Faculty Bibliography

INTRODUCTION:Although the treatment of epilepsy primarily focuses on prevention, recurrent seizures are unfortunately an ongoing reality, particularly in people with epilepsy who live with chronic refractory seizures. Rescue medications are agents which can be administered in urgent/emergent seizure episodes such as seizure clusters or prolonged seizures with the goal of terminating seizure activity, preventing morbidity, and decreasing the risk of further seizures. AREAS COVERED:This review first discusses clinical opportunities for rescue medications, with particular attention focused on seizure clusters and prolonged seizures, including their epidemiology, risk factors, and associated morbidity. Current rescue medications, their indications, efficacy, and adverse effects are discussed. We then discuss rescue medications and formulations which are currently under development, concentrating on practical aspects relevant for clinical care. EXPERT OPINION:Rescue medications should be considered for all people with epilepsy with ongoing seizures. Recent rescue medications including intranasal formulations provide considerable advantages. New rescue medications are being developed which may expand opportunities for effective treatment. In the future, combining rescue medications with seizure detection and seizure prediction technologies should further expand opportunities for use and should reduce the morbidity of seizures and provide increased comfort, control, and quality of life for people living with epilepsy.

OBJECTIVE:Current diazepam nasal spray labeling requires waiting 4 h before administering a second dose. The objective of the current analyses was to examine safety and pharmacokinetic profiles of second doses of diazepam nasal spray given 0-4 h after the first dose. METHODS:Two datasets were analyzed. The first, a long-term, repeat-dose safety study of diazepam nasal spray, compared rates of treatment-emergent adverse events (TEAEs), serious TEAEs, and treatment-related TEAEs for patients receiving ≥1 second dose ≤4 h versus all second doses >4 h after the first. The second was a population pharmacokinetic analysis using data from three phase 1 studies to model drug exposure when a second dose of diazepam nasal spray was administered across multiple time points (1 min-4 h) following the first dose. RESULTS:In the repeat-dose safety study, a second dose of diazepam nasal spray was administered ≤24 h after the first to treat 485 seizure clusters in 79 patients. Rates of TEAEs were similar between patients receiving ≥1 second dose in ≤4 h (89.5%, n = 38) compared with >4-24 h only (80.5%, n = 41). The most common treatment-related TEAEs were associated with nasal discomfort, which was mild or moderate and transient. There were no reports of respiratory or cardiac depression. The pharmacokinetic simulations of second doses predicted comparable elevations of plasma diazepam concentrations with administrations across a range of intervals after the first dose (1 min-4 h). SIGNIFICANCE/CONCLUSIONS:These data indicate that the safety and pharmacokinetic profiles of a second dose of diazepam nasal spray administered within 4 h of the first dose are consistent with those associated with current labeling. This is potentially important for patients with seizure clusters who have a recurrent seizure within 4 h of first treatment and might benefit from immediate retreatment to reduce the risk of progression to status epilepticus.

Attention-deficit/hyperactivity disorder (ADHD) significantly worsens quality of life and long-term functional outcomes in adults. Individual impairments in adults with ADHD can be further contextualized within considerable costs to society at large. Food and Drug Administration (FDA) approved stimulants and nonstimulant medications can significantly improve ADHD symptoms in adults. In the past 2 decades, the United States FDA has expanded approval of pharmacotherapeutic options for adult ADHD. However, limitations still persist in available psychotropics for certain patient populations such as those with comorbid substance use or cardiovascular illness. Clinicians therefore must appreciate several ongoing investigations into medications with unique mechanisms of action. This article reviews the current FDA approved and emerging medication options while providing guidelines for pharmacologic management of adult ADHD.

BACKGROUND:Viral induction of neurological syndromes has been a concern since parkinsonian-like features were observed in patients diagnosed with encephalitis lethargica subsequent to the 1918 influenza pandemic. Given the similarities in the systemic responses after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with those observed after pandemic influenza, there is a question whether a similar syndrome of postencephalic parkinsonism could follow coronavirus disease 2019 infection. OBJECTIVE:The goal of this study was to determine whether prior infection with SARS-CoV-2 increased sensitivity to a mitochondrial toxin known to induce parkinsonism. METHODS:K18-hACE2 mice were infected with SARS-CoV-2 to induce mild-to-moderate disease. After 38 days of recovery, mice were administered a non-lesion-inducing dose of the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and euthanized 7 days later. Subsequent neuroinflammation and substantia nigra pars compacta (SNpc) dopaminergic (DA) neuron loss were determined and compared with SARS-CoV-2 or MPTP alone. RESULTS:K18-hACE2 mice infected with SARS-CoV-2 or MPTP showed no SNpc DA neuron loss after MPTP. In mice infected and recovered from SARS-CoV-2 infection, MPTP induced a 23% or 19% greater loss of SNpc DA neurons than SARS-CoV-2 or MPTP, respectively (P < 0.05). Examination of microglial activation showed a significant increase in the number of activated microglia in both the SNpc and striatum of the SARS-CoV-2 + MPTP group compared with SARS-CoV-2 or MPTP alone. CONCLUSIONS:Our observations have important implications for long-term public health, given the number of people who have survived SARS-CoV-2 infection, as well as for future public policy regarding infection mitigation. However, it will be critical to determine whether other agents known to increase risk for PD also have synergistic effects with SARS-CoV-2 and are abrogated by vaccination. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND AND OBJECTIVE:This study characterizes the impact of race, ethnicity, insurance status, and geographic location on anti-vascular endothelial growth factor (VEGF) use for the treatment of diabetic macular edema (DME). PATIENTS AND METHODS:= 203,707). Multivariate regression analyses investigated associations between race, ethnicity, insurance status, and geographic location and anti-VEGF use and visual outcomes. RESULTS:< .01], respectively). CONCLUSION:.

This study investigated the utility of four Stroop Color and Word Test (SCWT) indices, including the raw score and T score for the word reading (WR) and color naming (CN) trials, as embedded performance validity tests (PVTs) within a sample referred for evaluation of suspected or known attention-deficit/hyperactivity disorder (ADHD). Data were analyzed from a final sample of 317 patients consecutively referred for ADHD evaluation, which was divided into groups with invalid (n = 43; 14%) and valid neuropsychological test performance (n = 274; 86%). A subset of the valid group with confirmed ADHD diagnoses (n = 226; 71%) were also analyzed separately. Classification accuracy for the overall valid sample was in the acceptable range (AUCs = .757-.794), with optimal cut scores of WR raw ≤75 (54% sensitivity/90% specificity), WR T score ≤ 28 (54% sensitivity/88% specificity), CN raw ≤57 (42% sensitivity/90% specificity), and CN T score ≤ 30 (40% sensitivity/90% specificity). Classification accuracy was also in the acceptable range for the ADHD-confirmed subgroup (AUCs = .750-.790), with optimal cut scores of WR Raw ≤ 75 (54% sensitivity/89% specificity), WR T score ≤ 28 (54% sensitivity/87% specificity), CN Raw ≤ 57 (42% sensitivity/90% specificity), and CN T score ≤ 30 (40% sensitivity/90% specificity). These findings indicate that embedded PVTs derived from the SCWT, particularly those derived from the WR trial, are effective measures for determining validity status in samples with suspected or confirmed ADHD. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

BACKGROUND:Prior studies have revealed remarkable phenotypic heterogeneity in KCNQ2-related disorders, correlated with effects on biophysical features of heterologously expressed channels. Here, we assessed phenotypes and functional properties associated with KCNQ2 missense variants R144W, R144Q, and R144G. We also explored in vitro blockade of channels carrying R144Q mutant subunits by amitriptyline. METHODS:Patients were identified using the RIKEE database and through clinical collaborators. Phenotypes were collected by a standardized questionnaire. Functional and pharmacological properties of variant subunits were analyzed by whole-cell patch-clamp recordings. FINDINGS/RESULTS:Detailed clinical information on fifteen patients (14 novel and 1 previously published) was analyzed. All patients had developmental delay with prominent language impairment. R144Q patients were more severely affected than R144W patients. Infantile to childhood onset epilepsy occurred in 40%, while 67% of sleep-EEGs showed sleep-activated epileptiform activity. Ten patients (67%) showed autistic features. Activation gating of homomeric Kv7.2 R144W/Q/G channels was left-shifted, suggesting gain-of-function effects. Amitriptyline blocked channels containing Kv7.2 and Kv7.2 R144Q subunits. INTERPRETATION/CONCLUSIONS:Patients carrying KCNQ2 R144 gain-of-function variants have developmental delay with prominent language impairment, autistic features, often accompanied by infantile- to childhood-onset epilepsy and EEG sleep-activated epileptiform activity. The absence of neonatal seizures is a robust and important clinical differentiator between KCNQ2 gain-of-function and loss-of-function variants. The Kv7.2/7.3 channel blocker amitriptyline might represent a targeted treatment. FUNDING/BACKGROUND:Supported by FWO, GSKE, KCNQ2-Cure, Jack Pribaz Foundation, European Joint Programme on Rare Disease 2020, the Italian Ministry for University and Research, the Italian Ministry of Health, the European Commission, the University of Antwerp, NINDS, and Chalk Family Foundation.