Faculty Bibliography

A transient ischemic attack is an acute neurologic event caused by focal ischemia affecting the brain, eye, or spinal cord, resolving quickly without infarction on magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI). It is a tissue-based diagnosis, highlighting the need for prompt recognition and risk stratification. Evaluation in the emergency department includes detailed history, risk assessment, neurologic examination, and initial noncontrast computed tomography (CT) to rule out other conditions, with MRI DWI as the gold standard for confirming no infarction. Vascular imaging, echocardiography, electrocardiogram (ECG), and laboratories help identify underlying causes. Central retinal artery occlusion (CRAO) requires urgent diagnosis and ophthalmology consultation to prevent permanent vision loss.

BACKGROUND AND IMPORTANCE/BACKGROUND:Rhino-orbital cerebral mucormycosis (ROCM) is an aggressive fungal infection involving the paranasal sinuses, orbit, and intracranial cavity, with a propensity for vascular invasion. This can lead to complications such as internal carotid artery (ICA) thrombosis and occlusion, presenting major neurosurgical challenges. Although surgical debridement and antifungal therapy are the mainstays of treatment, cases with significant neurovascular involvement require specialized intervention. We report a case of ROCM with severe flow-limiting ICA stenosis treated by direct extracranial-intracranial bypass. CLINICAL PRESENTATION/METHODS:tA 65-year-old man with diabetes presented with progressive left-sided blindness and facial numbness. Imaging revealed a left orbital mass extending into the paranasal sinuses and intracranially. Empiric antifungal therapy was started. Pathology confirmed Rhizopus species. Despite extensive surgical debridement and antifungal therapy, the patient developed progressive severe cavernous ICA stenosis, leading to watershed territory strokes. To restore cerebral perfusion, protect from distal emboli, and prepare for potential aggressive debridement, a flow-replacing direct (superficial temporal artery-middle cerebral artery (M2)) bypass was performed, and the supraclinoid carotid was trapped. Intraoperative angiography confirmed robust flow through the bypass. The patient was discharged on antifungal therapy and aspirin. At 6-month follow-up, the patient was neurologically intact with an modified Rankin Scale score of 1. Computed tomography angiography and transcranioplasty Doppler ultrasonography confirmed good flow through the bypass. CONCLUSION/CONCLUSIONS:In addition to antifungal therapy and surgical debridement, superficial temporal artery-middle cerebral artery bypass can be a lifesaving intervention in the management of ROCM with severe cerebrovascular compromise. This case highlights the critical role of cranial bypass in preserving cerebral perfusion in patients with flow-limiting ROCM-associated ICA invasion.

BACKGROUND:Identifying early neuropathological changes in Alzheimer's disease (AD) is important for improving treatment efficacy. Among quantitative MRI measures, transverse relaxation time (T2) has been shown to reflect tissue microstructure relevant in aging and neurodegeneration; however, findings regarding T2 changes in both normal aging and AD have been inconsistent. The association between T2 and amyloid-beta (Aβ) accumulation, a hallmark of AD pathology, is also unclear, particularly in cognitively normal individuals who may be in preclinical stages of the disease. PURPOSE/OBJECTIVE:To investigate longitudinal hippocampal T2 changes in a cognitively normal cohort of older adults and their association with global Aβ accumulation. STUDY TYPE/METHODS:Retrospective, longitudinal. SUBJECTS/METHODS:56 cognitively normal adults between 55 and 90 years of age (17 males and 39 females). FIELD STRENGTH/SEQUENCE/UNASSIGNED:3 Tesla; multi-echo spin echo sequence for T2 mapping; 18F-florbetaben positron emission tomography for Aβ measurement. ASSESSMENT/RESULTS:Bilateral hippocampal T2 and volume were extracted to relate to Aβ PET measurements. To understand variations in AD risk, participants were separated into Aβ-high and Aβ-low subgroups using a predetermined threshold. STATISTICAL TESTS/METHODS:Linear mixed-effect models and general linear models were used. A p-value < 0.025 was considered significant to account for bilateral comparisons. RESULTS:Older age was associated with increased T2 in the bilateral hippocampus (left: β = 0.30, right: β = 0.25) and smaller hippocampal volume on the left (β = -0.12). In the Aβ-low subgroup, both longitudinal T2 increase rates (β = 0.65) in the left hippocampus and bilateral cross-sectional T2 (left: β = 0.64, right: β = 0.46) were positively correlated with Aβ PET, independent of hippocampal volume. DATA CONCLUSION/CONCLUSIONS:This study provided in vivo evidence linking hippocampal T2 to Aβ accumulation in cognitively normal aging individuals, suggesting that quantitative T2 may be sensitive to microstructural changes accompanying early Aβ pathology, such as neuroinflammation, demyelination, and reduced tissue integrity. EVIDENCE LEVEL/METHODS:3. TECHNICAL EFFICACY/UNASSIGNED:Stage 2.

It is well recognized that many pandemic viruses are associated with neurologic complications, most recently with COVID-19. After the outbreak of the COVID-19 pandemic, neurologic surveillance platforms were implemented to characterize the complications of COVID-19. Surveillance platforms are invaluable in providing timely data, informing clinical practice, and directing future research. Lessons learned from recent neurologic surveillance networks include the importance of global and cross-specialty collaboration. It is critical for future surveillance systems to consider these aspects, as it will also serve to improve representation of low and middle-income countries (LMICs) and communities. Trainees played a critical role in the success of neurologic surveillance networks; as frontline health care workers, they were able to provide timely data collection, and their fresh insights are important for future pandemic surveillance system development. In this article, we review the methods of recent neurologic surveillance networks and discuss their strengths and limitations. We explore the outlook for pandemic surveillance platforms and the crucial role global collaboration plays in ensuring that LMICs are represented. We review the role of trainees in pandemic surveillance networks and discuss how it is vital to encourage their continued involvement to ensure that, as future health care leaders, they are prepared to manage future pandemics effectively.

We report a case of an 83-year-old female patient who presented with binocular diplopia associated with left periorbital pain. She was diagnosed with a left pupil-involving third nerve palsy initially believed to be either microvascular or aneurysmal. However, negative vascular neuroimaging and further serologic workup suggested the possibility of neurosyphilis. Her clinical course was significant for persistent periorbital pain and a new seventh nerve palsy, despite syphilis treatment, prompting repeat neuroimaging and lumbar puncture. This case highlights the importance of the clinical history, imaging, CSF studies, and repeated workup in distinguishing between infectious and noninfectious causes of cranial neuropathies.

OBJECTIVE:Sudden unexpected death in epilepsy (SUDEP) often follows generalized tonic-clonic seizures during sleep, likely resulting from impaired brainstem cardiorespiratory function. We used ictal electrocardiogram (ECG)-based cross-frequency phase-amplitude coupling (PAC) to detect cardiorespiratory disruptions, comparing SUDEP to non-SUDEP cohorts. Leveraging respiratory modulation of ECG signals can provide a robust indirect proxy of respiratory monitoring despite high-amplitude noise. METHODS:We analyzed ictal ECG and electroencephalographic recordings in 21 SUDEP cases and 21 non-SUDEP epilepsy controls. Ictal ECG segments from 76 seizures (38 SUDEP, 38 non-SUDEP) were processed using continuous wavelet transformation to compute PAC between respiratory (.1-.55 Hz, 6-33 breaths per minute) and cardiac (.7-3.7 Hz, 42-222 beats per minute) frequencies. Relative PAC coupling strength was evaluated for respiratory frequencies > .25 Hz (15 breaths per minute) and cardiac frequencies > 1.7 Hz (102 beats per minute). Furthermore, a 3 × 3 grid of PAC ranges was derived for each 20-s window, yielding 18 features (mean and SD) as inputs to a logistic regression model. RESULTS:Elevated ictal PAC at higher respiratory (>.25 Hz, p < .0001) and cardiac (>1.7 Hz, p < .0142) frequencies in SUDEP patients suggests ictal respiration modulates ictal tachycardia, leading to cardiorespiratory dysfunction, probably brainstem-mediated. The logistic model accurately distinguished 38 seizures in SUDEP cases from 38 seizures in non-SUDEP cases (receiver operating characteristic area under the curve = 91%). Seizures in SUDEP patients had higher propensity scores (p < .001) both per seizure and per patient. All six test seizures (three SUDEP, three non-SUDEP) were correctly classified using the optimal threshold. SIGNIFICANCE/CONCLUSIONS:Ictal ECG-based PAC analysis is a potential noninvasive biomarker for SUDEP risk, capturing cardiorespiratory dysregulation during seizures. Its integration into wearable ECG devices could enable real-time risk assessment, informing clinical interventions such as rescue medications, antiseizure medication adjustments, or surgical evaluations.

BACKGROUND:Familial dysautonomia (FD) is a hereditary neurodevelopmental disorder caused by aberrant splicing of the ELP1 gene, leading to a tissue-specific reduction in ELP1 protein expression. Preclinical models indicate that increasing ELP1 levels can mitigate disease manifestations. A blood-based ELP-1 protein assay may provide a reliable way to monitor gene target engagement. DESIGN AND METHODS/METHODS:Using a newly developed radioimmunoassay, we quantified ELP1 protein levels in peripheral blood samples collected from 59 homozygous FD patients carrying the IVS20 + 6T>C mutation and 66 heterozygous carriers. To assess the reproducibility of the measurement, replicate samples were collected in 43 participants. Longitudinal variability was evaluated in 22 participants who underwent repeat sampling 1 year later. RESULTS: = 0.827, p < 0.001). An ELP1 threshold of 492 pg/mL yielded a sensitivity of 80.2% (CI of 70.6 to 87.2%) and a specificity of 98.2% (95% CI of 90%-99%) with a positive likelihood ratio of 46.5, indicating that individuals with FD were over 46 times more likely to have ELP1 levels below this threshold compared to non-affected carriers. CONCLUSION/CONCLUSIONS:Blood ELP1 levels are robust and reproducible, with concentrations below 492 pg/mL strongly indicative of disease. Moreover, given their longitudinal stability, ELP1 can serve as a marker of target engagement to evaluate the efficacy of gene-targeted therapies aimed at correcting ELP1 gene splicing and protein production.

PURPOSE/OBJECTIVE:Examine sex-specific differences in Intracranial Aneurysms (IA) rupture at presentation and to retrospectively benchmark sex-stratified versus pooled classification models for their ability to discriminate rupture status, using a cross-sectional cohort. METHODS:We retrospectively analyzed 203 patients (46 males, 157 females) with 303 IAs from a single-center, IRB-approved registry. Of these, 76 IAs were ruptured and 227 unruptured at presentation. Clinical data and lesion characteristics were summarized into patient-level variables and used to develop sex-specific logistic regression models. Adjusted Odds ratios (ORs) were produced for clinical covariates. Cross-application assessed generalizability across sexes. RESULTS:Among females, 58.7% of ruptures were < 5 mm, with a median ruptured size of 4.2 mm at Anterior Communicating Artery (ACOM). Rupture likelihood in females peaked between ages 40 and 59 (aORs = 2.8 and 1.7), coinciding with perimenopause. In males, ACOM was the most frequent rupture site; although males had higher mean hemoglobin levels (14.1 vs. 12.5 g/dL, p < 0.0001), hemoglobin contributed less to rupture compared to sex-specific models incorporating age, location, and metabolic factors (hemoglobin concentration, blood glucose). Metabolic factors contributed significantly to the female-specific model, achieving strong discrimination (AUC-ROC: 0.80), while the male-specific model underperformed (AUC-ROC: 0.50), due to limited rupture events (n = 19). Cross-application of features between sexes drastically reduced performance, providing the first computational evidence that male and female rupture mechanisms represent distinct biological feature spaces requiring separate modeling architectures CONCLUSION: Women in this cohort more often presented with rupture IAs at smaller sizes and at midlife ages than men. These sex-specific patterns, though strictly cross-sectional and associative rather than predictive, highlight potential biological and clinical contributors to rupture presentation and may partly explain misclassification by pooled risk models. Future longitudinal, multicenter studies with balanced cohorts are required to validate these findings and to develop robust rupture-risk prediction tools that incorporate sex as a biological variable.

DNA methylation is a crucial epigenetic mechanism that regulates gene expression. Precise editing of DNA methylation has emerged as a promising tool for dissecting its biological function. However, challenges in delivery have limited most applications of DNA methylation editing to in vitro systems. Here, we develop two transgenic mouse lines harboring an inducible dCas9-DNMT3A or dCas9-TET1 editor to enable tissue-specific DNA methylation editing in vivo. We demonstrate that targeted methylation of the Psck9 promoter in the liver of dCas9-DNMT3A mice results in decreased Pcsk9 expression and a subsequent reduction in serum low-density lipoprotein cholesterol level. Targeted demethylation of the Mecp2 promoter in dCas9-TET1 mice reactivates Mecp2 expression from the inactive X chromosome and rescues neuronal nuclear size in Mecp2^+/- mice. Genome-wide sequencing analyses reveal minimal transcriptional off-targets, demonstrating the specificity of the system. These results demonstrate the feasibility and versatility of methylation editing, to functionally interrogate DNA methylation in vivo.