Dr Widjaja is a neuroradiologist interested in studying how epilepsy impacts the developing brain.
Developmental differences in structure and function have been reported along the longitudinal axis of the hippocampus.[1-3] A previous study indicated that the total volume of the hippocampus is unchanged from age 4–25 years; however, the posterior hippocampal volume decreases and the anterior hippocampal volume increases over time. A functional magnetic resonance imaging (fMRI) study showed that activity in the anterior hippocampus was associated with episodic retrieval in adults; in contrast, activity in the posterior hippocampus rather than the anterior hippocampus was associated with episodic retrieval in children.
Volume reduction in the hippocampus has been demonstrated in pediatric localization-related epilepsy, including mesial temporal lobe epilepsy (TLE) and extratemporal lobe epilepsy.[4-11] However, most of these studies have evaluated the whole hippocampus rather than subregions of the hippocampus. For the purpose of this study, the term “hippocampal subregions” was used to refer to hippocampal division to hippocampal head (HH), body (HB), and tail (HT), and not to subfields of the cornu ammonis (CA1, CA2, CA3, and CA4). Because developmental differences occur along the longitudinal axis of the hippocampus, vulnerability to seizure-related changes may also differ along the axis of the hippocampus in childhood epilepsy. Several studies of adult patients with mesial TLE have reported greater atrophy in subregions of the hippocampus.[12-14] The aims of this study were to determine if there were volumetric differences in hippocampal subregions (HH, HB, HT, and total hippocampus [TotH]) in children with nonlesional localization-related epilepsy (overall epilepsy group) relative to controls, and to examine for potential relations between the volume of subregions and performance on episodic memory tasks as well as clinical parameters. The secondary aims of this study were to determine if there were volumetric differences in hippocampal subregions in subgroups with frontal lobe epilepsy (FLE) and TLE relative to controls, and the relations between volume of hippocampal subregions and episodic memory tasks as well as clinical parameters in these subgroups.
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We have found that children with nonlesional localization-related epilepsy have reduced hippocampal volume, affecting HH, HB, HT, and TotH. However, we did not identify a gradient in volume reduction along the hippocampal axis. The hippocampal volume reduction was detected not only in children with TLE, but also in children with seizures remote from the hippocampus, including FLE. The reduction in left HH volume was significantly associated with reduced verbal memory in left lateralized epilepsy. There was no significant association between the volume of hippocampal subregions and clinical parameters.
Volumetric studies of the hippocampus in adults with mesial TLE have shown ipsilateral and in some cases contralateral hippocampal volume reduction.[14, 23-25] However, there is no consensus on whether regional reduction in hippocampal volume occurs. Quigg et al. found that overall volume loss in hippocampal sclerosis is diffuse, neither favoring the head nor body-tail. Bernasconi et al. found the HH was more atrophic than the HB and HT in patients with mesial TLE. Others have found greater atrophy in the HB than in the HH or HT[12, 13] in patients with mesial TLE.
Most studies on pediatric epilepsies have assessed the whole hippocampus rather than subregions of the hippocampus.[4-11] Previous studies have reported that children with localization-related epilepsy have unilateral or bilateral hippocampal atrophy. The reduction in hippocampal volume varied from 10% to 31%.[5, 6, 10] One study assessed subregions of the hippocampus in 19 children with complex partial seizures and showed a significant reduction in the anterior hippocampal volume, and a trend for smaller posterior hippocampal volume, with a reduction of 21.7% in TotH volume, 51.5% in anterior, and 11.8% in posterior hippocampal volume. The lack of a statistically significant reduction in posterior hippocampal volume may have been due to the relatively small sample size. We have found that the reduction in TotH volume varied from 7.5 to 10.2%, which was within the range of volume loss described in the literature. However, the reduction in HH (9.4–15.8%) was less than the reduction in anterior hippocampal volume reported by Daley et al.
We have assessed children with localization-related epilepsy and did not find a gradient in the severity of volume reduction along the hippocampal axis. Failure to identify regional differences along the hippocampal axis may be due to several reasons. First, we have used HH, HB, and HT to define the hippocampal subregions, which may not be differentially susceptible to seizure-related injury. Volumetric changes have been identified in different subfields of the cornu ammonis and dentate gyrus in adults with TLE with and without hippocampal sclerosis. Future study assessing volumetric changes within subfields of the cornu ammonis and dentate gyrus may shed light on the regions that are more susceptible to seizure-related injury in children with epilepsy. Second, volumetric measurement may not be sufficiently sensitive to identify subtle differences in hippocampal subregions. Further study using alternative technique such as shape analysis may uncover more subtle differences in hippocampal subregions. There were more subregions of the hippocampus that demonstrated volume reduction in left lateralized epilepsy than in right lateralized epilepsy, as well as in left FLE than right FLE. There were also several subregions that demonstrated volume reduction in left TLE, but not right TLE. The smaller number of patients in the right TLE subgroup may have confounded the findings, resulting in failure to detect volume changes in this subgroup. The greater number of subregions demonstrating volume reduction in left-sided epilepsy may be related to the involvement of the dominant hemisphere or different networks in left-sided epilepsy relative to right-sided epilepsy.
Previous study of children and young adults with seizures remote from the hippocampus has shown prolongation of T2 relaxation time in the hippocampus. We have found hippocampal volume reduction in children with focal seizures remote from the hippocampus. Together, these findings suggest that there is a network between the remote epileptogenic zone and hippocampus that facilitates spread of seizures to the hippocampus, thereby resulting in injury to the hippocampus. Histology from patients with extrahippocampal seizures has shown neuronal loss in the hippocampus.[29-31] The reduction in hippocampal volume in children with extrahippocampal seizures in our study may be secondary to neuronal loss from seizures. We did not detect a significant association between TotH or hippocampal subregions with age, age at seizure onset, and seizure frequency. The reason for this lack of significant association between hippocampal volume and clinical parameters was not apparent. Eroglu et al. also did not identify an association between hippocampal volume and age at seizure onset and duration of epilepsy, despite a reduction in corrected TotH volume. Similarly, Daley et al. did not detect an association between anterior hippocampal volume with age at seizure onset, duration of epilepsy, seizure frequency, and number of antiepileptic medications; the TotH and posterior hippocampal volume was associated with duration of epilepsy, but not with the other clinical parameters.
Despite the lack of significant differences in verbal and nonverbal memory in children with left and right lateralized epilepsy relative to controls, we found mild volume reduction in subregions of the hippocampus that was detected by quantitative measures but was not apparent on visual inspection. There may be a threshold volume loss before significant impairment in verbal or nonverbal memory is manifested. We found a significant association between reduced left HH volume with reduced verbal memory in left lateralized epilepsy. Previous studies have shown that greater HH volume was associated with higher delayed recall test scores in nondemented elderly subjects and elevated diffusivity in the left HH was significantly associated with verbal episodic memory impairment in early Alzheimer's disease. These data suggest that the left HH may play a greater role in verbal memory function than the rest of the hippocampus, both in children and adults. There was one prior study in children with TLE showing a correlation between left hippocampal volume and word recall, but paradoxically, the association was negative; there was no relation between story recall or visual memory with left or right hippocampal volume.
There are several limitations to this study. We have defined the epileptogenic zone noninvasively using seizure semiology, video-EEG, magnetoencephalography, and FDG-PET scan. It is possible that in some patients with FLE, the epileptogenic zone may have been more extensive and involved the temporal lobe as well. Due to the relatively small number of TLE patients, we have not categorized these patients to mesial TLE and neocortical TLE. Patients with mesial TLE may have greater volume reduction in the hippocampus relative to those with neocortical TLE.
We have used automated segmentation of the hippocampus. Manual segmentation of the hippocampus is more sensitive in detecting hippocampal atrophy than automated segmentation,[34-36] but it is time-consuming and prone to operator error. Automated segmentation of the hippocampus has the potential to provide rapid and accurate assessment of the hippocampal volume, and has been shown to be sensitive at detecting hippocampal atrophy.[34, 36-39] Automated segmentation using FreeSurfer has shown good correlation with expert manual segmentation (correlations ranging from 0.61 to 0.84).[34, 36, 39]
We have found hippocampal volume reduction in children with seizures remote from the hippocampus, suggesting that there may be an abnormal network that facilitates spread of seizures from the remote epileptogenic zone to the hippocampus, resulting in injury to the hippocampus. However, there was no gradient in the severity of volume reduction along the hippocampal axis. Further study evaluating the cornu ammonis subfields and dentate gyrus volume may shed light on the regions that are more susceptible to seizure-related injury. We have found a significant association between reduced left HH volume with reduced verbal memory in left lateralized epilepsy, suggesting that the left HH may play a greater role in verbal episodic memory than the remaining hippocampus. Longitudinal studies of adult patients with TLE have shown a decline in hippocampal volume with continuing seizures[40, 41] and cessation of seizures was associated with arrest in hippocampal volume loss. Longitudinal study is needed to clarify whether there is a differential rate of volume reduction along the axis of the hippocampus, in the cornu ammonis subfields and dentate gyrus in children with continuing seizures.