Researchers led by Professor Michael Johnson, at Imperial College London, have identified a network of genes that is associated with epilepsy.
The team believes that targeting the expression of this “epileptic network” of 320 genes, which they called M30, could be a new strategy to treat the condition.
In a news release, Professor Johnson said: “The discovery of this network of genes linked to epilepsy opens avenues for finding new treatments. This uses an approach that is entirely different to the past 100 years of anti-epilepsy drug development.”
The genes that are part of the network are widely expressed in the brain and code for proteins involved in the communications between brain cells.
When the network is impaired, due to genetic mutations or as a result of brain injury, epilepsy is triggered. According to the researchers, potential new treatments for epilepsy should focus on restoring the network.
The team analysed thousands of genes and mutations associated with epilepsy in people with and without the condition. They found that the genes in the M30 network were consistently dampened in the brains of people with epilepsy, as well as in mouse models of the condition. They then used a technique called network biology to determine how these genes interact with each other.
Finally, the researchers used a computer to ‘test’ 1.300 known drugs and predict which ones could increase the expression of these genes and restore the M30 network. They discovered that valproic acid, a drug already used to treat epilepsy, was one of the drugs that could restore the network. The team also identified a number of drugs such as withaferin A that were not formerly considered to be antiepileptic drugs.
“Until recently we have been looking for individual genes associated with diseases, which drug companies then target with treatments. However, we are increasingly aware that genes don’t work in isolation. Identifying groups of genes that work together, and then targeting these networks of genes, may lead to more effective treatments. Our proof of concept study suggests this network biology approach could help us identify new medications for epilepsy, and the methods can also be applied to other diseases,” the authors said.
The study was published in the scientific journal, Genome Biology.
Author: Dr Özge Özkaya
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A new study published in the scientific journal, Epilepsia, suggests that low-dose oral carbamazepine (CBZ – an antiepileptic drug) is safe and effective in newborn babies with benign familial neonatal epilepsy (BFNE); even in status epilepticus where the seizures occur very close together or last a long time. The authors therefore propose that CBZ should be the drug of choice in babies with this condition.
The researchers, led by Dr Maria Roberta Cilio, at the University of California, analysed 19 children with epilepsy from four different centres in the US and Italy. Sixteen children had a family history of newborn seizures and one child had a family history of infantile seizures. Seizures began at 2-5days of life for all children included in the study and happened several times a day. A total of four children developed status epilepticus.
Genetic analysis revealed that 14 of the children had a mutation in the KCNQ2 gene and two of them had a mutation in the KCNQ3 gene. These two genes encode for potassium channels and play an important role in the communication between neurons.
Twelve of the children were treated with up to four AEDs without satisfactory response before being switched to CBZ. These included phenobarbital, pyridoxine, levetiracetam, benzodiazepines and clonazepam. Seventeen of the children (88%) became seizure-free within hours of receiving CBZ or oxcarbazepine (OXC), another antiepileptic drug.
The earlier treatment with CBZ was started the shorter was the time spent in hospital. CBZ did not have any reported side effects.
The authors, who followed, the children for an average of 7.8 years wrote: “All patients had normal development and remain seizure-free”.
Author: Dr Özge Özkaya
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Please note that Epilepsy Research UK does not endorse/promote individual epilepsy treatments or pharmaceutical companies.
Treatment with cannabidiol (CBD) improves the frequency and severity of seizures in children and adults with epilepsy, according to research presented at the American Epilepsy Society annual meeting in Huston, Texas.
The findings are based on an open label,* expanded access clinical trial to test the effect of CBD in epilepsy.
The study involved 81 people (42 children and 39 adults) with drug-resistant epilepsy whose condition was confirmed by Video EEG. All participants had failed to respond to at least four antiepileptic drugs (AEDs) and experienced, on average, four seizures per month. The severity of the seizures was measured using the Chalfont Seizure Severity Scale.
The results showed that after one month of treatment with CBD, the frequency of seizures was reduced in the majority of participants. Two third of the subjects also experienced a reduction in the severity of their seizures of more than 50%. This reduction was maintained for up to six months.
In a press release, Senior Author Dr Jerzy Szaflarski, at the University of Alabama at Birmingham, said: “It is encouraging that both frequency and severity of seizures appear to improve in the majority of patients in our study, patients who have limited treatment options. Our research adds to the evidence that CBD may reduce frequency of seizures, but we also found that it appears to decrease the severity of seizures, which is a new finding”.
Dr Martina Bebin, also a senior author on the study, added: “These are encouraging results, but it is important to note that each patient may respond differently to CBD, and the dose for optimal seizures control varies. There appears to be an optimal CBD dose range where the patient achieves maximum benefit. If outside this CBD dosing range, the seizure frequency may not improve and may even increase.”
Author: Dr Özge Özkaya
* Open label clinical trials do not try to disguise the new drug or treatment, meaning that no standard treatment or placebo control is used. This creates bias, as both the patient and the physician are aware of which groups are receiving what type of treatment.
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Outcome of AED Therapy Similar in People with Epilepsy Related to Blood Vessel Malformation and People with General Epilepsy
The outcome of antiepileptic drug (AED) therapy in people with epilepsy related to blood vessel malformation in the brain is similar to the outcome of those with ‘general’ epilepsy, according to a study published in the scientific journal Seizure.
According to the authors, failure to achieve seizure-freedom after the adequate trial of two AEDs seems an appropriate criterion for surgical referral of people with epilepsy related to blood vessel malformation. The researchers note, however, that in cases when blood vessel malformation is in the temporal lobe, earlier pre-surgical evaluation may be justifiable (once the first AED has failed).
The study, conducted by scientists in the Republic of Korea, included 34 participants with epilepsy related to blood vessel malformation who had not previously been treated with an AED. Subjects were followed up for at least two years and their response to AED treatment was monitored .
Seizure remission for at least one year was achieved in 22 of the 34 people (64.7%). In 18 people (52.9%), this was following treatment with one AED, whilst in the remaining four it was following treatment with a second AED.
Nine people (26.5%) failed to respond to both AEDs and were diagnosed with drug-resistant epilepsy. Finally, three people (8.8%) had only one seizure in the past year and were classed as having “epilepsy with rare seizures”.
The location of the blood vessel malformation in the temporal lobe was the only factor that could predict poor seizure outcome. According to the authors, the location of the malformations and the probability that the epilepsy will be drug-resistant should be discussed with patients. The possibility of surgery should also be introduced.
This study provides important information about the long-term clinical outcome of medical treatment of epilepsy related to blood vessel malformation.
Author: Dr Özge Özkaya
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Interictal epileptiform discharges (IEDs) have been linked to memory impairment, but the spatial and temporal dynamics of this relationship remain elusive. In the present study, we aim to systematically characterize the brain areas and times at which IEDs affect memory.Methods
Eighty epilepsy patients participated in a delayed free recall task while undergoing intracranial electroencephalography (EEG) monitoring. We analyzed the locations and timing of IEDs relative to the behavioral data in order to measure their effects on memory.Results
Overall IED rates did not correlate with task performance across subjects (r = 0.03, p = 0.8). However, at a finer temporal scale, within-subject memory was negatively affected by IEDs during the encoding and recall periods of the task but not during the rest and distractor periods (p < 0.01, p < 0.001, p = 0.3, and p = 0.8, respectively). The effects of IEDs during encoding and recall were stronger in the left hemisphere than in the right (p < 0.05). Of six brain areas analyzed, IEDs in the inferior-temporal, medial-temporal, and parietal areas significantly affected memory (false discovery rate < 0.05).Significance
These findings reveal a network of brain areas sensitive to IEDs with key nodes in temporal as well as parietal lobes. They also demonstrate the time-dependent effects of IEDs in this network on memory.
Prognostic analysis of patients with epilepsy according to time of relapse after withdrawal of antiepileptic drugs following four seizure-free years
We performed a retrospective, prognostic analysis of a cohort of patients with epilepsy according to time of relapse after four seizure-free years.Methods
Planned withdrawal of antiepileptic drugs (AEDs) and at least 3 years of follow-up after AED discontinuation were performed. The following two groups were assessed: (1) an early relapse (ER) group of patients who experienced recurrence during AED withdrawal and (2) a late relapse (LR) group of patients who experienced recurrence after completion of the AED discontinuation process. After dichotomization, the relapse rate, prognostic factors, and their impacts for each group were compared with those of a group of patients who continued to be seizure-free after AED withdrawal (SF group) using multiple logistic regression analysis. The AED intake mode was also analyzed.Results
Two hundred seventeen (64.6%) of the 336 total patients experienced relapse. One hundred thirty-nine patients (41.4%) and 78 patients (23.2%) were included in the LR and ER groups, respectively. Symptom duration >120 months showed the strongest negative prognostic impact as demonstrated by the 4.7-fold higher risk of recurrence in the ER group compared with the SF group. Additional factors with a negative prognostic impact included an age at epilepsy onset of ≤20 years and the presence of localization-related epilepsy. No reliable predictor between the SF and LR groups was revealed. After exclusion of the SF group, post hoc analysis according to age at epilepsy onset and symptom duration showed that the above-mentioned negative prognostic factors significantly affected the relapse patterns of the LR and ER groups.Significance
The results suggest that longer symptom duration, which could be associated with intrinsic reactivation of epilepsy, is the strongest negative prognostic factor for relapse. Relapse after AED withdrawal in prolonged follow-up of seizure-free patients is one aspect of the natural history of epilepsy.