Faculty Bibliography

The International League Against Epilepsy (ILAE) seizure classification scheme has been periodically updated to improve its reliability and applicability to clinicians and researchers alike. Here, members of the Epilepsy Study Consortium propose a pragmatic seizure classification, based on the ILAE scheme, designed for use in clinical trials with a focus on outcome measures that have high reliability, broad interpretability across stakeholders, and clinical relevance in the context of the development of novel antiseizure medications. Controversies around the current ILAE classification scheme are discussed in the context of clinical trials, and pragmatic simplifications to the existing scheme are proposed, for intended use by investigators, industry sponsors, and regulatory agencies.

Multiple sclerosis is a chronic immune-mediated disease of the central nervous system that has aspects of repetitive inflammatory activity as well as a slow neurodegenerative process. The immune assault on the nervous system is triggered by a complex interaction between immunogenetic and environmental factors. Among the different environmental factors, a compelling case, buttressed by strong epidemiological, serological and other data, has been made for the role of Epstein-Barr virus (EBV) in the pathogenesis of MS. However, the ubiquity of EBV, lack of a well understood role in MS pathogenesis, and controversies regarding its presence in brains of people with MS has caused debate as to how exactly it contributes to MS. Recent years have seen the remarkable effect of anti-CD20 therapies on the inflammatory component of MS. How B cell depletion results in a salutary effect in MS remains incompletely understood. It has been proposed that depletion of CD20+ B-cells disrupts other pro-inflammatory pathways in the immune system, especially T-cells. In this paper, we make the case that the robust effect of anti-CD20 therapies on MS activity could actually be from removal of circulating EBV-infected memory B-cells that drive CNS inflammation and not through other immune pathways - in essence that this is from an anti-viral effect, and not necessarily an immuno-modulatory effect.

OBJECTIVE:Despite the overall success of responsive neurostimulation (RNS) therapy for drug-resistant focal epilepsy, clinical outcomes in individuals vary significantly and are hard to predict. Biomarkers that indicate the clinical efficacy of RNS-ideally before device implantation-are critically needed, but challenges include the intrinsic heterogeneity of the RNS patient population and variability in clinical management across epilepsy centers. The aim of this study is to use a multicenter dataset to evaluate a candidate biomarker from intracranial electroencephalographic (iEEG) recordings that predicts clinical outcome with subsequent RNS therapy. METHODS:We assembled a federated dataset of iEEG recordings, collected prior to RNS implantation, from a retrospective cohort of 30 patients across three major epilepsy centers. Using ictal iEEG recordings, each center independently calculated network synchronizability, a candidate biomarker indicating the susceptibility of epileptic brain networks to RNS therapy. RESULTS:Ictal measures of synchronizability in the high-γ band (95-105 Hz) significantly distinguish between good and poor RNS responders after at least 3 years of therapy under the current RNS therapy guidelines (area under the curve = .83). Additionally, ictal high-γ synchronizability is inversely associated with the degree of therapeutic response. SIGNIFICANCE/CONCLUSIONS:This study provides a proof-of-concept roadmap for collaborative biomarker evaluation in federated data, where practical considerations impede full data sharing across centers. Our results suggest that network synchronizability can help predict therapeutic response to RNS therapy. With further validation, this biomarker could facilitate patient selection and help avert a costly, invasive intervention in patients who are unlikely to benefit.

OBJECTIVE:To evaluate the role of intracranial electroencephalography monitoring in diagnosing and directing the appropriate therapy for MRI-negative epilepsy and to present the surgical outcomes of patients following treatment. METHODS:Retrospective chart review between 2015-2021 at a single institution identified 48 patients with no lesion on MRI, who received surgical intervention for their epilepsy. The outcomes assessed were the surgical treatment performed and the International League Against Epilepsy seizure outcomes at 1 year of follow-up. RESULTS:Eleven patients underwent surgery without invasive monitoring, including vagus nerve stimulation (10%), deep brain stimulation (8%), laser interstitial thermal therapy (2%), and callosotomy (2%). The remaining 37 patients received invasive monitoring followed by resection (35%), responsive neurostimulation (21%), and deep brain stimulation (15%) or no treatment (6%). At 1 year postoperatively, 39% were Class 1-2, 36% were Class 3-4 and 24% were Class 5. More patients with Class 1-2 or 3-4 outcomes underwent invasive monitoring (100% and 83% respectively) compared with those with poor outcomes (25%, P < .001). Patients with Class 1-2 outcomes more commonly underwent resection or responsive neurostimulation: 69% and 31%, respectively (P < .001). SIGNIFICANCE:The optimal management of MRI-negative focal epilepsy may involve invasive monitoring followed by resection or responsive neurostimulation in most cases, as these treatments were associated with the best seizure outcomes in our cohort. Unless multifocal onset is clear from the noninvasive evaluation, invasive monitoring is preferred before pursuing deep brain stimulation or vagal nerve stimulation directly.

BACKGROUND:Workforce diversity in vascular neurology is a crucial component of reducing disparities in stroke care and outcomes. The objective of this study is to describe trends in the racial and ethnic diversity of neurology residents pursuing vascular neurology fellowship and propose an actionable plan for improvement. METHODS:test for trend). RESULTS:=0.013). CONCLUSIONS:Racial/ethnic underrepresentation among all neurology residents as well as those pursuing vascular neurology fellowship has persisted across the study period. Concerted efforts should be pursued to increase diversity in neurology residents and vascular neurology fellowship training.

The care for the patients with end-stage heart failure has been revolutionized by the introduction of durable left ventricular assist devices, providing a substantial improvement in patient survival and quality of life and an alternative to heart transplantation. The newest devices have lower instances of mechanical dysfunction and associated pump thrombosis. Despite these improvements in complications, the use of continuous flow assist devices is still associated with high rates of thrombotic and hemorrhagic complications, most notably stroke in approximately 10% of continuous flow assist devices patients per year. With the newest HeartMate 3 devices, there have been lower observed rates of stroke, which has in part been achieved by both improvements in pump technology and knowledge of the risk factors for stroke and neurological complications. The therapeutic options available to clinicians to reduce the risk of stroke, including management of hypertension and antithrombotics, will be reviewed in this manuscript.

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.

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.