The neuropeptide relaxin-3 and its receptor relaxin family peptide receptor-3 (RXFP3) play key roles in modulating behavior such as memory and learning, food intake, and reward seeking. A linear relaxin-3 antagonist (R3 B1-22R) based on a modified and truncated relaxin-3 B-chain was recently developed. R3 B1-22R is unstructured in solution; thus, the binding conformation and determinants of receptor binding are unclear. Here, we have designed, chemically synthesized, and pharmacologically characterized more than 60 analogues of R3 B1-22R to develop an extensive understanding of its structure-activity relationships. We show that the key driver for affinity is the nonnative C-terminal Arg Additional contributors to binding include amino acid residues that are important also for relaxin-3 binding, including Arg, Ile, and Ile Intriguingly, amino acid residues that are not exposed in native relaxin-3, including Phe and Ala, also interact with RXFP3. We show that R3 B1-22R has a propensity to form a helical structure, and modifications that support a helical conformation are functionally well-tolerated, whereas helix breakers such as proline residues disrupt binding. These data suggest that the peptide adopts a helical conformation, like relaxin-3, upon binding to RXFP3, but that its smaller size allows it to penetrate deeper into the orthosteric binding site, creating more extensive contacts with the receptor.

Objectives:We aimed to estimate the rate of psychogenic nonepileptic seizures (PNES) among patients presenting to an emergency department with presumed seizures. We also wanted to identify factors that can assist health care professionals in determining whether these events are likely to be epileptic or nonepileptic. Methods:We performed two retrospective audits on patients who were treated for seizures in the department of emergency medicine at the Princess Alexandra Hospital, Brisbane, Australia. Exploratory analyses and logistic regressions were conducted to investigate the characteristics of the presentations and the relationships between our variables of interest. Results:In the group of all presentations with presumed seizures over a 3-month period (n = 157), a total of 151 presentations (96.2%) presentations were given a primary diagnosis of epileptic seizures. Of these 151 presentations, only 84 (55.6%) presented with epileptic seizures and 40 (26.5%) actually presented with PNES.In the group of patients who presented with prolonged and/or multiple events (n = 213) over a 1-year period, 196 (92.0%) were treated as epileptic seizures. Of these 196 presentations, only 85 (43.4%) presented with epileptic seizures and 97 (49.5%) actually presented with PNES. Several factors were identified to help risk stratify between epileptic seizures and PNES: Duration of events and of the postictal phase, number of events, presence of a structural brain pathology, mental health history, lactate levels and presence of tongue bite, incontinence, and/or vomiting.Significance: A large proportion of people who present to emergency departments with events resembling epileptic seizures actually have PNES rather than epilepsy-particularly those patients who present with prolonged and/or multiple events. The rate of misdiagnosis was high. Efforts need to be made to recognize patients with psychogenic nonepileptic seizures earlier and diagnose them correctly to avoid unnecessary iatrogenic harm and to provide adequate treatment.

Background and ObjectiveThe objectives of this study were to investigate health care utilization costs of patients with video-electroencephalography (VEEG)–confirmed functional seizures (FS), determine whether patients who received a satisfactory functional neurologic disorder (FND) diagnosis explanation had reduced health care utilization compared with those with a poor explanation; and to quantify the overall health care costs 2 years prediagnosis and postdiagnosis for those receiving a different explanation.MethodsPatients with VEEG-confirmed pure FS (pFS) or mixed (functional seizure plus epileptic seizures) diagnosis between July 1, 2017, and July 1, 2019, were evaluated. Explanation of the diagnosis was determined “unsatisfactory” or “satisfactory” using self-developed criteria, and health care utilization data were collected using an itemized list. The subsequent costs 2 years post-FND diagnosis were compared with those 2 years before, and cost outcomes were compared between both groups.ResultsIn patients who received a satisfactory explanation (n = 18), total health care costs were reduced from $169,803 to $117,133 USD (−31%). An increase in costs was found ($73,430 to $186,553 USD = +154%) in patients with pPNES after an unsatisfactory explanation (n = 7). On an individual level, 78% with a satisfactory explanation saw a reduction in total health care costs per year (mean $5,111 USD to $1,728 USD), and in 57%, an unsatisfactory explanation led to an increase (mean $4,425 to $20,524 USD). A similar effect was seen from explanation on patients with a dual diagnosis.DiscussionThe method of communicating an FND diagnosis has a significant impact on subsequent health care utilization. Those receiving satisfactory explanations demonstrated reduced health care utilization, whereas an unsatisfactory explanation resulted in additional expenses.

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