De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias.

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

Subcentimeter epilepsy surgery targets by resting state functional magnetic resonance imaging can improve outcomes in hypothalamic hamartoma.

OBJECTIVE: The purpose of this study is to investigate the outcomes of epilepsy surgery targeting the subcentimeter-sized resting state functional magnetic resonance imaging (rs-fMRI) epileptogenic onset zone (EZ) in hypothalamic hamartoma (HH). METHODS: Fifty-one children with HH-related intractable epilepsy received anatomical MRI-guided stereotactic laser ablation (SLA) procedures. Fifteen of these children were control subjects (CS) not guided by rs-fMRI. Thirty-six had been preoperatively guided by rs-fMRI (RS) to determine EZs, which were subsequently targeted by SLA. The primary outcome measure for the study was a predetermined goal of 30% reduction in seizure frequency and improvement in class I Engel outcomes 1 year postoperatively. Quantitative and qualitative volumetric analyses of total HH and ablated tissue were also assessed. RESULTS: In the RS group, the EZ target within the HH was ablated with high accuracy (>87.5% of target ablated in 83% of subjects). There was no difference between the groups in percentage of ablated hamartoma volume (P = 0.137). Overall seizure reduction was higher in the rs-fMRI group: 85% RS versus 49% CS (P = 0.0006, adjusted). The Engel Epilepsy Surgery Outcome Scale demonstrated significant differences in those with freedom from disabling seizures (class I), 92% RS versus 47% CS, a 45% improvement (P = 0.001). Compared to prior studies, there was improvement in class I outcomes (92% vs 76%-81%). No postoperative morbidity or mortality occurred. SIGNIFICANCE: For the first time, surgical SLA targeting of subcentimeter-sized EZs, located by rs-fMRI, guided surgery for intractable epilepsy. Our outcomes demonstrated the highest seizure freedom rate without surgical complications and are a significant improvement over prior reports. The approach improved freedom from seizures by 45% compared to conventional ablation, regardless of hamartoma size or anatomical classification. This technique showed the same or reduced morbidity (0%) compared to recent non-rs-fMRI-guided SLA studies with as high as 20% permanent significant morbidity.

Rapid Rescue Treatment with Diazepam Nasal Spray Leads to Faster Seizure Cluster Termination in Epilepsy: An Exploratory Post Hoc Cohort Analysis.

INTRODUCTION: Although prompt treatment of status epilepticus is standard of care, the effect of timing of rescue therapy administration for seizure clusters in epilepsy remains unknown. Seizure clusters are a rare but clinically important condition, and benzodiazepines are the cornerstone rescue therapy for seizure clusters in epilepsy. We characterized temporal patterns from a large dataset of treated seizure clusters in the safety study of diazepam nasal spray. METHODS: This post hoc analysis used timing data of treated seizure clusters recorded by care partners and patients in seizure diaries during a 1-year safety study. Data analysis used time from seizure start to administration of diazepam. RESULTS: From 4466 observations, 3225 had data meeting criteria for analysis. Overall, median times from seizure start to dose administration, dose administration to seizure termination, and total seizure duration were 2, 3, and 7 min, respectively. In seizure clusters treated in < 5 min (median 1.0 min), median time from dose to seizure termination was 2.0 min, and median total seizure duration was 4.0 min. Among seizure clusters treated in ≥ 5 min (median 10.0 min), median time to seizure termination was 10.0 min, and median total seizure duration was 23.0 min. Previously published safety results reported that over a mean participation of 1.5 years, 82.2% of patients had ≥ 1 treatment-emergent adverse events (TEAEs) irrespective of relationship to treatment, including 30.7% with serious TEAEs; 18.4% had TEAEs deemed at least possibly related to the study drug, none of which were serious. There were no events of cardiorespiratory depression. CONCLUSION: Echoing the importance of early use of benzodiazepines in status epilepticus, the findings from this exploratory analysis of patients with refractory epilepsy and frequent seizure clusters identify a potential benefit of early diazepam nasal spray treatment leading to faster seizure resolution within the seizure cluster. Trial Registration Information: ClinicalTrials.gov identifier NCT02721069 ( https://clinicaltrials.gov/ct2/show/NCT02721069 ).

Some people with epilepsy who take daily antiseizure drugs might still have seizures. Some of these seizures may be emergencies that can be treated with rescue medicine. For status epilepticus, rescue treatment should be given as soon as this seizure emergency is recognized. Seizure clusters are rare and might also become emergencies, but until now it had not been clear if earlier treatment would be better. Diazepam nasal spray is a rescue medicine approved to treat seizure clusters. The report used data from a study of the safety of diazepam nasal spray in people needing treatment ≥ 6 times a year. We looked at the time the seizure in a seizure cluster started to the time rescue treatment was given. We also looked at the time from taking rescue treatment to the time when that specific seizure stopped. For some seizure clusters, rescue medicine was given in < 5 min after the seizure started; on average, these seizures stopped within 2 min after rescue treatment. The total time from the start of the seizure in the seizure cluster to when it stopped was 4 min. In contrast, for seizure clusters treated after 5 min, the seizures stopped in an average of 10 min after treatment. Overall, these seizures lasted 23 min. In conclusion, this analysis found that seizures in a seizure cluster ended more quickly when diazepam nasal spray was given sooner. These findings are suggestive that select patients and caregivers should not wait to treat a seizure cluster once it has been identified.

Continuous video-EEG monitoring in pediatric intensive care units.

PURPOSE: Several studies indicate a higher occurrence than might be expected of seizures in intensive care unit patients, many of which are not clinically apparent. Few of these studies are devoted exclusively to pediatric patients. The purpose of this study is to determine the occurrence of seizures in a cohort of pediatric and neonatal intensive care unit patients. METHODS: Long-term video electroencephalography (EEG) monitoring studies performed in the pediatric and neonatal intensive care units were reviewed. Age, gender, diagnosis, EEG background, epileptiform activity, time of onset and duration of seizures, presence of electroclinical or electrographic seizures, and survival were collected. KEY FINDINGS: One hundred thirty-eight recordings encompassing 122 patients were identified. Thirty-four percent of the sessions identified seizures in the first 24 h (38% of the cohort experienced a seizure at some time during monitoring, which ranged from 1-22 days): 17% captured only electroclinical seizures, 49% were electrographic only, and 34% had both electroclinical and electrographic seizures. Seventy percent of those patients experiencing seizures had their first seizure within the first hour of EEG recording. Younger age and epileptiform activity (including periodic) were associated with the occurrence of seizures. Diagnoses of head trauma and status epilepticus/recent prior seizure were more likely than other at-risk diagnoses to be associated with seizures; cardiac arrest managed with hypothermia was less likely to be associated with seizures. One-fourth of the recordings identified nonepileptic events. SIGNIFICANCE: Seizures occurred in one-third of critically ill pediatric patients at risk for seizures who underwent video-EEG monitoring, and many of these seizures did not have a clinical correlate. In those at risk for seizures in intensive care units, there should be a low threshold for obtaining long-term monitoring.

Knowledge about epilepsy and confidence in instructing students with epilepsy: teachers' responses to a new scale.

Knowledgeable and confident teachers are crucial for students with epilepsy. In this study, 91 current teachers of a student with epilepsy (CTs) and 203 teachers in general (TiGs) were surveyed using a new scale. CTs knew more school-relevant epilepsy facts than TiGs, even after controlling for special education background, F(1, 293)=5.75, P=0.017, η(2)=0.02. Both groups of teachers, however, knew less than one-half of the facts (means=10.6 [CTs] 8.7 [TiGs] of 25 items). CTs also expressed greater confidence than TiGs in their ability to meet an array of instructional, safety, and psychosocial requirements, even when between-group differences in teachers' background in special education were controlled, F(1, 293)=34.97, P<0.001, η(2)=0.11. Still, neither group communicated a high absolute level of confidence. As expected, more knowledgeable teachers expressed greater confidence (r=0.43, P<0.001). Results suggest that some facts about epilepsy require additional dissemination to educators.

Technical tips: Electrode safety in pediatric prolonged EEG recordings.

Electrodes are an essential element of electroencephalography. Complications related to the use of recording electrodes are known to occur but not much is known about the mechanism, risk factors, and incidence of such complications. In this study, we wanted to identify the incidence and potential risk factors for electrode related skin injuries. We found that such injuries occur in 11.4% of children.

Efficacy and tolerability of a whey-based, medium-chain triglyceride-enhanced ketogenic formula in children with refractory epilepsy: A retrospective study.

PURPOSE: Ketogenic metabolic therapy (KMT) has demonstrated effectiveness in seizure reduction. However, patient compliance and adverse effects limit its use. Ready-to-feed (RTF) ketogenic formulas improve compliance and include components that mitigate adverse effects. This study is the first to evaluate the efficacy and tolerability of an RTF, whey-based, medium-chain triglyceride-enhanced (WBME) ketogenic formula. METHODS: Retrospective data from patients who received KMT between January 1, 2015, and February 28, 2018, were analyzed. Patients who received ≥75% of their total calories from the WBME formula and who were monitored for 3 months were included. Outcome measures were gastrointestinal issues, acidosis, serum blood glucose and beta-hydroxybutyrate levels, unintentional weight changes, diet response (≥50% reduction in seizures), seizure freedom, and change in formula or discontinuation of therapy. Patients with incomplete outcome data or who received <75% of total calories from the formula were excluded. RESULTS: Twenty-six patients (13 males; mean [SD] age, 6.1 [5.8] years) met the inclusion criteria. Thirteen patients were established patients who received a standard ketogenic formula before changing to the WBME formula; 13 were patients new to KMT whose therapy was initiated using the WBME formula. This formula was well tolerated; no patient in either group discontinued therapy or required a change in formula. The combined diet response rate (95% CI) for established and new patients was 96% (80-100%). Seizure-freedom (95% CI) for both groups at 3 months posttreatment was 20% (7-41%). The most prevalent adverse effect was constipation (69% [95% CI, 48-86%]). CONCLUSION: The WBME ketogenic formula appears to be effective and well tolerated by pediatric patients with refractory epilepsy.

Outcomes among patients with infantile spasms treated with hormonal therapy and adjuvant topiramate versus hormonal therapy alone.

Hormonal therapy is the first-line treatment for infantile spasms and is sometimes used in combination with topiramate for better seizure control and potentially improved developmental outcomes. Retrospective review of pediatric patients with infantile spasms, with data compiled on patient sex, age at onset, etiology, electroencephalographic and imaging findings, topiramate use, spasm resolution (at one, six, and 12 months), and developmental outcome (at 12 months). Of 105 patients screened, 55 (28 female) met inclusion criteria (28 [51%] had spasms with known etiology and 27 [49%] had spasms with unknown etiology). Forty-six patients were followed for 12 months or longer to determine seizure outcome; a 12-month developmental assessment was documented for 49 patients. Thirty-seven patients (67%) received combination therapy; 18 (33%) received hormonal therapy alone. Resolution of spasms was comparable among treatment groups, with no difference relative to spasm etiology (p>0.18 for all). No difference was found in developmental outcomes with and without adjunct topiramate (p=0.38). Combination therapy was the most common treatment at our institution. However, combination therapy was not found to be beneficial for the treatment of spasms or developmental outcomes when compared to hormonal therapy alone.

Resting-state functional MRI connectivity impact on epilepsy surgery plan and surgical candidacy: prospective clinical work.

OBJECTIVE: The authors' goal was to prospectively quantify the impact of resting-state functional MRI (rs-fMRI) on pediatric epilepsy surgery planning. METHODS: Fifty-one consecutive patients (3 months to 20 years old) with intractable epilepsy underwent rs-fMRI for presurgical evaluation. The team reviewed the following available diagnostic data: video-electroencephalography (n = 51), structural MRI (n = 51), FDG-PET (n = 42), magnetoencephalography (n = 5), and neuropsychological testing (n = 51) results to formulate an initial surgery plan blinded to the rs-fMRI findings. Subsequent to this discussion, the connectivity results were revealed and final recommendations were established. Changes between pre- and post-rs-fMRI treatment plans were determined, and changes in surgery recommendation were compared using McNemar's test. RESULTS: Resting-state fMRI was successfully performed in 50 (98%) of 51 cases and changed the seizure onset zone localization in 44 (88%) of 50 patients. The connectivity results prompted 6 additional studies, eliminated the ordering of 11 further diagnostic studies, and changed the intracranial monitoring plan in 10 cases. The connectivity results significantly altered surgery planning with the addition of 13 surgeries, but it did not eliminate planned surgeries (p = 0.003). Among the 38 epilepsy surgeries performed, the final surgical approach changed due to rs-fMRI findings in 22 cases (58%), including 8 (28%) of 29 in which extraoperative direct electrical stimulation mapping was averted. CONCLUSIONS: This study demonstrates the impact of rs-fMRI connectivity results on the decision-making for pediatric epilepsy surgery by providing new information about the location of eloquent cortex and the seizure onset zone. Additionally, connectivity results may increase the proportion of patients considered eligible for surgery while optimizing the need for further testing.

Temporal encephalocele: a novel indication for magnetic resonance-guided laser interstitial thermal therapy for medically intractable epilepsy.

Temporal encephalocele (TE) is a rare but surgically treatable/curable cause of temporal lobe epilepsy (TLE). The surgical intervention varies from local disconnection to extensive anterior temporal lobectomy and amygdalohippocampectomy (ATL/AH). Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) has evolved as a minimally invasive alternative for intractable epilepsy with good results, however, application of MRgLITT for intractable pediatric epilepsy secondary to TE has not been reported. We present a detailed technical report and clinical experience of MRgLITT in two adolescent children with medically intractable TLE secondary to TE. Pre-surgical evaluation revealed anterior inferior TE with concordant clinico-electrophysiological data. Both the patients underwent MRgLITT after review with the institutional multidisciplinary epilepsy team and discussion with the patient and the family. Both the patients were discharged on post-operative day one and have been seizure-free since the procedure at the last follow-up visit at 18 months and 6 months, respectively. The present series demonstrates first-ever clinical and technical experience of MRgLITT for TE with intractable pediatric epilepsy. The excellent post-operative seizure outcome and favorable postoperative course support MRgLITT as the first line of surgical intervention for TE with intractable TLE and broadens the application of MRgLITT.

Ketogenic diet treatment for pediatric super-refractory status epilepticus.

PURPOSE: We aimed to study whether ketogenic diet (KD) therapy leads to resolution of super-refractory status epilepticus in pediatric patients without significant harm. METHOD: A retrospective review was performed at Phoenix Children's Hospital on patients with super-refractory status epilepticus undergoing ketogenic diet therapy from 2011 to 2015. RESULTS: Ten children with super-refractory status epilepticus, ages 2-16 years, were identified. 4/10 patients had immune mediated encephalitis, including Rasmussen encephalitis, anti-N-methyl-d-aspartate receptor encephalitis, and post-infectious mycoplasma encephalitis. Other etiologies included Lennox Gastaut Syndrome, non-ketotic hyperglycinemia, PCDH19 and GABRG2 genetic epilepsy, New Onset Refractory Status Epilepticus, and Febrile Infection-Related Epilepsy Syndrome. 4/10 patients' EEG features suggested focal with status epilepticus, and 6/10 suggested generalized with status epilepticus. Median hospital length was 61days and median ICU length was 27days. The median number of antiepileptic medications prior to diet initiation was 3.0 drugs, and the median after ketogenic diet treatment was 3.5 drugs. Median duration of status epilepticus prior to KD was 18days. 9/10 patients had resolution of super-refractory status epilepticus in a median of 7days after diet initiation. 8/9 patients were weaned off anesthesia within 15days of diet initiation, and within 1day of achieving ketonuria. 1/10 patients experienced side effects on the diet requiring supplementation. CONCLUSION: Most patients achieved resolution of status epilepticus on KD therapy, suggesting it could be an effective therapy that can be utilized early in the treatment of children with super refractory status epilepticus.

Therapeutics in pediatric epilepsy, Part 1: The new antiepileptic drugs and the ketogenic diet.

Epilepsy is one of the most common and challenging neurologic disorders affecting children. Although various modalities exist to treat pediatric-onset seizures, seizures in 25% of children who are diagnosed as having epilepsy remain refractory to available therapies. Of the 8 new antiepileptic drugs (AEDs) (felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, and zonisamide), all but 2 (zonisamide and levetiracetam) have received Food and Drug Administration approval for adjunctive use in the pediatric population. However, most of the new AEDs used in adults have also been used in children, beyond the AEDs' approved indications. The ultimate goal of patient management is to choose the therapeutic option that provides the best chance of improving the patient's quality of life. Issues that relate to treatment choice include the likelihood of seizure recurrence, type and severity of seizures, available AED efficacies and toxicities, need for hematologic monitoring, ease of dosing, underlying medical conditions, medication interactions, urgency of initiating therapy, and cost. In this review, we discuss these issues for each of the 8 new AEDs; we also discuss the ketogenic diet and briefly review the older AEDs. Knowledge of the available AEDs will enable the practitioner to choose the best drug or drugs for individual patients.

Therapeutics in pediatric epilepsy, Part 2: Epilepsy surgery and vagus nerve stimulation.

When antiepileptic drugs fail to relieve seizures adequately in children and adolescents, more invasive therapies such as epilepsy surgery and an implanted device to stimulate the vagus nerve should be considered. Temporal lobectomy is an effective treatment of complex partial and secondarily generalized tonic-clonic seizures arising in the mesial structures or lateral temporal neocortex. Excellent outcomes (seizure free or rare, nondisabling seizures) are achieved in at least 70% of children. The most common adverse effect is a superior quadrant field cut that is usually asymptomatic. Transient and more long-lasting language difficulties have been reported when the surgery involves the dominant temporal lobe. The excellent outcome rate for extratemporal surgery ranges from approximately 20% to 80%, with better results seen in patients with an identifiable lesion. Potential morbidity is related to the region of resected neocortex. Corpus callosotomy is an excellent procedure for palliation but is not a cure for seizures that cause falls, with substantial improvement seen in more than 80% of patients. Potential adverse effects include more intense focal seizures and dysphasia, depending on the developmental level of the individual. Hemispherectomy provides seizure relief in 60% to 80% of patients with hemispherical pathologies such as Sturge-Weber or Rasmussen syndromes. Operative mortality has been reported in the range of 0% to 6%; other morbidities include infection and hydrocephalus. Stimulation of the vagus nerve has reduced partial seizures by 50% or more in approximately one third of patients. No adverse cognitive or systemic effects are associated with use of the implanted vagus nerve stimulator.

Text Classification towards Detecting Misdiagnosis of an Epilepsy Syndrome in a Pediatric Population.

When attempting to identify a specific epilepsy syndrome, physicians are often unable to make or agree upon a diagnosis. This is further complicated by the fact that the current classification and diagnosis of epilepsy requires specialized training and the use of resources not typically available to the average clinician, such as training to recognize specific seizure types and electroencephalography (EEG). Even when training and resources are available, expert epileptologists often find it challenging to identify seizure types and to distinguish between specific epilepsy syndromes. Information relevant to the diagnosis is present in narrative form in the medical record across several visits for an individual patient. Our ultimate goal is to create a system that will assist physicians in the diagnosis of epilepsy. This paper explores, as a baseline, text classification methods that attempt to correlate the narrative text features to the diagnosis of West syndrome (Infantile Spasms), using data from Phoenix Children's Hospital (PCH). We tested these methods against a dataset containing known (coded) diagnosis of West Syndrome, and found the best performing method to have a precision / recall / f-measure of 76.8 / 66.7 / 71.4 when evaluated with 10-fold cross validation.

Parental ranking of terms describing nonepileptic events.

Paroxysmal nonepileptic events of psychogenic etiology in children and adolescents are common. Patients and their parents are often confused by the terminology used to describe these events. This can lead to frustration and may result in the failure to obtain the necessary nonpharmacologic treatment. Various terms are used to describe such events, some of which might be considered offensive to some individuals. Surveys from 146 parents or guardians of patients identified from a general pediatric clinic, a general neurology clinic, and a pediatric epilepsy monitoring unit were completed with the aim of determining which words and phrases were least offensive. It was determined that nonepileptic events, functional seizures, and nonepileptic attack disorder were the least offensive labels; whereas "it is all in his or her head," hysterical seizures, and psychogenic seizures were the most offensive terms. This is the only study of its type in the pediatric population. Although each child and family requires individualized communication, we hope that this article will provide useful information to guide the practicing pediatric neurologist in informing families that their children are having events of nonepileptic etiology.

Radial nerve repetitive stimulation in myasthenia gravis.

The purpose of this study was to compare the diagnostic yield of repetitive radial nerve stimulation (RNS) while recording from extensor indicis proprius (EIP) to other commonly used muscle-nerve combinations in patients with myasthenia gravis (MG). Radial RNS with recording from EIP was performed in 20 controls and 20 patients with MG. It revealed an abnormal decrement at rest in 35% of patients compared to 11% with ulnar nerve stimulation, 64% with spinal accessory nerve stimulation, and 74% with facial nerve stimulation. Radial-EIP RNS is a reliable technique in the evaluation of MG and appears more sensitive than ulnar nerve RNS.