Association of EEG Background With Diffusion-Weighted Magnetic Resonance Neuroimaging and Short-Term Outcomes After Pediatric Cardiac Arrest.

BACKGROUND AND OBJECTIVES: EEG and MRI features are independently associated with pediatric cardiac arrest (CA) outcomes, but it is unclear whether their combination improves outcome prediction. We aimed to assess the association of early EEG background category with MRI ischemia after pediatric CA and determine whether addition of MRI ischemia to EEG background features and clinical variables improves short-term outcome prediction. METHODS: This was a single-center retrospective cohort study of pediatric CA with EEG initiated ≤24 hours and MRI obtained ≤7 days of return of spontaneous circulation. Initial EEG background was categorized as normal, slow/disorganized, discontinuous/burst-suppression, or attenuated-featureless. MRI ischemia was defined as percentage of brain tissue with apparent diffusion coefficient (ADC) <650 × 10-6 mm2/s and categorized as high (≥10%) or low (<10%). Outcomes were mortality and unfavorable neurologic outcome (Pediatric Cerebral Performance Category increase ≥1 from baseline resulting in ICU discharge score ≥3). The Kruskal-Wallis test evaluated the association of EEG with MRI. Area under the receiver operating characteristic (AUROC) curve evaluated predictive accuracy. Logistic regression and likelihood ratio tests assessed multivariable outcome prediction. RESULTS: We evaluated 90 individuals. EEG background was normal in 16 (18%), slow/disorganized in 42 (47%), discontinuous/burst-suppressed in 12 (13%), and attenuated-featureless in 20 (22%) individuals. The median percentage of MRI ischemia was 5% (interquartile range 1-18); 32 (36%) individuals had high MRI ischemia burden. Twenty-eight (31%) individuals died, and 58 (64%) had unfavorable neurologic outcome. Worse EEG background category was associated with more MRI ischemia (p < 0.001). The combination of EEG background and MRI ischemia burden had higher predictive accuracy than EEG alone (AUROC: mortality: 0.92 vs 0.87, p = 0.03) or MRI alone (AUROC: mortality: 0.92 vs 0.84, p = 0.02; unfavorable: 0.83 vs 0.73, p < 0.01). Addition of percentage of MRI ischemia to clinical variables and EEG background category improved prediction for mortality (χ2 = 19.1, p < 0.001) and unfavorable neurologic outcome (χ2 = 4.8, p = 0.03) and achieved high predictive accuracy (AUROC: mortality: 0.97; unfavorable: 0.92). DISCUSSION: Early EEG background category was associated with MRI ischemia after pediatric CA. Combining EEG and MRI data yielded higher outcome predictive accuracy than either modality alone. The addition of MRI ischemia to clinical variables and EEG background improved short-term outcome prediction.

Effect of patient factors, center, and era on Fontan timing: An observational study using the Pediatric Health Information Systems Database.

BACKGROUND: There are no consensus guidelines defining optimal timing for the Fontan operation, the last planned surgery in staged palliation for single-ventricle heart disease. OBJECTIVES: Identify patient-level characteristics, center-level variation, and secular trends driving Fontan timing. METHODS: A retrospective observational study of subjects who underwent Fontan from 2007 to 2021 at centers in the Pediatric Health Information Systems database was performed using linear mixed-effects modeling in which age at Fontan was regressed on patient characteristics and date of operation with center as random effect. RESULTS: We included 10,305 subjects (40.4% female, 44% non-white) at 47 centers. Median age at Fontan was 3.4 years (IQR 2.6-4.4). Hypoplastic left heart syndrome (-4.4 months, 95%CI -5.5 to -3.3) and concomitant conditions (-2.6 months, 95%CI -4.1 to -1.1) were associated with younger age at Fontan. Subjects with technology-dependence (+4.6 months, 95%CI 3.1-6.1) were older at Fontan. Black (+4.1 months, 95%CI 2.5-5.7) and Asian (+8.3 months, 95%CI 5.4-11.2) race were associated with older age at Fontan. There was significant variation in Fontan timing between centers. Center accounted for 10% of variation (ICC 0.10, 95%CI 0.07-0.14). Center surgical volume was not associated with Fontan timing (P = .21). Operation year was associated with age at Fontan, with a 3.1 month increase in age for every 5 years (+0.61 months, 95%CI 0.48-0.75). CONCLUSIONS: After adjusting for patient-level characteristics there remains significant inter-center variation in Fontan timing. Age at Fontan has increased. Future studies addressing optimal Fontan timing are warranted.

Cardiac magnetic resonance predictors for successful primary biventricular repair of unbalanced complete common atrioventricular canal.

BACKGROUND: Patients with unbalanced common atrioventricular canal can be difficult to manage. Surgical planning often depends on pre-operative echocardiographic measurements. We aimed to determine the added utility of cardiac MRI in predicting successful biventricular repair in common atrioventricular canal. METHODS: We conducted a retrospective cohort study of children with common atrioventricular canal who underwent MRI prior to repair. Associations between MRI and echocardiographic measures and surgical outcome were tested using logistic regression, and models were compared using area under the receiver operator characteristic curve. RESULTS: We included 28 patients (median age at MRI: 5.2 months). The optimal MRI model included the novel end-diastolic volume index (using the ratio of left ventricular end-diastolic volume to total end-diastolic volume) and the left ventricle-right ventricle angle in diastole (area under the curve 0.83, p = 0.041). End-diastolic volume index ≤ 0.18 and left ventricle-right ventricle angle in diastole ≤ 72° yield a sensitivity of 83% and specificity of 81% for successful biventricular repair. The optimal multimodality model included the end-diastolic volume index and the echocardiographic atrioventricular valve index with an area under the curve of 0.87 (p = 0.026). CONCLUSIONS: Cardiac MRI can successfully predict successful biventricular repair in patients with unbalanced common atrioventricular canal utilising the end-diastolic volume index alone or in combination with the MRI left ventricle-right ventricle angle in diastole or the echocardiographic atrioventricular valve index. A prospective cardiac MRI study is warranted to better define the multimodality characteristic predictive of successful biventricular surgery.

Longitudinal echocardiographic parameters before and after pacemaker placement in congenital complete heart block.

BACKGROUND: Congenital complete heart block (CCHB) is seen in 1:15,000-1:20,000 live births, with risk of left ventricular (LV) dysfunction or dilated cardiomyopathy in 7%-23% of subjects. OBJECTIVE: The purpose of this study was to investigate serial changes in LV size and systolic function in paced CCHB subjects to examine the effect of time from pacemaker on echocardiographic parameters. METHODS: Single-center retrospective cohort analysis of paced CCHB subjects was performed. Echocardiographic data were collected before and after pacemaker placement. Linear mixed effect regression of left ventricular end-diastolic dimension (LVEDD) z-score, left ventricular shortening fraction (LVSF), and left ventricular ejection fraction (LVEF) was performed, with slopes compared before and after pacemaker placement. RESULTS: Of 114 CCHB subjects, 52 had echocardiographic data before and after pacemaker placement. Median age at CCHB diagnosis was 0.6 [interquartile range 0.0-3.5] years; age at pacemaker placement 3.4 [0.5-9.0] years; and pacing duration 10.8 [5.2-13.7] years. Estimated LVEDD z-score was 1.4 at pacemaker placement and decreased -0.08 per year (95% confidence interval [CI] -0.12 to -0.04; P = .002) to 0.2 (95% CI -0.3 to +0.3) 15 years postplacement. Estimated LVSF decreased -1.1% per year (95% CI -1.7% to -0.6%; P <.001) from 6 months prepacemaker placement to 34% (95% CI 32%-37%) 4 years postplacement. There was no significant change in LVSF between 4 and 15 years postplacement. Estimated LVEF did not change significantly after pacemaker placement, with estimated LVEF 59% (95% CI 55%-62%) 15 years postplacement. CONCLUSION: In 52 paced CCHB subjects, estimated LVEDD z-score decreased significantly after pacemaker placement, and estimated LVSF and LVEF remained within normal limits at 15 years postpacemaker placement.

Biomarkers, Socioeconomic Factors, and Right Ventricular Function After Surgical Repair for Tetralogy of Fallot.

Right ventricular (RV) dysfunction early after tetralogy of Fallot (TOF) increases post-operative morbidity. We investigated associations of circulating biomarkers and socioeconomic factors with early post-operative RV systolic function. Single-center prospective cohort study of infants undergoing TOF repair. Six serologic biomarkers of myocardial fibrosis and wall stress collected at the time of surgery were measured with immunoassay. Geocoding was performed for socioeconomic factors. Multivariate adaptive regression splines (MARS) models identified factors associated with RV function parameters: fractional area change (FAC), global longitudinal strain and strain rate, and free wall strain and strain rate. Seventy-one patients aged 3.5 months (IQR 2.4, 5.2) were included. Galectin-3 was the highest ranked predictor for FAC, global longitudinal strain, and free wall strain, and procollagen type-I carboxy-terminal propeptide (PICP) was the highest ranked predictor for global longitudinal strain rate and free wall strain rate. Several neighborhood characteristics were also highly ranked. Models adjusted R2 ranged from 0.71 to 0.85 (FAC, global longitudinal strain/strain rate), and 0.55-0.57 (RV free wall strain/strain rate). A combination of serologic biomarkers, socioeconomic, and clinical variables explain a significant proportion of the variability in RV function after TOF repair. These factors may inform pre-operative risk-stratification for these patients.

Middle Ear Condition at the Time of Pediatric Myringotomy Tube Placement: Pain Associations Following Intraoperative Fentanyl/Ketorolac and Seasonal Variation.

BACKGROUND: Ketorolac-refractory pain behavior following bilateral myringotomy and pressure equalization tube placement (BMT) is associated with the absence of middle ear fluid. Intraoperative fentanyl/ketorolac affords more reliable pain control than ketorolac alone. We hypothesized that middle ear condition would correlate with postoperative pain despite such combination therapy. We further sought to demonstrate seasonal variation in ear condition and its influence on pain. METHODS: We conducted a single-institution retrospective cohort study of healthy children (9 months-7 years), who underwent BMT by a single surgeon from 2015 to 2020. Anesthetic care included sevoflurane/nitrous oxide/oxygen/air by mask and intramuscular fentanyl/ketorolac. Left/right middle ear fluid status was recorded at the time of BMT, and ear condition (primary exposure) was dichotomized as bilateral infected (mucoid or purulent) or normal/unilateral infected. The primary outcome was maximum postanesthesia care unit Face, Legs, Activity, Cry, and Consolability (FLACC) score: 4-10 (moderate-to-severe pain) versus 0-3 (no-to-low pain). Rescue oxycodone, acetaminophen administration, and emergence agitation were secondary outcomes. Statistical analysis incorporated generalized linear mixed-effect models (GLMMs) with random intercepts to account for clustering by anesthesia provider. A year-over-year monthly time-series analysis was conducted using an autoregressive integrated moving average (ARIMA) regression model. RESULTS: Excluding recurrent cases, 1149 unique evaluable subjects remained. Bilateral infection prevalence was 39.8% (457/1149; 95% confidence interval [CI], 37.0-42.6). Probability of moderate-to-severe pain behavior was 23.5% (270/1149; 95% CI, 21.1-26.0) overall. Compared to patients with bilateral infected middle ears, those with normal/unilateral infected ears were more likely to have a FLACC score ≥4 (26.7% [185/692] versus 18.6% [85/457]; odds ratio [95% CI], 1.7 [1.2-2.3]; P = .002). Variability in pain outcome explained by the multivariable GLMM was 4.7%. Fentanyl dose response was evidenced by oxycodone administration differences ( P ≤ 0.002). Moderate-to-severe pain and emergence agitation were more likely with reduced fentanyl dosing. Bilateral infection prevalence exhibited seasonality, peaking in March and nadiring in July. However, pain outcomes did not vary by season. CONCLUSIONS: Normal/unilateral infected ears at time of pediatric BMT are associated with higher incidence of moderate-to-severe postoperative pain following intraoperative fentanyl/ketorolac administration, but the predictive value of ear condition on pain is limited. Infections were less common in the summer.

Co-administration of Ketamine in Pediatric Patients with Neurologic Conditions at Risk for Intracranial Hypertension.

BACKGROUND: Ketamine has traditionally been avoided as an induction agent for tracheal intubation in patients with neurologic conditions at risk for intracranial hypertension due to conflicting data in the literature. The objective of this study was to evaluate and compare the effects of ketamine versus other medications as the primary induction agent on peri-intubation neurologic, hemodynamic and respiratory associated events in pediatric patients with neurologic conditions at risk for intracranial hypertension. METHODS: This retrospective observational study enrolled patients < 18 years of age at risk for intracranial hypertension who were admitted to a quaternary children's hospital between 2015 and 2020. Associated events included neurologic, hemodynamic and respiratory outcomes comparing primary induction agents of ketamine versus non-ketamine for tracheal intubation. RESULTS: Of 143 children, 70 received ketamine as the primary induction agent prior to tracheal intubation. Subsequently after tracheal intubation, all the patients received adjunct analgesic and sedative medications (fentanyl, midazolam, and/or propofol) at doses that were inadequate to induce general anesthesia but would keep them comfortable for further diagnostic workup. There were no significant differences between associated neurologic events in the ketamine versus non-ketamine groups (p = 0.42). This included obtaining an emergent computed tomography scan (p = 0.28), an emergent trip to the operating room within 5 h of tracheal intubation (p = 0.6), and the need for hypertonic saline administration within 15 min of induction drug administration for tracheal intubation (p = 0.51). There were two patients who had clinical and imaging evidence of herniation, which was not more adversely affected by ketamine compared with other medications (p = 0.49). Of the 143 patients, 23 had pre-intubation and post-intubation intracranial pressure values recorded; 11 received ketamine, and 3 of these patients had intracranial hypertension that resolved or improved, whereas the remaining 8 children had intracranial pressure within the normal range that was not exacerbated by ketamine. There were no significant differences in overall associated hemodynamic or respiratory events during tracheal intubation and no 24-h mortality in either group. CONCLUSIONS: The administration of ketamine as the primary induction agent prior to tracheal intubation in combination with other agents after tracheal intubation in children at risk for intracranial hypertension was not associated with an increased risk of peri-intubation associated neurologic, hemodynamic or respiratory events compared with those who received other induction agents.

Incidence of postoperative seizures in neonates following cardiac surgery with regional cerebral perfusion and deep hypothermic circulatory arrest.

Objectives: Historically, our center has primarily used deep hypothermic circulatory arrest, but in recent years some surgeons have selectively used regional cerebral perfusion as an alternative. We aimed to compare the incidence of postoperative electroencephalographic seizure incidence in neonates undergoing surgery with regional cerebral perfusion and deep hypothermic circulatory arrest. Methods: A retrospective analysis was performed in neonates who underwent surgery between 2012 and 2022 with either deep hypothermic circulatory arrest or regional cerebral perfusion with routine postoperative continuous electroencephalography monitoring for 48 hours. Propensity matching was performed to compare postoperative seizure risk between the 2 groups. Results: Among 1136 neonates undergoing cardiac surgery with cardiopulmonary bypass, regional cerebral perfusion was performed in 99 (8.7%) and deep hypothermic circulatory arrest in 604 (53%). The median duration of regional cerebral perfusion was 49 minutes (interquartile range, 38-68) and deep hypothermic circulatory arrest was 41 minutes (interquartile range, 31-49). The regional cerebral perfusion group had significantly longer total support, cardiopulmonary bypass, and aortic crossclamp times. Overall seizure incidence was 11% (N = 76) and 13% (N = 35) in the most recent era (2019-2022). The unadjusted seizure incidence was similar in neonates undergoing regional cerebral perfusion (N = 12, 12%) and deep hypothermic circulatory arrest (N = 64, 11%). After propensity matching, the seizure incidence was similar in neonates undergoing regional cerebral perfusion (N = 12, 12%) and deep hypothermic circulatory arrest (N = 37, 12%) (odds ratio, 0.97; 95% CI, 0.55-1.71; P = .92). Conclusions: In this contemporary single-center experience, the incorporation of regional cerebral perfusion did not result in a change in seizure incidence in comparison with deep hypothermic circulatory arrest. However, unmeasured confounders may have impacted these findings. Further studies are needed to determine the impact, if any, of regional cerebral perfusion on postoperative seizure incidence.

Peak Work Rate Increases With Lower Extremity-Focused Exercise Training in Adolescents With Fontan Circulation.

Background Skeletal muscle deficits are associated with worse exercise performance in the Fontan circulation and may be improved by exercise training. We aimed to assess the change in leg lean mass (a marker of skeletal muscle), exercise performance, and functional health status after a lower extremity-focused exercise intervention in adolescents with Fontan circulation. Methods and Results Densitometry for measurement of leg lean mass, cardiopulmonary exercise test, exercise cardiac magnetic resonance, peripheral vascular testing, physical activity questionnaire, and quality of life assessment were performed at baseline and after a 24-week, hybrid center- and home-based training program. Leg lean mass Z-scores were generated, and exercise parameters were expressed as percentage expected based on reference data. The effect of training was assessed by paired t-tests and simple linear regression. Twenty participants (15.6±1.7 years, 50% male) demonstrated low baseline leg lean mass Z-scores with no significant improvement with training (-1.38±1.02 pre versus -1.31±1.06 post, P=0.33). Maximum and percent predicted work increased from 121.9±29.8 (0.66±0.12) to 131.3±35.1 (0.70±0.15) watts (P=0.02). Peak respiratory exchange ratio increased (1.19±0.02 versus 1.25±0.01, P=0.02) but percent predicted oxygen consumption was unchanged, suggesting higher anaerobic activity after training. Physical activity questionnaire score positively associated with peak work at baseline (ß=18.13 [95% CI, 0.83-35.44], R2=0.21; P=0.04) but physical activity questionnaire, quality of life scores, exercise cardiac magnetic resonance performance, and peripheral vascular function were unchanged with training. Conclusions Peak work rate and anaerobic activity increased with lower extremity-focused training in adolescents with Fontan circulation. Larger studies should test the impact of these changes on functional status and quality of life.

Factors associated with discontinuation of pulmonary vasodilator therapy in children with bronchopulmonary dysplasia-associated pulmonary hypertension.

OBJECTIVE: To evaluate factors associated with discontinuation of pulmonary vasodilator therapy in bronchopulmonary dysplasia-related pulmonary hypertension (BPD-PH). STUDY DESIGN: Retrospective study of neonatal, echocardiographic, and cardiac catheterization data in 121 infants with BPD-PH discharged on pulmonary vasodilator therapy from 2009-2020 and followed into childhood. RESULT: After median 4.4 years, medications were discontinued in 58%. Those in whom medications were discontinued had fewer days of invasive support, less severe BPD, lower incidence of PDA closure or cardiac catheterization, and higher incidence of fundoplication or tracheostomy decannulation (p < 0.05). On multivariable analysis, likelihood of medication discontinuation was lower with longer period of invasive respiratory support [HR 0.95 (CI:0.91-0.99), p = 0.01] and worse RV dilation on pre-discharge echocardiogram [HR 0.13 (CI:0.03-0.70), p = 0.017]. In those with tracheostomy, likelihood of medication discontinuation was higher with decannulation [HR 10.78 (CI:1.98-58.59), p < 0.001]. CONCLUSION: In BPD-PH, childhood discontinuation of pulmonary vasodilator therapy is associated with markers of disease severity.

Trajectory of Long-Term Outcome in Severe Pediatric Diffuse Axonal Injury: An Exploratory Study.

Introduction: Pediatric severe traumatic brain injury (TBI) is one of the leading causes of disability and death. One of the classic pathoanatomic brain injury lesions following severe pediatric TBI is diffuse (multifocal) axonal injury (DAI). In this single institution study, our overarching goal was to describe the clinical characteristics and long-term outcome trajectory of severe pediatric TBI patients with DAI. Methods: Pediatric patients (<18 years of age) with severe TBI who had DAI were retrospectively reviewed. We evaluated the effect of age, sex, Glasgow Coma Scale (GCS) score, early fever ≥ 38.5°C during the first day post-injury, the extent of ICP-directed therapy needed with the Pediatric Intensity Level of Therapy (PILOT) score, and MRI within the first week following trauma and analyzed their association with outcome using the Glasgow Outcome Score-Extended (GOS-E) scale at discharge, 6 months, 1, 5, and 10 years following injury. Results: Fifty-six pediatric patients with severe traumatic DAI were analyzed. The majority of the patients were >5 years of age and male. There were 2 mortalities. At discharge, 56% (30/54) of the surviving patients had unfavorable outcome. Sixty five percent (35/54) of surviving children were followed up to 10 years post-injury, and 71% (25/35) of them made a favorable recovery. Early fever and extensive DAI on MRI were associated with worse long-term outcomes. Conclusion: We describe the long-term trajectory outcome of severe pediatric TBI patients with pure DAI. While this was a single institution study with a small sample size, the majority of the children survived. Over one-third of our surviving children were lost to follow-up. Of the surviving children who had follow-up for 10 years after injury, the majority of these children made a favorable recovery.

Longitudinal impact of cannabidiol on EEG measures in subjects with treatment-resistant epilepsy.

OBJECTIVE: To assess the longitudinal impact of highly purified cannabidiol (CBD) on the electroencephalogram (EEG) of children and adults. METHODS: Participants received an EEG prior to starting CBD, after approximately 12 weeks of CBD (FU1) and after approximately one year of CBD therapy (FU2). Longitudinal changes in five EEG measures (background frequency, focal slowing, reactivity, frequency of interictal, and ictal discharges) were examined following CBD exposure. Data were compared between pediatric and adult groups at two follow-up time points and within groups over time. Population-averaged models with generalized estimation equations or linear mixed effects models were used to analyze data where appropriate. Correlation analysis was used to assess any association between changes in seizure frequency and changes in EEG interictal discharge (IED) frequency. An alpha level of 5% was used to assess statistical significance. RESULTS: At FU1, the adult group showed significant decrease in IED/minute (IDR 0.07, 95% CI [0.04, 0.14], P < 0.001); a nonsignificant decrease was observed among children (IDR 0.87, 95% CI [0.47, 0.64], P = 0.67). The difference in changes over time between participant groups was significant after adjusting for last CBD dose (IDR 11.8, 95% CI [4.86, 28.65], P < 0.0001). At FU2 both groups showed significant reduction from baseline after controlling for last CBD dose. This decrease was more pronounced in children (IDR 15.38, 95% CI [4.93, 47.99], P < 0.001). There was no significant correlation between changes in seizure frequency and EEG IED frequency at each timepoint (P = 0.542, 0.917 and 0.989 from baseline to FU1, FU1 to FU2 and baseline to FU2, respectively). SIGNIFICANCE: This longitudinal EEG study shows that highly-purified plant-derived CBD has positive effects on interictal epileptiform discharge frequency but no effects on other EEG measures. The effect of CBD does not appear to be dose or treatment-duration dependent.

Long-term safety and efficacy of highly purified cannabidiol for treatment refractory epilepsy.

OBJECTIVE: To evaluate the safety, efficacy, and tolerability of highly purified cannabidiol (CBD) for the treatment of seizures in children and adults with treatment-resistant epilepsy (TRE) in an open-label, expanded access program (EAP). METHODS: One hundred sixty-nine participants (89 children and 80 adults) with TRE received plant-derived highly purified CBD (Epidiolex® in the U.S.; 100 mg/mL oral solution) with a starting dose of 5 mg/kg/day divided twice per day and titrated to a maximum dose of 50 mg/kg/day over the study period to seizure control and tolerability and followed for up to 2 years. Seizure frequency (calendars) and severity (Chalfont Seizure Severity Score; CSSS) were collected at every study visit. Adverse Events were reported at/between study visits as required, and participants also completed Adverse Events Profile (AEP) which generates a numerical representation of AEs. Response to CBD was defined as ≥50% reduction in seizure frequency. Given non-normal distribution of seizure frequency, a log transformation was applied after which the generalized least squares regression model for longitudinal data was used. RESULTS: Evidence from the adjusted model revealed a significant mean reduction in seizure frequency compared to baseline in children and adults at all time points (1 month and 1 and 2 years). Percentage of children achieving ≥50% seizure frequency reduction was 44% at month 1, and 41% at year 1, and 61% reduction at year 2, while adult responder rates were 34% at month 1, 53% at year 1, and 71% at year 2 (all P < 0.0001). CSSS showed a sustained reduction from baseline to all 3 time points. Children displayed 52% seizure reduction at month 1, a 51% reduction at year 1, and 75% reduction at year 2. Seizure reductions in adults were 60%, 81%, and 85%, respectively (all P < 0.0001). While there were no significant differences between seizure frequency reduction between children and adults at all time points, there was a significant difference in seizure severity reduction at year 1, with adults reporting greater improvement in seizure severity (P < 0.001). The most commonly reported adverse events in the study period were diarrhea, sedation, and decreased appetite. AEP revealed significant improvement from baseline at multiple time points in adults and children, and the mean AEP scores were always lower compared to baseline over the duration of the study. SIGNIFICANCE: Our study provides further evidence of sustained seizure frequency and severity reduction over two years of treatment with highly purified CBD in TRE. In addition, CBD was generally well tolerated with minority of participants experiencing adverse events resulting in stopping CBD.

Cognitive function and adaptive skills after a one-year trial of cannabidiol (CBD) in a pediatric sample with treatment-resistant epilepsy.

OBJECTIVE: Cannabidiol (CBD) is a nonpsychoactive derivative of cannabis. Studies indicate that it is safe and effective in treating certain types of epilepsy. The present study examined the presence of adverse or beneficial cognitive or functional adaptive effects associated with CBD in the treatment of children, adolescents, and teenagers with treatment-resistant epilepsy (TRE) as part of an ongoing prospective, open-label safety study. METHODS: Participants (N = 38) between the age of 3 and 19 years with TRE were enrolled in an open-label study of a pharmaceutical formulation of CBD (Epidiolex®; GW Research Ltd.) as an add-on treatment. In addition to baseline physical, neurological, and laboratory testing, cognitive assessment was completed prior to initiating CBD and after one year, both using the NIH Toolbox Cognition Battery (NIHTB-CB). Many participants were unable to complete the NIHTB-CB because of the magnitude of their cognitive impairment (n = 24), and in these cases, the participant's caregiver was asked to complete the Adaptive Behavior Assessment System - Second Edition (ABAS-II) as a measure of functional adaptive skills. RESULTS: There were no statistically significant changes in cognitive function, as measured by the NIHTB-CB, in those participants who were able to complete such testing, but there was a nonsignificant trend toward improvement in some cognitive domains. For participants who were unable to complete formal standardized cognitive testing because of the magnitude of their cognitive impairment, their functional adaptive skills, as measured by the ABAS-II, were unchanged after a one-year trial of CBD. SIGNIFICANCE: Our findings suggest that CBD, as an add-on drug for TRE in a pediatric sample, does not appear to cause adverse effects (AEs) involving cognition or adaptive function over one year of treatment.

Drug-drug interactions with cannabidiol (CBD) appear to have no effect on treatment response in an open-label Expanded Access Program.

OBJECTIVE: We have previously shown that cannabidiol (CBD; Epidiolex®) significantly affects levels of clobazam/N-desmethylclobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine. In the present study, we tested whether the presence of concomitant clobazam affected seizure frequency and severity (treatment response) 12 weeks after initiation of therapy with CBD in patients with treatment-resistant epilepsy (TRE). The secondary questions were whether the presence of any of the other antiepileptic drugs (AEDs) had an effect on seizure frequency or severity at 12, 24, or 48 weeks after therapy initiation. METHODS: One hundred and thirty-two adults and children with TRE receiving CBD were studied prospectively. Participants were separated into two groups - either taking (CBD + clobazam) or not taking concomitant clobazam (CBD - clobazam). In the secondary analyses, participants were divided into groups depending on whether they were taking at least 1/4 of the other AEDs shown to interact with CBD (iAED). Seizure counts and Chalfont Seizure Severity Scale (CSSS) were obtained at baseline, 12, 24, and 48 weeks. Groups were compared at each respective time point in the study using generalized estimating equations (GEE) analyses. RESULTS: All groups demonstrated statistically significant reductions in seizure frequency and severity from baseline (all P < 0.05). When participants on CBD + clobazam were compared with CBD - clobazam, there were no significant differences in seizure frequency and severity reduction between the groups at 12 weeks (both P > 0.05). When comparing groups with iAEDs vs. group without iAEDs, independent of coadministration of clobazam, no differences in treatment response were observed (all P > 0.05). Longitudinal analyses up to 48 weeks after therapy initiation did not reveal any differences in treatment response between groups. CONCLUSION: These analyses suggest that concomitant to CBD, AEDs may not have an effect on reducing seizure frequency and severity in patients with TRE.

Cognitive functioning following long-term cannabidiol use in adults with treatment-resistant epilepsy.

Cognitive dysfunction is a common comorbidity in adults with treatment-resistant epilepsy (TRE). Recently, cannabidiol (CBD) has demonstrated efficacy in epilepsy treatment. However, our understanding of CBD's cognitive effects in epilepsy is limited. We examined long-term cognitive effects of CBD in adults with TRE as part of an ongoing prospective, open-label safety study. Twenty-sevenadults with TRE (mean age: 34[SD +14], female 52%) enrolled in the UAB CBD program completed standardized cognitive testing (NIH Toolbox Cognition Battery (NIHTB-CB)) at pre-CBD administration baseline and at one-yearfollow-up. Participants were receiving stable CBD dose at the time of one-year testing (mean=36.5mg/kg/day). The NIHTB-CB consisted of two global composite scales (Fluid and Crystallized) and seven individual tests measuring aspects of working memory, episodic memory, executive function, processing speed, and language. All participants had recorded Chalfont Seizure Severity Scale (CSSS) scores at each visit. Statistical analyses consisted of t-test, Pearson correlation coefficient, and linear regression. At baseline, cognitive test performance was below average for both global composite scales (Fluid: 71 [±18] range: 46-117) and Crystallized (76 [±15] range: 59-112)]. Longitudinal analysis revealed no significant group change across the two global composite scales. Of the seven individual cognitive tests, none changed significantly over time. No correlation was found between the cognitive change scores and CBD dose (all P's≥0.21). Change in cognitive test performance was not associated change in seizure severity rating. These findings are encouraging and indicate that long-term administration of pharmaceutical grade CBD is overall cognitively well-tolerated in adults with TRE.

Higher cannabidiol plasma levels are associated with better seizure response following treatment with a pharmaceutical grade cannabidiol.

OBJECTIVE: The objective of this study was to determine the relationship between cannabidiol (CBD) dose, CBD plasma level, and seizure control in a large open-label single-center study. METHODS: All participants with treatment-refractory epilepsy participating in our expanded access program (EAP) were approached for participation. Highly purified grade CBD (Epidiolex®) dosing was weight-based and could be increased every 2 weeks by 5 mg/kg/day up to a maximum dosage of 50 mg/kg/day depending on tolerance and seizure control. Seizure counts were obtained at each visit with frequency calculated per 2-week periods. Cross-sectional plasma peak levels of CBD were obtained ~4 h after dosing in consecutively presenting patients. RESULTS: We evaluated 56 adults and 44 children (100 total; 54 female) at two time points - one before initiating CBD and one at the time of CBD plasma level testing. There was a positive linear correlation between CBD dosage (range from 5 to 50 mg/kg/day) and level (range from 7.1-1200 ng/mL) in all participants (r = 0.640; p < 0.001). The quantile regression model supported the notion of increased CBD levels being associated with improvement in seizure frequency after adjusting for age - specifically, a 100 ng/mL increase in CBD level was associated with approximately two counts reduction in seizure frequency per time period (1.87 96% confidence interval [CI] 0.34-3.39; p = 0.018). In participants with the same CBD level, differences in seizure improvement did not depend on age (p = 0.318). CONCLUSIONS: In this open-label study, we found evidence of a linear correlation between CBD dosage and plasma levels, and that higher dose/levels are associated with a higher response rate for seizure improvement. Children and adults responded to CBD similarly. However, seizure control response rates suggest children may respond to lower dosages/plasma levels than adults. Findings reported in this study are specific to Epidiolex® and should not be extrapolated to other CBD products.

Association between trace elements in the environment and stroke risk: The reasons for geographic and racial differences in stroke (REGARDS) study.

The disparities in stroke mortality between blacks and whites, as well as the increased stroke mortality in the "stroke belt" have long been noted. The reasons for these disparities have yet to be fully explained. The association between trace element status and cardiovascular diseases, including stroke, has been suggested as a possible contributor to the disparities in stroke mortality but has not been fully explored. The purpose of this study is to investigate distributions of four trace elements (arsenic, mercury, magnesium, and selenium) in the environment in relation to stroke risk. The study population (N=27,770) is drawn from the Reasons for Geographic and Racial Disparities in Stroke (REGARDS) cohort. Environmental distribution of each trace element was determined using data from the United States Geological Survey (USGS) and was categorized in quartiles. A proportional hazards model, adjusted for demographic data and stroke risk factors, was used to examine the association of interest. The results showed that higher selenium levels in the environment were associated with increased stroke risk, and the hazard ratio for the 4th quartile compared to the 1st quartile was 1.33 (95% CI: 1.09, 1.62). However, there was no statistically significant relationship between environmental arsenic, mercury or magnesium and the risk of stroke. Because of dietary and non-dietary exposure as well as bioavailability, further research using biomarkers is warranted to examine the association between these trace elements and the risk of stroke.

Fish oil supplementation ameliorates fructose-induced hypertriglyceridemia and insulin resistance in adult male rhesus macaques.

Fish oil (FO) is a commonly used supplemental source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), 2 n-3 (ω-3) polyunsaturated fatty acids (PUFAs) that have been shown to have a variety of health benefits considered to be protective against cardiometabolic diseases. Although the effects of EPA and DHA on lipid metabolism have been extensively studied, not all of the metabolic effects of FO-derived n-3 PUFAs have been characterized. Our laboratory recently showed that a high-fructose diet in rhesus monkeys induces the features of metabolic syndrome (MetS) similar to those observed in humans. Thus, we specifically wanted to evaluate the effects of FO in rhesus monkeys fed a high-fructose diet and hypothesized that FO supplementation would mitigate the development of fructose-induced insulin resistance, dyslipidemia, and other cardiometabolic risk factors. In this study, adult monkeys (aged 12-20 y) received either a standard unpurified diet plus 75 g fructose/d (control group; n = 9) or a standard unpurified diet, 75 g fructose/d, and 4 g FO (16% EPA + 11% DHA)/d (treatment group; n = 10) for 6 mo. Importantly, our results showed that daily FO supplementation in the monkeys prevented fructose-induced hypertriglyceridemia and insulin resistance as assessed by intravenous-glucose-tolerance testing (P ≤ 0.05). Moreover, FO administration in the monkeys prevented fructose-induced increases in plasma apolipoprotein (Apo)C3, ApoE, and leptin concentrations and attenuated decreases in circulating adropin concentrations (P ≤ 0.05). No differences between the control and FO-treated monkeys were observed in body weight, lean mass, fat mass, or fasting glucose, insulin, and adiponectin concentrations. In conclusion, FO administration in a nonhuman primate model of diet-induced MetS ameliorates many of the adverse changes in lipid and glucose metabolism induced by chronic fructose consumption.