Faculty Bibliography

Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system (CNS). B lymphocytes in the cerebrospinal fluid (CSF) of MS patients contribute to inflammation and secrete oligoclonal immunoglobulins^1,2. Epstein-Barr virus (EBV) infection has been linked to MS epidemiologically, but its pathological role remains unclear³. Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBNA1 and the CNS protein GlialCAM, and provide structural and in-vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements, and the crystal structure of the EBNA1-peptide epitope in complex with the autoreactive Fab fragment allowed for tracking the development of the naïve EBNA1-restricted antibody to a mature EBNA1/GlialCAM cross-reactive antibody. Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates the mouse model of MS and anti-EBNA1/GlialCAM antibodies are prevalent in MS patients. Our results provide a mechanistic link for the association between MS and EBV, and could guide the development of novel MS therapies.

Background: Sturge-Weber syndrome (SWS) involves the skin, brain, and eyes. The dermatologic manifestation is the facial port wine birthmark (PWB), while there are several potential neurologic and ophthalmologic manifestations, notably epilepsy and glaucoma, respectively. This consensus aims to develop evidence-based expert-defined recommendations for management of the neurologic and ophthalmic features and provides a framework for dermatologists to determine workup for patients with PWB who seek laser treatment. Study Design/Materials and Method: Thirteen national experts in neurology, radiology, and ophthalmology were assembled as part of a larger consensus statement for the management of SWS. Key topics and questions regarding risk stratification, referral indications, and treatment were formulated. A systematic PubMed search was performed. Evidence-based recommendations were developed.
Result(s): High-risk PWB distributions involve the hemifacial, forehead, or median locations, including the upper eyelids, especially when concerned for glaucoma. Any child with a high-risk facial PWB should be referred to a pediatric neurologist and pediatric ophthalmologist for a baseline evaluation, with periodic follow-up. Routine screening for brain involvement is not recommended for newborns and infants with a high-risk PWB and no history of seizures or neurological symptoms but can be performed in cases of extreme parental anxiety, an abnormal EEG, or when presymptomatic treatment is contemplated such as with extensive bilateral PWB. In children with stable neurocognitive symptoms, routine follow-up neuroimaging is not advised. In adults with a high-risk PWB and no prior imaging, neuroimaging should be obtained, but follow-up neuroimaging is not recommended in adults with established SWS and stable neurocognitive symptoms. The treatment of glaucoma varies depending on the patient's age and clinical presentation.
Conclusion(s): Recommendations were developed by experts in neurology, neuroradiology, and ophthalmology. These guidelines can guide evidence-based discussions between patients and providers and increase dermatologists' awareness regarding when and what workup is necessary in patients seeking laser treatment for PWB

The dominant paradigm in turbulent wall flows is that the mean velocity near the wall, when scaled on wall variables, is independent of the friction Reynolds number. This paradigm faces challenges when applied to fluctuations but has received serious attention only recently. Here, by extending our earlier work (Chen & Sreenivasan, J. Fluid Mech., vol. 908, 2021, p. R3) we present a promising perspective, and support it with data, that fluctuations displaying non-zero wall values, or near-wall peaks, are bounded for large values of, owing to the natural constraint that the dissipation rate is bounded. Specifically, where represents the maximum value of any of the following quantities: energy dissipation rate, turbulent diffusion, fluctuations of pressure, streamwise and spanwise velocities, squares of vorticity components, and the wall values of pressure and shear stresses; the subscript denotes the bounded asymptotic value of, and the coefficient depends on but not on. Moreover, there exists a scaling law for the maximum value in the wall-normal direction of high-order moments, of the form, where represents the streamwise or spanwise velocity fluctuation, and and are independent of. Excellent agreement with available data is observed. A stochastic process for which the random variable has the form just mentioned, referred to here as the 'linear -norm Gaussian', is proposed to explain the observed linear dependence of on.

Despite increased neuroscience interest at the undergraduate level, a significant shortage of neurologists in the United States (US) exists. To better understand how to generate more interest in neurology specifically at the undergraduate level, we conducted an anonymous cross-sectional online survey of 1085 undergraduates either in neuroscience courses or majoring/minoring in neuroscience from across the US to better understand their clinical neurology experiences and perspectives. The survey quantitatively and qualitatively assessed students' clinical neurology exposure inside and outside of the classroom, research experiences and career goals. Students were from a broad spectrum of undergraduate institutions (public research university (40.8%), liberal arts College (29.7%) and private research university (29.0%). Most students (89.9%) were looking to pursue graduate studies; 56.9% reported wanting to be a physician and 17.8% expressed interest in obtaining an MD/PhD. Importantly, students reported first exposure to neuroscience at age 16 but felt that they could be exposed to neuroscience as early as 13. Half (50.5%) decided to major in neuroscience before college and a quarter (25.6%) decided to major in their first year of college. Despite high interest in clinical neurology exposure, less than one-third of students had spoken with or shadowed a neurologist, and only 13.6% had interacted with clinical neurology populations. Only 20.8% of students felt volunteer and internship opportunities were sufficiently available. Qualitative results include student perspectives from those who did and did not work with a neurologist, describing how they were or were not able to obtain such opportunities. We discuss translating the survey findings into actionable results with opportunities to target the undergraduate neuroscience interest to improve the neurology pipeline. We describe existing programs that could be integrated into everyday neurology practices and new approaches to learning and training to help leverage the significant undergraduate neuroscience interest. We also raise questions for further research, including exploring (1) how students learn of neurologic conditions/expand their knowledge about additional neurologic conditions, (2) whether qualitative investigation of the experiences of neuroscience undergraduates at specific institutions might provide additional insight, and (3) systems to maintain interest in neuroscience/neurology as students enter medical school.

Importance:Current guidelines recommend against use of intravenous alteplase in patients with acute ischemic stroke who are taking non-vitamin K antagonist oral anticoagulants (NOACs). Objective:To evaluate the safety and functional outcomes of intravenous alteplase among patients who were taking NOACs prior to stroke and compare outcomes with patients who were not taking long-term anticoagulants. Design, Setting, and Participants:A retrospective cohort study of 163 038 patients with acute ischemic stroke either taking NOACs or not taking anticoagulants prior to stroke and treated with intravenous alteplase within 4.5 hours of symptom onset at 1752 US hospitals participating in the Get With The Guidelines-Stroke program between April 2015 and March 2020, with complementary data from the Addressing Real-world Anticoagulant Management Issues in Stroke registry. Exposures:Prestroke treatment with NOACs within 7 days prior to alteplase treatment. Main Outcomes and Measures:The primary outcome was symptomatic intracranial hemorrhage occurring within 36 hours after intravenous alteplase administration. There were 4 secondary safety outcomes, including inpatient mortality, and 7 secondary functional outcomes assessed at hospital discharge, including the proportion of patients discharged home. Results:Of 163 038 patients treated with intravenous alteplase (median age, 70 [IQR, 59 to 81] years; 49.1% women), 2207 (1.4%) were taking NOACs and 160 831 (98.6%) were not taking anticoagulants prior to their stroke. Patients taking NOACs were older (median age, 75 [IQR, 64 to 82] years vs 70 [IQR, 58 to 81] years for those not taking anticoagulants), had a higher prevalence of cardiovascular comorbidities, and experienced more severe strokes (median National Institutes of Health Stroke Scale score, 10 [IQR, 5 to 17] vs 7 [IQR, 4 to 14]) (all standardized differences >10). The unadjusted rate of symptomatic intracranial hemorrhage was 3.7% (95% CI, 2.9% to 4.5%) for patients taking NOACs vs 3.2% (95% CI, 3.1% to 3.3%) for patients not taking anticoagulants. After adjusting for baseline clinical factors, the risk of symptomatic intracranial hemorrhage was not significantly different between groups (adjusted odds ratio [OR], 0.88 [95% CI, 0.70 to 1.10]; adjusted risk difference [RD], -0.51% [95% CI, -1.36% to 0.34%]). There were no significant differences in the secondary safety outcomes, including inpatient mortality (6.3% for patients taking NOACs vs 4.9% for patients not taking anticoagulants; adjusted OR, 0.84 [95% CI, 0.69 to 1.01]; adjusted RD, -1.20% [95% CI, -2.39% to -0%]). Of the secondary functional outcomes, 4 of 7 showed significant differences in favor of the NOAC group after adjustment, including the proportion of patients discharged home (45.9% vs 53.6% for patients not taking anticoagulants; adjusted OR, 1.17 [95% CI, 1.06 to 1.29]; adjusted RD, 3.84% [95% CI, 1.46% to 6.22%]). Conclusions and Relevance:Among patients with acute ischemic stroke treated with intravenous alteplase, use of NOACs within the preceding 7 days, compared with no use of anticoagulants, was not associated with a significantly increased risk of intracranial hemorrhage.

INTRODUCTION/UNASSIGNED:Little is known about chaplains' views on brain death/death by neurologic criteria (BD/DNC). Thematic analysis of comments made by hospital chaplains about BD/DNC can illuminate their perspectives on working with patients, families, and interdisciplinary teams during assessment for BD/DNC. MATERIALS AND METHODS/UNASSIGNED:In an electronic survey distributed to members of five chaplaincy organizations between February and July 2019, we elicited free-text comments about BD/DNC. We performed a thematic analysis of the comments. RESULTS/UNASSIGNED:Four themes were present: (1) definition of life and death, (2) respect with a subtheme of physician obligation, (3) collaboration with a subtheme of communication, and (4) education with a subtheme of scepticism. CONCLUSIONS/UNASSIGNED:Hospital chaplains are essential members of the interdisciplinary team involved in BD/DNC evaluation. They aim to ensure the interaction between families and the interdisciplinary team at the boundary of life and death and the intersection between religion and medicine is respectful, collaborative, and educational.

Ambiguous images elicit bistable perception, wherein periods of momentary perceptual stability are interrupted by sudden perceptual switches. When intermittently presented, ambiguous images trigger a perceptual memory trace in the intervening blank periods. Understanding the neural bases of perceptual stability and perceptual memory during bistable perception may hold clues for explaining the apparent stability of visual experience in the natural world, where ambiguous and fleeting images are prevalent. Motivated by recent work showing the involvement of the right inferior frontal gyrus (rIFG) in bistable perception, we conducted a transcranial direct-current stimulation (tDCS) study with a double-blind, within-subject cross-over design to test a potential causal role of rIFG in these processes. Subjects viewed ambiguous images presented continuously or intermittently while under EEG recording. We did not find any significant tDCS effect on perceptual behavior. However, the fluctuations of oscillatory power in the alpha and beta bands predicted perceptual stability, with higher power corresponding to longer percept durations. In addition, higher alpha and beta power predicted enhanced perceptual memory during intermittent viewing. These results reveal a unified neurophysiological mechanism sustaining perceptual stability and perceptual memory when the visual system is faced with ambiguous input.

The standard neurology clinical experience in medical school focuses primarily on bedside patient encounters; however, the limitations of the clinical environment due to the current COVID-19 pandemic have accelerated the need for virtual curriculum development. To provide guidance to Neurology clerkship directors during this unprecedented time, the American Academy of Neurology (AAN) Undergraduate Education Subcommittee (UES) formed a workgroup to develop an outline for a virtual curriculum, provide recommendations, and describe models of integrating virtual curricula into the neurology clerkship. In this overview, we discuss different methods of virtual instruction, hybrid models of clerkship training and the challenges to its implementation, professionalism issues, and modification of feedback and assessment techniques specific to the virtual learning environment. We also offer suggestions for implementation of a hybrid virtual curriculum into the neurology clerkship. The virtual curriculum is intended to supplement the core neurology in-person clinical experience and should not be used for shortening or replacing the required neurology clinical clerkship.

INTRODUCTION/BACKGROUND:The neurofibromatoses (NF) are a group of rare, genetic diseases sharing a predisposition to develop multiple benign nervous system tumors. Given the wide range of NF symptoms and medical specialties involved in NF care, we sought to evaluate the level of awareness of, and agreement with, published NF clinical guidelines among NF specialists in the United States. METHODS:An anonymous, cross-sectional, online survey was distributed to U.S.-based NF clinicians. Respondents self-reported demographics, practice characteristics, awareness of seven NF guideline publications, and level of agreement with up to 40 individual recommendations using a 5-point Likert scale. We calculated the proportion of recommendations that each clinician rated "strongly agree", and assessed for differences in guideline awareness and agreement by respondent characteristics. RESULTS:Sixty-three clinicians (49% female; 80% academic practice) across > 8 medical specialties completed the survey. Awareness of each guideline publication ranged from 53%-79% of respondents; specialists had higher awareness of publications endorsed by their medical professional organization (p < 0.05). The proportion of respondents who "strongly agree" with individual recommendations ranged from 17%-83%; for 16 guidelines, less than 50% of respondents "strongly agree". There were no significant differences in overall agreement with recommendations based on clinicians' gender, race, specialty, years in practice, practice type (academic/private practice/other), practice location (urban/suburban/rural), or involvement in NF research (p > 0.05 for all). CONCLUSIONS:We identified wide variability in both awareness of, and agreement with, published NF care guidelines among NF experts. Future quality improvement efforts should focus on evidence-based, consensus-driven methods to update and disseminate guidelines across this multi-specialty group of providers. Patients and caregivers should also be consulted to proactively anticipate barriers to accessing and implementing guideline-driven care. These recommendations for improving guideline knowledge and adoption may also be useful for other rare diseases requiring multi-specialty care coordination.