Implementation of a Pediatric Neurocritical Care Program for Children With Status Epilepticus: Adherence to Continuous Electroencephalogram Monitoring.

OBJECTIVES: To describe adherence to continuous electroencephalogram (cEEG) monitoring as part of a pediatric neurocritical care (PNCC) program for status epilepticus (SE). DESIGN: Retrospective review of pre- and postintervention cohorts. SETTING: A pediatric referral hospital. PATIENTS: Children admitted to the PICU for SE. INTERVENTIONS: We restructured the care delivery model to include a pediatric neurointensive care unit (neuro-ICU) and expanded the cEEG capacity. We created a criteria-based cEEG pathway. We provided education to all providers including the nursing staff. MEASUREMENTS AND MAIN RESULTS: The main outcomes were: 1) the percentages of children meeting American Clinical Neurophysiology Society (ACNS) criteria who underwent cEEG monitoring and 2) the time interval between PICU arrival and cEEG initiation. PICU admissions with the diagnosis of SE from May 2017 to December 2017 served as the baseline, which was compared with the same periods in 2018 to 2020 (PNCC era).There were 60 admissions in the pre-PNCC period (2017), 111 in 2018, 118 in 2019, and 108 in 2020. The percentages of admissions from each period that met ACNS criteria for cEEG monitoring were between 84% and 97%. In the pre-PNCC era, 22 of 52 (42%) admissions meeting ACNS criteria underwent cEEG monitoring. In the PNCC era, greater than or equal to 80% of the qualified admissions underwent cEEG monitoring (74/93 [80%] in 2018, 94/115 [82%] in 2019, and 87/101 [86%] in 2020). Compared with the pre-PNCC era, the neuro-ICU had a shorter interval between PICU arrival and cEEG initiation (216 min [141-1,444 min] vs 138 min [103-211 min]). CONCLUSIONS: The implementation of a PNCC program with initiatives in care delivery, allocation of resources, and education was associated with increased adherence to best care practices for the management of SE.

Benzodiazepine administration patterns before escalation to second-line medications in pediatric refractory convulsive status epilepticus.

OBJECTIVE: This study was undertaken to evaluate benzodiazepine (BZD) administration patterns before transitioning to non-BZD antiseizure medication (ASM) in pediatric patients with refractory convulsive status epilepticus (rSE). METHODS: This retrospective multicenter study in the United States and Canada used prospectively collected observational data from children admitted with rSE between 2011 and 2020. Outcome variables were the number of BZDs given before the first non-BZD ASM, and the number of BZDs administered after 30 and 45 min from seizure onset and before escalating to non-BZD ASM. RESULTS: We included 293 patients with a median (interquartile range) age of 3.8 (1.3-9.3) years. Thirty-six percent received more than two BZDs before escalating, and the later the treatment initiation was after seizure onset, the less likely patients were to receive multiple BZD doses before transitioning (incidence rate ratio [IRR] = .998, 95% confidence interval [CI] = .997-.999 per minute, p = .01). Patients received BZDs beyond 30 and 45 min in 57.3% and 44.0% of cases, respectively. Patients with out-of-hospital seizure onset were more likely to receive more doses of BZDs beyond 30 min (IRR = 2.43, 95% CI = 1.73-3.46, p < .0001) and beyond 45 min (IRR = 3.75, 95% CI = 2.40-6.03, p < .0001) compared to patients with in-hospital seizure onset. Intermittent SE was a risk factor for more BZDs administered beyond 45 min compared to continuous SE (IRR = 1.44, 95% CI = 1.01-2.06, p = .04). Forty-seven percent of patients (n = 94) with out-of-hospital onset did not receive treatment before hospital arrival. Among patients with out-of-hospital onset who received at least two BZDs before hospital arrival (n = 54), 48.1% received additional BZDs at hospital arrival. SIGNIFICANCE: Failure to escalate from BZDs to non-BZD ASMs occurs mainly in out-of-hospital rSE onset. Delays in the implementation of medical guidelines may be reduced by initiating treatment before hospital arrival and facilitating a transition to non-BZD ASMs after two BZD doses during handoffs between prehospital and in-hospital settings.

Antiepileptic drug management in pediatric patients with brain tumor-related epilepsy.

BACKGROUND: Patients with brain tumor-related epilepsy (BTRE) are at a higher risk of significant morbidity, lower quality of life, and increased risk of mortality. We surveyed providers regarding anti-seizure medication (ASM) management in pediatric BTRE to determine if practices are standard or markedly variable. METHODS: An anonymous voluntary online survey was sent to members of the Child Neurology Society. Providers were asked specific questions regarding initiation and wean of ASMs and if this was dependent on multiple factors. Demographic information was collected. RESULTS: Fifty-one providers responded to the survey. Ninety-four percent of providers would start an ASM after a second seizure. Eighty-four percent chose levetiracetam as the preferred ASM. Management was variable when based on tumor location, extent of surgical resection, pathology, and tumor prognosis. Statistically significant differences in responses regarding management were identified when comparing neurologists and epileptologists, providers with formal neuro-oncology or epilepsy training, providers at large institutions, and years of experience. For patients who underwent a gross total resection of the tumor, neuro-oncology and epilepsy-trained providers were more likely to wean off ASMs (p < 0.049). Providers without formal training in neuro-oncology or epilepsy were more likely to get an EEG prior to making a decision about weaning off ASMs (p < 0.016). CONCLUSION: These results suggest that ASM management in BTRE varies greatly according to sub-specialty and experience. Further studies and potential development of guidelines are needed to identify the most appropriate management of ASMs for BTRE.

Super-Refractory Status Epilepticus in Children: A Retrospective Cohort Study.

OBJECTIVES: To characterize the pediatric super-refractory status epilepticus population by describing treatment variability in super-refractory status epilepticus patients and comparing relevant clinical characteristics, including outcomes, between super-refractory status epilepticus, and nonsuper-refractory status epilepticus patients. DESIGN: Retrospective cohort study with prospectively collected data between June 2011 and January 2019. SETTING: Seventeen academic hospitals in the United States. PATIENTS: We included patients 1 month to 21 years old presenting with convulsive refractory status epilepticus. We defined super-refractory status epilepticus as continuous or intermittent seizures lasting greater than or equal to 24 hours following initiation of continuous infusion and divided the cohort into super-refractory status epilepticus and nonsuper-refractory status epilepticus groups. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We identified 281 patients (157 males) with a median age of 4.1 years (1.3-9.5 yr), including 31 super-refractory status epilepticus patients. Compared with nonsuper-refractory status epilepticus group, super-refractory status epilepticus patients had delayed initiation of first nonbenzodiazepine-antiseizure medication (149 min [55-491.5 min] vs 62 min [33.3-120.8 min]; p = 0.030) and of continuous infusion (495 min [177.5-1,255 min] vs 150 min [90-318.5 min]; p = 0.003); prolonged seizure duration (120 hr [58-368 hr] vs 3 hr [1.4-5.9 hr]; p < 0.001) and length of ICU stay (17 d [9.5-40 d] vs [1.8-8.8 d]; p < 0.001); more medical complications (18/31 [58.1%] vs 55/250 [22.2%] patients; p < 0.001); lower return to baseline function (7/31 [22.6%] vs 182/250 [73.4%] patients; p < 0.001); and higher mortality (4/31 [12.9%] vs 5/250 [2%]; p = 0.010). Within the super-refractory status epilepticus group, status epilepticus resolution was attained with a single continuous infusion in 15 of 31 patients (48.4%), two in 10 of 31 (32.3%), and three or more in six of 31 (19.4%). Most super-refractory status epilepticus patients (30/31, 96.8%) received midazolam as first choice. About 17 of 31 patients (54.8%) received additional treatments. CONCLUSIONS: Super-refractory status epilepticus patients had delayed initiation of nonbenzodiazepine antiseizure medication treatment, higher number of medical complications and mortality, and lower return to neurologic baseline than nonsuper-refractory status epilepticus patients, although these associations were not adjusted for potential confounders. Treatment approaches following the first continuous infusion were heterogeneous, reflecting limited information to guide clinical decision-making in super-refractory status epilepticus.

Phenobarbital population pharmacokinetics across the pediatric age spectrum.

OBJECTIVE: Phenobarbital is frequently used in pediatric patients for treatment and prophylaxis of seizures. Pharmacokinetic data for this patient population is lacking and would assist in dosing decisions. METHODS: A retrospective population pharmacokinetic analysis was designed for all pediatric patients <19 years of age initiated on phenobarbital at our institution from January 2011 to June 2017. Patients were included if they were initiated on intravenous or enteral phenobarbital for treatment or prophylaxis of seizures and had a serum phenobarbital concentration monitored while an inpatient. Data collection included the following: age, weight, height, gestational age, core body temperature, serum creatinine, blood urea nitrogen, aspartase aminotransferase, alanine aminotransferase, urine output over the prior 12 hours, phenobarbital doses and serum concentrations, and potential drug-drug interactions. Descriptive statistical methods were used to summarize the data. Pharmacokinetic analysis was performed with NONMEM and simulation was performed for doses of 10, 20, 30, and 40 mg kg-1  dose-1 , iv, followed by enteral doses of 3, 4, 5, and 6 mg kg-1  d-1 . RESULTS: A total of 355 patients (50.3% male, median gestational age 39 weeks (interquartile range [IQR] 35, 40), median age 0.28 years (IQR 0.06, 0.82). Median phenobarbital dose was enteral = 2.6 (IQR 1.9, 3.9) mg kg-1  dose-1 ; intravenous = 2.6 (IQR 2.2, 4.9) mg kg-1  dose-1 ) and mean serum concentration was 41.1 ± 23.9 mg/L at median 6.5 (IQR 2.9, 11.1) hours after a dose. A one-compartment proportional error model best fit the data where clearance and volume of distribution were allometrically scaled using fat-free mass. Significant covariates included serum creatinine, postmenstrual age, and drug-drug interactions on clearance, and age in years on volume of distribution. SIGNIFICANCE: Phenobarbital dosing of 30 mg kg-1  dose-1 ,iv, followed by 4 mg kg-1  d-1 had the highest probability of attaining a therapeutic concentration at 7 days. Postmenstrual age and drug-drug interactions should be incorporated into dosing decisions.

Fosphenytoin Population Pharmacokinetics in the Acutely Ill Pediatric Population.

OBJECTIVE: The purpose of this study is to describe the pharmacokinetics of phenytoin in pediatric patients receiving fosphenytoin. DESIGN: Retrospective, population pharmacokinetic analysis. SETTING: Emergency department or PICU of a large tertiary care children's hospital. PATIENTS: Patients less than 19 years old who received fosphenytoin in the PICU or emergency center for treatment of seizures from January 2011 to June 2017 were included. INTERVENTIONS: Population pharmacokinetic analysis was performed with NONMEM v7.3 (Icon Plc, Dublin, Ireland). Simulation was performed to determine optimal loading dose and maintenance dosing regimens. MEASUREMENTS AND MAIN RESULTS: A total of 536 patients (55.4% male; median age, 3.4 yr [interquartile range, 0.92-8.5 yr]) met study criteria. Fosphenytoin was administered at median 15.1 mg/kg/dose (interquartile range, 6.3-20.7 mg/kg/dose). Mean serum concentrations of 17.5 ± 7.8 mg/L were at a median 4.2 hours (interquartile range, 2.5-7.8 hr) after a dose. A pharmacokinetic model with two compartments, allometrically scaled fat-free mass on all parameters, and serum creatinine and concomitant phenobarbital use on clearance had the best fit. Simulation demonstrated that a 20 mg/kg loading dose followed by 6 mg/kg/dose every 8 hours had the greatest percentage of concentrations in the 10-20 mg/L range, with reduced doses to achieve therapeutic in patients with reduced kidney function. CONCLUSIONS: A loading dose of 20 mg/kg followed by 6 mg/kg/dose every 8 hours based on fat-free mass is a reasonable empiric strategy for attainment and maintenance of therapeutic trough concentrations. Concomitant phenobarbital use may increase clearance of phenytoin and fosphenytoin dose reductions should occur in patients with reduced kidney function.

Application of envelope trend to analyze early EEG changes in the frontal regions during intracarotid amobarbital procedure in children.

BACKGROUND: Intracarotid amobarbital procedure (IAP) is acknowledged as the gold standard test for language lateralization. EEG is performed routinely during IAP to monitor the anesthetization of a brain hemisphere. Here, we studied the correlation between the early EEG changes using envelope trend and the clinical outcome of IAP. METHOD: Fifty consecutive patients underwent IAP at Texas Children's Hospital (2004-2009). Intracarotid amobarbital procedure was considered "complete" or "incomplete" based on the outcome if the procedure was completed or aborted due to behavior changes. Envelope trend was used to calculate the median EEG amplitude changes within the first 60s of IAP. Statistical analysis was performed to determine the role of EEG changes and clinical features on the procedure outcome. RESULTS: Only 30 IAP-EEG files were available for review. Amobarbital was administered at the dose of 60-150mg (mean: 110±20). The intracarotid amobarbital procedure was recorded as complete in 23 patients and incomplete in 7 patients. EEG changes occurred within the first few seconds following amobarbital injection. Following amobarbital injection, focal slowing was present in the ipsilateral frontal region or both ipsilateral and contralateral frontal regions. Elapsed time to the first EEG change or duration and change in median EEG amplitude in the ipsilateral frontal regions were indifferent between the complete and incomplete groups (p>0.05). However, the median amplitude changes between the ipsilateral and contralateral frontal regions within each group were found significant only in the complete group (p<0.05), suggesting ipsilateral without contralateral frontal slowing. Other than age at the time of IAP (p=0.03), none of the other clinical features correlated with the clinical outcome of IAP (p>0.05). CONCLUSION: Early EEG changes during IAP using envelope trend may predict successful completion of the IAP test. Younger children are at risk of behavioral changes during IAP.

Emergency Neurological Life Support: Status Epilepticus.

Patients with prolonged or rapidly recurring convulsions lasting more than 5 min are in status epilepticus (SE) and require immediate resuscitation. Although there are relatively few randomized clinical trials, available evidence and experience suggest that early and aggressive treatment of SE improves patient outcomes, for which reason this was chosen as an Emergency Neurological Life Support protocol. The current approach to the emergency treatment of SE emphasizes rapid initiation of adequate doses of first-line therapy, as well as accelerated second-line anticonvulsant drugs and induced coma when these fail, coupled with admission to a unit capable of neurological critical care and electroencephalography monitoring. This protocol will focus on the initial treatment of SE but also review subsequent steps in the protocol once the patient is hospitalized.

Neurological injury in pediatric heart disease: A review of developmental and acquired risk factors and management considerations.

Medical and surgical advancements have improved survival in children with acquired and congenital heart disease (CHD), but the burden of neurological morbidity is high. Brain disorders associated with CHD include white matter injury, stroke, seizure, and neurodevelopmental delays. While genetics and disease-specific factors play a substantial role in early brain injury, therapeutic management of the heart disease intensifies the risk. There is a growing interest in understanding how to reduce brain injury and improve neurodevelopmental outcomes in cardiac diseases. Pediatric neurologists serve a vital role in care teams managing these complex patients, providing interpretation of neuromonitoring and imaging, managing neurologic emergencies, assisting with neuro prognostication, and identifying future research aims.

Multimodal neuromonitoring in the pediatric intensive care unit.

Neuromonitoring is used to assess the central nervous system in the intensive care unit. The purpose of neuromonitoring is to detect neurologic deterioration and intervene to prevent irreversible nervous system dysfunction. Neuromonitoring starts with the standard neurologic examination, which may lag behind the pathophysiologic changes. Additional modalities including continuous electroencephalography (CEEG), multiple physiologic parameters, and structural neuroimaging may detect changes earlier. Multimodal neuromonitoring now refers to an integrated combination and display of non-invasive and invasive modalities, permitting tailored treatment for the individual patient. This chapter reviews the non-invasive and invasive modalities used in pediatric neurocritical care.

Characteristics of non-sleep related apneas in children with alternating hemiplegia of childhood.

BACKGROUND: Non-sleep related apnea (NSA) has been observed in alternating hemiplegia of childhood (AHC) but has yet to be characterized. GOALS: Investigate the following hypotheses: 1) AHC patients manifest NSA that is often severe. 2) NSA is usually triggered by precipitating events. 3) NSA is more likely in patients with ATP1A3 mutations. METHODS: Retrospective review of 51 consecutive AHC patients (ages 2-45 years) enrolled in our AHC registry. NSAs were classified as mild (not needing intervention), moderate (needing intervention but not perceived as life threatening), or severe (needing intervention and perceived as life threatening). RESULTS: 19/51 patients (37 %) had 52 NSA events (6 mild, 11 moderate, 35 severe). Mean age of onset of NSA (± Standard Error of the Mean (SEM)): 3.8 ± 1.5 (range 0-24) years, frequency during follow up was higher at younger ages as compared to adulthood (year 1: 2.2/year, adulthood: 0.060/year). NSAs were associated with triggering factors, bradycardia and with younger age (p < 0.008 in all) but not with mutation status (p = 0.360). Triggers, observed in 17 patients, most commonly included epileptic seizures in 9 (47 %), anesthesia, AHC spells and intercurrent, stressful, conditions. Management included use of pulse oximeter at home in nine patients, home oxygen in seven, intubation/ventilatory support in seven, and basic CPR in six. An additional patient required tracheostomy. There were no deaths or permanent sequalae. CONCLUSIONS: AHC patients experience NSAs that are often severe. These events are usually triggered by seizures or other stressful events and can be successfully managed with interventions tailored to the severity of the NSA.

Responsive neurostimulation of thalamic nuclei for regional and multifocal drug-resistant epilepsy in children and young adults.

OBJECTIVE: Responsive neurostimulation (RNS) is a US FDA-approved form of neuromodulation to treat patients with focal-onset drug-resistant epilepsy (DRE) who are ineligible for or whose condition is refractory to resection. However, the FDA approval only extends to use in patients with one or two epileptogenic foci. Recent literature has shown possible efficacy of thalamic RNS in patients with Lennox-Gastaut syndrome and multifocal epilepsy. The authors hypothesized that RNS of thalamic nuclei may be effective in seizure reduction for patients with multifocal or regionalized-onset DRE. METHODS: The authors performed a retrospective chart review of all patients who had an RNS device managed at Texas Children's Hospital between July 2016 and September 2023, with at least one active electrode in the thalamic nuclei and ≥ 12 months of postimplantation follow-up. Information conveyed by the patient or their caregiver provided data on the change in the clinical seizure frequency, quality of life (QOL), and seizure severity between the preimplantation baseline visit and the last office visit (LOV). RESULTS: Thirteen patients (ages 8-24 years) were identified with active RNS leads in thalamic nuclei (11 centromedian and 2 anterior nucleus). At LOV, 46% of patients reported 50%-100% clinical seizure reduction (classified as responders), 15% reported 25%-49% reduction, and 38% reported < 25% reduction or no change. Additionally, 42% of patients reported subjective improvement in QOL and 58% reported improved seizure severity. Patients with focal cortical dysplasia (FCD) responded strongly: 3 of 5 (60%) reported ≥ 80% reduction in seizure burden and improvement in seizure severity and QOL. Patients with multifocal epilepsy and bilateral thalamocortical leads also did well, with all 3 reporting ≥ 50% reduction in seizures. CONCLUSIONS: RNS of thalamic nuclei shows promising results in reducing seizure burden for patients with multifocal or regional-onset DRE, particularly in a bilateral thalamocortical configuration or when addressing an underlying FCD.

Brain tumor-related epilepsy management: A Society for Neuro-oncology (SNO) consensus review on current management.

Tumor-related epilepsy (TRE) is a frequent and major consequence of brain tumors. Management of TRE is required throughout the course of disease and a deep understanding of diagnosis and treatment is key to improving quality of life. Gross total resection is favored from both an oncologic and epilepsy perspective. Shared mechanisms of tumor growth and epilepsy exist, and emerging data will provide better targeted therapy options. Initial treatment with antiseizure medications (ASM) in conjunction with surgery and/or chemoradiotherapy is typical. The first choice of ASM is critical to optimize seizure control and tolerability considering the effects of the tumor itself. These agents carry a potential for drug-drug interactions and therefore knowledge of mechanisms of action and interactions is needed. A review of adverse effects is necessary to guide ASM adjustments and decision-making. This review highlights the essential aspects of diagnosis and treatment of TRE with ASMs, surgery, chemotherapy, and radiotherapy while indicating areas of uncertainty. Future studies should consider the use of a standardized method of seizure tracking and incorporating seizure outcomes as a primary endpoint of tumor treatment trials.

Electroencephalographic monitoring in the pediatric intensive care unit.

Continuous electroencephalographic (CEEG) monitoring is used with increasing frequency in critically ill children to provide insight into brain function and to identify electrographic seizures. CEEG monitoring use often impacts clinical management, most often by identifying electrographic seizures and status epilepticus. Most electrographic seizures have no clinical correlate, and thus would not be identified without CEEG monitoring. There are increasing data showing that electrographic seizures and electrographic status epilepticus are associated with worse outcome. Seizure identification efficiency may be improved by further development of quantitative electroencephalography trends. This review describes the clinical impact of CEEG data, the epidemiology of electrographic seizures and status epilepticus, the impact of electrographic seizures on outcome, the utility of quantitative electroencephalographic trends for seizure identification, and practical considerations regarding CEEG monitoring.

Treatment of status epilepticus: an international survey of experts.

BACKGROUND: As part of the development of the Neurocritical Care Society (NCS) Status Epilepticus (SE) Guidelines, the NCS SE Writing Committee conducted an international survey of SE experts. METHODS: The survey consisted of three patient vignettes (case 1, an adult; case 2, an adolescent; case 3, a child) and questions regarding treatment. The questions for each case focused on initial and sequential therapy as well as when to use continuous intravenous (cIV) therapy and for what duration. Responses were obtained from 60/120 (50%) of those surveyed. RESULTS: This survey reveals that there is expert consensus for using intravenous lorazepam for the emergent (first-line) therapy of SE in children and adults. For urgent (second-line) therapy, the most common agents chosen were phenytoin/fosphenytoin, valproate sodium, and levetiracetam; these choices varied by the patient age in the case scenarios. Physicians who care for adult patients chose cIV therapy for RSE, especially midazolam and propofol, rather than a standard AED sooner than those who care for children; and in children, there is a reluctance to choose propofol. Pentobarbital was chosen later in the therapy for all ages. CONCLUSION: There is close agreement between the recently published NCS guideline for SE and this survey of experts in the treatment of SE.

Focal resection of leptomeningeal angioma in a rare case of Sturge-Weber syndrome without facial nevus.

Sturge-Weber syndrome (SWS) is a neurocutaneous disorder comprised typically of a facial nevus, leptomeningeal angioma with calcifications, and seizures. SWS without a port-wine stain is a rare variant with only 30 cases reported in the literature. Here, a case of an 8-year-old girl with no cutaneous abnormalities presenting with medically intractable epilepsy and MRI and CT findings consistent with SWS is described. The patient underwent multistage surgery with subdural electrode monitoring before and after resection of the epileptogenic focus, with complete excision of the lesion and postoperative resolution of her seizures. This is the first reported case of three-stage surgery for localized resection of the seizure focus for SWS.

Systemic inflammatory markers and EEG features of children with FIRES receiving anakinra.

In a retrospective case series of 10 children with cryptogenic FIRES, we sought to describe the early clinical course and potential biomarkers following anakinra initiation. Six children achieved anesthetic withdrawal within 3 weeks of therapy and one in week four. Of the available cEEG (six children), CRP (10 children), and serum cytokine (six children) studies, there were temporal changes in highly epileptiform bursts (observed in three children), CRP, IL-6, and IL-10 levels that might parallel clinical progression. These observations may represent candidate biomarkers for monitoring clinical progression and therapeutic interventions including anakinra, which merits further investigation in future studies.

Responsive Neurostimulation for the Treatment of Children With Drug-Resistant Epilepsy in Tuberous Sclerosis Complex.

BACKGROUND: To review seizure outcomes in children with tuberous sclerosis complex (TSC) and drug-resistant epilepsy (DRE) treated with the responsive neurostimulation (RNS) System. METHODS: We retrospectively reviewed children (<21 years old) with TSC implanted with the RNS System at Texas Children's Hospital between July 2016 and May 2022. RESULTS: Five patients meeting the search criteria were identified (all female). The median age of the RNS implantation was 13 years (range: 5 to 20 years). The median epilepsy duration before the RNS implantation was 13 years (range: 5 to 20 years). Surgeries before RNS implantation included vagus nerve stimulator placement (n = 2), left parietal resection (n = 1), and corpus callosotomy (n = 1). The median number of antiseizure medications tried before RNS was 8 (range: 5 to 12). The rationale for the RNS System implantation included seizure onset in eloquent cortex (n = 3) and multifocal seizures (n = 2). The maximum current density for each patient ranged between 1.8 and 3.5 µC/cm2, with an average daily stimulation of 2240 (range: 400 to 4200). There was an 86% median seizure reduction (range 0% to 99%) at a median follow-up duration of 25 months (range: 17 to 25 months). No patient experienced implantation or stimulation-related complications. CONCLUSIONS: We observed a favorable improvement in seizure frequency in pediatric patients with DRE secondary to TSC treated with the RNS System. The RNS System may be a safe and effective treatment for DRE in children with TSC.

KCNA1 gain-of-function epileptic encephalopathy treated with 4-aminopyridine.

Precision medicine for Mendelian epilepsy is rapidly developing. We describe an early infant with severely pharmacoresistant multifocal epilepsy. Exome sequencing revealed the de novo variant p.(Leu296Phe) in the gene KCNA1, encoding the voltage-gated K+ channel subunit KV 1.1. So far, loss-of-function variants in KCNA1 have been associated with episodic ataxia type 1 or epilepsy. Functional studies of the mutated subunit in oocytes revealed a gain-of-function caused by a hyperpolarizing shift of voltage dependence. Leu296Phe channels are sensitive to block by 4-aminopyridine. Clinical use of 4-aminopyridine was associated with reduced seizure burden, enabled simplification of co-medication and prevented rehospitalization.