Marta García-Fiñana

The prevalence of neurodevelopmental disorders in children prenatally exposed to antiepileptic drugs

The aim of this study was to compare the prevalence of diagnosed neurodevelopmental disorders in children exposed, in utero, to different antiepileptic drug treatments. A prospective cohort of women with epilepsy and a control group of women without epilepsy were recruited from antenatal clinics. The children of this cohort were followed longitudinally until 6 years of age (n=415). Diagnosis of a neurodevelopmental disorder was made independently of the research team. Multiple logistic regression analysis revealed an increase in risk of neurodevelopmental disorders in children exposed to monotherapy sodium valproate (VPA) (6/50, 12.0%; aOR 6.05, 95%CI 1.65 to 24.53, p=0.007) and in those exposed to polytherapy with sodium VPA (3/20, 15.0%; aOR 9.97, 95% CI 1.82 to 49.40, p=0.005) compared with control children (4/214; 1.87%). Autistic spectrum disorder was the most frequent diagnosis. No significant increase was found among children exposed to carbamazepine (1/50) or lamotrigine (2/30). An accumulation of evidence demonstrates that the risks associated with prenatal sodium VPA exposure include an increased prevalence of neurodevelopmental disorders. Whether such disorders are discrete or represent the severe end of a continuum of altered neurodevelopmental functioning requires further investigation. Replication and extension of this research is required to investigate the mechanism(s) underpinning the relationship. Finally, the increased likelihood of neurodevelopmental disorders should be communicated to women for whom sodium VPA is a treatment option.

IQ at 6 years after in utero exposure to antiepileptic drugs A controlled cohort study

Objective: To delineate the risk to child IQ associated with frequently prescribed antiepileptic drugs. Methods: Children born to women with epilepsy (n = 243) and women without epilepsy (n = 287) were recruited during pregnancy and followed prospectively. Of these, 408 were blindly assessed at 6 years of age. Maternal and child demographics were collected and entered into statistical models. Results: The adjusted mean IQ was 9.7 points lower (95% confidence interval [CI] −4.9 to −14.6; p < 0.001) for children exposed to high-dose (>800 mg daily) valproate, with a similar significant effect observed for the verbal, nonverbal, and spatial subscales. Children exposed to high-dose valproate had an 8-fold increased need of educational intervention relative to control children (adjusted relative risk, 95% CI 8.0, 2.5–19.7; p < 0.001). Valproate at doses <800 mg daily was not associated with reduced IQ, but was associated with impaired verbal abilities (−5.6, 95% CI −11.1 to −0.1; p = 0.04) and a 6-fold increase in educational intervention (95% CI 1.4–18.0; p = 0.01). In utero exposure to carbamazepine or lamotrigine did not have a significant effect on IQ, but carbamazepine was associated with reduced verbal abilities (−4.2, 95% CI −0.6 to −7.8; p = 0.02) and increased frequency of IQ <85. Conclusions: Consistent with data from younger cohorts, school-aged children exposed to valproate at maternal doses more than 800 mg daily continue to experience significantly poorer cognitive development than control children or children exposed to lamotrigine and carbamazepine.

Orbital prefrontal cortex volume correlates with social cognitive competence

Intentionality, or Theory of Mind, is the ability to explain and predict the behaviour of others by attributing to them intentions and mental states and is hypothesised to be one of several social cognitive mechanisms which have impacted upon brain size evolution. Though the brain activity associated with processing this type of information has been studied extensively, the neuroanatomical correlates of these abilities, e.g. whether subjects who perform better have greater volume of associated brain regions, remain to be investigated. Because social abilities of this type appear to have evolved relatively recently, and because the prefrontal cortex (PFC) was the last brain region to develop both phylogenetically and ontogenetically, we hypothesised a relationship between PFC volume and intentional competence. To test this, we estimated the volume of four regional prefrontal subfields in each cerebral hemisphere, in 40 healthy adult humans by applying stereological methods on T(1)-weighted magnetic resonance images. Our results reveal a significant linear relationship between intentionality score and volume of orbital PFC (p=0.01). Since this region is known to be involved in the processing of social information our findings support the hypothesis that brain size evolution is, at least in part, the result of social cognitive mechanisms supporting social cohesion.

Sulcal variability, stereological measurement and asymmetry of Broca's area on MR images.

Leftward volume asymmetry of the pars opercularis and pars triangularis may exist in the human brain, frequently referred to as Brocas area, given the functional asymmetries observed in this region with regard to language expression. However, post‐mortem and magnetic resonance imaging (MRI) studies have failed to consistently identify such a volumetric asymmetry. In the present study, an analysis of the asymmetry of sulco‐gyral anatomy and volume of this anterior speech region was performed in combination with an analysis of the morphology and volume asymmetry of the planum temporale, located within the posterior speech region, in 50 healthy subjects using MRI. Variations in sulcal anatomy were documented according to strict classification schemes and volume estimation of the grey matter within the brain structures was performed using the Cavalieri method of stereology. Results indicated great variation in the morphology of and connectivity between the inferior frontal, inferior precentral and diagonal sulci. There were significant inter‐hemispheric differences in the presence of (1) the diagonal sulcus within the pars opercularis, and (2) horizontal termination of the posterior Sylvian fissure (relative to upward oblique termination), both with an increased leftward incidence. Double parallel inferior precentral sulci and absent anterior rami of the Sylvian fissure prevented stereological measurements in five subjects. Therefore volumes were obtained from 45 subjects. There was a significant leftward volume asymmetry of the pars opercularis (P = 0.02), which was significantly related to the asymmetrical presence of the diagonal sulcus (P < 0.01). Group‐wise pars opercularis volume asymmetry did not exist when a diagonal sulcus was present in both or neither hemispheres. There was no significant volume asymmetry of the pars triangularis. There was a significant leftward volume asymmetry of the planum temporale (P < 0.001), which was significantly associated with the shape of the posterior Sylvian fissure as a unilateral right or left upward oblique termination was always associated with leftward or rightward volume asymmetry respectively (P < 0.01). There was no relationship between volume asymmetries of the anterior and posterior speech regions. Our findings illustrate the extent of morphological variability of the anterior speech region and demonstrate the difficulties encountered when determining volumetric asymmetries of the inferior frontal gyrus, particularly when sulci are discontinuous, absent or bifid. When the intrasulcal grey matter of this region is exhaustively sampled according to strict anatomical landmarks, the volume of the pars opercularis is leftward asymmetrical. This manuscript illustrates the importance of simultaneous consideration of brain morphology and morphometry in studies of cerebral asymmetry.

In utero exposure to levetiracetam vs valproate Development and language at 3 years of age

Objective: To compare the cognitive and language development of children born to women with epilepsy (WWE) exposed in utero to levetiracetam (LEV) or sodium valproate (VPA) and control children born to women without epilepsy not taking medication during pregnancy. Methods: The children, aged between 36 and 54 months, were recruited from the United Kingdom and assessed using the Griffiths Mental Development Scales and the Reynell Language Development Scale. Maternal demographic and epilepsy information was also collected for use in statistical regression. This is an observational study with researchers not involved in the clinical management of the mothers enrolled. Results: After controlling for confounding variables, children exposed to LEV in utero (n = 53) did not differ from unexposed control children (n = 131) on any scale administered. Children exposed to VPA (n = 44) in utero scored, on average, 15.8 points below children exposed to LEV on measures of gross motor skills (95% confidence interval [CI] −24.5 to −7.1, p < 0.001), 6.4 points below on comprehension language abilities (95% CI −11.0 to −1.8, p = 0.005), and 9.5 points below on expressive language abilities (95% CI −14.7 to −4.4, p < 0.001). Conclusion: The current study indicates that children exposed to LEV in utero were superior in their language and motor development in comparison to children exposed to VPA. This information should be used collaboratively between health care professionals and WWE when deciding on womens preferred choice of antiepileptic drug.

Estimation of body composition in muscular dystrophy by MRI and stereology

We have applied the Cavalieri method of modern design stereology with magnetic resonance imaging for estimating the volume of whole‐body muscle and fat compartments in four patients with muscular dystrophy, a patient with myopathy, five controls, an anorexic subject, and a body builder. Detailed systematic series (ie, 50) of axial MR images (T1‐weighted, TR/TE 400/10 msec) were obtained throughout the whole body of each subject. The results showed that 15, 20, and 35 axial sections through the body are sufficient to secure coefficients of error (CEs) on the estimates of total muscle and fat volume of around 10%, 5%, and 3% respectively in muscular dystrophy patients and controls. The mean normalized volumes of muscle in four muscular dystrophy patients were decreased by 27% (t‐test: P < 0.05), and those of total fat were increased by 12% (t‐test: P > 0.05) relative to controls. The Cavalieri method provides a direct, efficient, and mathematically unbiased approach for studying human body compartments and may have application in assessing treatment efficacy in patients with muscular dystrophy. J. Magn. Reson. Imaging 2000;12:467–475.

Can the language-dominant hemisphere be predicted by brain anatomy?

It has long been suspected that cortical interhemispheric asymmetries may underlie hemispheric language dominance (HLD). To test this hypothesis, we determined interhemispheric asymmetries using stereology and MRI of three cortical regions hypothesized to be related to HLD (Brocas area, planum temporale, and insula) in healthy adults in whom HLD was determined using functional transcranial Doppler sonography and functional MRI (15 left HLD, 10 right HLD). We observed no relationship between volume asymmetry of the gyral correlates of Brocas area or planum temporale and HLD. However, we observed a robust relationship between volume asymmetry of the insula and HLD (p = .008), which predicted unilateral HLD in 88% individuals (86.7% left HDL and 90% right HLD). There was also a subtle but significant positive correlation between the extent of HLD and insula volume asymmetry (p = .02), indicating that a larger insula predicted functional lateralization to the same hemispheric side for the majority of subjects. We found no visual evidence of basic anatomical markers of HLD other than that the termination of the right posterior sylvian fissure was more likely to be vertical than horizontal in right HLD subjects (p = .02). Predicting HLD by virtue of gross brain anatomy is complicated by interindividual variability in sulcal contours, and the possibility remains that morphological and cytoarchitectural organization of the classical language regions may underlie HLD when analyses are not constrained by the natural limits imposed by measurement of gyral volume. Although the anatomical correlates of HLD will most likely be found to include complex intra- and interhemispheric connections, there is the possibility that such connectivity may correlate with gray matter morphology. We suggest that the potential significance of insular morphology should be considered in future studies addressing the anatomical correlates of human language lateralization.

Volume estimation of prefrontal cortical subfields using MRI and stereology

The objective of this protocol was to provide a rapid, neurofunctionally relevant alternative to region-drawing or automated gyral/sulcal-based techniques. The Cavalieri method and point counting [e.g. Br. J. Radiol. 73 (2000) 679] were used in conjunction with a previously established parcellation methodology [Arch. Gen. Psychiatry 57 (2000) 761] to estimate the volumes of anatomically defined subfields of the prefrontal cortex (PFC) based on landmarks visible on T(1)-weighted magnetic resonance (MR) images. Ten participants (n=5 healthy adults; n=5 patients) were studied. Regional PFC volume estimates derived from point counting methods were reproducible between raters (Intraclass Correlations (ICC)=0.92-0.95) and repeatable within rater (ICC=0.93-0.99). Predicted coefficients of error for individual volume estimates were less than 5%. This protocol provides an efficient means of calculating unbiased volume estimates of the PFC with predictable precision for use in both cognitive and clinical studies.

Improved variance prediction for systematic sampling on ℝ

Many problems, in stereology and elsewhere (geometric sampling, calculus, etc.) reduce to estimating the integral Q of a non-random measurement function f over a bounded support on ℝ. The unbiased estimator Qˆ based on systematic sampling of period T > 0 (such as the popular Cavalieri estimator) is usually convenient and highly precise. The purpose of this paper is twofold. First, to obtain a new, general representation of var(Qˆ) in terms of the smoothness properties of f. We extend the current theory, which holds for smoothness constant q ∈ ℕ, to any q ≥ 0; to this end we develop a new version of the Euler–MacLaurin summation formula, making use of fractional calculus. Our second purpose is to apply the mentioned representation to obtain a new variance estimator for any q ≥ 0; we concentrate on the useful case q ∈ [0, 1]. By means of synthetic data, and real data from a human brain, we show that the new estimator performs better than its current alternatives. *Current address: Centre for Medical Statistics and Health Evaluation, University of Liverpool, Brownlow Street, Liverpool L69 3GS, UK

New approximations for the variance in Cavalieri sampling

The theory of Cavalieri sampling − or systematic sampling along an axis − has received a recent impetus. The error variance may be represented by the sum of three components, namely the extension term, the ‘Zitterbewegung’, and higher order terms. The extension term can be estimated from the data, and it constitutes the standard variance approximation used so far. The Zitterbewegung oscillates about zero, and neither this nor higher order terms have hitherto been considered to predict the variance. The extension term is always a good approximation of the variance when the number of observations is very large, but not necessarily when this number is small. In this paper we propose a more general representation of the variance, and from it we construct a flexible extension term which approximates the variance satisfactorily for an arbitrary number of observations. Furthermore, we generalize the current connection between the smoothness properties of the measurement function (e.g. the section area function of an object when the target is the volume) and the corresponding properties of its covariogram to facilitate the computation of the new variance approximations; this enables us to interpret the behaviour of the variance from the ‘overall shape’ of the measurement function. Our approach applies mainly to measurement functions whose form is known analytically, but it helps also to understand the behaviour of the variance when the measurement function is known at sufficiently many points; in fact, we illustrate the concepts with both synthetic and real data.