Faculty Bibliography

OBJECTIVES/OBJECTIVE:To determine whether neuronal and neuroaxonal injury, neuroinflammation and synaptic dysfunction associate with clinical course and outcomes in antibody-mediated encephalitis (AME), we measured biomarkers of these processes in CSF from patients presenting with AME and cognitively normal individuals. METHODS:Biomarkers of neuronal (total-tau, VILIP-1) and neuroaxonal damage (neurofilament light chain [NfL]), inflammation (YKL-40) and synaptic function (neurogranin, SNAP-25) were measured in CSF obtained from 45 patients at the time of diagnosis of NMDA receptor (n=34) or LGI1/CASPR-2 (n=11) AME, and 39 age- and sex-similar cognitively normal individuals. The association between biomarkers and modified Rankin Scores were evaluated in a subset (n=20) of longitudinally followed patients. RESULTS:(YKL-40/SNAP-25) [(ρ=0.48; p=0.04] associated with greater disease severity (higher modified Rankin Score) in prospectively followed patients. Higher YKL-40 (ρ=0.60; p=0.02) and neurogranin (ρ=0.55; p=0.03) at presentation were associated with higher modified Rankin Scores 12-months following hospital discharge. CONCLUSIONS:CSF biomarkers suggest that neuronal integrity is acutely maintained in AME patients, despite neuroaxonal compromise. Low-levels of biomarkers of synaptic function may reflect antibody-mediated internalization of cell-surface receptors, and may represent an acute correlate of antibody-mediated synaptic dysfunction, with the potential to inform disease severity and outcomes.

Responsive neurostimulation is increasingly required to probe neural circuit function and treat neuropsychiatric disorders. We introduce a multiplex-then-amplify (MTA) scheme that, in contrast to current approaches (which necessitate an equal number of amplifiers as number of channels), only requires one amplifier per multiplexer, significantly reducing the number of components and the size of electronics in multichannel acquisition systems. It also enables simultaneous stimulation of arbitrary waveforms on multiple independent channels. We validated the function of MTA by developing a fully implantable, responsive embedded system that merges the ability to acquire individual neural action potentials using conformable conducting polymer-based electrodes with real-time onboard processing, low-latency arbitrary waveform stimulation, and local data storage within a miniaturized physical footprint. We verified established responsive neurostimulation protocols and developed a network intervention to suppress pathological coupling between the hippocampus and cortex during interictal epileptiform discharges. The MTA design enables effective, self-contained, chronic neural network manipulation with translational relevance to the treatment of neuropsychiatric disease.

BACKGROUND/UNASSIGNED:There are multiple factors that may cause end-of-life conflict in the critical care setting. These include severe illness, family distress, lack of awareness about a patient's wishes, prognostic uncertainty, and the participation of multiple providers in goals-of-care discussions. METHODS/UNASSIGNED:Case report and discussion of the associated ethical issues. RESULTS/UNASSIGNED:We present a case of a patient with a pontine stroke, in which the family struggled with decision-making about goals-of-care, leading to fluctuation in code status from Full Code to Do Not Resuscitate-Comfort Care, then back to Full Code, and finally to Do Not Resuscitate-Do Not Intubate. We discuss factors that contributed to this situation and methods to avoid conflict. Additionally, we review the effects of discord at the end-of-life on patients, families, and the healthcare team. CONCLUSION/UNASSIGNED:It is imperative that healthcare teams proactively collaborate with families to minimize end-of-life conflict by emphasizing decision-making that prioritizes the best interest and autonomy of the patient.

The neural mechanisms underlying conscious recognition remain unclear, particularly the roles played by the prefrontal cortex, deactivated brain areas and subcortical regions. We investigated neural activity during conscious object recognition using 7 Tesla fMRI while human participants viewed object images presented at liminal contrasts. Here, we show both recognized and unrecognized images recruit widely distributed cortical and subcortical regions; however, recognized images elicit enhanced activation of visual, frontoparietal, and subcortical networks and stronger deactivation of the default-mode network. For recognized images, object category information can be decoded from all of the involved cortical networks but not from subcortical regions. Phase-scrambled images trigger strong involvement of inferior frontal junction, anterior cingulate cortex and default-mode network, implicating these regions in inferential processing under increased uncertainty. Our results indicate that content-specific activity in both activated and deactivated cortical networks and non-content-specific subcortical activity support conscious recognition.

BACKGROUND:Assessing the impact of coronavirus disease 2019 (COVID-19) on intensive care unit (ICU) providers' perceptions of resource availability and evaluating the factors associated with emotional distress/burnout can inform interventions to promote provider well-being. METHODS:Between 23 April and 7 May 2020, we electronically administered a survey to physicians, nurses, respiratory therapists (RTs), and advanced practice providers (APPs) caring for COVID-19 patients in the United States. We conducted a multivariate regression to assess associations between concerns, a reported lack of resources, and 3 outcomes: a primary outcome of emotional distress/burnout and 2 secondary outcomes of (1) fear that the hospital is unable to keep providers safe; and (2) concern about transmitting COVID-19 to their families/communities. RESULTS:We included 1651 respondents from all 50 states: 47% were nurses, 25% physicians, 17% RTs, and 11% APPs. Shortages of intensivists and ICU nurses were reported by 12% and 28% of providers, respectively. The largest supply restrictions reported were for powered air purifying respirators (56% reporting restricted availability). Provider concerns included worries about transmitting COVID-19 to their families/communities (66%), emotional distress/burnout (58%), and insufficient personal protective equipment (PPE; 40%). After adjustment, emotional distress/burnout was significantly associated with insufficient PPE access (adjusted relative risk [aRR], 1.43; 95% confidence interval [CI], 1.32-1.55), stigma from community (aRR, 1.32; 95% CI, 1.24-1.41), and poor communication with supervisors (aRR, 1.13; 95% CI, 1.06-1.21). Insufficient PPE access was the strongest predictor of feeling that the hospital is unable to keep providers safe and worries about transmitting infection to their families/communities. CONCLUSIONS:Addressing insufficient PPE access, poor communication from supervisors, and community stigma may improve provider mental well-being during the COVID-19 pandemic.

Rett syndrome (RTT) is a rare neurodevelopmental disorder that is usually caused by mutations of the MECP2 gene. Patients with RTT suffer from severe deficits in motor, perceptual and cognitive domains. Electroencephalogram (EEG) has provided useful information to clinicians and scientists, from the very first descriptions of RTT, and yet no reliable neurophysiological biomarkers related to the pathophysiology of the disorder or symptom severity have been identified to date. To identify consistently observed and potentially informative EEG characteristics of RTT pathophysiology, and ascertain areas most worthy of further systematic investigation, here we review the literature for EEG abnormalities reported in patients with RTT and in its disease models. While pointing to some promising potential EEG biomarkers of RTT, our review identify areas of need to realize the potential of EEG including (1) quantitative investigation of promising clinical-EEG observations in RTT, e.g., shift of mu rhythm frequency and EEG during sleep; (2) closer alignment of approaches between patients with RTT and its animal models to strengthen the translational significance of the work (e.g., EEG measurements and behavioral states); (3) establishment of large-scale consortium research, to provide adequate Ns to investigate age and genotype effects.

BACKGROUND AND PURPOSE/OBJECTIVE:The National Institutes of Health Stroke Scale (NIHSS) measured at an early time point is an appealing surrogate marker for long-term functional outcome of stroke patients treated with endovascular therapy. However, definitions and analytical methods for an early NIHSS-based outcome measure that optimize power and precision in clinical studies are not well-established. METHODS:In this post-hoc analysis of our prospective observational study that enrolled endovascular therapy-treated patients at 12 comprehensive stroke centers across the US, we compared the ability of 24-hour NIHSS, ΔNIHSS (baseline minus 24-hour NIHSS), and percentage change (NIHSS×100/baseline NIHSS), analyzed as continuous and dichotomous measures, to predict 90-day modified Rankin Scale (mRS) using logistic regression (adjusted for age, baseline NIHSS, glucose, hypertension, Alberta Stroke Program Early CT Score, time to recanalization, recanalization status, and intravenous thrombolysis) and Spearman ρ. RESULTS:<0.001). CONCLUSIONS:Twenty-four-hour NIHSS, adjusted for baseline, was the strongest predictor of both dichotomous and ordinal 90-day mRS outcomes for endovascular therapy-treated patients. A dichotomous 24-hour NIHSS score of ≤7 was the second-best predictor. Although ΔNIHSS, continuous and dichotomized at ≥4, predicted 90-day outcomes, absolute 24-hour NIHSS definitions performed better.

Electromyography (EMG)-driven neuromusculoskeletal modeling (NMSM) enables simulating the mechanical function of multiple muscle-tendon units as controlled by nervous system in the generation of complex movements. In the context of clinical assessment this may enable understanding biomechanical factor contributing to gait disorders such as one induced by Parkinson's disease (PD). In spite of the challenges in the development of patient-specific models, this preliminary study aimed at establishing a feasible and noninvasive experimental and modeling pipeline to be adopted in clinics to detect PD-induced gait alterations. Four different NMSM have been implemented for three healthy controls using CEINMS, an OpenSim-compatible toolbox. Models differed in the EMG-normalization methods used for calibration purposes (i.e. walking trial normalization and maximum voluntary contraction normalization) and in the set of experimental EMGs used for the musculotendon-unit mapping (i.e. 4 channels vs. 15 channels). Model accuracy assessment showed no statistically significant differences between the more complete model (non-clinically viable) and the proposed reduced one (clinically viable). The clinically viable reduced model was systematically applied on a dataset including ten PD's and thirteen healthy controls. Results showed significant differences in the neuromuscular control strategy of the PD group in term of muscle forces and joint torques. Indeed, PD patients displayed a significantly lower magnitude on force production and revealed a higher amount of force variability with the respect of the healthy controls. The estimated variables could become a measurable biomechanical outcome to assess and track both disease progression and its impact on gait in PD subjects.

We reviewed the literature on cerebrospinal fluid (CSF) studies in patients who had a seizure in the setting of COVID-19 infection to evaluate for evidence of viral neuroinvasion. We performed a systematic review of Medline and Embase to identify publications that reported one or more patients with COVID-19 who had a seizure and had CSF testing preformed. The search ranged from December 1st 2019 to November 18th 2020. We identified 56 publications which described 69 unique patients who met our inclusion criteria. Of the 54 patients whose past medical history was provided, 2 (4%) had epilepsy and 1 (2%) had a prior seizure in the setting of hyperglycemia, but the remaining 51 (94%) had no history of seizures. Seizure was the initial symptom of COVID-19 for 15 (22%) patients. There were 26 (40%) patients who developed status epilepticus. SARS-CoV-2 PCR testing was performed in the CSF for 45 patients; 6 (13%) had a positive CSF SARS-CoV-2 PCR, only 1 (17%) of whom had status epilepticus. The cycle thresholds were not reported. Evaluation for CSF SARS-CoV-2 antibodies (directly or indirectly, via testing for CSF oligoclonal bands or immunoglobulins) was performed in 26 patients, only 2 (8%) of whom had evidence of intrathecal antibody synthesis. Of the 11 patients who had CSF autoimmune antibody panels tested, 1 had NMDA antibodies and 1 had Caspr-2 antibodies. Detection of SARS-CoV-2 in the CSF of patients with seizures who have COVID-19 is uncommon. Our review suggests that seizures in this patient population are not likely due to direct viral invasion of the brain.

OBJECTIVE:To determine the long-term safety and tolerability profile of M207 in the acute treatment of migraine. BACKGROUND:M207 is an investigational microneedle-based system for intracutaneous delivery of zolmitriptan for the treatment of migraine attacks. Following on the positive results of a Phase 2/3 placebo-controlled efficacy study (ZOTRIP), this study was designed to evaluate the safety of this novel product during repeated use for the treatment of migraine attacks. METHODS:In this 6-12 month open-label, multicenter observational study, participants used an eDiary to record headache symptoms and adverse events at specified intervals up to 48 h following treatment of a qualifying attack with M207 3.8 mg (intracutaneous zolmitriptan). Participants underwent clinical evaluations at specified intervals up to 12 months. RESULTS:Among 335 participants who treated ≥1 migraine attack, 257 completed 6 months and 127 completed 1 year of treatment. The most common reason for withdrawal from the study was a low frequency of reported attacks post randomization. Overall, 5963 migraine attacks were treated. Most participants (96%) experienced at least 1 adverse event, the vast majority of which concerned the application site, and > 95% of which were mild. Fifteen participants (4%) withdrew due to adverse events; 4 withdrew due to 7 application site reactions, 6 of which were mild. Participants achieved pain freedom in 2477/5617 (44%) of attacks, most bothersome symptom freedom in 3315/5330 (62%) of attacks, and pain relief 2 h post-dose in 4552/5617 (81%) of attacks. Sustained pain freedom 2-24 h was seen in 1761/4698 (38%) of attacks, and 2-48 h in 1534/4429 (35%) of attacks. CONCLUSIONS:The majority of participants experienced cutaneous adverse reactions such as application site erythema, swelling, and bleeding, and most reactions were scored as mild. These results are consistent with what was observed in the single migraine attack treatment ZOTRIP trial indicating that M207 is well tolerated in the setting of longer-term repeated use. Efficacy findings were also similar to those in the ZOTRIP trial. TRIAL REGISTRATION/BACKGROUND:Clinicaltrials.gov on September 13, 2017 ( NCT03282227 ).