Biomarker-Based Risk Stratification Tool in Pediatric Acute Respiratory Distress Syndrome: Single-Center, Longitudinal Validation in a 2014-2019 Cohort.

OBJECTIVES: The Pediatric Acute Respiratory Distress Syndrome Biomarker Risk Model (PARDSEVERE) used age and three plasma biomarkers measured within 24 hours of pediatric acute respiratory distress syndrome (ARDS) onset to predict mortality in a pilot cohort of 152 patients. However, longitudinal performance of PARDSEVERE has not been evaluated, and it is unclear whether the risk model can be used to prognosticate after day 0. We, therefore, sought to determine the test characteristics of PARDSEVERE model and population over the first 7 days after ARDS onset. DESIGN: Secondary unplanned post hoc analysis of data from a prospective observational cohort study carried out 2014-2019. SETTING: University-affiliated PICU. PATIENTS: Mechanically ventilated children with ARDS. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Between July 2014 and December 2019, 279 patients with ARDS had plasma collected at day 0, 266 at day 3 (11 nonsurvivors, two discharged between days 0 and 3), and 207 at day 7 (27 nonsurvivors, 45 discharged between days 3 and 7). The actual prevalence of mortality on days 0, 3, and 7, was 23% (64/279), 14% (38/266), and 13% (27/207), respectively. The PARDSEVERE risk model for mortality on days 0, 3, and 7 had area under the receiver operating characteristic curve (AUROC [95% CI]) of 0.76 (0.69-0.82), 0.68 (0.60-0.76), and 0.74 (0.65-0.83), respectively. The AUROC data translate into prevalence thresholds for the PARDSEVERE model for mortality (i.e., using the sensitivity and specificity values) of 37%, 27%, and 24% on days 0, 3, and 7, respectively. Negative predictive value (NPV) was high throughout (0.87-0.90 for all three-time points). CONCLUSIONS: In this exploratory analysis of the PARDSEVERE model of mortality risk prediction in a population longitudinal series of data from days 0, 3, and 7 after ARDS diagnosis, the diagnostic performance is in the "acceptable" category. NPV was good. A major limitation is that actual mortality is far below the prevalence threshold for such testing. The model may, therefore, be more useful in cohorts with higher mortality rates (e.g., immunocompromised, other countries), and future enhancements to the model should be explored.

Evolution of multiple omics approaches to define pathophysiology of pediatric acute respiratory distress syndrome.

Pediatric acute respiratory distress syndrome (PARDS), though both common and deadly in critically ill children, lacks targeted therapies. The development of effective pharmacotherapies has been limited, in part, by lack of clarity about the pathobiology of pediatric ARDS. Epithelial lung injury, vascular endothelial activation, and systemic immune activation are putative drivers of this complex disease process. Prior studies have used either hypothesis-driven (e.g., candidate genes and proteins, in vitro investigations) or unbiased (e.g., genome-wide association, transcriptomic, metabolomic) approaches to predict clinical outcomes and to define subphenotypes. Advances in multiple omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, have permitted more comprehensive investigation of PARDS pathobiology. However, omics studies have been limited in children compared to adults, and analyses across multiple tissue types are lacking. Here, we synthesized existing literature on the molecular mechanism of PARDS, summarized our interrogation of publicly available genomic databases to determine the association of candidate genes with PARDS phenotypes across multiple tissues and cell types, and integrated recent studies that used single-cell RNA sequencing (scRNA-seq). We conclude that novel profiling methods such as scRNA-seq, which permits more comprehensive, unbiased evaluation of pathophysiological mechanisms across tissue and cell types, should be employed to investigate the molecular mechanisms of PRDS toward the goal of identifying targeted therapies.

Endothelial Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference.

OBJECTIVES: To review, analyze, and synthesize the literature on endothelial dysfunction in critically ill children with multiple organ dysfunction syndrome and to develop a consensus biomarker-based definition and diagnostic criteria. DATA SOURCES: Electronic searches of PubMed and Embase were conducted from January 1992 to January 2020, using a combination of medical subject heading terms and key words to define concepts of endothelial dysfunction, pediatric critical illness, and outcomes. STUDY SELECTION: Studies were included if they evaluated critically ill children with endothelial dysfunction, evaluated performance characteristics of assessment/scoring tools to screen for endothelial dysfunction, and assessed outcomes related to mortality, functional status, organ-specific outcomes, or other patient-centered outcomes. Studies of adults or premature infants (≤36 weeks gestational age), animal studies, reviews or commentaries, case series with sample size ≤10, and non-English language studies with the inability to determine eligibility criteria were excluded. DATA EXTRACTION: Data were abstracted from each eligible study into a standard data extraction form along with risk of bias assessment. DATA SYNTHESIS: We identified 62 studies involving 84 assessments of endothelial derived biomarkers indirectly linked to endothelial functions including leukocyte recruitment, inflammation, coagulation, and permeability. Nearly all biomarkers studied lacked specificity for vascular segment and organ systems. Quality assessment scores for the collected literature were low. CONCLUSIONS: The Endothelial Subgroup concludes that there exists no single or combination of biomarkers to diagnose endothelial dysfunction in pediatric multiple organ dysfunction syndrome. Future research should focus on biomarkers more directly linked to endothelial functions and with specificity for vascular segment and organ systems.

Gaps and Opportunities in HIV Service Delivery in High Volume HIV Care Centers in Liberia: Lessons From the Field.

Background: Human Immunodeficiency Virus (HIV) infection continues to have a profound humanitarian and public health impact in western and central Africa, a region that risks being left behind in the global response to ending the AIDS epidemic. In Liberia, where the health system is being rebuilt following protracted civil wars and an Ebola virus disease outbreak, the Resilient and Responsive Health System (RRHS) is assisting with quality HIV services delivery through support from PEPFAR and HRSA but gaps remain across the cascade of care from diagnosis to viral load suppression. Objective: To highlight gaps in HIV service delivery in Liberia, identify opportunities and offer recommendations for improving the quality of service delivery. Methods: A narrative review of relevant literature was conducted following a search of all local and online databases known to the authors. Findings: Antiretroviral therapy (ART) has transformed the HIV response in Liberia by averting deaths, improving quality of life, and preventing new HIV infections but critical gaps remain. These include weak HIV prevention and testing strategies; suboptimal ART initiation and retention in care; low viral load testing volumes, commodity supply chain disruptions and a HIV workforce built on non-physician healthcare workers. In the context of the prevailing socioeconomic, heath system and programmatic challenges, these will impact achievement of the UNAIDS targets of 95-95-95 by 2030 and ending the epidemic. Conclusion: Combination prevention approaches are necessary to reach the most at risk populations, while a robust health workforce operating through facilities and communities will be needed to reach people with undiagnosed HIV earlier to provide efficient and effective services to ensure that people know their HIV status, receive and sustain ART to achieve viral suppression to maintain a long and healthy life within the framework of overall health system strengthening, achieving universal health coverage and the sustainable development goal.

Health Management Workforce Capacity-Building in Liberia, Post-Ebola.

Following the Ebola crisis in Liberia in 2014-15, the Liberian Ministry of Health developed a strategy to build a fit-for-purpose health workforce, focusing on both health care providers and health managers. To help fulfill national capacity-building goals for health management, a team of faculty, staff, and practitioners from the Yale School of Medicine, the University of Liberia, the National Public Health Institute of Liberia, and the Ministry of Health collaboratively developed and launched the health management program in Liberia in July 2017. The team worked to build specific management and leadership competencies for healthcare workers serving in management and leadership roles in Liberia's health sector using two concurrent strategies-1) implementation of a hospital-based partnership-mentorship model in the two largest hospitals in the capital city of Monrovia, and 2) establishment of an executive education-style advanced Certificate in Health Systems Leadership and Management at the University of Liberia. Here we describe the health management program in Liberia, its focus, and its evolution from program launch in 2017 to the present, as well as ongoing efforts to transition program activities to local partner ownership by the end of 2021.

Endothelial Biomarkers Are Associated With Indirect Lung Injury in Sepsis-Associated Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVES: Acute respiratory distress syndrome occurring in the setting of direct versus indirect lung injury may reflect different pathobiologies amenable to different treatment strategies. We sought to test whether a panel of plasma biomarkers differed between children with sepsis-associated direct versus indirect acute respiratory distress syndrome. We hypothesized that a biomarker profile indicative of endothelial activation would be associated with indirect acute respiratory distress syndrome. DESIGN: Observational cohort. SETTING: Academic PICU. SUBJECTS: Patients less than 18 years old with sepsis-associated direct (pneumonia, n = 52) or indirect (extrapulmonary sepsis, n = 46) acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 58 biomarkers examined, 33 differed by acute respiratory distress syndrome subtype. We used classification and regression tree methodology to examine associations between clinical and biochemical markers and acute respiratory distress syndrome subtype. The classification and regression tree model using only clinical variables (age, sex, race, oncologic comorbidity, and Pediatric Risk of Mortality-III score) performed worse than the classification and regression tree model using five clinical variables and 58 biomarkers. The best classification and regression tree model used only four endothelial biomarkers, including elevated angiopoietin-2/angiopoietin-1 ratio, vascular cell-adhesion molecule, and von Willebrand factor, to identify indirect acute respiratory distress syndrome. Test characteristics were 89% (80-97%) sensitivity, 80% (69-92%) specificity, positive predictive value 84% (74-93%), and negative predictive value 86% (76-96%). CONCLUSIONS: Indirect lung injury in children with acute respiratory distress syndrome is characterized by a biomarker profile indicative of endothelial activation, excess inflammation, and worse outcomes. A model using four biomarkers has the potential to be useful for more precisely identifying patients with acute respiratory distress syndrome whose pathobiology may respond to endothelial-targeted therapies in future trials.

Deployment of a Clinical Pathway to Improve Postcardiac Arrest Care: A Before-After Study.

OBJECTIVES: Postcardiac arrest care bundles following adult cardiac arrest are associated with improved survival to discharge. We aimed to evaluate whether a clinical pathway and computerized order entry were associated with improved pediatric postcardiac arrest care and discharge outcomes. DESIGN: Single-center retrospective before-after study. SETTING: Academic PICU. PATIENTS: Patients who suffered an in- or out-of-hospital cardiac arrest from January 2008 to December 2015 cared for in the PICU within 12 hours of sustained return of circulation. INTERVENTION: Deployment of a postcardiac arrest clinical pathway and computerized order entry system. MEASUREMENTS AND MAIN RESULTS: There were 380 patients included-163 in the pre-pathway period and 217 in the post-pathway period. Primary outcome was percent adherence to pathway clinical goals at 0-6 and 6-24 hours post-return of circulation and to diagnostics (continuous electroencephalogram monitoring, head CT for out-of-hospital cardiac arrests, echocardiogram). Secondary outcomes included survival to hospital discharge and survival with favorable neurologic outcome (Pediatric Cerebral Performance Category of 1-3 or no change from baseline). The pre-pathway and post-pathway groups differed in their baseline Pediatric Cerebral Performance Category scores and the following causes of arrest: airway obstruction, arrhythmias, and electrolyte abnormalities. Pathway adherence was not significantly different between the pre-pathway and post-pathway groups, with the exception of higher rates of continuous electroencephalogram monitoring (45% vs 64%; p < 0.001). There was no difference in survival to hospital discharge between the two groups (56% vs 67%; adjusted odds ratio, 1.68; 95% CI, 0.95-2.84; p = 0.05). Survival to discharge was higher in the post-pathway group for the in-hospital cardiac arrest cohort (55% vs 76%; adjusted odds ratio, 3.06; 95% CI, 1.44-6.51; p < 0.01). There was no difference in favorable neurologic outcome between all patients (adjusted odds ratio, 1.21; 95% CI, 0.72-2.04) or among survivors (adjusted odds ratio, 0.72; 95% CI, 0.27-1.43). CONCLUSIONS: After controlling for known potential confounders, the creation and deployment of a postcardiac arrest care pathway and computerized order entry set were not associated with improvement in pathway adherence or overall outcomes, but was associated with increased survival to hospital discharge for children with in-hospital cardiac arrests.

Systemic Endothelial Activation Is Associated With Early Acute Respiratory Distress Syndrome in Children With Extrapulmonary Sepsis.

OBJECTIVES: Systemic endothelial activation may contribute to sepsis-associated organ injury, including acute respiratory distress syndrome. We hypothesized that children with extrapulmonary sepsis with versus without acute respiratory distress syndrome would have plasma biomarkers indicative of increased endothelial activation and that persistent biomarker changes would be associated with poor outcome. DESIGN: Observational cohort. SETTING: Academic PICU. PATIENTS: Patients less than 18 years old with sepsis from extrapulmonary infection with (n = 46) or without (n = 54) acute respiratory distress syndrome and noninfected controls (n = 19). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Endothelial (angiopoietin-1, angiopoietin-2, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, soluble fms-like tyrosine kinase, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin) and inflammatory biomarkers (C-reactive protein, interleukin-6, and interleukin-8) were measured from peripheral plasma collected within 3 days (time 1) of sepsis recognition and at 3-6 days (time 2) and 7-14 days (time 3). Time 1 biomarkers and longitudinal measurements were compared for sepsis patients with versus without acute respiratory distress syndrome and in relation to complicated course, defined as greater than or equal to two organ dysfunctions at day 7 or death by day 28. Angiopoietin-2, angiopoietin-2/angiopoietin-1 ratio, tyrosine kinase with immunoglobulin-like loop epidermal growth factor homology domain 2, vascular endothelial growth factor, von Willebrand factor, E-selectin, intercellular adhesion molecule, vascular cell adhesion molecule, thrombomodulin, endocan, C-reactive protein, interleukin-6, and interleukin-8 were different between sepsis and noninfected control patients at time 1. Among patients with sepsis, those with acute respiratory distress syndrome had higher angiopoietin-2/angiopoietin-1 ratio, vascular endothelial growth factor, vascular cell adhesion molecule, thrombomodulin, endocan, interleukin-6, and interleukin-8 than those without acute respiratory distress syndrome (all p < 0.003). Angiopoietin-2 and angiopoietin-2/angiopoietin-1 ratio remained higher in sepsis with versus without acute respiratory distress syndrome after multivariable analyses. Time 1 measures of angiopoietin-2, angiopoietin-2/-1 ratio, von Willebrand factor, and endocan were indicative of complicated course in all sepsis patients (all area under the receiver operating curve ≥ 0.80). In sepsis without acute respiratory distress syndrome, soluble fms-like tyrosine kinase decreased more quickly and von Willebrand factor and thrombomodulin decreased more slowly in those with complicated course. CONCLUSIONS: Children with extrapulmonary sepsis with acute respiratory distress syndrome had plasma biomarkers indicative of greater systemic endothelial activation than those without acute respiratory distress syndrome. Several endothelial biomarkers measured near sepsis recognition were associated with complicated course, whereas longitudinal biomarker changes yielded prognostic information only in those without sepsis-associated acute respiratory distress syndrome.

Vascular Endothelial Growth Factor and Soluble Vascular Endothelial Growth Factor Receptor as Novel Biomarkers for Poor Outcomes in Children With Severe Sepsis and Septic Shock.

Vascular endothelial growth factor (VEGF) and its receptor, soluble fms-like tyrosine kinase (sFLT), are biomarkers of endothelial activation. Vascular endothelial growth factor and sFLT have been associated with sepsis severity among adults, but pediatric data are lacking. The goal of this study was to assess VEGF and sFLT as predictors of outcome for children with sepsis. METHODS: Biomarkers measured for each patient at time of presentation to the emergency department were compared in children with septic shock versus children with sepsis without shock. For children with septic shock, the associations between biomarker levels and clinical outcome measures, including intensive care unit and hospital length of stay, vasoactive inotrope score, and measures of organ dysfunction, were assessed. RESULTS: Soluble fms-like tyrosine kinase and VEGF were elevated in children with septic shock (n = 73) compared with those with sepsis (n = 93). Elevated sFLT but not VEGF was associated with longer intensive care unit length of stay (P = 0.003), longer time requiring vasoactive agents (P < 0.001), higher maximum vasoactive inotrope score (P < 0.001), and higher maximum pediatric logistic organ dysfunction score (P < 0.001). CONCLUSIONS: Vascular endothelial growth factor and sFLT measured in the emergency department are elevated in children with septic shock, and elevated sFLT but not VEGF is associated with worse clinical outcomes.

Systemic Angiopoietin-1/2 Dysregulation in Pediatric Sepsis and Septic Shock.

Background: Angiopoietin-1 and -2 are vascular growth factors that exert opposing effects on endothelial activation and dysfunction. The aim of this study was to assess the association of these biomarkers with outcomes in children with sepsis. Methods: Biomarkers were assayed from the blood collected in an emergency department prior to any intervention. Predictor variables were Ang-1 and Ang-2 levels and the Ang-2/Ang-1 ratio. Outcomes included mortality, length of time on vasopressors, and ICU and hospital lengths of stay. The Pediatric RISk of Mortality III Score was calculated. A vasoactive inotrope score was calculated every 12 hours. Results: Forty-five children with sepsis and 49 with septic shock were analyzed. The median Ang-2 was higher in septic shock. The Ang-2/Ang-1 ratio was approximately 2-fold greater in those with septic shock. The Ang-2/Ang-1 ratio was associated with higher doses of vasoactive agents at 12 hours and longer ICU length of stay. In septic shock, for every 0.35 unit increase in the Ang-2/Ang-1 ratio, the PRISM III score increased by 1. Conclusions: The Ang-2/Ang-1 ratio was higher in children with septic shock. Ang-2/Ang-1 was associated with higher vasoactive agents, longer ICU length of stay, and correlated with the severity of illness score.

A Pilot Study of the Association of Amino-Terminal Pro-B-Type Natriuretic Peptide and Severity of Illness in Pediatric Septic Shock.

OBJECTIVES: Biomarkers that can measure illness severity and predict the risk of delayed recovery may be useful in guiding pediatric septic shock. Amino-terminal pro-B-type natriuretic peptide has not been assessed in pediatric septic patients at the time of presentation to the emergency department prior to any interventions. The primary aim was to assess if emergency department amino-terminal pro-B-type natriuretic peptide is associated with worse outcomes and severity of illness. DESIGN: Prospective observational pilot study. SETTINGS: Tertiary free-standing children's hospital. PATIENTS: Children 0-17 years old with a diagnosis of septic shock were enrolled. Patients with preexisting cardiac and renal dysfunction were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Amino-terminal pro-B-type natriuretic peptide analysis was performed on samples obtained in the emergency department prior to any intervention. The association between biomarkers and clinical outcomes and illness severity using Pediatric RISk of Mortality 3 were assessed. Eighty-two patients with septic shock underwent analysis. The median (interquartile range) amino-terminal pro-B-type natriuretic peptide levels was 394 pg/mL (102-1,392 pg/mL). Each decile change increase in amino-terminal pro-B-type natriuretic peptide was associated with a change in ICU length of stay by 8.7%, (95% CI, 2.4-15.5), hospital length of stay by 5.7% (95% CI, 0.4-11.2), organ dysfunction by 5.1% (95% CI, 1.8-8.5), a higher inotropic score at 12, 24, and 36 hours, and longer time requiring vasoactive agents. There was a significant correlation between baseline amino-terminal pro-B-type natriuretic peptide and the Pediatric RISk of Mortality 3 score (Spearman rho = 0.247; p = 0.029). CONCLUSIONS: This pilot study shows an association between emergency department amino-terminal pro-B-type natriuretic peptide on presentation and worse septic shock outcomes and amino-terminal pro-B-type natriuretic peptide levels correlates with an ICU severity score.

Socio-emotional processing and functioning of youth at high risk for bipolar disorder.

BACKGROUND: The goal of this study was to investigate differences in socio-emotional processing and functioning in children and adolescents at high risk for bipolar disorder (BD) and healthy control participants. METHODS: Children and adolescents with a parent with bipolar disorder, who had mood dysregulation but not fully syndromal BD (high risk, HR, n=24), were compared to participants with no personal or family history of psychopathology (healthy control, HC, n=27) across several neuropsychological domains. Social reciprocity was measured by the Social Responsiveness Scale, theory of mind was measured by use of the NEPSY, and affect recognition was measured by the NEPSY and the Diagnostic Test of Nonverbal Accuracy 2 (DANVA). RESULTS: The HR group demonstrated significant impairment in social reciprocity, including impairments in social awareness, social cognition, social communication, social motivation, and autistic mannerisms. There were no significant group differences in performance on theory of mind or affect recognition tasks. LIMITATIONS: Lack of impairment in tasks associated with theory of mind or affect recognition indicate that social functioning difficulties are not likely due to impairments in these areas, or that the measures employed were not sufficiently sensitive to detect group differences. CONCLUSIONS: Youth at high risk for BD demonstrated impairments in numerous social domains, which may be due to innate differences in brain development governing socio-emotional functioning or may be due to disruptions in normal development caused by mood regulation difficulties.

Information processing in adolescents with bipolar I disorder.

BACKGROUND: Cognitive models of bipolar I disorder (BD) may aid in identification of children who are especially vulnerable to chronic mood dysregulation. Information-processing biases related to memory and attention likely play a role in the development and persistence of BD among adolescents; however, these biases have not been extensively studied in youth with BD. METHODS: We administered the self-referent encoding task and the dot-probe task to adolescents with bipolar I disorder (BD, n = 35) and a demographically similar healthy comparison group (HC, n = 25) at baseline, and at a 1-year follow-up in a subset of this cohort (n = 22 per group). RESULTS: At both baseline and 1-year follow-up, there were significant interactions of group (BD, HC) and valence of stimulus (positive, negative adjective) on endorsement and recall of self-referent adjectives. HC adolescents endorsed and recalled more positive self-referent adjectives at baseline and follow-up while adolescents with BD endorsed and recalled more negative self-referent adjectives at baseline but not follow-up. Over time, depression symptomatology was associated with impaired memory for positive self-referent adjectives. There were no group differences in attentional bias at either time points. CONCLUSIONS: Adolescents with BD exhibit bias away from endorsement and recall of positive adjectives, which remained stable over time and independent of mood state.

Elevated rates of ADHD in mothers of children with comorbid ADHD and epilepsy.

OBJECTIVES: To describe the prevalence of ADHD in mothers of children with comorbid ADHD and epilepsy (ADHD+E) and to compare ADHD symptoms in mothers with (Fam(+)) and without (Fam(-)) additional relative(s) with epilepsy. PATIENTS & METHODS: Mothers (n = 16) of children with ADHD+E were assessed by the Kiddie Schedule for Affective Disorders and Schizophrenia for School Age Children ADHD module and the ADHD Rating Scale IV. Information was collected on the presence (Fam(+)) or absence (Fam(-)) of first- or second-degree relatives with epilepsy in the sample. RESULTS: A total of 50% of mothers met the DSM-IV criteria for ADHD. ADHD was more prevalent in Fam(+) mothers (80%) compared with Fam(-) mothers (36%; p = 0.14). Fam(+) mothers had more current hyperactivity symptoms than Fam(-) mothers (p = 0.002), higher current ADHD severity (p = 0.02) and higher ADHD Rating Scale IV hyperactivity scores (p = 0.008). CONCLUSION: The prevalence of ADHD in mothers of children with ADHD+E is elevated in this pilot study, suggesting that ADHD symptoms in children with epilepsy and their mothers reflects shared familial genetic or environmental risks, potentially resulting in a higher prevalence of both disorders among family members. This is a pilot study and larger controlled studies are warranted.

Tolerability of atomoxetine for treatment of pediatric attention-deficit/hyperactivity disorder in the context of epilepsy.

To examine atomoxetine's tolerability in patients with epilepsy, we reviewed medical records of all patients with epilepsy who were treated with atomoxetine in a tertiary care pediatric psychopharmacology practice. Twenty-seven patients (10.1 ± 4.2 years, 63% male) with an average seizure frequency at baseline of 7 ± 24 per month (median: 0, range: 0-90) were found. Symptoms of attention-deficit/hyperactivity disorder in twenty-five patients (92.5%) had previously not responded to stimulants. Atomoxetine, average dose 35.2 ± 24.4 mg, was given for a median of 26 weeks (range: 4-141). Seventeen patients (63%) discontinued atomoxetine due to: inadequate response (n=7, 26%), worsening behavior such as increased irritability/activation (n = 7, 26%), nonadherence (n=1, 4%), emerging psychotic-like symptoms (n=1, 4%), and appetite decrease and tremor (n=1, 4%). There were no discontinuations because of seizure exacerbation. Atomoxetine dose, epilepsy etiology, seizure type, and comorbid psychiatric disorders did not predict discontinuation. No safety problems of sufficient magnitude to preclude prospective studies of atomoxetine in children with epilepsy were found.

Adaptive phase I study of OROS methylphenidate treatment of attention deficit hyperactivity disorder with epilepsy.

OBJECTIVE: The goal of this study was to pilot a randomized controlled trial of OROS methylphenidate (OROS-MPH) to treat attention deficit hyperactivity disorder (ADHD) plus epilepsy. METHODS: Thirty-three patients, 6-18years of age, taking antiepileptic drugs and with a last seizure 1-60months prior were assigned to a maximum daily dose of 18, 36, or 54mg of OROS-MPH in a double-blind placebo-controlled crossover trial. RESULTS: There were no serious adverse events and no carryover effects in the crossover trial. OROS-MPH reduced ADHD symptoms more than did placebo treatment. There were too few seizures during the active (5) and placebo arms (3) to confidently assess seizure risk; however, considering exposure time, we observed an increased daily risk of seizures with increasing dose of OROS-MPH, suggesting that potential safety concerns require further study. CONCLUSION: A larger study to assess the effect of OROS-MPH on seizure risk is needed. A crossover design including subjects with frequent seizures could maximize power and address high patient heterogeneity and recruitment difficulties.

An expert opinion on methylphenidate treatment for attention deficit hyperactivity disorder in pediatric patients with epilepsy.

Methylphenidate (MPH) is one of the most commonly prescribed medications to treat attention deficit hyperactivity disorder (ADHD). Despite the elevated rates of ADHD in children with epilepsy, few studies have examined the use of MPH in this population. Case reports have warned about new-onset seizures in patients treated with MPH, and drug-drug interactions between MPH and antiepileptic drugs (AEDs), as well as antidepressants. However, retrospective chart reviews, open-label trials and controlled trials of MPH in patients with epilepsy and ADHD have noted significant improvements in ADHD symptoms without an exacerbation of seizures or an adverse effect on AED serum levels. This paper reviews the chemistry and mechanisms of action of MPH, as well as preclinical, premarketing clinical trials and postmarketing data relevant to its use in patients with ADHD and epilepsy.

Attention-deficit/hyperactivity disorder in pediatric patients with epilepsy: review of pharmacological treatment.

Attention-deficit/hyperactivity disorder (ADHD) in children with epilepsy is a common source of impairment. Based on review of Medline indexed articles, meeting abstracts, and data requested from drug manufacturers, a summary of evidence that might guide treatment and research is presented. Methylphenidate (MPH) has shown high response rates and no increase in seizures in small trials. However, low baseline seizure rates, small numbers of subjects, and short observation periods limit the power of these studies to detect increases in seizure risk. Although longer-term effects of MPH and its effects in children with frequent seizures need to be studied, the evidence available at this time best supports use of MPH for the treatment of ADHD not amenable to changes in antiepileptic drugs or improvements in seizure control. This treatment should be part of a biopsychosocial approach. Other agents show promise. Preclinical, retrospective and open-label studies on amphetamines and atomoxetine support undertaking randomized controlled studies of these agents in patients with ADHD plus epilepsy. In contrast, additional data on guanfacine and modafinil should be gathered before undertaking randomized controlled studies with these agents.

Tolerability of selective serotonin reuptake inhibitors in thirty-nine children under age seven: a retrospective chart review.

OBJECTIVE: To characterize the adverse effects of treatment with selective serotonin reuptake inhibitors (SSRIs) started in children under age 7 yr. METHODS: We conducted a retrospective review of medical records for all children who had begun treatment with an SSRI under age 7 at an academic psychiatry department in Boston. RESULTS: Thirty-nine children (26 males, 13 females) met the inclusion criteria. Mean age at start of treatment was 5.9 +/- 0.8 yr, and median treatment duration was 5.0 months. The target diagnoses for SSRI treatment were anxiety disorders in 54%, depressive disorders in 23%, and both anxiety and depressive disorders in 20% of patients. There were no reports of suicidal ideation or attempt. No children were medically or psychiatrically hospitalized for adverse effects (AEs). Eleven patients (28%) reported an AE of at least moderate severity; 7 (18%) discontinued the SSRI due to the AE. Six patients discontinued due to behavioral activation and 1 due to gastrointestinal upset. The median time to onset of an AE was 23 days, and median resolution was 19 days from onset. CONCLUSIONS: The high rate of adverse effects, especially activation, in this sample argues for continued caution in using SSRIs in young children. Controlled trials are warranted.