Archive for category Epilepsy

[ARTICLE] Levetiracetam and brivaracetam: a review of evidence from clinical trials and clinical experience – Full Text

Until the early 1990s, a limited number of antiepileptic drugs (AEDs) were available. Since then, a large variety of new AEDs have been developed and introduced, several of them offering new modes of action. One of these new AED families is described and reviewed in this article. Levetiracetam (LEV) and brivaracetam (BRV) are pyrrolidone derivate compounds binding at the presynaptic SV2A receptor site and are thus representative of AEDs with a unique mode of action. LEV was extensively investigated in randomized controlled trials and has a very promising efficacy both in focal and generalized epilepsies. Its pharmacokinetic profile is favorable and LEV does not undergo clinically relevant interactions. Adverse reactions comprise mainly asthenia, somnolence, and behavioral symptoms. It has now been established as a first-line antiepileptic drug. BRV has been recently introduced as an adjunct antiepileptic drug in focal epilepsy with a similarly promising pharmacokinetic profile and possibly increased tolerability concerning psychiatric adverse events. This review summarizes the essential preclinical and clinical data of LEV and BRV that is currently available and includes the experiences at a large tertiary referral epilepsy center.

Since the introduction of bromides as the first effective antiepileptic drugs (AEDs),1 chronic AED treatment that consisted of the sustained prevention of epileptic seizures has remained the standard of epilepsy therapy.2 Before to the introduction of the newer generation of AEDs, a limited number of drugs were available that addressed the blockade of sodium channels, acting on gamma-aminobutyric acid (GABA) type A receptors, or interacting with calcium channels as the leading modes of action.3 With the introduction of the newer AEDs a heterogeneous group of drugs appeared, some of them offering new mechanisms of action2 including the blockade of GABA aminotransferase (vigabatrin [VGB]), GABA re-uptake from the synaptic cleft (tiagabine [TGB]), the modulation of calcium channels (gabapentin [GBP], pregabalin [PGB]), the selective non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolproprionic acid (AMPA) receptor antagonism (perampanel [PER]), and the binding to the presynaptic SV2A receptor site which is the unique mode of action of levetiracetam (LEV) and brivaracetam (BRV), the AEDs this review will cover. The authors will summarize the development of both compounds as derivatives of piracetam, review the currently available preclinical and clinical data, and discuss the question of whether BRV has the potential to be recognized as being superior to LEV and if it can replace it as the standard AED with the main mode of action both AEDs reflect.[…]

 

Continue —-> Levetiracetam and brivaracetam: a review of evidence from clinical trials and clinical experience – Bernhard J. Steinhoff, Anke M. Staack, 2019

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[Abstract] No prevention or cure of epilepsy as yet – Invited review

Highlights

  • Approximately 20% of all epilepsy is caused by acute acquired injury such as traumatic brain injury, stroke and CNS infection, with potential to prevent epilepsy
  • No treatment to prevent acquired epilepsy exists; and very few clinical studies have been done during the last 15 years to develop such treatment
  • We review possible reasons for this, possible ways to rectify the situations and note some of the ways currently under way to do so
  • We further review “cures” of epilepsy that occur spontaneously, and after surgical and sometimes medical antiseizure treatments. We note the limited understanding of the mechanisms of such remissions and thus, at present inability to replicate them with targeted therapy

Abstract

Approximately 20% of all epilepsy is caused by acute acquired injury such as traumatic brain injury, stroke and CNS infection. The known onset of the injury which triggers the epileptogenic process, early presentation to medical care, and a latency between the injury and the development of clinical epilepsy present an opportunity to intervene with treatment to prevent epilepsy. No such treatment exists and yet there has been remarkably little clinical research during the last 20 years to try to develop such treatment. We review possible reasons for this, possible ways to rectify the situations and note some of the ways currently under way to do so.

Resective surgical treatment can achieve “cure” in some patients but is sparsely utilized. In certain “self-limiting” syndromes of childhood and adolescence epilepsy remits spontaneously. In a proportion of patients who become seizure free on medications or with dietary treatment, seizure freedom persists when treatment is discontinued. We discuss these situations which can be considered “cures”; and note that at present we have little understanding of mechanism of such cures, and cannot therefore translate them into a treatment paradigm targeting a “cure” of epilepsy.

via No prevention or cure of epilepsy as yet – ScienceDirect

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[Abstract] Unintended pregnancy, prenatal care, newborn outcomes, and breastfeeding in women with epilepsy.

Abstract

Objective To compare the proportions of unintended pregnancies, prenatal vitamin or folic acid (PNVF) use, adequate prenatal care visits, and breastfeeding among women with epilepsy (WWE) to women without epilepsy (WWoE).

 

Methods The Pregnancy Risk Assessment Monitoring System (PRAMS) is an annual survey of randomly sampled postpartum women administered by the Centers for Disease Control and Prevention. We used PRAMS data from 13 states from 2009 to 2014 to compare the primary outcomes in WWE and WWoE, as well as our secondary outcomes of contraception practices, newborn outcomes, and time to recognition of pregnancy. We adjusted for maternal age, race, ethnicity, and socioeconomic status (SES), and we calculated odds ratios for these outcomes using logistic regression.

 

Results This analysis included 73,619 women, of whom 541 (0.7%) reported epilepsy, representing 3,442,128 WWoE and 26,635 WWE through weighted sampling. In WWE, 55% of pregnancies were unintended compared to 48% in WWoE. After adjustment for covariates, epilepsy was not associated with unintended pregnancy or with inadequate prenatal care. WWE were less likely to report breastfeeding but more likely to report daily PNVF use. Newborns of WWE had higher rates of prematurity.

 

Conclusions Although planning for pregnancy is of utmost importance for WWE, more than half the pregnancies in WWE were unintended. Maternal age and SES differences likely contribute to the higher rates in WWE compared to WWoE. The proportion of women reporting breastfeeding is lower in WWE despite studies indicating the safety of breastfeeding in WWE.

 

via Unintended pregnancy, prenatal care, newborn outcomes, and breastfeeding in women with epilepsy | Neurology

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[BLOG POST] Mozart and epilepsy: the rhythm beats on

 

I can’t seem to get away from the theme of Mozart and epilepsy. When I first looked at this, in a blog post titled Mozart and seizures? The links between epilepsy and music, I took the topic rather lightly, more a subscript than a headline you may say. But I have since learnt to take the links between epilepsy and music more seriously.

By Barbara Krafft – The Bridgeman Art Library, Object 574471, Public Domain, Link

 

The major trigger for my ‘road to Damascus’ conversion is a 2018 paper titled Study of the Mozart effect in children with epileptic electroencephalograms, published in the journal Seizure. The paper was an eye-opener because it gave a very helpful comprehensive context to the broader beneficial effect of music…not just in epilepsy, but in other neurological disorders such as Parkinson’s diseasedementia and sleep disordersThe authors, Elyza Grylls and colleagues, started on the established premise that Mozart’s music has a beneficial effect on epilepsy. What they wanted to know was if other forms of music have a similar settling effect on epilepsy, or if only Mozart’s music carries the magic touch. The authors therefore played Mozart’s Sonata for two pianos in D major (K448) to 40 children with epilepsy who were undergoing an EEG (electroencephalogram, or electrical brain wave test). They then compared this with the effect of playing other types of music. Remarkably, they found that only Mozart’s Sonata led to a significant reduction in EEG epileptic discharges.

Public Domain, Link

The authors concluded that there was indeed an anti-epileptic effect of Mozart’s music, the so-called  ‘Mozart therapy’. But what is so special about K448? They speculate that it has to do with the structure of Mozart’s music, containing as it does, long periodicities. Interestingly, the music of Yanni, which is similarly structured, has somewhat a similar effect on brain wave activity. On the contrary, and sorry to Beethoven fans, Fur Elise doesn’t have this effect.

By W.J. Baker (held the expired copyright on the photograph) – Library of Congress[1]Contrairement à une erreur fréquemment répandue le buste a été réalisé par Hugo Hagen, non pas à partir du masque mortuaire mais, comme de nombreux autres, d’après le masque réalisé en 1812 par Franz Klein pour un buste qu’il devait réaliser ensuite., Public Domain, Link

So what does the structure of Mozart’s music do to the brain? One suggestion is that Mozart’s music enhances the body’s parasympathetic drive; this reduces the heart rate, and thereby inhibits the brain’s propensity to epileptic seizures. The suppression of this parasympathetic drive is of course the theory behind using vagus nerve stimulation (VNS) to treat drug-resistant epilepsy. For more on VNS, see my previous blog, Vagus nerve stimulation: from neurology and beyond!

By Bionerd – MRI at Charite Mitte, Berlin (used with permission), CC BY 3.0Link

You have surely wondered by now if K448 is the only one of Mozart’s compositions to have an anti-epileptic effect. It doesn’t matter if you have not, because the authors of another interesting paper did. They titled their study, published in 2018, Mozart’s music in children with drug-refractory epileptic encephalopathies: comparison of two protocols. Published in the journal Epilepsy and Behaviour, the authors, Giangennaro Coppola and colleagues, compared the effect of K448 with a set of his other compositions. Intriguingly they found that the composition set actually had a greater effect in epilepsy than K448…by a wide margin of 70% to 20%! Furthermore, the set was better tolerated by the children; they were less irritable and had a better nighttime sleep quality.   

https://www.publicdomainpictures.net/en/view-image.php?image=76907&picture=dog-amp-child-painting

It therefore appears as if it all rosy in the garden of music and the brain. But it is not! As every rose grows on a thorny tree, so do some forms of music trigger epileptic seizures. This so-called musicogenic epilepsy is well-recognised, and two recent culprits are the music of Sean Paul, discussed in the journal Scientific American , and the music of Ne Yo, explored by NME. Therefore you should craft your playlist wisely.

By CLASSICNEYO – Own workCC BY-SA 4.0Link

So, is it time for neurologists to start prescribing music?

Or is it too much of a double-edged sword?

Music is #SimplyIrresistible. Luca Florio on Flickr. https://www.flickr.com/photos/elle_florio/29516744480

via Mozart and epilepsy: the rhythm beats on – The Neurology Lounge

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[VIDEO] What’s, Why’s and How’s of the Vagus Nerve Stimulator

Dr Nemechek Discusses the Vagus Nerve Stimulator, how it’s used and what it can do for a patient.

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[EDITORIAL] Reducing birth defects in women with epilepsy – Neurology

Merely 20 years ago, a report of the Quality Standards Subcommittee of the American Academy of Neurology recommended that antiepileptic drug (AED) selection for pregnant women with epilepsy should be based on the AED “deemed most appropriate for her seizure type.”1 Scientifically, lumping all AEDs together when chemical structures and mechanisms of action differ greatly was questionable, but the evidence for differential effects on fetal outcomes was sparse. Multiple research studies have now made it clear that the level of risk for major congenital malformation (MCMs) differs substantially among AEDs. The prevalence of MCMs is highest with valproate monotherapy2,3 compared to other monotherapies, and includes neural tube defects, heart malformations, cleft palate, hypospadias, and polydactyly. Likewise, the prevalence of MCMs is higher in polytherapy combinations that include valproate, compared to polytherapies that exclude valproate. MCM rates with some AED monotherapies even approximate the rates in the general population (e.g., levetiracetam, lamotrigine).2,3

via Reducing birth defects in women with epilepsy | Neurology

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[Abstract + References] Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy

Abstract

Cannabidiol (CBD) is a major active component of the Cannabis plant, which, unlike tetrahydrocannabinol (THC), is devoid of euphoria-inducing properties. During the last 10 years, there has been increasing interest in the use of CBD-enriched products for the treatment of epilepsy. In 2018, an oil-based highly purified liquid formulation of CBD (Epidiolex) derived from Cannabis sativa was approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS). The mechanisms underlying the antiseizure effects of CBD are unclear but may involve, among others, antagonism of G protein-coupled receptor 55 (GPR55), desensitization of transient receptor potential of vanilloid type 1 (TRPV1) channels, and inhibition of adenosine reuptake. CBD has complex and variable pharmacokinetics, with a prominent first-pass effect and a low oral bioavailability that increases fourfold when CBD is taken with a high-fat/high-calorie meal. In four randomized, double-blind, parallel-group, adjunctive-therapy trials, CBD given at doses of 10 and 20 mg/kg/day administered in two divided administrations was found to be superior to placebo in reducing the frequency of drop seizures in patients with LGS and convulsive seizures in patients with DS. Preliminary results from a recently completed controlled trial indicate that efficacy also extends to the treatment of seizures associated with the tuberous sclerosis complex. The most common adverse events that differentiated CBD from placebo in controlled trials included somnolence/sedation, decreased appetite, increases in transaminases, and diarrhea, behavioral changes, skin rashes, fatigue, and sleep disturbances. About one-half of the patients included in the DS and LGS trials were receiving concomitant therapy with clobazam, and in these patients a CBD-induced increase in serum levels of the active metabolite norclobazam may have contributed to improved seizure outcomes and to precipitation of some adverse effects, particularly somnolence.

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[WEB SITE] Can Stem Cells be Used to Treat Epilepsy?

The primary pathogenesis of genetic forms of epilepsy is an abnormal expression of certain receptors in the brain that lead to an enhanced excitation and reduced inhibition. Some cases occur following oxygenation deprivation during birth.

Other later-life forms of epilepsy may be attributed to damage to the brain e.g. stroke, brain tumours, traumatic brain injury, drug misuse or a brain infection.

To date, there are several key treatment strategies to help people have fewer seizures. Predominantly, anti-epileptic drugs are used to treat the frequency and severity of epilepsy. However, these have to be taken routinely, and are not a long-term solution. They also have many undesired side-effects. However, anti-epileptic drugs may not work for everyone, therefore other treatments are used, including surgery and dietary modifications (e.g. keto-diet). Therefore, the need to find effective long-term solutions is needed to treat epilepsy.

Epileptic seizure. Image Credit: Rainer Fuhrmann / Shutterstock

Epileptic seizure. Image Credit: Rainer Fuhrmann / Shutterstock

What are Stem Cells?

Stem cells are cells that have the ability to develop into different specialised cell types of the body. Most cells in the body are post-mitotic, meaning they are unable to divide and grow into new types of tissues. However, stem cells are able to divide after periods of no apparent activity and are able to transform into different body cell types, including muscle cells, nerve cells and blood cells.

Embryonic stem cells. Illustration Credit: Nobeastsofierce / Shutterstock

Embryonic stem cells. Illustration Credit: Nobeastsofierce / Shutterstock

Traditionally, stem cells were only able to be isolated from embryos (animal and human) and some adult somatic stem cells, such as those found in e.g. bone marrow. However, due to advances in science and technology, adult cells taken from tissues such as e.g. skin, are now able to be reprogrammed into stem-cell like cells called induced pluripotent stem cells (iPSCs). These iPSCs may be able to function in very similar ways to those previously only obtainable through embryo donation.

iPSCs can be genetically manipulated to form a variety of different body cells e.g. neurons and muscle cells. However, much more work is needed before iPSCs can be used to replace dysfunctional cells within the body, though many advances have been made, especially in animal studies, including successful replacement of damaged heart cells with lab grown heart cells from the animals.

Can Stem Cells be Used to Treat Epilepsy?

As most cases of epilepsy can be attributed to receptor expression differences within the brain (due to mutations), correcting these may in theory reduce the likelihood of electrical seizures developing in the brain.

In addition, during status epilepticus, the excitation overload sometimes kills neurons, especially within the hippocampus. This can actually worsen the condition over time and lead to the development of temporal lobe epilepsy (TLE). Whilst anti-epileptic medication may treat the seizures, the damage caused to the temporal lobe is often irreversible and permanent, and current therapies do not address this.

As previously discussed, the reduction in inhibition in the brain, primarily due to loss of GABA-ergic interneurons, coupled with increased excitation of neurons, is key in the development of epilepsy including TLE.

Scientists therefore have speculated that enhancing inhibition by GABA-neurons may alleviate status epilepticus due to renewed inhibitory balance.

A study by Upadhya and colleagues (published in 2019 in PNAS); aimed to investigate whether iPSCs grafted into the brain of rats could reduce seizures and reverse damage in the hippocampus. They found that medial ganglionic eminence (MGE) cells derived from human-derived iPSCs, grafted into the hippocampus successfully reduced the frequency of seizures and reduced GABA-ergic neuronal loss.

Furthermore, there was an improvement to cognition and mood. Although this study was performed in rats, the implications of this research has far reaching potential to be used clinically.

Another study, a Phase I clinical trial in 22 patients, using autologous mesenchymal stem cells in epilepsy patients was shown to reduce overall seizure frequency (published in Advances in Medical Sciences by Hlebokazov and colleagues in 2017). Stem cells were obtained from patients’ own bone marrow, and administered intravenously and through a single injection into the spinal cord. After 1 year, 3 out of 10 patients achieved complete remission (no seizures) and another 5 patients that previously did not respond to drugs began to respond favourably. No side effects were observed in any of the patients.

This study is promising and showed a good safety profile for the patients. It appears that stem cells were associated with  alleviation of pathological hallmarks as well as the symptoms of epilepsy. Though this was only a Phase I trial with a very small cohort, additional controlled trials with placebos are needed in a larger cohort to make any definitive conclusions on the efficacy and safety.

In summary, stem cell based therapies, show promising results in the treatment of diseases including epilepsy. Animal and clinical studies have shown the remarkable efficacy of stem cells’ regenerative properties. However, larger clinical trials are needed before stem cell therapy can become routine. It is also expensive with therapies starting at around $5,000-$8,000 per treatment, though they can be as expensive as $25,000. In the UK, the NHS does not offer stem cell therapy routinely, only for a very small number of people in designated centres for diseases such as MS.

In the United States, the only type of stem cell therapy that has been extensively studied and approved for human treatment involves use of hematopoietic stem cells for patients with certain types of cancer.

Sources:

  1. NHS.uk, 2019. Epilepsy. https://www.nhs.uk/conditions/epilepsy/
  2. NIH.gov, 2019. Stem Cell Information. https://stemcells.nih.gov/info/basics/1.htm
  3. Upadhya et al, 2019. Human induced pluripotent stem cell-derived MGE cell grafting after status epilepticus attenuates chronic epilepsy and comorbidities via synaptic integration. PNAS. 116(1):287-96. https://www.pnas.org/content/116/1/287.short?rss=1
  4. Hlebokazov et al, 2017. Treatment of refractory epilepsy patients with autologous mesenchymal stem cells reduces seizure frequency: An open label study. Adv Med Sci. 62(2):273-279. https://www.ncbi.nlm.nih.gov/pubmed/28500900

Further Reading

 

Last Updated: Jul 5, 2019

Osman Shabir

 

Written by

Osman Shabir

Osman is a Neuroscience PhD Research Student at the University of Sheffield studying the impact of cardiovascular disease and Alzheimer’s disease on neurovascular coupling using pre-clinical models and neuroimaging techniques.

 

via Can Stem Cells be Used to Treat Epilepsy?

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[Abstract] Epilepsy under the scope of ultra-high field MRI

Highlights

Ultra-high field magnetic resonance imaging can resolve sub-millimeter anatomy and quantify constitutive brain molecules.

Structural and susceptibility imaging can probe the brain for changes in the course of epilepsy.

Ex vivo high-resolution imaging can identify specific histological patterns related to demyelination and cell death.

Multimodal histological-MRI studies can help to confront preoperative diagnosis and postoperative outcome.

UHF-MRI offer potential biomarkers in epilepsy diagnosis and monitoring

Abstract

Ultra-high field magnetic resonance imaging (UHF-MRI) is capable of unraveling anatomical structures in a submillimeter range. In addition, its high resonance regime allows the quantification of constitutive molecules in a spatially sensitive manner, a crucial capability for determining the extent and localization of a probable epileptogenic region or the severity of the epilepsy. The main technical challenges for data acquisition under UHF are to produce a strong, homogeneous transverse field, while keeping the tissue power deposition within the safe regulatory guidelines. The nonuniformities caused by destructive and constructive interferences at UHFs required new technologies to accelerate and increase yield regarding time spent and quality achieved. Image quality is the paramount contribution of UHF high-resolution imaging, which is capable to disclose fine details of the hippocampal formation and its surroundings and their changes in the course of epilepsy. Other sequences like diffusion tensor imaging (DTI) and multiecho susceptibility imaging at 7 T in vivo can assist the creation of normative atlases of the hippocampal subfields or the reconstruction of the highly arborized cerebral blood vessels. In our review, we specify the impact of these advanced relevant techniques onto the study of epilepsy. In this context, we focused onto high field high-resolution scanners and clinically-enriched decision-making. Studies on focal dysplasias correlating ex vivo high-resolution imaging with specific histological and ultrastructural patterns showed that white matter hyperintensities were related to a demyelination process and other alterations. Preliminary results correlating thick serial sections through bioptic epileptogenic tissue could extend the strategy to localize degenerated tissue sectors, correlate nature and extent of tissue loss with preoperative diagnosis and postoperative outcome. Finally, this protocol will provide the neurosurgeon with a detailed depiction of the removed pathologic tissue and possible adverse effects by the pathologic tissue left in situ.

This article is part of the special issue “NEWroscience 2018”

via Epilepsy under the scope of ultra-high field MRI – ScienceDirect

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[Abstract] The Role of EEG in the Erroneous Diagnosis of Epilepsy

Summary

Errors in diagnosis are relatively common in medicine and occur in all specialties. The consequences can be serious for both patients and physicians. Errors in neurology are often because of the overemphasis on “tests” over the clinical picture. The diagnosis of epilepsy in general is a clinical one and is typically based on history. Epilepsy is more commonly overdiagnosed than underdiagnosed. An erroneous diagnosis of epilepsy is often the result of weak history and an “abnormal” EEG. Twenty-five to 30% of patients previously diagnosed with epilepsy who did not respond to initial antiepileptic drug treatment do not have epilepsy. Most patients misdiagnosed with epilepsy turn out to have either psychogenic nonepileptic attacks or syncope. Reasons for reading a normal EEG as an abnormal one include over-reading normal variants or simple fluctuations of background rhythms. Reversing the diagnosis of epilepsy is challenging and requires reviewing the “abnormal” EEG, which can be difficult. The lack of mandatory training in neurology residency programs is one of the main reasons for normal EEGs being over-read as abnormal. Tests (including EEG) should not be overemphasized over clinical judgment. The diagnosis of epilepsy can be challenging, and some seizure types may be underdiagnosed. Frontal lobe hypermotor seizures may be misdiagnosed as psychogenic events. Focal unaware cognitive seizures in elderly maybe be blamed on dementia, and ictal or interictal psychosis in frontal and temporal lobe epilepsies may be mistaken for a primary psychiatric disorder.

via The Role of EEG in the Erroneous Diagnosis of Epilepsy : Journal of Clinical Neurophysiology

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