Faculty Bibliography

INTRODUCTION/BACKGROUND:Neurologic complications, including seizures, are common in pediatric patients undergoing heart surgery, especially those requiring postoperative extracorporeal membrane oxygenation (ECMO), requiring prompt, vigilant postoperative monitoring. Prolonged EEG monitoring in critically ill children presents a risk of scalp/pressure injuries. The skin's sensitivity to microcirculatory changes can also provide valuable insights into the patient's overall tissue perfusion, making it a critical component in the management of these vulnerable patients. METHODS:We initiated a quality improvement (QI) project to assess and reduce scalp injuries related to prolonged EEG monitoring in critically ill neonates and infants. The project involved reviewing baseline data, which included 2336 inpatient video EEGs performed from January 2022 to December 2024, and implementing interventions to improve skin safety during electrode placement, while incorporating best practices from ACNS and ASET guidelines. RESULTS:Five critically ill infants developed deep tissue injuries (DTIs) related to EEG electrodes, with most injuries occurring over the occipital region. The frequency of scalp injuries decreased from 0.30% in 2022 to 0% in 2024 after implementing the QI protocol, and was observed in conditions with known hypoperfusion. DISCUSSION/CONCLUSIONS:Electrode-related skin injuries are a common complication of prolonged EEG monitoring, particularly in critically ill pediatric patients. Our findings suggest that adherence to expert guidelines and tailored skin care protocols focused on skin preparation, electrode application, and monitoring parameters can reduce the risk of electrode-related skin injuries. Further research is needed to refine safety protocols and address the unique skin care challenges faced by this high-risk population.

IMPORTANCE/UNASSIGNED:Leptomeningeal metastasis (LM) is associated with limited survival and few treatment options. Photon involved-field radiotherapy (IFRT) is the most common radiotherapy treatment for patients with LM from solid tumors. OBJECTIVE/UNASSIGNED:To assess whether proton craniospinal irradiation (pCSI) would result in superior central nervous system progression-free survival (CNS-PFS) compared with IFRT. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:A randomized, phase 2 trial of pCSI vs IFRT was conducted between April 16, 2020, and October 11, 2021, and included patients with non-small cell lung cancer and breast cancer with LM. Patients with other solid tumors were also enrolled in an exploratory pCSI cohort. INTERVENTION/UNASSIGNED:For the randomized groups, after stratifying by histology and systemic disease status, patients were assigned (2:1) to pCSI or IFRT. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary end point was CNS-PFS. Secondary end points included overall survival (OS). RESULTS/UNASSIGNED:Of 98 total patients, 72 individuals (73.5%) were female, and the median (IQR) age was 59 (50-65) years. A total of 42 and 21 patients were randomly assigned to pCSI and IFRT, respectively. At planned interim analysis, a significant benefit in CNS-PFS was observed with pCSI compared with IFRT, leading to the early discontinuation of the trial. In this final analysis, a significant benefit was continually observed in CNS-PFS with pCSI (median, 8.2 months; 95% CI, 6.6-15.3) vs IFRT (median, 2.3 months; 95% CI, 1.2-4.0; P < .001). A statistically significant and clinically meaningful OS benefit with pCSI (median, 11.3 months; 95% CI, 7.5-18.3) vs IFRT (median, 4.9 months; 95% CI, 3.9-15.0; P = .04) was also observed. For the exploratory pCSI cohort (n = 35), the median CNS-PFS was 5.8 months (95% CI, 4.4-9.1) and OS was 7.0 months (95% CI, 5.4-10.6). CONCLUSIONS AND RELEVANCE/UNASSIGNED:This randomized clinical trial that assessed the optimal radiotherapy treatment for LM found improved CNS-PFS and OS with pCSI compared with IFRT. The results suggest that pCSI should be considered when available. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT04343573.

Collagen VI-related dystrophies (COL6-RDs) manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterised by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognised later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and muscle pathology features highly suggestive of COL6-RD, some patients had remained without an identified causative variant in COL6A1, COL6A2 or COL6A3. With combined muscle RNA-sequencing and whole-genome sequencing we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterised an international cohort of forty-four patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen 6 genes. Patients manifest a consistently severe phenotype characterised by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD, except for one patient with somatic mosaicism for this COL6A1 intron 11 variant who manifests a milder phenotype consistent with Bethlem muscular dystrophy. Partial amelioration of the disease phenotype in this individual provides a strong rationale for the development of our pseudoexon skipping therapy to successfully suppress the pseudoexon insertion, resulting in normal COL6A1 transcripts. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 variant.

IMPORTANCE/UNASSIGNED:Olfactory dysfunction is common after SARS-CoV-2 infection and has been associated with cognitive loss in other conditions. Formal testing is needed to characterize the presence, severity, and patterns of olfactory dysfunction. OBJECTIVE/UNASSIGNED:To characterize long-term olfactory dysfunction after SARS-CoV-2 infection. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This prospective cohort study included adults enrolled in the Researching COVID to Enhance Recovery (RECOVER)-Adult study. All those with and a random sample of those without self-reported change or loss in smell or taste were offered olfactory testing, performed at 83 sites in 35 US states and territories. Participants included 2956 enrollees with prior infection (1393 with and 1563 without self-reported change or loss) and 569 without prior infection (9 with and 560 without self-reported change or loss in taste) who underwent olfactory testing a mean (SD) of 671.6 (417.8) days after the index date. Data were collected from October 29, 2021, to June 6, 2025. EXPOSURE/UNASSIGNED:SARS-CoV-2 infection. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Olfactory function, as defined by age- and sex-standardized performance on the University of Pennsylvania Smell Identification Test (UPSIT), a well-validated test comprising 40 unique odors. RESULTS/UNASSIGNED:The study included 3525 participants with a mean (SD) age of 47.6 (15.2) years; of 3520 with data available, 2548 (72.4%) were female or intersex. Among 1393 infected participants with self-reported change or loss, 1111 (79.8%) had hyposmia on the UPSIT, including 321 (23.0%) with severe microsmia or anosmia. Among 1563 infected participants without self-reported change or loss, 1031 (66.0%) had hyposmia, including 128 (8.2%) with severe microsmia or anosmia. Participants with prior infection and self-reported change or loss scored at the 16th age- and sex-standardized UPSIT percentile, compared with the 23rd and 28th percentiles for those without self-reported change or loss with and without prior known infection, respectively. Younger women had scores corresponding to lower mean age- and sex-standardized percentiles. Among participants who self-reported change or loss in smell, those with abnormal UPSIT scores more often reported cognitive problems (742 of 1111 [66.8%]) than those with normal UPSIT scores (179 of 282 [63.5%]). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this cohort study of RECOVER-Adult participants, self-reported change or loss in smell or taste was an accurate signal of verified hyposmia, but a high rate of hyposmia among those with no reported change or loss was also observed. Formal smell testing may be considered in those with prior SARS-CoV-2 infection to diagnose occult hyposmia and counsel patients about risks.

Pathogenic variants in over 1700 genes can cause neurogenetic disorders. Monogenetic diseases are ideal targets for genetic therapies; however, the blood-brain barrier (BBB), post-mitotic neurons, and inefficient delivery platforms make gene therapies for neurogenetic diseases challenging. Following nusinersen's 2016 approval, the development of gene therapies for neurogenetic disorders has advanced rapidly, with new delivery vehicles [e.g., BBB-crossing capsids, engineered viral-like proteins, lipid nanoparticles (LNPs)] and novel therapeutic strategies (e.g., regulatory elements, novel RNA therapeutics, tRNA therapies, epigenetic and gene editing). Patient-led disease foundations have accelerated treatment development by addressing trial readiness and supporting translational research. We review the current landscape and future directions in developing gene therapies for neurogenetic disorders.

OBJECTIVE:New-onset refractory status epilepticus (NORSE) occurs in people without pre-existing epilepsy or a rapidly identified structural, toxic, metabolic, or other cause. NORSE is a rare disorder with high morbidity and mortality rates and limited evidence for effective therapies. We aimed to assess whether the gut microbiome of NORSE and status epilepticus (SE) differs from that of chronic epilepsy, whether NORSE differs from SE at different disease time points, and to examine the correlations between specific gut microbiota and cytokines in NORSE and SE. METHODS:This longitudinal cohort study observed patients with NORSE (n = 15), SE (n = 17), and chronic epilepsy who were not in SE (n = 12). NORSE patients were recruited through the NORSE Consortium. Patients with NORSE and SE underwent longitudinal serial biospecimen collection. Fecal samples were subjected to whole-community shotgun metagenomics to characterize microbiome features. Cohorts were evaluated for prokaryotic, eukaryotic, and functional diversity. Correlations between blood inflammatory cytokine levels and microbiome features and covariate analysis with critical illness and clinical treatments were examined for NORSE and SE patients during and after SE resolution. RESULTS:During SE, NORSE and SE patients had significantly different prokaryotic, eukaryotic, and functional microbiome levels compared to chronic epilepsy patients without SE. Limited microbiome differences were observed within and between NORSE and SE, although these groups displayed differing correlation patterns between microbial species and cytokines. Patients who later died or were tube-fed harbored significantly different microbiomes than those who survived or were orally fed. SIGNIFICANCE/CONCLUSIONS:NORSE and SE patients present with a more variable and dramatically different fecal microbiome than chronic epilepsy patients, which may indicate gut dysbiosis that may be reciprocally linked to inflammatory responses. Although NORSE and SE patients had similar microbiome structures, fungal and bacterial correlates with inflammatory cytokines differed between NORSE and SE, with confounding factors influencing microbiome structure. Our data suggest a microbiome-specific response to NORSE and SE, with implications for future treatment strategies.

BACKGROUNDAND OBJECTIVE/UNASSIGNED:The authors compareocclusion rates in grade I-III AVMs in smokers and non-smokers, using propensity score matching (PSM). METHODS:The authors performed a subgroup analysis of the MISTA consortium, a multicenter registry that includes patients aged 1 to 89 years with AVMs treated between January 2010 and December 2023. Only grade I-III AVMs were included. PSM was used to control confounders. Primary endpoints included angiographic obliteration. RESULTS:A total of 353 patients with bAVMs, with a median age of 37, were included in this study: 236 were never smokers, and 117 were current or previous smokers. After 1:1 PSM of smokers and non-smokers, 33 matched pairs were obtained. The smokers were more likely to display complete obliteration at last imaging follow-up compared to non-smokers (57.6 % vs. 27.3 %;p < 0.01). The median time to last clinical(p = 0.45)and angiographic(p = 0.33)follow up was not statistically different between the two groups.There were no statistically significant differences between the two matched groups in the incidence of post-SRS edema (p = 0.23), post-treatment rupture (0 %), overall mortality (p = 0.31), and functional status at the last follow-up (p = 0.69). CONCLUSION/CONCLUSIONS:Individuals with a positive history of smoking are more likely to achieve complete obliteration of grades I-III bAVMs following SRS treatment. However, smokers do not differ from non-smokers in terms of the incidence of post-treatment rupture, overall mortality, or functional status at the last follow-up.

OBJECTIVE:In traditionally designed randomized clinical trials of antiseizure medications, participants take a blinded treatment for a prespecified number of weeks, irrespective of continued seizures. The alternative design time to prerandomization monthly seizure count (T-PSC) allows participants to end the blinded treatment after an individually prespecified number of seizures, which shortens exposure to placebo and ineffective treatment. Previous reanalyses have shown that T-PSC replicated the efficacy conclusions of trials; therefore, we evaluated whether T-PSC also could replicate tolerability and safety conclusions. METHODS:We retrospectively applied the T-PSC design to analyze treatment-emergent adverse events (TEAEs) from three blinded, placebo-controlled trials of perampanel for focal onset seizures (NCT00699972, NCT00699582, NCT00700310). We evaluated the incidences of TEAEs, treatment-related TEAEs, serious TEAEs, and TEAEs that prompted medication adjustment compared to those observed during the full-length trial. RESULTS:Of the 1480 participants in the three trials, 1093 experienced any TEAE, of whom 1006 (92%) had onset prior to T-PSC. When evaluating the differences in each type of TEAE for each dose of perampanel from placebo within each trial, there was no consistent pattern of under- or overestimation. Across the three studies, 23 of 79 (29%) serious TEAEs, most requiring hospitalization, occurred after T-PSC. SIGNIFICANCE/CONCLUSIONS:Almost all TEAEs occurred before T-PSC. Similar conclusions regarding the tolerability and safety of perampanel would have been reached if the T-PSC design had been used. This suggests that the T-PSC design may potentially benefit participants by allowing earlier change from an ineffective treatment to an alternate treatment, which could reduce the risk of serious consequences of ineffective treatment, such as hospitalization.

OBJECTIVE:A growing body of evidence indicates a strong genetic overlap between developmental and epileptic encephalopathies (DEEs) and movement disorders. De novo loss-of-function variants in NUS1 have been recently identified in DEE cases. Herein, we report a large cohort of cases with pathogenic NUS1 variants and describe their clinical presentation and the details of the associated epilepsy and movement disorders. METHODS:Cases with NUS1-related disorders were identified through a multicentric international collaboration made possible by the GeneMatcher platform. Clinical data were acquired through retrospective case-note review. RESULTS:We identified 41 subjects carrying 38 different pathogenic or likely pathogenic heterozygous NUS1 variants. The majority of cases displayed developmental delays and intellectual disability of variable severity. Epilepsy was present in 68.3% of cases (28/41) with onset typically in early childhood. Strikingly, 87.8% of cases (36/41) presented with movement disorders and for 13 of these cases the movement disorder was not accompanied by epilepsy. The phenomenology of the movement disorders was complex with myoclonus observed in 68.3% of cases (28/41), either in isolation or in combination with dystonia, ataxia, and/or parkinsonism. Seven cases that otherwise did not have prominent movement disorders had mild incoordination and intention tremor, suggestive of cerebellar dysfunction. There was no observed genotype-phenotype correlation, suggesting that other genetic or acquired factors impact the clinical presentation. INTERPRETATION/CONCLUSIONS:Heterozygous NUS1 pathogenic variants cause a complex neurological disorder, variably featuring developmental and epileptic encephalopathies and a broad spectrum of movement disorders, which represent the major source of neurological disability for most cases. ANN NEUROL 2025.

BACKGROUND AND IMPORTANCE/BACKGROUND:Marfan syndrome's association with intracranial aneurysms, though controversial, poses unique challenges for surgical intervention because of the inherent vascular fragility. Open surgical approaches carry considerable risk. Endovascular flow diversion with the Pipeline embolization device (PED) offers a less invasive alternative, and adjunctive coiling can decrease occlusion time for complex aneurysms. We report the first combined use of PED and coiling to treat a Marfan-associated intracranial aneurysm, detailing our operative approach and reviewing the literature. CLINICAL PRESENTATION/METHODS:mutation was incidentally found to have an unruptured paraophthalmic aneurysm during stroke workup. Diagnostic angiography revealed an irregular superior hypophyseal aneurysm along with tortuous and irregular internal carotid arteries suggesting previous dissections. The aneurysm was successfully treated with a PED and adjunctive coil embolization. The patient was discharged on aspirin and clopidogrel. Six-month follow-up angiography confirmed aneurysm occlusion. Although there was no residual or recurrent aneurysm at 2-year follow-up, imaging revealed 2 de novo intracranial aneurysms. The patient remains asymptomatic and under observation. CONCLUSION/CONCLUSIONS:mutations and cerebrovascular pathology.