Julia W. Tossell

Puberty-related influences on brain development

Puberty is a time of striking changes in cognition and behavior. To indirectly assess the effects of puberty-related influences on the underlying neuroanatomy of these behavioral changes we will review and synthesize neuroimaging data from typically developing children and adolescents and from those with anomalous hormone or sex chromosome profiles. The trajectories (size by age) of brain morphometry differ between boys and girls, with girls generally reaching peak gray matter thickness 1-2 years earlier than boys. Both boys and girls with congenital adrenal hyperplasia (characterized by high levels of intrauterine testosterone), have smaller amygdala volume but the brain morphometry of girls with CAH did not otherwise significantly differ from controls. Subjects with XXY have gray matter reductions in the insula, temporal gyri, amygdala, hippocampus, and cingulate-areas consistent with the language-based learning difficulties common in this group.

Pervasive developmental disorder and childhood-onset schizophrenia: comorbid disorder or a phenotypic variant of a very early onset illness?

BACKGROUND Childhood-onset schizophrenia (COS) is a severe form of the adult-onset disorder with a high rate of premorbid developmental abnormalities. Early symptoms of pervasive developmental disorder (PDD) have been reported in five independent studies of COS. In this study, we compared evidence for premorbid PDD as a nonspecific manifestation of impaired neurodevelopment seen in schizophrenia, or as an independent risk factor for COS. METHODS Diagnosis of past or current autism or PDD was made according to the DSM-IV criteria. COS patients with and without PDD were compared with respect to neuropsychological, clinical, and neurobiological measures. Several candidate genes for autism were examined in the entire COS sample and the subgroup with PDD using the Transmission Disequilibrium Test (TDT) and Quantitative TDT (QTDT). RESULTS Nineteen (25%) of COS probands had a lifetime diagnosis of PDD: one met criteria for autism, two for Aspergers disorder, and 16 for PDD not otherwise specified. Premorbid social impairment was most common feature for COS-PDD subjects. The PDD group did not differ from the rest of the COS sample with respect to age of onset, IQ, response to medications, and rate of familial schizotypy. Unexpectedly, two siblings of COS-PDD probands met criteria for nuclear autism. There was no difference between PDD and non-PDD groups with respect to initial brain magnetic resonance imaging (MRI) measures. However, rate of gray matter loss was greater for PDD (n = 12) than for the non-PDD (n = 27) subgroup (-19.5 +/- 11.3 mL/year vs. -9.6 +/- 15.3 mL/year; p =.05). None of eight candidate genes for autism were associated with COS or COS-PDD. CONCLUSIONS Premorbid PDD in COS is more likely to be a nonspecific marker of severe early abnormal neurodevelopment. However, the occurrence of two siblings of COS-PDD probands (17%) with nuclear autism remains to be understood.

XXY (Klinefelter Syndrome): A Pediatric Quantitative Brain Magnetic Resonance Imaging Case-Control Study

OBJECTIVE. An extra X chromosome in males (XXY), known as Klinefelter syndrome, is associated with characteristic physical, cognitive, and behavioral features of variable severity. The objective of this study was to examine possible neuroanatomical substrates of these cognitive and behavioral features during childhood and adolescence. METHODS. MRI brain scans were acquired for 42 XXY and 87 healthy XY age-matched control males. We compared these 2 groups on regional brain volumes and cortical thickness. RESULTS. Total cerebral volume and all lobar volumes except parietal white matter were significantly smaller in the XXY group, whereas lateral-ventricle volume was larger. Consistent with the cognitive profile, the cortex was significantly thinner in the XXY group in left inferior frontal, temporal, and superior motor regions. CONCLUSION. The brain-imaging findings of preferentially affected frontal, temporal, and motor regions and relative sparing of parietal regions are consistent with observed cognitive and behavioral strengths and weaknesses in XXY subjects.

Tolerability of transcranial direct current stimulation in childhood-onset schizophrenia

BACKGROUND In recent years, transcranial direct current stimulation (tDCS) has been used to study and treat many neuropsychiatric conditions. However, information regarding its tolerability in the pediatric population is lacking. OBJECTIVE This study aims to investigate the tolerability aspects of tDCS in the childhood-onset schizophrenia (COS) population. METHODS Twelve participants with COS completed this inpatient study. Participants were assigned to one of two groups: bilateral anodal dorsolateral prefrontal cortex (DLPFC) stimulation (n = 8) or bilateral cathodal superior temporal gyrus (STG) stimulation (n = 5). Patients received either 2 mA of active treatment or sham treatment (with possibility of open active treatment) for 20 minutes, for a total of 10 sessions (2 weeks). RESULTS tDCS was well tolerated in the COS population with no serious adverse events occurring during the study. CONCLUSIONS This is the first study to demonstrate that a 20-minute duration of 2 mA of bilateral anodal and bilateral cathodal DC polarization to the DLPFC and STG was well tolerated in a pediatric population.

A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders

A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders

Childhood Onset Schizophrenia: High Rate of Visual Hallucinations

OBJECTIVE To document high rates and clinical correlates of nonauditory hallucinations in childhood onset schizophrenia (COS). METHOD Within a sample of 117 pediatric patients (mean age 13.6 years), diagnosed with COS, the presence of auditory, visual, somatic/tactile, and olfactory hallucinations was examined using the Scale for the Assessment of Positive Symptoms (SAPS). We also compared hallucination modality membership (presence/absence) groups on gender, socioeconomic status, ethnicity, age of onset (of psychosis), Full Scale IQ, Verbal IQ, and clinical severity (Childrens Global Assessment Scale [CGAS) and Scale for the Assessment of Negative Symptoms [SANS]). RESULTS A total of 111 COS patients (94.9%) had auditory and 94 patients (80.3%) had visual hallucinations. Somatic/tactile (60.7%) and olfactory (29.9%) hallucinations occurred almost exclusively in patients who also had visual hallucinations. Children who had visual hallucinations had lower IQ, earlier age of onset, and more severe illness relative to children who did not have visual hallucinations. CONCLUSIONS In this study, we observed that patients with COS have high rates of hallucinations across all modalities. An increased rate of visual hallucinations is associated with greater clinical impairment and greater compromise in overall brain functioning. Somatic and olfactory hallucinations reflect an additive rather than alternative symptom pattern.

Clozapine-Induced Neutropenia in Children: Management with Lithium Carbonate

Clozapine, an atypical antipsychotic, is the most effective medication for treatment-resistant schizophrenia, but its use is limited by the high risk of neutropenia and agranulocytosis. In children, the rate of clozapine-induced neutropenia is even higher than in adults. We report two cases of children 7- and 12-years old diagnosed with very early onset schizophrenia, who developed neutropenia when treated with clozapine. In both cases addition of lithium carbonate elevated the white blood count (WBC) allowing clozapine rechallenge. WBC and total neutrophil count remained stable long-term with coadministration of clozapine (400-425 mg per day) and lithium with the blood level of 0.8-1.1 microg/mL. This report supports the use of adjunct lithium for clozapine-induced neutropenia as a safe and successful strategy in children.

Risk factors for neutropenia in clozapine-treated children and adolescents with childhood-onset schizophrenia.

OBJECTIVE The purpose of this study was to retrospectively analyze rates of neutropenia and risk factors for neutropenia in hospitalized children and adolescents treated with clozapine. METHODS A retrospective chart review was conducted for all patients who received clozapine at any time during a hospitalization at the National Institute of Mental Health (NIMH) between 1990 and 2011. All patients satisfied screening criteria for the NIMH childhood-onset schizophrenia study, including onset of psychosis before the age of 13 years. Absolute neutrophil count (ANC) values recorded during inpatient hospitalization were extracted for 87 eligible patients with a mean age of 13.35±2.46 years at hospitalization and a mean length of stay of 117±43 days. RESULTS Mild neutropenia only (lowest ANC<2000/mm3 but>1500/mm3) was observed in 27 (31%) patients and moderate neutropenia (any ANC<1500/mm3) was observed in 17 (20%) patients. There were no cases of agranulocytosis or severe infection. Significant risk factors for mild neutropenia compared with no hematologic adverse effects (HAEs) were male gender (p=0.012) and younger age (p<0.001). Male gender was also a significant risk factor for moderate neutropenia compared with no HAEs (p=0.003). If a child of African American ethnicity developed neutropenia during hospitalization at all that child was significantly more likely to develop moderate neutropenia than mild neutropenia only (p=0.017). African American boys had the highest rate of moderate neutropenia at 47%. Sixteen of the 17 patients exhibiting moderate neutropenia were successfully treated with clozapine by the time of discharge; 8 of these 16 required adjunctive lithium carbonate administration to maintain ANC>2000/mm3. CONCLUSIONS Our study shows that the rates of neutropenia in clozapine-treated children and adolescents are considerably higher than in the adult population. Younger age, African American ethnicity, and male gender were significant risk factors. These are also risk factors for benign neutropenia in healthy children and adolescents. Despite these high rates of neutropenia, all but one of the patients with neutropenia during hospitalization were successfully discharged on clozapine.

General absence of abnormal cortical asymmetry in childhood-onset schizophrenia: A longitudinal study

BACKGROUND Childhood-onset schizophrenia (COS) is a rare, severe form of the adult-onset illness, with more salient neurobiological causes. Previous cross-sectional structural neuroimaging research has suggested that normal cortical asymmetry patterns [(R-L)/(R+L)] may be altered in adult schizophrenia, although these findings were not well replicated. Recent studies show dynamic changes in brain asymmetry during childhood and adolescence. We hypothesized that COS patients would show a lack of normal development of asymmetry and decreased overall asymmetry. METHODS Prospective structural magnetic resonance scans were obtained at baseline and at two-year follow-up visits in 49 right-handed COS patients (mean baseline age: 14.72+/-2.63, 117 scans) and 50 age and sex-matched, right-handed healthy controls (mean baseline age: 15.15+/-3.37, 125 scans). Cortical thickness was calculated at 40,962 homologous points across each cerebral hemisphere using a fully automated, validated method. Differences in developmental asymmetry patterns across the cortical surface were analyzed using a linear mixed effects regression model. RESULTS No significant asymmetry differences were found either for cross-sectional comparisons of COS and healthy controls across the lateral and medial cortical surfaces or with respect to timing of developmental changes in asymmetry. CONCLUSIONS The present findings do not support asymmetry differences for this severe, early form of schizophrenia.

Adjunctive Use of Lithium Carbonate for the Management of Neutropenia in Clozapine-Treated Children

Clozapine, a dibenzodiazepine antipsychotic, is the most effective medication for treatment‐resistant schizophrenia. However, its use has been limited by the high risk of neutropenia. In children, the rate of neutropenia is higher when compared to adults. We decided to explore the use of lithium to manage neutropenia in childhood‐onset schizophrenia (COS) through a systematic audit of COS cases.