Early-life Insults Research Articles

Lesion lateralization in patients with epilepsy and precocious destructive insults

Destructive brain lesions that occur early in development are often unilateral or asymmetric. We analyzed the lateralization of lesions among a previously reported series of 51 patients with three kinds of destructive lesions based on their topography: specific arterial territory (AT), arterial borderzone territory (Bdz), hemispheric (H). Five patients (all from group Bdz) had bilateral nonlateralizing lesions. The distributions of left- and right-sided lesions were distinct among the groups ( P = 0.014): in group H, all patients except one presented with right-sided lesions (89%); in group Bdz, left-sided lesions (53%) were more frequent than right-sided lesions (17.7%); in group AT, left- and right-sided lesions were more equally distributed (56 and 44%). Our study suggests that there is a trend toward lesion lateralization among patients with different patterns of precocious destructive lesions. Differences in cerebral maturation and vulnerability between the hemispheres is a possible factor explaining lesion lateralization in early life insults.

258 Determinants of Altered Adipose Tissue Deposition in Preterm Infants at Term

Background and aims: Adiposity, particularly intra-abdominal, is associated with insulin resistance and type-2 diabetes. Insults in early life may programme long term risks but causal pathways are unclear. We have previously presented work to this Society showing that total adiposity in preterm infants at the age of term-equivalent is similar to term controls, but that the distribution is altered, with decreased subcutaneous (SC), and increased intra-abdominal (IA) AT. The aim of this part of the study was to explore possible determinants of total adiposity and altered AT partitioning, specifically the influence of gestational age(GA) at birth, postnatal growth, disease severity, and diet. Methods: Infants underwent whole body magnetic resonance AT imaging at term-equivalent. Individual AT compartments were quantified and summated to determine total AT volume. Total adiposity was expressed as a percentage of body weight (%ATM); AT partitioning was expressed as SC and IA AT as a percentage of total AT volume (%SCATV, %IAATV). We documented the number of days that breast milk was received, and number of days of level 1 and 2 care (BAPM 2001) and expressed these as percentage of total days from delivery to term-equivalent (% breast milk and % level 1&2 care). We used % level 1&2 care as an index of disease severity. We expressed weight gain as weight SDS gain (SDSG) (Child Growth Foundation, U.K). Results: We studied 38 infants (GA range 23–32 wk). Linear regression showed a significant correlation between % ATM and SDSG (r= 0.396, p= 0.014).There was significant positive correlation between %SCATV and GA (r= 0.388, p= 0.016) and SDSG (r= 0.404, p= 0.012), and a significant negative correlation with %level 1&2 care (r= −0.575, p= 0.0001). The negative impact of increased % level 1&2 care on %SCATV was confirmed in a multiple regression analysis allowing for GA, % breast milk and SDSG (adj. r square 31.7%, B= −0.087, SE= 0.028. p= 0.004). A multiple regression model incorporating the same variables showed increasing %IAATV with increasing % level 1&2 care (adj. r square 23.1%, B= 0.037, SE= 0.011, p= 0.002). Discussion: We have shown that rapid postnatal weight gain is accompanied by increased adiposity. We have also shown that increased disease severity results in decreased SC AT and increased IA AT. Establishing if rapid postnatal growth is a risk factor for later obesity and if altered AT partitioning is sustained and accompanied by metabolic abnormalities should be considered research priorities.

Critically timed ethanol exposure reduces GABA AR function on septal neurons developing in vivo but not in vitro

Six-day ‘binge’ ethanol intoxication postnatal days (PD) 4–9 delays up-regulation of γ-aminobutyric acid type A receptors (GABA ARs) in developing rat septal neurons [Dev. Brain Res. 130 (2001) 25]. This distortion occurs during synaptogenesis and could contribute to cognitive dysfunction in fetal alcohol syndrome (FAS). Here, we asked two questions concerning requirements for vulnerability to GABA AR blunting by ethanol. First, we asked whether receptor blunting required PD 4–9 ethanol exposure in rat pups and found that just a brief 2-day exposure (PD 8–9) was as effective as all 6 days. However, 2-day exposure on PD 4–5 was ineffective, showing that ‘binge’ timing was important. We also asked whether ‘binge’ exposure directly inhibited intrinsic processes of septal neurons and could blunt GABA ARs on cells maturing outside the brain. Embryonic septal neurons grown in serum-free dispersed culture developed extensive dendritic arborizations, spontaneous synaptic activity and robust whole-cell GABA AR function, but surprisingly, did not show developmental up-regulation of GABA ARs like septal neurons maturing in vivo [Brain Res. 810 (1998) 100]. Furthermore, age-matched 6-day ‘binge’ ethanol exposure did not blunt GABA AR function in septal neurons in vitro. These results suggest developmental mechanisms driving up-regulation of GABA AR function in septal neurons in vivo briefly becomes vulnerable to ethanol insult in early postnatal life. While septal neurons express comparable functional GABA ARs whether maturing in vivo or in vitro, vulnerability to ethanol-induced receptor blunting requires elements of an intact brain environment not replicated in culture.

Epilepsy and destructive brain insults in early life: a topographical classification on the basis of MRI findings

Destructive insults of early development can lead to a wide variety of lesional patterns and are a well known cause of epilepsy. The aim of this study is to present a topographic magnetic resonance imaging (MRI) classification of these lesions in adult patients with epilepsy. Thirty-three consecutive patients were divided in three groups according to the topographic distribution of their lesion on MRI: hemispheric (H, n=7); main arterial territory (AT, n=18); arterial borderzone (Bdz, n=8). We analyzed clinical, MRI and magnetic resonance angiography (MRA) data. Status epilepticus (SE) during childhood was more common in group H (7/7) than in the groups AT (1/18) and Bdz (0/8) ( P<0.001). MRA pattern of impaired flow signal in the distal segments of all three major arteries in the affected hemisphere was present in 85.7% of group H patients, and was exclusive to this group. 88.8% (16/18) of patients from group AT presented congenital motor deficit, in contrast to 37.5% (3/8) of group Bdz, and in none of group H ( P<0.001). All patients with Bdz lesions had antecedent of fetal distress, in contrast to 1/7 from group H and 5/18 of group AT ( P=0.001). The MRAs of patients with Bdz lesions were often normal except in those with larger lesions. Our data suggest that in adult patients with epilepsy due to precocious destructive brain insults, a MRI topographical classification distributes them in relatively homogenous clinical groups.

Epilepsy after early-life seizures can be independent of hippocampal injury.

Prolonged early-life seizures are considered potential risk factors for later epilepsy development, but mediators of this process remain largely unknown. Seizure-induced structural damage in hippocampus, including cell loss and mossy fiber sprouting, is thought to contribute to the hyperexcitability characterizing epilepsy, but a causative role has not been established. To determine whether early-life insults that lead to epilepsy result in similar structural changes, we subjected rat pups to lithium-pilocarpine-induced status epilepticus during postnatal development (day 20) and examined them as adults for the occurrence of spontaneous seizures and alterations in hippocampal morphology. Sixty-seven percent of rats developed spontaneous seizures after status epilepticus, yet only one third of these epileptic animals exhibited visible hippocampal cell loss or mossy fiber sprouting in dentate gyrus. Most epileptic rats had no apparent structural alterations in the hippocampus detectable using standard light microscopy methods (profile counts and Timm's staining). These results suggest that hippocampal cell loss and mossy fiber sprouting can occur after early-life status epilepticus but may not be necessary prerequisites for epileptogenesis in the developing brain.

Immune function in rural Gambian children is not related to season of birth, birth size, or maternal supplementation status

We previously showed that mortality from infectious diseases among young adults in rural Gambia is strongly correlated with the season of their birth. This suggests that early life insults that involve fetal malnutrition, exposure to natural toxins, or highly seasonal infections affecting the infant or pregnant mother cause permanent damage to the immune system. Excess mortality begins after puberty and has a maximal odds ratio of >10 for deaths between ages 25 and 50 y. We investigated the immune function of children according to birth weight, season of birth, and exposure to maternal dietary supplementation during pregnancy. Immune function was measured in 472 prepubertal children aged 6.5-9.5 y from 28 villages in rural Gambia. The mothers of these children had been randomly assigned to a high-energy prenatal supplementation program, which significantly increased birth weight. This permitted supplementation status, birth weight, and season of birth to be investigated as exposure variables. The outcome variables tested were naive responses to rabies and pneumococcus vaccines, delayed-type hypersensitivity skin reactions, and mucosal defense (secretory immunoglobulin A and dual-sugar permeability). Immune responses were strongly related to current age and sex, suggesting a high level of sensitivity, but were not consistently related to birth weight, season of birth, or maternal supplementation (control compared with intervention). Events in early life did not predict a measurable defect in immune response within this cohort of rural Gambian children. It is possible that the early programming of immune function may be mediated through a defect in immunologic memory or early senescence rather than through impairment of early responses.

Developmental seizures induced by common early-life insults: short- and long-term effects on seizure susceptibility.

The immature brain is highly susceptible to seizures induced by a variety of insults, including hypoxia, fever, and trauma. Unlike early life epilepsy associated with congenital dysplasias or genetic abnormalities, insults induce a hyperexcitable state in a previously normal brain. Here we evaluate the epileptogenic effects of seizure-inducing stimuli on the developing brain, and the age and regional specificity of these effects.