Three core findings emerge from this investigation. First, the nature and range of neuroanatomic abnormalities in persons with mean childhood/adolescent onset TLE are extensive. They include the hippocampus as expected, but also extrahippocampal temporal lobe regions, diverse subcortical structures, cerebellum, brainstem, and extratemporal lobe gray and white matter. Second, age-related changes are evident for many of these anatomic structures and regions, with the pattern of age-trajectories largely comparable between the groups, with the epilepsy group always showing less volume and/or thickness with aging. Third, the primary exception to the above is age-accelerated expansion of the ventricular system (third and lateral ventricles) in the epilepsy participants.
Anatomic abnormalities in temporal lobe epilepsy
The TLE group exhibited abnormal (decreased) volumes of hippocampus, caudate, thalamus, cerebral white and gray matter, cerebellar white and gray matter, pallidum, and brainstem. Between-group differences in the amygdala and putamen volumes were not statistically significant. Regarding cortical regions, the TLE group exhibited smaller volumes of the lateral temporal, parietal, medial temporal, and frontal regions, but not occipital lobe or cingulate region. The total anatomic burden associated with this localization-related form of epilepsy is therefore notable and consistent with examinations of the anatomic consequences of early onset TLE in quantitative MRI investigations of prevalent cases (Sisodiya et al., 1997; Bernasconi et al., 2004; Mueller et al., 2006; Lin et al., 2007; Keller & Roberts, 2008; McDonald et al., 2008a,b,c; Hermann et al., 2009; Bonilha et al., 2010a,b; Li et al., 2012). The general breadth of abnormality detected here is notable for the mean age of the sample (approximately 35 years). Because these are patients with average childhood/adolescent onset of recurrent seizures, these findings infer a significant adverse neurodevelopmental effect on diverse brain structures. (Hermann et al., 2002a,b; Weber et al., 2007).
As expected, given previous published cross-sectional research in healthy populations (e.g., Pfefferbaum et al., 1994; Blatter et al., 1995; Toga et al., 2006; Sowell et al., 2007; Raz et al., 2010; Walhovd et al., 2011), advancing chronologic age was associated with volumetric reductions in healthy controls. In the cerebral cortex, volume decreased until around age 50 after which it plateaued. This relationship was inverted for cerebral white matter where volume increased until age 40 before declining slightly at older ages. Volumes declined with age in the hippocampus and cerebellum cortex, whereas linear declines were seen in the volumes of the caudate, putamen, pallidum, and thalamus, with linear increases with age in the lateral ventricle, inferior lateral ventricle, and third ventricles. Within the lobar regions, both the frontal and lateral temporal lobes revealed a quadratic relationship with age in which volume declined until age 50, after which there was little change. The natural log of age provided the best fit for the parietal, occipital, and cingulate regions, which all showed decreases with age. In each case, these declines were larger at young than at older ages. The volume of the medial temporal lobe decreased linearly with age.
Of interest, there were few interaction effects of the type that would imply that within the age range investigated the participants with epilepsy exhibited accelerated brain aging effects compared with healthy controls. Such effects were observed only in the lateral and third ventricles, and in these areas patients with epilepsy exhibited an accelerated age effect. There were no significant age accelerated findings for the patients with epilepsy in the remaining regions. Hence, brain aging effects appeared largely comparable for the two groups, with the participants with epilepsy showing significantly reduced volumes compared with controls across a wide range of anatomic areas at any age. The primary exception was the volumes of the ventricles (lateral and third but not fourth ventricle), which showed greater age-related expansion in the epilepsy group compared to the controls.
Abnormal expansion of the ventricular system has been observed in many neurologic and psychiatric disorders, including dementia (Carmichael et al., 2007), multiple sclerosis (Dalton et al., 2006), and autism spectrum disorder (Palmen et al., 2005). The natural history of ventricular enlargement and its consequences have been increasingly investigated and in some disorders, such as schizophrenia, enlargement is present early in the course of the disorder (Sowell et al., 2000; Vita et al., 2006) and progresses over time (Kempton et al., 2010). Ventricular volume has been studied closely in normal and abnormal aging (e.g., Carmichael et al., 2007; Carlson et al., 2008; Hua et al., 2008; Fjell et al., 2009; Chou et al., 2010), and although expansion of the lateral, inferior lateral, and third ventricles is observed in normal aging (Fjell et al., 2009), age-accelerated ventricular expansion has been shown to be predictive of conversion from normal cognition to mild cognitive impairment 2 years later (Carlson et al., 2008; Weiner, 2008), as well as a precursor of dementia and its course (Carmichael et al., 2007a,b; Nestor et al., 2008; Driscoll et al., 2009). Current work has suggested that accelerated ventricular expansion may serve as a biomarker not only of incipient dementing disorders given its ability to predict changes (declines) in cognition and memory, but to predict clinical ratings of functional status as well (e.g., Chou et al., 2010). Although we suggest caution given the cross-sectional nature of our investigation, we have also found lateral and third ventricular volume to expand to a significantly greater degree than controls over a prospective 4-year test–retest interval (Tuchscherer et al., 2010). Monitoring ventricular volume and associated prospective changes in cognition may be an informative task for the future, especially in an older cohort of subjects.
Lastly, the cumulative anatomic abnormality reflected in Tables 2 and 3 and Figs. 1 and 2 is increasingly appreciated (Blanc et al., 2011; Engel & Thompson, 2012), consistent with neuropsychological evidence (Oyegbile et al., 2004), painting a picture of considerable neurobiologic abnormality that continues apace with increasing chronologic age. The outer limit of our sample is 60 years of age and distant from the point where traditional neurodegenerative disorders begin to appear. How these subjects fare with increasing chronologic age with this neuroanatomic profile would seem to be an important issue.