RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS.

SPOUT1/CENP-32 encodes a putative SPOUT RNA methyltransferase previously identified as a mitotic chromosome associated protein. SPOUT1/CENP-32 depletion leads to centrosome detachment from the spindle poles and chromosome misalignment. Aided by gene matching platforms, we identified 24 individuals with neurodevelopmental delays from 18 families with bi-allelic variants in SPOUT1/CENP-32 detected by exome/genome sequencing. Zebrafish spout1/cenp-32 mutants showed reduction in larval head size with concomitant apoptosis likely associated with altered cell cycle progression. In vivo complementation assays in zebrafish indicated that SPOUT1/CENP-32 missense variants identified in humans are pathogenic. Crystal structure analysis of SPOUT1/CENP-32 revealed that most disease-associated missense variants mapped to the catalytic domain. Additionally, SPOUT1/CENP-32 recurrent missense variants had reduced methyltransferase activity in vitro and compromised centrosome tethering to the spindle poles in human cells. Thus, SPOUT1/CENP-32 pathogenic variants cause an autosomal recessive neurodevelopmental disorder: SpADMiSS ( SPOUT1 Associated Development delay Microcephaly Seizures Short stature) underpinned by mitotic spindle organization defects and consequent chromosome segregation errors.

Multidisciplinary Care May Help to Reduce Disparities Associated With Race in Youth With Psychogenic Nonepileptic Seizures.

BACKGROUND: Psychogenic nonepileptic seizures (PNES) are a common type of functional neurological disorder in which patients experience seizurelike episodes. Health disparities based on race and socioeconomics, documented in children with epilepsy and adults with PNES, have not been reported in children and adolescents with PNES. We hypothesize that disparities exist in this population, which impact overall care and therefore influence outcomes. METHODS: We retrospectively analyzed youth referred to our multidisciplinary clinic from 2018 to 2020. All patient charts were screened by social work before the visit to identify potential barriers to care, and a nurse conducted follow-up calls. Patients' race was identified from the electronic health record and compared with several variables. Outcomes were collected via phone follow-up. Descriptive statistics were produced, and comparisons between white patients and patients of other races were completed using Fisher exact tests and multivariable logistic regressions. RESULTS: During the study period, 237 patients were eligible for the analysis. Sixty-eight patients (29%) identified as a race other than white. Only 60%, 56%, and 40% of the cohort were reached for follow-up at one, three, and 12 months, respectively. In general, outcomes were similar between racial groups; however, we found that patients of nonwhite race were more likely to receive support from social work due to barriers identified in screening (P = 0.045). CONCLUSIONS: Health disparities based on race may exist in youth with PNES. A multidisciplinary clinic including social work may help mitigate barriers leading to more equitable care and similar outcomes for white and nonwhite youth with PNES.

Multidisciplinary Care for Pediatric Patients With Psychogenic Nonepileptic Seizures May Be Associated With Decreased Health Care Utilization.

Background and Objectives: Psychogenic nonepileptic seizures (PNES) are paroxysmal events that resemble epileptic seizures but have psychological underpinnings. Patients with PNES have high health care utilization. We hypothesize that appropriate care would lead to decreases in utilization. The aim of this study was to measure the impact of a multidisciplinary PNES clinic in reducing health care utilization (HCU) in youth with PNES referred to the clinic. Methods: We reviewed the frequency of visits to the emergency department (ED), urgent care (UC), planned and unplanned hospitalizations, neurodiagnostic studies, and total charges associated with these encounters 12 months before and 12 months after initial referral to the clinic. Manual chart review of all patients referred from November 2017 to March 2020 was performed. Results: Two hundred and twelve unique patients were included in this retrospective study. Patient sex was identified as 71% female, 28% male, and 1% other, with an average age of 14 years at diagnosis. These patients visited the ED a total of 410 times before being seen in the PNES clinic, which decreased to 187 visits after (75% reduction). All measures of HCU decreased in the 12 months after the visit, and statistically significant differences were observed in all measures of HCU except for head MRIs, leading to an estimated potential cost savings of $7,978,447. Discussion: Patients with PNES were found to have decreased health care utilization in the 12 months after referral to the Nationwide Children's Hospital multidisciplinary clinic, including significant decreases in emergency services and unnecessary diagnostic testing, in the 12 months after the referral.

Brief Report: Psychogenic Nonepileptic Events in Pediatric Patients with Autism or Intellectual Disability.

This is a retrospective case series of pediatric patients referred to the psychogenic nonepileptic events clinic (PNEE) who had comorbid diagnoses of autism spectrum disorder (ASD) or intellectual disability (ID). We describe 15 patients, nine with ASD and six with ID who had a telephone visit follow-up at 12 months. There were higher rates of male gender (40%) and comorbid epilepsy (53%) compared to the larger PNEE cohort. Eleven patients were available for follow-up and ten patients had improvement in events or were event-free. We report that patients with ASD or ID can develop PNEE and experience improvement from events.

The Spike-Wave Index of the First 100 Seconds of Sleep Can Be a Reliable Scoring Method for Electrographic Status Epilepticus in Sleep.

INTRODUCTION: Electrical status epilepticus in sleep (ESES) is an electrographic pattern in which interictal epileptiform activity is augmented by the transition to sleep, with non-rapid eye movement sleep state characterized by near-continuous lateralized or bilateral epileptiform discharges. The aim of this study was to measure the reliability of the spike-wave index (SWI) of the first 100 seconds of sleep as a tool for the diagnosis of ESES. METHODS: One hundred forty studies from 60 unique patients met the inclusion. Two neurophysiologists calculated the SWI of the first 100 seconds of spontaneous stage II non-rapid eye movement sleep. This was compared with the SWI of the first 5 minutes of non-rapid eye movement sleep and the cumulative SWI of three 5-minute bins of sleep. Agreement between the three SWI methods were analyzed using several statistical tools and methods. RESULTS: Using an SWI of 50% as a diagnostic cutoff, 57% of records had a diagnosis of ESES based on the first 100 seconds of sleep. Fifty-four percent of records had a diagnosis of ESES based on the method of using the SWI of three bins. This resulted in a diagnostic accuracy of 92%, sensitivity of 96%, and specificity of 88%. Positive predictive values of children diagnosed with ESES using the first 100 seconds of sleep, compared with 3 combined bins, was determined to be 90% and a negative predictive value was determined to be 95%. CONCLUSIONS: This analysis confirmed the diagnostic accuracy of using the SWI of the first 100 seconds of sleep and the cumulative total of three 5-minute bins.

Prioritizing Hormone Therapy Over Vigabatrin as the First Treatment for Infantile Spasms: A Quality Improvement Initiative.

BACKGROUND AND OBJECTIVES: Infantile spasms (IS) are early childhood seizures with potentially devastating consequences. Standard therapies (adrenocorticotropic hormone [ACTH], high-dose prednisolone, and vigabatrin) are strongly recommended as the first treatment for IS. Although this recommendation comes without preference for one standard therapy over another, early remission rates are higher with hormone therapy (ACTH and high-dose prednisolone) when compared with vigabatrin. Using quality improvement (QI) methodology that included hormone therapy as the first treatment, we sought to increase the percentage of children with new-onset nontuberous sclerosis complex (TSC)-associated IS achieving 3-month electroclinical remission from a mean of 53.8% to ≥70%. METHODS: This was an observational consecutive sample cohort study at a single academic tertiary care hospital that compared a prospective intervention cohort (May 2019-January 2022, N = 57) with a retrospective baseline cohort (November 2015-April 2019, N = 67). Our initiative addressed key drivers such as the routine use of vigabatrin over hormone therapy as first treatment and the common initiation of a second treatment after 14 days for initial nonresponders. We included consecutive children without TSC presenting with new-onset IS diagnosed and treated between ages 2 and 24 months. We displayed our primary outcome and process measures as control charts in which the centerline is the quarterly (previous 3 months) mean based on statistical process control methodology. RESULTS: QI interventions that included the standardization of hormone therapy as the first treatment resulted in higher rates of 3-month remission, rising from 53.8% (baseline cohort) to 75.9% (intervention cohort). Process measure results included an increased rate of children receiving hormone therapy as first treatment (mean, 44.6%-100%) and a decreased number of days to both clinical follow-up after first treatment (mean, of 16.3-12.6 days) and starting a second treatment within 14 days for initial nonresponders (mean, 36.3-17.2 days). DISCUSSION: For children with IS, improved rates of 3-month electroclinical remission can be achieved with QI methodology. Implementation of similar QI initiatives at other centers may likewise improve local remission rates.

Delivering the Diagnosis: A Practical Approach to a Patient With a Functional Neurological Disorder.

Functional Neurological Disorders are a common and debilitating group of diseases that have been the subject of stigma and confusion across medical history. It is well-documented that prognosis and even possible resolution of symptoms are linked to successful delivery of the diagnosis by the clinician, and correct understanding of diagnosis by the patient. In the following article, we delineate the nature of these disorders and provide an overview to assist providers successfully navigate the communication of these diagnoses to patients and families.

Creating a New Set of Milestones for the Clinical Neurophysiology Fellowship.

INTRODUCTION: The Accreditation Council for Graduate Medical Education and the American Board of Psychiatry and Neurology first developed milestones for the clinical neurophysiology (CNP) fellowship in 2015. The milestones provide a comprehensive evaluation of the fellow's development based on six domains of competency. Here, we describe the development of a new set of milestones for CNP fellowship with level 1 as the incoming level, level 4 as the goal for graduation, and level 5 as the aspirational level that may not be achieved. METHODS: Committee members were nominated or volunteered to participate in the milestones update. Milestone development began with the creation of a shared mental model of the ideal skills and knowledge a graduating CNP fellow should attain. RESULTS: The CNP committee met virtually 7 times for a total of 14 meeting hours. Nine Patient Care and five Medical Knowledge milestones evolved from the seven Patient Care and six Medical Knowledge milestones that were in the first iteration. The committee incorporated 11 "Harmonized Milestones" into the revision and a supplemental guide was created. CONCLUSIONS: The revised Accreditation Council for Graduate Medical Education milestones for CNP fellowship contain important updates that program directors should review against their curricula to identify any gaps in learning. Program leadership should take note of two new Patient Care milestones for telemedicine and intraoperative monitoring. Clinical neurophysiology fellowships are not designed to provide level 4 competency across all milestones. The revised milestones should be viewed within the context of an individual program's goals.

Outcomes of children and adolescents 1 year after being seen in a multidisciplinary psychogenic nonepileptic seizures clinic.

OBJECTIVE: Psychogenic nonepileptic seizures (PNES) are paroxysmal events that may involve altered subjective experience and change in motor activity with a psychological cause. The aim of this work is to describe a population of pediatric patients with PNES and identify factors predictive of 12-month outcomes. METHODS: We conducted a prospective observational study of children and adolescents referred to the multidisciplinary Nationwide Children's Hospital PNES clinic between November 2017 and July 2019. Information was collected from patients during clinic visits and semistructured follow-up phone calls. Descriptive statistics and Fisher exact test were used for analysis. RESULTS: Of the 139 consecutive patients referred to the PNES clinic, 104 were seen in clinic and 63 answered 12-month follow-up calls. Patients with comorbid epilepsy had increased rates of participation at 12-month follow-up (p = .04). Complete remission was achieved by 32% (20/63) of patients at 12 months. Combined PNES remission and improvement was 89% (56/63) at 12 months. Patients and families who were linked with counseling at 1 month were more likely to achieve remission at 12 months (p = .005). Less than half (44%, 28/63) of patients reached at 12 months had their events documented on video-electroencephalogram (EEG) at diagnosis; however, those who did were not more likely to be accepting of the diagnosis at 12 months (p = 1.0), be linked with counseling at 12 months (p = .59), or be event-free at 12 months (p = .79). SIGNIFICANCE: Remission occurred in one third of patients by 12 months; however, improvement in events was seen in 89%. Connection to counseling by 1 month was associated with increased remission rates at 12 months. Capturing events on video-EEG was not associated with increased acceptance or event freedom at 12 months. Diagnosis should be followed by strong encouragement to connect with counseling quickly to achieve a goal of increasing 12-month PNES remission rates.

Improving time for administration of second-line antiseizure medications for children with generalized convulsive status epilepticus using quality improvement methodology.

OBJECTIVE: Status epilepticus is a life-threatening neurological emergency. However, delay in median time to administration of second-line antiseizure medication exists. The aim of this quality improvement initiative was to decrease the average delay before fosphenytoin is administered for pediatric patients with generalized convulsive status epilepticus from 30 min (baseline data collected in 2013) to 15 min (50% reduction) by December 2015 and sustain this for 1 year. METHODS: Our team conducted an analysis of baseline data for patients with continuous generalized convulsive status epilepticus who received fosphenytoin after receiving first-line benzodiazepine treatment. Using quality improvement methodology, areas for improvement were identified and specific interventions developed and implemented. A timeline of 15 min to initiate fosphenytoin administration after failure of first-line treatment was considered reasonable and achievable as a project aim. RESULTS: A total of 199 patients were included in the dataset for the project. The database included patients aged 1 month and older. Ninety-eight percent of patients were between 1 month and 19 years of age. The gender distribution was even, with 54% of patients being White or Caucasian, 30% African American or Black, and 16% classified as "other." From January 2014 through December 2019, the average time before initiating fosphenytoin administration after failure of benzodiazepine therapy, for patients with generalized convulsive status epilepticus, decreased from 30 min (SD = 45.7) to 11.4 min (SD = 8.2, p = .043), thus reducing time to administration by 62%. SIGNIFICANCE: Quality improvement methodology can be successfully applied to decrease administration time between first- and second-line antiseizure medications for status epilepticus.

A reliable interictal EEG grading scale for children with infantile spasms - The 2021 BASED score.

OBJECTIVE: To develop an improved interictal electroencephalogram (EEG) grading scale for children with infantile spasms founded on elements with adequate inter-rater reliability (IRR) to justify its further study for clinical and research purposes. METHODS: Three blinded reviewers assessed five-minute sleep epochs in 93 EEGs from 62 children (31 consecutive controls, 31 consecutive infantile spasms [pretreatment and posttreatment studies]) using a longitudinal bipolar montage. We determined the IRR of background amplitude, epileptiform discharges, >3 spike foci (including <50 % or >50 %), grouped multifocal spikes, paroxysmal voltage attenuations, and symmetry of sleep spindles. Data were used to finalize the 2021 BASED (Burden of AmplitudeS and Epileptiform Discharges) score. RESULTS: All elements included in the 2021 BASED score had moderate to near perfect IRR. Among controls, >200 µv background waves occurred commonly in the bilateral posterior temporal (T3-T5, T4-T6) and midline (Fz-Cz, Cz-Pz) regions. Excluding midline and occipital channels (which have normal high amplitude background waves), we designated abnormal high amplitude background waves as >200 µv for most channels, but >300 µv for T3-T5 and T4-T6. The IRR was moderate to near perfect for <50 % >3 spike foci, >50 % >3 spike foci, paroxysmal voltage attenuations, grouped multifocal spikes (GMFS), and symmetric sleep spindles. Paroxysmal voltage attenuations, GMFS, and >50 % >3 spike foci all significantly distinguished pretreatment from posttreatment studies whereas symmetric sleep spindles did not (as planned, the latter was not included in the 2021 BASED score). When the 2021 BASED score was applied to the 22 children with infantile spasms achieving clinical remission with treatment, 19 met criteria for electroclinical remission and three did not. SIGNIFICANCE: The 2021 BASED score includes elements with high levels of IRR and correlates well with the presence or absence of infantile spasms.

Improving Child Neurology Residents' Communication Skills Through Objective Structured Clinical Exams.

Introduction: Child neurology has unique challenges in communication due to complex disorders with a wide array of prognoses and treatments. Effective communication is teachable through deliberate practice and coaching. Objective structured clinical exams (OSCEs) are one method of providing practice while assessing communication skills. Yet OSCEs have not been reported for child neurology residents. Methods: We developed simulated clinical cases centering on communication skills for child neurology residents, all with challenging clinical scenarios (e.g., disclosure of a medical error, psychogenic nonepileptic events). Standardized patients (SPs) portrayed the parents of pediatric patients and, in some scenarios, an adolescent patient. We used a modified Gap-Kalamazoo Communication Skills Assessment Form to assess communication skills. The assessment was completed by faculty, SPs, and the resident, and we measured agreement among raters. Residents were surveyed afterward regarding their experience. Results: Nine cases were developed and piloted. A total of 27 unique resident-case encounters with 16 individual trainees occurred over three annual implementations. Scores on the 360-degree assessment of communication skills showed that residents overwhelmingly underassessed their skills compared to other rater groups. Among 18 responses on the post-OSCE survey, the majority (77%) found the experience useful to their education and felt that the feedback from the SPs was helpful (61%) and the case portrayals were realistic (89%). Discussion: We implemented simulated cases for assessment and formative feedback on communication skills for child neurology residents. We provide a blueprint to develop this educational activity in other programs.

Short-term outcomes in pediatric and adolescent patients with psychogenic nonepileptic events seen by telemedicine during the COVID-19 pandemic.

INTRODUCTION: Psychogenic nonepileptic events (PNEE) are a type of Functional Neurological Symptom Disorder that present with events that appear epileptic but are not associated with abnormal electrical activity in the brain. In response to the global COVID-19 pandemic, our PNEE clinic switched to a telemedicine format, and we present here our experience with providing care to children and adolescents with PNEE in this format. METHODS: The multidisciplinary clinic shifted to a telemedicine platform in March 2020 with the same joint provider format. Follow-up phone calls are completed at one and three months following the visit. Data are presented with descriptive statistics. Referral volume and outcomes data are compared to historical patients, including rates of diagnosis acceptance, linkage to counseling, and change in event frequency. RESULTS: Twenty-three patients were scheduled to be seen via telemedicine or hybrid visits from March through June, twenty completed their visits. Sixteen (70%) were reached for follow-up at one month. Of those reached, twelve (75%) accepted the diagnosis, eight (50%) were linked with counseling, and fourteen (88%) with improvement in event frequency. Of the sixteen reached at three months, eleven (69%) had accepted the diagnosis, ten (63%) were linked with counseling, and all but two reported improvement in event frequency. In comparison, the previously published results showed 3-month rates of 75% of patients accepting the diagnosis, 76% linked with counseling, and 75% with improvement in event frequency. CONCLUSIONS: Video telemedicine visits are a feasible and effective way to provide care for children and adolescents with PNEE. At 3 months, patients seen by telemedicine had similar acceptance rates, decreased connection to counseling, and increased rate of improvement in event frequency. This study suggests telemedicine may have some benefits over traditional clinic visits, such as improved show rates and access to clinic; so should be considered a reasonable alternative to in-person visits.

An Objective Structured Clinical Examination of Communication Skills for Child Neurology Residents.

BACKGROUND: The purpose of this study was to implement an objective structured clinical examination for child neurology trainees for formative feedback regarding communication skills. Effective communication skills are essential and teachable, but tools to formally assess them are limited. An objective structured clinical examination is one such tool, but these examinations have not been developed for child neurology residents. METHODS: We developed nine standardized scenarios that highlighted communication challenges commonly encountered in child neurology. Child neurology trainees participated in three objective structured clinical examination events with three scenarios each over three academic years. Standardized patients portrayed patients or their parents. Each trainee-standardized patient encounter was evaluated by an observing faculty member using a modified Gap-Kalamazoo Communication Skills Assessment Form, the standardized patient who provided direct feedback, and by the participating trainee. RESULTS: We refined the process of case writing, standardized patient training, and trainee evaluation throughout the three-year pilot. Results indicated rater agreement ranging from 32% to 56%. Trainees reported that the cases were challenging and reflective of real life and that the experience helped improve their communication skills. CONCLUSIONS: An objective structured clinical examination can provide a standardized setting for formative feedback regarding communication skills in child neurology residency programs. The communication challenges posed by common clinical scenarios involving critically ill children, children with undetermined prognosis, and the triad of parent, child, and physician can be realistically modeled in an objective structured clinical examination. We developed cases and a process that were valuable and that we plan to sustain for resident education related to communication skills.

Developing a New Set of ACGME Milestones for Child Neurology Residency.

BACKGROUND: The Educational Milestones developed by the Accreditation Council for Graduate Medical Education (ACGME) are a construct used to evaluate the development of core competencies during residency and fellowship training. The milestones were developed to create a framework for professional development during graduate medical education. The first iteration of milestones for the child neurology residency was implemented in 2015. In the years that followed, the ACGME received and reviewed feedback about the milestones and set out to revise them. METHODS: A committee was assembled to review the original milestones and develop a new set of milestones. The group was also encouraged to not only consider the child neurology residency graduate of today but also the graduate of tomorrow, taking into account growing fields such as genetics and technology. RESULTS: A diverse group of 12 individuals, including 10 child neurologists (all of whom were current or previous program directors or associate program directors), one child neurology resident, and one non-physician program coordinator, were recruited from programs of varying size across the country. CONCLUSIONS: The committee developed a revision to the child neurology milestones. All changes made were with a focus on how the milestones can be useful to trainees, program directors, and clinical competency committee members. Implementation and further feedback should help guide future revisions. These changes should help trainees, clinical competency committee members, and program directors find more meaning from their use.

The Impact of COVID-19 on Epilepsy Care: A Survey of the American Epilepsy Society Membership.

The COVID-19 pandemic has impacted the delivery of care to people with epilepsy (PWE) in multiple ways including limitations on in-person contact and restrictions on neurophysiological procedures. To better study the effect of the pandemic on PWE, members of the American Epilepsy Society were surveyed between April 30 and June 14, 2020. There were 366 initial responses (9% response rate) and 337 respondents remained for analysis after screening out noncompleters and those not directly involved with clinical care; the majority were physicians from the United States. About a third (30%) of respondents stated that they had patients with COVID-19 and reported no significant change in seizure frequency. Conversely, one-third of respondents reported new onset seizures in patients with COVID-19 who had no prior history of seizures. The majority of respondents felt that there were at least some barriers for PWE in receiving appropriate clinical care, neurophysiologic procedures, and elective surgery. Medication shortages were noted by approximately 30% of respondents, with no clear pattern in types of medication involved. Telehealth was overwhelmingly found to have value. Among the limitation of the survey was that it was administered at a single point in time in a rapidly changing pandemic. The survey showed that almost all respondents were affected by the pandemic in a variety of ways.

Training in Neurology: Rapid implementation of cross-institutional neurology resident education in the time of COVID-19.

In-person resident didactics are traditionally limited to the faculty within a single institution. Tele-education efforts have been implemented in neurology to various degrees historically, but the coronavirus disease 2019 (COVID-19) pandemic has necessitated a broad and immediate overhaul in neurology didactic training. To respond to the immediate need for resident didactics, we created a rapid onset, volunteer tele-education didactic series publicized on online forums to the American Academy of Neurology A.B. Baker Section via Synapse and the Women Neurologists Group via Facebook. We describe how, with just 1 week of lead time, we created an ongoing neurology lecture series featuring faculty from across the country lecturing on a diverse range of neurology topics. The series is ongoing and draws upwards of 120 residents per lecture. Tele-education offers unique benefits to enhance the education of all neurology trainees everywhere.