Faculty Bibliography

Seizure frequency has been the primary endpoint in epilepsy trials, with enrollment usually requiring ≥4 seizures per month. This threshold is more and more misaligned with clinical reality, as the availability of more treatment options has reduced baseline seizure burden, with a risk of excluding a proportion of patients from trials. Although cognitive and developmental outcomes are gaining prominence, seizure control remains essential due to its impact on morbidity and mortality. We have tools to study all types of seizure frequency: Time-to-event designs, including time-to-pre-randomization seizure count or time to the Nth seizure, offer a validated alternative by enabling inclusion across a wider range of seizure frequencies while maintaining methodological rigor. Future trial designs should study cognitive outcomes, while studies focusing on anti-seizure efficacy remain critical.

BACKGROUND:Carotid webs are increasingly recognized as a cause of ischemic stroke, but less is known about morphologically similar lesions in other arteries. We present the first study characterizing the clinical and radiographic features of extra-carotid arterial webs through a single-center case series and systematic review. METHODS:Patients with possible extra-carotid webs were identified from 2017 to 2025 using a natural language processing search of radiology reports at our institution. Candidate cases underwent imaging review with multiplanar and 3-dimensional reconstructions to distinguish webs from fenestrations, vessel tortuosity, dissection, or atherosclerotic plaque. In parallel, we performed a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review (Web of Science and PubMed, inception to September 2025) to identify published cases of extra-carotid web. Data on demographics, vascular location, imaging modality, clinical presentation, treatment, and outcomes were extracted and synthesized descriptively. RESULTS:Four extra-carotid webs were identified at our institution (3 basilar and 1 subclavian). None were associated with stroke, and all patients remained stable on conservative management during 9 months to 4 years of follow-up. Across 16 published studies, 22 additional extra-carotid webs were identified, yielding 26 patients in aggregate (mean age, 52.7 years; 61.5% male). The vertebral artery was the most common site (53.8%), followed by the basilar (30.8%) and subclavian (15.4%) arteries. Ten patients with vertebral or basilar web presented with posterior circulation ischemic stroke, with recurrent events in 4 patients. Most patients were managed with antiplatelet therapy or observation, while 3 vertebral webs with recurrent stroke were successfully treated with stenting. CONCLUSIONS:Extra-carotid webs share morphological and clinical features with carotid webs and may represent a unified disease spectrum of cervical artery webs. Vertebral and basilar webs, though rare, may be an underrecognized source of posterior circulation stroke. Recognition of these lesions may broaden the differential for cryptogenic stroke though the lack of histopathologic visualization remains a critical limitation of our study.

INTRODUCTION/BACKGROUND:Measuring plasma biomarkers effectively assesses early-stage Alzheimer's disease. METHODS:Subjects were categorized as cognitively unimpaired (CU) (n = 66), CU with subjective cognitive decline (SCD) (n = 100), and mild cognitive impairment (MCI) (n = 25). Plasma biomarkers measured were amyloid beta (Aβ) 40, Aβ42, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau phosphorylated at threonine 181 (pTau181), neuroinflammatory biomarkers, and blood-brain barrier biomarkers. Amyloid and tau positron emission tomography (PET) imaging was performed in 186 and 144 subjects, respectively. RESULTS:Comparing those having MCI, both CU and SCD participants had significantly lower amyloid PET standardized uptake value ratio (SUVR) (p < 0.001; p = 0.005). Higher amyloid PET SUVR was significantly associated with higher pTau181 (p = 0.001) and a higher pTau181/Aβ42 ratio (p < 0.001). Higher tau PET SUVR was associated with lower plasma Aβ42 (p = 0.020), older age (p = 0.005), higher GFAP (p = 0.020), and lower interleukin-8 levels (p < 0.001). DISCUSSION/CONCLUSIONS:Our study supports plasma biomarker monitoring of at-risk patients at various stages of pre-dementia.

BACKGROUND:There is significant heterogeneity related to the use of prophylactic antiseizure medications (ASM) following supratentorial craniotomy. METHODS:We conducted a systematic review and meta-analysis assessing ASM primary prophylaxis in adults hospitalized following supratentorial neurosurgery with no prior seizure history. The following population, intervention, comparator, and outcome (PICO) questions were assessed: (1) Should ASM versus no ASM be used as seizure prophylaxis in adult patients undergoing supratentorial neurosurgery? (2) If an ASM is used, should levetiracetam (LEV) or phenytoin/fosphenytoin (PHT) be preferentially used? and (3) Should a long (> 7 days) versus short (≤ 7 days) duration of prophylaxis be used? The main outcomes were early seizure (≤ 14 days), late seizures (> 14 days), adverse events, mortality, and functional and cognitive outcomes. We utilized Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to generate recommendations. RESULTS:The initial literature search yielded 1988 articles, and 16 formed the basis of the recommendations. PICO 1: while meta-analysis of randomized controlled trials (RCTs) demonstrated a significant benefit for early seizure prevention, meta-analyses including all study designs was nonsignificant. Further, there were no differences in late seizure or mortality rates, and there was a trend toward higher adverse event rates with ASM. PICO 2: LEV was associated with significantly lower early seizure rates than PHT, and there were trends toward fewer late seizures and adverse events with LEV. PICO 3: only three studies examined the duration of ASM treatment, and there was no significant difference in seizure events between subjects treated for a short versus long duration. CONCLUSIONS:We suggest that either prophylactic ASM or no ASM be used for seizure prophylaxis in patients undergoing supratentorial neurosurgery (conditional recommendation, low quality of evidence). If an ASM is used, we suggest LEV over PHT (conditional recommendation, very low quality of evidence) for a short duration (conditional recommendation, very low quality of evidence).

Human pluripotent stem cells (hPSCs) are a valuable tool for disease modeling. Further stem cells can be reprogrammed from adult somatic cells, called induced pluripotent stem cells (iPSC). iPSC technology allows for the evaluation of specific study participants and populations and ventures into personalized medicine. Blood is routinely taken and cryopreserved for research purposes. These samples are processed either as buffy coats, a blood sample containing white blood cells and platelets, or as peripheral blood mononuclear cells (PBMCs), which represent a more purified population of white blood cells without eosinophils, basophils, platelets, or red blood cells. Both are a readily available and relatively non-invasive source for reprogrammable somatic cells. Several reports detail reprogramming from PBMCs, whereas only one describes this process from frozen buffy coats. Recent experience revealed PBMC reprogramming protocols available in the literature and from manufacturers to be unsuccessful when applied to frozen buffy coat samples, necessitating the adaptations and troubleshooting strategies described here. For many researchers, who employ iPSC technologies, it is imperative to have thorough protocols with a high success rate, especially in cases, where patient samples may contain only few cells, are obtained in wide time intervals, are from limited participant pool, or are otherwise highly valuable. Here, checkpoints and troubleshooting strategies are identified to increase the chance of reprogramming human frozen buffy coats or purified PBMCs. Ultimately, this protocol will allow researchers to identify predictors of reprogramming success and strategize alternative approaches to improve the chances of successful iPSC derivation.

BACKGROUND:Carotid webs are increasingly recognized as a significant cause of cryptogenic stroke in young adults, yet they remain frequently underdiagnosed due to their subtle radiographic appearance and atypical presentations. The natural history of untreated carotid webs includes high rates of recurrent ipsilateral ischemic events despite optimal medical therapy. OBSERVATIONS/METHODS:The authors present the case of a 44-year-old man with four recurrent right hemispheric ischemic events over 5 years. Despite multiple angiographic studies, an underlying carotid web was initially misinterpreted. Digital subtraction angiography ultimately revealed a subtle posterolateral carotid web. Prior to endarterectomy, intraoperative ultrasound uniquely visualized a large thrombus adherent to the web, a critical finding not appreciated on preoperative angiography. Successful en bloc removal of the web and thrombus was performed with histopathological confirmation. The patient remained stroke free at the 1-year follow-up. LESSONS/CONCLUSIONS:Atypical carotid webs may lack classic radiographic features and can be misclassified on noninvasive imaging. Intraoperative ultrasound provides real-time assessment of thrombus burden not visible on preoperative angiography, allowing for improved surgical planning. This case demonstrates that web-associated thrombi are dynamic and may not be apparent even on high-resolution angiography performed shortly before surgery. Surgical intervention with intraoperative ultrasound guidance offers definitive treatment and excellent long-term outcomes. https://thejns.org/doi/10.3171/CASE2610.

Alzheimer's disease (AD) remains a major global health challenge, with prevalence projected to increase dramatically in the coming decades and no effective treatments available. Current therapies offer only symptomatic relief, reinforcing the need for disease-modifying strategies targeting underlying pathogenic mechanisms. Advances in understanding amyloid-β (Aβ) and tau pathology have propelled the development of targeted interventions, particularly monoclonal antibodies (mAbs) and small-molecule therapeutics. Recent anti-Aβ antibodies, such as aducanumab, lecanemab, and donanemab, have demonstrated significant biological activity and reductions in amyloid burden, leading to regulatory approvals that represent important proof-of-concept milestones. However, these therapies face ongoing controversies related to modest clinical efficacy, accessibility, cost, and safety concerns. In parallel, small-molecule development has expanded beyond failed secretase inhibitors toward more refined mechanisms, including tau aggregation inhibition, kinase modulation, mitochondrial stabilization, and anti-inflammatory pathways. These compounds offer advantages in oral administration, blood-brain barrier penetration, and multi-target engagement. Together, mAbs and small molecules represent complementary therapeutic strategies addressing different aspects of AD pathophysiology. Their integration with emerging biomarkers, genetic profiling, and early diagnostic frameworks is driving a transition toward personalized and stage-specific treatment approaches. This review synthesizes current mechanistic insights, clinical evidence, and translational challenges of both modalities, highlighting how their convergence may shape the next-generation of AD therapeutics.

Ceramide transporter syndrome (CerTra syndrome) is a rare neurodevelopmental disorder caused by pathogenic variants in CERT1 gene encoding ceramide transporter (CERT). These variants disrupt ceramide transport and sphingolipid homeostasis, leading to a clinical phenotype that includes developmental delay, movement abnormalities, and structural brain anomalies. Despite growing recognition of this condition, detailed neuroimaging and neuropathological characterization remain limited. Here, we present a 12-year-old girl with a pathogenic CERT1 variant complicated by sudden unexplained death, who presented with unreported neuroimaging abnormalities in choroid plexus (ChP) and perivascular space (PVS). Clinical Magnetic Resonance Imaging (MRI) obtained approximately 10 years prior to death, as well as postmortem MRI, revealed bilateral cystic enlargement of the ChP and prominent PVS filled with abundant proteinaceous material in white matter. Neuropathological examination demonstrated marked ChP epithelial disorganization, reduced aquaporin-1 (AQP1) expression, cyst formation, and focal calcifications, which may be associated with disturbances in cerebrospinal fluid (CSF) dynamics. These findings raise the possibility that CERT1 variants may be associated with ChP architectural changes and altered perivascular clearance.

IMPORTANCE/UNASSIGNED:Seizure-induced brain injury is central to the treatment urgency of new-onset refractory status epilepticus (NORSE). Identifying biomarkers that reflect ongoing neuronal damage could inform therapeutic timing and improve outcomes. OBJECTIVE/UNASSIGNED:To quantify acute brain injury in patients with cryptogenic NORSE (cNORSE), etiology-defined status epilepticus (eSE), and chronic epilepsy. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This was an international cross-sectional study conducted between 2013 and 2025. Patients were enrolled at 36 hospitals in the US, 2 in Canada, and 1 in Italy, France, and Belgium. Patients with cNORSE and eSE for which biological samples were obtained during ongoing seizure activity were enrolled in the study. Comparison groups without status epilepticus comprised individuals with chronic epilepsy and healthy participants. None were excluded. EXPOSURES/UNASSIGNED:Neurofilament light chain (NfL) and S100-beta (S100B) protein concentrations in serum and cerebrospinal fluid (CSF). MAIN OUTCOMES AND MEASURES/UNASSIGNED:Degree of neuronal and glial damage, indexed by NfL and S100B levels, and their association with short-term functional outcomes. RESULTS/UNASSIGNED:A total of 78 patients with cNORSE (mean [95% CI] age, 37 [30-41] years; 44 female [56%]) and 2 independent cohorts of 211 patients (mean [95% CI] age, 69 [66-71] years; 128 female [61%]) and 73 patients (mean [95% CI] age, 56 [45-65] years; 39 male [53%]) with eSE were included. NfL concentrations were markedly elevated in cNORSE-approximately 10-fold higher in CSF and 4-fold higher in serum-compared with the eSE cohorts (CSF: median [IQR], 6408 [1503-22 963] pg/mL compared with 694 [219-2389] pg/mL; serum: median [IQR], 231 [99-855] pg/mL compared with 55 [20-135] pg/mL; P <.001). Serum NfL levels were nearly 20-fold higher in cNORSE than in the cohort with epilepsy and in healthy controls (median [IQR], 11 [7-19 ] and 7 [5-14 ] pg/mL, respectively). Serum and CSF NfL levels were strongly correlated (Spearman ρ = 0.75; P < .001) and rose sharply between week 1 (median [IQR], 101 [51-137] pg/mL), week 2 (median [IQR], 197 [117-324] pg/mL), and week 3 (median [IQR], 598 [163-1000] pg/mL) after onset (P < .001). In contrast, S100B concentrations did not differ between groups and showed no consistent temporal pattern. NfL discriminated cNORSE from eSE (area under the receiver operating characteristic curve [AUROC], 0.79; 95% CI, 0.68-0.90) and from cohorts without status epilepticus (AUROC, 0.99; 95% CI, 0.78-1.00). Higher serum NfL was independently associated with poor functional outcome at discharge (Glasgow Outcome Scale extended score, 1-4; odds ratio, 1.01; 95% CI, 1.00-1.03; P = .03). CONCLUSIONS AND RELEVANCE/UNASSIGNED:Results of this cross-sectional study suggest that acute neuroaxonal injury, as reflected by elevated NfL levels, was substantially greater in cNORSE than in the cohorts with eSE and in controls without status epilepticus. The rapid early rise in NfL highlights a narrow therapeutic window, emphasizing the need for prompt, effective, and potentially neuroprotective interventions in cNORSE.