Enduring Language Deficits in Children of Women With Epilepsy and the Potential Role of Intrauterine Exposure to Antiepileptic Drugs

Abstract, originally published in Epilepsia

Objective: Exposure to certain intrauterine antiepileptic drugs (AEDs) can negatively influence the language skills and intelligence of young children. It remains unanswered whether these deficits are transient or persist as children grow up. This study aims to evaluate the language function of children of women with epilepsy (CWE) aged 9-13 years in comparison with their peers, and its relationship with intrauterine AED exposure.

Methods: We included 191 CWE in our study from the Kerala Registry of Epilepsy and Pregnancy. Children in the same age group (n = 144) and without maternal epilepsy or antenatal AED exposure served as controls. We used Clinical Examination for Language Function version IV to assess language in both groups. Relevant data related to maternal epilepsy and AED use were obtained from the registry records.

Results: The average Core Language Scaled Score (CLSS) was significantly lower in CWE as compared to controls (83.19 vs 90.18, P = .001). Similarly, the mean scaled scores in other language parameters were also significantly lower in CWE. In the multivariate analysis, compared to control children, the average CLSS in CWE was 4.5 units lower (95% confidence interval [CI] = -8.8 to -0.2, P = .04) with AED monotherapy exposure and 7.3 units lower with exposure to AED polytherapy (95% CI = -13.8 to -0.8, P = .03). Intrauterine exposure to phenobarbitone (n = 61) and valproate (n = 55) as either monotherapy or polytherapy showed a negative effect on CLSS in CWE as compared to control children. However, carbamazepine (n = 75) and phenytoin (n = 37) use was not associated with significant variation of CLSS. In head-to-head comparisons between AED monotherapies in CWE, phenobarbitone showed a negative effect on CLSS (-14.7, 95% CI = -23.1 to -6.4, P = .001) as compared to carbamazepine.

Significance: Intrauterine exposure to phenobarbitone and valproate impairs language development in children with epilepsy, with effects persisting into the second decade.

College of Medicine Researcher Makes Novel Discoveries in Preventing Epileptic Seizures

Article, originally published by Florida State University News

A team of researchers from the Florida State University College of Medicine has found that an amino acid produced by the brain could play a crucial role in preventing a type of epileptic seizure.

Temporal lobe epileptic seizures are debilitating and can cause lasting damage in patients, including neuronal death and loss of neuron function.

Sanjay Kumar, an associate professor in the College of Medicine’s Department of Biomedical Sciences, and his team are paving the way toward finding effective therapies for this disease.

The research team found a mechanism in the brain responsible for triggering epileptic seizures. Their research indicates that an amino acid known as D-serine could work with the mechanism to help prevent epileptic seizures, thereby also preventing the death of neural cells that accompanies them.

The team’s findings were published in the journal Nature Communications.

Machine Learning From Wristband Sensor Data for Wearable, Noninvasive Seizure Forecasting

Abstract, originally published in Epilepsia

Objective: Seizure forecasting may provide patients with timely warnings to adapt their daily activities and help clinicians deliver more objective, personalized treatments. Although recent work has convincingly demonstrated that seizure risk assessment is in principle possible, these early approaches relied largely on complex, often invasive setups including intracranial electrocorticography, implanted devices, and multichannel electroencephalography, and required patient-specific adaptation or learning to perform optimally, all of which limit translation to broad clinical application. To facilitate broader adaptation of seizure forecasting in clinical practice, noninvasive, easily applicable techniques that reliably assess seizure risk without much prior tuning are crucial. Wristbands that continuously record physiological parameters, including electrodermal activity, body temperature, blood volume pulse, and actigraphy, may afford monitoring of autonomous nervous system function and movement relevant for such a task, hence minimizing potential complications associated with invasive monitoring and avoiding stigma associated with bulky external monitoring devices on the head.

Methods: Here, we applied deep learning on multimodal wristband sensor data from 69 patients with epilepsy (total duration > 2311 hours, 452 seizures) to assess its capability to forecast seizures in a statistically significant way.

Results: Using a leave-one-subject-out cross-validation approach, we identified better-than-chance predictability in 43% of the patients. Time-matched seizure surrogate data analyses indicated forecasting not to be driven simply by time of day or vigilance state. Prediction performance peaked when all sensor modalities were used, and did not differ between generalized and focal seizure types, but generally increased with the size of the training dataset, indicating potential further improvement with larger datasets in the future.

Significance: Collectively, these results show that statistically significant seizure risk assessments are feasible from easy-to-use, noninvasive wearable devices without the need of patient-specific training or parameter optimization.

Epilepsy Research News: October 2020

This month’s research news features two studies advancing Dravet syndrome research, both utilizing mouse models mimicking the disorder. One study, featuring the work of former CURE Grantee Dr. Lori Isom, tested a new type of drug and found that it decreased the frequency of Sudden Unexplained Death in Epilepsy (SUDEP) in these mice.

In other news, a recent study has increased our understanding of the unique way epilepsy can affect women, showing that women who have seizures that increase in frequency during their menstrual cycle are also more likely to have drug-resistant epilepsy.

Finally, research has helped pinpoint individuals with epilepsy who may be at risk for obstructive sleep apnea, a finding that may help physicians identify who is most at risk and who would likely benefit from treatment.

Summaries of these research discoveries and more are below.

Research Discoveries

Dravet Syndrome (Featuring the work of former CURE Grantee, Dr. Lori Isom)
A new treatment curbs deadly seizures in a mouse model of Dravet syndrome, a severe form of epilepsy, according to a new study. This new drug counteracts the effects of mutations in a gene known as SCN1A, which cause Dravet syndrome. In this study, the drug significantly decreased the overall frequency of SUDEP, lowering the likelihood of a fatal seizure. A clinical trial is evaluating the drug’s safety in children with the syndrome.

Learn more

Dravet Syndrome
A study has utilized a gene therapy technique to reduce seizures and improve behaviors in a mouse model of Dravet syndrome. Researchers used the technique to activate the SCN1A gene, a gene with decreased activity in individuals with Dravet syndrome. The authors note that although more work must be done before the technique can be tested in people, the study supports a potential new approach to treating this cause of epilepsy.

Learn more

Epilepsy Genetics
Researchers have identified a critical new step in how brain cells function in people with one of the most common forms of epilepsy. Using mice, researchers found certain changes in gene activity and regulation in an area of the brain important in temporal lobe epilepsy. The researchers note that the study could eventually lead to targeted treatments that prevent a person from developing epilepsy.

Learn more

Epilepsy and Fetal Alcohol Spectrum Disorder
A study has found a much higher prevalence of epilepsy or history of seizures in individuals with fetal alcohol spectrum disorder (FASD), a disorder that refers to a range of developmental problems that result from maternal drinking during pregnancy. Although more research is needed to establish a direct cause-effect relationship between FASD and epilepsy, the study, which examined the medical histories of individuals from two FASD clinics, supports the link between maternal drinking during pregnancy and a wide array of health impacts to the child.

Learn more

Drug Resistant Epilepsy and Women
More frequent seizures during the menstrual cycle in women with genetic generalized epilepsy have been linked for the first time to drug-resistant epilepsy. Women with catamenial epilepsy, a generalized epilepsy characterized by increased seizure frequency during the menstrual cycle, were nearly four times more likely to have drug-resistant epilepsy than women who experience no changes in frequency.

Learn more

Epilepsy and Sleep Apnea
People with generalized epilepsy who have seizures arising from both sides of the brain simultaneously have a higher risk of obstructive sleep apnea than those who have focal epilepsy where seizures emanate from one area of the brain, according to a new study. These findings may help physicians better understand who is most at risk for obstructive sleep apnea and, therefore, who will benefit most from treatment.

Learn more

Efficacy and Safety of Fenfluramine Hydrochloride (Fintepla®) for the Treatment of Seizures in Dravet Syndrome: A Real-world Study

Abstract, originally published in Epilepsia

Objective: Dravet syndrome (DS) is a drug-resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, fenfluramine (FFA) proved to be safe and effective in DS.

Methods: DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add-on, twice daily at an initial dose of 0.2 mg/kg/d up to 0.7 mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months.

Results: Fifty-two patients were enrolled, with a median age of 8.6 years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0 months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥ 50% reduction of convulsive seizures, 24 (53.3%) had a ≥ 75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA.

Significance: In this real-world study, fenfluramine provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated.

Important Update on NAYZILAM® Availability

NAYZILAM® (midazolam) nasal spray, a rescue medicine manufactured by UCB, is experiencing a manufacturing delay.

This shortage is expected to be temporary, lasting until the end of October 2020. If you need medication and are having challenges finding it at your pharmacy, please do one of the following:

Contact your physician
Contact: UCBCares® at (844) 599 2273
Email: UCBCares@ucb.com

If you have any questions or concerns, please contact your physician.

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.

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.

STAY UP TO DATE