Faculty Bibliography

Nocturnal events of wide variety and concern are frequently reported by patients and their caregivers. To evaluate suspected abnormal events, primary care physicians must first be familiar with normal behaviors, movements and breathing patterns. Abnormal nocturnal events can then be categorized as nocturnal seizure, parasomnia, sleep-related movement disorder or sleep-related breathing disorder. Diagnoses in the above categories can be made clinically; however, it is important to know when to refer for additional evaluation. Comprehensive literature review was undertaken of nocturnal and sleep-related disorders. This guide reviews nocturnal seizures, normal and abnormal nonepileptic movements and behaviors, discusses broad indications for referral for electroencephalography (EEG) or polysomnography (PSG), and guides counseling and management for patients and their families, ultimately aiding in interpretation of both findings and prognosis. Epilepsy syndromes can result in seizures during sleep or adjacent periods of wakefulness. Parasomnias and sleep-related movement disorders tend to also occur in childhood and may be distinguished clinically. Referral to additional specialists for specific studies including EEG or PSG can be necessary, while other times a knowledgeable and vigilant clinician can contribute to a prompt diagnosis based on clinical features. Nocturnal events often can be managed with parental reassurance and watchful waiting, but treatment or evaluation may be needed. Sleep-related breathing disorders are important to recognize as they present very differently in children than in adults and early intervention can be life-saving. This review should allow both primary and subspecialty non-neurologic pediatric and adolescent health care providers to better utilize EEG and PSG as part of a larger comprehensive clinical approach, distinguishing and managing both epileptic and nonepileptic nocturnal disorders of concern while fostering communication across providers to facilitate and coordinate better holistic long-term care of pediatric and adolescent patients.

OBJECTIVES/OBJECTIVE:Residual next-day effects of sleep-promoting drugs are common and an important safety issue. Lemborexant is a dual orexin receptor antagonist approved in the United States and Japan for treatment of insomnia in adults. We evaluated the potential of lemborexant for residual morning and next-day effects, including somnolence, based on lemborexant clinical study findings. METHODS:This paper reports findings from 9 lemborexant clinical studies that incorporated next-day assessments of residual drug effects, based on published findings and data on file. Results are reported for healthy subjects or subjects with insomnia disorder treated with lemborexant 5 mg/day or 10 mg/day, placebo, or active comparator before bedtime. Outcomes assessed included next-morning postural stability (body sway measured by ataxiameter), cognitive performance (Cognitive Performance Assessment Battery), impact on driving (standard deviation of lateral position during highway driving test), subjective sleepiness (sleep diary entries), and adverse events of somnolence. RESULTS:Change from baseline in postural stability the morning after lemborexant administration did not differ from placebo. Among 4 Cognitive Performance Assessment Battery measures, only power of attention declined significantly more with lemborexant treatment compared with placebo in 1 of 2 studies, whereas zolpidem differed from placebo on multiple measures. On the highway-driving test, lemborexant did not significantly impair driving performance versus placebo, however, zopiclone did differ. In large phase 3 trials, next-morning sleep diary ratings showed significantly greater alertness with lemborexant compared with placebo after up to 6 months of treatment. As expected, somnolence was the most common adverse event reported with lemborexant treatment. Somnolence was typically mild to moderate in severity and rarely caused discontinuation of study drug. CONCLUSION/CONCLUSIONS:Across 9 clinical studies, lemborexant did not substantially impair next-day functioning among healthy subjects and subjects with insomnia.

We characterize the whole-brain N-acetyl-aspartate (WBNAA) and brain tissue fractions across the adult lifespan and test the hypothesis that, despite age-related atrophy, neuronal integrity (reflected by WBNAA) is preserved in normal aging. Two-hundred-and-seven participants: 133 cognitively intact older adults (73.6 ± 7.4 mean ± standard deviation, range: 60-90 year old) and 84 young (37.9 ± 11, range: 21-59 year old) were scanned with proton magnetic resonance spectroscopy and T₁-weighted MRI. Their WBNAA, fractional brain parenchyma, and gray and white matter volumes (fBPV, fGM, and fWM) were compared and modeled as functions of age and sex. Compared with young, older-adults' WBNAA was lower by ~35%, and fBPV, fGM and fWM were lower by ~10%. Linear regressions found 0.5%/year WBNAA and 0.2%/year fBPV and fGM declines, whereas fWM rose to age ~40 years, and declined thereafter. fBPV and fGM were 1.8% and 4% higher in women, with no sex decline rates difference. We conclude that contrary to our hypothesis, atrophy was accompanied by WBNAA decline. Across the entire age range, women's brains showed less atrophy than men's. Formulas to estimate WBNAA and brain tissue fractions in healthy adults are provided to help differentiate normal from abnormal aging.

Gain-of-function (GOF) variants in K⁺ channels cause severe childhood epilepsies, but there are no mechanisms to explain how increased K⁺ currents lead to network hyperexcitability. Here, we introduce a human Na⁺-activated K⁺ (K_Na) channel variant (KCNT1-Y796H) into mice and, using a multiplatform approach, find motor cortex hyperexcitability and early-onset seizures, phenotypes strikingly similar to those of human patients. Although the variant increases K_Na currents in cortical excitatory and inhibitory neurons, there is an increase in the K_Na current across subthreshold voltages only in inhibitory neurons, particularly in those with non-fast-spiking properties, resulting in inhibitory-neuron-specific impairments in excitability and action potential (AP) generation. We further observe evidence of synaptic rewiring, including increases in homotypic synaptic connectivity, accompanied by network hyperexcitability and hypersynchronicity. These findings support inhibitory-neuron-specific mechanisms in mediating the epileptogenic effects of KCNT1 channel GOF, offering cell-type-specific currents and effects as promising targets for therapeutic intervention.

Background: Zinc impairs replication of RNA viruses such as SARS-CoV-1, and may be effective against SARS-CoV-2. However, to achieve adequate intracellular zinc levels, administration with an ionophore, which increases intracellular zinc levels, may be necessary. We evaluated the impact of zinc with an ionophore (Zn+ionophore) on COVID-19 in-hospital mortality rates. Methods: A multicenter cohort study was conducted of 3,473 adult hospitalized patients with reverse-transcriptase-polymerase-chain-reaction (RT-PCR) positive SARS-CoV-2 infection admitted to four New York City hospitals between March 10 through May 20, 2020. Exclusion criteria were: death or discharge within 24h, comfort-care status, clinical trial enrollment, treatment with an IL-6 inhibitor or remdesivir. Patients who received Zn+ionophore were compared to patients who did not using multivariable time-dependent cox proportional hazards models for time to in-hospital death adjusting for confounders including age, sex, race, BMI, diabetes, week of admission, hospital location, sequential organ failure assessment (SOFA) score, intubation, acute renal failure, neurological events, treatment with corticosteroids, azithromycin or lopinavir/ritonavir and the propensity score of receiving Zn+ionophore. A sensitivity analysis was performed using a propensity score-matched cohort of patients who did or did not receive Zn+ionophore matched by age, sex and ventilator status. Results: Among 3,473 patients (median age 64, 1947 [56%] male, 522 [15%] ventilated, 545[16%] died), 1,006 (29%) received Zn+ionophore. Zn+ionophore was associated with a 24% reduced risk of in-hospital mortality (12% of those who received Zn+ionophore died versus 17% who did not; adjusted Hazard Ratio [aHR] 0.76, 95% CI 0.60-0.96, P=0.023). More patients who received Zn+ionophore were discharged home (72% Zn+ionophore vs 67% no Zn+ionophore, P=0.003) Neither Zn nor the ionophore alone were associated with decreased mortality rates. Propensity score-matched sensitivity analysis (N=1356) validated these results (Zn+ionophore aHR for mortality 0.63, 95%CI 0.44-0.91, P=0.015). There were no significant interactions for Zn+ionophore with other COVID-19 specific medications. Conclusions: Zinc with an ionophore was associated with increased rates of discharge home and a 24% reduced risk of in-hospital mortality among COVID-19 patients, while neither zinc alone nor the ionophore alone reduced mortality. Further randomized trials are warranted.

PURPOSE OF REVIEW/OBJECTIVE:This review paper aims to update readers on the importance of screening for attention-deficit/hyperactivity disorder (ADHD) in adults and to provide a primer on how best to screen and diagnose this condition in an efficient and reliable manner. RECENT FINDINGS/RESULTS:The ASRS Screening Scale was updated in 2017 to reflect the changes made to identify ADHD based on the DSM-5 criteria and to reflect our understanding that adult ADHD is characterized by executive functioning deficits that are not explicitly reflected in the DSM-5 criteria. The use of the ASRS Screening Scale improves the clinician's ability to rapidly identify adult patients who require a comprehensive evaluation to diagnose ADHD and/or other comorbid psychiatric conditions. The scale has been validated for use in both the general population and in the ADHD specialty treatment population, which supports its use by both general clinicians and mental health clinicians. Identification of adult ADHD is critical due to the profound personal, familial, and societal costs associated with this condition.

Coronavirus disease 2019 (COVID-19) is associated with a high inflammatory burden that can induce severe respiratory disease among other complications; vascular and neurological damage has emerged as a key threat to COVID-19 patients. Risk of severe infection and mortality increases with age, male sex, and comorbidities including cardiovascular disease, hypertension, obesity, diabetes, and chronic pulmonary disease. We review clinical and neuroradiological findings in five patients with COVID-19 who suffered severe neurological disease and illustrate the pathological findings in a 7-year-old boy with COVID-19-induced encephalopathy whose brain tissue sample showed angiocentric mixed mononuclear inflammatory infiltrate. We summarize the structural and functional properties of the virus including the molecular processes that govern the binding to its membrane receptors and cellular entry. In addition, we review clinical and experimental evidence in patients and animal models that suggests coronaviruses enter into the central nervous system (CNS), either via the olfactory bulb or through hematogenous spread. We discuss suspected pathophysiological mechanisms including direct cellular infection and associated recruitment of immune cells and neurovirulence, at least in part, mediated by cytokine secretion. Moreover, contributing to the vascular and neurological injury, coagulopathic disorders play an important pathogenic role. We survey the molecular events that contribute to the thrombotic microangiopathy. We describe the neurological complications associated with COVID-19 with a focus on the potential mechanisms of neurovascular injury. Our thesis is that following infection, three main pathophysiological processes-inflammation, thrombosis, and vascular injury-are responsible for the neurological damage and diverse pathology seen in COVID-19 patients.

Patients with essential tremor, vocal tremor, torticollis, myoclonus-dystonia and posthypoxic myoclonus often benefit in a surprisingly rapid and robust manner from ingestion of a modest amount of alcohol (ethanol). Despite considerable investigation, the mechanism of ethanol's ability to produce this effect remains a mystery. In this paper, we review the pharmacology of ethanol and its analogue GHB (or sodium oxybate), summarize the published literature of alcohol-responsive hyperkinetic movement disorders, and demonstrate videos of patients we have treated over the last fifteen years with either an ethanol challenge or with chronic sodium oxybate therapy. We then propose a novel explanation for this phenomenon-namely, that ingestion of