Altered cortical thickness following prenatal sodium valproate exposure

Prenatal exposure to sodium valproate (VPA) is associated with neurodevelopmental impairments. Cortical thickness was measured in 16 children exposed prenatally to VPA and 16 controls. We found increased left inferior frontal gyrus (IFG; BA45) and left pericalcarine sulcus (BA18) thickness, an association between VPA dose and right IFG thickness, and a close relationship between verbal skills and left IFG thickness. A significant interaction between group and hemispheric IFG thickness showed absence of the normal asymmetry in the IFG region of VPA-exposed children. These data provide preliminary insights into the putative neural basis of difficulties experienced by some VPA-exposed children

Cognitive and behavioural outcomes of school aged children exposed prenatally to antiepileptic drugs

Although antiepileptic drug (AED) use during pregnancy is common, our understanding of the longer term impact of prenatal AED exposure remains incomplete. Although most women with epilepsy give birth to healthy babies, some AEDs are known to increase the risk of birth defects and other abnormalities. Despite this, pharmacotherapy is typically continued throughout pregnancy because of the increased risk of complications due to recurrent seizures. Some AEDs appear to carry greater risk of negative cognitive or behavioural sequelae than others. Previous studies have suggested that, in particular, prenatal exposure to valproate or polytherapy may result in impaired Verbal IQ. This research aimed to improve our understanding of the nature of the intellectual deficits of children prenatally exposed to VPA and polytherapy. Verbal intellectual abilities, working memory, language and autistic traits were identified as factors that may contribute to children’s performance on measures of Verbal IQ. These factors were investigated through standardised assessment of a prospectively recruited cohort of AED-exposed children. The sample included 23 children exposed to valproate monotherapy, 15 to polytherapy with valproate and 19 to polytherapy without valproate. Results were consistent with previous findings that intellectual abilities, and particularly verbal intellectual abilities, are negatively affected by exposure to valproate and polytherapy. In addition, valproate exposure was associated with poorer performance on tests of language and working memory, and was also associated with elevated rates of autistic traits. There was evidence for a dose-response relationship, with higher valproate doses being associated with poorer outcomes. Analyses further suggested that intellectual abilities may be affected at lower doses than are required to cause major malformations. In comparison, polytherapy per se (i.e. once the effects of valproate were controlled for) appeared to have a relatively modest impact, with the predominant effects identified in this research being on higher level intellectual skills and processing speed. The risks associated with prenatal exposure to valproate and polytherapy need to be carefully considered when prescribing AEDs to women of childbearing age. Women with epilepsy should be advised of the potential risks that may accompany AED treatment during pregnancy, and exposed children should be monitored from birth into the school-aged years to enable early identification and intervention for at-risk children. In any decision to change drug or dose, the adverse consequences of AED exposure need to be weighed against the risks that may accompany inadequate seizure or disease control. The findings of this research may also be relevant to the growing number of women taking AEDs for conditions other than epilepsy, such as pain and psychiatric disorders. Further research is needed to better understand the effects of valproate and polytherapy, improve identification and intervention for at-risk children, and to explain the underlying mechanisms

Cognitive and behavioural outcomes of school aged children exposed prenatally to antiepileptic drugs

Although antiepileptic drug (AED) use during pregnancy is common, our understanding of the longer term impact of prenatal AED exposure remains incomplete. Although most women with epilepsy give birth to healthy babies, some AEDs are known to increase the risk of birth defects and other abnormalities. Despite this, pharmacotherapy is typically continued throughout pregnancy because of the increased risk of complications due to recurrent seizures. Some AEDs appear to carry greater risk of negative cognitive or behavioural sequelae than others. Previous studies have suggested that, in particular, prenatal exposure to valproate or polytherapy may result in impaired Verbal IQ. This research aimed to improve our understanding of the nature of the intellectual deficits of children prenatally exposed to VPA and polytherapy. Verbal intellectual abilities, working memory, language and autistic traits were identified as factors that may contribute to children’s performance on measures of Verbal IQ. These factors were investigated through standardised assessment of a prospectively recruited cohort of AED-exposed children. The sample included 23 children exposed to valproate monotherapy, 15 to polytherapy with valproate and 19 to polytherapy without valproate. Results were consistent with previous findings that intellectual abilities, and particularly verbal intellectual abilities, are negatively affected by exposure to valproate and polytherapy. In addition, valproate exposure was associated with poorer performance on tests of language and working memory, and was also associated with elevated rates of autistic traits. There was evidence for a dose-response relationship, with higher valproate doses being associated with poorer outcomes. Analyses further suggested that intellectual abilities may be affected at lower doses than are required to cause major malformations. In comparison, polytherapy per se (i.e. once the effects of valproate were controlled for) appeared to have a relatively modest impact, with the predominant effects identified in this research being on higher level intellectual skills and processing speed. The risks associated with prenatal exposure to valproate and polytherapy need to be carefully considered when prescribing AEDs to women of childbearing age. Women with epilepsy should be advised of the potential risks that may accompany AED treatment during pregnancy, and exposed children should be monitored from birth into the school-aged years to enable early identification and intervention for at-risk children. In any decision to change drug or dose, the adverse consequences of AED exposure need to be weighed against the risks that may accompany inadequate seizure or disease control. The findings of this research may also be relevant to the growing number of women taking AEDs for conditions other than epilepsy, such as pain and psychiatric disorders. Further research is needed to better understand the effects of valproate and polytherapy, improve identification and intervention for at-risk children, and to explain the underlying mechanisms

The Australian brain and cognition and antiepileptic drugs study: IQ in school-aged children exposed to sodium valproate and polytherapy

Prenatal exposure to sodium valproate (VPA) and polytherapy has been linked with increased risk of birth defects and cognitive impairment in young children. We evaluated the cognitive impact of prenatal exposure to VPA and polytherapy in school-aged children. Fifty-seven children exposed to VPA (n = 23), polytherapy with VPA (n = 15), or polytherapy without VPA (n = 19) were assessed using the Wechsler Intelligence Scale for Children-Fourth Edition. Information on maternal epilepsy, pregnancy, and medical history was obtained prospectively through the Australian Pregnancy Register for Women with Epilepsy and Allied Disorders. All groups had elevated frequencies of Extremely Low

Neurological consequences of diabetic ketoacidosis at initial presentation of type 1 diabetes in a prospective cohort study of children

OBJECTIVE To investigate the impact of new-onset diabetic ketoacidosis (DKA) during child- hood on brain morphology and function. RESEARCH DESIGN AND METHODS Patients aged 6–18 years with and without DKA at diagnosis were studied at four time points: <48 h, 5 days, 28 days, and 6 months postdiagnosis. Patients under- went magnetic resonance imaging (MRI) and spectroscopy with cognitive assess- ment at each time point. Relationships between clinical characteristics at presentation and MRI and neurologic outcomes were examined using multiple linear regression, repeated-measures, and ANCOVA analyses. RESULTS Thirty-six DKA and 59 non-DKA patients were recruited between 2004 and 2009. With DKA, cerebral white matter showed the greatest alterations with increased total white matter volume and higher mean diffusivity in the frontal, temporal, and parietal white matter. Total white matter volume decreased over the first 6 months. For gray matter in DKA patients, total volume was lower at baseline and increased over 6 months. Lower levels of N-acetylaspartate were noted at base- line in the frontal gray matter and basal ganglia. Mental state scores were lower at baseline and at 5 days. Of note, although changes in total and regional brain volumes over the first 5 days resolved, they were associated with poorer delayed memory recall and poorer sustained and divided attention at 6 months. Age at time of presentation and pH level were predictors of neuroimaging and functional outcomes. CONCLUSIONS DKA at type 1 diabetes diagnosis results in morphologic and functional brain changes. These changes are associated with adverse neurocognitive outcomes in the medium term

Neurobehavioral consequences of prenatal antiepileptic drug exposure

Despite elevated rates of birth defects associated with prenatal antiepileptic drug exposure, pharmacotherapy is typically continued throughout pregnancy because of the risks posed to mother and child by recurrent seizures. Emerging data suggest that prenatal exposure to valproate or polytherapy may also be associated with increased risk of cognitive impairment. However, our understanding of the longer-term sequelae of prenatal antiepileptic drug exposure remains incomplete. Improved understanding of the neurobehavioral consequences of prenatal antiepileptic drug exposure is essential to ensure accurate information is available for women with epilepsy planning a pregnancy, and to achieve optimal outcomes for mothers and children