Karol H. Katz

Prematurely Born Children Demonstrate White Matter Microstructural Differences at 12 Years of Age, Relative to Term Control Subjects : An Investigation of Group and Gender Effects

OBJECTIVE. The goal was to use diffusion tensor imaging to test the hypothesis that prematurely born children demonstrate long-term, white matter, microstructural differences, relative to term control subjects. METHODS. Twenty-nine preterm subjects (birth weight: 600–1250 g) without neonatal brain injury and 22 matched, term, control subjects were evaluated at 12 years of age with MRI studies, including diffusion tensor imaging and volumetric imaging; voxel-based morphometric strategies were used to corroborate regional diffusion tensor imaging results. Subjects also underwent neurodevelopmental assessments. RESULTS. Neurodevelopmental assessments showed significant differences in full-scale, verbal, and performance IQ and Developmental Test of Visual Motor Integration scores between the preterm and term control subjects. Diffusion tensor imaging studies demonstrated widespread decreases in fractional anisotropy (a measure of fiber tract organization) in the preterm children, compared with the control subjects. Regions included both intrahemispheric association fibers subserving language skills, namely, the right inferior frontooccipital fasciculus and anterior portions of the uncinate fasciculi bilaterally, and the deep white matter regions to which they project, as well as the splenium of the corpus callosum. These changes in fractional anisotropy occurred in subjects with significant differences in frontal, temporal, parietal, and deep white matter volumes. Fractional anisotropy values in the left anterior uncinate correlated with verbal IQ, full-scale IQ, and Peabody Picture Vocabulary Test-Revised scores for preterm male subjects. In addition, preterm male subjects were found to have the lowest values for fractional anisotropy in the right anterior uncinate fasciculus, and fractional anisotropy values in that region correlated with both verbal IQ and Peabody Picture Vocabulary Test-Revised scores for the preterm groups; these findings were supported by changes identified with voxel-based morphometric analyses. CONCLUSIONS. Compared with term control subjects, prematurely born children with no neonatal ultrasound evidence of white matter injury manifest changes in neural connectivity at 12 years of age.

Lasting effects of preterm birth and neonatal brain hemorrhage at 12 years of age.

OBJECTIVES. Our goals were to compare cognitive, language, behavioral, and educational outcomes of preterm children to term controls and to evaluate the impact of neonatal brain injury, indomethacin, and environmental risk factors on intellectual function at 12 years of age. METHODS. A total of 375 children born in 1989–1992 with birth weights of 600 to 1250 g enrolled in the Indomethacin Intraventricular Hemorrhage Prevention Trial and 111 controls were evaluated. Neuropsychometric testing, neurologic examination, and interviews on educational needs were completed. Severe brain injury was defined as the presence of grade 3 to 4 indomethacin intraventricular hemorrhage, periventricular leukomalacia, or severe ventriculomegaly on cranial ultrasound. RESULTS. On the Wechsler Scales of Intelligence for Children, the preterm cohort obtained a full-scale IQ of 87.9 ± 18.3, verbal IQ of 90.8 ± 18.9, and performance IQ of 86.8 ± 17.9. Preterm children obtained scores 6 to 14 points lower than term controls on all psychometric tests after adjustment for sociodemographic factors. On the Clinical Evaluation of Language Fundamentals (test of basic language skills), 22% to 24% of preterm children scored in the abnormal ranges (<70) as opposed to 2% to 4% of controls. Preterm children with and without brain injury required more school services (76% and 44% vs 16%), and support in reading (44% and 28% vs 9%), writing (44% and 20% vs 4%), and mathematics (47% and 30% vs 6%) compared with controls. Preterm children also displayed more behavior problems than their term counterparts. Severe neonatal brain injury was the strongest predictor of poor intelligence. Antenatal steroids, higher maternal education, and 2-parent family were associated with better cognition, whereas minority status incurred a disadvantage. Indomethacin did not affect intellectual function among preterm children. CONCLUSIONS. Preterm children born in the early 1990s, especially those with severe brain injury, demonstrate serious deficits in their neuropsychological profile, which translates into increased use of school services at 12 years.

Prognostic Factors for Survival in Patients with Metastatic Renal Cancer Treated with Biological Response Modifiers

PURPOSE Clinical characteristics prognostic of survival in patients with metastatic renal cell carcinoma treated with biological response modifiers are poorly understood. Understanding these prognostic features may help with better stratification of patients in clinical trials and define further appropriate treatment for each prognostic subgroup. MATERIALS AND METHODS A retrospective study of 84 patients with recurrent or metastatic renal cancer was conducted to identify prognostic factors for survival in patients who received biological response modifiers (alpha-interferon, beta-interferon, gamma-interferon and interleukin-2). RESULTS Univariate analysis identified Eastern Cooperative Oncology Group (ECOG) performance status (1 versus 0, p < 0.001), bone metastasis (p = 0.008), recent weight loss (greater than 10% of total body weight versus no loss, p = 0.028), history of nephrectomy (no versus yes, p = 0.025), recurrence at the renal bed (p = 0.043) and sarcomatoid histology (yes versus no, p < 0.001) as important prognostic indicators. Multivariate analysis of prognostic factors in this patient population indicated that ECOG performance status, sarcomatoid histology and bone metastasis were most significant, while other factors were less significant (p > 0.05) after adjusting for ECOG performance status and sarcomatoid histology. Based on the total positive number of 5 risk factors defined previously the study population separates into 3 risk groups, with a median survival from the low to high risk groups of 14.4, 10.9 and 1.3 months, respectively. Prognostic scores based only on ECOG performance status, sarcomatoid histology and bone metastasis allowed for stratification of our patients into 3 distinct groups with median survivals of 18.6, 8.4 and 3.8 months, which were also predictive of survival (p < 0.05). CONCLUSIONS Risk factors of ECOG performance status, sarcomatoid histology, bone metastasis, history of nephrectomy, recent weight loss and recurrence at the renal bed are predictive of survival in patients treated with biological response modifiers. In addition to previous findings of prognostic factors in renal cancer patients treated with chemotherapy, we identified sarcomatoid histology as an important risk factor in patients treated with biological response modifiers.

Brain Volume Reductions within Multiple Cognitive Systems in Male Preterm Children at Age Twelve

OBJECTIVES To more precisely examine regional and subregional microstructural brain changes associated with preterm birth. STUDY DESIGN We obtained brain volumes from 29 preterm children, age 12 years, with no ultrasound scanning evidence of intraventricular hemorrhage or cystic periventricular leukomalacia in the newborn period, and 22 age- and sex-matched term control subjects. RESULTS Preterm male subjects demonstrated significantly lower white matter volumes in bilateral cingulum, corpus callosum, corticospinal tract, prefrontal cortex, superior and inferior longitudinal fasciculi compared with term male subjects. Gray matter volumes in prefrontal cortex, basal ganglia, and temporal lobe also were significantly reduced in preterm male subjects. Brain volumes of preterm female subjects were not significantly different from those of term female control subjects. Voxel-based morphometry results were not correlated with perinatal variables or cognitive outcome. Higher maternal education was associated with higher cognitive performance in preterm male subjects. CONCLUSIONS Preterm male children continue to demonstrate abnormal neurodevelopment at 12 years of age. However, brain morphology in preterm female children may no longer differ from that of term female children. The neurodevelopmental abnormalities we detected in preterm male subjects appear to be relatively diffuse, involving multiple neural systems. The relationship between aberrant neurodevelopment and perinatal variables may be mediated by genetic factors, environmental factors, or both reflected in maternal education level.

Alterations in functional connectivity for language in prematurely born adolescents

Recent data suggest recovery of language systems but persistent structural abnormalities in the prematurely born. We tested the hypothesis that subjects who were born prematurely develop alternative networks for processing language. Subjects who were born prematurely (n = 22; 600–1250 g birth weight), without neonatal brain injury on neonatal cranial ultrasound, and 26 term control subjects were examined with a functional magnetic resonance imaging (fMRI) semantic association task, the Wechsler Intelligence Scale for Children-III (WISC-III) and the Clinical Evaluation of Language Fundamentals (CELF). In-magnet task accuracy and response times were calculated, and fMRI data were evaluated for the effect of group on blood oxygen level dependent (BOLD) activation, the correlation between task accuracy and activation and the functional connectivity between regions activating to task. Although there were differences in verbal IQ and CELF scores between the preterm (PT) and term control groups, there were no significant differences for either accuracy or response time for the in-magnet task. Both groups activated classic semantic processing areas including the left superior and middle temporal gyri and inferior frontal gyrus, and there was no significant difference in activation patterns between groups. Clear differences between the groups were observed in the correlation between task accuracy and activation to task at P < 0.01, corrected for multiple comparisons. Left inferior frontal gyrus correlated with accuracy only for term controls and left sensory motor areas correlated with accuracy only for PT subjects. Left middle temporal gyri correlated with task accuracy for both groups. Connectivity analyses at P < 0.001 revealed the importance of a circuit between left middle temporal gyri and inferior frontal gyrus for both groups. In addition, the PT subjects evidenced greater connectivity between traditional language areas and sensory motor areas but significantly fewer correlated areas within the frontal lobes when compared to term controls. We conclude that at 12 years of age, children born prematurely and children born at term had no difference in performance on a simple lexical semantic processing task and activated similar areas. Connectivity analyses, however, suggested that PT subjects rely upon different neural pathways for lexical semantic processing when compared to term controls. Plasticity in network connections may provide the substrate for improving language skills in the prematurely born.

PRETERM BIRTH RESULTS IN ALTERATIONS IN NEURAL CONNECTIVITY AT AGE 16 YEARS

Very low birth weight preterm (PT) children are at high risk for brain injury. Employing diffusion tensor imaging (DTI), we tested the hypothesis that PT adolescents would demonstrate microstructural white matter disorganization relative to term controls at 16 years of age. Forty-four PT subjects (600-1250 g birth weight) without neonatal brain injury and 41 term controls were evaluated at age 16 years with DTI, the Wechsler Intelligence Scale for Children-III (WISC), the Peabody Picture Vocabulary Test-Revised (PPVT), and the Comprehensive Test of Phonological Processing (CTOPP). PT subjects scored lower than term subjects on WISC full scale (p=0.003), verbal (p=0.043), and performance IQ tests (p=0.001), as well as CTOPP phonological awareness (p=0.004), but scored comparably to term subjects on PPVT and CTOPP Rapid Naming tests. PT subjects had lower fractional anisotropy (FA) values in multiple regions including bilateral uncinate fasciculi (left: p=0.01; right: p=0.004), bilateral external capsules (left: p<0.001; right: p<0.001), the splenium of the corpus callosum (p=0.008), and white matter serving the inferior frontal gyrus bilaterally (left: p<0.001; right: p=0.011). FA values in both the left and right uncinate fasciculi correlated with PPVT scores (a semantic language task) in the PT subjects (left: r=0.314, p=0.038; right: r=0.336, p=0.026). FA values in the left and right arcuate fasciculi correlated with CTOPP Rapid Naming scores (a phonologic task) in the PT subjects (left: r=0.424, p=0.004; right: r=0.301, p=0.047). These data support for the first time that dual pathways underlying language function are present in PT adolescents. The striking bilateral dorsal correlations for the PT group suggest that prematurely born subjects rely more heavily on the right hemisphere than typically developing adults for performance of phonological language tasks. These findings may represent either a delay in maturation or the engagement of alternative neural pathways for language in the developing PT brain.

Alterations in neural connectivity in preterm children at school age.

Converging data suggest recovery from injury in the preterm brain. We used functional magnetic resonance imaging (fMRI) to test the hypothesis that cerebral connectivity involving Wernickes area and other important cortical language regions would differ between preterm (PT) and term (T) control school age children during performance of an auditory language task. Fifty-four PT children (600-1250 g birth weight) and 24 T controls were evaluated using an fMRI passive language task and neurodevelopmental assessments including: the Wechsler Intelligence Scale for Children - III (WISC-III), the Peabody Individual Achievement Test - Revised (PIAT-R) and the Peabody Picture Vocabulary Test - Revised (PPVT-R) at 8 years of age. Neural activity was assessed for language processing and the data were evaluated for connectivity and correlations to cognitive outcomes. We found that PT subjects scored significantly lower on all components of the WISC-III (p<0.009), the PIAT-R Reading Comprehension test (p=0.013), and the PPVT-R (p=0.001) compared to term subjects. Connectivity analyses revealed significantly stronger neural circuits in PT children between Wernickes area and the right inferior frontal gyrus (R IFG, Brocas area homologue) and both the left and the right supramarginal gyri (SMG) components of the inferior parietal lobules (p</=0.02 for all). We conclude that PT subjects employ neural systems for auditory language function at school age differently than T controls; these alterations may represent a delay in maturation of neural networks or the engagement of alternate circuits for language processing.

Longitudinal Brain Volume Changes in Preterm and Term Control Subjects During Late Childhood and Adolescence

OBJECTIVE. Although preterm very low birth weight infants have a high prevalence of neuroanatomical abnormalities when evaluated at term-equivalent age, patterns of brain growth in prematurely born infants during school age and adolescence remain largely unknown. Our goal was to test the hypothesis that preterm birth results in long-term dynamic changes in the developing brain. METHODS. We performed serial volumetric MRI studies at ages 8 and 12 years in 55 preterm infants born weighing 600 to 1250 g and 20 term control children who participated in the follow-up component of a prospective, randomized, placebo-controlled intraventricular hemorrhage prevention study. RESULTS. Total brain volumes increased 2% to 3% between the ages of 8 and 12 years for both preterm and term children. These changes involved reductions in cerebral gray matter while white matter increased. Between 8 and 12 years of age, preterm subjects experienced a 2% decrease in left cerebral gray matter compared with a 10% reduction in left cerebral gray for term controls. For right cerebral gray matter, preterm children experienced a 3% decrease in volume between years 8 and 12, compared with 9% for term controls (group-by-time). In contrast, preterm subjects had a 10% increase in cerebral white matter volumes bilaterally between ages 8 and 12 years, compared with >26% increases for both hemispheres for term controls. Significant differences in regional volume changes between study groups were found in bilateral temporal gray and in parietal white matter. CONCLUSIONS. Preterm birth continues to perturb the trajectory of cerebral development during late childhood and early adolescence with preterm children, showing both lower gray matter reduction and less white matter gain over time compared with term control subjects.

Low-dose indomethacin therapy and extension of intraventricular hemorrhage: a multicenter randomized trial.

We enrolled 61 neonates of 600 to 1250 gm birth weight with evidence of low-grade intraventricular hemorrhage at 6 to 11 hours of age in a prospective, randomized, placebo-controlled trial to test the hypothesis that indomethacin (0.1 mg/kg given intravenously at 6 to 12 postnatal hours and every 24 hours for two more doses) would prevent extension of intraventricular hemorrhage. Twenty-seven infants were assigned to receive indomethacin; 34 infants received saline placebo. There were no significant differences between the two groups in birth weight, gestational age, sex, Apgar scores, percentage of infants treated with surfactant, or distribution of hemorrhages at the time of the first cranial sonogram (echo-encephalogram). Within the first 5 days, 9 of 27 indomethacin-treated and 12 of 34 saline solution-treated infants had extension of their initial intraventricular hemorrhage (p = 1.00). Four indomethacin-treated and three saline solution-treated infants had parenchymal extension of the hemorrhage. Indomethacin was associated with closure of a patent ductus arteriosus by the fifth day of life (p = 0.003). There were no differences in adverse events attributed to indomethacin. We conclude that in very low birth weight infants with low grade intraventricular hemorrhage within the first 6 postnatal hours, prophylactic indomethacin therapy promotes closure of the patent ductus arteriosus and is not associated with adverse events, but does not affect the cascade of events leading to parenchymal involvement of intracranial hemorrhage.

Microstructural and Functional Connectivity in the Developing Preterm Brain

Prematurely born children are at increased risk for cognitive deficits, but the neurobiological basis of these findings remains poorly understood. Because variations in neural circuitry may influence performance on cognitive tasks, recent investigations have explored the impact of preterm birth on connectivity in the developing brain. Diffusion tensor imaging studies demonstrate widespread alterations in fractional anisotropy, a measure of axonal integrity and microstructural connectivity, throughout the developing preterm brain. Functional connectivity studies report that preterm neonates, children and adolescents exhibit alterations in both resting state and task-based connectivity when compared with term control subjects. Taken together, these data suggest that neurodevelopmental impairment following preterm birth may represent a disease of neural connectivity.