Eslicarbazepine Acetate Reduced Seizures in Adults With Treatment-Resistant Focal Epilepsy

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.

First Specific Drug Therapy for a Severe Early Form of 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.

Ciprofloxacin for Treatment of Drug-Resistant Epilepsy

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.

CURE Epilepsy Discovery: Beyond Pharmacological Therapy for the Treatment of Epilepsy: Creating Electrodes to Prevent Seizures by Stimulating the Brain

Dr. Brian Litt at the University of Pennsylvania has dedicated his research career to the creation and improvement of flexible, active, implantable electrodes to monitor and stimulate the brain with the goal of curing epilepsy.

Key Points:

Dr. Brian Litt, MD, Professor in both the Departments of Neurology and Bioengineering at the University of Pennsylvania, obtained a research grant from CURE Epilepsy in 2011 to develop active, flexible, implantable electrodes to treat epilepsy by stimulating the brain.

  • The flexible electrodes are ideal to insert into brain tissue and are able to record brain activity as well as stimulate specific brain areas when a seizure arises, thereby mitigating it.
  • Dr. Litt considers the CURE Epilepsy grant that he received to be pivotal to the development of his laboratory. His laboratory has since grown tremendously and has proven to be a very fertile environment, especially for the training of young researchers who have gone on to work on various research strategies to cure epilepsy.

Deep Dive:

Dr. Litt studied Engineering and Applied Sciences at Harvard University and obtained his medical degree at Johns Hopkins University. When he started treating patients as a neurologist, he realized that the treatments that were available for patients with drug-resistant epilepsy were mostly based on traditional pharmacological interventions and had limited capacity to significantly change the course of the disease. The lack of alternatives for patients who were resistant to pharmacological treatments inspired him to research electrical stimulation as a new method to treat epilepsy, with the goal of preventing seizures to control the disease.

A research grant from CURE Epilepsy in 2011 for “Flexible Implantable Devices for Epilepsy” was instrumental in the development of these technologies, and in defining Dr. Litt’s research trajectory when he started his laboratory at the University of Pennsylvania.

Dr. Litt´s laboratory collaborated with Dr. John Rogers, also at the University of Pennsylvania, who had developed the first flexible electrodes but had not tried implanting them in live tissue at the time. Together, their laboratories developed and tested the first brain implants incorporating active electronics for recording seizure activity and stimulating the brain to control seizures.

Dr. Litt’s research has always been on the forefront of advancing the relationship between medicine and engineering, and he has actively fostered collaborations between these two areas at his university. Dr. Litt belongs to both the Departments of Neurology and Bioengineering and collaborates extensively with research groups with varied areas of expertise and at different institutions all over the country.  

Dr. Litt believes the CURE Epilepsy grant he received many years ago had a great impact on his career. In addition to contributing to epilepsy research in an essential way, it has enabled him to train the next generation of epilepsy researchers. Over the years, he has trained over 50 PhD students and post-doctoral researchers with the majority of them still successfully working on epilepsy today. Several of his trainees have started their independent research careers in epilepsy and secured NIH funding for their projects. 

Dr. Litt wants donors to know how important CURE Epilepsy has been to his successful career.  “I can’t tell you how grateful I am to the organization and the donors. […] Probably the biggest impact of CURE Epilepsy is that the organization doesn’t spend dollars foolishly. You carefully bet on the people as well as the projects. You’re very good stewards of the money.” Additionally, he commented, “Research is incremental. It builds on itself with time. Getting the result of the research is just one piece of the puzzle, but what’s even more important is getting a lot of smart young people to think about epilepsy and work on it, so you build this critical mass and this community.”  

The CURE Epilepsy grant allowed Dr. Litt to start his research to develop implantable electrodes to stimulate the brain. Considering the limitations of pharmacological therapy for many epilepsy patients, it is essential to increase the range of available treatments, and the work from Dr. Litt’s laboratory makes a cure for epilepsy closer to becoming a reality. Dr. Litt and his group members, past and present, are at the frontline of this fascinating and fundamental endeavor, and CURE Epilepsy is a proud supporter of this enterprise. 

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A special thank you to Irene Sanchez Brualla, PhD, for her assistance with this article. 

Molecular Diagnostics Reveal Novel Causal Lesions in Drug-Resistant Focal 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.

Breath Test to Determine Correct Treatment for Epilepsy

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.

Defining Dravet syndrome: An Essential Pre-Requisite for Precision Medicine Trials

Abstract, originally published in Epilepsia

Objective: The classical description of Dravet syndrome, the prototypic developmental and epileptic encephalopathy, is of a normal 6-month-old infant presenting with a prolonged, febrile, hemiclonic seizure and showing developmental slowing after age 1 year. SCN1A pathogenic variants are found in >80% of patients. Many patients have atypical features resulting in diagnostic delay and inappropriate therapy. We aimed to provide an evidence-based definition of SCN1A-Dravet syndrome in readiness for precision medicine trials.

Methods: Epilepsy patients were recruited to the University of Melbourne Epilepsy Genetics Research Program between 1995 and 2020 by neurologists from around the world. Patients with SCN1A pathogenic variants were reviewed and only those with Dravet syndrome were included. Clinical data, including seizure and developmental course, were analyzed in all patients with SCN1A-Dravet syndrome.

Results: Two hundred and five patients were studied at a median age of 8.5 years (range 10 months to 60 years); 25 were deceased. The median seizure-onset age was 5.7 months (range 1.5–20.6 months). Initial seizures were tonic-clonic (52%) and hemiclonic (35%), with only 55% being associated with fever. Only 34% of patients presented with status epilepticus (seizure lasting ?30 minutes). Median time between first and second seizure was 30 days (range 4 hours to 8 months), and seven patients (5%) had at least 6 months between initial seizures. Median ages at onset of second and third seizure types were 9.1 months (range 3 months–25.4 years) and 15.5 months (range 4 months–8.2 years), respectively. Developmental slowing occurred prior to 12 months in 27%.

Significance: An evidence-based definition of SCN1A-Dravet syndrome is essential for early diagnosis. We refine the spectrum of Dravet syndrome, based on patterns of seizure onset, type, and progression. Understanding of the full spectrum of SCN1A-Dravet syndrome presentation is essential for early diagnosis and optimization of treatment, especially as precision medicine trials become available.

Early Vagus Nerve Stimulator Implantation as a Main Predictor of Positive Outcome in Pediatric Patients with Epileptic Encephalopathy

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.

New Optogenetic Tool May Find Application in Understanding Epileptic Seizures

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.

Brain-Repair Discovery Could Lead to New Epilepsy Treatments

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.”