Review Paper: Inflammatory and Immune Mechanisms Underlying Epileptogenesis and Epilepsy: From Pathogenesis to Treatment Target

Abstract, originally published in Seizure

Epilepsy is a brain disease associated with epileptic seizures as well as with neurobehavioral outcomes of this condition. In the last century, inflammation emerged as a crucial factor in epilepsy etiology. Various brain insults through activation of neuronal and non-neuronal brain cells initiate a series of inflammatory events.

Growing observations strongly suggest that abnormal activation of critical inflammatory processes contributes to epileptogenesis, a gradual process by which a normal brain transforms into the epileptic brain. Increased knowledge of inflammatory pathways in epileptogenesis has unveiled mechanistic targets for novel antiepileptic therapies. Molecules specifically targeting the pivotal inflammatory pathways may serve as promising candidates to halt the development of epilepsy.

The present paper reviews the pieces of evidence conceptually supporting the potential role of inflammatory mechanisms and the relevant blood-brain barrier (BBB) disruption in epileptogenesis. Also, it discusses the mechanisms underlying inflammation-induced neuronal-glial network impairment and highlights innovative neuroregulatory actions of typical inflammatory molecules. Finally, it presents a brief analysis of observations supporting the therapeutic role of inflammation-targeting tiny molecules in epileptic seizures.

Study Finds Sleep Abnormalities Are a Major Issue in up to ¾ of Children With Drug-Resistant Epilepsy

Abstract, originally published in Seizure

Purpose: This study aims to assess the prevalence of sleep abnormalities in children with drug-resistant epilepsy (DRE) and characterize their polysomnographic profile and to further compare it with well-controlled epilepsy (WCE) and age-matched typically developing children (TDC).

Methods: A cross-sectional study consisting of 40 children in each group (DRE, WCE, and TDC) was conducted. Children’s sleep habits questionnaire (CSHQ) and modified pediatric Epworth daytime sleepiness scale (MPEDSS) were administered to all three groups. Thirty-five children each in the DRE and WCE group and 17 TDC underwent single night polysomnography (PSG).

Results: The prevalence of sleep abnormalities by the administration of CSHQ in DRE group was 72.5% (95% C.I-58.7 to 86.3%, mean score: 47.5 ± 7.1) compared to 32.5% (42.4 ± 6.2) and 15% (37.3 ± 5) in WCE and TDC groups respectively (P = 0.01). On MPEDSS, 52.5% of children in the DRE group had excessive daytime sleepiness compared to 12.5% in WCE and 5% in TDC groups respectively (p-0.03). On overnight PSG, sleep efficiency and REM sleep duration were significantly reduced in the DRE group in comparison to WCE and TDC. N2 duration, REM latency, arousal, and apnea-hypopnea index were significantly increased in the DRE group when compared to WCE and TDC groups.

Conclusion: Sleep-related problems are major comorbidity in up to three-fourths of patients with DRE and sleep architecture is significantly affected particularly in the DRE group.

Study Finds That Psychotherapy via Telehealth Is a Viable Treatment Option for Psychogenic Nonepileptic Seizures (PNES)

Abstract, originally published in Epilepsia

Objective: Previous studies have shown the effectiveness of manual-based treatment for psychogenic nonepileptic seizures (PNES), but access to mental health care still remains a problem, especially for patients living in areas without medical professionals who treat conversion disorder. Thus, we evaluated patients treated with cognitive behavioral therapy–informed psychotherapy for seizures with clinical video telehealth (CVT). We evaluated neuropsychiatric and seizure treatment outcomes in veterans diagnosed with PNES seen remotely via telehealth. We hypothesized that seizures and comorbidities will improve with treatment.

Methods: This was a single–arm, prospective, observational, cohort, consecutive outpatient study. Patients with video–electroencephalography–confirmed PNES (n = 32) documented their seizure counts daily and comorbid symptoms prospectively over the course of treatment. Treatment was provided using a 12–session manual–based psychotherapy treatment given once per week, via CVT with a clinician at the Providence Veterans Affairs Medical Center.

Results: The primary outcome, seizure reduction, was 46% (P = .0001) per month over the course of treatment. Patients also showed significant improvements in global functioning (Global Assessment of Functioning, P = < .0001), quality of life (Quality of Life in Epilepsy Inventory–31, P = .0088), and health status scales (Short Form 36 Health Survey, P < .05), and reductions in both depression (Beck Depression Inventory–II, P = .0028) and anxiety (Beck Anxiety Inventory, P = .0013) scores.

Significance: Patients with PNES treated remotely with manual-based seizure therapy decreased seizure frequency and comorbid symptoms and improved functioning using telehealth. These results suggest that psychotherapy via telehealth for PNES is a viable option for patients across the nation, eliminating one of the many barriers of access to mental health care.

The Path to a Cure: Improving Genetic-Based Outcomes

Dr. Heather Mefford is a current CURE Grantee who is as dedicated to driving science toward cures for epilepsy as she is to treating people in her clinical practice. As Associate Professor of Pediatrics at the University of Washington and attending physician at Seattle Children’s Hospital, Dr. Mefford is making an impact both in and out of the laboratory.

Severe Pediatric Epilepsy is Often Genetic

Dr. Heather Mefford, 2019 CURE Epilepsy Grantee

As a physician who cares for pediatric patients living with severe epilepsy syndromes, Dr. Mefford has firsthand knowledge of the devastating impacts of seizures in children. These treatment-resistant epilepsy syndromes are usually caused by a genetic mutation and knowing what that mutation is can potentially inform the treatment plan. As such, genetic testing is a critical part of the epilepsy diagnosis and care process. Dr. Mefford describes what genetic testing involves and what kinds of tests are available in an episode of our Seizing Life® podcast. Watch or listen to learn more.

The DNA of Dr. Mefford’s Genetic Research
When not seeing patients, Dr. Mefford heads a research laboratory at the University of Washington. Over the last 10 years, Dr. Mefford’s team has identified many new epilepsy-related genes and mutations. Dr. Mefford’s lab is currently investigating a type of genetic change that does not alter the sequence of the gene itself but instead affects how the gene functions. This field of research, known as epigenetics, is relatively new and now, excitingly, is being applied to epilepsy. For her CURE-funded project, Dr. Mefford is studying a type of epigenetic change called methylation, in people with severe early-onset, treatment-resistant seizure disorders known as developmental and epileptic encephalopathies (DEE). Despite advanced genetic testing, more than 50% of people with DEE still do not have a genetic diagnosis and work like Dr. Mefford’s could ultimately improve the prognosis for children with these epilepsies.

Leading the Next Generation
To support the future of research, Dr. Mefford has helped launch the careers of the next generation of epilepsy scientists. One of her former trainees, Dr. Gemma Carvill, is also making a big impact on the field of epilepsy research. Dr. Carvill was awarded a CURE grant early in her career and now leads her own independent research program at Northwestern University in Chicago, where she also investigates the underlying genetic and epigenetic mechanisms of epilepsy.

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.

Preparing Adolescents With Epilepsy to Manage Care Through Adulthood

Article, originally published on UofMHealth

As children with epilepsy get older, managing their own care is critical to their independence, ability to drive, go to college, seek employment and eventually start a family if they choose to do so.

And as more children with the neurological disorder survive into adulthood, ensuring a smooth transition in care is even more important.

Now, clinicians at Michigan Medicine have developed a tool to help them better prepare adolescents and young adults to take ownership of their disease well before the time comes.

Through a customized screening tool for 16 to 26 year-olds, doctors are effectively able to monitor their patients’ development of knowledge and self-management skills regarding their condition, according to a report in Epilepsia Open. This structure allows providers to proactively address gaps in readiness that may impact long term health outcomes.

Localizing Epilepsy ‘Hotspots’

Article, originally published on PennToday

By applying tools of machine learning and network analysis, the Davis Lab in the Penn Epilepsy Center was assisted by a team of Penn interns this summer to target the ‘missing electrode problem,’ identifying regions of the brain that cause epilepsy.

One percent of the U.S. population, or three million people, lives with epilepsy. Approximately one-third of those will have a drug-resistant form of epilepsy that, often, demands surgery. The challenge: Localizing where their seizures are coming from before surgery has historically been done with the implantation of EEG electrodes in the brain—an extraordinarily invasive procedure that comes with its own set of limitations.

Enter, the lab of Kathryn Davis, an assistant professor of neurology in the Penn Epilepsy Center at the Perelman School of Medicine.

“The problem with intracranial EEG electrodes is mainly a sampling issue. To solve this problem, we are leveraging information captured from whole-brain neuroimaging to better localize the seizure onset zone,” says Andrew Revell, a fifth-year MD/Ph.D. student in the Davis Lab, who explains that implanted electrodes can miss the areas implicated in seizure generation. “When planning for epilepsy surgery to remove the seizure onset zone, you want to precisely localize the seizure generating areas and avoid eliminating any functional brain tissue, such as areas associated with hand movement or language generation. This is where an MRI can help.”

The Davis lab is studying how an MRI of the brain may help with the sampling issue of intracranial EEG, or the so-called “missing electrode problem,” where surgical limitations and safety restrict implantation of the entire brain. Patients routinely undergo an MRI of their brain before implantations, but they may also participate in research scans to acquire different imaging sequences, such as High-Angular Resolution Diffusion Imaging (HARDI). With these MRI sequences, the lab is modeling how the brain is connected, building networks of the brain, and making predictions of seizure activity in regions where electrodes were not implanted. They take an interdisciplinary approach, drawing from their expertise in imaging analysis, machine learning, network analysis, and signal analysis to solve a very relevant clinical problem.

Risk-Benefit Assessment of Treatment of Epileptic Women of Childbearing Age With Valproic Acid

Abstract, originally published in Seizure

Aim: Valproic acid (VPA) is a widely used anti-epileptic drug (AED) of demonstrated efficacy. However, its teratogenic effects have resulted in many regulatory agencies recommending that it should not be administered to women of childbearing age unless they are taking contraceptives. The aim of this study was to determine the willingness of candidate patients to change their treatment and to monitor the evolution of their attitude.

Methods: We identified patients aged between 15 and 45 years old who had been diagnosed with epilepsy and were being treated with VPA. A shared decision-making visit was arranged, during which variables related to their epilepsy were recorded. The patients were informed about the teratogenic effects of VPA and the risks/benefits of a change in treatment. The patient, or legal guardian, then freely chose the course of treatment that they wished to follow. On a follow-up visit, six months later, seizure control and tolerance to the chosen treatment were recorded. The variables related to each patient’s willingness to their change treatment were analysed.

Results: A total of 60 patients, with a median age of 32.7 years, were included in the study. Of these, 25 (41.7%) suffered some form of intellectual disability. Only one (1.7%) had poor seizure control. After the initial visit, 41 patients (68%) opted to continue with the VPA treatment, six opted to stop receiving VPA, and 13 decided to switch to another AED. The median age of the patients who opted to change treatment was significantly lower than that of those who opted to continue with the VPA treatment (29.1 vs. 34.4, p = 0.024). The absence of intellectual disability (p = 0.047) and a length of treatment of less than five years (0.016) were both significantly associated with the decision to change treatment. Of the 19 patients who changed treatment, nine (47%) returned to the initial treatment with VPA.

Conclusions: Despite being informed of the teratogenic risk associated with VPA, a significant number of patients and legal guardians opted to continue with this treatment; the reasons given for this were the low possibility of pregnancy and the risk of breakthrough seizures. In almost half the cases studied, the pharmacological alternatives to VPA were poorly tolerated and did not provide a good level of seizure control.

Researchers Develop Wearable Device for Predicting Epileptic Seizures

Article, originally posted on

Ben-Gurion University of the Negev researchers have developed Epiness, a device for detecting and predicting epileptic seizures based on machine-learning algorithms. The wearable device can generate an advanced warning about an upcoming seizure that will be sent to a smartphone up to an hour prior to its onset. The system was out-licensed for further development and commercialization to NeuroHelp, a startup company that was recently founded by BGN Technologies, the technology transfer company of BGU and Dr. Oren Shriki, of BGU’s Department of Cognitive and Brain Sciences and NeuroHelp’s scientific founder.

Epiness is a seizure prediction and detection device that is based on a new, ground-breaking combination of EEG-based monitoring of brain activity together with proprietary machine-learning algorithms. The device combines a wearable EEG device with state-of-the-art software that minimizes the number of necessary EEG electrodes and optimizes electrode placement on the scalp. The sophisticated machine-learning algorithms are designed to filter noise that is not related to brain activity, extract informative measures of the underlying brain dynamics, and distinguish between brain activity before an expected epileptic seizure and brain activity when a seizure is not expected to occur.

Controlling Seizure Effects Using a New Potassium Channel Activator

Article, originally posted on

A group from The Mount Sinai Hospital / Mount Sinai School of Medicine have identified and characterized a novel potassium-channel activator, GiGA1, capable of selectively opening a subset of potassium channels to produce an antiseizure effect in animal models.

This study presents an integrated approach to GIRK1-specific activators, employing both computational modeling and subsequent biochemical and physiological studies. The resultant seizure mitigation produced in an acute epilepsy mouse model demonstrates a potential role for this compound in the treatment of brain disorders.

Mortality Implications and Factors Associated With Nonengagement in a Public Epilepsy Care Initiative in a Transient Population

Abstract, published in Epilepsy & Behavior

Background: Community-based, public care programs are a requisite to close the epilepsy treatment gap in disadvantaged communities in low- and middle-income countries (LMICs). Potential beneficiaries may, however, choose not to engage in these programs.

Aims: The aim of the study was to describe factors associated with and mortality consequences of nonacceptance of a public epilepsy care initiative.

Methods: In this cross-sectional study, we contacted 207 (36%) people out of 575 who screened positive for epilepsy during a population-based survey of 59,509 people. They were invited for neurological evaluation and care provision (including antiseizure medications (ASMs)) but chose not to engage. Structured questionnaires and qualitative interviews were conducted to determine reason for their nonengagement. Factors associated with nonengagement were evaluated by univariate and multivariate analysis. We conducted verbal autopsies for those who had died.

Results: Ten (5%) of the 207 individuals died since the initial screening; six with epilepsy-related causes. Of those who could be contacted (n = 48), 40 (19%) were confirmed to have epilepsy. Nonengaging individuals were likely to be older (odds ratio (OR): 1.02; 95% confidence interval (CI), 1.01, 1.11), locals (OR: 4.32; 95% CI, 1.55, 12.03), and earn less than US$ 78/month (OR: 3.6; 95% CI, 1.62, 8.06). Reasons for not engaging included a belief that epilepsy is inconsequential, loss of daily wages owing to healthcare facility visit and physical infirmity.

Conclusions: Nonacceptance of a community-based public epilepsy care initiative is associated with high premature mortality, mostly attributed to epilepsy-related causes. Older age, ethnic status, and economic deprivation are factors associated with nonacceptance, though the underlying reasons may be varied.