Faculty Bibliography

OBJECTIVE:The CDKL5 Clinical Severity Assessment (CCSA) is a comprehensive, content-validated measurement tool capturing the diverse challenges of cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD), a genetically caused developmental epileptic encephalopathy (DEE). The CCSA is divided into clinician-reported (CCSA-Clinician) and caregiver-reported (CCSA-Caregiver) assessments. The aim of this study was to evaluate the factor structure of these measures through confirmatory factor analysis (CFA) and evaluate their validity and reliability. METHODS:Participants were recruited from the International CDKL5 Clinical Research Network to take part in an in-clinic CCSA-Clinician evaluation (n = 148) and/or complete the CCSA-Caregiver questionnaire (n = 198). CFA was used to determine domains, and factor loadings and validity were assessed. For the CCSA-Clinician, inter-rater reliability was assessed by nine CDD experienced clinicians via 14 pre-recorded evaluations. Eight clinicians re-viewed and re-scored the videos after 4 weeks to evaluate intra-rater reliability. The CCSA-Caregiver was completed on a second occasion by 34 caregivers after 2-4 weeks to assess test-retest reliability. RESULTS:CFA resulted in three domains for the CCSA-Clinician (motor and movement, communication, vision) and four domains for the CCSA-Caregiver (seizures, behavior, alertness, feeding), with good item loadings across both measures. Structural statistics, internal consistency, discriminant validity, and reliability were satisfactory for both measures, and scores were consistent between known groups. SIGNIFICANCE/CONCLUSIONS:This study provides strong evidence that the CCSA measures are suitable to assess the clinical severity of individuals with CDD, supporting their use in clinical trials. Further evaluation of responsiveness to change in a longitudinal assessment is planned. Use may also be appropriate in similar DEEs but would require validation in those populations.

Public health systems reported low mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in East Asia, in low-income countries, and for children during the first year of the SARS-CoV-2 pandemic. These reports led commentators to suggest that cross-reactive immunity from prior exposure to other pathogens reduced fatality risk. Resolution of initial infection waves also contributed to speculation that herd immunity prevented further waves prior to vaccination. Serology instead implied that immunity was too limited to achieve herd immunity and that there was little impact from cross-reactive protection. Paediatric deaths exceeded those from influenza, with higher age-specific fatality risk in lower-income nations and similar fatality risk in East Asia compared with demographically similar regions. Neither pre-outbreak exposure to related pathogens nor immunity induced by initial infection waves are necessarily a reliable response to future pathogen outbreaks. Preparedness for future pathogen outbreaks should instead focus on strategies such as voluntary behavioural changes, nonpharmaceutical interventions, and vaccination.

OBJECTIVE:To characterize the experience of people with epilepsy and aligned healthcare workers (HCWs) during the first 18 months of the COVID-19 pandemic and compare experiences in high-income countries (HICs) with non-HICs. METHODS:Separate surveys for people with epilepsy and HCWs were distributed online in April 2020. Responses were collected to September 2021. Data were collected for COVID-19 infections, the effect of COVID-related restrictions, access to specialist help for epilepsy (people with epilepsy), and the impact of the pandemic on work productivity (HCWs). The frequency of responses for non-HICs and HICs were compared using non-parametric Chi-square tests. RESULTS:Two thousand one hundred and  five individuals with epilepsy from 53 countries and 392 HCWs from 26 countries provided data. The same proportion of people with epilepsy in non-HICs and HICs reported COVID-19 infection (7%). Those in HICs were more likely to report that COVID-19 measures had affected their health (32% vs. 23%; p < 0.001). There was no difference between non-HICs and HICs in the proportion who reported difficulty in obtaining help for epilepsy. HCWs in non-HICs were more likely to report COVID-19 infection than those in HICs (18% vs 6%; p = 0.001) and that their clinical work had been affected by concerns about contracting COVID-19, lack of personal protective equipment, and the impact of the pandemic on mental health (all p < 0.001). Compared to pre-pandemic practices, there was a significant shift to remote consultations in both non-HICs and HICs (p < 0.001). SIGNIFICANCE/CONCLUSIONS:While the frequency of COVID-19 infection was relatively low in these data from early in the pandemic, our findings suggest broader health consequences and an increased psychosocial burden, particularly among HCWs in non-HICs. Planning for future pandemics should prioritize mental healthcare alongside ensuring access to essential epilepsy services and expanding and enhancing access to remote consultations. PLAIN LANGUAGE SUMMARY/CONCLUSIONS:We asked people with epilepsy about the effects of COVID-19 on their health and healthcare. We wanted to compare responses from people in high-income countries and other countries. We found that people in high-income countries and other countries had similar levels of difficulty in getting help for their epilepsy. People in high-income countries were more likely to say that their general health had been affected. Healthcare workers in non-high-income settings were more likely to have contracted COVID-19 and have the care they deliver affected by the pandemic. Across all settings, COVID-19 associated with a large shift to remote consultations.

Cenobamate has demonstrated efficacy in patients with treatment-resistant epilepsy, including patients who continued to have seizures after epilepsy surgery. This article provides recommendations for cenobamate use in patients referred for epilepsy surgery evaluation. A panel of six senior epileptologists from the United States and Europe with experience in presurgical evaluation of patients with epilepsy and in the use of antiseizure medications (ASMs) was convened to provide consensus recommendations for the use of cenobamate in patients referred for epilepsy surgery evaluation. Many patients referred for surgical evaluation may benefit from ASM optimization; both ASM and surgical treatment should be individualized. Based on previous clinical studies and the authors' clinical experience with cenobamate, a substantial proportion of patients with treatment-resistant epilepsy can become seizure-free with cenobamate. We recommend a cenobamate trial and ASM optimization in parallel with presurgical evaluations. Cenobamate can be started before phase two monitoring, especially in patients who are found to be suboptimal surgery candidates. As neurostimulation therapies are generally palliative, we recommend trying cenobamate before vagus nerve stimulation (VNS), deep brain stimulation, or responsive neurostimulation (RNS). In surgically remediable cases (mesial temporal sclerosis, benign discrete lesion in non-eloquent cortex, cavernous angioma, etc.), cenobamate use should not delay imminent surgery; however, a patient may decide to defer or even cancel surgery should they achieve sustained seizure freedom with cenobamate. This decision should be made on an individual, case-by-case basis based on seizure etiology, patient preferences, potential surgical risks (mortality and morbidity), and likely surgical outcome. The addition of cenobamate after unsuccessful surgery or palliative neuromodulation may also be associated with better outcomes.

BACKGROUND:Isolated psychiatric symptoms can be the initial symptom of pediatric anti-N-methyl-d-aspartate (NMDA) receptor autoimmune encephalitis (pNMDARE). Here we report on the prevalence of isolated psychiatric symptoms in pNMDARE. We also assess whether initial neurodiagnostic tests (brain magnetic resonance imaging [MRI], electroencephalography [EEG], and/or cerebrospinal fluid [CSF] white blood cell count) are abnormal in children with isolated psychiatric symptoms and pNMDARE. METHODS:This multicenter retrospective cohort study from CONNECT (Conquering Neuroinflammation and Epilepsies Consortium) from 14 institutions included children under age 18 years who were diagnosed with pNMDARE. Descriptive statistics using means, medians, and comparisons for continuous versus discrete data was performed. RESULTS:Of 249 children included, 12 (5%) had only psychiatric symptoms without other typical clinical features of autoimmune encephalitis at presentation. All but one (11 of 12 = 92%) had at least one abnormal finding on initial ancillary testing: eight of 12 (67%) had an abnormal EEG, six of 12 (50%) had an abnormal MRI, and five of 12 (42%) demonstrated CSF pleocytosis. The single patient with a normal MRI, EEG, and CSF profile had low positive CSF NMDA antibody (titer of 1:1), and symptoms improved without immunotherapy. CONCLUSIONS:Isolated first-episode psychiatric symptoms in pNMDARE are uncommon, and the majority of children will exhibit additional neurodiagnostic abnormalities. Delaying immunotherapy in a child with isolated psychiatric symptoms and normal neurodiagnostic testing may be warranted while awaiting confirmatory antibody testing.

OnabotulinumtoxinA (onabotA) is approved in the US for 12 therapeutic indications. Real-world data on onabotA multi-indication use are limited, often leading to delayed or reduced treatment. This study provides real-world evidence on the safety of onabotA when treating multiple indications concomitantly. SYNCHRONIZE was a multicenter, retrospective, chart-review study evaluating onabotA's safety for adults treated for ≥2 therapeutic indications within a 3-month period. The primary outcome was treatment-emergent adverse events (TEAEs) within 6 months post-treatment. A total of 279 patients were included. The most common concomitant indications treated were cervical dystonia and chronic migraine (43.4%). The average 3-month cumulative dose for multiple indications was 282.2 U. The treatment interval for multiple indications was ≤24 h for most patients (62.4%). Overall, 28.7% of patients reported ≥1 TEAE with no apparent trends in TEAEs and dose interval or cumulative dose. Reported TEAEs included UTI (5.7%), neck pain (5.0%), and headache (4.3%). No patient had a lack of effect according to clinical objective measurements. SYNCHRONIZE described the real-world safety of onabotA for patients treated concomitantly for ≥2 indications within a 3-month period. TEAEs were generally consistent with the known safety profiles of individual indications. No new safety signals were identified).

Nilotinib, a tyrosine kinase inhibitor that targets the Abelson tyrosine kinase (c-Abl) signaling pathway, is FDA-approved to treat chronic myeloid leukemia. Nilotinib has properties indicative of a possible utility in neuroprotection that have prompted exploration of repurposing the drug for the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD). AD is a progressive age-related neurodegenerative disorder characterized by the deposition of extracellular amyloid-β plaques and intracellular neurofibrillary tangles. It is incurable and affects approximately 50 million patients worldwide. Nilotinib reduces c-Abl phosphorylation, amyloid-β levels, and dopaminergic neuron degeneration in preclinical AD models. This study explores the effects of nilotinib on amyloid processing and mitochondrial functioning in the SH-SY5Y human neuroblastoma cell line. SH-SY5Y cells were exposed to nilotinib (1, 5, and 10 µM). Real-time PCR and immunoblot analysis were performed to quantify the expression of genes pertaining to amyloid-β processing and neuronal health. Nilotinib did not significantly change APP, BACE1, or ADAM10 mRNA levels. However, BACE1 protein was significantly increased at 1 µM, and ADAM10 was increased at 10 µM nilotinib without affecting APP protein expression. Further, nilotinib treatment did not affect the expression of genes associated with neuronal health and mitochondrial functioning. Taken together, our findings do not support the efficacy of nilotinib treatment for neuroprotection.

DHPS deficiency syndrome is an ultra-rare neurodevelopmental disorder (NDD) which results from biallelic mutations in the gene encoding the enzyme deoxyhypusine synthase (DHPS). DHPS is essential to synthesize hypusine, a rare amino acid formed by post-translational modification of a conserved lysine in eukaryotic initiation factor 5 A (eIF5A). DHPS deficiency syndrome causes epilepsy, cognitive and motor impairments, and mild facial dysmorphology. In mice, a brain-specific genetic deletion of Dhps at birth impairs eIF5A^HYP-dependent mRNA translation. This alters expression of proteins required for neuronal development and function, and phenotypically models features of human DHPS deficiency. We studied the role of DHPS in early brain development using a zebrafish loss-of-function model generated by knockdown of dhps expression with an antisense morpholino oligomer (MO) targeting the exon 2/intron 2 (E2I2) splice site of the dhps pre-mRNA. dhps knockdown embryos exhibited dose-dependent developmental delay and dysmorphology, including microcephaly, axis truncation, and body curvature. In dhps knockdown larvae, electrophysiological analysis showed increased epileptiform activity, and confocal microscopy analysis revealed reduced arborisation of GABAergic neurons. Our findings confirm that hypusination of eIF5A by DHPS is needed for early brain development, and zebrafish with an antisense knockdown of dhps model features of DHPS deficiency syndrome.

BACKGROUND:Disorders of consciousness (DoC) are frequently encountered in both, acute and chronic brain injuries. In many countries, early withdrawal of life-sustaining treatments is common practice for these patients even though the accuracy of predicting recovery is debated and delayed recovery can be seen. In this review, we will discuss theoretical concepts of consciousness and pathophysiology, explore effective strategies for management, and discuss the accurate prediction of long-term clinical outcomes. We will also address research challenges. MAIN TEXT/METHODS:DoC are characterized by alterations in arousal and/or content, being classified as coma, unresponsive wakefulness syndrome/vegetative state, minimally conscious state, and confusional state. Patients with willful modulation of brain activity detectable by functional MRI or EEG but not by behavioral examination is a state also known as covert consciousness or cognitive motor dissociation. This state may be as common as every 4th or 5th patient without behavioral evidence of verbal command following and has been identified as an independent predictor of long-term functional recovery. Underlying mechanisms are uncertain but intact arousal and thalamocortical projections maybe be essential. Insights into the mechanisms underlying DoC will be of major importance as these will provide a framework to conceptualize treatment approaches, including medical, mechanical, or electoral brain stimulation. CONCLUSIONS:We are beginning to gain insights into the underlying mechanisms of DoC, identifying novel advanced prognostication tools to improve the accuracy of recovery predictions, and are starting to conceptualize targeted treatments to support the recovery of DoC patients. It is essential to determine how these advancements can be implemented and benefit DoC patients across a range of clinical settings and global societal systems. The Curing Coma Campaign has highlighted major gaps knowledge and provides a roadmap to advance the field of coma science with the goal to support the recovery of patients with DoC.

INTRODUCTION AND PROBLEM STATEMENT/UNASSIGNED:A chief resident's role incorporates administrative, academic, and interpersonal responsibilities essential to managing a successful residency program. However, rising chief residents receive little formal exposure to leadership training. OBJECTIVES/UNASSIGNED:To (1) define leadership styles; (2) understand the effect of cultural competence on leadership styles; (3) learn effective methods to advocate as the chief resident; (4) provide effective peer feedback; (5) provide effective supervisor feedback; (6) learn effective conflict management; (7) ensure psychological safety. METHODS AND CURRICULUM DESCRIPTION/UNASSIGNED:We developed a 1-day curriculum combining didactics and simulation activities for our program's rising chief residents. Implementation of our curricular design included a morning session focusing on small groups and didactic-based lectures on specific topics pertinent to leadership, along with a debriefing of a psychometric evaluation tool administered before the curriculum day. The simulation activity consisted of 3 group objective structured clinical examination (G-OSCE) scenarios: (1) providing a struggling junior trainee with feedback; (2) debriefing an adverse clinical outcome as the team leader; (3) navigating a challenging situation with a supervising physician. Standardized participants were surveyed for specific objectives. Learners completed precurricular and postcurricular surveys on their familiarity and preparedness for their chief year. RESULTS AND ASSESSMENT DATA/UNASSIGNED:= 0.421), learner-reported use of wellness resources was noted to be reduced after the curricular intervention and remains a result of further interest for exploration. DISCUSSION AND LESSONS LEARNED/UNASSIGNED:A 1-day leadership development curriculum combining didactics and simulation is an effective means of preparing rising chief residents to succeed in their transition to this leadership role.