The behavioral consequences of exposure to antiepileptic drugs in utero

The aim of the study was to examine the behavior of 242 children, aged between 6 and 16 years, born to mothers with epilepsy. Exposure to sodium valproate (VPA) in utero was associated with high levels of parental stress induced by the child's maladaptive behavior. These children were also poorer for daily living skills and skills relating to socialization. The outcomes on both measures were strongly affected by the Full Scale IQ (FSIQ) of the child; however, no significant differences were found between the groups and therefore this pattern of results cannot simply be attributed to a lower FSIQ. The results of this study suggest that exposure to VPA in utero and the presence of a lowered FSIQ are risk factors for the development of poorer adaptive behavior and a higher rate of maladaptive behaviors.     

Elevation of fetal dopamine following exposure to methamphetamine in utero

The effect of methamphetamine on fetal dopaminergic function was examined following treatment of pregnant mice twice daily with 40 mg/kg methamphetamine from either gestational day (GD) 7-13 or from GD 7-15. Dopamine levels were elevated in fetal GD 16 corpus striatum and rostral mesencephalon following both treatment regimens. This increase in fetal dopamine is consistent with our findings that exposure to methamphetamine in utero results in adult dopaminergic neurons which are more responsive in terms of methamphetamine induced release of the neurotransmitter and more sensitive to the neurotoxic effects of the drug.     

Meningocele and ankyloblepharon following in utero exposure to olanzapine.

Although atypical antipsychotics are widely used during pregnancy, their safety is not well established. This case highlights the possible teratogenic effect of olanzapine, in which the baby was born with meningocele and ankyloblepharon. It is suggested that olanzapine may interfere with embryonic development at different stages of pregnancy.     

Acute response of fetal rat telencephalon to ultrasound exposure in utero

Pregnant rats were exposed to ultrasound or microwaves from transducers located over one uterine horn. Ultrasound intensity (SPTA) was 0.78 W/cm2 for 30 min at a frequency of 2.5 MHz. Microwave exposure was used to reproduce approximately the rate of rise of uterine temperature of the rats exposed to ultrasound. The average peak temperature was 40.1 degrees C for ultrasound exposure and 42.2 degrees C for microwave exposure. On Gestational Day 16, 24 h after exposure, fetuses were removed and prepared for morphological examination of the developing cerebral cortical mantle. Morphometric measurements were made of nuclear area of subventricular zone cells, number of mitoses per mm in the ventricular zone, number of pyknotic cells in the mantle per mm, and number of ventricular macrophages per mm. Both exposures increased nuclear size and numbers of pyknotic cells and macrophages, and decreased the number of mitotic figures. The data from the four measurements were evidence of damage from ultrasound similar to the effects produced by microwave heating. The thermal effects of ultrasound, even at relatively low levels of rise in temperature, may have been the cause of the damage to the fetal cortex in these experiments or may have interacted with other effects of ultrasound energies to produce damage to developing neurons.     

Regional differences in cortical dendrite morphology following in utero exposure to cocaine

In utero exposure to cocaine has been shown to affect dopaminergic populations of developing neurons in the central nervous system (CNS). To determine if this was a regionally specific effect or the result of a global phenomenon, we used a Golgi-Cox analysis to measure several parameters of neuronal development in murine neurons from frontal cortex, a region of the cortex containing monoamine innervation, and somatosensory cortex, a monoamine sparse part of the cortex. Results of these analyses show that in utero exposure to cocaine affects total dendrite length in histotypical layers III and IV and dendritic volume in layer III of the frontal cortex. These effects are not present in the somatosensory cortex.     

Synaptic density of caudate-putamen and visual cortex following exposure to ethanol in utero

Pregnant Long-Evans rats were fed a liquid diet containing ethanol (30% of total calories) during days 3–19 of gestation. Controls were given ad libitum access to liquid diet lacking ethanol, or pair-fed isocaloric amounts based on consumption by the animals in the ethanol group. Brain development of female offspring was evaluated by analysis of electron micrographs of caudate-putamen and visual cortex. Numbers of presynaptic terminals and synaptic junctions (synaptic density) per unit area were compared for 14- and 28-day-old offspring of dams from the three treatment groups. Synaptic density of the caudate-putamen and visual cortex was not affected by ethanol at 14 or 28 days. Although exposure to ethanol during a period comparable to the first two trimesters of human development with minimal or no undernutrition did not affect numerical density of synapses in visual cortex or caudateputamen, synaptogenesis of caudate-putamen was altered in offspring of pair-fed animals.     

Assessment of visual functions following prenatal exposure to organic solvents

Prenatal exposure to organic solvents has been previously associated with increased risk of color vision deficits and reduced visual acuity in young children. These findings prompted us to evaluate visual functioning in solvent-exposed infants using more sensitive non-invasive visual evoked potential (VEP) techniques. VEP techniques are described in the context of an ongoing prospective longitudinal cohort study of infants exposed to organic solvents in utero. VEPs are recorded via three active electrodes fitted over the occipital cortex while infants view changing visual stimuli. The sweep VEP is used to assess contrast detection and visual acuity by presenting sinusoidal gratings that "sweep" across a range of contrasts and spatial frequencies. Transient VEPs are used to assess responses to equiluminant chromatic- and luminance-modulated sinusoidal gratings presented in pattern onset-offset format. A single case study is presented showing abnormal chromatic responses and reduced contrast sensitivity in a 2.5-year-old boy following prenatal exposure to perchloroethylene (PCE). These VEP techniques therefore appear promising for the clinical assessment of visual toxicity in pediatric populations.     

In utero exposure to antiepileptic drugs: Teratogenicity and neonatal morbidity

Clinical studies have extensively documented the various risks posed by in utero exposure to antiepileptic drugs (AEDs). However, it is difficult to sort out the extent to which any given AED is responsible for a particular outcome, given the disparities in patients taking the drugs, their type and severity of epilepsy, and the various possible AEDs, as well as the vast number of outcomes that could be assessed. This review focuses on AED exposure during pregnancy and how it affects the risks of neonatal morbidity and major congenital malformations.     

In utero exposure to vigabatrin: no indication of visual field loss

The purpose of the study was to determine whether in utero exposure to vigabatrin caused visual field loss.
  Three mothers with four children who had been exposed to vigabatrin in utero and who were subsequently formula fed were identified. All seven individuals underwent perimetry and imaging of the retinal nerve fiber layer (RNFL).
  All individuals yielded reliable outcomes to perimetry and RNFL images of acceptable quality. Two of the three mothers exhibited vigabatrin-attributed visual field loss and an abnormally attenuated RNFL. The third exhibited an upper left quadrantanopia, consistent with previous temporal lobe surgery, and a normal RNFL. All four children yielded normal visual fields and RNFL thicknesses.
  The presence of the normal findings for the children is reassuring and, if representative, suggests a lack of vigabatrin visual toxicity and therefore obviates the need for ophthalmological examination of those exposed to vigabatrin prenatally.     

Encephalomyeloradiculoneuropathy following exposure to an industrial solvent.

A 19-year-old male developed complaints including weakness of the lower extremities and right hand, numbness, dysphagia and urinary difficulties following a 2 month exposure to an industrial solvent constituted mainly of 1-bromopropane, but also containing butylene oxide, 1,3 dioxolane, nitromethane, and other components. Nerve conduction studies revealed evidence of a primary, symmetric demyelinating polyneuropathy. Evidence of CNS involvement came from gadolinium enhanced MRI scans of the brain, showing patchy areas of increased T2 signal in the periventricular white matter, similar scans of the spinal cord revealing root enhancement at several lumbar levels, and SSEP studies. The patient's symptoms had started to resolve following the discontinuation of the exposure, before he was lost to follow-up. Similar findings have been reported following 1-bromopropane exposure in rats. I hypothesize that this patient's symptoms may have been due to 1-bromopropane-induced neurotoxicity.     

Developmental PCB exposure increases susceptibility to audiogenic seizures in adulthood

Developmental exposure to polychlorinated biphenyls (PCBs) causes auditory deficits. Thus, we recently conducted a study to investigate if developmental PCB exposure would exacerbate noise-induced hearing loss in adulthood. Unexpectedly, some PCB-exposed rats exhibited seizure-like behaviors when exposed to loud noise. Therefore, we conducted the current experiment to determine if adult rats perinatally exposed to PCBs are more susceptible to audiogenic seizures when tested in a standard audiogenic seizure paradigm. Adult male and female rats exposed to PCBs during gestation and lactation (0, 1, 3 or 6 mg/kg/day) and previously tested in the noise-induced hearing loss study were presented with a 100 dB noise stimulus. If they did not exhibit clonus in response to the 100 dB noise, they were exposed to a 105 dB stimulus 24–48 h later. This was followed by an 110 dB stimulus 24–48 h later if they did not exhibit clonus at 105 dB. Female and male rats exposed to either 3 or 6 mg/kg PCBs exhibited a significantly higher incidence of audiogenic seizures, shorter latency to onset of seizures, and greater severity of seizures compared to controls. Thyroxine measured in littermates at weaning was significantly lower in all PCB groups compared to controls, suggesting a potential mechanism for the increased incidence of audiogenic seizures. This is the first study to show that developmental PCB exposure increases the susceptibility to audiogenic seizures in adulthood.     

Panic disorder precipitated by exposure to organic solvents in the work place

The authors describe three cases of idiosyncratic response to occupational solvent exposure, with symptoms characteristic of panic disorder (DSM-III). The specific treatment and prognostic implications of this panic-like reaction to solvents are discussed. Sodium lactate infusion is proposed as an objective test to aid in the diagnosis.