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.

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.

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.

Fulminant Anti-Myelin Oligodendrocyte Glycoprotein-Associated Cerebral Cortical Encephalitis: Case Series of a Severe Pediatric Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease Phenotype.

BACKGROUND: We describe a cohort of children with severe myelin oligodendrocyte glycoprotein (MOG)-IgG-associated cerebral cortical encephalitis (CCE), manifesting with bilateral cortical cytotoxic edema and critical neurological illness. METHODS: We retrospectively reviewed our pediatric MOG antibody-associated disease (MOGAD) database and identified patients with specific radiographic pattern of bilateral, multifocal cortical cytotoxic lesions. We collected demographic, clinical, and outcomes data from these patients and compared select variables with radiographically distinct cerebral MOGAD syndromes (case-control analysis). We assessed the correlation of quantitative clinical variables with severity/outcomes measures using simple linear regression. RESULTS: Sixty-five of 88 total MOGAD cases had cerebral disease, and six of 88 met inclusion criteria for fulminant CCE (f-CCE). Age range was 2 to 7 years; five of six were male. Six of six were critically ill with severe encephalopathy and seizures, two of six required barbiturate coma, and two of six required invasive intracranial pressure monitoring. Six of six required treatment escalation beyond steroids. Four of six had favorable outcome; two of six had moderate-severe disability. Compared with other cerebral MOGAD cases (n = 59), children with f-CCE were more likely to have critical illness and poor neurological outcomes scores. Neurofilament light chain and treatment latency positively correlated with intensive care unit length of stay and outcomes scores; cerebrospinal fluid (CSF) white blood cell count and neutrophil-to-lymphocyte ratio did not. CONCLUSIONS: Pediatric CCE with bilateral cytotoxicity is associated with more fulminant disease and worse outcomes than other cerebral MOGAD syndromes.

Pediatric status epilepticus management by Emergency Medical Services (the pSERG cohort).

PURPOSE: Delayed treatment in status epilepticus (SE) is independently associated with increased treatment resistance, morbidity, and mortality. We describe the prehospital management pathway and Emergency Medical Services (EMS) timeliness in children who developed refractory convulsive status epilepticus (RCSE). METHODS: Retrospective multicenter study in the United States using prospectively collected observational data from June 2011 to March 2020. We selected pediatric patients (one month-21 years) with RCSE initiated outside the hospital and transported to the hospital by EMS. RESULTS: We included 91 patients with a median (percentile25-percentile75) age of 3.0 (1.5-7.3) years. The median time from seizure onset to hospital arrival was 45 (30-67) minutes, with a median time cared for by EMS of 24 (15-36) minutes. Considering treatment by caregivers and EMS before hospital arrival, 20 (22%) patients did not receive any anti-seizure medications (ASM) and 71 (78%) received one to five doses of benzodiazepines (BZD), without non-BZD ASM. We provided the prehospital treatment flow path of these patients through caregivers and EMS including relevant time points. Patients with a history of SE were more likely to receive the first BZD in the prehospital setting compared to patients without a history of SE (adjusted HR 3.25, 95% CI 1.72-6.12, p<0.001). CONCLUSION: In this multicenter study of pediatric RCSE, prehospital treatment may be streamlined further. Patients with a history of SE were more likely to receive prehospital rescue medication.

Inaccuracies in Parental Reporting of Treated Epileptic Spasms: Both Under- and Over-Reporting.

BACKGROUND: The purpose of this study was to evaluate the accuracy of parental reporting of epileptic spasms (ES) after 14 days of appropriate medical therapy for new-onset ES by comparison with extended video electroencephalography (vEEG) monitoring results. METHODS: Fifty-eight patients were identified from August 2019 to February 2021 with new-onset ES, confirmed on vEEG. Patients were initiated on appropriate treatment (high-dose steroids or vigabatrin). After two weeks of therapy, patients underwent overnight (18 to 24 hours) vEEG monitoring in the epilepsy monitoring unit. Parental reporting of presence or absence of ES on admission was compared with results of vEEG monitoring. RESULTS: The 58 patients ranged in age from three to 20 months (average 7.8 months). An underlying etiology was identified in 78%, whereas 22% patients had unknown etiology. The overall accuracy of parental reporting was 74% (43 of 58) when compared with results of vEEG within 14 to 18 days of starting therapy. Of these, 65% (28 of 43) reported ES resolution and 35% (15 of 43) reported continued ES. Of the 26% (15 of 58) families who were incorrect at two-week follow-up, 67% (10 of 15) reported resolution of ES. However, a minority of families, 33% (five of 15), who continued to report spasms clinically, were inaccurate. CONCLUSIONS: Although a majority of inaccurate parental reports at two weeks of treatment were due to unrecognized ES (a widely known phenomenon), a minority were conversely inaccurate due to persistent over-reporting of ES. This fact highlights the importance of correlating parental history with objective vEEG monitoring, to prevent inappropriate escalation of medication therapy.

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.

Early Clinical Variables Associated With Refractory Convulsive Status Epilepticus in Children.

BACKGROUND AND OBJECTIVES: The objective of this study was to determine patient-specific factors known proximate to the presentation to emergency care associated with the development of refractory convulsive status epilepticus (RSE) in children. METHODS: An observational case-control study was conducted comparing pediatric patients (1 month-21 years) with convulsive SE whose seizures stopped after benzodiazepine (BZD) and a single second-line antiseizure medication (ASM) (responsive established status epilepticus [rESE]) with patients requiring more than a BZD and a single second-line ASM to stop their seizures (RSE). These subpopulations were obtained from the pediatric Status Epilepticus Research Group study cohort. We explored clinical variables that could be acquired early after presentation to emergency medical services with univariate analysis of the raw data. Variables with p < 0.1 were retained for univariable and multivariable regression analyses. Multivariable logistic regression models were fit to age-matched and sex-matched data to obtain variables associated with RSE. RESULTS: We compared data from a total of 595 episodes of pediatric SE. Univariate analysis demonstrated no differences in time to the first BZD (RSE 16 minutes [IQR 5-45]; rESE 18 minutes [IQR 6-44], p = 0.068). Time to second-line ASM was shorter in patients with RSE (RSE 65 minutes; rESE 70 minutes; p = 0.021). Both univariable and multivariable regression analyses revealed a family history of seizures (OR 0.37; 95% CI 0.20-0.70, p = 0.0022) or a prescription for rectal diazepam (OR 0.21; 95% CI 0.078-0.53, p = 0.0012) was associated with decreased odds of RSE. DISCUSSION: Time to initial BZD or second-line ASM was not associated with progression to RSE in our cohort of patients with rESE. A family history of seizures and a prescription for rectal diazepam were associated with a decreased likelihood of progression to RSE. Early attainment of these variables may help care for pediatric rESE in a more patient-tailored manner. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that patient and clinical factors may predict RSE in children with convulsive seizures.

An Initial Experience of Completion Hemispherotomy via Magnetic Resonance-Guided Laser Interstitial Therapy.

INTRODUCTION: In carefully selected patients with medically refractory epilepsy, disconnective hemispherotomy can result in significant seizure freedom; however, incomplete disconnection can result in ongoing seizures and poses a significant challenge. Completion hemispherotomy provides an opportunity to finish the disconnection. We describe the use of magnetic resonance-guided laser interstitial thermal ablation (MRgLITT) for completion hemispherotomy. METHODS: Patients treated with completion hemispherotomy using MRgLITT at our institution were identified. Procedural and seizure outcomes were evaluated retrospectively. RESULTS: Five patients (3 males) underwent six MRgLITT procedures (one child treated twice) for completion hemispherotomy at a median age of 6 years (range 1.8-12.9). Two children had hemimegalencephaly, two had Rasmussen encephalitis, and one had polymicrogyria. All five children had persistent seizures likely secondary to incomplete disconnection after their functional hemispherotomy. The mean time from open hemispherotomy to MRgLITT was 569.5 ± 272.4 days (median 424, range 342-1,095). One patient underwent stereoelectroencephalography before MRgLITT. The mean number of ablation targets was 2.3 ± 0.47 (median 2, range 2-3). The mean length of the procedure was 373 min ± 68.9 (median 374, range 246-475). Four of the five patients were afforded improvement in their neurocognitive functioning and speech performance after ablation, with mean daily seizure frequency at 1 year of 1.03 ± 1.98 (median 0, range 0-5). Two patients achieved Engel Class I outcomes at 1 year after ablation, one was Engel Class III, and two were Engel Class IV. The mean follow-up time was 646.8 ± 179.5 days (median 634, range 384-918). No MRgLITT-related complications occurred. Delayed retreatment (>1 year) occurred in three patients: one child underwent redo ablation and two underwent anatomic hemispherectomy. CONCLUSION: We have demonstrated the feasibility of a minimally invasive approach for completion hemispherotomy using MRgLITT. Delayed retreatment was needed in three patients; thus, further study of this technique with comparison to other surgical techniques is warranted.

Survey of Pediatric ICU EEG Monitoring-Reassessment After a Decade.

PURPOSE: In 2011, the authors conducted a survey regarding continuous EEG (CEEG) utilization in critically ill children. In the interim decade, the literature has expanded, and guidelines and consensus statements have addressed CEEG utilization. Thus, the authors aimed to characterize current practice related to CEEG utilization in critically ill children. METHODS: The authors conducted an online survey of pediatric neurologists from 50 US and 12 Canadian institutions in 2022. RESULTS: The authors assessed responses from 48 of 62 (77%) surveyed institutions. Reported CEEG indications were consistent with consensus statement recommendations and included altered mental status after a seizure or status epilepticus, altered mental status of unknown etiology, or altered mental status with an acute primary neurological condition. Since the prior survey, there was a 3- to 4-fold increase in the number of patients undergoing CEEG per month and greater use of written pathways for ICU CEEG. However, variability in resources and workflow persisted, particularly regarding technologist availability, frequency of CEEG screening, communication approaches, and electrographic seizure management approaches. CONCLUSIONS: Among the surveyed institutions, which included primarily large academic centers, CEEG use in pediatric intensive care units has increased with some practice standardization, but variability in resources and workflow were persistent.

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.

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.

Epilepsy Surgery in Young Children With Tuberous Sclerosis Complex: A Novel Hybrid Multimodal Surgical Approach.

BACKGROUND: Surgery has become integral in treating children with tuberous sclerosis complex (TSC)-related drug-resistant epilepsy (DRE). OBJECTIVE: To describe outcomes of a multimodal diagnostic and therapeutic approach comprising invasive intracranial monitoring and surgical treatment and compare the complementary techniques of open resection and magnetic resonance-guided laser interstitial thermal therapy. METHODS: Clinical and radiographic data were prospectively collected for pediatric patients undergoing surgical evaluation for TSC-related DRE at our tertiary academic hospital. Seizure freedom, developmental improvement, and Engel class were compared. RESULTS: Thirty-eight patients (20 females) underwent treatment in January 2016 to April 2019. Thirty-five underwent phase II invasive monitoring with intracranial electrodes: 24 stereoencephalography, 9 craniotomy for grid/electrode placement, and 2 grids + stereoencephalography. With the multimodal approach, 33/38 patients (87%) achieved >50% seizure freedom of the targeted seizure type after initial treatment; 6/9 requiring secondary treatment and 2/2 requiring a third treatment achieved >50% freedom. The median Engel class was II at last follow-up (1.65 years), and 55% of patients were Engel class I/II. The mean age was lower for children undergoing open resection (2.4 vs 4.9 years, P = .04). Rates of >50% reduction in seizures (86% open resection vs 88% laser interstitial thermal therapy) and developmental improvement (86% open resection vs 83% magnetic resonance-guided laser interstitial thermal therapy) were similar. CONCLUSION: This hybrid approach of using both open surgical and minimally invasive techniques is safe and effective in treating DRE secondary to TSC. Clinical trials focused on treatment method with longer follow-up are needed to determine the optimal candidates for each approach and compare the treatment modalities more effectively.

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.

Creating a Robust Community of Practice as a Foundation for the Successful Development of a Pediatric Neurocritical Care Program.

BACKGROUND: There has been a growing impetus for developing pediatric neurocritical care (PNCC) programs to improve care delivery for children with critical neurological conditions. We sought to develop a unique PNCC program using the concept of Community of Practice (CoP). METHODS: This is a process improvement project in an academic Children's Hospital. Using CoP framework (domain, community, practice), we created a domain of PNCC with a stated vision and formal organizational structure, a core community of intensivists and neurologists interested in PNCC, and a standardized practice approach by establishing core competencies for PNCC and implementing practice guidelines. RESULTS: We evaluated the program through the Four-Frame Model of Organizational Theory and Behavior (structural, human resource, political, symbolic) and by the Neurocritical Care Society's (NCS's) standards for a Level I Neurocritical Care Unit (Neuro-ICU). Structural frame included opening a pediatric Neuro-ICU, identifying PNCC leaders across specialties, and developing a multidisciplinary care delivery model. Human resource frame included forming physician and nurse groups with a primary role in PNCC and ongoing education through workshops, lecture series, and certification. Politically, program implementation was tailored to each department gaining institution-wide support for program initiatives. Symbolically, the PNCC program highlighted the vision to advance knowledge and best practices. Our program met 232 of 252 (92%) proposed NCS standards. CONCLUSIONS: The CoP as the foundation for program development has enabled us to achieve the majority of standards proposed by NCS for a Level I Neuro-ICU. The generalizability of these frameworks may facilitate the development of a PNCC program for other institutions.

A Virtual Community of Practice: An International Educational Series in Pediatric Neurocritical Care.

Pediatric neurocritical care (PNCC) is a rapidly growing field. Challenges posed by the COVID-19 pandemic on trainee exposure to educational opportunities involving direct patient care led to the creative solutions for virtual education supported by guiding organizations such as the Pediatric Neurocritical Care Research Group (PNCRG). Our objective is to describe the creation of an international, peer-reviewed, online PNCC educational series targeting medical trainees and faculty. More than 1600 members of departments such as pediatrics, pediatric critical care, and child neurology hailing from 75 countries across six continents have participated in this series over a 10-month period. We created an online educational channel in PNCC with over 2500 views to date and over 130 followers. This framework could serve as a roadmap for other institutions and specialties seeking to address the ongoing problems of textbook obsolescence relating to the rapid acceleration in knowledge acquisition, as well as those seeking to create new educational content that offers opportunities for an interactive, global audience. Through the creation of a virtual community of practice, we have created an international forum for pediatric healthcare providers to share and learn specialized expertise and best practices to advance global pediatric health.

KCNQ2 R144 variants cause neurodevelopmental disability with language impairment and autistic features without neonatal seizures through a gain-of-function mechanism.

BACKGROUND: Prior studies have revealed remarkable phenotypic heterogeneity in KCNQ2-related disorders, correlated with effects on biophysical features of heterologously expressed channels. Here, we assessed phenotypes and functional properties associated with KCNQ2 missense variants R144W, R144Q, and R144G. We also explored in vitro blockade of channels carrying R144Q mutant subunits by amitriptyline. METHODS: Patients were identified using the RIKEE database and through clinical collaborators. Phenotypes were collected by a standardized questionnaire. Functional and pharmacological properties of variant subunits were analyzed by whole-cell patch-clamp recordings. FINDINGS: Detailed clinical information on fifteen patients (14 novel and 1 previously published) was analyzed. All patients had developmental delay with prominent language impairment. R144Q patients were more severely affected than R144W patients. Infantile to childhood onset epilepsy occurred in 40%, while 67% of sleep-EEGs showed sleep-activated epileptiform activity. Ten patients (67%) showed autistic features. Activation gating of homomeric Kv7.2 R144W/Q/G channels was left-shifted, suggesting gain-of-function effects. Amitriptyline blocked channels containing Kv7.2 and Kv7.2 R144Q subunits. INTERPRETATION: Patients carrying KCNQ2 R144 gain-of-function variants have developmental delay with prominent language impairment, autistic features, often accompanied by infantile- to childhood-onset epilepsy and EEG sleep-activated epileptiform activity. The absence of neonatal seizures is a robust and important clinical differentiator between KCNQ2 gain-of-function and loss-of-function variants. The Kv7.2/7.3 channel blocker amitriptyline might represent a targeted treatment. FUNDING: Supported by FWO, GSKE, KCNQ2-Cure, Jack Pribaz Foundation, European Joint Programme on Rare Disease 2020, the Italian Ministry for University and Research, the Italian Ministry of Health, the European Commission, the University of Antwerp, NINDS, and Chalk Family Foundation.