David Breiger

Multiagent Chemotherapy and Deferred Radiotherapy in Infants With Malignant Brain Tumors: A Report From the Children’s Cancer Group

PURPOSE To evaluate response rate, event-free survival (EFS), and toxicity of two chemotherapeutic regimens for treatment of children younger than 36 months with malignant brain tumors and to estimate control intervals without irradiation in children with no residual tumor after initial surgery and induction chemotherapy and with delayed irradiation in patients with residual tumor or metastatic disease at diagnosis. PATIENTS AND METHODS Patients were randomly assigned to one of two regimens of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, and etoposide v vincristine, carboplatin, ifosfamide, and etoposide). Maintenance chemotherapy began after induction in children without progressive disease. Children with no residual tumors after induction therapy and no metastatic disease at diagnosis were not to receive radiation therapy unless their tumors progressed. RESULTS Two hundred ninety-nine infants were enrolled. Forty-two percent of patients responded to induction chemotherapy. At 5 years from study entry, the EFS rate was 27% +/- 3%, and the survival rate was 43% +/- 3%. There was no significant difference between the two arms in terms of response rate or EFS. For medulloblastoma, supratentorial primitive neuroectodermal tumor, ependymoma, and rhabdoid tumors, 5-year EFS rates were 32% +/- 5%, 17% +/- 6%, and 32% +/- 6%, and 14% +/- 7%, respectively. Fifty-eight percent of patients who were alive 5 years after study entry had not received radiation therapy. CONCLUSION Intensified induction chemotherapy resulted in a high response rate of malignant brain tumors in infants. Survival was comparable to that of previous studies, and most patients who survived did not receive radiation therapy.

Neuropsychological functioning in early onset psychotic disorders

This paper examines whether neuropsychological profiles of youth with early onset psychotic disorders predicted diagnostic or clinical status. Youth with schizophrenia (n=27), bipolar disorder (n=22), and psychosis NOS (n=20) were included. Subjects received an extensive neuropsychological evaluation, including measures of general cognition, attention, memory, and executive functioning. Medication status was not controlled. No statistically significant neurocognitive differences across diagnostic groups were found. Compared to standardized norms, youth with schizophrenia demonstrated deficits in general cognition, verbal learning, recall, sustained effort, and social knowledge. Subjects with bipolar disorder and psychosis NOS exhibited deficits on measures of verbal learning, recall, and sustained effort similar to those of youth with schizophrenia. Neurocognitive deficits in memory and attention appeared to be common among youth with psychotic illnesses, regardless of diagnosis. Those with schizophrenia may have greater global cognitive deficits and problems with social knowledge. Across diagnoses, subjects demonstrated relative strengths on tests that provided them with immediate feedback, and performed most poorly on tests requiring delayed recall.

HHV-6 reactivation and its effect on delirium and cognitive functioning in hematopoietic cell transplantation recipients.

Human herpesvirus 6 (HHV-6) is detected in the plasma of approximately 40% of patients undergoing hematopoietic cell transplantation (HCT) and sporadically causes encephalitis in this population. The effect of HHV-6 reactivation on central nervous system function has not been fully characterized. This prospective study aimed to evaluate associations between HHV-6 reactivation and central nervous system dysfunction after allogeneic HCT. Patients were enrolled before HCT. Plasma samples were tested for HHV-6 at baseline and twice weekly after transplantation until day 84. Delirium was assessed at baseline, 3 times weekly until day 56, and weekly on days 56 to 84 using a validated instrument. Neurocognitive testing was performed at baseline and at approximately day 84. HHV-6 was detected in 111 (35%) of the 315 included patients. Patients with HHV-6 were more likely to develop delirium (adjusted odds ratio = 2.5; 95% confidence interval, 1.2-5.3) and demonstrate neurocognitive decline (adjusted odds ratio = 2.6; 95% confidence interval, 1.1-6.2) in the first 84 days after HCT. Cord blood and unrelated transplantation increased risk of HHV-6 reactivation. These data provide the basis to conduct a randomized clinical trial to determine whether prevention of HHV-6 reactivation will reduce neurocognitive morbidity in HCT recipients.

Premorbid functioning in early-onset psychotic disorders.

OBJECTIVE To examine the premorbid characteristics of youths with early-onset psychotic disorders. METHOD Subjects with early-onset psychotic disorders received an extensive diagnostic evaluation upon entry into the study, including a historic review of premorbid functioning using the Premorbid Adjustment Scale. RESULTS Youths with schizophrenia (n = 27), bipolar disorder (n = 22), and psychosis not otherwise specified (NOS) (n = 20) were included. High rates of premorbid behavioral problems and academic difficulties were noted across all subjects. Youths with schizophrenia had higher rates of premorbid social withdrawal and global impairment. They also tended to have fewer friends. The psychosis NOS group had significantly higher rates of abuse histories and posttraumatic stress disorder. CONCLUSIONS Premorbid abnormalities are common features of early-onset psychotic disorders. The social withdrawal and peer problems specific to youths with schizophrenia likely represent early manifestations of negative symptoms. The abuse histories in the psychosis NOS group may explain the atypical nature of their reported psychotic symptoms, which in many cases are likely posttraumatic phenomena.

Neurodevelopmental Implications of "deformational" Plagiocephaly

ABSTRACT. Over the past decade there has been a dramatic increase in referrals to specialty clinics, craniofacial centers, plastic surgeons, and neurosurgeons for assessment and treatment of deformational plagiocephaly (DP). Though considered a medically benign condition, preliminary reports suggest that DP may be associated with developmental problems. However, mechanisms to account for this association have not been hypothesized or empirically tested. Although treatment justifications often center on prevention of atypical appearance, little is known about the cosmetic outcomes of treated and untreated children. In this review we hypothesize different etiological pathways linking DP with neurodevelopment (e.g., environmental positioning limitations with and without underlying CNS pathology). We outline directions for research on incidence and prevalence, developmental outcomes, sex differences, determinants of treatment participation, and craniofacial appearance. Despite the paucity of existing research, preliminary findings suggest that children with this condition should be screened and monitored for developmental delays or deficits, as we await more conclusive information from future studies.

Comparison of Neurocognitive Functioning in Children Previously Randomly Assigned to Intrathecal Methotrexate Compared With Triple Intrathecal Therapy for the Treatment of Childhood Acute Lymphoblastic Leukemia

PURPOSE For the majority of children with acute lymphoblastic leukemia (ALL), CNS prophylaxis consists of either intrathecal (IT) methotrexate or triple IT therapy (ie, methotrexate with both cytarabine and hydrocortisone). The long-term neurotoxicities of these two IT strategies have not yet been directly compared. PATIENTS AND METHODS In this multisite study, 171 children with standard-risk ALL, age 1 to 9.99 years at diagnosis, previously randomly assigned to IT methotrexate (n = 82) or to triple IT therapy (n = 89) on CCG 1952, underwent neurocognitive evaluation by a licensed psychologist at a mean of 5.9 years after random assignment. RESULTS Patients who received IT methotrexate had a mean Processing Speed Index that was 3.6 points lower, about one fourth of a standard deviation, than those who received triple IT therapy (P = .04) after analysis was adjusted for age, sex, and time since diagnosis. Likewise, 19.5% of children in the IT methotrexate group had a Processing Speed Index score in the below-average range compared with 6.9% in the triple IT therapy group (P = .02). Otherwise, the groups performed similarly on tests of full-scale intelligence quotient, academic achievement, attention/concentration, memory, and visual motor integration. The association of treatment with measures of cognitive functioning was not modified by sex or age at diagnosis. In the post-therapy period, there were no group differences in special education services, neurologic events, or use of psychotropic medications. CONCLUSION This study did not show any clinically meaningful differences in neurocognitive functioning between patients previously randomly assigned to IT methotrexate or triple IT therapy except for a small difference in processing speed in the IT methotrexate group.

Sexual Behavior Associated with Low Verbal IQ in Youth Who Have Severe Mental Illness.

A retrospective chart review was used to examine sexual behavior (hypersexual, exposing, and victimizing) and cognitive impairment in 200 youth who had serious mental illness. Lower IQ was associated with increased sexual acting-out. For more serious victimizing sexual behaviors, only Verbal IQ differences reached statistical significance. Overall, sexual behavior was strongly associated with a history of sexual abuse. Sexual abuse history was significantly associated only with lower Performance IQ. Therefore, the association between low Verbal IQ and sexual victimizing behavior is distinct from the effects of sexual abuse. Results underscore the importance of verbal cognitive abilities, regardless of overall cognitive level, in the etiology and treatment of sexual behaviors, especially among individuals without a history of sexual abuse.

Neurocognitive Outcomes in the Treatment of Early-Onset Schizophrenia Spectrum Disorders Study

OBJECTIVE To assess neurocognitive outcomes following antipsychotic intervention in youth enrolled in the National Institute of Mental Health (NIMH)-funded Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS). METHOD Neurocognitive functioning of youth (ages 8 to 19 years) with schizophrenia or schizoaffective disorder was evaluated in a four-site, randomized, double-blind clinical trial comparing molindone, olanzapine, and risperidone. The primary outcomes were overall group change from baseline in neurocognitive composite and six domain scores after 8 weeks and continued treatment up to 52 weeks. Age and sex were included as covariates in all analyses. RESULTS Of 116 TEOSS participants, 77 (66%) had post-baseline neurocognitive data. No significant differences emerged in the neurocognitive outcomes of the three medication groups. Therefore, the three treatment groups were combined into one group to assess overall neurocognitive outcomes. Significant modest improvements were observed in the composite score and in three of six domain scores in the acute phase, and in four of six domain scores in the combined acute and maintenance phases. Partial correlation analyses revealed very few relationships among Positive and Negative Syndrome Scale (PANSS) baseline or change scores and neurocognition change scores. CONCLUSIONS Antipsychotic intervention in youth with early-onset schizophrenia spectrum disorders (EOSS) led to modest improvement in measures of neurocognitive function. The changes in cognition were largely unrelated to baseline symptoms or symptom change. Small treatment effect sizes, easily accounted for by practice effects, highlight the critical need for the development of more efficacious interventions for the enduring neurocognitive deficits seen in EOSS. Clinical trial registry information-Treatment of Early-Onset Schizophrenia Spectrum Disorders (TEOSS); http://www.clinicaltrials.gov; NCT00053703.

Pediatric Cancer and the Quality of Children’s Dyadic Peer Interactions

OBJECTIVE To use observational methods to assess the quality of peer relationships in 51 7- to 12-year-old acute lymphoblastic leukemia survivors as compared to healthy children. METHODS Children were audiotaped as they engaged in free play with their best friend and interactions were coded to assess their ability to maintain engagement with one another during play as well as the affective dimension of their play. RESULTS Results indicated that dyads with survivors of childhood cancer were less likely to be highly engaged with their best friend and more likely to experience disengagement than dyads with healthy participants. There were no group differences in positive or negative affect. CONCLUSIONS Overall, these data suggest that survivors of childhood cancers relationships with their best friend may be compromised in some specific areas when compared to the relations of healthy children. Implications for intervention are discussed.

Diagnostic Classification of ADHD Versus Control: Support Vector Machine Classification Using Brief Neuropsychological Assessment.

Objective: Common methods for clinical diagnosis include clinical interview, behavioral questionnaires, and neuropsychological assessment. These methods rely on clinical interpretation and have variable reliability, sensitivity, and specificity. The goal of this study was to evaluate the utility of machine learning in the prediction and classification of children with ADHD–Combined presentation (ADHD-C) using brief neuropsychological measures (d2 Test of Attention, Children with ADHD-C and typically developing control children completed semi-structured clinical interviews and measures of attention/concentration and parents completed symptom severity questionnaires. Method: We used a forward feature selection method to identify the most informative neuropsychological features for support vector machine (SVM) classification and a decision tree model to derive a rule-based model. Results: The SVM model yielded excellent classification accuracy (100%) of individual children with and without ADHD (1.0). Decision tree algorithms identified individuals with and without ADHD-C with 100% sensitivity and specificity. Conclusion:This study observed highly accurate statistical diagnostic classification, at the individual level, in a sample of children with ADHD-C. The findings suggest data-driven behavioral algorithms based on brief neuropsychological data may present an efficient and accurate diagnostic tool for clinicians.