Clinical trial: Rolandic Epilepsy Genomewide Association International Study (REGAIN)

Approximately 25% of child patients have Rolandic Epilepsy or RE, also known as Benign Epilepsy with Centrotemporal Spikes (BECTS). RE has a complex genetic basis, probably made up of combinations of susceptibility variants in different genes. Children with RE quite often have other symptoms that affect their speech, attention, reading ability or coordination. The goal of this study is to find the genetic basis for susceptibility to seizures and associated comorbidities for RE using genomewide association approaches.

We know that RE has a genetic basis and we recently discovered the genetic cause of the EEG pattern seen in RE. The goal of REGAIN is to now find the genetic basis for susceptibility to seizures and the associated symptoms above. Our hope is to be able to improve diagnosis and understand why each child with RE is different, and perhaps point us towards new treatments that are more effective and have fewer side effects.

We will compare the genetic code of 3,000 children with RE against a similar number of people not affected by epilepsy. With the proposed large sample of participants, we will be able to pinpoint the exact changes that might lead to seizures or attention problems for example. Learning the genetic basis for these problems will deepen our understanding of the mechanisms and lead to new treatments or cures.

Estimated study start date: June 1, 2018
Estimated study completion date: December 31, 200

Eligibility Criteria

Ages Eligible for Study: 6 Years to 25 Years (Child, Adult)
Sexes Eligible for Study: All
Accepts Healthy Volunteers: No
Sampling Method: Non-Probability Sample

Inclusion Criteria:

  • Diagnosis of Rolandic Epilepsy in accordance with the following international criteria:
    • Age of first afebrile seizure 3-12 years
    • Seizures comprising focal sensorimotor seizures affecting the vocal tract and face, with or without involvement of the arm
    • Predominant sleep-related seizures
    • EEG interictal centro-temporal spikes with normal background
  • Current age 6-25 years

 

Exclusion Criteria:

  • No history of focal seizure
  • Normal EEG or abnormal background features on EEG
  • Known structural causes (stroke, tuberous sclerosis, infection, post-infectious or metabolic)
  • Primary diagnosis of autism or global learning disability
  • Focal central neurological deficit on clinical exam,
  • Unable to provide informed consent
  • Unable to provide blood sample

Variability in Gene-Sequencing Panels Could Mean Missed Early-Life Epilepsy Diagnoses: Work Featuring CURE Grantee Annapurna Poduri

Epilepsy genetics is an emerging field with increasing therapeutic implications resulting from genetic findings. Despite an overall enthusiasm for precision medicine in epilepsy and other disciplines, there remains no consensus on the approach to genetic testing. A recent study by Berg et al demonstrated a relatively similar diagnostic yield of epilepsy next-generation sequencing (NGS) gene panels compared with whole-exome sequencing (27% vs 33%). Although the utility of NGS panels are consistently demonstrated to our knowledge, no study has systematically evaluated the variability in genes tested among clinically available NGS panels. We compared the potential diagnostic yield of commercially available NGS epilepsy panels to detect the genetic findings identified in a recently published cohort of early-life epilepsy.

Dr. Annapurna Poduri [a CURE grantee] and colleagues from Boston Children’s Hospital compared 10 commercially available NGS gene panels from three major vendors (Athena Diagnostics, Ambry Genetics and GeneDx).

Wearable Devices for Sudden Unexpected Death in Epilepsy Prevention

Sudden unexpected death in epilepsy (SUDEP) is most often associated with the occurrence of generalized tonic-clonic seizures (GTCS), a seizure type that can now be detected with high sensitivity and specificity by wearable or bed devices. The recent development in such devices and their performance offer multiple opportunities to tackle SUDEP and its prevention. Reliable GTCS detection might help physicians optimize antiepileptic treatment, which could in turn reduce the risk of SUDEP. GTCS?triggered alarms can lead to immediate intervention by caregivers that are also likely to decrease the odd of SUDEP.

The biosignals used to detect GTCS might provide novel SUDEP biomarkers, in particular, by informing on several important characteristics of the ictal and postictal periods (type of GTCS duration of tonic phase, rotation in the prone position, presence and duration of postictal immobility and bradycardia, rise in electrodermal activity). Other biosensors not yet used for detecting GTCS might provide complementary information, such as the presence and intensity of ictal/postictal hypoxemia.

The above biomarkers, if strongly predictive, could help identify patients at very high risk of SUDEP, enabling better assessment of individual risk, as well as selection of appropriate patients for clinical studies aiming at preventing SUDEP. The same biosignals could also be used as ancillary biomarkers to test the impact of various interventions before moving to highly challenging randomized controlled trials with SUDEP as a primary outcome.

User-Based Evaluation of Applicability and Usability of a Wearable Accelerometer Device for Detecting Bilateral Tonic-Clonic Seizures: A field Study

Clinical validation studies of seizure detection devices conducted in epilepsy monitoring units (EMUs) can be biased by the artificial environment. We report a field (phase 4) study of a wearable accelerometer device (Epi?Care) that has previously been validated in EMUs for detecting bilateral tonic–clonic seizures (BTCS). Seventy?one patients using the device (or their caregivers) completed the modified Post?Study System Usability Questionnaire. Median time patients had been using the device was 15 months (range = 24 days?6 years).

In 10% of cases, patients stopped using the device due to reasons related to the device. The median sensitivity (90%) and false alarm rate (0.1/d) were similar to what had been determined in EMUs. Patients and caregivers were overall satisfied with the device (median = 5.5 on the 7?point Likert scale), considered the technical aspects satisfactory, and considered the device comfortable and efficient. Adverse effects occurred in 11%, but were only mild: skin irritation at the wrist and interference with home electronic appliances. In 55% the device influenced the number of seizures logged into the seizure diary, and in 40% it contributed to fewer seizure?related injuries. This field study demonstrates the applicability and usability of the wearable accelerometer device for detecting bilateral tonic-clonic seizures.

Whole-Brain MEG Connectivity-Based Analyses Reveals Critical Hubs in Childhood Absence Epilepsy

Absence seizures are thought to be linked to abnormal interplays between regions of a thalamocortical network. However, the complexity of this widespread network makes characterizing the functional interactions among various brain regions challenging. Using whole-brain functional connectivity and network analysis of magnetoencephalography (MEG) data, we explored pre-treatment brain hubs (“highly connected nodes”) of patients aged 6 to 12 years with childhood absence epilepsy.

We analyzed ictal MEG data of 74 seizures from 16 patients. We employed a time-domain beamformer technique to estimate MEG sources in broadband (1-40?Hz) where the greatest power changes between ictal and preictal periods were identified. A phase synchrony measure, phase locking value, and a graph theory metric, eigenvector centrality (EVC), were utilized to quantify voxel-level connectivity and network hubs of ictal?>?preictal periods, respectively. A volumetric atlas containing 116 regions of interests (ROIs) was utilized to summarize the network measures. ROIs with EVC (z-score) > 1.96 were reported as critical hubs. ROIs analysis revealed functional-anatomical hubs in a widespread network containing bilateral precuneus (right/left, z?=?2.39, 2.18), left thalamus (z?=?2.28), and three anterior cerebellar subunits of lobule “IV-V” (z?=?3.9), vermis “IV-V” (z?=?3.57), and lobule “III” (z?=?2.03).

Findings suggest that highly connected brain areas or hubs are present in focal cortical, subcortical, and cerebellar regions during absence seizures. Hubs in thalami, precuneus and cingulate cortex generally support a theory of rapidly engaging and bilaterally distributed networks of cortical and subcortical regions responsible for seizures generation, whereas hubs in anterior cerebellar regions may be linked to terminating motor automatisms frequently seen during typical absence seizures. Whole-brain network connectivity is a powerful analytic tool to reveal focal components of absence seizures in magnetoencephalography. Our investigations can lead to a better understanding of the pathophysiology of childhood absence epilepsy.

Timing in the Treatment of Status Epilepticus: From Basics to the Clinic

CONCLUSIONS: Morbidity and mortality may be avoided with rapid, effective treatment of status epilepticus (SE). Treatment application and escalation remains delayed especially in outpatient settings, potentially leading to suboptimal outcomes. Implementation techniques and quality improvement methodologies may provide avenues for improving outcomes in status epilepticus.

OBJECTIVE: Describe basic science, animal models, and clinical data related to timing of treatment in status epilepticus.

METHODS: We summarized the results of 15 studies that reported time to treatment in SE and reviewed basic and clinical literature.

RESULTS: SE is a life-threatening and time-sensitive emergency that requires immediate treatment. Current guidelines recommend escalation of anti-seizure medications (ASM) within specified time frames. Prolonged seizures may lead to changes in the composition and location of gamma-aminobutyric acid A receptors (GABAAR) and N-Methyl-d-aspartic acid receptors (NMDAR), leading to loss of inhibition and increased excitation. These biochemical changes are apparent in specific animal models having progressive resistance to benzodiazepines (BZD) with longer seizures. Later treatments lead to decreased response to BZD, longer seizures, greater need of continuous infusions, potential brain injury and increased in-hospital mortality.

Despite mounting evidence that early treatment of SE is more effective and safer, treatment and ASM escalation is often delayed compared to protocols. Literature review of 2212 patients with SE showed an average time to treatment of 42.4?min and time to hospital arrival of 56?min. Also, only 51.8% of patients received treatment by emergency medical services and 12.8% by their families, including patients with a previous diagnosis of epilepsy or with prior SE.

UCB Receives CHMP Positive Opinion for Adjunctive Use of BRIVIACT as Paediatric Treatment for Epilepsy Patients

UCB announced on June 1 that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion for BRIVIACT(R) (brivaracetam) to extend the therapeutic indication to include adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in patients with epilepsy from 4 years of age.

The European Commission is expected to make a decision based on this CHMP positive opinion over the coming weeks. When approved, BRIVIACT’s paediatric indication will represent an important new treatment option for children with epilepsy, their family and care-givers, as well as European healthcare professionals.

BRIVIACT is the newest medicine in the family of the synaptic vesicle protein 2A (SV2A) anti-epileptic drugs (AED) – a class of medicines discovered and developed by UCB. BRIVIACT demonstrates a high and selective affinity for SV2A in the brain which may contribute to its anticonvulsant effects.

“We’re very proud to be at the forefront of global epilepsy management, and to be able to provide healthcare professionals, their patients and their family members with new and additional choices to support them in their individual epilepsy journeys.” said Jeff Wren, Executive Vice-President, Head of UCB’s Neurology Patient Value Unit. “Today’s positive CHMP opinion for BRIVIACT(R) is another important step forwards in our efforts to realize true patient value and to further improve the lives of this highly impacted patient population by providing additional treatment options.”

Comparative Effectiveness of Levetiracetam vs Phenobarbital for Infantile Epilepsy

Objective: To compare the effectiveness of levetiracetam vs phenobarbital for nonsyndromic infantile epilepsy.

Main Outcomes and Measures: The binary outcome was freedom from monotherapy failure at 6 months, defined as no second prescribed antiepileptic medication and freedom from seizures beginning within 3 months of initiation of treatment. Outcomes were adjusted for demographics, epilepsy characteristics, and neurologic history, as well as for observable selection bias using propensity score weighting and for within-center correlation using generalized estimating equations.

Results: Of the 155 infants in the study (81 girls and 74 boys; median age, 4.7 months [interquartile range, 3.0-7.1 months]), those treated with levetiracetam (n?=?117) were older at the time of the first seizure than those treated with phenobarbital (n?=?38) (median age, 5.2 months [interquartile range, 3.5-8.2 months] vs 3.0 months [interquartile range, 2.0-4.4 months]; P?<?.001). There were no other significant bivariate differences. Infants treated with levetiracetam were free from monotherapy failure more often than those treated with phenobarbital (47 [40.2%] vs 6 [15.8%]; P?=?.01). The superiority of levetiracetam over phenobarbital persisted after adjusting for covariates, observable selection bias, and within-center correlation (odds ratio, 4.2; 95% CI, 1.1-16; number needed to treat, 3.5 [95% CI, 1.7-60]).

Conclusions and Relevance: Levetiracetam may have superior effectiveness compared with phenobarbital for initial monotherapy of nonsyndromic epilepsy in infants. If 100 infants who received phenobarbital were instead treated with levetiracetam, 44 would be free from monotherapy failure instead of 16 by the estimates in this study. Randomized clinical trials are necessary to confirm these findings.

Research Reveals Underappreciated Role of Brainstem in Epilepsy

New research from Vanderbilt suggests that repeated seizures reduce brainstem connectivity, a possible contributor to unexplained neurocognitive problems in epilepsy patients.

The brainstem has been rarely studied in epilepsy because seizures typically originate in the temporal lobe or other areas of the cortex. Noting that people with temporal lobe epilepsy often lose consciousness even though the temporal lobe does not control wakefulness, Dario Englot, MD, PhD, surgical director of epilepsy at Vanderbilt University Medical Center, said he decided to focus on the region that does control wakefulness — the brainstem. He hypothesized that connectivity disruptions with the brainstem resulting from a history of seizures might play a role in diminished cognitive functions that are not related to the temporal lobe.

The research, published online May 30 in Neurology, is the first to investigate how epilepsy affects the ascending reticular activating system (ARAS) — circuitry that is responsible for regulating wakefulness — within the brainstem. Functional magnetic resonance imaging revealed that ARAS disruptions occurred, with decreases in circuitry being quantitatively associated with disease severity.

“Seizures do not start in areas deep below the surface of the brain called subcortical nuclei,” said Englot, the study’s lead author and assistant professor of Neurological Surgery, Radiology and Radiological Sciences and Biomedical Engineering. “So these areas are not often studied in epilepsy. But we think that problems develop in some deep subcortical circuits that may contribute to some of the unexplained global brain problems in temporal lobe epilepsy, including progressive neurocognitive problems and problems with arousal that can’t be explained by problems in the temporal lobe.”

Early Seizures and Temporal Lobe Trauma Predict Post-Traumatic Epilepsy: A Longitudinal Study

CONCLUSION: Our results indicate that in a cohort of patients with a moderate-severe Traumatic Brain Injury (TBI), 1) lesion location specificity (e.g. the temporal lobe) is related to both a high incidence of early seizures and longitudinal development of Post-Traumatic Epilpesy (PTE), 2) early seizures, whether convulsive or non-convulsive in nature, are associated with an increased risk for PTE development, and 3) patients who develop PTE have greater chronic temporal lobe atrophy and worse functional outcomes, compared to those who do not develop PTE, despite matched injury severity characteristics. This study provides the foundation for a future prospective study focused on elucidating the mechanisms and risk factors for epileptogenesis.

OBJECTIVE: Injury severity after TBI is a well-established risk factor for the development of PTE. However, whether lesion location influences the susceptibility of seizures and development of PTE longitudinally has yet to be defined. We hypothesized that lesion location, specifically in the temporal lobe, would be associated with an increased incidence of both early seizures and PTE. As secondary analysis measures, we assessed the degree of brain atrophy and functional recovery, and performed a between-group analysis, comparing patients who developed PTE with those who did not develop PTE.

METHODS: We assessed early seizure incidence (n?=?90) and longitudinal development of PTE (n?=?46) in a prospective convenience sample of patients with moderate-severe TBI. Acutely, patients were monitored with prospective cEEG and a high-resolution Magnetic Resonance Imaging (MRI) scan for lesion location classification. Chronically, patients underwent a high-resolution MRI, clinical assessment, and were longitudinally monitored for development of epilepsy for a minimum of 2?years post-injury.

RESULTS: Early seizures, occurring within the first week post-injury, occurred in 26.7% of the patients (n?=?90). Within the cohort of subjects who had evidence of early seizures (n?=?24), 75% had a hemorrhagic temporal lobe injury on admission. For longitudinal analyses (n?=?46), 45.7% of patients developed PTE within a minimum of 2?years post-injury. Within the cohort of subjects who developed PTE (n?=?21), 85.7% had a hemorrhagic temporal lobe injury on admission and 38.1% had early (convulsive or non-convulsive) seizures on cEEG monitoring during their acute ICU stay. In a between-group analysis, patients with PTE (n?=?21) were more likely than patients who did not develop PTE (n?=?25) to have a hemorrhagic temporal lobe injury (p?<?0.001), worse functional recovery (p?=?0.003), and greater temporal lobe atrophy (p?=?0.029).