Faculty Bibliography

BACKGROUND/UNASSIGNED:The complications of coronavirus disease 2019 (COVID-19), the clinical entity caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are not limited to the respiratory system. Leukoencephalopathy with microbleeds is increasingly seen in patients with COVID-19. New information is needed to delineate better the clinical implications of this infectious disease. CASE REPORT/UNASSIGNED:A 46-year-old man with confirmed SARS-CoV-2 infection was admitted to the intensive care unit (ICU) with severe COVID-19. After transfer to the general wards, the patient was noted drowsy, disorientated, with slow thinking and speech. A brain MRI showed bilateral symmetrical hyperintense lesions in the deep and subcortical whiter matter, involving the splenium of the corpus callosum, as well as multiple microhemorrhages implicating the splenium and subcortical white matter. No contrast-enhanced lesions were observed in brain CT or MRI. CSF analysis showed no abnormalities, including a negative rtRT-PCR for SARS-CoV-2. An outpatient follow-up visit showed near-complete clinical recovery and resolution of the hyperintense lesions on MRI, without microbleeds change. CONCLUSION/UNASSIGNED:We present the case of a survivor of severe COVID-19 who presented diffuse posthypoxic leukoencephalopathy, and microbleeds masquerading as acute necrotizing encephalopathy. We postulate that this kind of cerebral vasogenic edema with microbleeds could be the consequence of hypoxia, inflammation, the prothrombotic state and medical interventions such as mechanical ventilation and anticoagulation.

The relationship between anatomic and resting state functional connectivity of large-scale brain networks is a major focus of current research. In previous work, we introduced a model based on eigen decomposition of the Laplacian which predicts the functional network from the structural network in healthy brains. In this work, we apply the eigen decomposition model to two types of epilepsy; temporal lobe epilepsy associated with mesial temporal sclerosis, and MRI-normal temporal lobe epilepsy. Our findings show that the eigen relationship between function and structure holds for patients with temporal lobe epilepsy as well as normal individuals. These results suggest that the brain under TLE conditions reconfigures and rewires the fine-scale connectivity (a process which the model parameters are putatively sensitive to), in order to achieve the necessary structure-function relationship.

COVID-19 associated coagulopathy and mortality related to thrombotic complications have been suggested as biological mediators in racial disparities related to COVID-19. We studied the adjusted prevalence of acute ischemic stroke, pulmonary embolism, myocardial infarction, and deep venous thrombosis stratified by race in hospitalized patients in one New York City borough during the local COVID-19 surge. The multi-racial cohort included 4299 patients hospitalized with COVID-19, 9% of whom were white, 40% black, 41% Hispanic and 10% Asian or other. We found a 6.1% prevalence of composite thrombotic events. There were no significant race-specific differences in thrombotic events when adjusting for basic demographics, socioeconomic factors, medical comorbidities or biomarkers using a stepwise regression model. We therefore found no evidence that the racial disparities related to COVID-19, and specifically thrombotic complications, are caused by biological differences in race.

Freezing of Gait (FoG) is a common symptom in Parkinson's Disease (PD) occurring with significant variability and severity and is associated with increased risk of falls. FoG detection in everyday life is not trivial, particularly in patients manifesting the symptom only in specific conditions. Various wearable devices have been proposed to detect PD symptoms, primarily based on inertial sensors. We here report the results of the validation of a novel system based on a pair of pressure insoles equipped with a 3D accelerometer to detect FoG episodes. Twenty PD patients attended a motor assessment protocol organized into eight multiple video recorded sessions, both in clinical and ecological settings and both in the ON and OFF state. We compared the FoG episodes detected using the processed data gathered from the insoles with those tagged by a clinician on video recordings. The algorithm correctly detected 90% of the episodes. The false positive rate was 6% and the false negative rate 4%. The algorithm reliably detects freezing of gait in clinical settings while performing ecological tasks. This result is promising for freezing of gait detection in everyday life via wearable instrumented insoles that can be integrated into a more complex system for comprehensive motor symptom monitoring in PD.

OBJECTIVE/UNASSIGNED:Findings highlight concerns regarding the usefulness of the RCFT in TLE lateralization, regardless of scoring approach.

BACKGROUND AND PURPOSE/OBJECTIVE:Delayed evaluation of stroke may contribute to COVID-19 pandemic-related morbidity and mortality. This study evaluated patient characteristics, process measures and outcomes associated with the decline in stroke presentation during the early pandemic. METHODS:Volumes of stroke presentations, intravenous thrombolytic administrations, and mechanical thrombectomies from 52 hospitals from January 1-June 30, 2020 were analyzed with piecewise linear regression and linear spline models. Univariate analysis compared pandemic (case) and pre-pandemic (control) groups defined in relation to the nadir of daily strokes during the study period. Significantly different patient characteristics were further evaluated with logistic regression, and significantly different process measures and outcomes were re-analyzed after propensity score matching. RESULTS:Analysis of 7,389 patients found daily stroke volumes decreased 0.91/day from March 12-26 (p < 0.0001), reaching a nadir 35.0% less than expected, and increased 0.15 strokes/day from March 27-June 23, 2020 (p < 0.0001). Intravenous thrombolytic administrations decreased 3.3/week from February 19-March 31 (p = 0.0023), reaching a nadir 33.4% less than expected, and increased 1.4 administrations/week from April 1-June 23 (p < 0.0001). Mechanical thrombectomy volumes decreased by 1.5/week from February 19-March 31, 2020 (p = 0.0039), reaching a nadir 11.3% less than expected. The pandemic group was more likely to ambulate independently at baseline (p = 0.02, OR = 1.60, 95% CI = 1.08-2.42), and less likely to present with mild stroke symptoms (NIH Stroke Scale ≤ 5; p = 0.04, OR = 1.01, 95% CI = 1.00-1.02). Process measures and outcomes of each group did not differ, including door-to-needle time, door-to-puncture time, and successful mechanical thrombectomy rate. CONCLUSION/CONCLUSIONS:Stroke presentations and acute interventions decreased during the early COVID-19 pandemic, at least in part due to patients with lower baseline functional status and milder symptoms not seeking medical care. Public health messaging and initiatives should target these populations.

Programmed cell death protein 1 (PD-1) is a critical inhibitory receptor that limits excessive T cell responses. Cancer cells have evolved to evade these immunoregulatory mechanisms by upregulating PD-1 ligands and preventing T cell mediated anti-tumor responses. Consequently, therapeutic blockade of PD-1 enhances T cell mediated anti-tumor immunity but many patients do not respond and a significant proportion develops inflammatory toxicities. To improve anti-cancer therapy, it is critical to reveal the mechanisms by which PD-1 regulates T cell responses. We performed global quantitative phosphoproteomic interrogation of PD-1 signaling in T cells. By complementing our analysis with functional validation assays, we show that PD-1 targets tyrosine phosphosites that mediate proximal T cell receptor signaling, cytoskeletal organization and immune synapse formation. PD-1 ligation also led to differential phosphorylation of serine and threonine sites within proteins regulating T cell activation, gene expression, and protein translation. In silico predictions revealed kinase/substrate relationships engaged downstream of PD-1 ligation. These insights uncover the phosphoproteomic landscape of PD-1 triggered pathways and reveal novel PD-1 substrates that modulate diverse T cell functions and may serve as future therapeutic targets. These data are a useful resource in the design of future PD-1-targeting therapeutic approaches.

Multiparametric flow cytometry (FC) of CSF allows one to easily estimate the percentage of lymphocyte subpopulations in CSF. We hypothesized that an increased ratio of B-lineage cells in CSF of MS patients, as assessed with FC, could be useful for diagnostics. We analyzed CSF of 137 patients (70 MS, 24 infectious/autoimmune neurologic disorders (INDs), and 43 non-infectious/autoimmune neurologic disorders (NINDs)), and showed that CSF plasmablasts of >0.1% had a sensitivity of 40% for MS and specificity of 92% when comparing MS and IND, while plasmablasts of >0.25% had sensitivity of 36%, and 100% specificity.

BACKGROUND:Among women with epilepsy, studies regarding changes in seizure frequency during pregnancy have been limited by the lack of an appropriate nonpregnant comparator group to provide data on the natural course of seizure frequency in both groups. METHODS:In this prospective, observational, multicenter cohort study, we compared the frequency of seizures during pregnancy through the peripartum period (the first 6 weeks after birth) (epoch 1) with the frequency during the postpartum period (the following 7.5 months after pregnancy) (epoch 2). Nonpregnant women with epilepsy were enrolled as controls and had similar follow-up during an 18-month period. The primary outcome was the percentage of women who had a higher frequency of seizures that impaired awareness during epoch 1 than during epoch 2. We also compared changes in the doses of antiepileptic drugs that were administered in the two groups during the first 9 months of epoch 1. RESULTS:We enrolled 351 pregnant women and 109 controls with epilepsy. Among the 299 pregnant women and 93 controls who had a history of seizures that impaired awareness and who had available data for the two epochs, seizure frequency was higher during epoch 1 than during epoch 2 in 70 pregnant women (23%) and in 23 controls (25%) (odds ratio, 0.93; 95% confidence interval [CI], 0.54 to 1.60). During pregnancy, the dose of an antiepileptic drug was changed at least once in 74% of pregnant women and in 31% of controls (odds ratio, 6.36; 95% CI, 3.82 to 10.59). CONCLUSIONS:Among women with epilepsy, the percentage who had a higher incidence of seizures during pregnancy than during the postpartum period was similar to that in women who were not pregnant during the corresponding epochs. Changes in doses of antiepileptic drugs occurred more frequently in pregnant women than in nonpregnant women during similar time periods. (Funded by the National Institutes of Health; MONEAD ClinicalTrials.gov number, NCT01730170.).

Children with attention deficit hyperactivity disorder (ADHD) have an increased risk of seizures, and children with epilepsy have an increased prevalence of ADHD. Adults with epilepsy often have varying degrees of attentional dysfunction due to multiple factors, including anti-seizure medications, frequent seizures, interictal discharges, underlying lesions, and psychiatric comorbidities. Currently, there are no approved medications for the treatment of epilepsy-related attentional dysfunction. Methylphenidate (MPH) is a stimulant, FDA-approved for the treatment of ADHD, and often used for ADHD in the setting of pediatric epilepsy. Large database and registry studies indicate safety of MPH in children with ADHD and epilepsy, with no significant effect on seizure frequency. Small single-dose and open-label studies suggest efficacy of MPH in adults with epilepsy-related attention deficits. Methylphenidate represents a possible treatment for attentional dysfunction due to epilepsy, but large, randomized, placebo-controlled, double-blinded studies are needed.