Faculty Bibliography

Cerebral malaria is a major complication of Plasmodium falciparum infection that occurs upon the sequestration of infected red blood cells (iRBCs) in brain capillaries, resulting in the loss of endothelial barrier integrity, brain swelling, and frequently long-term sequelae or death. P. falciparum-iRBCs cause the disruption of human brain microvascular endothelial cell barrier integrity in vitro, mimicking the microenvironment of cerebral malaria, yet the specific mechanisms mediating this process remain unknown. Upon infection of the host RBCs, P. falciparum produces hemozoin, a crystal form of heme generated following the degradation of hemoglobin by the parasite. Here, we show that the endothelial barrier-disrupting activity is found entirely in the hemozoin fraction of P. falciparum-iRBCs. This activity is not caused by the hemozoin crystal itself, which is not able to induce barrier disruption, but by the biomolecules that are associated with it. Treatment of purified P. falciparum hemozoin with proteases inhibits the disruption of endothelial barrier integrity caused by the hemozoin, indicating an important role for proteins in the disruption of the barrier. Conversely, treatment with nucleases did not affect hemozoin barrier-disrupting activity. These results identify a key molecular mechanism in the P. falciparum-mediated brain endothelial barrier disruption during cerebral malaria and may open new avenues for the treatment of this complication.IMPORTANCEWhile several specific biomolecules have been proposed to contribute to the disruption of endothelial barrier integrity in cerebral malaria, no single Plasmodium falciparum- or host-derived factor has been definitively identified as the primary driver of this disruption. Here, we identify the brain endothelial barrier-disruptive P. falciparum-infected red blood cell (iRBC)-derived activity to be caused by biomolecules bound to hemozoin, identifying a key, novel mechanism in the pathogenesis of cerebral malaria. The finding that P. falciparum hemozoin also disrupts a pulmonary endothelial cell barrier opens the possibility that this mechanism underlies other severe malaria complications. The implication of P. falciparum-iRBC-derived proteins in this mechanism is in line with previous reports, providing a novel interpretation of these findings in the context of hemozoin-binding. This knowledge provides a new perspective in the search for specific molecules and mechanisms involved in barrier disruption, which may lead to the development of much-needed specific treatments for cerebral malaria.

Rasmussen syndrome (RS) includes a well-described constellation of refractory focal seizures, often including epilepsia partialis continua, hemiplegia with progressive unilateral cortical atrophy, and cognitive/language decline. However, the precise early pathogenesis and reliable biomarkers remain elusive. In addition, we lack operational management guidelines, including diagnostic evaluation, disease-monitoring assessments, and medical and surgical treatment approaches. We aimed to create an expert consensus statement to guide and standardize the treatment of RS, with the goal of providing recommendations applicable to a global population. An expert panel was convened to complete three rounds of a modified Delphi procedure given the lack of high-level evidence, with a focus on workup to exclude mimicking diagnoses, disease-activity metrics, and treatment. Consensus was defined as ≥75% of responses being agree/strongly agree in either two subsequent rounds or in the third and final round. A total of 122 of 143 statements met consensus. Proposed diagnostic evaluation in patients with possible RS is outlined, including physical examination, blood/cerebrospinal fluid analyses, neuroimaging, electroencephalography (EEG), and biopsy. Suggested disease-monitoring assessments include neuropsychological testing and serial magnetic resonance imaging (MRI). Intravenous corticosteroids are recommended as first-line, acute immunotherapy for seizure exacerbations and status epilepticus, with or without the addition of intravenous immunoglobulin. Options for maintenance immunotherapy are outlined, with lack of evidence noted for comparing efficacy of these treatments. Hemispheric disconnection remains the most effective seizure treatment, with parameters including age, function, seizure burden, and patient values influencing candidacy for surgery. This consensus statement offers a guideline to standardize management, as well as suggests future directions to further elucidate underlying pathophysiology and target more-effective, better-tolerated treatments.

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: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.

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).

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.

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.

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.

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.