted literature review of ASMs commonly used in the treatment of developmental and epileptic encephalopathies to discuss the latest evidence on their effects on behaviour, mood, cognition, sedation and sleep. The ASMs include valproate (VPA), clobazam, topiramate (TPM), cannabidiol (CBD), fenfluramine (FFA), levetiracetam (LEV), brivaracetam (BRV), zonisamide (ZNS), perampanel (PER), ethosuximide, stiripentol, lamotrigine (LTG), rufinamide, vigabatrin, lacosamide (LCM) and everolimus. Bromide, felbamate and other sodium channel ASMs are discussed briefly. Overall, the current evidence suggest that LEV, PER and to a lesser extent BRV are associated with psychobehavioural adverse events including aggressiveness and irritability; TPM and to a lesser extent ZNS are associated with language impairment and cognitive dulling/memory problems. Patients with a history of behavioural and psychiatric comorbidities may be more at risk of developing psychobehavioural adverse events. Topiramate and ZNS may be associated with negative effects in some aspects of cognition; CBD, FFA, LEV, BRV and LTG may have some positive effects, while the remaining ASMs do not appear to have a detrimental effect. All the ASMs are associated with sedation to a certain extent, which is pronounced during uptitration. Cannabidiol, PER and pregabalin may be associated with improvements in sleep, LTG is associated with insomnia, while VPA, TPM, LEV, ZNS and LCM do not appear to have detrimental effects. There was variability in the extent of evidence for each ASM: for many first-generation and some second-generation ASMs, there is scant documented evidence; however, their extensive use suggests favourable tolerability and safety (e.g. VPA); second-generation and some third-generation ASMs tend to have the most robust evidence documented over several years of use (TPM, LEV, PER, ZNS, BRV), while evidence is still being generated for newer ASMs such as CBD and FFA. Finally, we discuss how a variety of factors can affect mood, behaviour and cognition, and untangling the associations between the effects of the underlying syndrome and those of the ASMs can be challenging. In particular, there is enormous heterogeneity in cognitive, behavioural and developmental impairments that is complex and can change naturally over time; there is a lack of standardised instruments for evaluating these outcomes in developmental and epileptic encephalopathies, with a reliance on subjective evaluations by proxy (caregivers); and treatment regimes are complex involving multiple ASMs as well as other drugs.
Topics: Autism Spectrum Disorder; Bromides; Cannabidiol; Clobazam; Cognition; Ethosuximide; Everolimus; Felbamate; Fenfluramine; Humans; Lacosamide; Lamotrigine; Levetiracetam; Pregabalin; Spasms, Infantile; Sulfides; Topiramate; Valproic Acid; Vigabatrin; Zinc Compounds; Zonisamide
PubMed: 36194365
DOI: 10.1007/s40263-022-00955-9 -
Nature Communications Jun 2023Voltage-gated sodium (Na) channels are targeted by a number of widely used and investigational drugs for the treatment of epilepsy, arrhythmia, pain, and other...
Voltage-gated sodium (Na) channels are targeted by a number of widely used and investigational drugs for the treatment of epilepsy, arrhythmia, pain, and other disorders. Despite recent advances in structural elucidation of Na channels, the binding mode of most Na-targeting drugs remains unknown. Here we report high-resolution cryo-EM structures of human Na1.7 treated with drugs and lead compounds with representative chemical backbones at resolutions of 2.6-3.2 Å. A binding site beneath the intracellular gate (site BIG) accommodates carbamazepine, bupivacaine, and lacosamide. Unexpectedly, a second molecule of lacosamide plugs into the selectivity filter from the central cavity. Fenestrations are popular sites for various state-dependent drugs. We show that vinpocetine, a synthetic derivative of a vinca alkaloid, and hardwickiic acid, a natural product with antinociceptive effect, bind to the III-IV fenestration, while vixotrigine, an analgesic candidate, penetrates the IV-I fenestration of the pore domain. Our results permit building a 3D structural map for known drug-binding sites on Na channels summarized from the present and previous structures.
Topics: Humans; Analgesics; Carbamazepine; Lacosamide; Pain; Protein Domains; Voltage-Gated Sodium Channels; Voltage-Gated Sodium Channel Blockers
PubMed: 37270609
DOI: 10.1038/s41467-023-38942-3 -
Current Opinion in Oncology Nov 2022A concise review of recent findings in brain tumor-related epilepsy (BTRE), with focus on the effect of antitumor treatment on seizure control and the management of... (Review)
Review
PURPOSE OF REVIEW
A concise review of recent findings in brain tumor-related epilepsy (BTRE), with focus on the effect of antitumor treatment on seizure control and the management of antiepileptic drugs (AEDs).
RECENT FINDINGS
Isocitrate dehydrogenase mutation and its active metabolite d -2-hydroxyglutarate seem important contributing factors to epileptogenesis in BTRE. A beneficial effect of antitumor treatment (i.e. surgery, radiotherapy, and chemotherapy) on seizure control has mainly been demonstrated in low-grade glioma. AED prophylaxis in seizure-naïve BTRE patients is not recommended, but AED treatment should be initiated after a first seizure has occurred. Comparative efficacy randomized controlled trials (RCTs) are currently lacking, but second-generation AED levetiracetam seems the preferred choice in BTRE. Levetiracetam lacks significant drug-drug interactions, has shown favorable efficacy compared to valproic acid in BTRE, generally causes no hematological or neurocognitive functioning adverse effects, but caution should be exercised with regard to psychiatric adverse effects. Potential add-on AEDs in case of uncontrolled seizures include lacosamide, perampanel, and valproic acid. Ultimately, in the end-of-life phase when oral intake of medication is hampered, benzodiazepines via nonoral administration routes are potential alternatives.
SUMMARY
Management of seizures in BTRE is complex and with currently available evidence levetiracetam seems the preferred choice. Comparative efficacy RCTs in BTRE are warranted.
Topics: Anticonvulsants; Benzodiazepines; Brain Neoplasms; Epilepsy; Humans; Isocitrate Dehydrogenase; Lacosamide; Levetiracetam; Seizures; Valproic Acid
PubMed: 35838207
DOI: 10.1097/CCO.0000000000000876 -
Brain : a Journal of Neurology Nov 2022Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with...
Brain voltage-gated sodium channel NaV1.1 (SCN1A) loss-of-function variants cause the severe epilepsy Dravet syndrome, as well as milder phenotypes associated with genetic epilepsy with febrile seizures plus. Gain of function SCN1A variants are associated with familial hemiplegic migraine type 3. Novel SCN1A-related phenotypes have been described including early infantile developmental and epileptic encephalopathy with movement disorder, and more recently neonatal presentations with arthrogryposis. Here we describe the clinical, genetic and functional evaluation of affected individuals. Thirty-five patients were ascertained via an international collaborative network using a structured clinical questionnaire and from the literature. We performed whole-cell voltage-clamp electrophysiological recordings comparing sodium channels containing wild-type versus variant NaV1.1 subunits. Findings were related to Dravet syndrome and familial hemiplegic migraine type 3 variants. We identified three distinct clinical presentations differing by age at onset and presence of arthrogryposis and/or movement disorder. The most severely affected infants (n = 13) presented with congenital arthrogryposis, neonatal onset epilepsy in the first 3 days of life, tonic seizures and apnoeas, accompanied by a significant movement disorder and profound intellectual disability. Twenty-one patients presented later, between 2 weeks and 3 months of age, with a severe early infantile developmental and epileptic encephalopathy and a movement disorder. One patient presented after 3 months with developmental and epileptic encephalopathy only. Associated SCN1A variants cluster in regions of channel inactivation associated with gain of function, different to Dravet syndrome variants (odds ratio = 17.8; confidence interval = 5.4-69.3; P = 1.3 × 10-7). Functional studies of both epilepsy and familial hemiplegic migraine type 3 variants reveal alterations of gating properties in keeping with neuronal hyperexcitability. While epilepsy variants result in a moderate increase in action current amplitude consistent with mild gain of function, familial hemiplegic migraine type 3 variants induce a larger effect on gating properties, in particular the increase of persistent current, resulting in a large increase of action current amplitude, consistent with stronger gain of function. Clinically, 13 out of 16 (81%) gain of function variants were associated with a reduction in seizures in response to sodium channel blocker treatment (carbamazepine, oxcarbazepine, phenytoin, lamotrigine or lacosamide) without evidence of symptom exacerbation. Our study expands the spectrum of gain of function SCN1A-related epilepsy phenotypes, defines key clinical features, provides novel insights into the underlying disease mechanisms between SCN1A-related epilepsy and familial hemiplegic migraine type 3, and identifies sodium channel blockers as potentially efficacious therapies. Gain of function disease should be considered in early onset epilepsies with a pathogenic SCN1A variant and non-Dravet syndrome phenotype.
Topics: Humans; Arthrogryposis; Epilepsies, Myoclonic; Epilepsy; Gain of Function Mutation; Migraine with Aura; Movement Disorders; NAV1.1 Voltage-Gated Sodium Channel; Phenotype; Spasms, Infantile; Infant, Newborn; Infant
PubMed: 35696452
DOI: 10.1093/brain/awac210 -
Journal of the Neurological Sciences Mar 2023Epilepsy is the most common symptom in patients with brain tumors. The shared genetic, molecular, and cellular mechanisms between tumorigenesis and epileptogenesis... (Review)
Review
Epilepsy is the most common symptom in patients with brain tumors. The shared genetic, molecular, and cellular mechanisms between tumorigenesis and epileptogenesis represent 'two sides of the same coin'. These include augmented neuronal excitatory transmission, impaired inhibitory transmission, genetic mutations in the BRAF, IDH, and PIK3CA genes, inflammation, hemodynamic impairments, and astrocyte dysfunction, which are still largely unknown. Low-grade developmental brain tumors are those most commonly associated with epilepsy. Given this strict relationship, drugs able to target both seizures and tumors would be of extreme clinical usefulness. In this regard, anti-seizure medications (ASMs) are optimal candidates as they have well-characterized effects and safety profiles, do not increase the risk of developing cancer, and already offer well-defined seizure control. The most important ASMs showing preclinical and clinical efficacy are brivaracetam, lacosamide, perampanel, and especially valproic acid and levetiracetam. However, the data quality is low or limited to preclinical studies, and results are sometimes conflicting. Future trials with a prospective, randomized, and controlled design accounting for different prognostic factors will help clarify the role of these ASMs and the clinical setting in which they might be used. In conclusion, brain tumor-related epilepsies are clear examples of how close, multidisciplinary collaborations among investigators with different expertise are warranted for pursuing scientific knowledge and, more importantly, for the well-being of patients needing targeted and effective therapies.
Topics: Humans; Anticonvulsants; Epilepsy; Levetiracetam; Valproic Acid; Brain Neoplasms
PubMed: 36842341
DOI: 10.1016/j.jns.2023.120584 -
Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.The Cochrane Database of Systematic... Apr 2022This is an updated version of the original Cochrane Review published in 2017. Epilepsy is a common neurological condition with a worldwide prevalence of around 1%.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an updated version of the original Cochrane Review published in 2017. Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term remission from seizures, and most achieve that remission shortly after starting antiepileptic drug treatment. Most people with epilepsy are treated with a single antiepileptic drug (monotherapy) and current guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom for adults and children recommend carbamazepine or lamotrigine as first-line treatment for focal onset seizures and sodium valproate for generalised onset seizures; however, a range of other antiepileptic drug (AED) treatments are available, and evidence is needed regarding their comparative effectiveness in order to inform treatment choices.
OBJECTIVES
To compare the time to treatment failure, remission and first seizure of 12 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, eventrate, zonisamide, eslicarbazepine acetate, lacosamide) currently used as monotherapy in children and adults with focal onset seizures (simple focal, complex focal or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus).
SEARCH METHODS
For the latest update, we searched the following databases on 12 April 2021: the Cochrane Register of Studies (CRS Web), which includes PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Epilepsy Group Specialised Register and MEDLINE (Ovid, 1946 to April 09, 2021). We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators and experts in the field.
SELECTION CRITERIA
We included randomised controlled trials of a monotherapy design in adults or children with focal onset seizures or generalised onset tonic-clonic seizures (with or without other generalised seizure types).
DATA COLLECTION AND ANALYSIS
This was an individual participant data (IPD) and network meta-analysis (NMA) review. Our primary outcome was 'time to treatment failure', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', and 'time to first seizure post-randomisation'. We performed frequentist NMA to combine direct evidence with indirect evidence across the treatment network of 12 drugs. We investigated inconsistency between direct 'pairwise' estimates and NMA results via node splitting. Results are presented as hazard ratios (HRs) with 95% confidence intervals (CIs) and we assessed the certainty of the evidence using the CiNeMA approach, based on the GRADE framework. We have also provided a narrative summary of the most commonly reported adverse events.
MAIN RESULTS
IPD were provided for at least one outcome of this review for 14,789 out of a total of 22,049 eligible participants (67% of total data) from 39 out of the 89 eligible trials (43% of total trials). We could not include IPD from the remaining 50 trials in analysis for a variety of reasons, such as being unable to contact an author or sponsor to request data, data being lost or no longer available, cost and resources required to prepare data being prohibitive, or local authority or country-specific restrictions. No IPD were available from a single trial of eslicarbazepine acetate, so this AED could not be included in the NMA. Network meta-analysis showed high-certainty evidence that for our primary outcome, 'time to treatment failure', for individuals with focal seizures; lamotrigine performs better than most other treatments in terms of treatment failure for any reason and due to adverse events, including the other first-line treatment carbamazepine; HRs (95% CIs) for treatment failure for any reason for lamotrigine versus: eventrate 1.01 (0.88 to 1.20), zonisamide 1.18 (0.96 to 1.44), lacosamide 1.19 (0.90 to 1.58), carbamazepine 1.26 (1.10 to 1.44), oxcarbazepine 1.30 (1.02 to 1.66), sodium valproate 1.35 (1.09 to 1.69), phenytoin 1.44 (1.11 to 1.85), topiramate 1.50 (1.23 to 1.81), gabapentin 1.53 (1.26 to 1.85), phenobarbitone 1.97 (1.45 to 2.67). No significant difference between lamotrigine and eventrate was shown for any treatment failure outcome, and both AEDs seemed to perform better than all other AEDs. For people with generalised onset seizures, evidence was more limited and of moderate certainty; no other treatment performed better than first-line treatment sodium valproate, but there were no differences between sodium valproate, lamotrigine or eventrate in terms of treatment failure; HRs (95% CIs) for treatment failure for any reason for sodium valproate versus: lamotrigine 1.06 (0.81 to 1.37), eventrate 1.13 (0.89 to 1.42), gabapentin 1.13 (0.61 to 2.11), phenytoin 1.17 (0.80 to 1.73), oxcarbazepine 1.24 (0.72 to 2.14), topiramate 1.37 (1.06 to 1.77), carbamazepine 1.52 (1.18 to 1.96), phenobarbitone 2.13 (1.20 to 3.79), lacosamide 2.64 (1.14 to 6.09). Network meta-analysis also showed high-certainty evidence that for secondary remission outcomes, few notable differences were shown for either seizure type; for individuals with focal seizures, carbamazepine performed better than gabapentin (12-month remission) and sodium valproate (six-month remission). No differences between lamotrigine and any AED were shown for individuals with focal seizures, or between sodium valproate and other AEDs for individuals with generalised onset seizures. Network meta-analysis also showed high- to moderate-certainty evidence that, for 'time to first seizure,' in general, the earliest licensed treatments (phenytoin and phenobarbitone) performed better than the other treatments for individuals with focal seizures; phenobarbitone performed better than both first-line treatments carbamazepine and lamotrigine. There were no notable differences between the newer drugs (oxcarbazepine, topiramate, gabapentin, eventrate, zonisamide and lacosamide) for either seizure type. Generally, direct evidence (where available) and network meta-analysis estimates were numerically similar and consistent with confidence intervals of effect sizes overlapping. There was no important indication of inconsistency between direct and network meta-analysis results. The most commonly reported adverse events across all drugs were drowsiness/fatigue, headache or migraine, gastrointestinal disturbances, dizziness/faintness and rash or skin disorders; however, reporting of adverse events was highly variable across AEDs and across studies.
AUTHORS' CONCLUSIONS
High-certainty evidence demonstrates that for people with focal onset seizures, current first-line treatment options carbamazepine and lamotrigine, as well as newer drug eventrate, show the best profile in terms of treatment failure and seizure control as first-line treatments. For people with generalised tonic-clonic seizures (with or without other seizure types), current first-line treatment sodium valproate has the best profile compared to all other treatments, but lamotrigine and eventrate would be the most suitable alternative first-line treatments, particularly for those for whom sodium valproate may not be an appropriate treatment option. Further evidence from randomised controlled trials recruiting individuals with generalised tonic-clonic seizures (with or without other seizure types) is needed.
Topics: Adult; Anticonvulsants; Child; Epilepsies, Partial; Epilepsy; Humans; Network Meta-Analysis; Phenytoin
PubMed: 35363878
DOI: 10.1002/14651858.CD011412.pub4