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The New England Journal of Medicine Nov 2019The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied. (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied.
METHODS
In a randomized, blinded, adaptive trial, we compared the efficacy and safety of three intravenous anticonvulsive agents - levetiracetam, fosphenytoin, and valproate - in children and adults with convulsive status epilepticus that was unresponsive to treatment with benzodiazepines. The primary outcome was absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication. The posterior probabilities that each drug was the most or least effective were calculated. Safety outcomes included life-threatening hypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence, and death.
RESULTS
A total of 384 patients were enrolled and randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118), or valproate (121). Reenrollment of patients with a second episode of status epilepticus accounted for 16 additional instances of randomization. In accordance with a prespecified stopping rule for futility of finding one drug to be superior or inferior, a planned interim analysis led to the trial being stopped. Of the enrolled patients, 10% were determined to have had psychogenic seizures. The primary outcome of cessation of status epilepticus and improvement in the level of consciousness at 60 minutes occurred in 68 patients assigned to levetiracetam (47%; 95% credible interval, 39 to 55), 53 patients assigned to fosphenytoin (45%; 95% credible interval, 36 to 54), and 56 patients assigned to valproate (46%; 95% credible interval, 38 to 55). The posterior probability that each drug was the most effective was 0.41, 0.24, and 0.35, respectively. Numerically more episodes of hypotension and intubation occurred in the fosphenytoin group and more deaths occurred in the levetiracetam group than in the other groups, but these differences were not significant.
CONCLUSIONS
In the context of benzodiazepine-refractory convulsive status epilepticus, the anticonvulsant drugs levetiracetam, fosphenytoin, and valproate each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients, and the three drugs were associated with similar incidences of adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ESETT ClinicalTrials.gov number, NCT01960075.).
Topics: Adolescent; Adult; Anticonvulsants; Benzodiazepines; Child; Child, Preschool; Double-Blind Method; Drug Resistance; Female; Humans; Hypotension; Infusions, Intravenous; Injections, Intramuscular; Levetiracetam; Male; Middle Aged; Phenytoin; Status Epilepticus; Valproic Acid; Young Adult
PubMed: 31774955
DOI: 10.1056/NEJMoa1905795 -
Pharmacological Reviews Jul 2020Epilepsy is a chronic neurologic disorder that affects over 70 million people worldwide. Despite the availability of over 20 antiseizure drugs (ASDs) for symptomatic... (Review)
Review
Epilepsy is a chronic neurologic disorder that affects over 70 million people worldwide. Despite the availability of over 20 antiseizure drugs (ASDs) for symptomatic treatment of epileptic seizures, about one-third of patients with epilepsy have seizures refractory to pharmacotherapy. Patients with such drug-resistant epilepsy (DRE) have increased risks of premature death, injuries, psychosocial dysfunction, and a reduced quality of life, so development of more effective therapies is an urgent clinical need. However, the various types of epilepsy and seizures and the complex temporal patterns of refractoriness complicate the issue. Furthermore, the underlying mechanisms of DRE are not fully understood, though recent work has begun to shape our understanding more clearly. Experimental models of DRE offer opportunities to discover, characterize, and challenge putative mechanisms of drug resistance. Furthermore, such preclinical models are important in developing therapies that may overcome drug resistance. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of ASD resistance and discuss how to overcome this problem. Encouragingly, better elucidation of the pathophysiological mechanisms underpinning epilepsies and drug resistance by concerted preclinical and clinical efforts have recently enabled a revised approach to the development of more promising therapies, including numerous potential etiology-specific drugs ("precision medicine") for severe pediatric (monogenetic) epilepsies and novel multitargeted ASDs for acquired partial epilepsies, suggesting that the long hoped-for breakthrough in therapy for as-yet ASD-resistant patients is a feasible goal. SIGNIFICANCE STATEMENT: Drug resistance provides a major challenge in epilepsy management. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of drug resistance in epilepsy and discuss how the problem might be overcome.
Topics: Animals; Anticonvulsants; Drug Resistance; Epilepsy; Humans; Randomized Controlled Trials as Topic
PubMed: 32540959
DOI: 10.1124/pr.120.019539 -
Advances in Experimental Medicine and... 2020In our society, anxiety and depression are serious health issues that affect a large proportion of the population. Unfortunately, drug therapies are not always effective... (Review)
Review
In our society, anxiety and depression are serious health issues that affect a large proportion of the population. Unfortunately, drug therapies are not always effective and can lead to drug abuse, delay of therapeutic effect, dependence, and tolerance. Traditionally, aromatherapy has also been used for anxiety relief and mood improvement. The use of essential oils, in relieving anxiety and depression, does not have the disadvantages associated with currently used drug therapies. In-vivo studies on animal models have verified the anxiolytic effects of these essential oils and the interactions of their major components with central nervous system receptors. Therefore, it seems reasonable to argue that the modulation of glutamate and GABA neurotransmitter systems are likely to be the critical mechanisms responsible for the sedative, anxiolytic, and anticonvulsant proprieties of linalool and essential oils containing linalool in significant proportions. Popular anxiolytic essential oils are generally rich in terpenoid alcohols like linalool, geraniol and citronellol, and the monoterpene limonene (or citral). Therefore, other essential oils or formulations that contain these terpenoids as major components may serve as important aromatherapeutics for relief of anxiety.
Topics: Animals; Anti-Anxiety Agents; Anticonvulsants; Anxiety; Aromatherapy; Depression; Humans; Hypnotics and Sedatives; Oils, Volatile; Terpenes
PubMed: 32304038
DOI: 10.1007/978-3-030-42667-5_11 -
Developmental Medicine and Child... Mar 2021Sunflower syndrome is a rare photosensitive epilepsy which has received little attention in recent medical literature. The historical cases documenting the epilepsy's... (Review)
Review
Sunflower syndrome is a rare photosensitive epilepsy which has received little attention in recent medical literature. The historical cases documenting the epilepsy's stereotyped handwaving motion in front of light characterized the behavior as self-inducing seizures via mimic of stroboscopic effect. However, the relationship between handwaving episodes and attendant generalized electroencephalogram abnormalities, and an appreciation of the compulsive attraction the sun and other light sources hold for these patients, suggest the handwaving motion may be a part of the seizure rather than a mechanism of self-induction. The lack of awareness of Sunflower syndrome often leads to misdiagnosis. The seizures are often refractory to traditional anticonvulsant medication, and patients resort to behavioral intervention, such as hats and sunglasses, to reduce handwaving episodes. Further study is required to determine the syndrome's natural history and to identify more effective treatment options. WHAT THIS PAPER ADDS: Sunflower syndrome is a rare condition that is often misdiagnosed. Awareness of the clinical and electroencephalogram characteristics of Sunflower syndromemay reduce the prevalence of misdiagnosis.
Topics: Anticonvulsants; Epilepsy, Reflex; Humans; Photic Stimulation; Syndrome
PubMed: 33135153
DOI: 10.1111/dmcn.14723 -
CNS Drugs Jan 2021Lennox-Gastaut syndrome (LGS), a childhood-onset severe developmental and epileptic encephalopathy (DEE), is an entity that encompasses a heterogenous group of... (Review)
Review
Lennox-Gastaut syndrome (LGS), a childhood-onset severe developmental and epileptic encephalopathy (DEE), is an entity that encompasses a heterogenous group of aetiologies, with no single genetic cause. It is characterised by multiple seizure types, an abnormal EEG with generalised slow spike and wave discharges and cognitive impairment, associated with high morbidity and profound effects on the quality of life of patients and their families. Drug-refractory seizures are a hallmark and treatment is further complicated by its multiple morbidities, which evolve over the patient's lifetime. This review provides a comprehensive overview of the current and future options for the treatment of seizures associated with LGS. Six treatments are specifically indicated as adjunct therapies for the treatment of seizures associated with LGS in the US: lamotrigine, clobazam, rufinamide, topiramate, felbamate and most recently cannabidiol. These therapies have demonstrated reductions in drop seizures in 15%-68% of patients across trials, with responder rates (≥ 50% reduction in drop seizures) of 37%-78%. Valproate is still the preferred first-line treatment, generally in combination with lamotrigine or clobazam. Other treatments frequently used off-label include the broad spectrum anti-epileptic drugs (AED) levetiracetam, zonisamide and perampanel, while recent evidence from observational studies has indicated that a newer AED, the levetiracetam analogue brivaracetam, may be effective and well tolerated in LGS patients. Other treatments in clinical development include fenfluramine in late phase III, perampanel, soticlestat-OV953/TAK-953, carisbamate and ganaxolone. Non-pharmacologic interventions include the ketogenic diet, vagus nerve stimulation and surgical interventions; these are also expanding, with the potential for less invasive techniques for corpus callosotomy that have promise for reducing complications. However, despite these advancements, patients continue to experience a significant burden. Because LGS is not a single entity, tailoring of treatment is needed as opposed to a 'one size fits all' approach. Further research is needed into the underlying aetiologies and pathophysiology of LGS, together with advancements in treatments that encompass the spectrum of seizures associated with this complex syndrome.
Topics: Animals; Anticonvulsants; Child; Diet, Ketogenic; Drug Development; Electroencephalography; Humans; Lennox Gastaut Syndrome; Off-Label Use; Quality of Life; Vagus Nerve Stimulation
PubMed: 33479851
DOI: 10.1007/s40263-020-00784-8 -
The Lancet. Neurology Jun 2020Since 1989, 18 second-generation antiseizure medications have reached the market, resulting in a greatly increased range of treatment options for patients and... (Review)
Review
Since 1989, 18 second-generation antiseizure medications have reached the market, resulting in a greatly increased range of treatment options for patients and prescribers. 30 years have passed and now is the time for an appraisal of the effect of these medications on clinical outcomes. Every antiseizure medication needs to be assessed individually, but overall second-generation drugs are less likely to cause pharmacokinetic interactions than their older counterparts. Some second-generation antiseizure medications have shown advantages in tolerability and safety, particularly in the treatment of older patients and women of childbearing potential. Disappointingly, however, none of these medications appear to be more efficacious than first-generation antiseizure medications, highlighting the need for novel strategies in epilepsy drug development. Although second-generation antiseizure medications have not substantially reduced the proportion of patients with pharmacoresistant epilepsy, their availability has enabled more opportunities to tailor treatment choice to the characteristics of the individual.
Topics: Anticonvulsants; Epilepsy; History, 20th Century; History, 21st Century; Humans; Seizures; Treatment Outcome
PubMed: 32109411
DOI: 10.1016/S1474-4422(20)30035-1 -
Food and Chemical Toxicology : An... Aug 2020Phenytoin is a long-standing, anti-seizure drug widely used in clinical practice. It has also been evaluated in the context of many other illnesses in addition to its... (Review)
Review
Phenytoin is a long-standing, anti-seizure drug widely used in clinical practice. It has also been evaluated in the context of many other illnesses in addition to its original epilepsy indication. The narrow therapeutic index of phenytoin and its ubiquitous daily use pose a high risk of poisoning. This review article focuses on the chemistry, pharmacokinetics, and toxicology of phenytoin, with a special focus on its mutagenicity, carcinogenicity, and teratogenicity. The side effects on human health associated with phenytoin use are thoroughly described. In particular, DRESS syndrome and cerebellar atrophy are addressed. This review will help in further understanding the benefits phenytoin use in the treatment of epilepsy.
Topics: Anticonvulsants; Carcinogenicity Tests; Humans; Mutagenicity Tests; Phenytoin; Teratogens
PubMed: 32376339
DOI: 10.1016/j.fct.2020.111393 -
Journal of Clinical Neurophysiology :... Jan 2020Epilepsy is a chronic disease characterized by recurrent unprovoked seizures. Up to 30% of children with epilepsy will be refractory to standard anticonvulsant therapy,... (Review)
Review
Epilepsy is a chronic disease characterized by recurrent unprovoked seizures. Up to 30% of children with epilepsy will be refractory to standard anticonvulsant therapy, and those with epileptic encephalopathy can be particularly challenging to treat. The endocannabinoid system can modulate the physiologic processes underlying epileptogenesis. The anticonvulsant properties of several cannabinoids, namely Δ-tetrahydrocannabinol and cannabidiol (CBD), have been demonstrated in both in vitro and in vivo studies. Cannabis-based therapies have been used for millennia to treat a variety of diseases including epilepsy. Several studies have shown that CBD, both in isolation as a pharmaceutical-grade preparation or as part of a CBD-enriched cannabis herbal extract, is beneficial in decreasing seizure frequency in children with treatment-resistant epilepsy. Overall, cannabis herbal extracts appear to provide greater efficacy in decreasing seizure frequency, but the studies assessing cannabis herbal extract are either retrospective or small-scale observational studies. The two large randomized controlled studies assessing the efficacy of pharmaceutical-grade CBD in children with Dravet and Lennox-Gastaut syndromes showed similar efficacy to other anticonvulsants. Lack of data regarding appropriate dosing and pediatric pharmacokinetics continues to make authorization of cannabis-based therapies to children with treatment-resistant epilepsy challenging.
Topics: Anticonvulsants; Cannabinoids; Cannabis; Child; Epilepsy; Epilepsy, Generalized; Humans; Medical Marijuana; Retrospective Studies; Seizures
PubMed: 31895184
DOI: 10.1097/WNP.0000000000000641 -
Folia Medica Dec 2021Epilepsy is a chronic neurological disease with recurrent seizures. Its incidence, the social and psychological aspects of epilepsy-associated stigmatization in society,...
Epilepsy is a chronic neurological disease with recurrent seizures. Its incidence, the social and psychological aspects of epilepsy-associated stigmatization in society, the medical risk of severe seizures, and the challenges in treatment confirm its medical and social significance. The pathogenesis of the diseases is associated with abnormal activity of a population of neurons due to various mechanisms, the most frequent being oxidative stress, glutamate excitotoxicity, and mitochondrial dysfunction. In the last 3-4 decades, the possible connection between epilepsy and melatonin - a neurohormone secreted by the pineal gland - has been sought and studied. Various physiological functions of melatonin in humans have been proven - regulation of circadian rhythms (diurnal, seasonal), sleep and wakefulness, participation in the processes of thermoregulation, tumour growth and aging, sexual activity and reproductive functions. It also has immunomodulatory, cytoprotective and antioxidant activity. The results from the studies with experimental models with animals conducted so far in search of a correlation between melatonin and epileptogenesis are mainly in support of the hypothesis of its anticonvulsant effect. The studies with humans are diverse in design, with a smaller number of participants, and the results are not always in explicit support of this hypothesis. The correlation between melatonin concentration and the course of the disease in patients with epilepsy has been discussed. The possibility of adding melatonin to anti-epileptic therapy has also been studied recently.
Topics: Animals; Anticonvulsants; Circadian Rhythm; Epilepsy; Humans; Melatonin; Seizures
PubMed: 35851222
DOI: 10.3897/folmed.63.e58637 -
The Annals of Pharmacotherapy Mar 2021Epilepsy is one of the most common neurological diseases, and uncontrolled seizures remain a significant problem for one-third of patients with epilepsy on drug therapy....
Epilepsy is one of the most common neurological diseases, and uncontrolled seizures remain a significant problem for one-third of patients with epilepsy on drug therapy. Ongoing seizures affect the morbidity and mortality of patients with epilepsy. Premature death is up to 3 times higher in those with epilepsy than in the general population. Quality of life is affected by refractory epilepsy with physical, social, and psychological consequences. Patients may be stigmatized by society, institutions, and their own shame surrounding seizures. Questions remain on how to treat refractory epilepsy, also called drug-resistant, pharmacoresistant, or intractable epilepsy. Cenobamate, a novel antiseizure medication, may provide additional benefit for refractory epilepsy treatment.
Topics: Anticonvulsants; Drug Resistant Epilepsy; Female; Humans; Male; Quality of Life
PubMed: 32795085
DOI: 10.1177/1060028020948056