We report on temporally clustered seizures detected from continuous long-term ambulatory human electroencephalographic data. The objective was to investigate short-term seizure clustering, which we have termed bursting, and consider implications for patient care, seizure prediction, and evaluating therapies.Methods
Chronic ambulatory intracranial electroencephalography (EEG) data collected for the purpose of seizure prediction were annotated to identify seizure events. A detection algorithm was used to identify bursts of events. Burst events were compared to nonburst events to evaluate event dispersion, duration and dynamics.Results
Bursts of seizures were present in 6 of 15 subjects, and detections were consistent over long-term monitoring (>2 years). Subjects with bursts of seizures had highly overdispersed seizure rates, compared to other subjects. There was a complicated relationship between bursts and clinical seizures, although bursts were associated with multimodal distributions of seizure duration, and poorer predictive outcomes. For three subjects, bursts demonstrated distinctive preictal dynamics compared to clinical seizures.Significance
We have previously hypothesized that there are distinct physiologic pathways underlying short- and long-duration seizures. Herein we show that burst seizures fall almost exclusively within the short population of seizure durations; however, a short duration event was not sufficient to induce or imply bursting. We can therefore conclude that in addition to distinct mechanisms underlying seizure duration, there are separate factors regulating bursts of seizures. We show that bursts were a robust phenomenon in our patient cohort, which were consistent with overdispersed seizure rates, suggesting long-memory dynamics.
Carvacrol after status epilepticus (SE) prevents recurrent SE, early seizures, cell death, and cognitive decline
Carvacrol is a naturally occurring monoterpenic phenol that has been suggested to have an action at transient receptor potential cation subfamily M7 (TRPM7) channels, γ-aminobutyric acid (GABAA receptors, and sodium channels, and has been shown to be antiinflammatory. Carvacrol is neuroprotective in models of cerebral ischemia in vivo and in vitro, probably through its action at TRPM7 channels. We therefore aimed to determine the effect of carvacrol on status epilepticus (SE), chronic epilepsy, cell death, and post-SE cognitive decline.Methods
We performed long-term, continuous wireless electroencephalography (EEG) monitoring in vivo in rats who underwent perforant path stimulation (PPS) to induce SE and were then randomized to treatment with carvacrol or saline. We also evaluated TRPM7 receptor expression and quantified seizure-induced cell death. The alternating T-maze paradigm was used to assess memory function.Results
Immunostaining showed that TRPM7 channels are widely expressed in neurons within the hippocampus. We found that carvacrol inhibited recurrent SE and early seizures in vivo, but had no detectable effect in the hippocampus on paired-pulse inhibition or the fiber volley, indicating that it was not acting through sodium channel inhibition or GABA receptors. Although the development and severity of chronic epilepsy were not altered by carvacrol, cognitive decline was significantly improved in animals treated with carvacrol. In keeping with preserved memory functions in animals treated with carvacrol, carvacrol had a protective effect against SE-induced cell death in CA1 and hilus, the hippocampal regions most affected by cell loss in the PPS epilepsy model.Significance
Carvacrol, a naturally occurring inhibitor of TRPM7 channels, is a novel, promising treatment to prevent early recurrence of SE, SE-related neuronal damage, and cognitive decline.
Genetic epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome characterized by heterogeneous phenotypes ranging from mild disorders such as febrile seizures to epileptic encephalopathies (EEs) such as Dravet syndrome (DS). Although DS often occurs with de novo SCN1A pathogenic variants, milder GEFS+ spectrum phenotypes are associated with inherited pathogenic variants. We identified seven cases with non-EE GEFS+ phenotypes and de novo SCN1A pathogenic variants, including a monozygotic twin pair. Febrile seizures plus (FS+) occurred in six patients, five of whom had additional seizure types. The remaining case had childhood-onset temporal lobe epilepsy without known febrile seizures. Although early development was normal in all individuals, three later had learning difficulties, and the twin girls had language impairment and working memory deficits. All cases had SCN1A missense pathogenic variants that were not found in either parent. One pathogenic variant had been reported previously in a case of DS, and the remainder were novel. Our finding of de novo pathogenic variants in mild phenotypes within the GEFS+ spectrum shows that mild GEFS+ is not always inherited. SCN1A screening should be considered in patients with GEFS+ phenotypes because identification of pathogenic variants will influence antiepileptic therapy, and prognostic and genetic counseling.
Drug-resistant epilepsy poses a challenge in neonatal patients, especially those in the neonatal intensive care unit (NICU), who have various secondary comorbidities. We present results of four children with a history of drug-resistant epilepsy for whom a ketogenic diet was initiated and used in the NICU. A nonfasting induction into ketosis over 1–2 weeks was utilized, with gradual increases in the ketogenic ratio every 2–3 days. Data were collected retrospectively from a database, which included medical history, daily progress notes, relevant laboratory data, and imaging and diagnostic information. The ketogenic diet was well tolerated in all cases. The most common side effects observed were constipation, hypoglycemia, and weight loss. Serum β-hydroxybutyrate levels demonstrated improved reliability as a marker of ketosis when compared to urine ketones in this population. Perceived benefits to the infants included improved seizure control, increased alertness, and decreased need for invasive respiratory support. These cases demonstrate that the use of the ketogenic diet for treatment of neonatal encephalopathy and refractory epilepsy can be undertaken safely in the NICU and is well tolerated by carefully screened neonates and infants.
People with nonlesional neocortical epilepsy could benefit from brain surgery and become seizure-free in the long term according to a study published in the scientific journal JAMA Neurology.
Dr Dong Wook Kim and colleagues explored factors that might help select people with nonlesional neocortical epilepsy who are most likely to benefit from surgery. The researchers analysed data from 109 people, aged seven to 56,with drug resistant neocortical epilepsy (which arises from the surface of the brain), and who attended Seoul National University Hospital in South Korea between 1995 and 2005.
All of the patients had failed to respond to treatment with at least two antiepileptic drugs (AEDs) but none had abnormalities or lesions in the brain identifiable by MRI (hence “nonlesional”). Nevertheless, all of the patients underwent surgery to remove the part of the brain that their doctors believed to be responsible for their seizures.
One year after surgery, 59 of the 109 patients (54%) were completely free from seizures and a further 37 patients (34%)had notable reductions in seizure frequencybut without achieving complete remission.
All of the patients, except one, were then followed up clinically for at least 10 years, and some for as long as 21 years after surgery. A total of 64 patients (59.3%) were seizure-free and 33 patients (30.6%) had a lower seizure frequency at their last clinical follow-up, suggesting that the effectiveness of surgery was maintained in the longer-term.
Although the chance of achieving seizure freedom was lower than would be expected for people with mesial temporal lobe epilepsy or lesional neocortical epilepsy, according to the authors “it was notable that nearly 90% of patients benefited from resection surgery for nonlesional neocortical epilepsy.”
People with nonlesional neocortical epilepsy are not usually considered optimal candidates for surgery, but recent studies have shown that a greater proportion of people with this type of epilepsy are being offered surgical intervention. This study supports the benefits of surgery in those patients but further research is needed to confirm the results presented here.
Author: Dr Özge Özkaya
Click here for more articles about other treatments for epilepsy.
The pharmaceutical company Neurelis Inc. recently announced that the US Food and Drug Administration (FDA) has granted fast-track designation for NRL-1, a special formulation of diazepam, for the treatment of epilepsies that are characterised by clusters of seizures. This means that the new formulation could become available more quickly.
“We are very excited to have received Fast Track Designation status with the FDA,” said Craig Chambliss, President and Chief Executive Officer of Neurelis, in a press release. “We are looking forward to working with the FDA as we complete our clinical development work….. and prepare for the commercialization of NRL-1. We are focused on providing epilepsy patients and health care providers with an effective, well-tolerated, and user-friendly product for the treatment of acute repetitive or cluster seizures.”
Diazepam is a drug used to treat anxiety, alcohol withdrawal, muscle spasms, and some types of seizures. NRL-1 is a diazepam nasal spray, which is being developed for the treatment of children and adults with epilepsy who require recurrent use of the drug to control bouts of acute repetitive seizure activity, also known as cluster seizures.
Previous clinical studies have shown that NRL-1 is generally safe and well tolerated and that there is little variability from dose to dose. The new formulation is in its final stage of clinical testing, after which the company will submit a New Drug Application (NDA) to the FDA requesting marketing authorisation for NLR-1. The company says that they plan to market NRL-1 worldwide.
For many years, the only treatment option for people with cluster seizures was to administer diazepam rectally, which was challenging under some circumstances. That changed with licensing of buccal midazolam in the UK in 2011. It is hoped that NRL-1 will offer a further treatment option for people with cluster seizures and allow the delivery of a therapeutic dose of diazepamvia a nasal spray rapidly and easily in many settings.
Please note that Epilepsy Research UK does not endorse/promote individual epilepsy treatments or pharmaceutical companies.
Author: Dr Özge Özkaya
Click here for more articles about anti-epileptic drugs and pregnancy risks.
We explored the current practice with respect to the neuropsychological assessment of surgical epilepsy patients in European epilepsy centers, with the aim of harmonizing and establishing common standards. Twenty-six epilepsy centers and members of “E-PILEPSY” (a European pilot network of reference centers in refractory epilepsy and epilepsy surgery), were asked to report the status of neuropsychological assessment in adults and children via two different surveys. There was a consensus among these centers regarding the role of neuropsychology in the presurgical workup. Strong agreement was found on indications (localization, epileptic dysfunctions, adverse drugs effects, and postoperative monitoring) and the domains to be evaluated (memory, attention, executive functions, language, visuospatial skills, intelligence, depression, anxiety, and quality of life). Although 186 different tests are in use throughout these European centers, a core group of tests reflecting a moderate level of agreement could be discerned. Variability exists with regard to indications, protocols, and paradigms for the assessment of hemispheric language dominance. For the tests in use, little published evidence of clinical validity in epilepsy was provided. Participants in the survey reported a need for improvement concerning the validity of the tests, tools for the assessment of everyday functioning and accelerated forgetting, national norms, and test co-normalization. Based on the present survey, we documented a consensus regarding the indications and principles of neuropsychological testing. Despite the variety of tests in use, the survey indicated that there may be a core set of tests chosen based on experience, as well as on published evidence. By combining these findings with the results of an ongoing systematic literature review, we aim for a battery that can be recommended for the use across epilepsy surgical centers in Europe.