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Sudden unexpected death in epilepsy (SUDEP) has been linked to respiratory dysfunction, but the mechanisms underlying this association remain unclear. Here we found that both focal and generalized convulsive seizures (GCSs) in epilepsy patients caused a prolonged decrease in the hypercapnic ventilatory response (HCVR; a measure of respiratory CO 2 chemoreception). We then studied Scn1a R1407X /+ (Dravet syndrome; DS) and Scn8a N1768D /+ (D/+) mice of both sexes, two models of SUDEP, and found that convulsive seizures caused a postictal decrease in ventilation and severely depressed the HCVR in a subset of animals. Those mice with severe postictal depression of the HCVR also exhibited transient postictal hypothermia. A combination of blunted HCVR and abnormal thermoregulation is known to occur with dysfunction of the serotonin (5-hydroxytryptamine; 5-HT) system in mice. Depleting 5-HT with para -chlorophenylalanine (PCPA) mimicked seizure-induced hypoventilation, partially occluded the postictal decrease in the HCVR, exacerbated hypothermia, and increased postictal mortality in DS mice. Conversely, pretreatment with the 5-HT agonist fenfluramine reduced postictal inhibition of the HCVR and hypothermia. These results are consistent with the previous observation that seizures cause transient impairment of serotonergic neuron function, which would be expected to inhibit the many aspects of respiratory control dependent on 5-HT, including baseline ventilation and the HCVR. These results provide a scientific rationale to investigate the interictal and/or postictal HCVR as noninvasive biomarkers for those at high risk of seizure-induced death, and to prevent SUDEP by enhancing postictal 5-HT tone. SIGNIFICANCE STATEMENT There is increasing evidence that seizure-induced respiratory dysfunction contributes to the pathophysiology of sudden unexpected death in epilepsy (SUDEP). However, the cellular basis of this dysfunction has not been defined. Here, we show that seizures impair CO 2 chemoreception in some epilepsy patients. In two mouse models of SUDEP we found that generalized convulsive seizures impaired CO 2 chemoreception, and induced hypothermia, two effects reported with serotonergic neuron dysfunction. The defects in chemoreception and thermoregulation were exacerbated by chemical depletion of serotonin and reduced with fenfluramine, suggesting that seizure-induced respiratory dysfunction may be due to impairment of serotonin neuron function. These findings suggest that impaired chemoreception because of transient inhibition of serotonergic neurons may contribute to the pathophysiology of SUDEP., (Copyright © 2023 the authors.)

Background: Prior research demonstrates Crohn's disease patients often do well in pregnancy; however, less is known about the risk of flare in the postpartum period., Methods: A retrospective chart review was conducted at a tertiary care inflammatory bowel disease center. All pregnant women with Crohn's disease who were followed in the postpartum period, defined as 6 months after delivery, were included. Statistical analysis included χ 2 analysis, Wilcoxon rank sum test, and logistic regression analysis. The primary outcome of interest was rate of flare in the postpartum period., Results: There were 105 patients included in the study, with a majority (68%) on biologic medication during pregnancy. Thirty-one patients (30%) had a postpartum flare at a median of 9 weeks (range 2-24 weeks). Twenty-five patients (81%) had their postpartum flare managed in the outpatient setting with medications (only 4 of these patients required prednisone). 6 of 31 patients (19%) were hospitalized at a median of 4 weeks (range 2-26 weeks) after delivery, requiring intravenous corticosteroids or surgery. In multivariable regression, there was no significant increase in risk of postpartum flare with increasing maternal age, flare during pregnancy, or steroid or biologic use during pregnancy. Smoking during pregnancy increased risk of postpartum flare (odds ratio, 16.2 [1.72-152.94], P < 0.05)., Conclusion: In a cohort of Crohn's disease patients, 30% experienced a postpartum flare despite being on medical therapy, but most were able to be managed in the outpatient setting., (© 2021 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), nonadherence to biologic therapy increases risk of disease flare. The aim of this study was to identify risk factors for nonadherence., Methods: This was a single-center retrospective study evaluating patients with IBD treated at a tertiary care center and prescribed self-injectable biologic therapy using the center's specialty pharmacy. Adherence was defined using medication possession ratio (MPR). Nonadherence was defined as MPR <0.86., Results: Four hundred sixty patients (n = 393 with CD and n = 67 with UC) were evaluated with mean MPR (interquartile range) equaling 0.89 (0.48-1). Overall, 69% of patients were adherent (defined as MPR ≥0.86), 66% of patients with CD and 87% of patients with UC. In univariate analysis, several factors increased risk of nonadherence: CD diagnosis, insurance type, psychiatric history, smoking, prior biologic use, and narcotic use (P < 0.05). In multivariable analysis, Medicaid insurance (odds ratio [OR], 5.5; 95% confidence interval [CI], 1.85-15.6) and CD diagnosis (OR, 2.8; 95% CI, 1.3-6.0) increased risk of nonadherence. In CD, as the number of risk factors increased (narcotic use, psychiatric history, prior biologic use, and smoking), the probability of nonadherence increased. Adherence was 72% in patients with 0-1 risk factors, decreasing to 62%, 61%, and 42% in patients with 2, 3, and 4 risk factors, respectively (P < 0.05)., Conclusions: This study identified risk factors for nonadherence to biologic therapy. In patients with CD, the probability of nonadherence increased as the number of risk factors increased., (Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation 2019.)

Background: Ustekinumab was approved for moderate and severe Crohn's disease (CD) in 2016, but little is known about long-term outcomes., Methods: A retrospective study evaluated all patients with CD treated with ustekinumab, including patients with reinduction. C-reactive protein (CRP), Harvey-Bradshaw Index (HBI), Short Inflammatory Bowel Disease (SIBDQ), and endoscopy outcomes were collected prospectively., Results: Ninety-six patients received ustekinumab, resulting in improvement in CRP, HBI, and SIBDQ scores with 68% endoscopic improvement/remission. Thirty-four patients underwent reinduction, resulting in improved HBI and CRP., Conclusions: Ustekinumab in refractory CD results in significant clinical and endoscopic improvement and reinduction may be a viable option to recapture response., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn's & Colitis Foundation.)

Background: Perianal disease is a manifestation of Crohn's disease (CD) that has poor long-term treatment outcomes. The aim was to determine if rectal endoscopic ultrasound (EUS)-guided therapy with adalimumab (ADA) can improve outcomes for patients with perianal fistulizing CD., Methods: This is a randomized prospective study comparing serial EUS guidance of fistula treatment versus standard of care in fistulizing perianal CD. At enrollment, all patients underwent a rectal EUS and an EUA with seton placement and/or I&D. Treatment was maximized with immunomodulators, antibiotics, and ADA induction. Surgical interventions were determined by the surgeon's discretion in the control group and assisted by every 12th week EUS in the intervention group. Primary and secondary endpoints where complete drainage cessation at week 48 was fistula status per EUS, respectively., Results: Twenty patients were enrolled: 11 control and 9 EUS guidance. At 24 weeks, 7/9 (78%) in EUS group and 3/11 (27%) in control group had drainage cessation (P = 0.04). This significant difference was lost at week 48 (P = 0.44). Three patients in the EUS and 1 in the control group had additional surgical intervention. Those in the EUS group had more rapid escalation of ADA dosing (P = 0.003). There was no difference in the change in PDAI at week 48 versus baseline (P = 0.81)., Conclusions: Rectal EUS-guided ADA therapy for CD perianal fistulas showed an initial benefit at 24 weeks, which was lost at week 48. This is likely due to small sample size and higher fistula closure in the controls. However, the faster rate of fistula resolution is a clinically significant finding.