Faculty Bibliography

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.

Decreased brain levels of coenzyme Q₁₀ (CoQ₁₀), an endogenously synthesized lipophilic antioxidant^1,2, underpin encephalopathy in primary CoQ₁₀ deficiencies^3,4 and are associated with common neurodegenerative diseases and the ageing process^5,6. CoQ₁₀ supplementation does not increase CoQ₁₀ pools in the brain or in other tissues. The recent discovery of the mammalian CoQ₁₀ headgroup synthesis pathway, in which 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) makes 4-hydroxymandelate (4-HMA) to synthesize the CoQ₁₀ headgroup precursor 4-hydroxybenzoate (4-HB)⁷, offers an opportunity to pharmacologically restore CoQ₁₀ synthesis and mechanistically treat CoQ₁₀ deficiencies. To test whether 4-HMA or 4-HB supplementation promotes CoQ₁₀ headgroup synthesis in vivo, here we administered 4-HMA and 4-HB to Hpdl^-/- mice, which model an ultra-rare, lethal mitochondrial encephalopathy in humans. Both 4-HMA and 4-HB were incorporated into CoQ₉ and CoQ₁₀ in the brains of Hpdl^-/- mice. Oral treatment of Hpdl^-/- pups with 4-HMA or 4-HB enabled 90-100% of Hpdl^-/- mice to live to adulthood. Furthermore, 4-HB treatment stabilized and improved the neurological symptoms of a patient with progressive spasticity due to biallelic HPDL variants. Our work shows that 4-HMA and 4-HB can modify the course of mitochondrial encephalopathy driven by HPDL variants and demonstrates that CoQ₁₀ headgroup intermediates can restore CoQ₁₀ synthesis in vivo.

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.

Synaptic spine loss is an early pathophysiologic hallmark of Alzheimer disease (AD) that precedes overt loss of dendritic architecture and frank neurodegeneration. While spine loss signifies a decreased engagement of postsynaptic neurons by presynaptic targets, the degree to which loss of spines and their passive components impacts the excitability of postsynaptic neurons and responses to surviving synaptic inputs is unclear. Using passive multicompartmental models of CA1 pyramidal neurons (PNs), implicated in early AD, we find that spine loss alone drives a boosting of remaining inputs to their proximal and distal dendrites, targeted by CA3 and entorhinal cortex (EC), respectively. This boosting effect is higher in distal versus proximal dendrites and can be mediated by spine loss restricted to the distal compartment, enough to impact synaptic input integration, somatodendritic backpropagation, and plateau potential generation. This has particular relevance to very early stages of AD in which pathophysiology extends from EC to CA1.

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.

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: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:Recent studies have suggested that favorable venous outflow (VO) may be a promising imaging biomarker to predict clinical outcomes following reperfusion therapy in patients with acute ischemic stroke caused by large vessel occlusion (AIS-LVO). METHODS:A comprehensive literature search was conducted in PubMed, Scopus, WOS, and Cochrane to identify studies that evaluated VO profiles, assessed using the Cortical Vein Opacification Score (COVES). The risk ratio (RR) and 95% confidence interval (CI) for the outcomes, including functional independence, assessed by modified rankin scale at 90 days (mRS 0-2), hemorrhagic infarction, parenchymal hematoma, 90-day mortality, intracranial hemorrhage (ICH), and symptomatic ICH (sICH), were calculated and analyzed using the 'meta' package in R version 4.4.1. RESULTS:A total of six studies encompassing 2249 patients were included. Patients with favorable VO had a higher likelihood of achieving functional independence at 90 days (RR = 2.15; 95% CI: 1.35, 3.42; p = 0.01) and a lower incidence of 90-day mortality (RR = 0.39; 95% CI: 0.30, 0.51; p < 0.01), parenchymal hematoma (RR = 0.36; 95% CI: 0.27, 0.47; p < 0.01). Furthermore, sICH was less frequent in patients with favorable VO (RR = 0.39; 95% CI: 0.17, 0.89; p = 0.03). However, hemorrhagic infarction and any ICH did not differ significantly between the two groups (p-values: 0.06 and 0.32, respectively). CONCLUSION/CONCLUSIONS:VO is a promising imaging biomarker for predicting outcomes in patients with AIS-LVO following reperfusion therapy. Prospective clinical trials are warranted to investigate the predictive value of VO, assessed on multiphasic computed tomography angiography (CTA), as a prognostic marker in this patient population.

Between 1919 and 1936, American physiologist Walter B. Cannon and Spanish physician Gregorio Marañón engaged in a sustained transatlantic correspondence that shed light on emerging ideas about the physiologic basis of emotion. Drawing on letters preserved at Harvard's Countway Library of Medicine and the Fundación Ortega-Marañón in Madrid, we examine how their dialogue bridged experimental physiology and clinical neuroendocrinology during a formative era in modern neuroscience. Cannon, widely known for introducing the concepts of "homeostasis" and the "fight-or-flight" response, saw in Marañón's clinical observations a compelling complement to his laboratory findings. In particular, Cannon repeatedly cited Marañón's work on the emotional effects of adrenaline, which distinguished between purely physiologic visceral reactions without subjective emotion ("cold emotion") and full subjective emotional states ("hot emotion"). This nuanced differentiation anticipated later cognitive and constructivist theories of emotion. Their exchange helped shape foundational concepts in affective and autonomic neuroscience by linking internal affective states to neuroendocrine mechanisms and observable bodily responses. These ideas would later cohere in Cannon's The Wisdom of the Body (1932), where traces of their correspondence are evident. Beyond their scientific importance, the Cannon-Marañón letters offer a rare window into the international and interdisciplinary networks that shaped biomedical thought in the early 20th century. It also reflects broader commitments because both men had a relevant political involvement. By recovering this epistolary exchange, we shed light on an overlooked chapter in the history of neuroscience and the enduring value of scientific dialogue.

IMPORTANCE/UNASSIGNED:Acute necrotizing encephalopathy (ANE) is a rare, but severe, neurologic condition for which epidemiologic and management data remain limited. During the 2024-2025 US influenza season, clinicians at large pediatric centers anecdotally reported an increased number of children with influenza-associated ANE, prompting this national investigation. OBJECTIVE/UNASSIGNED:To understand the clinical presentation, interventions, and outcomes among US children diagnosed with influenza-associated ANE. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This study was a multicenter case series of children diagnosed with ANE with longitudinal follow-up. A call for cases was issued via academic societies, public health agencies, and by directly contacting pediatric specialists at 76 US academic centers, requesting cases between October 1, 2023, and May 30, 2025. Inclusion criteria required acute encephalopathy with radiologic evidence of acute thalamic injury and laboratory confirmation of influenza infection in individuals aged 21 years or younger. EXPOSURE/UNASSIGNED:Influenza-associated ANE. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Presenting symptoms, vaccination history, laboratory and genetic findings, interventions, and clinical outcomes, including modified Rankin Scale score (0: no symptoms; 1-2: mild disability; 3-5: moderate to severe disability; 6: death), length of stay, and functional outcomes. RESULTS/UNASSIGNED:Of 58 submitted cases, 41 cases (23 females; median age, 5 years [IQR, 2-8]) from 23 US hospitals met inclusion criteria. Thirty-one cases (76%) had no significant medical history; 5 (12%) were medically complex. Clinical presentation included fever in 38 patients (93%), encephalopathy in 41 (100%), and seizures in 28 (68%). Thirty-nine patients (95%) had influenza A (14 with A/H1pdm/2009, 7 with A/H3N2, and 18 with no subtype) and 2 had influenza B. Laboratory deviations included elevated liver enzymes (78%), thrombocytopenia (63%), and elevated cerebrospinal fluid protein (63%). Among 32 patients (78%) with genetic testing, 15 (47%) had genetic risk alleles potentially related to risk of ANE including 11 (34%) with RANBP2 variants. Among 38 patients with available vaccination history, only 6 (16%) had received age-appropriate seasonal influenza vaccination. Most patients received multiple immunomodulatory treatments, including methylprednisolone (95%), intravenous immunoglobulin (66%), tocilizumab (51%), plasmapheresis (32%), anakinra (5%), and intrathecal methylprednisolone (5%). Median intensive care unit and hospital lengths of stay were 11 days (IQR, 4-19) and 22 days (IQR, 7-36), respectively. Eleven patients (27%) died a median of 3 days (IQR, 2-4) from symptom onset, primarily from cerebral herniation (91%). Among the 27 survivors with 90-day follow-up, 63% had at least moderate disability (modified Rankin Scale score ≥3). CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this case series of children with influenza-associated ANE from the 2 most recent influenza seasons in the US, the condition was associated with high morbidity and mortality in this cohort of predominantly young and previously healthy children. The findings emphasize the need for prevention, early recognition, intensive treatment, and standardized management protocols.