Researchers at the University of Gothenburg, in Sweden, have found neural stem cells in epileptic brain tissue where they normally do not reside. This work is published in the scientific journal, Cerebral Cortex.
Neural stem cells are immature cells in the brain that are able to mature into neurons, astrocytes (non-neuronal support cells) or oligodendrocytes (producers of myelin, which is needed for effective neuronal signalling). They are normally found in the hippocampus, an area of the brain that is involved in learning and memory, and in the subventricular domains.
This finding helps improve scientists’ understanding of how the brain responds to epilepsy.
The team, led, Dr Milos Pekny, analysed the brain tissue obtained from people with drug-resistant epilepsy who underwent surgery. In eight out of 14 tissue samples (57%), they discovered neural stem cells in areas where these types of cells are not normally found.
According to the authors of the study, “This may point to a greater plasticity in the epileptic tissue, which to some extent can be compared to the brain tissue of a newborn.”
When the scientists cultured the brain samples, they saw that the cells that gave rise to neural stem cells were not astrocytes as was previously thought.
New neurons are formed in the brain of adults throughout life. These originate from neural stem cells that are found in the subventricular zone, hippocampus and striatum of the brain. Experiments conducted on mice have shown that in neurological conditions such as brain injury or stroke, astrocytes exhibit neural stem cell-like properties. This study shows that this is not the case in the human brain, at least not in epilepsy.
Author: Dr Özge Özkaya
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Time to onset of sustained ≥50% responder status in patients with focal (partial-onset) seizures in three phase III studies of adjunctive brivaracetam treatment
Time to onset of sustained ≥50% responder status (SRS) was assessed for the pooled patient population receiving brivaracetam (BRV) 50, 100, or 200 mg/day or placebo in three randomized phase III studies (NCT00464269, NCT00490035, and NCT01261325). Patients were aged ≥16 years with well-characterized focal (partial-onset) seizures (FS) uncontrolled by 1–2 concomitant antiepileptic drugs. After an 8-week baseline period, patients received study drug without up-titration for a 12-week (84-day) treatment period. A patient was a sustained ≥50% responder on a particular day if they completed the entire treatment period through day 84 and was a ≥50% responder (based on percent reduction in FS frequency from baseline) both on that day and every successive day until day 84 (end of treatment period). In the pooled efficacy population (N = 1,160), 15.5%, 18.1%, and 19.4% of patients taking BRV 50, 100, or 200 mg/day, respectively, achieved SRS on day 1 versus 6.7% for placebo (p < 0.001). Statistically significant SRS was also achieved for most of the BRV-treated groups in the three separate studies. This suggests that BRV has an early, sustained onset of action in a subset of responders. The incidence of adverse events during the first week was similar to that in the overall treatment period.
To comprehensively analyze ictal asystole (IA) on a large number of subjects.Methods
We performed a systematic review of case report studies of patients diagnosed with IA (1983–2016). Each included case was characterized with respect to patient history, IA seizure characteristics, diagnostic workup, and therapy. In addition, comparative analyses were also carried out: two alignments were developed based on the delay between epilepsy onset and IA onset (“new-onset” if <1 year, “late-onset” if ≥1 year) and asystole duration (asystole was “very prolonged” if lasted >30 s).Results
One hundred fifty-seven cases were included. All patients had focal epilepsy. In 7% of cases IA developed during a secondary generalized tonic–clonic seizure. Both the seizure-onset zone and the focal seizure activity at asystole beginning were usually temporal (p < 0.001 and p = 0.001, respectively) and were lateralized to the left hemisphere in 62% (p = 0.005 and p = 0.05, respectively). Asystole duration was 18 ± 14 s (mean±SD) (range 3–96 s); 73% of patients had late-onset, 27% had new-onset IA. Compared to late-onset IA, new-onset IA was associated with female gender (p = 0.023), preexisting heart condition (p = 0.014), focal seizure activity at asystole beginning (p = 0.012), normal neuroimaging (p = 0.013), normal interictal EEG (p < 0.001), auditory aura (p = 0.012), and drug-responsive epilepsy (p < 0.001). “Very prolonged” asystole was associated with secondary generalized tonic–clonic seizures (p = 0.003) and tended to occur in extratemporal lobe seizures (p = 0.074). No IA-related death was reported.Significance
Characteristics considered to be typical of IA (focal, left temporal seizures appearing on grounds of a long-lasting, intractable epilepsy) seem only partially legitimate. We suggest that in new-onset IA, female gender and a preexisting heart condition could serve as predispositions in an otherwise benign epilepsy. We speculate that in late-onset IA, male-predominant changes in neuronal networks in chronic, intractable epilepsy and an accompanying autonomic dysregulation serve as facilitating factors.
Perampanel effects in the WAG/Rij rat model of epileptogenesis, absence epilepsy, and comorbid depressive-like behavior
Perampanel (PER), a selective non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-receptor antagonist, exhibits broad-spectrum anticonvulsant activity in several seizure models, but its potential disease-modifying effects have not been investigated. Because of the relevance of AMPA receptors in epileptogenesis and psychiatric comorbidities, we studied the effects of PER in the WAG/Rij rat model of epileptogenesis, absence epilepsy, and depressive-like comorbidity.Methods
We investigated the effects of acute, subchronic, and chronic treatment with PER (0.25–3 mg/kg) on absence seizures, their development, and related psychiatric/neurologic comorbidity in WAG/Rij rats. Depression-related behavior was studied by using the forced swimming and the sucrose preference test; anxiety-related behavior by using the open field and elevated plus maze test; and memory by using the passive avoidance test.Results
PER (3 mg/kg/day orally for 17 weeks starting from P30) significantly reduced the development of absence seizures at 6 months of age (1 month after treatment withdrawal), but this effect was not maintained when reassessed 4 months later. Attenuated absence seizure development was accompanied by reduced depressive-like behavior in the forced swimming test (FST), whereas no effects were observed on anxiety-related behavior and memory. Subchronic (1 and 3 mg/kg/day orally for 1 week) and acute PER (0.25–1 mg/kg, i.p.) dosing did not affect established absence seizures and behavior.Significance
These results suggest that AMPA receptors are involved in mechanisms of epileptogenesis in an established model of absence epilepsy, and that these mechanisms differ from those responsible for seizure generation and spread when epilepsy has become established.
Premature mortality of epilepsy in low- and middle-income countries: A systematic review from the Mortality Task Force of the International League Against Epilepsy
To determine the magnitude of risk factors and causes of premature mortality associated with epilepsy in low- and middle-income countries (LMICs). We conducted a systematic search of the literature reporting mortality and epilepsy in the World Bank-defined LMICs. We assessed the quality of the studies based on representativeness; ascertainment of cases, diagnosis, and mortality; and extracted data on standardized mortality ratios (SMRs) and mortality rates in people with epilepsy. We examined risk factors and causes of death. The annual mortality rate was estimated at 19.8 (range 9.7–45.1) deaths per 1,000 people with epilepsy with a weighted median SMR of 2.6 (range 1.3–7.2) among higher-quality population-based studies. Clinical cohort studies yielded 7.1 (range 1.6–25.1) deaths per 1,000 people. The weighted median SMRs were 5.0 in male and 4.5 in female patients; relatively higher SMRs within studies were measured in children and adolescents, those with symptomatic epilepsies, and those reporting less adherence to treatment. The main causes of death in people with epilepsy living in LMICs include those directly attributable to epilepsy, which yield a mean proportional mortality ratio (PMR) of 27.3% (range 5–75.5%) derived from population-based studies. These direct causes comprise status epilepticus, with reported PMRs ranging from 5 to 56.6%, and sudden unexpected death in epilepsy (SUDEP), with reported PMRs ranging from 1 to 18.9%. Important causes of mortality indirectly related to epilepsy include drowning, head injury, and burns. Epilepsy in LMICs has a significantly greater premature mortality, as in high-income countries, but in LMICs the excess mortality is more likely to be associated with causes attributable to lack of access to medical facilities such as status epilepticus, and preventable causes such as drowning, head injuries, and burns. This excess premature mortality could be substantially reduced with education about the risk of death and improved access to treatments, including AEDs.
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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