Leveraging electronic patient diaries in SUDEP risk evaluation.

OBJECTIVE: Our aim was to describe the risk factors known to be related to sudden unexpected death in epilepsy (SUDEP) that can be extracted from patients that utilizes an online seizure diary tool (SeizureTracker™). METHOD: We conducted a descriptive analysis of SeizureTracker™ users across factors relevant to SUDEP risk. We also compared our app-using cohort to published SUDEP case-control studies. RESULTS: We report across seven risk factors from 30,813 users of SeizureTracker™ who had a median length of time using the app of 5.69 years (range from 1 month to 15 years). We found that they are at greater risk for SUDEP than groups from published studies (p < .00001) based on the risk factor of generalized tonic-clonic seizures. SIGNIFICANCE: We demonstrated that the population using the SeizureTracker™ tool can be a valuable population for expanding investigation of SUDEP risk factors and is a first step towards establishing a large sample with a method to ascertain data prospectively that might be critical to developing a SUDEP risk algorithm.

Cardiac-based detection of seizures in children with epilepsy.

INTRODUCTION: We evaluated a multi-parametric approach to seizure detection using cardiac and activity features to detect a wide range of seizures across different people using the same model. METHODS: Electrocardiogram (ECG) and accelerometer data were collected from a chest-worn sensor from 62 children aged 2-17 years undergoing video-electroencephalogram monitoring for clinical care. ECG data from 5 adults aged 31-48 years who experienced focal seizures were also analyzed from the PhysioNet database. A detection algorithm was developed based on a combination of multiple heart rhythm and motion parameters. RESULTS: Excluding patients with multiple seizures per hour and myoclonic jerks, 25 seizures were captured from 18 children. Using cardiac parameters only, 11/12 generalized seizures with clonic or tonic activity were detected as well as 7/13 focal seizures without generalization. Separately, cardiac parameters were evaluated using electrocardiogram data from 10 complex partial seizures in the PhysioNet database of which 7 were detected. False alarms averaged one per day. Movement-based parameters did not identify any seizures missed by cardiac parameters, but did improve detection time for 4 of the generalized seizures. CONCLUSION: Our data suggest that cardiac measures can detect seizures with bilateral motor features with high sensitivity, while detection of focal seizures depends on seizure duration and localization and may require customization of parameter thresholds.

Differential activation of neuroinflammatory pathways in children with seizures: A cross-sectional study.

PURPOSE: Inflammation plays a crucial role in epileptogenesis. We analyzed inflammatory cytokines in plasma and saliva from children with seizures and healthy controls and measured their associations with HHV6 and EBV infection. METHODS: We analyzed plasma from 36 children within 24 h of seizures (cases) and 43 healthy controls and saliva from 44 cases and 44 controls with a multiplex immunoassay. Saliva from all controls and 65 cases and blood from 26 controls and 35 cases were also analyzed by PCR for viral DNA. Primary outcome was cytokine levels in cases vs. controls. Secondary outcomes included detection of HHV-6 and EBV viral DNA in cases vs. controls and viral loads in cases vs. controls. Statistical analysis included the Wilcoxon Rank Sum test, Fisher's exact test, ANOVA, and Spearman correlation. RESULTS: Compared to controls, patients had higher levels of CCL11 (p = 0.0018), CCL26 (p<0.001), IL10 (p = 0.044), IL6 (p<0.001), IL8 (p = 0.018), and MIP1ß (p = 0.0012). CCL11 was higher with 3 or more seizures (p = 0.01), seizures longer than 10 min (p = 0.001), and when EEG showed focal slowing (p = 0.02). In saliva, febrile seizures had higher levels of IL-1ß (n = 7, p = 0.04) and new onset seizures had higher IL-6 (n = 15, p = 0.02). Plasma and saliva cytokine levels did not show a correlation. The frequency of HHV-6 and EBV detection was similar across groups and not different than controls. We found no correlation between viral load and cytokine levels. CONCLUSIONS: We showed differential activation of neuroinflammatory pathways in plasma from different seizure etiologies compared to controls, unrelated to viral infection.

Risk factors, etiologies, and comorbidities in urban pediatric epilepsy.

The Seizures and Outcomes Study in Children (SOS-KIDS) identifies risk factors, etiologies, and comorbidities in a pediatric epilepsy population in a major city with diversity in socioeconomic levels. A thorough understanding of the range of issues impacting children with epilepsy is critical to establishing treatment that will produce better health outcomes. SOS-KIDS is a cross-sectional cohort study of pediatric epilepsy patients who live in Washington D.C. and are evaluated at Children's National Hospital. Families were recruited at the time of the child's routine clinic appointment or inpatient visit. Information was extracted from participants' electronic medical records (EMR) and parent reports; participants were screened for comorbidities using standardized screening measures. Data were collected from 289 participants (47% female, 53% male), and mean age was 7.9 years (2 months to 17 years). Twenty-nine percent of participants had primary generalized epilepsy, 63% focal epilepsy, 0.3% combined generalized and focal epilepsy, and 8% could not be distinguished. There were a variety of epilepsy risk factors including prematurity (10%), intraventricular hemorrhage (7%), neonatal seizures (8%), and febrile seizures (17%). The most common etiologies were cerebral malformations (13%) and genetic disorders (25%). Numerous participants had documented comorbidities including developmental delay (56%), intellectual disability (20%), headaches (16%), attention-deficit hyperactivity disorder (23%), and autism (7%). Of participants aged six years and older, depression, and anxiety were reported in 5% and 6% within the EMR, 14% and 19% in parent surveys, and 22% and 33% with standardized screening measures. We identified a wide variety of risk factors and etiologies among urban pediatric epilepsy patients, with genetic and structural being the most common. Neurologic and psychiatric comorbidities were common, but the prevalence of several psychiatric disorders reported within the EMR was substantially lower compared to that found when using parent surveys and standardized screening measures.

Children with refractory epilepsy demonstrate alterations in myocardial strain.

OBJECTIVE: To test whether children with epilepsy have impairments in myocardial mechanics compared to controls without epilepsy. METHODS: Children with refractory epilepsy with epilepsy duration of at least 3 years underwent echocardiography including conventional measurements and speckle tracking to assess longitudinal and circumferential strain. Parent-completed surveys, capturing critical aspects of the children's seizure history and cardiac risk factors, complemented retrospective chart reviews, which also included antiepileptic drug history. Normal echocardiograms from controls, matched for age and gender, were obtained from our institutional database and evaluated for strain. RESULTS: Forty-one patients (median age = 10 years, interquartile range [IQR] = 5-15; 58.5% male) were enrolled. Epilepsy etiology included genetic (n = 26), structural (n = 6), genetic and structural (n = 5), infection (n = 3), and unknown (n = 1). No cardiac structural abnormalities were identified. Both longitudinal and circumferential strain were impaired (P < .03) in patients compared to controls (median [IQR] = 22.7% [21.2-24.2] vs 23.6% [22.2-26.1] and 22.0% [20.3-25.4] vs 24.5% [22.3-27.0], respectively), indicating decreased myocardial deformation/contraction. Shortening fraction was higher in patients (37.6% [35.7-39.7] vs 34.9% [32.5-38.7], P = .009); mitral valve E wave inflow velocity (84.8 cm/s [78.4-92.8] vs 97.2 cm/s [85.9-105.8], P = .005) and tissue Doppler lateral E' wave (13.9 cm/s [12.3-16.1] vs 17.3 cm/s [15.4-18.5], P < .001) were decreased compared to controls. Findings were similar in the pairs with epilepsy patients distinguished by the ability to independently ambulate. There was no difference between patients and controls in ejection fraction. Among the epilepsy patients, there were no associations between cardiac measurements and epilepsy characteristics, including seizure type and frequency and cardiotoxic antiseizure medication exposure after correction for multiple comparisons. SIGNIFICANCE: Children with refractory epilepsy had impaired systolic ventricular strain compared to controls, not correlated with epilepsy history. Further studies are needed to determine the significance of these changes.

A multi-disciplinary clinic for SCN8A-related epilepsy.

OBJECTIVE: We endeavored to evaluate a cohort of patients diagnosed with SCN8A-related epilepsy in a multi-disciplinary clinic and to create a bio-repository. METHODS: We recruited patients with epilepsy due to SCN8A variants at Children's National Medical Center, through family organizations, or SCN8A.net. Study procedures included medical record review, review of EEG and MRI data, clinical evaluation, the Vineland Adaptive Behavior Scales, Third Edition (VABS-3), DNA extraction, and preparation of peripheral blood mononuclear cells. RESULTS: Seventeen patients (9 months - 19 years) completed the study. Age at seizure onset was 1 day to 4 years old (median age 4 months). Epilepsy phenotype ranged from mild epilepsy to severe developmental and epileptic encephalopathy. Medications targeting the voltage-gated sodium channel were most often effective, while levetiracetam resulted in worsening seizures and/or developmental regression in 7/16 (p < 0.05). VABS-3 scores were below age expectations for most children; older children had lower scores. Neurological examination revealed hypotonia (13), spastic quadriparesis (1), ataxia (9), dyskinesia (2)/ dystonia (7), and four non-ambulatory. CONCLUSIONS: This is the first report of a large series of patients with epilepsy due to SCN8A variants evaluated in a single multi-disciplinary clinic. By utilizing a more comprehensive and consistent evaluation, we clarify specific seizure and epilepsy types, describe a distinct epilepsy phenotype in a patient with a nonsense variant, delineate patterns of developmental delay, language, and swallow function (specifically anomic aphasia and flaccid dysarthria), identify and characterize movement disorders, report common findings on physical exam, and demonstrate clinical worsening with levetiracetam.

Using EHRs to advance epilepsy care.

The improved use of Electronic Health Record (EHR) Systems provides an opportunity to improve the overall efficiency and quality of care of patients with epilepsy. Tools and strategies that may be incorporated into the use of EHRs include utilizing patient generated data, clinical decision support systems and natural language processing systems. Standardization of data from EHR systems may lead to improvement in clinical research through the creation of data collections and multi-center collaborations. Challenges to collaborative use of EHR Systems across centers include costs and the diversity of EHR systems.

Parental perspectives on provider adherence to AAN epilepsy quality measures in rural and urban tertiary care centers.

Several American Academy of Neurology (AAN) epilepsy practice guidelines recommend conversations that neurologists should have with patients and their parents. We sought to determine whether parents of pediatric patients with epilepsy had knowledge of epilepsy quality measures (EQMs) and whether they recalled having discussions with their child's neurologist about each of the EQM. Surveys were distributed to parents at five clinic sites associated with epilepsy centers in Washington, DC and Charlottesville, Virginia. Key questions on the parent survey included whether neurologists had discussed, or parents had knowledge of, EQM topics which included medication side effects, safety, reproductive health, transition to adult care, learning and attention problems, bone health, sudden unexpected death in epilepsy (SUDEP), and risk of epilepsy-related death. No data were collected from the neurologist or the medical record about EQM discussions. Among 233 completed surveys, parental knowledge and neurologist discussion of EQM were highly correlated (p < .00001). Epilepsy quality measures most discussed with high parental knowledge were medication side effects, safety, learning and attention problems, and bone health. Sudden unexpected death in epilepsy was least discussed and known. We found consistent care practices in adherence to EQM across settings from urban to rural communities, with patients of all ages and epilepsy severities and staffed by neurologists with various levels of epilepsy expertise. Despite reported high rates of adherence on several measures, we identified opportunities for improvement. Querying and counseling about EQM should be an ongoing conversation which evolves with the child's age and epilepsy-associated risks.

Detection of HHV-6 and EBV and Cytokine Levels in Saliva From Children With Seizures: Results of a Multi-Center Cross-Sectional Study.

Background and Objective: One third of children with epilepsy are refractory to medications. Growing data support a role of common childhood infections with neurotropic viruses and inflammation in epileptogenesis. Our objective was to determine the frequency of Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) infection and cytokine levels in saliva from children with seizures compared to healthy controls and to controls with a febrile illness without seizures. Methods: In this cross-sectional multi-center study, we collected saliva from 115 consecutive children with acute seizures (cases), 51 children with a fever and no seizures or underlying neurological disease (fever controls) and 46 healthy children (healthy controls). Specimens were analyzed by a novel droplet digital PCR for HHV-6 and EBV viral DNA and a bead-based immunoassay for neuroinflammatory cytokines. Results: Cases included febrile seizures (n = 30), acute seizures without (n = 53) and with fever (n = 4) in chronic epilepsy, new onset epilepsy (n = 13), febrile status epilepticus (n = 3), and first lifetime seizure (n = 12). HHV-6 DNA was found in 40% of cases vs. 37% fever controls and 35% healthy controls, with no statistically significant differences. EBV DNA was also detected with no differences in 17% cases, 16% fever controls, and 28% healthy controls. IL-8 and IL-1ß were increased in saliva of 32 random samples from cases compared with 30 fever controls: IL-8 cases mean (SD): 1158.07 pg/mL (1427.41); controls 604.92 (754.04); p = 0.02. IL-1ß 185.76 (230.57); controls 86.99 (187.39); p = 0.0002. IL-1ß level correlated with HHV6 viral load (p = 0.007). Conclusion: Increase in inflammatory cytokines may play a role in the onset of acute seizures and saliva could represent an inexpensive and non-invasive method for detection of viral DNA and cytokines.

Parental Perspectives of the Impact of Epilepsy and Seizures on Siblings of Children with Epilepsy.

INTRODUCTION: To assess parental perspectives of the impact of epilepsy and seizures on siblings of children in the Seizures and Outcomes Study. METHODS: Parents completed surveys about their child with epilepsy, their own health and well-being, and the impact of epilepsy on unaffected siblings. RESULTS: The most common parental responses about the sibling were witnessing a seizure, protectiveness of the child with epilepsy, worry about seizures, belief that seizures cause pain, and pride toward the child with epilepsy. Embarrassment and keeping epilepsy a secret were rare. Parent reports supported that siblings that worried were more likely to have witnessed a seizure, feel sad or angry, think seizures cause pain, and have a parent with anxiety disorder. DISCUSSION: Some siblings of children with epilepsy are at risk for psychosocial problems. Primary and specialty care providers are well positioned to identify and monitor these children through evaluations and referrals as necessary.

Sudden Death in Epilepsy: Knowledge among Pediatric Providers.

A survey of 146 pediatric care providers (PCPs) revealed that 75.3% were unaware that children with epilepsy were at risk of death, specifically from sudden unexpected (or unexplained) death in epilepsy (SUDEP). PCPs assume that the treating neurologist discusses these risks. Increasing PCPs' knowledge of SUDEP will help address the care gap related to informing families about SUDEP.