A multicenter pilot study evaluating simplified central vein assessment for the diagnosis of multiple sclerosis.

BACKGROUND: The central vein sign (CVS) is a proposed magnetic resonance imaging (MRI) biomarker for multiple sclerosis (MS); the optimal method for abbreviated CVS scoring is not yet established. OBJECTIVE: The aim of this study was to evaluate the performance of a simplified approach to CVS assessment in a multicenter study of patients being evaluated for suspected MS. METHODS: Adults referred for possible MS to 10 sites were recruited. A post-Gd 3D T2*-weighted MRI sequence (FLAIR*) was obtained in each subject. Trained raters at each site identified up to six CVS-positive lesions per FLAIR* scan. Diagnostic performance of CVS was evaluated for a diagnosis of MS which had been confirmed using the 2017 McDonald criteria at thresholds including three positive lesions (Select-3*) and six positive lesions (Select-6*). Inter-rater reliability assessments were performed. RESULTS: Overall, 78 participants were analyzed; 37 (47%) were diagnosed with MS, and 41 (53%) were not. The mean age of participants was 45 (range: 19-64) years, and most were female (n = 55, 71%). The area under the receiver operating characteristic curve (AUROC) for the simplified counting method was 0.83 (95% CI: 0.73-0.93). Select-3* and Select-6* had sensitivity of 81% and 65% and specificity of 68% and 98%, respectively. Inter-rater agreement was 78% for Select-3* and 83% for Select-6*. CONCLUSION: A simplified method for CVS assessment in patients referred for suspected MS demonstrated good diagnostic performance and inter-rater agreement.

A Comparison of Neuropsychological Outcomes following Responsive Neurostimulation and Anterior Temporal Lobectomy in Drug-Resistant Epilepsy.

Neuropsychological outcomes following temporal lobe resection for drug-resistant epilepsy (DRE) are well established. For instance, left anterior temporal lobectomy (LATL) is associated with a greater risk for cognitive morbidity compared to right (RATL). However, the impact of neuromodulatory devices, specifically responsive neurostimulation (RNS), remains an area of active interest. There are currently no head-to-head comparisons of neuropsychological outcomes after surgical resection and neuromodulation. This study reports on a cohort of 21 DRE patients with the RNS System who received comprehensive pre- and post-implantation neuropsychological testing. We compared both cognitive and seizure outcomes in the RNS group to those of 307 DRE patients who underwent LATL (n = 138) or RATL (n = 169). RNS patients had higher seizure rates pre-intervention. While fewer in the RNS group achieved Class I Engel outcomes compared to the ATL cohorts, RNS patients also showed seizure frequency declines from pre- to post-intervention that were similar to those who underwent resective surgery. Moreover, the RNS and RATL groups were similar in their neuropsychological outcomes, showing no significant cognitive decline post-intervention. In contrast, the LATL group notably declined in object naming and verbal list learning. Direct comparisons like this study may be used to guide clinicians in shared decision making to tailor management plans for patients' overall treatment goals.

Evaluation of the Rothman Index in Predicting Readmission after Colorectal Resection.

The Rothman Index (RI) is a real-time health indicator score that has been used to quantify readmission risk in several fields but has never been studied in gastrointestinal surgery. In this retrospective single-institution study, the association between RI scores and readmissions after unplanned colectomy or proctectomy was evaluated in 427 inpatients. Patient demographics and perioperative measures, including last RI, lowest RI, and increasing/decreasing RI score, were collected. In the selected cohort, 12.4% of patients were readmitted within 30 days of their initial discharge. Last RI, lowest RI, decreasing RI, and increasing RI scores remained significant after controlling for covariates in separate multivariate regression analyses. The last RI score at the time of discharge was found to be the most strongly associated with 30-day readmission risk following colorectal resection. These findings support the RI as a potential tool in the inpatient management of postoperative patients to identify those at high risk of readmission.

Intersite brain MRI volumetric biases persist even in a harmonized multisubject study of multiple sclerosis.

BACKGROUND AND PURPOSE: Multicenter study designs involving a variety of MRI scanners have become increasingly common. However, these present the issue of biases in image-based measures due to scanner or site differences. To assess these biases, we imaged 11 volunteers with multiple sclerosis (MS) with scan and rescan data at four sites. METHODS: Images were acquired on Siemens or Philips scanners at 3 Tesla. Automated white matter lesion detection and whole-brain, gray and white matter, and thalamic volumetry were performed, as well as expert manual delineations of T1 magnetization-prepared rapid acquisition gradient echo and T2 fluid-attenuated inversion recovery lesions. Random-effect and permutation-based nonparametric modeling was performed to assess differences in estimated volumes within and across sites. RESULTS: Random-effect modeling demonstrated model assumption violations for most comparisons of interest. Nonparametric modeling indicated that site explained >50% of the variation for most estimated volumes. This expanded to >75% when data from both Siemens and Philips scanners were included. Permutation tests revealed significant differences between average inter- and intrasite differences in most estimated brain volumes (P < .05). The automatic activation of spine coil elements during some acquisitions resulted in a shading artifact in these images. Permutation tests revealed significant differences between thalamic volume measurements from acquisitions with and without this artifact. CONCLUSION: Differences in brain volumetry persisted across MR scanners despite protocol harmonization. These differences were not well explained by variance component modeling; however, statistical innovations for mitigating intersite differences show promise in reducing biases in multicenter studies of MS.

Responsive Neurostimulation of the Anterior Thalamic Nuclei in Refractory Genetic Generalized Epilepsy: A Case Series.

Genetic generalized epilepsies (GGEs) are thought to represent disorders of thalamocortical networks. There are currently no well-established non-pharmacologic treatment options for patients with drug-resistant GGE. NeuroPace's Responsive Neurostimulation (RNS) System was approved by the United States Food and Drug Administration to treat focal seizures with up to two ictal foci. We report on three adults with drug-resistant GGE who were treated with thalamic RNS. Given the severity of their epilepsies and the potential ictogenic role of the thalamus in the pathophysiology of GGE, the RNS System was palliatively implanted with leads in the bilateral anterior thalamic nuclei (ANT) of these patients. The ANT was selected because it was demonstrated to be a safe target. We retrospectively evaluated metrics including seizure frequency over 18-32 months. One patient required explantation due to infection. The other two patients were clinical responders. By the end of the observation period reported here, one patient was seizure-free for over 9 months. All three self-reported an improved quality of life. The clinical response observed in these patients provides 'proof-of-principle' that GGE may be treatable with responsive thalamic stimulation. Our results support proceeding to a larger study investigating the efficacy and safety of thalamic RNS in drug-resistant GGE.

Effect of GBCA Use on Detection and Diagnostic Performance of the Central Vein Sign: Evaluation Using a 3-T FLAIR* Sequence in Patients With Suspected Multiple Sclerosis.

BACKGROUND. The central vein sign (CVS) is a proposed MRI biomarker of multiple sclerosis (MS). The impact of gadolinium-based contrast agent (GBCA) administration on CVS evaluation remains poorly investigated. OBJECTIVE. The purpose of this study was to assess the effect of GBCA use on CVS detection and on the diagnostic performance of the CVS for MS using a 3-T FLAIR* sequence. METHODS. This study was a secondary analysis of data from the pilot study for the prospective multicenter Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS), which recruited adults with suspected MS from April 2018 to February 2020. Participants underwent 3-T brain MRI including FLAIR and precontrast and post-contrast echo-planar imaging T2*-weighted acquisitions. Postprocessing was used to generate combined FLAIR and T2*-weighted images (hereafter, FLAIR*). MS diagnoses were established using the 2017 McDonald criteria. Thirty participants (23 women, seven men; mean age, 45 years) were randomly selected from the CAVS-MS pilot study cohort. White matter lesions (WMLs) were marked using FLAIR* images. A single observer, blinded to clinical data and GBCA use, reviewed marked WMLs on FLAIR* images for the presence of the CVS. RESULTS. Thirteen of 30 participants had MS. Across participants, on precontrast FLAIR* imaging, 218 CVS-positive and 517 CVS-negative WMLs were identified; on post-contrast FLAIR* imaging, 269 CVS-positive and 459 CVS-negative WMLs were identified. The fraction of WMLs that were CVS-positive on precontrast and postcontrast images was 48% and 58% in participants with MS and 7% and 10% in participants without MS, respectively. The median patient-level CVS-positivity rate on precontrast and postcontrast images was 43% and 67% for participants with MS and 4% and 8% for participants without MS, respectively. In a binomial model adjusting for MS diagnoses, GBCA use was associated with an increased likelihood of at least one CVS-positive WML (odds ratio, 1.6; p < .001). At a 40% CVS-positivity threshold, the sensitivity of the CVS for MS increased from 62% on precontrast images to 92% on postcontrast images (p = .046). Specificity was not significantly different between precontrast (88%) and postcontrast (82%) images (p = .32). CONCLUSION. GBCA use increased CVS detection on FLAIR* images, thereby increasing the sensitivity of the CVS for MS diagnoses. CLINICAL IMPACT. The postcontrast FLAIR* sequence should be considered for CVS evaluation in future investigational trials and clinical practice.

Developmental coupling of cerebral blood flow and fMRI fluctuations in youth.

The functions of the human brain are metabolically expensive and reliant on coupling between cerebral blood flow (CBF) and neural activity, yet how this coupling evolves over development remains unexplored. Here, we examine the relationship between CBF, measured by arterial spin labeling, and the amplitude of low-frequency fluctuations (ALFF) from resting-state magnetic resonance imaging across a sample of 831 children (478 females, aged 8-22 years) from the Philadelphia Neurodevelopmental Cohort. We first use locally weighted regressions on the cortical surface to quantify CBF-ALFF coupling. We relate coupling to age, sex, and executive functioning with generalized additive models and assess network enrichment via spin testing. We demonstrate regionally specific changes in coupling over age and show that variations in coupling are related to biological sex and executive function. Our results highlight the importance of CBF-ALFF coupling throughout development; we discuss its potential as a future target for the study of neuropsychiatric diseases.

Performance of middle cerebral artery doppler for prediction of recurrent fetal anemia.

OBJECTIVE: To assess the predictive value of middle cerebral artery Doppler peak systolic velocity (MCA-PSV) for moderate-severe fetal anemia following one intrauterine transfusion (IUT) and test the performance of alternate cutoffs to the recommended threshold ≥1.69 multiples of the median (MoM). METHODS: This was a retrospective cohort study of patients with pregnancies affected by alloimmunization who underwent percutaneous umbilical blood sampling (PUBS) procedures from 2000 to 2020. An MCA-PSV ≥1.69 MoM was the indication for the second IUT. The primary outcome was recurrent moderate-severe fetal anemia. Receiver-operating characteristic (ROC) curves assessed the predictive ability of MCA-PSV for the primary outcome and the Youden index identified the "optimal" cutoff value. Predictive characteristics of MCA-PSV ≥1.69 MoM and the "optimal" cutoff were compared. RESULTS: Of the 58 patients who underwent IUT during the study period, 36 (62%) did not meet inclusion criteria. Of the remaining 22 patients who underwent a second PUBS, 12 (54.6%) fetuses had moderate or severe anemia. Following one IUT, the AUC for MCA-PSV was 0.86 (95% CI 0.70-1.00) for the primary outcome. The "optimal" cutoff MCA-PSV value was 1.74 MoM, which had a greater specificity than ≥1.69 MoM (90 vs. 50%, p = .05), but was not statistically significant. The sensitivity was similar between the two cutoff values of ≥1.69 and ≥1.74 MoM (83.3 vs. 75.0%, p = .65) (Table 2). CONCLUSION: Raising the recommended MCA-PSV cutoff to ≥1.74 MoM for recurrent moderate-severe fetal anemia after one IUT would decrease the number of unnecessary procedures without significantly changing the sensitivity of this screening test.

The impact of physical activity during pregnancy on labor and delivery.

BACKGROUND: Physical activity in pregnancy is associated with decreased risks of adverse pregnancy outcomes such as gestational diabetes and preeclampsia. However, the relationship between the amount and type of physical activity during pregnancy and subsequent labor outcomes remains unclear. OBJECTIVE: This study aimed to test the hypothesis that higher levels of physical activity across different lifestyle domains in pregnancy are associated with a shorter duration of labor. STUDY DESIGN: This study is a secondary analysis of a prospective cohort study in which patients with singleton pregnancies without a major fetal anomaly were administered the Kaiser Physical Activity Survey in each trimester. The Kaiser Physical Activity Survey was designed specifically to quantify various types of physical activities in women and includes 4 summative indices-housework/caregiving, active living habits, sports, and occupation. The study included women at full-term gestations admitted for induction of labor or spontaneous labor. The primary outcome of this analysis was duration of the second stage of labor. Secondary outcomes were duration of the active stage, prolonged first and second stage, mode of delivery, rates of second-stage cesarean delivery, operative vaginal delivery, severe perineal lacerations, and postpartum hemorrhage. These outcomes were compared between patients with and without high physical activity levels, defined as overall Kaiser Physical Activity Survey score ≥75th percentile in the third trimester. Multivariable logistic regression was used to adjust for obesity and epidural use. In addition, a subgroup analysis of nulliparous patients was performed. RESULTS: A total of 811 patients with complete Kaiser Physical Activity Survey data in the third trimester were included in this analysis. The median Kaiser Physical Activity Survey score was 9.5 (8.2-10.8). Of the 811 patients, 203 (25%) had higher levels of physical activity in pregnancy. There was no difference in the duration of the second stage of labor between patients with and without higher physical activity levels (1.29±2.94 vs 0.97±2.08 hours; P=.15). The duration of active labor was significantly shorter in patients with higher levels of physical activity (5.77±4.97 vs 7.43±6.29 hours; P=.01). Patients with higher physical activity levels were significantly less likely to have a prolonged first stage (9.8% vs 19.4%; P<.01; adjusted relative risk, 0.55; 95% confidence interval, 0.34-0.83). However, rates of prolonged second-stage cesarean delivery, operative vaginal deliveries, and perineal lacerations were similar between the 2 groups. CONCLUSION: Patients who are more physically active during pregnancy have a shorter duration of active labor.

Placental H3K27me3 establishes female resilience to prenatal insults.

Although sex biases in disease presentation are well documented, the mechanisms mediating vulnerability or resilience to diseases are unknown. In utero insults are more likely to produce detrimental health outcomes for males versus females. In our mouse model of prenatal stress, male offspring experience long-term dysregulation of body weight and hypothalamic pituitary adrenal stress axis dysfunction, endophenotypes of male-biased neurodevelopmental disorders. Placental function is critical for healthy fetal development, and we previously showed that sex differences in placental O-linked N-acetylglucosamine transferase (OGT) mediate the effects of prenatal stress on neurodevelopmental programming. Here we show that one mechanism whereby sex differences in OGT confer variation in vulnerability to prenatal insults is by establishing sex-specific trophoblast gene expression patterns and via regulation of the canonically repressive epigenetic modification, H3K27me3. We demonstrate that high levels of H3K27me3 in the female placenta create resilience to the altered hypothalamic programming associated with prenatal stress exposure.