Christine Mrakotsky

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.

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.

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 Childrens 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 (Crohns 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.

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.

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.

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 Childrens Depression Inventory (CDI) in adolescents with inflammatory bowel disease (IBD) to better understand the CDIs 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.

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 ⩽ 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 ⩽ 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 ⩽ 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.

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.

O-018 New Evidence for Structural Brain Differences in Pediatric Crohn's Disease: Impact of Underlying Disease Factors

Background:Structural brain changes in gray matter volume, cortical thickness, and white matter density have been recently found in adults with Crohns disease (CD), with the potential to affect cognitive and emotional functions. Intestinal and systemic inflammation during active disease as well as anti-inflammatory steroid therapy have been considered as possible underlying mechanisms, however to date there is little data for other disease factors, particularly in pediatric CD. We previously demonstrated decreased white matter density, cortical thickness and subcortical volume in a small sample of children with CD compared to healthy controls with independent effects of inflammation and steroids (Mrakotsky et al., 2012, 2013, 2015). We also found inflammation associated with poorer cognition and mood, and CD patients to report poorer school function. This CCFA SRA aims to replicate earlier findings of brain involvement in a larger independent sample of pediatric CD patients. Methods:Structural magnetic resonance and diffusion tensor imaging (MRI, DTI) was performed in 34 children age 10 to 14 years (CD patients: n = 25, age-and sex-matched healthy controls: n = 10) using a 3 Tesla Siemens Trio MRI system. Anatomical whole brain T1-weighted images were acquired at 1 mm3 voxel size. Diffusion-weighted images were acquired using simultaneous multislice echo planar imaging (2 mm3 voxel size, 70 directions). All subjects also underwent neuropsychological assessments (tests of attention, memory, IQ, emotional functions), disease severity ratings (HBAI), and phlebotomy to obtain inflammatory markers. CD patients were scanned and tested during an active disease flare or in clinical remission. Cortical thickness and volume was measured using Freesurfer, average fractional anisotropy (FA) reflecting white matter fiber density was computed for several fiber tracts with TBSS. Analyses were adjusted for age, sex, and intracranial volume, and included correlation, regression and group comparisons. Groups were comparable on demographics. Results:Compared to controls, CD patients showed once again widespread reduced cortical thickness in posterior regions (bilateral inferior parietal, superior parietal, supramarginal [<0.001–0.01]) and middle frontal gyrus (<0.05), reduced subcortical volume (bilateral putamen, hippocampi, and right thalamus [<0.01–0.05]) altered FA in limbic tracts (cingulate, uncinate fasciculus [<0.05]) and poorer verbal memory and cognitive function. Inflammation during active disease was associated with cortical thinning (<0.001–0.05), lower FA, (<0.05), and poorer memory and cognition (<0.05–0.01), although direct relationship between brain structure and function was less clear. In addition, higher disease severity and steroid medication was negatively associated with brain structures (<0.001–0.05), as was lifetime use of steroids. Infliximab and chemotherapeutic medication were not significant contributors in this sample. Conclusions:These results confirm our prior findings of both disease and treatment on gray and white matter structures in pediatric CD, suggesting brain involvement as an extraintestinal manifestation of CD. The posterior brain regions implicated mediate higher cognitive and emotional processes and are potentially linked to poorer function in these areas. Current multi array analysis will provide further insight into pathways by which inflammation and disease process transmits to brain and behavior, with the goal to inform medical and psychological therapies.

Chronic Inflammation and Its Association With Neurobehavioral Functions in Pediatric Crohnʼs Disease: P-150

carried out in 30 children age 9-14 years (CD patients: n 1⁄4 11, age-matched healthy controls: n 1⁄4 19). Participants were scanned on a 3 Tesla Siemens Trio MRI system, with a 32-channel head coil. Diffusion-weighted imaging data were acquired using a single shot spin-echo echo planar imaging sequence. A total of 30 diffusion sensitization directions were acquired. Voxel sizes were 1.7 1.7 1.7 mm. Average fractional anisotropy (FA), a measure reflecting white matter fiber density and myelination was computed for several fiber tracts across the brain. All CD patients were scanned during steroid treatment for an acute flare (prednisone dose: M 1⁄4 30.7, SD 1⁄4 9.6 mg/day). Serum markers of inflammation included hsCRP, IL-6, and TNFR2. Demographics, SES and general cognitive ability were comparable between groups. Inflammation was higher in CD patients than healthy controls. RESULTS: CD patients had lower FA than controls in several limbic (temporal) and subcortical fiber tracts including the left and right cingulum angular bundle, the right uncinate and temporal part of the superior longitudinal fasciculus (P<.05 to <.10). Regression models including all subjects accounting for inflammation levels and steroid dose revealed higher inflammation (hsCRP, IL6, TNFR2) but not steroid dose to be a significant predictor (P <.01 to <.05) for lower FA in the cingulum, particularly on the left. Conversely, higher steroid dose but not inflammation predicted lower FA in the right uncinate and temporal part of the superior longitudinal fasciculus (p <.05). Correlations between inflammation and FA adjusted for steroid yielded similar findings for the overall sample and for CD patients only (see table). CONCLUSION(S): Results of this first association between pediatric CD and brain development suggest differential impact of steroids and inflammatory markers on white matter microstructure. The inverse correlation between left cingulum integrity and circulating inflammation is of clinical interest as the cingulum is integral part of the limbic system, connecting prefrontal with medial temporal cortex and thus has been linked to emotion processing, memory and executive functions, all previously associated with inflammation. Further neuroimaging and behavioral studies including CD patients off steroids are warranted to elucidate these initial findings.