This article is for awareness and is not intended to raise alarm.
Antiepileptic drugs may induce psychotic disorders in a small minority of people, according to a new study published in the leading journal Brain.
The study also showed, however, that antiepileptic drug-induced psychotic disorder (AIPD) generally has a better outcome than psychotic disorders caused by other factors.
The authors speculate that AIPD could be improved by stopping the causative antiepileptic drug. They state: “If treated properly, the cases with AIPD might have shorter duration of the psychotic episode than other types of psychosis. The timely cessation of the offending drug and avoidance of prescription again would offer protection against further AIPD.”
Professor Patrick Kwan, Chair of Neurology at the University of Melbourne, and his team, analysed the medical records of 2630 people with epilepsy obtained between 1993 and 2015 at the Royal Melbourne Hospital.
They found that 98 people (3.7%) also had psychotic disorders, which in 14 (14.4%) was triggered by the use of antiepileptic drugs. The researchers concluded from this that in approximately 1/7 cases, psychotic disorders seen in people with epilepsy could be induced by the use of AEDs.
Female gender, temporal lobe epilepsy and use of levetiracetam showed significant association with AIPD compared with other types of psychosis. Carbamazepine, on the other hand, was associated with a decreased risk of AIPD (this was the drug mostly used by the group that did not develop AIPD).
It is recognised that people with epilepsy have a higher risk of developing psychiatric problems. The present study suggests that certain antiepileptic drugs might also contribute to this risk.
Psychotic disorders are severe mental disorders characterised by delusions (false believes) and hallucinations (false perceptions). They can be caused by alcohol, some drugs, brain tumours, brain infections and stroke.
Author: Dr Özge Özkaya
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Interictal epileptiform discharges have an independent association with cognitive impairment in children with lesional epilepsy
The relative contribution of interictal epileptiform discharges (IEDs) to cognitive dysfunction in comparison with the underlying brain pathology is not yet understood in children with lesional focal epilepsy.Methods
The current study investigated the association of IEDs with intellectual functioning in 103 children with medication-resistant focal epilepsy. Hierarchical multiple regression analyses were used to determine the independent contribution of IED features on intellectual functioning, after controlling for effects of lesional pathology, epilepsy duration, and medication. Exploratory analyses were conducted for language and memory scores as well as academic skills available in a subset of participants.Results
The results reveal that IEDs have a negative association with IQ with independent, additive effects documented for frequent and bilaterally distributed IEDs as well as discharge enhancement in sleep. Left-lateralized IEDs had a prominent effect on verbal intelligence, in excess of the influence of left-sided brain pathology. These effects extended to other cognitive functions, most prominently for sleep-enhanced IEDs to be associated with deficits in expressive and receptive language, reading, spelling and numerical skills.Significance
Overall, IED effects on cognition were of a magnitude similar to lesional influences or drug effects (topiramate use). This study demonstrates an association between IEDs and cognitive dysfunction, independent of the underlying focal brain pathology.
The hippocampal form of an essential muscle protein called dystrophin is found in higher levels in people with temporal lobe epilepsy (TLE), according to a new study published in the scientific journal Frontiers in Cellular Neuroscience.
This could be the result of a compensatory mechanism – in response to too much excitation in the brain (hyperexcitation) – that tries to restore the inhibitory balance. Exploring the relationship between the different forms of dystrophin found in the central nervous system and hyperexcitation may highlight a new treatment target for epileptic seizures.
The researchers, led by Dr Johan Vles, at Maastricht University Medical Centre in the Netherlands, took biopsies from the brains of people with TLE and looked at the distribution of the dystrophin protein within them. They compared this to similar samples obtained from deceased donors who did not have epilepsy (controls).
They found that the level of full-length dystrophin in the hippocampus (an important memory structure) was 60% higher in people with TLE than in controls.
The team then looked at the levels of dystrophin in the hippocampus and the cerebellum (which helps regulate muscle activity) of a rat model of TLE, and compared them to control animals; however they saw no differences between the two groups in either region.
Taken together, these results suggest that the increase in dystrophin in TLE is specific to the hippocampus and also unique to human epilepsy. Investigation of the mechanisms behind the increase in hippocampal dystrophin in response to hyperexcitation could lead to new therapies.
Dystrophin is an essential muscle protein and mutations in the dystrophin gene that result in the absence of the protein cause a muscle-wasting condition known as Duchenne muscular dystrophy. In addition to the role it plays in muscle tissue, dystrophin also functions as an anchoring protein within the central nervous system, which explains why Duchenne muscular dystrophy may be accompanied by cognitive and behavioural difficulties and epilepsy.
Author: Dr Özge Özkaya
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Research published in the scientific journal PLOS One suggests that children with epilepsy have irregularities in their pattern of saccadic eye movement. This refers to the fast, jerking movement of the eyes that allows people to scan their environment and build a mental 3D image of it.
According to the authors of the study, these irregularities may be indicative of abnormal development of the cerebral cortex – the outer layer of the brain that plays a role in memory, attention, perception, awareness, thought, language and consciousness – and disrupted communication between different areas of the brain.
These results suggest that it may be beneficial to assess eye movement as part of neuropsychological assessments in people with epilepsy, because it could provide doctors with valuable information about the person’s cognitive function, the progress of their condition and the effectiveness of treatment.
The researchers, led by Dr Trevor Crawford, Reader of Neuropsychology at Lancaster University, analysed the saccadic eye movement of 26 children with epilepsy aged 8 to 18 and compared this to the saccadic eye movement of 48 healthy controls in the same age range.
The team asked the children to look at a fixation point and presented them with a visual target. They then asked the children to make a saccade away from the target (known as antisaccade) or towards the target (known as (prosaccade).
The researchers analysed a number of factors about the subjects’ eye movements, including speed of response, accuracy, error rate and maximum speed of eye movement, and then compared the results of those with epilepsy who were taking antiepileptic drug (AEDs), those with epilepsy who were not taking AEDs and healthy controls.
They found that children with epilepsy who were taking AEDs had a more variable processing speed, reduced accuracy, increased maximum eye speed and made a greater number of errors.
Younger children with epilepsy who were not taking AEDs showed deficits in realising their own errors (error monitoring), which were related to attention problems that had been reported in them.
Saccadic eye movements can be used to evaluate different aspects of brain function. In epilepsy they could be used to follow how the condition progresses and assess how well an AED works.
Author: Dr Özge Özkaya
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Family-centered care in children with epilepsy: Evaluating the Measure of Processes of Care (MPOC-20)
The objective was to test whether the five-domain structure of the Measure of Processes of Care (MPOC-20) was observed in a sample of children with epilepsy and, if not, to propose adaptations to improve its utility in this population.Methods
Data came from the Health-Related Quality of Life in Children with Epilepsy Study (HERQULES)—a multicenter prospective cohort study (n = 374) following children 4–12 years of age for 2 years after diagnosis. Confirmatory factor analysis (CFA) tested the applicability of the five domains/factors in a sample of children with epilepsy approximately 6 months following diagnosis (n = 311). Goodness-of-fit statistics were used to examine sources of ill model fit, and modification indices guided the model modification process where there was strong theoretical rationale for changes.Results
The five-factor model described by the originators of the MPOC-20 was found to be inadmissible in children with epilepsy, with four of the five factors demonstrating high correlations (r > 0.85). Upon merging the intercorrelated factors, a two-factor solution with a mediocre fit emerged (Root Mean Square Error of Approximation (RMSEA) = 0.080, Comparative Fit Index (CFI) = 0.902, Standardized Root Mean Square Residual (SRMR) = 0.060). Modification indices identified four items as the source of poor model fit. Removing these four items and reperforming the CFA resulted in an adequate model fit and a revised 16-item MPOC (RMSEA = 0.057, CFI = 0.958, SRMR = 0.036). The two factors are “Family/Care Provider Interaction” and “Providing Information.”Significance
Results suggest that the MPOC-16 better reflects family-centered care (FCC) in children with epilepsy than the original MPOC-20. The benefit of having fewer factors is that scoring is simpler and the interpretation of the results is easier. This was the first investigation of the factor structure of the MPOC-20 on a sample entirely composed of children with epilepsy. These results add to evidence that the factor structure (and how family-centered care is delivered and perceived) differs across treatment environments and treatment populations.
Midazolam–ketamine dual therapy stops cholinergic status epilepticus and reduces Morris water maze deficits
Pharmacoresistance remains an unsolved therapeutic challenge in status epilepticus (SE) and in cholinergic SE induced by nerve agent intoxication. SE triggers a rapid internalization of synaptic γ-aminobutyric acid A (GABAA) receptors and externalization of N-methyl-d-aspartate (NMDA) receptors that may explain the loss of potency of standard antiepileptic drugs (AEDs). We hypothesized that a drug combination aimed at correcting the consequences of receptor trafficking would reduce SE severity and its long-term consequences.Methods
A severe model of SE was induced in adult Sprague-Dawley rats with a high dose of lithium and pilocarpine. The GABAA receptor agonist midazolam, the NMDA receptor antagonist ketamine, and/or the AED valproate were injected 40 min after SE onset in combination or as monotherapy. Measures of SE severity were the primary outcome. Secondary outcomes were acute neuronal injury, spontaneous recurrent seizures (SRS), and Morris water maze (MWM) deficits.Results
Midazolam–ketamine dual therapy was more efficient than double-dose midazolam or ketamine monotherapy or than valproate–midazolam or valproate–ketamine dual therapy in reducing several parameters of SE severity, suggesting a synergistic mechanism. In addition, midazolam–ketamine dual therapy reduced SE-induced acute neuronal injury, epileptogenesis, and MWM deficits.Significance
This study showed that a treatment aimed at correcting maladaptive GABAA receptor and NMDA receptor trafficking can stop SE and reduce its long-term consequences. Early midazolam–ketamine dual therapy may be superior to monotherapy in the treatment of benzodiazepine-refractory SE.
Epilepsy is one of the most common serious neurologic conditions. It is characterized by the tendency to have recurrent seizures, which arise against a backdrop of apparently normal brain activity. At present, clinical diagnosis relies on the following: (1) case history, which can be unreliable; (2) observation of transient abnormal activity during electroencephalography (EEG), which may not be present during clinical evaluation; and (3) if diagnostic uncertainty occurs, undertaking prolonged monitoring in an attempt to observe EEG abnormalities, which is costly. Herein, we describe the discovery and validation of an epilepsy biomarker based on computational analysis of a short segment of resting-state (interictal) EEG. Our method utilizes a computer model of dynamic networks, where the network is inferred from the extent of synchrony between EEG channels (functional networks) and the normalized power spectrum of the clinical data. We optimize model parameters using a leave-one-out classification on a dataset comprising 30 people with idiopathic generalized epilepsy (IGE) and 38 normal controls. Applying this scheme to all 68 subjects we find 100% specificity at 56.7% sensitivity, and 100% sensitivity at 65.8% specificity. We believe this biomarker could readily provide additional support to the diagnostic process.
News from the University of Glasgow
What’s the difference between good and bad quality research? Why do the findings in one study appear to contradict the results in another? Which piece of expert advice should I really trust?
Although health research appears in the media almost every day, most people find it difficult to know which studies are good quality and which ones are not. At present, only a small section of society, mainly clinicians and researchers, are taught how to critically appraise scientific health evidence.
Now academics behind a new online tool that will help people “ask the right questions” and “understand and evaluate” health research, hope to change that.
Understanding Health Research is a new website that has been created by the MRC/CSO Social and Public Health Sciences Unit (MRC/CSO SPHSU), University of Glasgow, in collaboration with an advisory panel of academics. The site, which is launched today, offers a free, interactive, online service designed to help people better understand complex health research and “go beyond the headlines”.
Designed to be useful for a range of people including patients, carers, students, policymakers, health professionals, researchers and those working in the third sector, the site guides users through the process of understanding health research.
Users are presented with a step-by-step series of questions to answer about the piece of research they are interested in, and given guidance on what these questions mean and why the answers matter to them. The line of questioning varies according to the answers given, and it attempts to raise critical thinking about what to look out for when trying to work out what might be good research – e.g. funding sources, peer review, and ethics – as well as asking about the specific type of research being appraised.
Ultimately the site hopes to further understanding of a piece of published health research, explaining and reinforcing key scientific concepts along the way.
At the end of the process, the user is provided with a summary of their answers so that they can use these to come to their own conclusions about the research they have been looking at.
Dr Shona Hilton, Deputy Director MRC/CSO SPHSU, said: “Understanding Health Research is a tool that can really help people to ask the right questions to understand and evaluate research studies.
“Without the tools to assess contradictory health messages and claims about new discoveries and treatments, the public are vulnerable to false hope, emotional distress, financial exploitation and serious health risks.”
With an increasing focus on ‘open access’ publishing in science, scientific health research is easier to access than ever, but the content of research remains largely inaccessible to people without scientific training.
The Understanding Health Research site also provides succinct, Plain English introductions to complex scientific concepts and links to resources that help promote health literacy.
Dr David Ogilvie, MRC Epidemiology Unit, University of Cambridge, said: “More and more scientific papers are out there on the internet, freely available for anyone to read. But providing access to papers is not the same thing as making research accessible to people.
“Tools like Understanding Health Research can help make science more democratic and more useful by making it easier for people to engage with it, whether they work with health evidence in their jobs or are just interested citizens.”
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Please note that Epilepsy Research UK does not endorse/promote individual epilepsy treatments or pharmaceutical companies.
Zynerba Pharmaceuticals, a US-based pharmaceutical company, has ‘dosed’ the first participant in its STAR1 clinical trial, which aims to evaluate the safety and effectiveness of a cannabidiol gel called ZYN002 in adults with refractory focal epilepsy.
Armando Anido, Chairman and Chief Executive Officer of Zynerba Pharmaceuticals, said in a press release: “The dosing of the first patients in the STAR 1 clinical trial in adults with refractory epilepsy is a significant milestone for the company.” He added: “We are pleased by the pace of the clinical program for ZYN002.”
The randomised phase two clinical trial aims to recruit 180 adults with refractory, or drug resistant, epilepsy. Following an eight-week baseline period to assess their seizure types and frequencies, the participants will receive one of two different doses of the drug, or an identical looking placebo, every 12 hours for 12 weeks.
Researchers will evaluate the change in the participants’ seizure frequency over the 12-week period of treatment. The first results from the trial are expected in the first half of 2017.
The study is currently being conducted in Australia and New Zealand and there are currently no sites in the UK recruiting participants; however any results arising from this trial may also be beneficial for people in the UK.
Previous research has shown that cannabidiol treatment may be beneficial in reducing seizure frequency in people with drug-resistant epilepsy. The ZYN002 gel is a synthetic cannabidiol designed to be transmitted through patches on the skin in a consistent and controlled way. As the drug is absorbed through the skin directly, it does not go through the gastrointestinal system and is not degraded by stomach acids. In addition, liver metabolism is avoided, potentially allowing lower doses of the drug to be used to obtain a beneficial effect.
Click here for more articles about anti-epileptic drugs and pregnancy risks.
The progression of electrophysiologic abnormalities during epileptogenesis after experimental traumatic brain injury
Posttraumatic epilepsy (PTE) accounts for 20% of acquired epilepsies. Experimental models are important for studying epileptogenesis. We previously reported that repetitive high-frequency oscillations with spikes (rHFOSs) occur early after lateral fluid percussion injury (FPI) and may be a biomarker for PTE. The objective of this study was to use multiple electrodes in rat hippocampal and neocortical regions to describe the long-term electroencephalographic and behavioral evolution of rHFOSs and epileptic seizures after traumatic brain injury (TBI).Methods
Adult male rats underwent mild, moderate, or severe FPI or sham injury followed by video–electroencephalography (EEG) recordings with a combination of 16 neocortical and hippocampal electrodes at an early, intermediate, or late time-point after injury, up to 52 weeks. Recordings were analyzed for the presence of rHFOSs and seizures.Results
Analysis was done on 28 rats with FPI and 7 shams. Perilesional rHFOSs were recorded in significantly more rats after severe (70.3%) than mild (20%) injury or shams (14.3%). Frequency of occurrence was significantly highest in the early (10.8/h) versus late group (3.2/h). Late focal seizures originating from the same electrodes were recorded in significantly more rats in the late (87.5%) versus early period (22.2%), occurring almost exclusively in injured rats. Seizure duration increased significantly over time, averaging 19 s at the beginning of the early period and 27 s at the end of the late period. Seizure frequency also increased significantly over time, from 4.4 per week in the early group to 26.4 per week in the late group. Rarely, rats displayed early seizures or generalized seizures.Significance
FPI results in early rHFOSs and later spontaneous focal seizures arising from peri-lesional neocortex, supporting its use as a model for PTE. Epilepsy severity increased over time and was related to injury severity. The association between early rHFOSs and later focal seizures suggests that rHFOSs may be a potential noninvasive biomarker of PTE.
Almost 80% of children with epilepsy also have an accompanying disorder, known as a comorbidity, according to a new study published in the scientific journal Pediatrics. This highlights the importance of a comprehensive approach to care.
The authors state: “The management should not only focus on the epileptic seizures, but should also include thorough assessments of all aspects of health, including development, psychiatric symptoms, nutrition, growth, and sleep.”
The researchers, led by Dr Richard Chin, at the University of Edinburgh, analysed data obtained between 2008 and 2013 for more than one million children born in Norway between 1996 and 2013. They divided the children into three groups: those with ‘complicated’ epilepsy (who also had accompanying medical/neurological/developmental disorders (comorbidities)), those with ‘uncomplicated’ epilepsy (who had no additional disorders) and those without epilepsy.
They found that, of these children, 0.6% had epilepsy and, of these, approximately 80% also had at least one comorbidity.
The team found that children with epilepsies that were difficult to treat, or worsened/evolved, had higher rates of comorbidity than both children with ‘easier to treat’ epilepsies and children without epilepsy. However, the rate of comorbidity was still high in children whose epilepsy was easier to manage.
The prevalence of all medical conditions was higher in children with epilepsy and almost 50% of the children with epilepsy had developmental or psychiatric difficulties. This figure was less than 10% for the general population.
Children with epilepsy are known to be at higher risk of other neurological disorders such as intellectual disability and autism, as well as developmental and psychiatric conditions. The present study is one of few nationwide studies assessing a broad range of medical conditions in children with epilepsy.
Author: Dr Özge Özkaya
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A mutation in a gene called RyR2 may increase the risk of sudden unexpected death in epilepsy (SUDEP), according to a new study published in the leading scientific journal Proceedings of the National Academy of Sciences (PNAS).
The authors believe that this is an important step towards being able to predict the risk of SUDEP in a person with epilepsy and take necessary measures to avoid it.
In a press release, Senior Author Dr Jeffrey L. Noebels, from the Baylor College of Medicine in Houston, said: “We have been looking for genes that cause epilepsy to see if any of them might give us a clue as to who might be at risk (of SUDEP). Specifically, we have been looking at genes that might explain what appears to be a collapse of the cardiac and respiratory system after a seizure.”
Dr Noebels and his team have identified mutations in several genes expressed* in the brain and heart that cause an abnormal heartbeat and epilepsy in rodents. Most recently, they have shown that a mutation in the RyR2 gene causes both heart problems and seizures in mice.
The Ryr2 (or ryanodine receptor 2) gene encodes a protein that plays a role in regulating the level of calcium inside cells. Calcium levels inside neurons influence their communication by mediating the amount of neurotransmitter that is released from them. The mutation in the Ryr2 gene causes the amount of calcium inside cells to be higher than normal, resulting in the amount of neurotransmitter released from neurons to be too high. This triggers seizures.
The authors found that it was much easier to experimentally trigger blackouts in the brainstem of mice carrying a mutation in the Ryr2 gene than in mice that did not have the mutation. Mice that had these blackouts in the brain stem, where breathing and heart function are regulated, were prone to sudden death.
Approximately 6% of people with epilepsy have a higher than usual incidence of SUDEP, and SUDEP is the most common cause of premature death in people with epilepsy.
* The term ‘gene expression’ refers to the process by which information from a gene is used to create a functioning gene product, very often a protein.
Author: Dr Özge Özkaya
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