This is the first investigation to use surface based 3-D cortical morphometry to examine the relationship between age and morphometric measures in children with CPS of varying intellectual levels. Normal cerebral maturation from early childhood to adolescence involves cortical thickening and thinning accompanied by an increase in white matter volume and myelination (Reiss, et al. 1996
; Shaw, et al. 2006
). However, our cross-sectional findings identified significant differences in the association of age with cortical thickness in the healthy control group compared to the Average+ IQ CPS and Below average IQ CPS groups, as well as between these two epilepsy subgroups. Unlike the age-related bilateral thinning in the frontal and parietal cortex and in the right temporal cortex of the healthy controls, the Average+ IQ CPS patients demonstrated significantly thicker cortex with age in left language-related cortex (middle frontal, pars triangularis, pars orbitalis), motor (inferior precentral), posterior cingulate, as well as right medial superior frontal cortex. In contrast, Average+ IQ CPS subgroup also showed significantly greater cortical thinning with age than the control group in both the left paracentral and right medial superior frontal regions. The Below average IQ CPS group had significantly thicker cortex with older age than the normal group that was involving the left fronto-temporal (middle orbital frontal, rostral middle frontal, inferior temporal, fusiform) and left lateral occipital cortices, as well as in the right fusiform cortex. However, this epilepsy subgroup also showed significantly greater cortical thinning with age than the control group widespread in both the left (precentral, caudal middle frontal, parahippocampal cortices) and right hemispheres (rostral middle frontal, inferior aspects of post-central, superior aspects of pre-central, superior parietal, and precuneus cortices).
Thus, the predicted (Shaw et al., 2006
; Shaw et al., 2008
) age related cortical thinning particularly in the frontal lobe (-) of the control group was locally disturbed in both CPS subgroups. Specifically, Average+ IQ CPS group shows thickening or less cortical thinning with age locally in the left middle frontal and pars triangularis and pars orbitalis regions. In contrast, Below average IQ CPS group consistently shows localized greater cortical thinning with age in both left and right frontal. These findings are similar to volumetric and VBM findings in children with chronic epilepsy and with new onset epilepsy, respectively, in which the epilepsy and control groups had different age and IQ relationships with brain volumes (Caplan et al., 2010
; Daley et al., 2007
; Hermann et al., 2006
; Keller and Roberts, 2008
). The review of the VBM literature in (Keller and Roberts, 2008
) summarizes the widespread abnormalities noted in the temporal and extratemporal lobe both ipsilateral as well as contralateral to the side of seizure onset, including hippocampus, thalamus and cerebellum in temporal lobe epilepsy.
The importance of IQ in children with epilepsy is further emphasized by the role of IQ rather than seizure variables in the cognitive, linguistic, and psychiatric comorbidities (see review in (Caplan, 2010
)) as well as the quality of life of these children and their parents (Bower et al., under review). Although cross-sectional studies find a relationship between IQ and seizure variables, this is not the case in follow-up studies of children with new onset and chronic epilepsy (see review in (Caplan, 2010
)). Furthermore, these prospective studies show no change over time in the mean IQ scores of children with epilepsy. The morphometric findings of the current study, showing a lack of a relationship with clinical seizure variables in the context of differential patterns of widespread thickening and thinning in the Below Average IQ versus Average IQ CPS therefore, while the finding may infer that IQ could be an epiphenomenon of the extent of the underlying neuropathology and effects on brain development in epilepsy, the cross-sectional nature of our investigation cannot infer causality of this sort. A prospective study would prove more definitive in this regard. This explanation is supported by the consistent trajectory of the neurobehavioral findings in children with cognitive, linguistic, learning, and behavior problems before the onset of epilepsy and those without these comorbidities two and four years after the onset of seizures that are related to IQ irrespective of seizure control (Hermann et al., 2008
; Oostrom et al., 2005
Different relationships between age and cortical thickness in the CPS subgroups encompassing the left and right hemisphere including regions involved in language, executive function, social behavior, and regulation of emotions are in line with evidence for linguistic (Caplan et al., 2010
) and executive function deficits (Hermann and Jones, 2006
), as well as behavior, emotional, and social problems in children with epilepsy with normal range of cognition (see reviews in (Austin and Caplan, 2007
; Drewel and Caplan, 2007
Although CPS is considered as a localization-related epilepsy, our morphometric findings clearly demonstrate widespread involvement of the cortex. Whereas prior volumetric studies demonstrated reduced gray matter volumes in the orbital frontal gyrus and larger white matter temporal lobe volumes (Caplan et al., 2010
; Caplan et al., 2009
) applications of surface based 3-D cortical morphometry identifies a more widespread abnormality, which is in keeping with the marked neurobehavioral morbidity found in pediatric CPS. These finding are particularly striking given similar thinning involving the frontal, temporal, temporo-occipital regions in both hemispheres of surgically treated adult temporal lobe epilepsy patients with CPS and focal temporal epileptic activity on EEG particularly related to longer duration of illness and childhood onset (Bernhardt et al., 2008
Study limitations include the study’s cross sectional design, heterogeneous localization of epileptic activity, inclusion of study subjects with new onset and chronic epilepsy recruited at two different centers and tested on scanners, as well as the wide age range and relatively small sample size of the study’s subjects. Prospective studies are needed to further investigate how epilepsy impacts brain development over time in terms of effects of on-going seizures (e.g., frequency, focal or generalized, localization of epileptic activity), the illness, or a combined effect of seizure control and having epilepsy. In terms of the heterogeneity of the study sample, neurobehavioral studies of large samples of children with new onset and chronic epilepsy demonstrate similar neurobehavioral findings (see review in (Caplan et al., 2010
)). In addition, as described in the data analysis section, we controlled for scanner differences in these analyses. Our findings are limited by the wide age range of the children in the study because of the normal age related thinning of gray matter in different brain regions. A conceptual limitation relates to the selection of a surface-based analysis to study the cortical thickness. Although, surface-based registration provides generally better spatial normalization of cortical data, the price one pays is the restriction of the analysis to cortical regions. In contrast, a voxel-based approach provides insight into subcortical developmental differences, but generally at the expense of less accurate cortical registrations. Restriction to linear, time-invariant association between cortical morphometry and age is an additional technical limitation of our study. This is likely a gross simplification because thickening and thinning of cortical tissue may be a compounding and dynamic process, which varies during neurodevelopment. Therefore, models with nonlinear cortical morphometry – age characteristics might lead to different results; however, such models are not always robust, given the limited number of cross-sectional MRI measurements and they also require careful validation. Finally, the cognitive measure of interest was Full Scale IQ—clearly a marker of ability that is a synthesis of many component intellectual processes. The fact that these interesting relationships were obtained using what some might view as a global cognitive indicator certainly underscores that examination of pure cognitive abilities would be of interest. Finally, further studies need to be pursued to better understand the age-gender interaction on cortical morphometry and how it differs among the Average+ IQ Controls, Average+ IQ CPS, and Below average IQ CPS groups.
In conclusion, this first morphometric study of the relationship between cortical thickness and age in children with epilepsy with average+ IQ and below average IQ demonstrated different patterns compared to healthy control subjects and in the two epilepsy groups. Prospective studies are needed to determine if these findings reflect aberrant or delayed developmental trajectories related to the etiology of the disorder, on going seizures, treatment, or a combination of these or other factors on brain development.