C. Jane Tavaré

Epidemiology of seizures in children with brain tumors

SummaryWe examined potential clinical and pathologic correlates of seizures among the 3,291 children in the Childhood Brain Tumor Consortium database. Fourteen percent had seizures prior to their hospitalization for a brain tumor. Among children who had a supratentorial tumor, seizures occurred in 22% of those less than 14 years of age. The prevalence of seizures increased to 68% of older teenagers. Among children with an infratentorial tumor, the prevalence of seizures was relatively constant at 6% over all age groups. The onset of seizures began more than one year prior to surgical tumor removal in over half of the children aged five or more with supratentorial tumors, significantly longer than for those of the same age with infratentorial tumors. Almost all children (98.9%) with an infratentorial tumor and seizures had at least one other symptom and more than three-fourths of them had at least three. Eighty-nine percent of children with a supratentorial tumor and seizures had at least one other symptom and more than one-half had at least three symptoms. Regardless of whether the tumor was above or below the tentorium, confusion or stupor and coma were more common in children with seizures than in children without seizures. Among children with supratentorial tumors, symptoms of a declining academic performance or an abnormality of personality, speech, walking, or sensation were significantly more frequent in children with seizures, while visual symptoms (other than visual loss or diplopia) and nausea or vomiting were less frequent. Among children with supratentorial tumors, those who had seizures were more likely to have paralysis of an arm, hand, or face, confusion or stupor, or coma and less likely to exhibit irritability, papilledema, optic atrophy, decreased visual acuity, pupillary abnormalities, or abducens paresis. Among children with infratentorial tumors, those with seizures were significantly less likely to have truncal ataxia, but more likely to experience confusion.

Limitations of the World Health Organization classification of childhood supratentorial astrocytic tumors

In the context of many implied but not rigorously stated histologic feature combinations, the World Health Organization (WHO) classification of astrocytic tumors specifies only the presence or absence of endothelial proliferation, necrosis, and mitosis to distinguish astrocytoma, anaplastic astrocytoma, and glioblastoma multiforme.

Pathologist Interobserver Variability of Histologic Features in Childhood Brain Tumors: Results from the CCG-945 Study

In the Childrens Cancer Group–945 trial, study design allowed estimation of overall interpathologist observational agreement for 6 histologic features frequently used in brain tumor diagnoses. We evaluated agreement between pairs of 5 experienced neuropathologists, who had knowledge of the general diagnoses prior to slide readings. We performed this study in an attempt to further improve pathologist interinstitutional agreement. The features mitosis, necrosis, and giant cells had “fair” overall kappa estimates of reproducibility of around 0.5, while endothelial proliferation had only a “poor” overall kappa of 0.35. The Rogot reproducibility index averaged 0.5 for pleomorphism and hyperchromia. The upper bounds for the 10 pair summary agreement estimates were at best 0.65 (“good”) for all 6 features. These relatively low-reproducibility estimates for the very small number of histologic features being assessed in tumors institutionally diagnosed as high-grade gliomas indicate that neuropathologists either used different operational definitions or interpreted them differently. We found that we could rank the histologic features from best to worst agreement among study pathologists as necrosis, giant cells, mitosis, endothelial proliferation, hyperchromic nuclei, and pleomorphic cells. We suggest that neuropathologists involved in multi-institutional studies of putative therapies not discard these traditional histologic features, but rather develop standardized operational definitions and measure their variability before beginning the studies. Only after such histologic feature variability studies are conducted will we have the data to identify specific histologic features of value to clinicians and researchers. Agreement and strict adherence to improved nonsubjective diagnostic criteria would improve histologic feature reliability and, consequently, their usefulness in studies.

Atypical Antipsychotic Medications to Control Symptoms of Delirium in Children and Adolescents

BACKGROUND Atypical antipsychotics have been documented to be effective in the management of delirium in adults, but despite considerable need, their use has been less studied in pediatric patients. OBJECTIVE A retrospective chart review was done to describe the use of atypical antipsychotics in controlling symptoms of delirium in children and adolescents. METHODS Pharmacy records at Childrens Hospital Los Angeles were reviewed to identify patients to whom antipsychotic agents were dispensed over a 24-month period. Psychiatric inpatient consultations during the same 24-month period were reviewed. Patients 1-18 years old diagnosed with delirium given antipsychotics constituted the study population. Delirium Rating Scale-Revised-98 (DRS-R98) scores were retrospectively calculated, when possible, at time antipsychotic was started to confirm the initial diagnosis of delirium and evaluate symptom severity, and again when antipsychotic was stopped, to assess symptom response. RESULTS Olanzapine (n=78), risperidone (n=13), and quetiapine (n=19) were used during the 2 years of the study. Mean patient age, length of treatment, and response were comparable for the three medications. For patients with two DRS-R98 scores available (n=75/110), mean DRS-R98 scores decreased significantly (p<0.001) with antipsychotic without significant adverse side effects. CONCLUSION Although randomized placebo-controlled studies are needed, atypical antipsychotic medications appeared to be effective and safe for managing delirium symptoms in pediatric patients while underlying etiology was addressed.

Age-related Changes in Diagnoses, Histological Features, and Survival in Children with Brain Tumors: 1930???1979

In the Childhood Brain Tumor Consortium database, the proportions of older children (> or = 11 yr) with pilocytic astrocytomas, fibrillary astrocytomas, and ependymomas significantly increased (P < 0.05) over the 50 years (1930-1979) of the study. The increased proportions of pilocytic astrocytomas occurred whether the tumors were located in the supratentorial or infratentorial compartments. The increases in fibrillary astrocytomas and ependymomas were found only within the supratentorial tumor location. Some histological features found in pilocytic astrocytomas (e.g., Rosenthal fibers, granular bodies, and very low cell density) were more likely to be found in older children. Other histological features were also more likely to be found in older children (e.g., parenchymal calcification, intertwined fascicles, intermediate and large-size nuclei, pleomorphic, elongated, or irregular nuclei, prominent nucleoli, multinucleated cells, thick hyaline blood vessels, hemosiderin, and parenchymal and perivascular lymphocytes). The probability of 5-year survival for young children with supratentorial ependymomas remained at approximately 0.4 in contrast to that for young children with infratentorial ependymomas, for whom it improved, but without significant linear trend. The probability of 5-year survival for both younger and older children with primitive neuroectodermal tumors (medulloblastomas) improved, but without significant linear trend. The changes in the proportions of childhood brain tumors and histological features occurred without similar changes in the proportions of older and younger children in the cities involved between 1930 and 1979. These changes were so distinctive as to raise the possibility of significant shifts in environmental exposures in younger and older children over the 50 years of this study.

Histologic features and prognosis in pediatric medulloblastoma.

Because individual histologic features in childhood medulloblastoma alter survival likelihood, the recent 4th edition of the World Health Organization (WHO) Classification of Brain Tumors recognizes desmoplastic/nodular medulloblastoma, medulloblastoma with extensive nodularity, large cell medulloblastoma, and anaplastic medulloblastoma, in addition to medulloblastoma with no other distinguishing features. To identify features affecting survival likelihood, we investigated 33 histologic features in 556 childhood tumors diagnosed as medulloblastoma in the Childhood Brain Tumor Consortium (CBTC) database; all features have CBTC verified read-reread reliability and those features important in the classification of medulloblastoma and its WHO variants regardless of their measured reliability. Nineteen features had no effect on survival likelihood, and 8 features were too prevalent or too rare to measure their effect on survival. Nodules, balls, high cell density, and fine fibrillary stroma improved survival likelihood; necrosis and prominent nucleoli worsened survival likelihood. Of note, the presence of desmoplasia, currently a defining feature (along with nodules) for desmoplastic/nodular medulloblastoma, had no effect on survival likelihood. We conclude that the presence of nodularity in medulloblastoma is important to improved survival likelihood, particularly when combined with balls and fine fibrillary stroma. Given the “overlap” of desmoplastic/nodular medulloblastoma and nodular medulloblastoma, we suggest they be combined into a diagnosis of nodular medulloblastoma, with nodules, balls, and fine fibrillary stroma as defining criteria. We also suggest that because of the considerable overlap of anaplastic medulloblastoma and large cell medulloblastoma they be combined into 1 diagnosis of anaplastic/large cell medulloblastoma, with necrosis and prominent nucleoli among the defining criteria.

Survival of Children with Infratentorial Neuroglial Tumors

OBJECTIVE The goal of this study is the improvement of the prognostic information associated with conventional diagnoses. Our previous factor analysis of 26 reliably identified histological features in infratentorial childhood neuroglial tumors yielded five interpretable, uncorrelated, quantitative histological factors that we named spongy, fibrillary, proliferative, nuclear, and ring. Five quantitative scores, one for each of the five factors, provide an objective method for quantifying the histological heterogeneity of a tumor. The scores, alone or in conjunction with conventional diagnoses, identify groups of histologically homogeneous tumors. METHODS Multivariate Cox proportional hazards models were developed to assess the contribution of each factor to survival prognosis, after allowing patient-specific demographic and clinical data in the models as covariates. Hazard ratios, estimated for each statistically significant factor and covariate in the multivariate model, provide the basis for the determination of the prognosis. The hazard ratio is the ratio of the hazard function for subjects with an attribute, e.g., an age of 10 years, to the hazard function for subjects who have some chosen baseline attribute, e.g., an age of 1 year. The important criterion of this ratio is beta, a statistic estimated from the survival data in the Childhood Brain Tumor Consortium database of infratentorial neuroglial tumors. Kaplan-Meier survival curves were used to investigate differences in the survival of factor-determined subgroups of patients with various diagnoses. RESULTS An increased likelihood of survival is associated with older age, more tumor removal, more recent decade of surgical intervention, and high spongy and fibrillary factor scores. A decreased likelihood of survival is associated with high nuclear, proliferative, and ring factor scores. Gender, location within the infratentorial compartment, and subsequent treatment did not add prognostic information. For certain subgroups of astrocytoma and for ependymoma and medulloblastoma, factors are important in predicting survival with greater accuracy. CONCLUSION Factor scores provide clinically useful quantitative estimates of survival probability that are more specific and accurate than the general estimates based on the conventional diagnosis alone.

The diagnosis and management of delirium in infancy.

OBJECTIVE Atypical antipsychotics have been documented to be effective in the management of delirium in adults and older children, but despite considerable need, their use has been less studied in the very young. A retrospective chart review was undertaken to describe the use of atypical antipsychotics in controlling symptoms of delirium in infants and toddlers. METHODS All psychiatric inpatient consultations performed during a 3 year period were reviewed to identify children <36 months old diagnosed with delirium. Delirium Rating Scale (DRS) scores were retrospectively calculated when the antipsychotic was initiated and discontinued, to confirm the diagnosis of delirium and evaluate symptom severity, and then to assess symptom response to pharmacologic intervention. RESULTS There were 10 boys and 9 girls in the study population (ages 7-30 months, mean 20.5 months). Olanzapine (n=16) and risperidone (n=3) were used, and length of treatment and response were comparable for both medications. Mean DRS scores decreased significantly (p<0.001) with antipsychotic administration, without significant adverse side effects. CONCLUSIONS Although randomized placebo controlled studies are needed to better characterize the indications, risks, and benefits, these atypical antipsychotic medications appeared to be effective and safe for managing delirium symptoms in very young pediatric patients.

Symptoms before and after posterior fossa surgery in pediatric patients.

The posterior fossa syndrome (PFS) is common after cerebellar tumor resection in pediatric patients. It is characterized by postoperative mutism and ataxia and associated with persistent abnormalities in mood and cognition. Method: A 2-year prospective study of children and adolescents with cerebellar tumors identified by neuroimaging was performed at the Children’s Hospital Los Angeles. Results: There were 8 girls and 14 boys in the study, aged 14 months to 17 years. The tumor sizes ranged from 2 to 6.5 cm in diameter. The patients presented with ataxia, headache, vomiting, depressed or irritable mood and inattention. Symptoms of PFS were present postoperatively in all except for the 2 patients with lateral tumors. The symptoms began before resection, were most prominent immediately after surgery, and improved over time. Neuropsychological assessment of 10 patients documented a persistent cognitive decrement. Conclusion: This small, descriptive study provides information on the natural history of pediatric posterior fossa tumors from before surgery through the postoperative period.

Prognostic Limitations of the Daumas-Duport Grading Scheme in Infratentorial Neuroglial Tumors in Children

The Daumas-Duport grading scheme (DDGS) utilizes four histologic features in an additive method (grade 1 if none present, grade 2 if only one is present, etc.). Its efficacy in achieving prognostically homogeneous groups of childhood infratentorial neuroglial tumors and its concordance with World Health Organization (WHO) diagnoses has not been evaluated. We investigated these questions using the Childhood Brain Tumor Consortium (CBTC) database of 1241 neuroglial tumors limited to the infratentorial compartment. We calculated survival function estimates for various DDGS grades as well as the histologic features within each grade. The feature of endothelial prominence improved survival expectation, whereas the remaining three features of nuclear atypia, mitoses, and necrosis were associated with worsened survival. Survival estimates for tumors with DDGS grades 2 and 3 did not differ. Some grades contained feature subsets with significantly different survival distributions. The survival distributions of DDGS grade 1, DDGS grade 2 with only endothelial prominence, and DDGS grade 3 with nuclear atypia and endothelial prominence were not significantly different. DDGS grade within WHO diagnoses had no significant effect on survival expectation. We conclude that grading by summation of only four histologic features, as in the DDGS, is inappropriate for assessment of childhood neuroglial tumors. A classification scheme considering the complete histologic content is more likely to provide clinically useful diagnoses. Such a scheme, based on the CBTC database is available. This scheme uses 26 histologic features identified as reliable in read–reread studies.