Oxcarbazepine (OXC) is a widely used antiepileptic drug for the treatment of partial seizures that was developed through structural variation of carbamazepine. Although OXC has a lower risk of cutaneous adverse drug reactions (cADRs) than carbamazepine, cADRs ranging from maculopapular eruption (MPE) to the more severe Stevens-Johnson syndrome and toxic epidermal necrolysis still limit the use of OXC in some patients. A few human leukocyte antigen (HLA)–related genetic risk factors for carbamazepine-induced cADRs have been identified. However, the HLA-related genetic risk factors associated with OXC-induced cADRs are unknown.Methods
A total of 40 patients who experienced OXC-induced MPE and 70 patients who were tolerant to OXC treatment were included in the study. Genomic DNA was extracted from the peripheral blood of these patients, and high-resolution HLA genotyping was performed.Results
The HLA-B*40:02 and HLA-DRB1*04:03 alleles were significantly associated with OXC-induced MPE compared with the OXC-tolerant group (odds ratio [OR] 4.33, p = 0.018 and OR 14.64, p = 0.003, respectively) and the general Korean population (OR 4.04, p = 0.001 and OR 3.11, p = 0.019, respectively). The HLA-B*15:01 genetic frequency was significantly lower in the OXC-MPE group compared to the OXC-tolerant group (OR 0.18, p = 0.016) and the Korean population (OR 0.22, p = 0.030). The allele frequencies of well-known HLA-related risk factors for carbamazepine-induced cADRs (HLA-B*15:02, A*31:01 and B*15:11) were not different among the three groups.Significance
This study is the first to demonstrate an association of HLA-B*40:02 and HLA-DRB1*04:03 with OXC hypersensitivity using a large cohort of patients with OXC-induced MPE. These findings should be confirmed in future studies in different ethnic groups.
The patterns of postoperative seizure control and response to antiepileptic drugs (AEDs) in tumor-associated epilepsy (TAE) are poorly understood. We aim to document these characteristics in patients with supratentorial gliomas.Methods
This was a retrospective analysis of 186 patients with supratentorial gliomas. Seizure patterns were classified into four groups: A, no postoperative seizure; B, early postoperative seizure control within 6 months; C, fluctuating seizure control; and D, never seizure-free. Rates and duration of seizure freedom, subsequent seizure relapse, and response to AED were analyzed.Results
Among patients included, 49 (26.3%) had grade II, 28 (15.1%) had grade III, and 109 (58.6%) had grade IV glioma. Outcome pattern A was observed in 95 (51.1%), B in 22 (11.8%), C in 45 (24.2%), and D in 24 (12.9%). One hundred nineteen patients had at least one seizure and were classified as having TAE. Compared to pattern A, pattern B was predicted by histologic progression; pattern C by tumor grade, preoperative seizure, and histologic progression, and pattern D by preoperative seizure and gross total resection. Among patients with TAE, 57.5% of grade II, 68.2% of grade III, and 26.3% of grade IV experienced a period of 12-month seizure freedom. After first 12-month seizure remission, 39.1%, 60.0%, and 13.3% of grade II, III, and IV gliomas, respectively, experienced subsequent seizure; 22.6% of those with TAE reached terminal seizure freedom of at least 12 months on their first postoperative AED regimen, 6.5% on their second regimen, and 5.4% on subsequent regimens.Significance
Distinct patterns of postoperative seizure control exist in gliomas; they have specific risk factor profiles, and we hypothesize these correspond to unique pathogenic mechanisms. Twelve-month seizure freedom with subsequent relapse is frequent in grade II–III gliomas. Response to AEDs is markedly poorer than with non-TAE, highlighting the complex epileptogenicity of gliomas.
Temporal lobe epilepsy following maintenance electroconvulsive therapy—Electrical kindling in the human brain?
Maintenance electroconvulsive therapy (ECT) is sometimes prescribed for refractory psychiatric conditions. We describe five patients who received maintenance ECT and developed florid temporal epileptiform abnormalities on electroencephalography (EEG) despite no history of epilepsy and normal neuroimaging. All patients had received regular ECT for at least 8 months. Three patients had clinical events consistent with epileptic seizures, and video-EEG monitoring captured electrographic seizures in two patients. After cessation of ECT the EEGs normalized in all patients, and no further clinical seizures occurred. Maintenance ECT may predispose to epilepsy with a seizure focus in the temporal lobe.
Implementation of an established algorithm and modifications for the identification of epilepsy patients in the veterans health administration
A panel of international researchers has discovered that mutations in a gene called GRIN2D could cause severe epileptic encephalopathy.
GRIN2D is part of a gene family containing the information necessary to make proteins called NMDARs. These are ion channels found on the surface of nerve cells, and they play an important role in electrical signalling between them.
Mutations in NMDAR proteins are already known to cause childhood epilepsy by over-stimulating nerve signals and causing a toxic build-up of an important neurotransmitter called glutamate. However, until now, it was not known that GRIN2D could harbour disease-causing mutations.
The team, led by Dr Marni Falk, from the University of Pennsylvania and The Children’s Hospital of Philadelphia, reported a case of two unrelated children with epileptic encephalopathy in an article published in the American Journal of Human Genetics.
The researchers analysed the genes of both children and found a recurrent mutation in the GRIN2D gene in both. Conducting experiments on nerve cells grown in the laboratory, the scientists showed that this mutation causes NMDAR to remain open for too long, resulting in excess electrical signals that kill the neurons.
Based on this finding, the scientists gave the children a medicine called memantine, which blocks NMDAR and is already approved to treat people with Alzheimer’s disease. This led to a mild improvements and a modest reduction in their seizures.
However, one of the children began to deteriorate over time and had to be placed in an induced coma. Based on the results of previous animal studies, the researchers decided to treat the child with two other NMDAR blockers – magnesium and ketamine. Although neither drug is considered a standard treatment for epilepsy, they produced dramatic improvements, stopping the repeated non-convulsive seizures that the child was experiencing and allowed her to regain some developmental skills.
In a press release, Dr Falk said: “Much more work, including randomised clinical trials, remains to be done to learn whether therapies such as these, targeted to a specific gene disorder, can be applied to other patients with similar subtypes of epilepsy.”
This is a great example of how basic scientific research can be applied to develop treatments suitable to the unique genetic profile of a patient and reflect the potential of precision medicine.
Epileptic encephalopathy is a condition linked to neurodevelopmental disabilities and characterised by frequent seizures that cannot be controlled by common antiepileptic drugs.
Author: Dr Özge Özkaya
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Continuous Electrical Brain Stimulation Could be a Treatment Option for People with Drug-Resistant Epilepsy
Continuous electrical brain stimulation could help to suppress epileptic seizures, offering a new treatment option for people who have epilepsy that cannot be treated with surgery or medication. These findings are published in JAMA Neurology,
First Author Dr Brian Lundstrom, at Mayo Clinic in Rochester, US, said: “We think this approach not only provides an effective treatment for those with focal epilepsy, but will allow us to develop ways of assessing seizure likelihood for all epilepsy patients. It would be of enormous clinical benefit if we could personalise treatment regimens for individual patients without waiting for seizures to happen.”
Doctors have attempted to suppress seizures by electrically stimulating the focus, or area in the brain where they originate. However, this approach rarely stopped seizures altogether.
In the present study, researchers found that electrical brain stimulation that couldn’t be felt by the patient was able to suppress electrical discharges that occur intermittently during normal brain function. It was also able to reduce the frequency and, in some cases, the intensity and duration of seizures.
Dr Lundstrom and colleagues conducted their study on 13 people with drug-resistant epilepsy who were also not eligible for surgery. They placed a grid of electrical contacts on their brains and sent stimulation at levels unnoticeable by the participants. In people for whom the electrical stimulation provided clinical benefits, the researchers replaced the temporary grid with a more permanent one that could offer continuous stimulation.
They found that 10 of the 13 patients (77%) reported improvement in both the severity of the epilepsy and their life satisfaction. The majority experienced more than a 50% reduction in seizures, and 44% were free of disabling seizures.
Epileptic seizures can be controlled with drugs in approximately two third of cases. However, one third of people with epilepsy have drug-resistant epilepsy. A proportion of these patients may be eligible for surgery where the focus, or portion of the brain in which seizures arise, is removed. Sometimes the focus is situated in an area of the brain that controls speech, language, vision, sensation or movement. In these cases surgery cannot be performed and electrical brain stimulation may be the only option.
Dr Lundstrom said that the risks associated with this approach are relatively minimal and include the risk of infection, bleeding and the stimulation being noticed by the patient.
According to the authors, further studies are needed to measure the exact effects of this treatment and examine the mechanism by which it suppresses seizures. They hope to examine the efficacy of this approach in more depth in the near future.
Author: Dr Özge Özkaya
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A new study, published in the scientific journal Epilepsia, shows that people with epilepsy still feel discriminated against a lot more than the ‘general population’.
According to the authors, this could lead to psychological and social problems and may even lead to the development of psychiatric problems.
First Author on the study, Dr Victoria Nimmo-Smith, from the University of Bristol, said: “This paper demonstrates that despite all of the advances made over the last 100 years, the experience of discrimination continues to be a significant problem for people with epilepsy.”
Senior Author, Dr Dheeraj Rai, added: “We still don’t know enough about why people with epilepsy develop depression and anxiety disorders much more often than the general population. Our findings suggest that adverse life events such as discrimination may be important (…) if true, it may be possible to design interventions to help prevent mental health problems in some people with epilepsy.”
For the study, the researchers recruited people in England who were aged over 16 and living in private households. During the first part of the assessment, subjects were asked to declare whether or not they had received a diagnosis of epilepsy, asthma, diabetes or migraine from a doctor. The scientists then used the Adult Psychiatric Morbidity Survey 2007 to collect and quantify information about each person’s experiences of discrimination, domestic violence, abuse and other stressful life events. They collated all of the complete data sets and analysed them (taking care to avoid biases and incorrect conclusions).
The results showed that people with epilepsy were seven times more likely to report experiencing discrimination due to health problems compared to people without epilepsy. This figure was considerably higher than for people with diabetes, asthma and migraines; when compared with people without each of these conditions respectively.
According to the data, people with epilepsy were more likely to have suffered domestic violence and sexual abuse than the ‘general population’; however, these associations were similar in the people with other chronic conditions (diabetes, asthma and migraines).
It is recognised that people with epilepsy are more likely to have common mental health problems such as depression and anxiety disorders than persons in the ‘general population’. This may be linked to common neurobiological factors, but psychological and social factors may also contribute.
Author: Dr Özge Özkaya
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Valproic acid may be more effective than lamotrigine as a first-line drug for the treatment newly diagnosed idiopathic generalized tonic-clonic seizures (GTCS) in adults. This is according to a study published in the Journal of Clinical and Diagnostic Research.
Opinions among medical professionals differ as to which drug is more effective in adults newly diagnosed with idiopathic GTCS, and this prompted researchers in India to carry out a comparison of the two.
For the study, the team recruited 60 participants with idiopathic GTCS and divided them into two groups. Half of the participants received valproic acid while the other half received lamotrigine.
The results showed that, after 12 months, more than 75% of participants taking valproic acid and approximately 57% of participants taking lamotrigine were seizure-free. Adverse side effects were seen in almost a third of cases in the group taking valproic acid and included sedation, ataxia (lack of voluntary coordination of muscle movements) and tremor. More than half of the lamotrigine group experienced adverse effects, including nausea, indigestion, headache and skin rash.
According to the authors, both valproic acid and lamotrigine are effective as first-line treatments for newly diagnosed adults with idiopathic GTCS. However, valproic acid appears to be preferable to lamotrigine because it is more effective and better tolerated.
Further studies on a larger number of subjects, who are followed for a longer period of time, are needed to confirm the results obtained in this study and evaluate the long-term effects of these drugs.
Author: Dr Özge Özkaya
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Please note that Epilepsy Research UK does not endorse/promote individual epilepsy treatments or pharmaceutical companies.
Long-term use (up to two and a half years) of the antiepileptic drug (AED) Fycompa (perampanel), in addition to other AEDs, gives sustained seizure control in poorly-controlled idiopathic generalised epilepsy with primary generalised tonic clonic seizures. This is according to data presented at the 12thEuropean Congress on Epileptology, was held in Prague in September 2016.
Scientists had previously tested the safety and efficiency of the drug in a phase three clinical trial called study 332. Here they presented the results of an extension to this study, in which all of the participants received Fycompa, regardless of what they had received in the original ‘core’ study. Unlike the core study, the extension was open label, meaning that both the subjects and the clinicians knew what was being administered.
For the extension study, researchers recruited 138 participants and gave them a daily dose of Fycompa for up to 136 weeks. This followed a six-week ‘conversion period’, in which people who had received a placebo in the core trial were switched to Fycompa.
By the end of the conversion period, participants had achieved a similar average reduction in seizure frequency whether they had originally received Fycompa or a placebo (a 100% and a 93.1% reduction respectively). Seizure control that was achieved during the core study was maintained throughout the course of the extension.
A total of 120 patients (87%) experienced adverse side effects associated with the treatment, including dizziness, upper respiratory tract infection, irritability, headache, sleepiness and common cold-like symptoms.
The results were announced in a press release by the drug’s manufacturer Eisai.
Fycompa is an orally available adjunctive drug for the treatment of partial-onset seizures, with or without secondarily generalized seizures, and primary generalized tonic clonic seizures, in people with epilepsy aged 12 years and above.
Author: Dr Özge Özkaya
Click here for more articles about anti-epileptic drugs and pregnancy risks.
Discrimination, domestic violence, abuse, and other adverse life events in people with epilepsy: Population-based study to assess the burden of these events and their contribution to psychopathology
To quantify the experience of discrimination, domestic violence, abuse, and other stressful life events in people with epilepsy in comparison with the general population and people with other chronic conditions. To assess whether any excess relative burden of these adversities could explain the higher rates of depression in people with epilepsy.Methods
The Adult Psychiatric Morbidity Survey 2007 used comprehensive interviews with 7,403 individuals living in private residences in England. Doctor-diagnosed epilepsy and other chronic conditions were established by self-report. Discrimination, domestic violence, physical and sexual abuse, and other stressful life events were assessed using computerized self-completion and a face-to-face interview, respectively.Results
People with epilepsy were sevenfold more likely to have reported experiencing discrimination due to health problems (adjusted odds ratio [OR] 7.1; 95% confidence interval [CI] 3.1–16.3), than the general population without epilepsy. This estimate was substantially greater in people with epilepsy than for people with other chronic conditions. People with epilepsy also had greater odds of experiencing domestic violence and sexual abuse than the general population, although these associations were also found in people with other chronic conditions. There was less evidence of an association between epilepsy and a history of physical abuse or having a greater burden of other stressful life events. In exploratory analyses, assuming they lie on the causal pathway, discrimination, domestic violence, and sexual abuse explained 42.7% of the total effect of the relationship between epilepsy and depression or anxiety disorders.Significance
People with epilepsy can face a range of psychosocial adversities and extensively report feeling discriminated against as compared to the general population. In addition, if confirmed in longitudinal studies, the results suggest that these psychosocial adversities may have a significant role in the development of psychiatric comorbidity and may be targets for future interventions.