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1.
Rational Small Molecule Treatment for Genetic Epilepsies.
Goldberg, EM
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2021;(3):1490-1499
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Abstract
Genetic testing has yielded major advances in our understanding of the causes of epilepsy. Seizures remain resistant to treatment in a significant proportion of cases, particularly in severe, childhood-onset epilepsy, the patient population in which an underlying causative genetic variant is most likely to be identified. A genetic diagnosis can be explanatory as to etiology, and, in some cases, might suggest a therapeutic approach; yet, a clear path from genetic diagnosis to treatment remains unclear in most cases. Here, we discuss theoretical considerations behind the attempted use of small molecules for the treatment of genetic epilepsies, which is but one among various approaches currently under development. We explore a few salient examples and consider the future of the small molecule approach for genetic epilepsies. We conclude that significant additional work is required to understand how genetic variation leads to dysfunction of epilepsy-associated protein targets, and how this impacts the function of diverse subtypes of neurons embedded within distributed brain circuits to yield epilepsy and epilepsy-associated comorbidities. A syndrome- or even variant-specific approach may be required to achieve progress. Advances in the field will require improved methods for large-scale target validation, compound identification and optimization, and the development of accurate model systems that reflect the core features of human epilepsy syndromes, as well as novel approaches towards clinical trials of such compounds in small rare disease cohorts.
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2.
Identifying patients with epilepsy at high risk of cardiac death: signs, risk factors and initial management of high risk of cardiac death.
Surges, R, Shmuely, S, Dietze, C, Ryvlin, P, Thijs, RD
Epileptic disorders : international epilepsy journal with videotape. 2021;(1):17-39
Abstract
People with epilepsy have a three-fold increased risk of dying prematurely, and a significant proportion is due to sudden cardiac death or acute myocardial infarctions. The causes of increased cardiovascular morbidity and mortality in epilepsy are manifold and include acute or remote effects of epileptic seizures, the longstanding epilepsy itself or antiseizure treatments. Seizure-related cardiac arrhythmias are common and comprise bradyarrhythmia and asystole, atrial fibrillation and ventricular tachycardia. The most frequent clinically relevant seizure-related arrhythmia is ictal asystole that may require implantation of a cardiac pacemaker, whereas seizure-related ventricular tachycardias are only rarely reported. Takotsubo cardiomyopathy and myocardial infarction are rare complications and predominantly described in association with tonic-clonic seizures. Epilepsy-related cardiac complications include a disturbed cardiac autonomic nervous system and acquired dysfunction of the heart (recently defined as 'epileptic heart'), probably contributing to the abnormalities of cardiac repolarisation and elevated risk of sudden cardiac death in people with epilepsy. If successful, the use of antiseizure medication prevents seizure-related cardiac arrhythmias and remote cardiac complications. However, enzyme-inducing antiseizure medications have a negative impact on cardiovascular risk factors, which may further be aggravated by weight gain linked to specific antiseizure drugs. Given the severe consequences of cardiac risks, the aim of this educational review is to explain the many facets of cardiac complications and their underlying causes, and to enable the reader to recognize and manage these risks with the goal to mitigate the cardiac risks in people with epilepsy. Features of syncope are explained in detail, as syncope of all origins can be mistaken as epileptic seizures in people with or without epilepsy, and ictal syncope (i.e. seizure-induced syncope) can easily be ignored.
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3.
Advances in the management of generalized convulsive status epilepticus: what have we learned?
Neligan, A, Rajakulendran, S, Walker, MC
Brain : a journal of neurology. 2021;(5):1336-1341
Abstract
Convulsive status epilepticus is the most serious manifestation of an epileptic diathesis. In the early stages (5-30 min), there exists class A evidence to support the efficacy of benzodiazepines as first-line treatment. As status epilepticus progresses into the later stages, the evidence for treatment becomes less robust until we are depending upon short case series and case reports for the treatment of refractory status epilepticus. However, the past year saw the publication of three randomized controlled trials in the setting of benzodiazepine-resistant established convulsive status epilepticus: the EcLiPSE and ConSEPT studies, compared levetiracetam to phenytoin in children; and the ESETT study compared fosphenytoin, levetiracetam and sodium valproate in adults and children. In addition, the emergence of data from the SENSE study, a multicentre multinational prospective cohort study and the publication of a systematic review and meta-analysis of the mortality of status epilepticus over the past 30 years, has brought the treatment of status epilepticus into sharp focus. In this update we provide a detailed analysis of these studies and their impact on clinical practice. We review contentious areas of management in status epilepticus where a consensus is lacking and advance the case for more research on existing and alternative treatment strategies.
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4.
Epilepsy in Nicolaides-Baraitser Syndrome: Review of Literature and Report of 25 Patients Focusing on Treatment Aspects.
Hofmeister, B, von Stülpnagel, C, Betzler, C, Mari, F, Renieri, A, Baldassarri, M, Haberlandt, E, Jansen, K, Schilling, S, Weber, P, et al
Neuropediatrics. 2021;(2):109-122
Abstract
Nicolaides-Baraitser syndrome (NCBRS), caused by a mutation in the SMARCA2 gene, which goes along with intellectual disability, congenital malformations, especially of face and limbs, and often difficult-to-treat epilepsy, is surveyed focusing on epilepsy and its treatment. Patients were recruited via "Network Therapy of Rare Epilepsies (NETRE)" and an international NCBRS parent support group. Inclusion criterion is NCBRS-defining SMARCA2 mutation. Clinical findings including epilepsy classification, anticonvulsive treatment, electroencephalogram (EEG) findings, and neurodevelopmental outcome were collected with an electronic questionnaire. Inclusion of 25 NCBRS patients with epilepsy in 23 of 25. Overall, 85% of the participants (17/20) reported generalized seizures, the semiology varied widely. EEG showed generalized epileptogenic abnormalities in 53% (9/17), cranial magnetic resonance imaging (cMRI) was mainly inconspicuous. The five most frequently used anticonvulsive drugs were valproic acid (VPA [12/20]), levetiracetam (LEV [12/20]), phenobarbital (PB [8/20]), topiramate (TPM [5/20]), and carbamazepine (CBZ [5/20]). LEV (9/12), PB (6/8), TPM (4/5), and VPA (9/12) reduced the seizures' frequency in more than 50%. Temporary freedom of seizures (>6 months) was reached with LEV (4/12), PB (3/8), TPM (1/5, only combined with PB and nitrazepam [NZP]), and VPA (4/12). Seizures aggravation was observed under lamotrigine (LTG [2/4]), LEV (1/12), PB (1/8), and VPA (1/12). Ketogenic diet (KD) and vagal nerve stimulation (VNS) reduced seizures' frequency in one of two each. This first worldwide retrospective analysis of anticonvulsive therapy in NCBRS helps to treat epilepsy in NCBRS that mostly shows only initial response to anticonvulsive therapy, especially with LEV and VPA, but very rarely shows complete freedom of seizures in this, rather genetic than structural epilepsy.
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5.
Research Progress on the Effect of Epilepsy and Antiseizure Medications on PCOS Through HPO Axis.
Li, S, Zhang, L, Wei, N, Tai, Z, Yu, C, Xu, Z
Frontiers in endocrinology. 2021;:787854
Abstract
Epilepsy is a common chronic neurological disease that manifests as recurrent seizures. The incidence and prevalence of epilepsy in women are slightly lower than those in men. Polycystic ovary syndrome (PCOS), a reproductive endocrine system disease, is a complication that women with epilepsy are susceptible to, and its total prevalence is 8%-13% in the female population and sometimes as high as 26% in female epilepsy patients. The rate of PCOS increased markedly in female patients who chose valproate (VPA), to 1.95 times higher than that of other drugs. In addition, patients receiving other anti-seizure medications (ASMs), such as lamotrigine (LTG), oxcarbazepine (OXC), and carbamazepine (CBZ), also have reproductive endocrine abnormalities. Some scholars believe that the increase in incidence is related not only to epilepsy itself but also to ASMs. Epileptiform discharges can affect the activity of the pulse generator and then interfere with the reproductive endocrine system by breaking the balance of the hypothalamic-pituitary-ovarian (HPO) axis. ASMs may also cause PCOS-like disorders of the reproductive endocrine system through the HPO axis. Moreover, other factors such as hormone metabolism and related signalling pathways also play a role in it.
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6.
Drug Exposure in Newborns: Effect of Selected Drugs Prescribed to Mothers During Pregnancy and Lactation.
Rentsch, KM
Therapeutic drug monitoring. 2020;(2):255-263
Abstract
The number of newborns exposed to therapeutic drugs during pregnancy is growing because of the increased use of drugs during pregnancy. In recent years, advances in our understanding of drug placental transfer have augmented the likelihood of a healthy baby in mothers with chronic diseases needing drug therapy. Globally, for example, more than 1.4 million pregnancies in 2015 have been burdened with antiretroviral drugs due to an increasing number of HIV-positive women treated with these drugs, particularly in low- and middle-income countries. In most cases, the fetus is exposed to much higher drug doses in utero than the newborn nursed by the mother. Drug transfer through the placenta takes place by passive diffusion, active transport, or facilitated transport, and drug concentrations in the fetal circulation may be comparable to that in the mother's blood concentration. The excretion of drugs into breastmilk predominantly occurs by passive diffusion, allowing only the non-protein-bound fraction of the blood drug concentration to penetrate. Drug agencies in the United States and Europe highly recommend performing clinical trials in pregnant or breastfeeding women. However, only a few drugs have reported statistically sound data in these patient groups. Most available results concerning pregnancy are obtained from observational studies after birth, assessing outcomes in the newborn or by measuring drug concentrations in the mother and umbilical cord blood. In the case of the lactation period, some studies have evaluated drug concentrations in breastmilk and blood of the mother and/or infant. In this review, exposure to antiretrovirals, immunosuppressants used after solid organ transplantation, and antiepileptics during pregnancy and lactation has been discussed in detail.
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7.
Drivers for the comorbidity of type 2 diabetes mellitus and epilepsy: A scoping review.
Shlobin, NA, Sander, JW
Epilepsy & behavior : E&B. 2020;:107043
Abstract
Epilepsy, a common neurologic condition, is associated with a greater prevalence of type 2 diabetes mellitus (T2DM). We examined potential drivers for the comorbidity of epilepsy and T2DM in an attempt to elucidate possible biological mechanisms underlying the development of processes in individuals. We searched PubMed and Medline up to December 2019. Our search yielded 3361 articles, of which 82 were included in the scoping review. We reviewed articles focusing on the association of epilepsy and T2DM, drivers, and biological mechanisms. We found that epilepsy is associated with obesity and obesity is associated with T2DM. Treatment with valproate (either sodium or acid) is associated with weight increase and hyperinsulinemia, while topiramate causes weight loss. People with epilepsy are less likely to exercise, which is protective against obesity. Mitochondrial dysfunction and adiponectin deficiency are common to epilepsy and T2DM. One possible mechanism for the comorbidity is mitochondrial dysfunction and adiponectin deficiency, which promotes epilepsy, obesity, and T2DM. Another possible mechanism is that people with epilepsy are more likely to be obese because of the lack of exercise and the effects of some antiseizure medications (ASMs), which makes them susceptible to T2DM because of the development of mitochondrial dysfunction and adiponectin deficiency. A third mechanism is that people with epilepsy have greater mitochondrial dysfunction and lower adiponectin levels than people without epilepsy at baseline, which may exacerbate after treatment with ASMs. Future research involving a combined genetic and molecular pathway approach will likely yield valuable insight regarding the comorbidity of epilepsy and T2DM.
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8.
Medical management of status epilepticus: Emergency room to intensive care unit.
Crawshaw, AA, Cock, HR
Seizure. 2020;:145-152
Abstract
In convulsive status epilepticus (SE), achieving seizure control within the first 1-2 hours after onset is a significant determinant of outcome. Treatment is also more likely to work and be cost effective the earlier it is given. Initial first aid measures should be accompanied by establishing intravenous access if possible and administering thiamine and glucose if required. Calling for help will support efficient management, and also the potential for video-recording the events. This can be done as a best interests investigation to inform later management, provided adequate steps to protect data are taken. There is high quality evidence supporting the use of benzodiazepines for initial treatment. Midazolam (buccal, intranasal or intramuscular) has the most evidence where there is no intravenous access, with the practical advantages of administration outweighing the slightly slower onset of action. Either lorazepam or diazepam are suitable IV agents. Speed of administration and adequate initial dosing are probably more important than choice of drug. Although only phenytoin (and its prodrug fosphenytoin) and phenobarbitone are licensed for established SE, a now considerable body of evidence and international consensus supports the utility of both levetiracetam and valproate as options in established status. Both also have the advantage of being well tolerated as maintenance treatment, and possibly a lower risk of serious adverse events. Two adequately powered randomized open studies in children have recently reported, supporting the use of levetiracetam as an alterantive to phenytoin. The results of a large double blind study also including valproate are also imminent, and together likely to change practice in benzodiazepine-resistant SE.
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9.
(‒)-Cannabidiolic Acid, a Still Overlooked Bioactive Compound: An Introductory Review and Preliminary Research.
Formato, M, Crescente, G, Scognamiglio, M, Fiorentino, A, Pecoraro, MT, Piccolella, S, Catauro, M, Pacifico, S
Molecules (Basel, Switzerland). 2020;(11)
Abstract
Cannabidiolic acid (CBDA) is the main phytocannabinoid in fiber and seed-oil hemp (Cannabis sativa L.) plants, but its potential health-related capabilities have been masked for years by a greater scientific interest towards its neutral derivative cannabidiol (CBD). This review aims to collect from the literature and critically discuss all the information about this molecule, starting from its biosynthesis, and focusing on its bioactivity, as an anti-inflammatory, anti-emetic, anti-convulsant, and anti-cancerogenic drug. Furthermore, in the awareness that, despite its multiple bioactive effects, currently poor efforts have been made to achieve its reliable purification, herein, we propose a relatively simple, fast, and inexpensive procedure for its recovery from pollen of industrial hemp cultivars. Spectroscopic and spectrometric techniques allowed us to unequivocally identify pure isolated CBDA and to distinguish it from the constitutional isomer tetrahydrocannabinolic acid (THCA-A).
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10.
The evolving indications of KD therapy.
Armeno, M, Caraballo, R
Epilepsy research. 2020;:106340
Abstract
Despite the rapid increase of clinical and basic-science knowledge on ketogenic diet therapies over the past years, it has not always been easy to determine the adequate indications of this treatment. Over the nearly 100 years of use, from being a last resource in the therapeutic algorithm, the diet has become one of the four main treatments for patients with difficult-to-control epilepsy together with antiepileptic drugs, surgery, and vagus nerve stimulation. The use of the diet has also changed. The current paper will briefly discuss the history of the diet together with a review of the literature regarding its most important indications and how they have evolved. The concept of the importance of defining the type of seizure, type of syndrome, and etiology in the selection of patients and timing of diet initiation has been gaining importance. This paper explores how the indications of the diet changed together with the shifting focus of epilepsy teams towards its use in different types of epilepsy and epilepsy syndromes and according to etiologies and as an alternative option in refractory and superrefractory status epilepticus.