The eTHINK Study: Cognitive and Behavioral Outcomes in Children with Hemophilia.

OBJECTIVE: To assess cognitive, behavioral, and adaptive functions in children and young adults with hemophilia treated according to contemporary standards of care. STUDY DESIGN: eTHINK was a US-based, prospective, cross-sectional, observational study (September 2018 through October 2019). Males (aged 1-21 years) with hemophilia A or B of any severity, with or without inhibitors, were eligible. Participants underwent neurological examinations and age-appropriate neuropsychological assessments, including standardized tests/ratings scales of early development, cognition, emotional/behavioral adjustment, and adaptive skills. RESULTS: 551 males with hemophilia A (n=433) or B (n=101) were enrolled. Performance on cognitive tests was largely comparable with that of age-matched US population norms, although participants in certain age groups (4-5 and 10-21 years) performed worse on measures of attention and processing speed. Furthermore, adolescents and young adults and those with comorbid attention-deficit/hyperactivity disorder (ADHD; n=64) reported more adaptive and executive function problems in daily life. Incidence of ADHD in adolescents (21%) was higher than expected in the general population. CONCLUSIONS: In general, males with hemophilia demonstrated age-appropriate intellectual, behavioral, and adaptive development. However, specific patient/age groups showed poorer attention performance and concerns for executive and adaptive development. This study established a normative data set for monitoring neurodevelopment in individuals with hemophilia and highlights the importance of screening and intervention for challenges with cognitive and adaptive skills in this population.

Nonacog beta pegol prophylaxis in children with hemophilia B: safety, efficacy, and neurodevelopmental outcomes for up to 8 years.

Background: Nonacog beta pegol (N9-GP) is an extended half-life PEGylated factor (F)IX product with established efficacy and short-term safety in persons with hemophilia B (HB). Long-term safety has been evaluated for polyethylene glycol exposure but not N9-GP. Objectives: To assess safety, neurodevelopmental, and efficacy outcomes of children with HB receiving N9-GP prophylaxis across 2 open-label, single-arm, phase 3 studies: paradigm5 (previously treated patients [PTPs]) and paradigm6 (previously untreated patients [PUPs]) in this interim analysis. Methods: PTPs (aged ≤12 years) and PUPs (aged <6 years) with severe/moderate (≤2% FIX level) HB were recruited to N9-GP prophylaxis (40 IU/kg once weekly) in paradigm5 and paradigm6, respectively. Safety assessments included FIX inhibitor incidence, adverse events, neurocognitive and neurologic outcomes, polyethylene glycol concentration in plasma, and medical events of special interest. Efficacy endpoints included bleeds, N9-GP hemostatic effect, and FIX consumption. Results: Overall, 25 patients in paradigm5 and 50 patients in paradigm6 received N9-GP and were followed for up to 8 and 6 years, respectively. No inhibitory antibodies were reported in PTPs; 4 of the 50 PUPs developed inhibitors. Extensive evaluation revealed no neurocognitive or neurologic concerns with N9-GP use in children during the study period. Across both studies, few adverse events were reported as possibly related to N9-GP. High hemostatic response rate, high treatment adherence, low annualized bleeding rates, and no new target joints were reported. Conclusion: These data provide the longest follow-up for an extended half-life FIX and confirm the long-term efficacy of N9-GP prophylaxis in children with HB with no observed neurocognitive or neurologic safety concerns.

Roadmap for the Assessment and Management of Outcomes in Pediatric Stroke.

Neurological morbidity is common after pediatric stroke, with moderate to severe deficits that can significantly impact education and social function. Care and recovery occur in phases distinguished by the time interval after stroke onset. These phases include the hyperacute and acute periods in which the focus is on cerebral reperfusion and prevention of neurological deterioration, followed by the subacute and chronic phases in which the focus is on secondary stroke prevention and mitigation of disability through rehabilitation, adaptation, and reintegration into the community. In this article, a multidisciplinary group of pediatric stroke experts review the stages of recovery after pediatric stroke with an emphasis on critical assessment time points. Our goal is to encourage increased standardization of outcome assessment to facilitate future clinical trials comparing various treatment and intervention options and advance optimized care for children with stroke.

Rehabilitation in Pediatric Stroke: Cognition and Behavior.

Pediatric stroke is associated with a range of maladaptive cognitive and behavioral outcomes that often require targeted intervention. Despite increasing research on neuropsychological outcomes over the past decade, evidence for effective therapies and interventions for the most commonly reported cognitive and behavioral challenges is still limited. The most widely prescribed interventions address more overt deficits in sensorimotor and speech/language functions, yet interventions for higher-order cognitive, linguistic and behavioral deficits are notably less defined. Moreover, concepts of rehabilitation in adult stroke cannot be easily translated directly to pediatric populations because the effect of stroke and recovery in the developing brain takes a very different course than in the mature brain. In pediatric stroke, neuropsychological deficits often emerge gradually over time necessitating a long-term approach to intervention. Furthermore, family and school context often play a much larger role. The goal of this review is to describe cognitive and behavioral interventions for perinatal and childhood stroke, as motor rehabilitation is covered elsewhere in this issue. We also discuss cognitive aspects of current rehabilitative therapies and technology. Acknowledging the current limited state of stroke-specific rehabilitation research in children, findings from pediatric acquired brain injury intervention and use of transdiagnostic approaches lend important insights. Because there is limited support for single domain (cognitive) trainings and translation of research rehabilitation programs to clinical practice can be challenging, the value of holistic multidisciplinary approaches to improve everyday function in children and adolescents following stroke is emphasized.

Recent Advances in Neuropsychological Outcomes and Intervention in Pediatric Stroke.

Over the past 15 years, there have been significant advances in the treatment of acute and chronic medical consequences of stroke in childhood. Given high rates of survival in pediatric stroke, practitioners are tasked with treating the ongoing motor and neuropsychological sequelae in patients over the course of their development. This article provides a review of the current literature on neuropsychological outcomes in pediatric stroke, including intelligence, academics, language, visual-spatial skills, attention, executive functions, memory, and psychosocial function. Recent developments in functional neuroimaging are discussed, with a particular focus on language outcomes. We further review the current research on cognitive and behavioral rehabilitation and introduce intervention models in pediatric stroke. In the final section, we discuss future directions for clinical practice and research in pediatric stroke.

Functional abdominal pain symptom severity: Associations between cognition and emotion in a pediatric sample.

Functional abdominal pain (FAP) is a common physical complaint in children and adolescents. Prior research has documented associations between FAP symptoms and mood, especially internalizing behaviors. Limited research is available examining the association between symptom burden and cognitive function in this pediatric population. This study explored associations between FAP symptoms, internalizing behaviors, and cognitive and school function in children and adolescents. Twenty-seven participants (mean age = 12.6 years, range 8.8-16.5; 33% male) diagnosed with FAP completed assessments of cognitive, emotional, and behavioral function, as well as FAP symptom severity. Mean performances on cognitive tests were within age-expected ranges. Within this context, however, higher overall burden of FAP symptoms was associated with slower processing speed, more self-reported metacognitive problems and internalizing behaviors, and more school absences. Cognitive function was systematically associated with internalizing behaviors but not physical symptoms. Overall, findings revealed that FAP may be associated with cognitive inefficiencies in addition to internalizing problems. Cognitive symptoms may be linked to internalizing behaviors associated with FAP.

Adverse effects of erenumab on cerebral proliferative angiopathy: A case report.

BACKGROUND: Cerebral proliferative angiopathy is a vascular malformation associated with compromised blood-brain barrier and with migraine-like headache. Treating blood-brain barrier-compromised patients with erenumab, an anti-calcitonin gene-related peptide receptor monoclonal antibody, may be risky. CASE: We describe a case of a 22-year-old chronic migraine patient with cerebral proliferative angiopathy who presented to our hospital in status epilepticus 2 d after his first dose of erenumab. Serial magnetic resonance imaging (MRI) studies demonstrated progressive areas of diffusion restriction including the brain tissue adjacent to the cerebral proliferative angiopathy, bilateral white matter and hippocampi. His 6-month post-presentation magnetic resonance imaging was notable for white matter injury, encephalomalacia surrounding cerebral proliferative angiopathy and bilateral hippocampal sclerosis. He remains clinically affected with residual symptoms, including refractory epilepsy and cognitive deficits. CONCLUSION: The evidence presented in this case supports further investigation into potential deleterious side effects of erenumab in patients with compromised blood-brain barrier, such as individuals with intracranial vascular malformations.

Prevalence of Symptoms of Anxiety, Depression, and Post-traumatic Stress Disorder in Parents and Children Following Pediatric Stroke.

Post-traumatic stress disorder (PTSD), anxiety, and depression are seen in parents and children following critical illness. Whether this exists in parents and children following pediatric stroke has not been thoroughly studied. We examined emotional outcomes in 54 mothers, 27 fathers, and 17 children with stroke. Parents of children 0-18 years and children 7-18 years who were within 2 years of stroke occurrence were asked to complete questionnaires to determine their emotional outcomes. Of participating mothers, 28% reported PTSD, 26% depression, and 4% anxiety; in fathers, 15% reported PTSD, 24% depression, and none reported anxiety. Further, children reported significant emotional difficulty, with 24% having depression, 14% anxiety, and 6% PTSD by self-report ratings. Maternal PTSD, anxiety and depression, and paternal anxiety were all negatively associated with the child's functional outcome. Clinically significant anxiety (based on clinical thresholds) was not found in fathers; however, continuous scores were still analyzed for association between subclinical anxiety and functional outcome, which revealed a statistically significant association between more reported symptoms and higher Recovery and Recurrence Questionnaire scores. Prevalence of PTSD and depression are greater in parents compared to the general population in this preliminary study.

Neuropsychological function in children with hemophilia: A review of the Hemophilia Growth and Development Study and introduction of the current eTHINK study.

Almost all of what is known about neurologic and cognitive development in hemophilia derives from the Hemophilia Growth and Development Study, conducted during an era when treatment regimens and comorbidities differed significantly from the current environment. Results suggested hemophilia and human immunodeficiency virus had independent effects, and hemophilia negatively impacts academic achievement, attention, and behavior. The introduction of prophylaxis treatment in hemophilia has created the need for re-evaluation of the effects of hemophilia on neurodevelopment and cognition. We outline the Evolving Treatment of Hemophilia's Impact on Neurodevelopment, Intelligence, and Other Cognitive Functions (NCT03660774) study, which aims to meet this need.

Pediatric inflammatory bowel disease and depression: treatment implications.

PURPOSE OF REVIEW: Depression in pediatric inflammatory bowel disease is increasingly recognized to be a heterogeneous condition with diverse underlying predisposing and precipitating factors. Although there is a growing awareness regarding the benefits of integrating behavioral health into medical care, the way psychiatric treatments can best target different aspects of depression and related dysfunction has not been systematically explored. RECENT FINDINGS: This review discusses neurobiological risk factors for depression in inflammatory bowel disease including inflammation, associated anti-inflammatory treatment with corticosteroids, pain, and sleep disturbance, as well as psychosocial factors including reactions to illness, illness perception, and disease and environmental stressors with an emphasis on how these factors can influence treatment decisions. Empirically supported psychosocial and psychopharmacological interventions are discussed within this context. SUMMARY: Understanding the diverse pathways that can lead to depression in youths with inflammatory bowel disease can lead to the development of more targeted interventions and better integration of psychosocial care into the medical treatment of inflammatory bowel disease.

Comparing stimulant effects in youth with ADHD symptoms and epilepsy.

To retrospectively examine response to stimulant treatment in patients with epilepsy and ADHD symptoms as predicted by seizure freedom for six months, use of methylphenidate (MPH) versus amphetamine (AMP) preparations, cognitive level, and medical records were searched for patients under the age of 18 with epilepsy and ADHD symptoms treated with MPH or AMP (n=36, age=10.4 ± 3.5; male=67%). "Responders" had a CGI-improvement score of ≤ 2 and did not stop medication because of adverse effects. "Worsened" patients discontinued medication because of agitation/emotional lability. Seizure freedom did not predict treatment response. Lower cognitive level was associated with increased rate of worsening (p=0.048). No patients who were seizure-free at the start of the medication trial experienced an increase in seizures. Of the patients having seizures at the start of trial, one patient on MPH and two patients on AMP had increased seizures during the trial. Seizures returned to baseline frequency or less after stimulant discontinuation or anticonvulsant adjustment. Methylphenidate was associated with a higher response rate, with 12 of 19 given MPH (0.62 ± 0.28 mg/kg/day) compared with 4 of 17 given AMP (0.37 ± 0.26 mg/kg/day) responding (p=0.03). Methylphenidate treatment and higher cognitive level were associated with improved treatment outcome, while seizure freedom had no clear effect. Confidence in these findings is limited by the study's small, open-label, and uncontrolled design.

Depression subtypes in pediatric inflammatory bowel disease.

OBJECTIVE: The association between inflammatory bowel disease (IBD) and depression provides a unique opportunity to understand the relation between systemic inflammation and depressive symptom profiles. METHODS: Youth (n = 226) ages 9 to 17 years with comorbid IBD and depression underwent psychiatric assessment and evaluation of IBD activity. Latent profile analysis (LPA) identified depressive subgroups based on similar responses to the Children's Depression Rating Scale-Revised. Demographic factors, depression severity, anxiety, IBD activity, inflammatory markers, IBD-related medications, and illness perception were evaluated as predictors of profile membership. RESULTS: Mean age was 14.3 years; 75% had Crohn disease; 31% were taking systemic corticosteroids. Mean depressive severity was moderate, whereas IBD activity, which reflects inflammation, was mild. LPA identified 3 subgroups: Profile-1 (mild, 75%) had diverse low-grade depressive symptoms and highest quality of life; Profile-2 (somatic, 19%) had severe fatigue, appetite change, anhedonia, decreased motor activity, and depressed mood with concurrent high-dose steroid therapy and the highest IBD activity; and Profile-3 (cognitive, 6%) had the highest rates of self-reported depressive symptoms, ostomy placements, and anxiety with IBD symptoms in the relative absence of inflammation. CONCLUSIONS: Evidence was found for 3 depression profiles in youth with IBD and depression. Our analyses determined that patients with predominantly somatic or cognitive symptoms of depression comprised 25% of our cohort. These findings may be used to design subgroup-specific interventions for depression in adolescents with IBD and other physical illnesses associated with systemic inflammation.

Acute cognitive and behavioral effects of systemic corticosteroids in children treated for inflammatory bowel disease.

Systemic corticosteroids are a mainstay of treatment for many pediatric medical conditions. Although their impact on the central nervous system has been well-studied in animal models and adults, less is known about such effects in pediatric populations. The current study investigated acute effects of corticosteroids on memory, executive functions, emotion, and behavior in children and adolescents with inflammatory bowel disease (IBD). Patients 8-17 years with IBD (Crohn's disease, CD; ulcerative colitis, UC) on high-dose prednisone (n = 33) and IBD patients in remission off steroids (n = 33) completed standardized neuropsychological tests and behavior rating scales. In the IBD sample as a whole, few steroid effects were found for laboratory cognitive measures, but steroid-treated patients were rated as exhibiting more problems with emotional, and to a lesser extent with cognitive function in daily life. Steroid effects, assessed by laboratory measures and questionnaires, were more prevalent in CD than UC patients; UC patients on steroids sometimes performed better than controls. Sleep disruption also predicted some outcomes, diminishing somewhat the magnitude of the steroid effects. Corticosteroid therapy can have acute effects on cognition, emotion, and behavior in chronically ill children; the clinical and long-term significance of these effects require further investigation.

Using the Children's Depression Inventory in youth with inflammatory bowel disease: support for a physical illness-related factor.

The objective of the present investigation was to evaluate the factor structure of the Children's Depression Inventory (CDI) in adolescents with inflammatory bowel disease (IBD) to better understand the CDI's psychometric properties in a medically complicated population. An exploratory factor analysis was performed on CDI data collected from a clinical sample of 191 youth with IBD, aged 11 to 17 years. Exploratory factor analysis with quartimax rotation yielded 3 factors: mood, behavioral/motivational, and somatic complaints. Only the somatic factor (ie, fatigue, sleep, decreased appetite, and worry about aches and pain) showed a significant positive correlation with IBD severity. The CDI holds promise as a brief measure for the assessment of depressive features psychometrically independent of IBD severity and common steroid treatments as well as of nongastrointestinal specific somatic complaints in a sample of adolescents with IBD. Continued work in this area of research appears promising in honing the assessment of depressive and somatic symptoms in youths with IBD.

Neurobehavioral side effects of corticosteroids during active treatment for acute lymphoblastic leukemia in children are age-dependent: report from Dana-Farber Cancer Institute ALL Consortium Protocol 00-01.

BACKGROUND: Although corticosteroids remain a mainstay of treatment for acute lymphoblastic leukemia (ALL), they can cause troublesome neurobehavioral changes during active treatment, especially in young children. We evaluated acute neurobehavioral side effects of corticosteroid therapy in preschool versus school-age children by obtaining structured reports weekly for 1 month. PROCEDURE: Parents of 62 children (2-17 years) treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 00-01 participated during the continuation phase of treatment. Patients received cyclical twice-daily 5-day courses of prednisone (PRED; 40 mg/m(2) /day) or dexamethasone (DEX; 6 mg/m(2) /day). Parents completed behavior rating scales about their child weekly during one steroid cycle [baseline (Day 0), active steroid (Day 7), post-steroid (Days 14 and 21)]. RESULTS: Behavioral side effects increased significantly (P < 0.001) during the steroid week for preschool children (<6 years) on measures of emotional control, mood, behavior regulation, and executive functions, returning to baseline during the two "off-steroid" weeks. In contrast, school-age children (≥ 6 years) did not demonstrate an increase in side effects during the steroid week. Steroid type (PRED vs. DEX) was not a significant predictor of neurobehavioral side effects. CONCLUSIONS: Preschool children are at greater risk for neurobehavioral side effects during active steroid treatment for ALL than school-age children and adolescents. DEX was not associated with more neurobehavioral side effects than PRED. Counseling of families about side-effects should be adapted according to age. The observed effects, moreover, were transient, reducing concerns about longer-term neurobehavioral toxicities.

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.

Comparative clinical responses to risperidone and divalproex in patients with pediatric bipolar disorder.

OBJECTIVE: To compare clinical responses of patients with pediatric bipolar disorder being treated with risperidone versus divalproex. METHODS: Medical records of outpatients younger than 18 years of age were reviewed to gather data on those who received risperidone or divalproex monotherapy for the treatment of bipolar disorder. Effectiveness was assessed using the Clinical Global Impressions Severity (CGI-S) and Improvement (CGI-I) scales assigned by the treating clinician at visits during the initial 3 months of treatment with risperidone or divalproex. Change in CGI-S score over time was the primary outcome variable. The number of patients with a CGI-I score of < or = 2 at endpoint who did not discontinue the index medication because of adverse events was also compared. RESULTS: A total of 28 patients aged 5-14 years who were being treated for bipolar disorder were identified (risperidone n = 16; divalproex n = 12). Regression analysis of change in CGI-S scores revealed greater reductions in bipolar symptoms (p = 0.022) and a faster reduction in CGI-S scores (p = 0.016) in patients receiving risperidone than divalproex. A significantly shorter time to achieving a CGI-I score of < or = 2 was observed with risperidone than divalproex (26.8 +/- 20.7 days vs. 33.8 +/- 11.3 days; p = 0.048). However, the proportion of patients with a CGI-I score < or = 2 at endpoint was not significantly different (risperidone 69% versus divalproex 42%, p = 0.250). Three patients discontinued risperidone and 2 discontinued divalproex. Of these, none of the patients treated with risperidone and only 1 patient treated with divalproex discontinued treatment because of a documented adverse event. Risperidone was associated with significantly more weight gain then divalproex at 3 months (risperidone 2.46 +/- 1.16 kg versus divalproex 0.43 +/- 0.77 kg, p = 0.034). CONCLUSIONS: Patients receiving risperidone experienced a faster decrease in the severity of their bipolar symptoms, as measured by faster decreases in CGI-S scores, than did those who received divalproex. However, risperidone was also associated with significantly greater weight gain.

Prospective open-label pilot trial of mirtazapine in children and adolescents with social phobia.

Mirtazapine is indicated for major depression and used for anxiety in adults; however, little is known about its application in pediatric populations. This is an 8-week open-label pilot study of mirtazapine in children with social phobia age 8-17 years. Primary outcomes were symptom improvement based on clinician rating and self-report, as well as tolerability based on rates of discontinuation due to adverse effects. Fifty-six percent (10/18) responded to treatment, 17% (3/18) achieved full remission. Social phobia symptoms improved significantly during the first 2 weeks of treatment, as did comorbid symptoms of depression and anxiety. Eleven patients (61%) did not complete all 8 weeks of treatment; four patients (22%) discontinued due to adverse effects including fatigue and irritability. The others discontinued due to study burden (28%), insufficient response (6%), or to pursue herbal treatment (6%). Significant weight gain was observed. Larger controlled trials are needed to further evaluate efficacy and safety.

Psychiatric disorders and behavioral characteristics of pediatric patients with both epilepsy and attention-deficit hyperactivity disorder.

OBJECTIVE: Attention-deficit hyperactivity disorder (ADHD) coexisting with epilepsy is poorly understood; thus, we compared the clinical correlates and psychiatric comorbid conditions of 36 children with epilepsy and ADHD aged 6 to 17 years enrolled in an ADHD treatment trial, with those reported in the literature on children with ADHD without epilepsy. METHODS: Measures included the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children (KSADS), the Wechsler Abbreviated Scale of Intelligence (WASI), and the Scales for Independent Behavior-Revised (SIB-R). RESULTS: Mean IQ was 86+/-19, and SIB-R Standard Score was 72+/-26. The ADHD-Combined subtype, composed of both inattentive and hyperactive symptoms, was most frequent (58%). Sixty-one percent exhibited a comorbid disorder, including anxiety disorders (36%) and oppositional defiant disorder (31%). CONCLUSIONS: Comorbidity in ADHD with epilepsy is similar to that in ADHD without epilepsy reported in the literature. These preliminary data argue that the pathophysiology of ADHD has common components in both populations.

Risperidone in preschool children with autistic spectrum disorders: an investigation of safety and efficacy.

INTRODUCTION: Early intervention in autism spectrum disorders (ASDs) appears promising and may represent a window of opportunity for more effective treatment. Whereas the safety and efficacy of risperidone have been established for children aged 5 and older, they has not been adequately tested in preschool children. METHODS: A randomized placebo-controlled study of risperidone in preschool children was conducted in a sample of young children, most of whom were also undergoing intensive behavioral treatment. RESULTS: Preschool children tolerated low-dose risperidone well with no serious adverse effects observed over a 6-month treatment period. Weight gain and hypersalivation were the most common side effects reported, and hyperprolactinemia without lactation or related signs was observed. Significant differences between groups found at baseline complicated the analyses; however, controlling for some of these differences revealed that preschoolers on risperidone demonstrated greater improvements in autism severity. The change in autism severity scores from baseline to 6-month follow up for the risperidone group was 8% compared to 3% for the placebo group. Notably, both groups significantly improved over the 6-month treatment period. CONCLUSIONS: Study findings suggest that risperidone is well tolerated in preschoolers over a 6-month period, but that only minimally greater improvement in target symptoms was evident in the risperidone group, possibly due to the differences between groups at baseline or due to the small sample size. Although these findings are not sufficient to direct treatment, they suggest that larger-scale, double-blind, placebo-controlled investigations of risperidone in preschoolers with ASDs should now be conducted.