Rita J. Jeremy

Clinical Neonatal Seizures are Independently Associated with Outcome in Infants at Risk for Hypoxic-Ischemic Brain Injury

OBJECTIVE To examine whether neonatal seizures are associated with neurodevelopmental outcomes in infants with hypoxia-ischemia independent of the presence and severity of brain injury seen on magnetic resonance imaging (MRI). STUDY DESIGN We used multivariate regression to examine the independent effect of clinical neonatal seizures and their treatment on neurodevelopment in 77 term newborns at risk for hypoxic-ischemic brain injury. Clinical seizures were recorded prospectively, and high-resolution newborn MRI measured the severity of brain injury. The outcome measure was the Full-Scale Intelligence Quotient (FSIQ) of the Wechsler Preschool and Primary Scale of Intelligence-Revised and neuromotor score at age 4 years. RESULTS After controlling for severity of injury on MRI, the children with neonatal seizures had worse motor and cognitive outcomes compared with those without seizures. The magnitude of effect varied with seizure severity; children with severe seizures had a lower FSIQ than those with mild/moderate seizures (P < .0001). CONCLUSIONS Clinical neonatal seizures in the setting of birth asphyxia are associated with worse neurodevelopmental outcome, independent of the severity of hypoxic-ischemic brain injury. Randomized controlled trials are needed to determine whether differences in seizure treatment can improve outcome.

Neuropsychological functioning and viral load in stable antiretroviral therapy-experienced HIV-infected children

Objective. Neuropsychological functioning and its correlation with viral load were investigated for previously treated HIV-infected children who underwent a change in treatment regimen. Methods. Thirteen age-appropriate measures of cognitive, neurologic, and behavioral functioning were administered to 489 HIV-infected children who were aged 4 months to 17 years and had been treated previously for at least 16 weeks with antiretroviral therapy. These clinically and immunologically stable children were randomized onto 1 of 7 drug treatment combinations, 6 of which included a protease inhibitor (PI), and evaluated prospectively for 48 weeks with respect to changes in neuropsychological performance and viral load. Results. Neuropsychological functioning was significantly poorer at baseline for the HIV-infected children as compared with established norms for their age. Children with higher viral load had poorer cognitive, both-hands fine-motor, and neurologic signs at baseline, but single-hand fine-motor and behavioral functioning were not correlated with viral load. After 48 weeks of treatment with PI-containing combination therapy, there was significant improvement in only the vocabulary score. Neuropsychological changes did not differ among the 6 PI-containing combination regimens. At week 48, even children with a viral load response below the level of detection (RNA ≤400 copies/mL) still showed poorer neuropsychological functioning compared with established norms. Conclusion. Poor neuropsychological functioning was seen for HIV-infected children and was worse for children with higher viral loads. Only 1 measure of neuropsychological functioning showed improvement after treatment with PI-containing combination therapy, and the extent of that improvement was relatively minor. Treatment strategies for children with HIV disease need to be reevaluated so that they consider restoration of neuropsychological functioning in addition to lowering the viral load.

Variability of Homotopic and Heterotopic Callosal Connectivity in Partial Agenesis of the Corpus Callosum : A 3T Diffusion Tensor Imaging and Q-Ball Tractography Study

BACKGROUND AND PURPOSE: Little is known about the anatomic connectivity of callosal axons in individuals with partial agenesis of the corpus callosum (pAgCC). We used tractography based on both diffusion tensor imaging (DTI) and high angular resolution diffusion imaging (HARDI) to investigate interhemispheric white matter connectivity in pAgCC. MATERIALS AND METHODS: DTI and HARDI were performed at 3T on 6 individuals with pAgCC and 8 control subjects. For HARDI analysis, a Q-ball reconstruction method capable of visualizing multiple intravoxel fiber orientations was used. In both DTI and HARDI, whole-brain 3D fiber tractography was performed by using deterministic streamline algorithms. Callosal fibers were then segmented to identify separately connections between homologous cortical regions (homotopic fibers) and nonhomologous regions (heterotopic fibers) by using manually drawn regions of interest. RESULTS: In control individuals, we observed densely connected homotopic fibers. However, in individuals with pAgCC, we identified not only homotopic connections but also heterotopic connections in 4 of 6 subjects. Furthermore, the observed homotopic connections in pAgCC did not necessarily correlate with the position or size of the residual callosum. The nature of homotopic and heterotopic connectivity varied considerably among subjects with pAgCC, and HARDI recovered more callosal fibers than DTI. CONCLUSION: Individuals with pAgCC demonstrate a remarkable diversity of callosal connectivity, including a number of heterotopic tracts that are absent in healthy subjects. The patterns of their callosal connections cannot be predicted from the appearance of their callosal fragments on conventional MR imaging. More tracts and more extensive fibers within tracts are recovered with HARDI than with DTI.

The Role of Corpus Callosum Development in Functional Connectivity and Cognitive Processing

The corpus callosum is hypothesized to play a fundamental role in integrating information and mediating complex behaviors. Here, we demonstrate that lack of normal callosal development can lead to deficits in functional connectivity that are related to impairments in specific cognitive domains. We examined resting-state functional connectivity in individuals with agenesis of the corpus callosum (AgCC) and matched controls using magnetoencephalographic imaging (MEG-I) of coherence in the alpha (8–12 Hz), beta (12–30 Hz) and gamma (30–55 Hz) bands. Global connectivity (GC) was defined as synchronization between a region and the rest of the brain. In AgCC individuals, alpha band GC was significantly reduced in the dorsolateral pre-frontal (DLPFC), posterior parietal (PPC) and parieto-occipital cortices (PO). No significant differences in GC were seen in either the beta or gamma bands. We also explored the hypothesis that, in AgCC, this regional reduction in functional connectivity is explained primarily by a specific reduction in interhemispheric connectivity. However, our data suggest that reduced connectivity in these regions is driven by faulty coupling in both inter- and intrahemispheric connectivity. We also assessed whether the degree of connectivity correlated with behavioral performance, focusing on cognitive measures known to be impaired in AgCC individuals. Neuropsychological measures of verbal processing speed were significantly correlated with resting-state functional connectivity of the left medial and superior temporal lobe in AgCC participants. Connectivity of DLPFC correlated strongly with performance on the Tower of London in the AgCC cohort. These findings indicate that the abnormal callosal development produces salient but selective (alpha band only) resting-state functional connectivity disruptions that correlate with cognitive impairment. Understanding the relationship between impoverished functional connectivity and cognition is a key step in identifying the neural mechanisms of language and executive dysfunction in common neurodevelopmental and psychiatric disorders where disruptions of callosal development are consistently identified.

Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human immunodeficiency virus type 1.

The relative potency and tolerability of multidrug regimens used to treat infants and children infected with human immunodeficiency virus type 1 (HIV-1) are largely unknown. In Pediatric AIDS Clinical Trials Group (PACTG) Protocol 377, 181 infants and children were assigned to receive stavudine (d4T) plus nevirapine (NVP) and ritonavir (RTV); d4T plus lamivudine (3TC) and nelfinavir (NFV); d4T plus NVP and NFV; or d4T plus 3TC, NVP, and NFV. Eleven additional children received d4T and NVP plus NFV given twice daily. All subjects had not previously received protease inhibitors or nonnucleoside reverse-transcriptase inhibitors and all had been immunologically stable while receiving reverse-transcriptase inhibitor therapy. After 48 weeks of therapy, 17 (41%) of 41 subjects receiving d4T-NVP-RTV, 13 (30%) of 44 receiving d4T-NVP-NFV, 21 (42%) of 50 receiving d4T-3TC and NFV (3 times daily), and 22 (52%) of 42 receiving d4T-3TC-NVP-NFV were still receiving their assigned therapy and had HIV-1 RNA suppression to </= 400 copies/mL. These regimens were similar in their drug activity, but the 4-drug regimen offered slightly more durable suppression of viremia.

Hypoglycemia is Associated with Increased Risk for Brain Injury and Adverse Neurodevelopmental Outcome in Neonates at Risk for Encephalopathy

OBJECTIVE To investigate the contribution of hypoglycemia in the first 24 hours after birth to brain injury in term newborns at risk for neonatal encephalopathy. STUDY DESIGN A prospective cohort of 94 term neonates born between 1994 and 2010 with early postnatal brain magnetic resonance imaging studies were analyzed for regions of brain injury. Neurodevelopmental outcome was assessed at 1 year of age. RESULTS Hypoglycemia (glucose <46 mg/dL) in the first 24 hours after birth was detected in 16% of the cohort. Adjusting for potential confounders of early perinatal distress and need for resuscitation, neonatal hypoglycemia was associated with a 3.72-fold increased odds of corticospinal tract injury (P=.047). Hypoglycemia was also associated with 4.82-fold increased odds of 1-point worsened neuromotor score (P=.038) and a 15-point lower cognitive and language score on the Bayley Scales of Infant Development (P=.015). CONCLUSION Neonatal hypoglycemia is associated with additional risks in the setting of neonatal encephalopathy with increased corticospinal tract injury and adverse motor and cognitive outcomes.

Risk factors for epilepsy in children with neonatal encephalopathy.

We examined neonatal predictors of epilepsy in term newborns with neonatal encephalopathy (NE) by studying children enrolled in a longitudinal, single center cohort study. Clinical data were obtained through chart review, and MRI was performed in the neonatal period. We administered a seizure questionnaire to parents of children aged ≥12 mo (range, 12 mo to 16.5 y) to determine the outcome of epilepsy. The association between clinical predictors and time to onset of epilepsy was assessed using Cox proportional hazards regression. Thirteen of 129 children developed epilepsy: all had neonatal seizures and brain injury on neonatal MRI. Of the newborns with neonatal seizures, 25% (15.8/1000 person-years) developed epilepsy, with the highest hazard ratios (HRs) in the newborns with status epilepticus (HR, 35.8; 95% CI, 6.5–196.5). Children with severe or near-total brain injury were more likely to develop epilepsy compared with those with only mild or moderate injury (HR, 5.5; 95% CI, 1.8–16.8). In a multivariable analysis adjusting for degree of encephalopathy and severe/near-total brain injury, status epilepticus was independently associated with epilepsy. These data add to information regarding epilepsy pathogenesis and further aid clinicians to counsel parents regarding the likelihood that a newborn with NE will develop epilepsy.

Hypothermia is correlated with seizure absence in perinatal stroke.

Within a single-center prospective cohort study of neonatal encephalopathy involving 315 subjects, 15 neonates were found to have a focal stroke on magnetic resonance imaging. These 15 patients were matched on the basis of gender and degree of encephalopathy to 30 neonates without stroke from the same cohort. On Bayley Scales of Infant Development, the stroke group had Mental Development Index scores that were 1.7 standard deviations lower compared with controls (P = .007). This association was no longer seen after adjustment for the presence of neonatal seizures (P = .11). Of the 15 patients with stroke, 5 had been treated with hypothermia. None of these 5 had seizures in the neonatal period, compared with 7 of the untreated 10. This is the first human study to demonstrate a potential treatment effect of therapeutic hypothermia on perinatal stroke. It was also shown that seizures are associated with worse cognitive outcomes for stroke that presents with encephalopathy.

Genomic microarray analysis identifies candidate loci in patients with corpus callosum anomalies.

Absence of the corpus callosum is often associated with cognitive deficits, autism, and epilepsy. Using a genomic microarray, the authors analyzed DNA from 25 patients with radiographically confirmed callosal anomalies and identified three patients with de novo copy number changes in chromosome regions 2q37, 6qter, and 8p. Chromosomal deletions and duplications may be a relatively common cause of cerebral malformations.

Diffusion Abnormalities and Reduced Volume of the Ventral Cingulum Bundle in Agenesis of the Corpus Callosum: A 3T Imaging Study

BACKGROUND AND PURPOSE: Patients with agenesis of the corpus callosum (AgCC) exhibit cognitive and behavioral impairments that are not replicated by surgical transection of the callosum, suggesting that other anatomic changes may contribute to the observed clinical findings. The purpose of this study was to determine whether the ventral cingulum bundle (VCB) is affected in patients with AgCC by using diffusion tensor imaging (DTI) and volumetry. MATERIALS AND METHODS: Twelve participants with AgCC (8 males and 4 females; mean age, 30 ± 20) and 12 control subjects matched for age and sex (mean age, 37 ± 19) underwent MR imaging and DTI at 3T. 3D fiber tracking of the VCB was generated from DTI and the average fractional anisotropy (FA) was computed for the tracked fibers. Additionally, the volume, cross-sectional area, and length of the VCB were measured by manually drawn regions of interest on thin-section coronal T1-weighted images. The Student t test was used to compare these results. RESULTS: Compared with controls, subjects with AgCC demonstrated significantly reduced FA in the right VCB (P = .0098) and reduced volume and cross-sectional areas of both the left and right VCB (P < .001 for all metrics). The length of the VCB was also significantly reduced in the complete AgCC subgroup compared with controls (P = .030 in the right and P = .046 in the left, respectively). CONCLUSIONS: Patients with AgCC have abnormal microstructure and reduced volume of the VCB, suggesting that abnormalities in intrahemispheric white matter tracts may be an important contributor to the clinical syndrome in patients with AgCC.