Researchers at the Mario Negri Institute for Pharmacological Research in Milan, Italy led by Mattia Maroso and colleagues have found that giving mice repeated doses of a specific enzyme inhibitor significantly reduced both chronic epileptic activity and acute seizures.
Their findings, published online in the Springer journal Neurotherapeutics, open up the possibility of a new target system for anticonvulsant drug intervention, to control epileptic activity that does not respond to certain anticonvulsant treatments.
An enzyme known as ICE/Caspase-1 is involved in epileptic seizures; it induces inflammatory processes by producing IL-1beta, a pro-inflammatory molecule, in brain regions where epileptic activity originates and spreads. Mattia Maroso and colleagues looked at the elective inhibitor for this enzyme, in a mouse model of acute seizures and in mice with chronic epilepsy showing spontaneous recurrent epileptic activity.
The researchers artificially induced chronic epileptic seizures in 21 adult male mice and acute seizures in 46 mice. They then injected them with the enzyme inhibitor (VX-765) and recorded the resulting epileptic activity in brains of the mice.
They found that the enzyme inhibitor had powerful anticonvulsant effects. Repeated systemic administration reduced chronic epileptic activity in mice in a dose-dependent manner, and the effect was reversible after four days of treatment when the drug regime was discontinued. The same dose regimen also reduced acute seizures in the mice.
The authors concluded that their results support a new target system for anticonvulsant drug intervention opening new perspectives for the clinical use of this anti-inflammatory strategy for treating established drug-resistant epileptic conditions.
Citation
Maroso M, Balosso S, Ravizza T, Iori V, Wright CI, French J, et al. Interleukin-1β Biosynthesis Inhibition Reduces Acute Seizures and Drug Resistant Chronic Epileptic Activity in Mice. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2011 Mar ( 
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A newly published report reveals that children with epilepsy are more likely to have psychiatric symptoms, with gender a determining factor in their development. Findings showed that girls had more emotional problems, while boys had more hyperactivity/inattention problems and issues regarding peer relationships. Details of this study in Norwegian children are now available online in Epilepsia, a journal published by Wiley-Blackwell on behalf of the International League Against Epilepsy.
Previous studies have shown that children with epilepsy are at increased risk of developing behavioral problems and psychiatric disorders including anxiety, depression, and attention-deficit/hyperactivity disorder (ADHD). In a 2003 population-based study, psychiatric disorders were reported in 37% of children with epilepsy, while children with diabetes and those in the healthy control group were much lower at 11% and 9%, respectively (Davies et al., 2003). Medical evidence, however, has not clearly established when children or teens with epilepsy may be vulnerable to developing psychiatric issues, or how gender influences psychopathology in epilepsy.
The current study used data collected by the Norwegian Health Services Research Centre in a 2002 health profile questionnaire. For children in the 8-13 years of age group, there were 14,699 (response rate of 78%) parents who completed the questionnaire which included questions on topics such as sociodemographic conditions, physical and mental health, and psychosocial conditions. To assess psychiatric symptoms, researchers used the parent report of the Strengths and Difficulties Questionnaire (SDQ) which included questions covering four problem domains - emotional symptoms, conduct problems, hyperactivity-inattention, and peer problems - and prosocial behavior. The SDQ scores were classified as normal, borderline, or abnormal.
Based upon parent's response to the health questionnaire, 111 children were identified with epilepsy (a frequency of 0.8%), of whom 110 completed the questions included in the SDQ (64 boys and 46 girls). Researchers found that children with epilepsy had a significantly higher frequency of psychiatric symptoms (38%) compared with healthy controls (17%). Boys had a higher risk of psychiatric symptoms than girls in both the epilepsy population and in controls.
Additional risk factors were low socioeconomic status (living in a single family home, family income below poverty limit), having another chronic disease (asthma/diabetes) and epilepsy. However, these independent risk factors contributed with different prominence (odds ratio) to psychiatric problems in boys and girls in the epilepsy population. Having or having had epilepsy was a much stronger risk factor of developing psychiatric problems in girls, whereas boys with epilepsy seemed almost as affected by low socioeconomic status as having epilepsy. The authors say the reason for this remains unclear, however a previous study found a more negative attitude towards having epilepsy in girls than in boys.
Further results showed that 33% of children with epilepsy who were 8-9 years had a borderline/abnormal SDQ score compared with 18% of healthy children of the same age; 41% compared to 16% in the 10-13 year age group. "We chose to divide the groups at the age of ten years as this is the start of preadolescence. The wish 'to be like the others' and to participate in different activities as an equal may be issues of particular importance for children with epilepsy," said Dr. Kristin Alfstad of the National Centre for Epilepsy at Oslo University Hospital in Norway, and lead study author. Analysis also showed an increased risk of psychiatric problems for girls with epilepsy in the 10-13 year age group.
The current study findings confirm the psychiatric co-morbidity of epilepsy reported in prior studies. The authors noted that a lack of a standard age groups and methodology differences makes comparison of these studies difficult. "Multiple risk factors contribute to the high prevalence of psychiatric symptoms, differently in boys and girls, it seems," concluded Dr. Alfstad. "Identifying high risk groups may help clinicians who can implement interventions that prevent more serious psychiatric problems."
Source:
Dawn Peters
Wiley-Blackwell
Citation
Alfstad KÅ, Clench-Aas J, Van Roy B, Mowinckel P, Gjerstad L, Lossius MI. Psychiatric symptoms in Norwegian children with epilepsy aged 8-13 years: Effects of age and gender? Epilepsia. 2011 Mar ( Free Full Text )
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Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. Researchers have now identified a gene, called HLA-A*3101, in Caucasian patients that increases the risk of developing a reaction to the drug from 5% to 26%.
The research undertaken, in collaboration with the Wellcome Trust Sanger Institute, screened more than a million variants in DNA across the human genome to understand why some patients are more prone to the drug's side-effects than others. Research in Taiwan has already shown that carbamazepine-induced Steven Johnson Syndrome–Toxic Epidermal Necropysis is strongly associated with the HLA-B*1502 allele gene in the south east asian population , but Liverpool scientists discovered that this gene could not be used to predict the reaction in Caucasian people.
Dr Ana Alfirevic, from the University's Wolfson Centre for Personalised Medicine, said: "This is a significant finding that highlights the importance and advancement of new genetic technologies. We aim to support the development of medicines based on a patient's unique genetic make-up to allow clinicians to prescribe the most effective and safe treatments."
Citation
McCormack M, Alfirevic A, Bourgeois S, Farrell JJ, Kasperavičiūtė D, Carrington M, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. The New England journal of medicine. 2011 Mar ;364(12):1134-43. [pubmed]
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Researchers at Concordia University have pioneered a computer-based method to detect epileptic seizures as they occur - a new technique that may open a window on the brain's electrical activity. Their paper, "A Novel Morphology-Based Classifier for Automatic Detection of Epileptic Seizures," presented at the annual meeting of the Engineering in Medicine and Biology Society, documents the very successful application of this new seizure-detection method.
An epileptic seizure, which is caused by disruptions in the normal electrical activity of the brain, can produce a range of symptoms including convulsions and unconsciousness. To learn more about the timing and nature of seizures, the electrical activity of patients' brains is often recorded using electroencephalograms (EEGs). At the moment, however, epilepsy experts must review these recordings manually - a time-consuming process.
"EEG recordings may cover a period of several weeks," explains study co-author Rajeev Agarwal, a professor in Concordia's Department of Electrical and Computer Engineering. "That's a lot of data to review. Automating the process is difficult, because there's no exact definition for a seizure, so there's no template to look for. Every seizure is different with every patient."
However, seizures have certain recognizable characteristics. They occur when neurons fire in a synchronous or rhythmic manner. As seizures progress, the EEG signals have very strong transitions. Seen on an EEG recording, the waves of electrical activity tend to be spike-like.
The Concordia team, led by PhD candidate and lead author Rajeev Yadav, devised an algorithm to check the sharpness of the electrical signals on the EEG recordings as measured by their angle or slope. A series of sharp signals indicate a seizure.
This approach proved extremely successful. In the study of EEG recordings of seven patients, the new method detected every seizure while scoring an extremely low rate of false positives. Results are far better than those obtained with existing methods.
This method of detecting seizures may have applications beyond epilepsy. "Patterns of sharp electrical activity in the brain are generally not a good thing," says Agarwal, who is also co-founder, chief technical officer and vice-president of Leap Medical Inc.
"Think of comatose patients in the ICU for example," he continues. "Some of them may be having seizures or epileptic form like activity, but there's no way to know at the moment. Our method may allow health professionals to gain a much clearer picture of patients' brain function."
The research team continues to evaluate and refine this method of seizure detection. More patient data from several different centres is being reviewed, and further publications on the subject are planned. So far, according to Agarwal, results are promising.
Partners in research:
This research was supported by the Natural Sciences and Engineering Research Council of Canada and the Regroupement Stratégique en Microsystèmes du Québec.
Source:
Concordia University
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New data suggest that the drug Topamax (topiramate) and its generic versions increase the risk for the birth defects cleft lip and cleft palate in babies born to women who use the medication during pregnancy, the U.S. Food and Drug Administration said today.
Before prescribing topiramate, approved to treat certain types of seizures in people who have epilepsy, health care professionals should warn patients of childbearing age about the potential hazard to the fetus if a woman becomes pregnant while using the drug.
Topiramate also is approved to prevent migraine headaches, but not to relieve the pain of migraines.
“Health care professionals should carefully consider the benefits and risks of topiramate when prescribing it to women of childbearing age,” said Russell Katz, M.D., director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. “Alternative medications that have a lower risk of birth defects should be considered.”
Cleft lip and cleft palate, collectively called oral clefts, are birth defects that occur when parts of the lip or palate do not completely fuse together early in the first trimester of pregnancy, a time when many women do not know they are pregnant. The defects range from a small notch in the lip to a groove that runs into the roof of the mouth and nose, possibly leading to problems with eating, talking, and to ear infections. Surgery often is performed to close the lip and palate and most children do well after treatment.
Data from the North American Antiepileptic Drug (AED) Pregnancy Registry indicate an increased risk of oral clefts in infants exposed to topiramate during the first trimester of pregnancy. Infants exposed to topiramate as a single therapy experienced a 1.4 percent prevalence of oral clefts, compared with a prevalence of 0.38 percent – 0.55 percent in infants exposed to other antiepileptic drugs.
Infants of mothers who did not have epilepsy and were not being treated with other antiepileptic drugs had a prevalence of 0.07 percent. Similar data from the United Kingdom Epilepsy and Pregnancy Register supported the North American AED Pregnancy Registry data.
Based on the data, topiramate will have a stronger warning in its prescribing information (labeling). The pregnancy category will be changed to Pregnancy Category D. This means that there is positive evidence of human fetal risk based on human data, but the potential benefits of the drug in pregnant women may outweigh the risks in certain situations. The FDA previously designated the drug as Pregnancy Category C because of the lack of human data. More information about the Pregnancy Categories can be found in the FDA’s Drug Safety Communication.
The patient medication guide and prescribing information for Topamax and generic topiramate will be updated with the new information.
Before starting topiramate, pregnant women and women of childbearing potential should discuss other treatment options with their health care professional. Women taking topiramate should tell their health care professional immediately if they are planning to or become pregnant. Patients taking topiramate should not stop taking it unless told to do so by their health care professional.
Women who become pregnant while taking topiramate should talk to their health care professional about registering with theNorth American Antiepileptic Drug Pregnancy Registry, a group that collects information about outcomes in infants born to women treated with antiepileptic drugs during pregnancy.
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