Eslicarbazepine acetate was effective when used as an add-on treatment for patients with drug-resistant focal epilepsy, according to authors of a Cochrane review published in Cochrane Database Systematic Reviews.

While most patients with epilepsy have a good prognosis, up to 30% of patients with epileptic seizures have drug-resistant epilepsy, which can adversely impact their psychosocial, psychiatric, and medical status. Eslicarbazepine acetate, an antiepileptic drug that blocks voltage-gated sodium channels, has been suggested to reduce seizure frequency in these patients.

The objective of the current updated version of a Cochrane Review originally published in 2011 was to determine the efficacy and tolerability of eslicarbazepine acetate when used in combination with other medications for patients with drug-resistant focal epilepsy.

Press release, originally published in Science Translational Medicine (2021)

Medicine used to treat multiple sclerosis also helps in a rare form of genetic epilepsy – drug precisely targets underlying genetic defect

Epilepsy comes in a variety of forms. Those affected by a genetically determined variety have severe epileptic seizures as early as the first year of life. The disease is accompanied by severe developmental disorders: it is difficult for them to walk, they have difficulty concentrating and later have problems with speech, spelling and calculations. Until now, this form of epilepsy has been difficult to treat with the usual drugs. Researchers from Tübingen have now used a drug for the first time that is actually approved for the treatment of multiple sclerosis. It directly counteracts the underlying genetic defect and successfully alleviates the symptoms of the patients, reports the team led by Dr. Ulrike Hedrich-Klimosch, Dr. Stephan Lauxmann and Prof. Dr. Holger Lerche from the Hertie Institute for Clinical Brain Research, the University Hospital and the University of Tübingen. This implies that for the first time, affected children and adults will have access to a pharmacological treatment. The results have been published in the journal Science Translational Medicine.

The cause of this form of early childhood epilepsy is a rare genetic defect. Mutations in the KCNA2 gene lead to defective potassium channels in the brain. “Potassium channels are small pores located in the cell membrane of nerve cells and are important for the transmission of electrical signals,” explains first author and biologist Hedrich-Klimosch. “In some subtypes of the disease, the mutations lead to increased activity of the channel. In these cases, we speak of a gain-of-function mutation.”

For the first time, the research team utilized a therapy medication that specifically targets this point. “In this case, a cause-related therapy must inhibit the increased channel activity,” explains co-first author and neurologist Lauxmann. “One such channel blocker is the active substance 4-aminopyridine. It specifically inhibits the overactivity of the potassium channels and is the active compound of a drug approved for the treatment of gait disorders in multiple sclerosis patients.” In cooperation with eight other centers worldwide, the team treated eleven patients in n-of-1 trials with the drug. The results were encouraging: The symptoms improved in nine of them. “The number of daily epileptic seizures was reduced or disappeared completely. The patients were generally much more alert and mentally fitter in everyday life. Their speech also improved after starting the drug treatment.”

The drug does not work for all subtypes of the disease. In some cases, the gene mutation leads to restricted activity of the potassium channels. The researchers have created a database so that doctors can quickly decide whether the drug can help a patient with a newly diagnosed KCNA2 gene defect or not. It lists the different mutations from the KCNA gene family and the associated effects on the potassium channel. In this way, a therapy can be started quickly and the often severe course of the disease can be alleviated.

Abstract, originally published in Epilepsy Research

Purpose: To investigate the efficacy of short-term treatment with ciprofloxacin in alteration of gut microbiota pattern and reduction of seizure frequency in adult patients with drug-resistant epilepsy.

Methods: In a prospective study, we investigated the effect of a 5-day course of treatment with ciprofloxacin on gut microbiota pattern and seizure frequency of 23 adults with drug-resistant epilepsy. Fecal samples were collected before and after treatment and were analyzed for microbial load and species. Changes in seizure frequency were registered for 12 weeks. Responders were defined as patients who experienced ?50 % seizure reduction in comparison to baseline. Outcome measures were specified as alteration in fecal microbial burden in days 5-7 and responder rate in 4th and 12th weeks.

Results: The mean baseline frequency of seizures was5.6 ±7.7 per week. All patients were on polytherapy with a mean of 3 ± 1.2 anti-seizure medications. Microbial analysis showed a considerable increase in Bacteroidetes/Firmicutes ratio after treatment. Seizure frequency significantly decreased at the end of first week and the therapeutic effect continued to week 12 (P < 0.001). The responder rate at 4th and 12th weeks were 69.6 % and 73.9 % respectively with a more prominent response in patients with symptomatic generalized epilepsy (P:0.06).

Conclusion: Alteration of abnormal gut microbiota pattern by methods such as short-course antibiotic therapy, prescription of probiotics and fecal microbiota transplant might be effective in treatment of drug-resistant epilepsy.

Summary, originally published in Neurology Advisor

For patients with drug-resistant focal epilepsy, taking into account genetic data has improved clinical decision-making and has led to the definition of new disease entities, according to a review published in Brain Pathology.

Structural brain lesions such as glioneuronal tumors or malformations of cortical development are often causal for drug-resistant focal epilepsy. The process of identifying causal lesions includes magnetic resonance imaging and intracerebral electroencephalogram. These methods have been found to lack specificity and accuracy in the diagnosis of the type of the causal lesion with high interobserver variability.

Recently, a brain tumor classifier which uses epigenetic profiling has been formulated. It uses CpG sites to best discriminate between tumor groups. This method has been used to successfully identify multiple novel tumor entities such as isomorphic diffuse glioma, glioneuronal tumors with oligodendroglioma-life features and nuclear clusters, primary mismatch repair-deficient isocitrate dehydrogenase (IDH)-mutant astrocytoma, and primary intracranial spindle cell sarcoma with rhabdomyosarcoma-like features DICER1-mutant, among others. These lesions tend to be morphologically heterogeneous and would likely not be properly diagnosed without molecular approaches.

The review authors discussed 14 lesion types that have been associated with specific molecular markers. The lesions are caused by a mixture of somatic and germline variants, often affecting the mechanistic target of rapamycin (mTOR) signaling, receptor tyrosine kinase (RTK)/mitogen-activated protein kinase (MAPK) signaling, or glycosylation.

Lesions caused by somatic mutations have the potential to be assessed through cell-free DNA and may not require biopsy. Instead, a sample of cerebrospinal fluid collected by dural puncture may be used to diagnose some lesions caused by somatic variants. The review authors caution, however, that this method requires additional validation.

Article, originally published in Science Daily(r)

Breath instead of blood: researchers from the University of Basel have developed a new test method to measure treatment success in epilepsy patients. They hope that this will enable doctors to react more precisely when treating the disease.

Epilepsy affects some 50 million people worldwide and pharmaceutical treatment of the disease is a tightrope walk, as the dose must be tailored precisely to the individual patient: “Slightly too little and it isn’t effective. Slightly too much and it becomes toxic,” explains Professor Pablo Sinues.

Sinues is Botnar Research Professor of Pediatric Environmental Medicine at the University of Basel and University Children’s Hospital Basel (UKBB). He is also a member of the Department of Biomedical Engineering at the University of Basel. Together with colleagues from University Hospital Zurich (UHZ), he spent two and a half years looking for a way to tailor the dosage of drugs administered to epilepsy patients as precisely as possible. They ultimately achieved this goal with the help of a breath test. The advantage is that monitoring does not require a blood sample, which can always be a stress factor for children. And as the sample doesn’t need to be sent to the laboratory first, the results are available immediately.

Searching for the tiniest concentrations

“You can think of it as being like the alcohol test that police use when they stop drivers,” Sinues explains. The difference is that this breath measurement device is actually a big machine. “Because alcohol is present at high concentrations in-breath, one only needs a small device. But we’re searching for a droplet in 20 swimming pools,” he says. The researchers want to use the results to determine whether the active substances are present at the right concentrations in the body and whether they have the desired effect on the disease.

Their efforts have not been in vain: both among the young patients at UKBB and the adult reference group at the University Hospital Zurich, the breath tests produced the same results as conventional blood tests, as reported by the research group in their study published in Communications Medicine. This means that in addition to blood tests, there is a second way of monitoring epilepsy treatment — and the method also provides further information on the patient’s metabolism that doctors can use in the therapy.

Abstract, published in Epileptic Disorders

We describe a multicenter experience with VNS implantation in pediatric patients with epileptic encephalopathy. Our goal was to assess VNS efficacy and identify potential predictors of favorable outcome. This was a retrospective study. Inclusion criteria were: ?18 years at the time of VNS implantation and at least one year of follow-up. All patients were non-candidates for excisional procedures. Favorable clinical outcome and effective VNS therapy were defined as seizure reduction >50%. Outcome data were reviewed at one, two, three and five years after VNS implantation. Fisher’s exact test, Kaplan-Meier and multiple logistic regression analysis were employed. Twenty-seven patients met inclusion criteria. Responder rate (seizure frequency reduction ? 50%) at one-year follow-up was 25.9%, and 15.3% at last follow-up visit. The only variable significantly predicting favorable outcome was time to VNS implantation, with the best outcome achieved when VNS implantation was performed within five years of seizure onset (overall response rate of 83.3% at one year of follow-up and 100% at five years). In total, 63% of patients evidenced improved QOL at last follow-up visit. Only one patient exited the study due to an adverse event at two years from implantation. Early VNS implantation within five years of seizure onset was the only predictor of favorable clinical outcome in pediatric patients with epileptic encephalopathy. Improved quality of life and a very low incidence of adverse events were observed.

Article, originally published in Genetic Engineering & Biotechnology News

The discovery of natural and engineered light-sensitive proteins has developed a versatile and easy-to-use method in neuroscience called optogenetics that uses a light stimulus to precisely regulate neural activity in time and space, and has had an immense impact on understanding neural networks, neuronal function, and signaling pathways.

Scientists at the Ruhr-University Bochum, Germany, have now discovered a new optogenetic tool and demonstrated its potential in epilepsy research. This tool, a member of a family of proteins called opsins found in the brain and eyes in zebrafish, continuously activates an important intracellular signaling pathway called the Gi/o pathway.

Unlike other optogenetic proteins that are turned on when light is shone on them, this protein (Opn7b) is turned off by blue or green light. Characterization of Opn7b that the scientists reported in an article in Nature Communications, “Reverse optogenetics of G protein signaling by zebrafish non-visual opsin Opn7b for synchronization of neuronal networks,” will allow researchers to interrupt the continuously active Gi/o signaling pathway transiently, by shining blue or green light on Opn7b.

“So far in all seizure models, seizure induction is time-consuming and demands long-lasting light activation protocols with unreliable onset of seizures,” the authors noted. To demonstrate the application of Opn7b as a tool in epilepsy research, the Bochum researchers Jan Claudius Schwitalla, PhD, and Johanna Pakusch, PhD, engineered cells called pyramidal cells, in the cerebral cortex of mice to express the zebrafish receptor protein, Opn7b. When Opn7b is deactivated by light, the researchers showed, it triggers seizures in the animals that can be specifically controlled with light. The researchers hope it will be possible to use this optogenetic tool to better understand the underlying mechanisms and timeline of the development of epileptic seizures.

Article, originally published in Cell Reports

University of Virginia School of Medicine researchers have discovered a previously unknown repair process in the brain that they hope could be harnessed and enhanced to treat seizure-related brain injuries.

Common seizure-preventing drugs do not work for approximately a third of epilepsy patients, so new and better treatments for such brain injuries are much needed. UVA’s discovery identifies a potential avenue, one inspired by the brain’s natural immune response.

Using high-powered imaging, the researchers were able to see, for the first time, that immune cells called microglia were not just removing damaged material after experimental seizures but actually appeared to be healing damaged neurons.

“There has been mounting generic support for the idea that microglia could be used to ameliorate seizures, but direct, visualized evidence for how they could do this has been lacking,” said researcher Ukpong B. Eyo, PhD, of UVA’s Department of Neuroscience, the UVA Brain Institute and UVA’s Center for Brain Immunology and Glia (BIG). “Our results indicate that microglia may not be simply clearing debris but providing structural support for neuronal integrity that may have implications even beyond the scope of seizures and epilepsy.”

A Surprising Response to Seizures

The new findings come from a collaboration of scientists at UVA, Mayo Clinic, and Rutgers University. They used an advanced imaging technique called two-photon microscopy to examine what happened in the brains of lab mice after severe seizures. What they saw was strange and unexpected.

Rather than simply cleaning up debris, the microglia began forming pouches. These pouches didn’t swallow up damaged material, as many immune cells do. Instead, they began tending to swollen dendrites – the branches of nerve cells that transmit nerve impulses. They weren’t removing, the scientists realized; they appeared to be healing.

These odd little pouches – the scientists named them “microglial process pouches” – stuck around for hours. They often shrank, but they were clearly doing something beneficial because the dendrites they targeted ended up looking better and healthier than those they didn’t.

“We did not find microglia to be ‘eating’ the neuronal elements in this context,” Eyo said. “Rather, we saw a strong correlation between these interactions and a structural resolution of injured neurons suggestive of a ‘healing’ process.”

The new insights into the brain’s immune response points scientists in promising new directions. “Although these findings are exciting, there is yet a lot to follow-up on them. For example, the precise mechanisms that regulate the interactions remain to be identified. Moreover, at present, the ‘healing’ feature is suggested from correlational results, and more definitive studies are required to certify the nature of the ‘healing,'” Eyo said. “If these questions can be answered, they will provide a rationale for developing approaches to enhance this process … in seizure contexts.”

Eyo has already received two grants totaling almost $5 million from the National Institutes of Health to continue his study of microglia. The funding will allow him to study how the immune cells help regulate vascular function, which could be important in diseases such as Alzheimer’s, and their role in brain-hyperactivity disorders such as febrile seizures that can trigger epilepsy.

“With this new funding, we are eager to clarify roles for microglia in seizure disorders and vascular function,” he said. “UVA’s continued investment in neuroscience research provides a suitable home for our lab’s research.”