Generalized, Focal, and Combined Epilepsies in Families: New Evidence for Distinct Genetic Factors

Abstract, originally published in Epilepsia

Objective: To determine the roles of shared and distinct genetic influences on generalized and focal epilepsy operating in individuals who manifest features of both types (combined epilepsies), and in families manifesting both generalized and focal epilepsies in separate individuals (mixed families).

Methods: We analyzed the deeply phenotyped Epi4K cohort of multiplex families (≥3 affected individuals per family) using methods that quantify the aggregation of phenotypes within families and the relatedness of individuals with different phenotypes within family pedigrees.

Results: The cohort included 281 families containing 1021 individuals with generalized (n = 484), focal (304), combined (51), or unclassified (182) epilepsies. The odds of combined epilepsy was higher in relatives of participants with combined epilepsy than in relatives of those with other epilepsy types (odds ratio [OR] 5.2, 95% confidence interval [CI] 1.7-16.1, P = .004). Individuals with combined epilepsy co-occurred in families more often than expected by chance (P = .03). Within mixed families, individuals with each type of epilepsy were more closely related to relatives with the same type than to relatives with other types (P < .001).

Significance: These findings suggest that distinct genetic influences underlie the recently recognized entity of combined epilepsies, just as generalized epilepsies and focal epilepsies each have distinct genetic influences. Mixed families may in part reflect chance co-occurrence of these distinct genetic influences. These conclusions have important implications for molecular genetic studies aimed at identifying genetic determinants of the epilepsies.

The COVID-19 Outbreak and Approaches to Performing Eeg in Europe

Abstract, originally published in Epileptic Disord.

The coronavirus SARS-CoV-2 disease (COVID-19) pandemic affects availability and performance of neurophysiological diagnostic methods, including EEG. Our objective was to outline the current situation regarding EEG-based investigations across Europe. A web-based survey was distributed to centers within the European Reference Network on rare and complex epilepsies (ERN EpiCARE). Responses were collected between April 9 and May 15, 2020. Results were analysed with Microsoft Excel, Python Pandas and SciPy. Representants from 47 EpiCARE centers from 22 countries completed the survey. At the time of completing the survey, inpatient video-EEGs had been stopped or restricted in most centers (61.7% vs. 36.2% for adults, and 38.3% vs. 53.2% for children). Invasive investigations and epilepsy surgery were similarly affected. Acute EEGs continued to be performed, while indications for outpatient EEGs were limited and COVID-19 triage put in place. The strictness of measures varied according to extent of the outbreak in a given country. The results indicate a profound impact of COVID-19 on neurophysiological diagnostics, especially inpatient video-EEGs, invasive investigations, and epilepsy surgery. The COVID-19 pandemic may hamper care for patients in need of EEG-based investigations, particularly patients with seizure disorders. ERN EpiCARE will work on recommendations on how to rapidly adapt to such situations in order to alleviate consequences for our patients.

Review: Utilizing the Brain Activity Called High Frequency Oscillations as an EEG Biomarker to Predict the Development of Epilepsy and Seizures

Abstract, originally published in Epilepsy Curr

The study of high frequency oscillations (HFO) [a type of brain activity] in the electroencephalogram (EEG) as biomarkers of epileptic activity has merely focused on their spatial location and relationship to the epileptogenic zone. It has been suggested in several ways that the amount of HFO at a certain point in time may reflect the disease activity or severity. This could be clinically useful in several ways, especially as noninvasive recording of HFO appears feasible. We grouped the potential hypotheses into 4 categories: (1) HFO as biomarkers to predict the development of epilepsy; (2) HFO as biomarkers to predict the occurrence of seizures; (3) HFO as biomarkers linked to the severity of epilepsy, and (4) HFO as biomarkers to evaluate outcome of treatment. We will review the literature that addresses these 4 hypotheses and see to what extent HFO can be used to measure seizure propensity and help determine prognosis of this unpredictable disease.

CURE Epilepsy Discovery: Epilepsy Surgery May Be Beneficial in Reducing SUDEP

Key Points:

  • To understand how epilepsy surgery can affect the risk of SUDEP, CURE Epilepsy-grantee Dr. Lisa Bateman and her collaborator, Dr. Catherine Schevon, analyzed rates and causes of mortality in people who had epilepsy surgery versus those who hadn’t.
  • Their analysis suggests that for those who have had epilepsy surgery, there was a reduction in the occurrence of death, and significantly fewer deaths from SUDEP.
  • The reduction in the occurrence of SUDEP for those who have had surgery appeared to be most significant in the first 10 years post-surgery.

Deep Dive:

Frequent, uncontrolled seizures, particularly generalized tonic-clonic seizures (GTCS), are a risk factor for Sudden Unexpected Death in Epilepsy or SUDEP[1]. Epilepsy surgery can be an option to control or eliminate seizures in people with drug-resistant seizures. In addition to helping achieve seizure control, epilepsy surgery is also thought to reduce the risk of SUDEP, however, the evidence for this is limited. A strong understanding of how epilepsy surgery can affect SUDEP occurrence is important as it can help guide treatment decisions.

Dr. Lisa Bateman, Cedars Sinai Medical CenterCURE Epilepsy-grantee, Dr. Lisa Bateman and her collaborator, Dr. Catherine Schevon recently published results from their study comparing the number and causes of death, including SUDEP, in people who had epilepsy surgery versus those who did not undergo surgery[2].

For their study, which was generously funded by the Henry Lapham Memorial Award, the team analyzed mortality in 590 patients who had undergone epilepsy surgery between 1977 and 2014. Deaths in this surgical group were compared to those in a group of 122 people with drug-resistant epilepsy who did not have epilepsy surgery because they were either not considered suitable candidates or refused surgery.

The team found that number of deaths was significantly reduced in the surgical group versus the non-surgical group, and SUDEP was the main cause of death in both groups. Additional causes included tumors, suicide, accidental death, status epilepticus and other conditions.

Dr. Catherine Schevon, Columbia UniversityUpon further analysis, the researchers discovered that the surgical group had a statistically significant lower rate of SUDEP (1.9 per 1000 patient-years* in the surgical group versus 4.6 per 1000 patient-years in the non-surgical group), as well as a delay in the occurrence of SUDEP relative to the non-surgical group. In the surgical group, on average, SUDEP occurred 10.1 years after surgery, but in the non-surgical group it occurred an average of 5.9 years after the surgery was discussed, but not performed.

The team also found that there was a reduction in SUDEP occurrence in the first 10 years after surgery, however, this benefit appeared to lessen after this time- period. While a larger study is needed to confirm it, this finding suggests that long-term follow up of epilepsy surgery patients is important even if they are seizure-free after surgery.

This CURE Epilepsy-funded study provides evidence for the beneficial effects of epilepsy surgery in reducing overall mortality including SUDEP. A larger study will be helpful in determining how long the benefit can last and whether there are any factors that can predict who might be at greater risk for SUDEP post-surgery.

*Patient-years is a statistical term used to account for the total time all subjects spend in a study and is a more accurate measure of the rate at which an event, in this case SUDEP, occurs in the study population.

Dr. Lisa Bateman is the Director of Surgical Epilepsy Programs at Cedar Sinai Medical Center. Dr. Catherine Schevon is an Associate Professor of Neurology at Columbia University. 

Literature Cited

[1] Harden C., Tomson T., et. al. Practice guideline summary: Sudden unexpected death in epilepsy incidence rates and risk factors: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2017 Apr 25;88(17):1674-1680.

[2] Casadei C.H., Carson K.W., et. al. All-cause mortality and SUDEP in a surgical epilepsy population. Epilepsy & Behavior 2020 Jul;108:107093

Your support makes this research possible. Our researchers’ important work continues through the current public health crisis and beyond thanks to generous donors who, like us, envision a world without epilepsy.

Seizure-Related Injuries in Inadequately Treated Epilepsy Patients: A Case-Control Study

Abstract, originally published in Seizure

Purpose: To compare epilepsy-related injuries in untreated or inadequately treated patients and patients on adequate treatment.

Methods: In a cross-sectional case-control study, seizure-related injuries in patients who were either on no treatment or inadequate treatment were compared with another group of patients receiving appropriate evidence-based epilepsy treatment. The inadequately treated patients or ‘cases’ were drawn from an outreach epilepsy clinic while the adequately treated patients or ‘controls’ were recruited from a tertiary care facility providing comprehensive epilepsy management.

Results: The odds of injury were eight times higher in inadequately treated patients or cases compared to the adequately treated patients or controls. After adjusting for gender, epilepsy duration, seizure frequency, current medication, and number of AEDs, the odds of injury were 15. 8 times higher in the cases. Major injuries such as burns, fractures, and tooth injuries were also higher in the cases.

Conclusion: Untreated or inadequately treated epilepsy patients have a significantly higher risk of injuries. With adequate treatment, some of the risks of injury can be mitigated.

Nasal Pain as an Aura: Amygdala Origin?

Abstract, originally published in Seizure

Purpose: Nasal pain, as an epileptic aura, has been poorly recognized. This study aims to demonstrate clinical features of patients with epilepsy who have nasal pain as an aura.

Methods: We retrospectively investigated consecutive patients who visited the epilepsy clinic of tertiary hospital from April 2000 to September 2019. All included patients underwent epilepsy-dedicated, high-resolution magnetic resonance imaging (MRI) examinations. All MRI studies were analyzed by visual inspection.

Results: Seven patients who presented nasal pain as an aura, were identified. Four patients reported nasal pain as the first aura. Four patients had right amygdala enlargement (isolated amygdala enlargement in three patients; amygdala enlargement in addition to hippocampal sclerosis in one patient), and one patient with compression of an internal carotid-posterior communicating artery aneurysm to right amygdala on brain MRI. Interictal epileptiform or ictal discharges on EEG were found in the right temporal region in five patients. In all four patients with amygdala enlargement, amygdala enlargement was ipsilateral to EEG anomalies. In all patients, nasal pain was accompanied by ictal semiological features, such as autonomic, olfactory, abdominal, or psychic auras, and focal impaired awareness seizures, which are typically associated with mesial temporal lobe epilepsy.

Conclusions: Our findings suggest that nasal pain can occur as an epileptic aura in patients with temporal lobe epilepsy with probable involvement of the amygdala.

Cenobamate (Xcopri): Can Preclinical and Clinical Evidence Provide Insight Into Its Mechanism of Action?

Abstract, originally published in Epilepsia

Approximately one-third of people living with epilepsy are unable to obtain seizure control with the currently marketed antiseizure medications (ASMs), creating a need for novel therapeutics with new mechanisms of action. Cenobamate (CBM) is a tetrazole alkyl carbamate derivative that received US Food and Drug Administration approval in 2019 for the treatment of adult partial onset (focal) seizures. Although CBM displayed impressive seizure reduction in clinical trials across all seizure types, including focal aware motor, focal impaired awareness, and focal to bilateral tonic-clonic seizures, the precise mechanism(s) through which CBM exerts its broad-spectrum antiseizure effects is not known. Experimental evidence suggests that CBM differentiates itself from other ASMs in that it appears to possess dual modes of action (MOAs); that is, it predominately blocks persistent sodium currents and increases both phasic and tonic γ-aminobutyric acid (GABA) inhibition.

In this review, we analyze the preclinical efficacy of CBM alongside ASMs with similar MOAs to better understand the mechanism(s) through which CBM achieves such broad-spectrum seizure protection. CBM’s preclinical performance in tests, including the mouse 6-Hz model of treatment-resistant seizures, the chemoconvulsant seizure models of generalized epilepsy, and the rat hippocampal kindling model of focal epilepsy, was distinct from other voltage-gated sodium channel blockers and GABAA modulators. This distinction, in light of its proposed mechanism(s) of action, provides insight into the impressive clinical efficacy of CBM in the adult patient with focal onset epilepsy. The results of this comparative reverse translational analysis suggest that CBM is a mechanistically distinct ASM that offers an important advancement in drug development for treatment of therapy-resistant epilepsy.

Focal Epilepsy Often Overlooked

Article, originally featured on EurekAlert

Having subtler symptoms, a form of epilepsy that affects only one part of the brain often goes undiagnosed long enough to cause unexpected seizures that contribute to car crashes, a new study finds.

The study, published online Oct. 20 in the journal Epilepsia, addressed focal epilepsy, the most common form of this brain disorder. Researchers say the study is among the first to outline failure to recognize symptoms of subtle seizures as a main reason for the delay in diagnosis.

Led by researchers at NYU School of Medicine, the study shows that it can take on average two years for physicians to recognize the early signs of focal epilepsy, particularly in a subset of patients with seizures that do not involve uncontrolled movements of their arms and legs. Symptoms of these “non-motor seizures” instead may include a recurring brief hallucination, a strong sense of déjà vu, or sensations of a dreamlike state while awake.

Subtler cases are often not diagnosed until they have progressed to disruptive “motor” seizures, say the study authors, which can cause the unrestrained, whole-body spasms often portrayed in popular culture.

Study Findings Suggest Animal Model Replicates Key Molecular Features of Human Drug-Resistant Temporal Lobe Epilepsy

Abstract, originally published in Epilepsia

Objective: Pharmacoresistance and the lack of disease-modifying actions of current antiseizure drugs persist as major challenges in the treatment of epilepsy. Experimental models of chemoconvulsant-induced status epilepticus remain the models of choice to discover potential antiepileptogenic drugs, but doubts remain as to the extent to which they model human pathophysiology. The aim of the present study was to compare the molecular landscape of the intra-amygdala kainic acid model of status epilepticus in mice with findings in resected brain tissue from patients with drug?resistant temporal lobe epilepsy (TLE).

Methods: Status epilepticus was induced via intra-amygdala microinjection of kainic acid in C57BL/6 mice, and gene expression was analyzed via microarrays in hippocampal tissue at acute and chronic time-points. Results were compared to reference datasets in the intraperitoneal pilocarpine and intrahippocampal kainic acid model and to human resected brain tissue (hippocampus and cortex) from patients with drug-resistant TLE.

Results: Intra-amygdala kainic acid injection in mice triggered extensive dysregulation of gene expression that was ~3-fold greater shortly after status epilepticus (2729 genes) when compared to epilepsy (412). Comparison to samples from patients with TLE revealed a particularly high correlation of gene dysregulation during established epilepsy. Pathway analysis found suppression of calcium signaling to be highly conserved across different models of epilepsy and patients. cAMP response element-binding protein (CREB) was predicted as one of the main upstream transcription factors regulating gene expression during acute and chronic phases, and inhibition of CREB reduced seizure severity in the intra-amygdala kainic acid model.

Significance: Our findings suggest the intra-amygdala kainic acid model faithfully replicates key molecular features of human drug-resistant temporal lobe epilepsy and provides potential rational target approaches for disease-modification through new insights into the unique and shared gene expression landscape in experimental epilepsy.

Where Have the Children With Epilepsy Gone? An Observational Study of Seizure-Related Accesses to Emergency Department at the Time of COVID-19

Abstract, originally published in Seizure

Purpose: The COVID-19 pandemic and related lockdown measures drastically changed health care and emergency services utilization. This study evaluated trends in emergency department (ED) access for seizure-related reasons in the first 8 weeks of lockdown in Italy.

Methods: All ED accesses of children (<14 years of age) at two university hospitals, in Turin and Rome, Italy, between January 6, 2020 and April 21, 2020, were examined and compared with the corresponding periods of 2019.

Results: During the COVID-19 lockdown period (February 23-April 21, 2020), there was a 72 % decrease in all pediatric ED accesses over the corresponding 2019 period (n = 3,395 vs n = 12,128), with a 38 % decrease in seizure-related accesses (n = 41 vs n = 66). The observed decrease of seizure-related ED accesses was not accompanied by significant changes in age, sex, type of seizure, or hospitalization rate after the ED visit.

Conclusion: The COVID-19 lockdown was accompanied by a sudden decrease in seizure-related hospital emergency visits. School closure, social distancing, reduced risk of infection, and increased parental supervision are some of the factors that might have contributed to the finding.