A new small molecule that can be taken orally, called ADX71149, could have antiepileptic effects on its own or when used in combination with the widely available anti-seizure drug levetiracetam according to experiments conducted in a mouse model of epilepsy, the results of which were published in the scientific journal Epilepsia.
Robert Lütjens, Head of Discovery of Addex Therapeutics that co-developed ADX71149, said in a press release: “These studies performed by our collaborator Janssen Pharmaceuticals, Inc. suggest there is a positive pharmacodynamic relationship or strong synergistic effect for ADX71149 and levetiracetam when given in combination”. He added that if this effect can be translated into the clinic, it could offer a potential treatment option for people with epilepsy.
ADX71149 is a molecule that binds to a receptor called metabotropic glutamate receptor 2 or mGluR2, which is involved in most aspects of normal brain function. In order to test the efficacy of the compound, researchers led Professor Steve White at the University of Utah used an approach called the 6 Hz psychomotor seizure test. The test assesses the ability of new compounds to block a psychomotor seizure, which is induced by long-duration, low frequency (6 Hz) stimulation, a model of therapy-resistant complex partial seizures.
The results showed that ADX71149 is able to reduce seizures on its own and in combination with LEV. Importantly, the use of ADX71149 enables the reduction of the dose of levetiracetam necessary to obtain a full response. This is important because high doses of levetiracetam are associated with adverse side effects, such as aggression, nervousness, anxiety, somnolence, and fatigue, which limits its use.
When scientists used a fixed dose of ADX71149, they saw that the effect of levetiracetam was increased almost 35 fold. When they kept the dose of levetiracetam constant and used different doses of ADX71149, they found that the efficacy of ADX71149 was increased 14 fold. These results suggest that ADX71149 and levetiracetam increase each others efficacy and a combination of the two compounds could potentially be a therapeutic option for people with drug-resistant epilepsy.
“Treatment-resistant epilepsy remains a high unmet medical need, with new avenues of treatment urgently needed,” said Tim Dyer, the chief executive officer of Addex Therapeutics. “We are continuing to explore with Janssen how best to move ADX71149 into a Phase 2a proof of concept study,”
Author: Dr Özge Özkaya
“I would like to introduce myself as the newly appointed Chief Executive of Epilepsy Research UK. It is a real honour to have been given the opportunity to lead a charity that my family and I had already been supporting and I am looking forward to working with all of you, the incredibly hard working staff here, and the Board of Trustees to further the ambitions of the charity.
Without you we would not be able to fund the valuable research that we all know is needed. Your activity and fundraising is the lifeblood of the charity and after 25 successful years, we are keen to get your opinions on how the charity should now develop into the future.
We are setting ambitious targets. £1m into research by the end of 2018 and £2m by the end of 2020. With your support we can achieve these targets.
We also want to make more people aware of the importance of epilepsy research and the impact that it can have on this potentially debilitating condition. Research not only improves the life of people right now, but will also improve the lives of the many people who will develop epilepsy in the future. We believe that research is essential if we are going to find a cure, new treatments, or greater understanding of the condition that may lead to those things. At Epilepsy Research UK we aim to provide the funding for the research that will help change lives. This is something we can all do together.
Over the next couple of months I am keen to speak to as many people as possible about how you think we can realise our ambition. I would like to know what more we could do to help your fundraising, things you think we should focus on and even, maybe things that you do not think we should do.
I aim to speak to supporters, researchers and anyone else with an interest in epilepsy research and I want people to be honest about what we are doing well and what we are not doing so well. I have put aside time to speak to people directly and you can click here to book me to call you at your convenience for a longer discussion.
Over the past 25 years in our various guises as the British Epilepsy Research Foundation, the Epilepsy Research Foundation, the Fund for Epilepsy and now as Epilepsy Research UK, we have raised millions of pounds for epilepsy research. I am determined to work with you to continue that proud tradition.”
Mike Rich, Chief Executive, Epilepsy Research UK
March contains much good news. Spring starts to break, for the more somnolent of us it is National Bed month and it is also National Free Wills month. This is an ideal time to tackle one of those things that many of us put off, and off, and off. Due to our membership of the Free Wills Network it is possible for you to get a simple Will written, or your existing Will changed, by a local solicitor at no cost to you.
There is absolutely no obligation on you to leave a gift to Epilepsy Research UK in your Will but, obviously, we hope that you do as gifts in Wills are a major source of our research funding every year.
It is a very simple process. Call us on 020 8747 5024, or email us your name and address with reply code ‘Free Wills’, and we will arrange for the National Free Wills Network to send you the names and addresses of at least two local firms of solicitors taking part in the scheme. The solicitor will then draw up your Will and you won’t have to pay the bill.
So, this March, forget National Bed Month and do something you may well have been putting off. Exercise your free Will.
This is a limited offer without any obligation on those who take up the offer to include a bequest to Epilepsy Research UK.
To identify features of ablations and trajectories that correlate with optimal seizure control and minimize the risk of neurocognitive deficits in patients undergoing laser interstitial thermal therapy (LiTT) for mesiotemporal epilepsy (mTLE).Methods
Clinical and radiographic data were reviewed from a prospectively maintained database of all patients undergoing LiTT for the treatment of mTLE at the University of Miami Hospital. Standard preoperative and postoperative evaluations, including contrast-enhanced magnetic resonance imaging (MRI) and neuropsychological testing, were performed in all patients. Laser trajectory and ablation volumes were computed both by manual tracing of mesiotemporal structures and by nonrigid registration of ablation cavities to a common reference system based on 7T MRI data.Results
Among 23 patients with at least 1-year follow-up, 15 (65%) were free of disabling seizures since the time of their surgery. Sparing of the mesial hippocampal head was significantly correlated with persistent disabling seizures (p = 0.01). A lateral trajectory through the hippocampus showed a trend for poor seizure outcome (p = 0.08). A comparison of baseline and postoperative neurocognitive testing revealed areas of both improvement and worsening, which were not associated with ablation volume or trajectory.Significance
At 1-year follow-up, LiTT appears to be a safe and effective tool for the treatment of mTLE, although a longer follow-up period is necessary to confirm these observations. Better understanding of the impact of ablation volume and location could potentially fine-tune this technique to improve seizure-freedom rates and associated neurologic and cognitive changes.
Association of CYP2C9, CYP2A6, ACSM2A, and CPT1A gene polymorphisms with adverse effects of valproic acid in Chinese patients with epilepsy
Lack of oxygen, not excessive stimulation, cause for half of seizure-related brain damage in epilepsy
Children whose mothers used antiepileptic drugs (AEDs) while pregnant are not more likely to visit their GP during their childhood, according to a population-based study by Danish scientists.
It is important to note that the study only analyzed the frequency of primary healthcare visits and did not take into account complications such as malformations at birth and neurological and psychiatric disorders later in life, found to be associated with the use of AEDs by the mother, in previous studies.
Instead, the present study only looked at the general health of children whose mothers used AEDs while they were pregnant and compared this to that of children who were not exposed to AEDs before birth.
The team of researchers led by Dr Bodil Hammer Bech, at Aarhus University in Denmark identified all babies born in Denmark between 1997 and 2012 and followed them until 31 December 2013, through the Danish National Patient Register. They found that 963,010 babies were born in this period of time.
The researchers obtained information on whether or not the babies were exposed to AEDs before birth from the Danish Register of Medicinal Product Statistics. This revealed that 4,478 children (0.46%) were exposed to AEDs before birth.
The team then analyzed the number of GP visits for reasons other than routine checks and vaccinations. They found that children who were exposed to AEDs before birth had 3% more GP contacts during the study period compared to children who were not exposed to AEDs before birth. This was primarily in the form of phone contacts. The researchers did not find any difference between children who were exposed to AEDs before birth and those who were not, in terms of specific services provided by the GP.
The first author of the study Anne Mette Lund Würtz said in a press release: ”Our results are generally reassuring for women who need to take anti-epilepsy medicine during their pregnancy”.
The analysis took into account factors such as the child’s gender and date of birth, the mother’s age, the family’s income level, education status, the presence of any mental illnesses, the use of psychiatric medicines and insulin, and substance abuse.
The results were published in the scientific journal BMJ Open.
Author: Özge Özkaya
To respond to recommendations put forth by the Institute of Medicine to improve self-management resources for youth with epilepsy by conducting a systematic review of the self-management literature in pediatric epilepsy.Methods
Inclusion criteria: youth birth to 18 years with a seizure disorder or an epilepsy diagnosis and/or their caregivers, published 1985–2014 in English, and conducted in countries with a very high human development index. Abstract and keywords had to explicitly refer to “self-care” (pre-1996) and/or self-management (post-1996). The review was conducted in seven phases: (1) identification of bibliographical search criteria and databases; (2) abstract assessment; (3) full article review; (4) organization of final citations into instrument development, intervention, factors associated with self-management categories; (5) American Academy of Neurology level of evidence (LOE) assessment for intervention studies; (6) CONsolidated Standards of Reporting Trials (CONSORT) evaluation of LOE level III articles utilizing a control group; and (7) categorization of intervention outcomes across four self-management domains.Results
Of the 87 articles that met eligibility criteria, 24 were interventions and received LOE scores of level III or IV. Most studies (n = 20, 80%) were scored at level III; however, only eight had a control group and adhered to CONSORT guidelines. They largely neglected information on intervention components (e.g., implementation, treatment fidelity), randomization, participant flow, missing data, and effect size or confidence intervals. The 24 intervention studies reported significant impact in four domains: individual (n = 13), family (n = 6), health care system (n = 3), and community (n = 2).Significance
There are no level I or II studies. No study met full CONSORT guidelines. Outcomes were well described; however, the nature of self-management interventions (e.g., multiple foci, skills targeted) and the observed heterogeneity in outcomes complicates comparisons across studies. Randomized controlled trials (RCTs) that include large sample sizes, impact of the intervention, treatment fidelity, and power analyses are necessary to further this evidence base.
Carisbamate (CRS) is a novel monocarbamate compound that possesses antiseizure and neuroprotective properties. However, the mechanisms underlying these actions remain unclear. Here, we tested both direct and indirect effects of CRS on several cellular systems that regulate intracellular calcium concentration [Ca2+]i.Methods
We used a combination of cellular electrophysiologic techniques, as well as cell viability, Store Overload-Induced Calcium Release (SOICR), and mitochondrial functional assays to determine whether CRS might affect [Ca2+]i levels through actions on the endoplasmic reticulum (ER), mitochondria, and/or T-type voltage-gated Ca2+ channels.Results
In CA3 pyramidal neurons, kainic acid induced significant elevations in [Ca2+]i and long-lasting neuronal hyperexcitability, both of which were reversed in a dose-dependent manner by CRS. Similarly, CRS suppressed spontaneous rhythmic epileptiform activity in hippocampal slices exposed to zero-Mg2+ or 4-aminopyridine. Treatment with CRS also protected murine hippocampal HT-22 cells against excitotoxic injury with glutamate, and this was accompanied by a reduction in [Ca2+]i. Neither kainic acid nor CRS alone altered the mitochondrial membrane potential (ΔΨ) in intact, acutely isolated mitochondria. In addition, CRS did not affect mitochondrial respiratory chain activity, Ca2+-induced mitochondrial permeability transition, and Ca2+ release from the ER. However, CRS significantly decreased Ca2+ flux in human embryonic kidney tsA-201 cells transfected with Cav3.1 (voltage-dependent T-type Ca2+) channels.Significance
Our data indicate that the neuroprotective and antiseizure activity of CRS likely results in part from decreased [Ca2+]i accumulation through blockade of T-type Ca2+ channels.
Risk of vigabatrin-associated brain abnormalities on MRI in the treatment of infantile spasms is dose-dependent
Although the link between vigabatrin (VGB) and retinotoxicity is well known, little attention has been focused on the risk of VGB-associated brain abnormalities on magnetic resonance imaging (MRI) (VABAM), namely reversible—and largely asymptomatic—signal changes in the thalami, basal ganglia, brainstem tegmentum, and cerebellar nuclei. Using a large infantile spasms cohort, we set out to identify predictors of these phenomena.Methods
Children with infantile spasms were retrospectively identified. Brain MRI reports were serially reviewed without knowledge of VGB exposure. Upon VABAM discovery, records were systematically reviewed to ascertain presence of symptoms attributable to VGB. Separately, progress notes were sequentially reviewed to identify and quantify VGB exposure.Results
We identified 507 brain MRI studies among 257 patients with infantile spasms. VGB treatment was documented in 143 children, with detailed exposure data available for 104, of whom 45 had at least one MRI study during VGB treatment. Among the limited subset of asymptomatic children who underwent MRI (n = 40), 6 exhibited VABAM. Risk of asymptomatic VABAM was dose-dependent, as peak (but not cumulative) VGB dosage was strongly associated with asymptomatic VABAM (p = 0.0028). In an exploratory analysis, we encountered 4 children with symptomatic VABAM among 104 patients with detailed VGB exposure data. Risk of symptomatic VABAM was seemingly dose-independent, and potentially associated with concomitant hormonal therapy (i.e., prednisolone and adrenocorticotropic hormone [ACTH]) (p = 0.039).Significance
We have demonstrated dose-dependent risk of asymptomatic VABAM and uncovered a possible association between symptomatic VABAM and concomitant hormonal therapy. Caution should be exercised in the use of high VGB dosage (i.e., >175 mg/kg/day), and further study is warranted to confirm the potential impact of hormonal therapy.