Altered Gut Microbiome Composition in Children with Refractory Epilepsy After Ketogenic Diet

OBJECTIVE: The aim of this study was to investigate the characteristics and composition of intestinal microbiota in children with refractory epilepsy after ketogenic diet (KD) therapy and to explore the bacterial biomarkers related to clinical efficacy.

METHODS: We prospectively analyzed 20 patients (14 males, 6 females) treated with KD. Clinical efficacy, electroencephalogram (EEG) changes, and laboratory tests were evaluated, and fecal specimens were obtained prior to and 6 months after therapy. The composition of gut microbiota was analyzed by 16S rDNA sequencing, and we screened the possible flora associated with efficacy of the KD.

RESULTS: After 6 months of treatment, 2 patients were seizure free, 3 had ? 90% seizure reduction, 5 had a reduction of 50-89%, and 10 had < 50% reduction. All 10 responders showed an improvement in EEG. Compared with baseline, fecal microbial profiles showed lower alpha diversity after KD therapy and revealed significantly decreased abundance of Firmicutes and increased levels of Bacteroidetes. We also observed that Clostridiales, Ruminococcaceae, Rikenellaceae, Lachnospiraceae, and Alistipes were enriched in the non-responsive group.

CONCLUSIONS: The results show that the ketogenic diet can reduce the species richness and diversity of intestinal microbiota. The changes of gut microbiota may be associated with different efficacy after ketogenic diet, and specific gut microbiota may serve as an efficacy biomarker and a potential therapeutic target in patients with refractory epilepsy.

Accuracy of an Online Tool to Assess Appropriateness for an Epilepsy Surgery Evaluation: A Population-Based Swedish Study

OBJECTIVE: The Canadian Appropriateness of Epilepsy Surgery (CASES) tool was developed to help physicians identify patients who should be referred for an epilepsy surgery evaluation. The aim of this study was to determine the accuracy of this tool using a population-based cohort registry (the Swedish National Epilepsy Surgery Register) of patients who underwent epilepsy surgery between 1990 and 2012.

METHODS: Overall, 1044 patients met eligibility criteria for the study and were deemed to be surgical candidates by epilepsy experts. Demographic and epilepsy related characteristics were examined and summarized using descriptive statistics. A CASES appropriateness score was calculated for each of these patients. Chi squared analyses or fisher’s exact tests were used to determine if there were any relationships between demographic and epilepsy related characteristics not captured in the tool and appropriateness scores.

RESULTS: The mean appropriateness score was 8.6 and 985 (Sensitivity: 94.35%; 95% CI, 92.77%-95.60%) patients were appropriate, 46 (4.41%; 95% CI, 3.31%-5.84%) were uncertain, and 13 (1.25%; 95% CI, 0.72%-2.13%) were inappropriate for an epilepsy surgery evaluation. The mean necessity score, which was only calculated for the 985 appropriate patients, was 8.7. All 13 inappropriate patients had tried less than two anti-epileptic drugs (AEDs). In addition, age at onset of epilepsy and age at epilepsy surgery were both significantly associated with appropriateness score.

CONCLUSIONS: These results demonstrate that the Canadian Appropriateness of Epilepsy Surger tool is highly sensitive as it designated 94.3% of epilepsy surgery patients as appropriate for an epilepsy surgery evaluation. All of those classified as inappropriate were not drug resistant, as they had not yet tried two anti-epileptic drugs.

Structure of Major Brain Receptor that is Treatment Target for Epilepsy, Anxiety Solved

UT Southwestern researchers published the first atomic structure of a brain receptor bound to a drug used to reverse anesthesia and to treat sedative overdoses.

“This study reveals the first high-resolution structural information for one of the most abundant and important neurotransmitter receptors in the brain,” said Dr. Ryan Hibbs, corresponding author of the study published in Nature and Assistant Professor of Neuroscience and Biophysics with the Peter O’Donnell Jr. Brain Institute at UT Southwestern. “We are tremendously excited about it.”

Many drugs – both legal and illegal – work on the GABAA receptor. Particularly well-known are the benzodiazepines, which are used for anesthesia during surgery and prescribed to treat epilepsy, anxiety, and insomnia, he said, adding that solving the structure of the receptor could someday lead to better treatments for those conditions.

‘Baby Whale’ Electrical Zaps May Shed Light on Epilepsy

A fish that uses electrical charges to sense and communicate with the world around it could provide new insights into diseases such as epilepsy, according to new research.

Brienomyrus brachyistius, commonly known as the baby whale, sends out electrical spurts that last only a few tenths of a thousandth of a second and allow it to navigate without letting predators know it’s there.

In a new paper in Current Biology, scientists outline how the fish developed a unique bioelectric security system that lets them produce incredibly fast and short pulses of electricity so they can communicate without jamming one another’s signals, while also steering clear of the highly sensitive electric detection systems of predatory catfish.

“These fish have a real ‘need for speed’ when it comes to their electric signals,” says Jason Gallant, assistant professor of integrative biology at Michigan State University. “Many of the genes involved in making electric discharge signals, including these potassium channels, show signatures of natural selection that emphasize this need.”

CURE Discovery: New Cause of Severe Childhood Epilepsy Found – Genetic Mutation in the CUX2 Gene

CURE Grantee Dr. Gemma Carvill has identified a new cause of epilepsy: a mutation in the gene CUX2. Dr. Carvill’s discovery was recently published in the Annals of Neurology.1

The discovery provides an important advance in our understanding of the causes of a class of severe childhood epilepsies. This class includes childhood epileptic encephalopathy, an aggressive and severe group of treatment-resistant epilepsy disorders in which children can have profound cognitive and neurological deficits.2,3

Dr. Carvill began her research into the ways specific genetic mutations lead to childhood epileptic encephalopathy in 2015 as the result of a 1-year CURE Taking Flight Award. This award program encourages young investigators to conduct independent research which could lead to a cure for epilepsy. When Dr. Carvill recieved the CURE Taking Flight Award, she was a Postdoctoral Fellow at the University of Washington.

Dr. Carvill studied the ways genetic mutations lead to epilepsy. Her initial findings suggested that mutations in a class of genes important in determining the structure of DNA could impact several genes involved in epilepsy, making this class of genes a potential target of future epilepsy therapy development.

Since receiving her CURE award, Dr. Carvill’s career has certainly “taken flight” – she is now Assistant Professor of Neurology and Pharmacology at Northwestern University. Still, Dr. Carvill has remained committed to her quest to understand the genetic mechanisms behind severe childhood epilepsy. In her latest study, Dr. Carvill partnered with Dr. Gaetan Lesca of the Lyon University Hospital, located in France, to identify de novo mutations in the gene CUX2 as a new cause of epilepsy. De novo mutations are changes present only in the affected patient and not in their healthy parents. CUX2 is important in binding DNA and promoting the expression of certain target genes. Mutations in CUX2 cause errors in this process that can lead to epilepsy.

Dr. Carvill’s report details her international study of 9 patients aged 6 months to 21 years who first began having seizures early in life. To identify the mutation in the CUX2 gene, Dr. Carvill and her team used, among other techniques, a test called whole exome sequencing. This test analyzes a person’s genes to identify changes in their DNA. All 9 patients had the same CUX2 mutation. The team found that the majority of these patients had severe treatment-resistant epilepsy that started early in life, severe intellectual disability, and did not have speech appropriate for their age.

Besides finding an important genetic cause of severe childhood epilepsy, which can now be targeted for the development of therapeutic interventions, Dr. Carvill’s collaboration with Dr. Lesca highlights the importance of international efforts to identify new genes important in epilepsy. As Dr. Carvill notes, these genetic mutations are very rare and therefore collaborative efforts with multiple patient populations make it more likely that a rare genetic mutation can be identified and studied.

In the future, Dr. Carvill plans to further explore the genetic mechanisms behind these devastating childhood epilepsies. Her goal, which we at CURE share, is that treatments and cures can be found for all of the amazing children affected by epilepsy and their wonderful families, too.

Citations

1 Chatron N et al. The epilepsy phenotypic spectrum associated with recurrent CUX2 variant. Ann Neurol2018; 6 [Epub ahead of print]
2 Cross H and Guerrini R. The epileptic encephalopathies. Handb Clin Neurol 2013; 111:619-626.
3 Jehi L, Wylie E, Devinsky O. Epileptic encephalopathies: Optimizing seizure control and developmental outcome. Epilepsia 2015; 56(10):1486-1489.

Use of Brivaracetam in Genetic Generalized Epilepsies and for Acute, Intravenous Treatment of Absence Status Epilepticus

SIGNIFICANCE: Use of brivaracetam in genetic generalized epilepsies is well tolerated, and 50% responder rates are similar to those observed in the regulatory trials for focal epilepsies. An immediate switch from levetiracetam to brivaracetam at a ratio of 15:1 is feasible. The occurrence of psychobehavioral adverse events seems less prominent than under levetiracetam, and a switch to brivaracetam can be considered in patients with levetiracetam-induced adverse events.

OBJECTIVE: The objective of this study was to evaluate effectiveness, retention, and tolerability of brivaracetam (BRV) in genetic generalized epilepsies (GGE) in clinical practice.

METHODS: A multicenter, retrospective cohort study recruiting all patients that started BRV in 2016 and 2017.

RESULTS: A total of 61 patients (mean age = 29.8, range = 9-90 years, 41 female [67%]) were treated with BRV. They were difficult to control, with 2.4 failed antiepileptic drugs (AEDs) in the past, taking 1.9 AEDs on average at baseline.

The length of exposure to BRV ranged from 7 days to 24 months, with a mean retention time of 7.9 months, resulting in a total exposure time to BRV of 483 months. The retention rate was 82% at 3 months and 69% at 6 months. Efficacy at 3 months was 36% (50% responder rate), with 25% seizure-free for 3 months. Patients with juvenile myoclonic epilepsy showed a responder rate of 60%, with 40% being free of any seizures. Long-term 50% responder rate was present in 17 patients (28%; 11 seizure-free [18%]) for >6 months and in 14 patients (23%; 10 seizure-free [16%]) for >12 months.

Treatment-emergent adverse events were observed in 26% of the patients, with the most common being somnolence, ataxia, and psychobehavioral adverse events. Use of intravenous BRV with bolus injection of 200-300 mg in two females with absence status epilepticus was well tolerated, but did not result in cessation of status epilepticus.

Vigabatrin and High-Dose Prednisolone Therapy for Patients with West Syndrome

CONCLUSION: Using a treatment protocol involving vigabatrin and prednisolone for West syndrome (WS), 72.7% of patients showed resolution of spasms and a BASED score of ?2. This study also found that this drug administration protocol was safe. However, further studies are warranted as this study describes results from observational study with limited sample size.

OBJECTIVE: Hormonal therapy and vigabatrin are now accepted as the first-line or standard therapies for WS. However, the superiority of these drugs in terms of monotherapy or combination therapy is still in question. In this study, we designed a treatment protocol for WS and prospectively assessed the efficacy of these therapies in controlling spasms, stabilizing electroencephalography (EEG), and allowing for developmental catch-up.

METHODS: In patients diagnosed with WS, vigabatrin was first administered alone for 2 weeks, and then prednisolone was administered in combination with vigabatrin if patients did not respond to vigabatrin. The detailed drug administration protocol was as follows: vigabatrin 50?mg/kg/day for 1 day, followed by vigabatrin 100?mg/kg/day for 3 days, vigabatrin 150?mg/kg/day if spasms were still present or the burden of amplitudes and epileptiform discharges (BASED) score on EEG was ?3 on day 5; 40?mg/day of prednisolone was added if spasms were still present or the BASED score was ?3 on day 14. The prednisolone dose was increased to 60?mg/day if spasms were still present or the BASED score was ?3 on day 21.

RESULTS: Sixty-six patients newly diagnosed with WS (median seizure onset age: 5.7 [IQR, 4.1-7.1] months, median age at diagnosis: 6.6 [IQR, 5.4-8.1] months, n?=?40 [60.6%] boys) were subjected to the vigabatrin and prednisolone therapy protocol. Of the 66 patients, 22 (33.3%) patients showed resolution of spasms and a BASED score of ?2 after vigabatrin alone, and 26 (39.4%) patients showed resolution of spasms and a BASED score of ?2 after a combination of vigabatrin and prednisolone, for a total of 48 (72.7%) patients who were responsive to the protocol without relapse for at least 7 months after WS diagnosis. The mental and psychomotor age quotients were higher at the time of diagnosis and remained significantly higher 6 months after the diagnosis in responsive patients (p?<? 0.001). No serious adverse reactions leading to discontinuation or reduction of drug doses were observed.

Epilepsy in Classic Rett Syndrome: Course and Characteristics in Adult Age

PURPOSE: Rett syndrome (RTT) is a neurodevelopmental disorder that almost exclusively affects females. Epilepsy is a major clinical feature, but its long-term course in RTT has not been sufficiently explored. This study addresses the development of the epilepsy in adults with RTT.

METHODS: Available females diagnosed with RTT in Norway were asked to participate. Parents/caregivers were interviewed, the girls/women were examined and their medical records reviewed. Participants were categorized according to age, epilepsy, seizure patterns and mutation severity groups. RTT severity was assessed (epilepsy score excluded).

RESULTS: 70 females with classic RTT were included. A presumed pathogenic mutation in MECP2 was found in 96%. The presence of active epilepsy (seizures last five years) was similar in all age groups above the age of ten: 11 (65%) in adolescents (11-20 years), 9 (60%) in young adults (21-30 years) and 14 (67%) in participants above 30 years of age. Tonic-clonic seizures within the last year were present in 55, 67 and 64%, and???weekly seizures occurred in 27, 45 and 50% in the respective age groups. Among participants with active epilepsy, 69% had unremitting seizures, whereas 31% had experienced remissions for more than six months during the last five years. In the oldest group (>30 years), only 19% had obtained seizure control for >5 years, and 14% had never experienced seizures. Seizure activity correlated with RTT severity score, whereas the relationship to mutation type remained ambiguous.

CONCLUSION: Epilepsy continues to be a major concern in adults with RTT. Two thirds of women above 30 years of age remained with active epilepsy and 50% of them had seizures at least weekly.

MTOR Pathway in Focal Cortical Dysplasia Type 2: What Do We Know?

Focal cortical dysplasia (FCD) is the most commonly encountered developmental malformation that causes refractory epilepsy. Focal cortical dysplasia type 2 is one of the most usual neuropathological findings in tissues resected therapeutically from patients with drug-resistant epilepsy. Unlike other types of FCD, it is characterized by laminar disorganization and dysplastic neurons, which compromise the organization of the six histologically known layers in the cortex; the morphology and/or cell location can also be altered.

A comprehensive review about the pathogenesis of this disease is important because of the necessity to update the results reported over the past years. Here, we present an updated review through Pubmed about the mammalian target of rapamycin (MTOR) pathway in FCD type 2. A wide variety of aspects was covered in 44 articles related to molecular and cellular biology, including experiments in animal and human models. The first publications appeared in 2004, but there is still a lack of studies specifically for one type of focal cortical dysplasia.

With the advancement of techniques and greater access to molecular and cellular experiments, such as induced pluripotent stem cells (iPSCs) and organoids, it is believed that the trend is increasing the number of publications contributing to the achievement of new discoveries.

Panic and Epilepsy in Adults: A Systematic Review

The purpose of the current paper was to review the empirical literature on the co-occurrence of panic and epilepsy, in order to determine whether there is an increased risk of panic attacks and panic disorder among adults with epilepsy and an increased risk of epilepsy among adults with panic disorder.

Given the overlap between panic and ictal fear, a preliminary aim of the current review was to critically evaluate the methodology used to differentiate between diagnoses of panic disorder and epilepsy in existing research. A literature search was conducted in relevant electronic databases, and articles that directly focused on panic and epilepsy among adults were selected for the current review (n?=?17).

Overall, results suggest that rates of epilepsy are elevated among individuals with panic disorder and that panic attacks are elevated among individuals with epilepsy, but rates of panic disorder among people with epilepsy are inconsistent. However, most studies did not use sufficiently rigorous methods to differentiate between panic disorder and epilepsy. Therefore, a critical next step in this area of research is to develop a standard procedure for differentiating ictal fear from panic attacks and panic disorder