Child Neurology and Neurodevelopmental Disabilities Program Directors' Opinions on Preference Signaling in the 2023-2024 National Resident Matching Program Match: A Survey.

BACKGROUND: Changes in residency recruitment have significantly altered how programs and applicants evaluate each other including virtual interviews, discontinuation of the United States Medical Licensing Exam Step 2 Clinical Skills exam, and transition of United States Medical Licensing Exam Step 1 to pass-fail scoring. To improve program-applicant fit, the Electronic Residency Application Service introduced supplemental application features including geographic preference, program signaling, and the opportunity to highlight impactful and meaningful experiences. We sought to evaluate child neurology (CN) and neurodevelopmental disabilities (NDD) program director's (PD) opinions regarding these changes. METHODS: A 10-question anonymous survey was sent to CN (n=75) and NDD (n=8) PDs. The questions centered on PDs' opinions regarding components of the supplemental application, having a standard application review period and in-person recruitment activities. Answer choices to the questions were all close-ended. Respondents could select questions to complete. RESULTS: Thirty-eight CN residency PDs (49%) and 4 NDD residency PDs (50%) responded to the survey. Among CN PDs, there was strong support for use of the supplemental application questions and for the use of 3 program signals per applicant. Most PDs supported a standardized application review period prior to programs sending interview offers; however, there was no consensus on the appropriate length of time. Nearly half agreed with virtual-only interviews, and 62% agreed with the option of in-person second-look visits. CONCLUSIONS: CN PDs generally support many of the recent or proposed changes to residency recruitment. The impact of these changes on recruitment will be a topic of future investigation.

Evidence and Recommendation for Guanidinoacetate Methyltransferase Deficiency Newborn Screening.

Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessive disorder of creatine biosynthesis due to pathogenic variants in the GAMT gene that lead to cerebral creatine deficiency and neurotoxic levels of guanidinoacetate. Untreated, GAMT deficiency is associated with hypotonia, significant intellectual disability, limited speech development, recurrent seizures, behavior problems, and involuntary movements. The birth prevalence of GAMT deficiency is likely between 0.5 and 2 per million live births. On the basis of small case series and sibling data, presymptomatic treatment with oral supplements of creatine, ornithine, and sodium benzoate, and a protein-restricted diet to reduce arginine intake, appear to substantially improve health and developmental outcomes. Without newborn screening, diagnosis typically happens after the development of significant impairment, when treatment has limited utility. GAMT deficiency newborn screening can be incorporated into the tandem-mass spectrometry screening that is already routinely used for newborn screening, with about 1 per 100 000 newborns screening positive. After a positive screen, diagnosis is established by finding an elevated guanidinoacetate concentration and low creatine concentration in the blood. Although GAMT deficiency is significantly more rare than other conditions included in newborn screening, the feasibility of screening, the low number of positive results, the relative ease of diagnosis, and the expected benefit of presymptomatic dietary therapy led to a recommendation from the Advisory Committee on Heritable Disorders in Newborns and Children to the Secretary of Health and Human Services that GAMT deficiency be added to the Recommended Uniform Screening Panel. This recommendation was accepted in January 2023.

Institutional Evaluation of Fetal Neurology Consults and Postnatal Outcomes: A 10-Year Retrospective Cohort Review.

Background and Objectives: An increasing number of centers are offering fetal neurology consultation services; however, there is limited information available in overall institutional experiences. Data are lacking on the fetal characteristics, pregnancy course, and the influence of fetal consultation on perinatal outcomes. The aim of this study is to provide insight on the institutional fetal neurology consult process and areas of strengths and weaknesses. Methods: We performed a retrospective electronic chart review of fetal consults from April 2, 2009, to August 8, 2019, at Nationwide Children's Hospital. The objectives were to summarize clinical characteristics, agreement of prenatal and postnatal diagnoses based on best available imaging, and postnatal outcomes. Results: Of the 174 maternal-fetal neurology consults placed, 130 qualified for inclusion based on data available for review. Of the 131 anticipated fetuses, 5 experienced fetal demise, 7 underwent elective termination, and 10 died in the postnatal period. The majority were admitted to the neonatal intensive care unit; 34 (31%) required supportive intervention for feeding, breathing, or hydrocephalus, and 10 (8%) experienced seizures during their neonatal intensive care unit (NICU) stay. Imaging results from 113 babies who had prenatal and postnatal imaging of the brain were analyzed based on the primary diagnosis. The most common malformations were as follows (prenatal % vs postnatal %): midline anomalies (37% vs 29%), posterior fossa abnormalities (26% vs 18%), and ventriculomegaly (14% vs 8%). Additional disorders of neuronal migration were not seen on fetal imaging but were present in 9% of the postnatal studies. Analysis of agreement between prenatal and postnatal diagnostic imaging for the 95 babies who had MRIs at both time points found moderate concordance (Cohen kappa: 0.62, 95% CI 0.5-0.73; percent agreement: 69%, 95% CI 60%-78%). Consult recommendations for neonatal blood tests affected postnatal care in 64 of 73 cases in which the infant survived and data were available. Discussion: Establishing a multidisciplinary fetal clinic can provide timely counseling and create rapport with families to have continuity of care for birth planning and postnatal management. Prognosis based on radiographic prenatal diagnosis requires caution as some neonatal outcomes may vary considerably.

Molecular characterization of an intronic RNASEH2B variant in a patient with Aicardi-Goutières syndrome.

Aicardi-Goutières syndrome (AGS) is a progressive multisystem disorder including encephalopathy with significant impacts on intellectual and physical abilities. An early diagnosis is becoming ever more crucial, as targeted therapies are emerging. A deep understanding of the molecular heterogeneity of AGS can help guide the early diagnosis and clinical management of patients, and inform recurrence risks. Here, we detail the diagnostic odyssey of a patient with an early presentation of AGS. Exome and genome sequencing detected an intronic RNASEH2B variant missed in a conventional leukodystrophy NGS gene panel. RNA studies demonstrated that a c.322-17 A > G variant affected splicing and caused 16-nucleotide intronic retention in the RNASEH2B transcript, introducing an out-of-frame early termination codon. RNASEH2B expression in the patient's blood was reduced when compared to controls. Our study highlights the pathogenicity of this intronic variant and the importance of its inclusion in variant assessment.

Evidence and recommendation for mucopolysaccharidosis type II newborn screening in the United States.

Mucopolysaccharidosis type II (MPS II), also known as Hunter syndrome, is an X-linked condition caused by pathogenic variants in the iduronate-2-sulfatase gene. The resulting reduced activity of the enzyme iduronate-2-sulfatase leads to accumulation of glycosaminoglycans that can progressively affect multiple organ systems and impair neurologic development. In 2006, the US Food and Drug Administration approved idursulfase for intravenous enzyme replacement therapy for MPS II. After the data suggesting that early treatment is beneficial became available, 2 states, Illinois and Missouri, implemented MPS II newborn screening. Following a recommendation of the Advisory Committee on Heritable Disorders in Newborns and Children in February 2022, in August 2022, the US Secretary of Health and Human Services added MPS II to the Recommended Uniform Screening Panel, a list of conditions recommended for newborn screening. MPS II was added to the Recommended Uniform Screening Panel after a systematic evidence review reported the accuracy of screening, the benefit of presymptomatic treatment compared with usual case detection, and the feasibility of implementing MPS II newborn screening. This manuscript summarizes the findings of the evidence review that informed the Advisory Committee's decision.

The COVID-19 Pandemic and Pregnancy: Impact on Mothers and Newborns.

The severe acute respiratory syndrome coronavirus 2 pandemic has markedly, and likely permanently, changed health care. This includes changing the obstetric and perinatal care of mothers and infants, and by extension, the care of their families. Infection during pregnancy is associated with an increased risk for severe coronavirus disease 2019 illness and related complications that can significantly impact maternal health and the health of the neonate. Viral transmission from mother to fetus is possible, but rare during pregnancy, and current health care policies focusing on maternal masking, and hand washing allows infected mothers to safely care for neonates (including nursing or feeding with expressed breast milk). The newly developed vaccines have been shown to be safe and effective for pregnant and breast-feeding mothers, with measurable antibody levels in cord blood and breast milk potentially providing a level of passive immunity to neonates. While studies looking at short-term outcomes for neonates have been reassuring, it is critical that we continue to work to understand and improve the care of pregnant woman and newborns with coronavirus disease 2019 to optimize long term outcomes. Although the knowledge base continues to evolve, the available evidence influencing the care of pregnant women and their infants is summarized in this focused review.

A Neurologist's Practical Guide to Conducting a Fetal Consultation.

Fetal and neonatal neurology is increasingly recognized as a subspecialty within child neurology and fellowship training programs are emerging. Most child neurologists have not received formal training in the interpretation of fetal data and the practice of fetal neurology consultation. However, they can be valuable members of the fetal care team and bring important perspective to the diagnosis of fetal neurologic conditions. With a systematic approach and a planned format for counseling, child neurologists without formal training in fetal consultations can apply their postnatal neurology expertise to the prenatal neurology patient. In this article we offer a brief practical guide to assist child neurologists in their approach to and practice of fetal neurology consultation.

Benefits of newborn screening and hematopoietic cell transplant in infantile Krabbe disease.

Infantile Krabbe disease (IKD) can be treated with hematopoietic cell transplantation (HCT) if done during the first weeks of life before symptoms develop. To facilitate this, newborn screening (NBS) has been instituted in 8 US states. An application to add IKD to the recommended NBS panel is currently under review. In this report, the outcomes of newborns with IKD diagnosed through NBS and treated with HCT are presented. The unique challenges associated with NBS for this disease are discussed, including opportunities for earlier diagnosis and streamlining treatment referrals. This is a retrospective review of six infants with IKD detected by NBS who were referred for HCT. The timing from diagnosis to HCT was examined, and both HCT and neurodevelopmental outcomes are described. Neurologic testing before HCT revealed evidence of active IKD in all infants. All underwent HCT between 24 and 40 days of age, were successfully engrafted, and are alive 30 to 58 months later (median, 47.5 months). All are gaining developmental milestones albeit at a slower pace than unaffected age-matched peers. Gross motor function is most notably affected. NBS for these patients enabled early access to HCT, the only currently available treatment of infants with IKD. All children are alive and have derived developmental and neurologic benefits from timely HCT. Long-term follow up is ongoing. Optimization of HCT and further development of emerging therapies, all of which must be delivered early in life, are expected to further improve outcomes of infants with IKD.

Virtual Residency Interview Experience: The Child Neurology Residency Program Perspective.

BACKGROUND: The COVID-19 pandemic presented many challenges for graduate medical education, including the need to quickly implement virtual residency interviews. We investigated how different programs approached these challenges to determine best practices. METHODS: Surveys to solicit perspectives of program directors, program coordinators, and chief residents regarding virtual interviews were designed through an iterative process by two child neurology residency program directors. Surveys were distributed by email in May 2021. Results were summarized using descriptive statistics. RESULTS: Responses were received from 35 program directors and 34 program coordinators from 76 programs contacted. Compared with the 2019-2020 recruitment season, in 2020-2021, 14 of 35 programs received >10% more applications and most programs interviewed ≥12 applicants per position. Interview days were typically five to six hours long and were often coordinated with pediatrics interviews. Most programs (13/15) utilized virtual social events with residents, but these often did not allow residents to provide quality feedback about applicants. Program directors could adequately assess most applicant qualities but felt that virtual interviews limited their ability to assess applicants' interpersonal communication skills and to showcase special features of their programs. Most respondents felt that a combination of virtual and in-person interviewing should be utilized in the future. CONCLUSIONS: Residency program directors perceived some negative impacts of virtual interviewing on their recruitment efforts but in general felt that virtual interviews adequately replaced in-person interviews for assessing applicants. Most programs felt that virtual interviewing should be utilized in the future.

Recent Advancements in the Diagnosis and Treatment of Leukodystrophies.

Leukodystrophies and genetic leukoencephalopathies comprise a growing group of inherited white matter disorders. Diagnostic rates have improved with increased utilization of next generation sequencing. As treatment options continue to advance for leukodystrophies, so will candidacy for inclusion in the United States' newborn Recommended Universal Screening Panel as was achieved for X-linked adrenoleukodystrophy. Stem cell therapies have become standard of care for selected leukodystrophies. However, transplantation-related risks remain high and outcomes are not fully satisfactory. Transduction of autologous hematopoietic stem cells with lentiviral vectors, referred to as ex vivo gene therapy, circumvents some, but not all, of the risks of traditional transplantation and has recently been demonstrated to be safe and efficective in clinical studies of X-linked adrenoleukodystrophy and metachromatic leukodystrophy. Gene therapy, through direct infusion of adeno-associated virus vectors, has emerged as a safer alternative for many monogenetic pediatric neurological disorders. Numerous preclinical studies have shown safety and efficacy of adeno-associated virus gene therapy in leukodystrophies allowing expanded access treatment for Canavan disease prior to initiation of a clinical trial. For inherited white matter disorders resulting from overexpression of a protein, such as Pelizaeus-Merzbacher disease, emerging RNA therapies have shown success in preclinical studies and promise for rapid translation to the clinic. Lastly, small molecule and protein therapies remain a long-term treatment option for a number of leukodystrophies, including intrathecal enzyme replacement therapy for metachromatic leukodystrophy. Herein we review recent advances in diagnosis and treatment of inherited white matter disorders.

Consensus recommendations for the classification and long-term follow up of infants who screen positive for Krabbe Disease.

OBJECTIVE: To provide updated evidence and consensus-based recommendations for the classification of individuals who screen positive for Krabbe Disease (KD) and recommendations for long-term follow-up for those who are at risk for late onset Krabbe Disease (LOKD). METHODS: KD experts (KD NBS Council) met between July 2017 and June 2020 to develop consensus-based classification and follow-up recommendations. The resulting newly proposed recommendations were assessed in a historical cohort of 47 newborns from New York State who were originally classified at moderate or high risk for LOKD. RESULTS: Infants identified by newborn screening with possible KD should enter one of three clinical follow-up pathways (Early infantile KD, at-risk for LOKD, or unaffected), based on galactocerebrosidase (GALC) activity, psychosine concentration, and GALC genotype. Patients considered at-risk for LOKD based on low GALC activity and an intermediate psychosine concentration are further split into a high-risk or low-risk follow-up pathway based on genotype. Review of the historical New York State cohort found that the updated follow-up recommendations would reduce follow up testing by 88%. CONCLUSION: The KD NBS Council has presented updated consensus recommendations for efficient and effective classification and follow-up of NBS positive patients with a focus on long-term follow-up of those at-risk for LOKD.

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.

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.

The critical role of psychosine in screening, diagnosis, and monitoring of Krabbe disease.

PURPOSE: Newborn screening (NBS) for Krabbe disease (KD) is performed by measurement of galactocerebrosidase (GALC) activity as the primary test. This revealed that GALC activity has poor specificity for KD. Psychosine (PSY) was proposed as a disease marker useful to reduce the false positive rate for NBS and for disease monitoring. We report a highly sensitive PSY assay that allows identification of KD patients with minimal PSY elevations. METHODS: PSY was extracted from dried blood spots or erythrocytes with methanol containing d5-PSY as internal standard, and measured by liquid chromatography-tandem mass spectrometry. RESULTS: Analysis of PSY in samples from controls (N = 209), GALC pseudodeficiency carriers (N = 55), GALC pathogenic variant carriers (N = 27), patients with infantile KD (N = 26), and patients with late-onset KD (N = 11) allowed for the development of an effective laboratory screening and diagnostic algorithm. Additional longitudinal measurements were used to track therapeutic efficacy of hematopoietic stem cell transplantion (HSCT). CONCLUSION: This study supports PSY quantitation as a critical component of NBS for KD. It helps to differentiate infantile from later onset KD variants, as well as from GALC variant and pseudodeficiency carriers. Additionally, this study provides further data that PSY measurement can be useful to monitor KD progression before and after treatment.

Status Epilepticus in the Neonate: Updates in Treatment Strategies.

PURPOSE OF REVIEW: The purpose of this review is to report recent advances in treatment of neonatal seizures, with a specific focus on new literature since a 2013 systematic review performed by this author (Slaughter) and others. There is a paucity of data with regard to well-defined status epilepticus (SE) in neonates, so treatment of recurrent seizures was also included in this inquiry. We aimed to summarize the efficacy and safety profiles of current therapeutic options as well as describe trends in medication selection in the neonatal intensive care unit (NICU) setting. RECENT FINDINGS: Phenobarbital remains first-line therapy in practice, though there is increasing evidence of its neurotoxicity and long-term sequelae. Bumetanide failed an open-label trial for efficacy, demonstrated an increased risk for hearing loss, and has since fallen out of favor for use in this population. New agents, such as levetiracetam and topiramate, still have very limited data but appear to be as efficacious as older medications, with more favorable side effect profiles. There are limited high-level evidence-based data to guide treatment of neonatal seizures. Emerging research focusing on drug mechanisms and safety profiles may provide additional information to guide decisions; however, further research is needed.

A Boy With Red Ears.

Vague complaints of ear pain can bring frustration in the neurology office as the differential is broad and often nonneurologic. Herein, we present a case of red ear syndrome, a treatable migraine variant that can cause significant distress and lead to delayed treatment if not considered as a diagnostic possibility.

Neurologic Consequences of Preterm Birth.

PURPOSE OF REVIEW: Preterm birth is the leading cause of death worldwide in children < 5 years of age; however, technology and advances in medical knowledge are increasing the survival of children born even at the fringes of viability. With increased survival comes increased risk of long-term neurologic impairments. This paper aims to review recent findings related to changes in brain development associated with prematurity and its impact on neurodevelopmental disabilities. RECENT FINDINGS: Advanced imaging techniques, longitudinal follow-up of individuals born extremely preterm into adulthood and improved understanding of risk factors associated with neurologic impairment contribute to recent discoveries. Sensory impairments are often associated with later cognitive and social impairments and therefore represent targets for therapy. All aspects of neurologic development can be affected by preterm delivery. Future research is needed to further elucidate targets for prenatal and postnatal interventions for neuroprotection and to improve outcomes of prematurity.

Hypomelanosis of Ito.

Hypomelanosis of Ito, initially referred to as incontinentia pigmenti achromians, is a rare neurocutaneous disorder. Hypopigmented lesions following the lines of Blaschko are usually the presenting feature. Multiple organ systems can be involved including brain, musculoskeletal, cardiovascular, eyes, kidneys, and teeth. The neurologic complications can include seizures, hemimegalencephaly, developmental delay and abnormalities in tone. Genetic mosaicism is the most likely explanation for its inheritance. It must be distinguished from incontinentia pigmenti because at early stages, skin lesions can appear similar between the two conditions. Consensus recommendations for screening of associated extracutaneous conditions do not exist and management is symptomatic, but regular evaluation of somatic growth, neurodevelopment, endocrine status, eyes, and teeth should occur. Initial screening of renal function has also been recommended. Awareness of this disorder will allow for diagnosis, genetic counseling and appropriate screening.