Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:While reductions in optical coherence tomography (OCT) pRNFL and ganglion cell-inner plexiform layer thicknesses have been shown to be associated with brain atrophy in adult-onset MS (AOMS) cohorts, the relationship between OCT and brain MRI measures is less established in pediatric-onset MS (POMS). Our aim was to examine the associations of OCT measures with volumetric MRI in a cohort of patients with POMS to determine whether OCT measures reflect CNS neurodegeneration in this patient population, as is seen in AOMS cohorts. METHODS:This was a cross-sectional study with retrospective ascertainment of patients with POMS evaluated at a single center with expertise in POMS and neuro-ophthalmology. As part of routine clinical care, patients with POMS are evaluated by a POMS expert and undergo volumetric brain MRI, including whole-brain (WB), subregional, and gray matter (GM) volume analyses. Patients with POMS are routinely referred to neuro-ophthalmology for evaluation that includes high-contrast visual acuity, color vision testing, and OCT. Generalized estimating equation (GEE) models, accounting for within-patient, intereye correlations (both eyes of each patient were included), MS disease duration, and disease-modifying therapy efficacy, were used to determine the relationship between visual pathway structure and function and volumetric MRI measures. RESULTS:= 0.015, respectively). DISCUSSION/CONCLUSIONS:Our results demonstrate that changes in visual pathway structures are associated with reductions in overall brain volume and GM volumes, as well as greater lesion and black hole burden. Collectively, our results emphasize the importance of visual assessment in POMS and suggest that OCT reflects overall CNS neurodegeneration in this cohort.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Pediatric multiple sclerosis (MS) affects children and adolescents at an important time for neurologic and cognitive development. Although cognitive impairment has been described, few longitudinal studies of cognitive functioning in pediatric MS with matched controls are available. Here, we report the 2-year follow-up cognitive results of a cohort of participants with MS and healthy controls (HCs) recruited from multiple regions of the United States. METHODS:Three cohorts-participants with pediatric MS, age-matched pediatric HC, and adults with early-onset MS-were recruited across 7 sites through the United States Network of Pediatric MS Centers. Two cognitive batteries, Cogstate Brief Battery (CBB) and Brief International Cognition Assessment for MS (BICAMS), were administered at baseline and follow-up. The primary outcome was the change in CBB composite z-score compared between groups. Change in BICAMS composite z-score was also compared, as were change in z-scores of individual measures. Reliable change indices (RCIs) were calculated to determine meaningful change over time. RESULTS:= 0.022. DISCUSSION/CONCLUSIONS:Most individuals with pediatric MS early in their disease showed stable cognitive function over a 2-year period and had longitudinal changes that were largely similar to pediatric controls. A subset of participants with pediatric MS declined in cognitive processing speed relative to pediatric controls.

A 65-year-old woman presented with 3 months of progressive hand weakness, initially with distal-predominant symptoms. EMG was notable for diminished amplitudes in bilateral radial nerves without evidence of conduction block and with normal sensory nerve action potentials. Anti-acetylcholine receptor and antistriated muscle antibodies were positive, but subsequent EMG did not reveal abnormalities on repetitive nerve stimulation. Muscle biopsy was performed, revealing extensive inflammatory infiltrates with significant associated fibrosis. This case discusses the approach to localization within the motor pathway and the use of serologic studies, imaging, and electrodiagnostic testing to supplement history and examination.

State death determination acts require brain death/death by neurologic criteria (BD/DNC) determination to be in accordance with "accepted medical standards." The American Academy of Neurology/American Academy of Pediatrics/Child Neurology Society/Society of Critical Care Medicine published updated BD/DNC guidelines in October 2023 to replace earlier iterations of separate guidelines for BD/DNC determination in adults and pediatric persons. There are no other medical society guidelines for BD/DNC determination in the United States. As of early 2024, only Nevada, New Jersey, and New York identified the 2023 BD/DNC guidelines as the "accepted medical standards." Delineation of the "accepted medical standards" in state death determination acts or by state health organizations (SHOs) could help facilitate consistency and accuracy in BD/DNC determination, prevent false-positive death determination, and promote public trust. SHOs are comprised of policy experts and medical professionals responsible for addressing medical, ethical, and legislative problems related to health. In April 2024, we began iteratively contacting state health departments, medical boards, medical societies, and hospital associations requesting acknowledgment of the 2023 BD/DNC guidelines as the "accepted medical standards." From April 2024 to March 2025, we contacted 168 SHOs and received responses from 108 of 168 (64%, median: 2 per state, range: 0-4 per state). The effects of this advocacy effort continue to evolve, but as of March 31, 2025, 4 states had an SHO that acknowledged the 2023 BD/DNC guidelines as the "accepted medical standards" (Delaware, Louisiana, Oklahoma, and Vermont), 9 states had an SHO discussing acknowledgment, 4 states had an SHO that would consider a resolution submitted by a member about acknowledgment, and 30 states showed no SHO interest in acknowledgment. The Medical Society of Delaware and the Oklahoma State Medical Association formalized acknowledgment in a resolution while the Louisiana Department of Health and the Vermont Department of Health and Board of Medical Practice disseminated communication about acknowledgment. This effort also prompted discussion about the "accepted medical standards" by the American Medical Association. Ongoing advocacy may expand recognition of the 2023 BD/DNC guidelines as the "accepted medical standards" for BD/DNC determination. Communication to hospitals indicating that adherence to these guidelines is crucial and regulations to ensure adherence are essential.

BACKGROUND:Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described inflammatory disorder of the central nervous system. Unlike other demyelinating disorders of the central nervous system, the impact of pregnancy and the postpartum period on MOGAD disease activity remains uncertain. A better understanding of pregnancy-related relapse risk in MOGAD is essential to inform management. METHODS:We conducted a retrospective chart review of all patients followed in two large referral centers in the Northeastern United States with a confirmed diagnosis of MOGAD and at least one post-MOGAD onset pregnancy carried to the third trimester. Demographic, neurological, obstetric, and treatment-related data were extracted from electronic medical records, centered around the 12-month pre-pregnancy, pregnancy, and 12-month post-pregnancy periods, for each of which the annualized relapse rates (ARRs) were calculated. RESULTS:We identified 15 women diagnosed with MOGAD who had 22 post-MOGAD onset pregnancies. No relapses were observed during any of the 22 pregnancies, but 2 relapses were observed in the postpartum period in a single patient with a steroid-dependent relapsing course. The mean ARR was 0.26 ± 0.86 during the 12-month pre-pregnancy period, 0 during pregnancy, and 0.09 ± 0.42 in the 12-month postpartum period. Twelve of 22 pregnancies (55 %) were exposed to disease-modifying therapy (DMT) at conception, and 59 % were continued on DMT into the postpartum period. Obstetric complications were recorded in 5 of 22 pregnancies (22 %). CONCLUSIONS:The two main findings of our retrospective study are: 1) the relapse risk is very low during pregnancy in women with MOGAD, and 2) postpartum relapse risk does not appear to be elevated in patients with a low pre-pregnancy relapse rate. Approximately half of the women in our series were receiving disease-modifying therapies during the postpartum period, which may have decreased relapse rates. Larger prospective studies are needed to validate our observations.

BACKGROUND:Primary brain calcifications are observed in several inherited diseases due to different pathogenic mechanisms, including the disruption of the neurovascular unit, mitochondrial dysfunction, and impaired nucleic acid metabolism. OBJECTIVE:The aim of the study was to identify a novel genetic cause of brain calcifications in genetically unresolved cases. METHODS:Exome sequencing data from two unrelated Pakistani patients with generalized dystonia and primary brain calcifications were analyzed. The best candidate gene (ie, RRP12) was then investigated in two large cohorts of patients with brain calcifications from France (n = 111) and China (n = 543). RRP12 loss-of-function phenotype was explored through Western blot and immunocytofluorescence studies on patient-derived fibroblasts and in a knockdown zebrafish model. RESULTS:A combined approach of exome sequencing and homozygosity mapping allowed the prioritization of a rare homozygous variant in RRP12 (c.1558C>T, p.R520C) in two apparently unrelated Pakistani patients from consanguineous families, presenting with infantile-onset generalized dystonia, spasticity, and widespread brain calcifications. Screening of two large cohorts of patients with unresolved brain calcifications revealed two affected French siblings and one unrelated Chinese individual, each carrying rare, biallelic, missense variants in the RRP12 gene (c.1429G>A, p.E477K and c.2634T>G, p.F878L, respectively). Molecular studies revealed a significant reduction in RRP12 protein and abnormal nucleolar morphology in patient'derived fibroblasts. Consistent with its essential role in RNA metabolism, rrp12 knockdown in zebrafish caused severe developmental delay, crimping, and early lethality. CONCLUSIONS:RRP12 is a novel candidate gene for autosomal recessive brain calcifications, possibly associated with a wide clinical spectrum ranging from early-onset severe forms to adult-onset paucisymptomatic presentations. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The CSF-BAM assay, developed by Pearlman, Wang, and colleagues, integrates the detection of somatic mutations, genome aneuploidy, and B- and T-cell receptor clonality from a single cerebrospinal fluid DNA library to increase the sensitivity of cerebrospinal fluid to diagnosis and track brain tumors. See related article by Pearlman et al., p. 2002.

BACKGROUND:Sudden unexpected death in epilepsy (SUDEP) is the most common category of epilepsy-related mortality. Centrally mediated respiratory dysfunction has been observed to lead to death in the majority of cases of SUDEP. SUDEP also mainly occurs during nighttime sleep. This study seeks to identify sleep EEG and sleep-related respiratory biomarkers of SUDEP risk. METHODS:In this case-control study, we compared demographic, clinical, EEG, and respiratory data from people with epilepsy who later died of SUDEP (the SUDEP group) with data from age and sex-matched living people with epilepsy, classified as high risk of SUDEP (with ≥1 generalised tonic-clonic seizure [GTCS] per year), low risk of SUDEP (no history of GTCS), and non-epilepsy controls. These data were prospectively collected as part of a multicentre National Institutes of Health study. We analysed sleep macroarchitecture and microarchitecture features and measured sleep homoeostasis by calculating overnight change in slow wave activity (SWA; 0·5-4·0 Hz) in non-rapid eye movement (NREM) sleep during seizure-free nights using linear regression models. We also analysed sleep respiratory metrics, including inter-breath interval variability. We used receiver operating characteristic analysis to assess the individual discriminative performance of demographic, clinical, sleep EEG, and sleep-related respiratory features to predict the risk of SUDEP. FINDINGS/RESULTS:Between Sept 1, 2011, and Oct 15, 2022, 41 participants who later died of SUDEP and 123 matched controls (41 people living with epilepsy at hight risk of SUDEP, 41 people living with epilepsy at low-risk of SUDEP, and 41 non-epilepsy controls) were enrolled. The SUDEP group showed an abnormal lack of overnight decline and an increase in the slope of SWA power compared with the other groups (SUDEP group mean 0·005 standardised error of the mean [SEM] 0·003; high-SUDEP risk group -0·005, 0·002; low-SUDEP risk group -0·003, 0·002; non-epilepsy controls -0·007, 0·003; p=0·017). The overnight increase in the SWA slope was more pronounced in males compared with females (males mean 0·012, SEM 0·001; females 0·001, 0·002; p=0·005). The variability of the inter-breath interval was significantly higher in the SUDEP (coefficient of variation mean 0·15, SD 0·09; SD mean 0·54 s SD 0·35 s) and high-SUDEP risk groups (0·11, 0·03; 0·46 s, 0·19 s) compared with low-SUDEP risk group (0·08, 0·03; 0·30 s, 0·14 s) and non-epilepsy controls (0·08, 0·02; 0·31 s, 0·11 s; p<0·0001). The coefficient of variation of inter-breath interval had the greatest predictive power of SUDEP risk (between-group point estimate difference 0·30, AUC 0·80; 95% CI 0·70-0·90; p<0·0001). INTERPRETATION/CONCLUSIONS:This study identifies impaired sleep homoeostasis in the form of altered SWA progression during NREM sleep overnight in people with epilepsy who later died of SUDEP, and an increase in respiratory variability during NREM sleep in people with epilepsy who later died of SUDEP and in people with epilepsy at high risk of SUDEP. Multiday polysomnography studies are needed to validate sleep homoeostasis and respiratory variability during sleep as potential biomarkers of SUDEP risk. Further studies are required to explore possible sleep interventions that could mitigate SUDEP risk. FUNDING/BACKGROUND:National Institutes of Health-National Institute of Neurological Disorders and Stroke.