Faculty Bibliography

BACKGROUND:Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by the aggregation of α-synuclein in glia and neurons. Sirolimus (rapamycin) is an mTOR inhibitor that promotes α-synuclein autophagy and reduces its associated neurotoxicity in preclinical models. OBJECTIVE:To investigate the efficacy and safety of sirolimus in patients with MSA using a futility design. We also analyzed 1-year biomarker trajectories in the trial participants. METHODS:Randomized, double-blind, parallel group, placebo-controlled clinical trial at the New York University of patients with probable MSA randomly assigned (3:1) to sirolimus (2-6 mg daily) for 48 weeks or placebo. Primary endpoint was change in the Unified MSA Rating Scale (UMSARS) total score from baseline to 48 weeks. (ClinicalTrials.gov NCT03589976). RESULTS:The trial was stopped after a pre-planned interim analysis met futility criteria. Between August 15, 2018 and November 15, 2020, 54 participants were screened, and 47 enrolled and randomly assigned (35 sirolimus, 12 placebo). Of those randomized, 34 were included in the intention-to-treat analysis. There was no difference in change from baseline to week 48 between the sirolimus and placebo in UMSARS total score (mean difference, 2.66; 95% CI, -7.35-6.91; P = 0.648). There was no difference in UMSARS-1 and UMSARS-2 scores either. UMSARS scores changes were similar to those reported in natural history studies. Neuroimaging and blood biomarker results were similar in the sirolimus and placebo groups. Adverse events were more frequent with sirolimus. Analysis of 1-year biomarker trajectories in all participants showed that increases in blood neurofilament light chain (NfL) and reductions in whole brain volume correlated best with UMSARS progression. CONCLUSIONS:Sirolimus for 48 weeks was futile to slow the progression of MSA and had no effect on biomarkers compared to placebo. One-year change in blood NfL and whole brain atrophy are promising biomarkers of disease progression for future clinical trials. © 2022 International Parkinson and Movement Disorder Society.

The Uniform Determination of Death Act (UDDA), the recommended legal statute for determination of death in the United States, was initially formulated in 1981. Forty years later, because of the concerns of experts in medicine, law, ethics, and philosophy, the Uniform Law Commission (ULC) created a drafting committee to update the UDDA. The drafting committee, which has until 2023 to propose revisions to the ULC Executive Committee, will need to determine how to address the following key questions about the UDDA: (1) Should the term "irreversible" be replaced by the term "permanent"? (2) Is absence of hypothalamic-pituitary-axis-induced antidiuretic hormone secretion included in "all functions of the entire brain," and if so, how can we reconcile the fact that this is not tested in the medical standards for determination of death by neurologic criteria published by the American Academy of Neurology and the Society of Critical Care Medicine, American Academy of Pediatrics, and Child Neurology Society? (3) What are the accepted medical standards for determination of death? (4) Is consent needed to determine death? and (5) How should objections to the use of neurologic criteria to declare death be handled? Once the ULC finalizes revisions to the UDDA, individual states will have the opportunity to decide whether to adopt the revisions in whole or in part. Hopefully, the revised UDDA will provide clarity and consistency about the legal distinction between life and death for physicians, lawyers, and the public at large. The events that led to the formation of the drafting committee and the potential consequences of revising the UDDA are discussed herein.

Light flashes, patterns, or color changes can provoke seizures in up to 1 in 4000 persons. Prevalence may be higher because of selection bias. The Epilepsy Foundation reviewed light-induced seizures in 2005. Since then, images on social media, virtual reality, three-dimensional (3D) movies, and the Internet have proliferated. Hundreds of studies have explored the mechanisms and presentations of photosensitive seizures, justifying an updated review. This literature summary derives from a nonsystematic literature review via PubMed using the terms "photosensitive" and "epilepsy." The photoparoxysmal response (PPR) is an electroencephalography (EEG) phenomenon, and photosensitive seizures (PS) are seizures provoked by visual stimulation. Photosensitivity is more common in the young and in specific forms of generalized epilepsy. PS can coexist with spontaneous seizures. PS are hereditable and linked to recently identified genes. Brain imaging usually is normal, but special studies imaging white matter tracts demonstrate abnormal connectivity. Occipital cortex and connected regions are hyperexcitable in subjects with light-provoked seizures. Mechanisms remain unclear. Video games, social media clips, occasional movies, and natural stimuli can provoke PS. Virtual reality and 3D images so far appear benign unless they contain specific provocative content, for example, flashes. Images with flashes brighter than 20 candelas/m² at 3-60 (particularly 15-20) Hz occupying at least 10 to 25% of the visual field are a risk, as are red color flashes or oscillating stripes. Equipment to assay for these characteristics is probably underutilized. Prevention of seizures includes avoiding provocative stimuli, covering one eye, wearing dark glasses, sitting at least two meters from screens, reducing contrast, and taking certain antiseizure drugs. Measurement of PPR suppression in a photosensitivity model can screen putative antiseizure drugs. Some countries regulate media to reduce risk. Visually-induced seizures remain significant public health hazards so they warrant ongoing scientific and regulatory efforts and public education.

Understanding how consciousness arises from neural activity remains one of the biggest challenges for neuroscience. Numerous theories have been proposed in recent years, each gaining independent empirical support. Currently, there is no comprehensive, quantitative and theory-neutral overview of the field that enables an evaluation of how theoretical frameworks interact with empirical research. We provide a bird's eye view of studies that interpreted their findings in light of at least one of four leading neuroscientific theories of consciousness (N = 412 experiments), asking how methodological choices of the researchers might affect the final conclusions. We found that supporting a specific theory can be predicted solely from methodological choices, irrespective of findings. Furthermore, most studies interpret their findings post hoc, rather than a priori testing critical predictions of the theories. Our results highlight challenges for the field and provide researchers with an open-access website ( https://ContrastDB.tau.ac.il ) to further analyse trends in the neuroscience of consciousness.

BACKGROUND:Early neurorehabilitation improves outcomes in patients with disorders of consciousness (DoC) after brain injury, but its applicability in COVID-19 is unknown. We describe our experience implementing an early neurorehabilitation protocol for patients with COVID-19-associated DoC in the intensive care unit (ICU) and evaluate factors associated with recovery. METHODS:During the initial COVID-19 surge in New York City between March 10 and May 20, 2020, faced with a disproportionately high number of ICU patients with prolonged unresponsiveness, we developed and implemented an early neurorehabilitation protocol, applying standard practices from brain injury rehabilitation care to the ICU setting. Twenty-one patients with delayed recovery of consciousness after severe COVID-19 participated in a pilot early neurorehabilitation program that included serial Coma Recovery Scale-Revised (CRS-R) assessments, multimodal treatment, and access to clinicians specializing in brain injury medicine. We retrospectively compared clinical features of patients who did and did not recover to the minimally conscious state (MCS) or better, defined as a CRS-R total score (TS) ≥ 8, before discharge. We additionally examined factors associated with best CRS-R TS, last CRS-R TS, hospital length of stay, and time on mechanical ventilation. RESULTS:Patients underwent CRS-R assessments a median of six (interquartile range [IQR] 3-10) times before discharge, beginning a median of 48 days (IQR 40-55) from admission. Twelve (57%) patients recovered to MCS after a median of 8 days (IQR 2-14) off continuous sedation; they had lower body mass index (p = 0.009), lower peak serum C-reactive protein levels (p = 0.023), higher minimum arterial partial pressure of oxygen (p = 0.028), and earlier fentanyl discontinuation (p = 0.018). CRS-R scores fluctuated over time, and the best CRS-R TS was significantly higher than the last CRS-R TS (median 8 [IQR 5-23] vs. 5 [IQR 3-18], p = 0.002). Earlier fentanyl (p = 0.001) and neuromuscular blockade (p = 0.015) discontinuation correlated with a higher last CRS-R TS. CONCLUSIONS:More than half of our cohort of patients with prolonged unresponsiveness following severe COVID-19 recovered to MCS or better before hospital discharge, achieving a clinical benchmark known to have relatively favorable long-term prognostic implications in DoC of other etiologies. Hypoxia, systemic inflammation, sedation, and neuromuscular blockade may impact diagnostic assessment and prognosis, and fluctuations in level of consciousness make serial assessments essential. Early neurorehabilitation of these patients in the ICU can be accomplished but is associated with unique challenges. Further research should evaluate factors associated with longer-term neurologic recovery and benefits of early rehabilitation in patients with severe COVID-19.

OBJECTIVES/OBJECTIVE:Medical cannabis formulations with cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) are widely used to treat epilepsy. We studied the safety and efficacy of two formulations. METHODS:We prospectively observed 29 subjects (12 to 46 years old) with treatment-resistant epilepsies (11 Lennox-Gastaut syndrome; 15 with focal or multifocal epilepsy; three generalized epilepsy) were treated with medical cannabis (1THC:20CBD and/or 1THC:50CBD; maximum of 6 mg THC/day) for ≥24 weeks. The primary outcome was change in convulsive seizure frequency from the pre-treatment baseline to the stable optimal dose phase. RESULTS:There were no significant differences during treatment on stable maximal doses for convulsive seizure frequency, seizure duration, postictal duration, or use of rescue medications compared to baseline. No benefits were seen for behavioral disorders or sleep duration; there was a trend for more frequent bowel movements compared to baseline. Ten adverse events occurred in 6/29 patients, all were transient and most unrelated to study medication. No serious adverse events were related to study medication. INTERPRETATION/CONCLUSIONS:Our prospective observational study of two high-CBD/low-THC formulations found no evidence of efficacy in reducing seizures, seizure duration, postictal duration, or rescue medication use. Behavioral disorders or sleep duration was unchanged. Study medication was generally well tolerated. The doses of CBD used were lower than prior studies. Randomized trials with larger cohorts are needed, but we found no evidence of efficacy for two CBD:THC products in treating epilepsy, sleep, or behavior in our population.

BACKGROUND:To analyse the clinical characteristics of COVID-19 with acute ischaemic stroke (AIS) and identify factors predicting functional outcome. METHODS:Multicentre retrospective cohort study of COVID-19 patients with AIS who presented to 30 stroke centres in the USA and Canada between 14 March and 30 August 2020. The primary endpoint was poor functional outcome, defined as a modified Rankin Scale (mRS) of 5 or 6 at discharge. Secondary endpoints include favourable outcome (mRS ≤2) and mortality at discharge, ordinal mRS (shift analysis), symptomatic intracranial haemorrhage (sICH) and occurrence of in-hospital complications. RESULTS:A total of 230 COVID-19 patients with AIS were included. 67.0% (154/230) were older than 60 years, while 33.0% (76/230) were younger. Median (IQR) National Institutes of Health Stroke Scale (NIHSS) at presentation was 12.0 (17.0) and 42.8% (89/208) presented with large vessel occlusion (LVO). Approximately 50.2% (102/203) of the patients had poor outcomes with an observed mortality rate of 38.8% (35/219). Age >60 years (aOR: 4.60, 95% CI 1.89 to 12.15, p=0.001), diabetes mellitus (aOR: 2.53, 95% CI 1.14 to 5.79, p=0.025), increased NIHSS at admission (aOR: 1.10, 95% CI 1.05 to 1.16, p<0.001), LVO (aOR: 3.02, 95% CI 1.27 to 7.44, p=0.014) and no IV tPA (aOR: 2.76, 95% CI 1.06 to 7.64, p=0.043) were significantly associated with poor functional outcome. CONCLUSION/CONCLUSIONS:There may be a relationship between COVID-19 associated AIS and severe disability or death. We identified several factors that predict worse outcomes, and these outcomes were more frequent compared with global averages. We found that elevated neutrophil-to-lymphocyte ratio, rather than D-dimer, predicted both morbidity and mortality.

OBJECTIVE:Blacks have the highest incidence and mortality rates for prostate cancer (PCa) in the U.S. Black PCa patients (PCaP) also report high psychological distress. Identifying culturally specific coping strategies that lower distress among Black PCaP could help improve psychological interventions for this group. African-centered coping (strategies unique to the structure of Black personality and the African-centered worldview) have been identified. We hypothesized that these coping strategies and resilience would be associated with lower psychological distress (anxiety and depression) in Black PCaP. METHODS:Black PCaP (N = 95) completed a survey assessing African-centered coping strategies, resilience, anxiety, and depression. Multiple regression was employed to examine African-centered coping strategies and resilience as predictors of psychological distress. RESULTS:Participants were aged M = 67 ± 9 years and 52% had late-stage PCa. Twenty percent met criteria for clinically significant anxiety, and 17% for depression. African-centered coping strategies were not associated with lower anxiety or depression, while resilience was associated with decreased anxiety (r = -0.45, p < 0.001) and depression (r = -0.54, p < 0.001). Mediation analyses did not support an indirect association among African-centered coping strategies, resilience, and anxiety and depression. CONCLUSIONS:Contrary to hypotheses, African-centered coping strategies were not associated with psychological distress. However, as predicted, greater resilience was associated with lower anxiety and depression. These findings support the relevancy of resilience in Blacks' psychological adjustment to PCa. It might be worthwhile to explore African-centered coping strategies that help Black PCaP cope with distress.

While the COVID-19 pandemic has catalyzed the expansion of telemedicine into nearly every specialty of medicine, few articles have summarized current practices and recommendations for integrating virtual care in the practice of neuro-oncology. This article identifies current telemedicine practice, provides practical guidance for conducting telemedicine visits, and generates recommendations for integrating virtual care into neuro-oncology practice. Practical aspects of telemedicine are summarized including when to use and not use telemedicine, how to conduct a virtual visit, who to include in the virtual encounter, unique aspects of telehealth in neuro-oncology, and emerging innovations.