Histologically Confirmed Hippocampal Structural Features Revealed by 3T MR Imaging: Potential to Increase Diagnostic Specificity of Mesial Temporal Sclerosis

Discussion

Epilepsy is prevalent in 0.6% of the population, and poorly controlled by medications in almost 30% of these patients.¹⁴ In appropriate surgical candidates, there is an approximately 80% chance of being seizure-free at 1 year postoperatively, with outcomes being influenced by several factors including preoperative hippocampal sclerosis and seizure localized to the anterior temporal lobe.¹⁵ Patient selection, therefore, requires an interdisciplinary approach with multiple assessment modalities. Visual (ie, qualitative) analysis identifying hippocampal atrophy (surrogate for the pathologic diagnosis of MTS) on radiographic imaging remains a cornerstone of this process. While methodologies exist to perform quantitative analysis (eg, volumetry and T2 relaxometry, reviewed by Knowlton¹⁶), there is no universal acceptance of their use due to concerns over lengthy operator time and significantly variable software programs. It is promising that with the advent of new imaging modalities, such as 3T MR imaging, previously unrecognized ultrastructural details may provide new means of assessing patients with temporal lobe epilepsy for radiologic evidence of MTS. In this study, we applied a previously reported fast quantitative analysis method derived from an anatomic detail unique to 3T MR imaging as a means to identify MTS, highlighting the potential utility of this tool. Furthermore, we identified this new landmark as the stratum lacunosum and provided a pathophysiologic correlate for the structural differences detected by our measurement tool through ex vivo imaging and histopathologic analysis showing neuronal loss and gliosis.

Our application of a fast quantitative analysis tool to confirmed cases of MTS supports the work of Bhuta et al,⁸ in which select measurements at the head of the hippocampus by using landmarks seen on 3T MR imaging were used to identify atrophy. Here we determined that patients with MTS have significantly diminished hippocampal tissue height at the superior, inferior, and lateral margins, regions bordered by a band of low-intensity signal on coronal FSTIR sequences. This observation was even more robust when comparison of the cumulative values was made. We subsequently defined a threshold measurement of ≤3.3 mm (1 SD below the cumulative mean), which identified MTS with an SN and SP of 70% and 85%, respectively. While Bhuta et al similarly identified 3.4 mm as a threshold measurement, the SN and SP of their test differed (SN 64% and SP 96%). Selection of control measurements may account for the variation between these 2 studies because we had an internal control using the contralateral hippocampus, while the earlier study compared MTS measurements with age-matched healthy controls from non-temporal lobe disease studies. It is difficult to determine if 1 type of control has greater value because the contralateral measurement can help lateralize a disease process that may be bilateral,¹⁷ while age-matched healthy individuals provide a measure against which absolute disease thresholds can be set. Future studies could address this issue by directly comparing measurements of age-matched healthy individuals with those acquired in this study.

Implementing a universally accepted quantitative analysis tool has been difficult to date. The tool described in this study has limitations as well. The use of 1 SD in generating a threshold measurement represents a value that optimized test utility because extending the range of normal measurements (eg, 2 SDs) significantly increased the false-negatives, thereby affecting SN. Given that these measurements are quantifying a sclerotic process in terms of millimeters of lost tissue height and that bilateral disease may be present, the use of a more stringent threshold value seems fitting. Moreover, our tool will not replace visual analysis as a single mode of assessment without further improvement, given that visual analysis has a test SN and SP of 86% and 83%, respectively.¹⁸ It may, however, enable more novice radiologists or indeterminate imaging to benefit from additional but time-efficient evaluation.

To characterize the low-intensity signal-landmark and correlate altered hippocampal measurements with a pathophysiologic process, we scanned and analyzed a small subset of surgical en bloc resections obtained during a 5-month period, for regions of neuronal loss and gliosis. With the exception of all 5 patients being female (random occurrence), patient demographics were comparable and all patients were seizure-free at 1 year postoperatively. Similar to the in situ preoperative imaging, a white matter tract was consistently identified on ex vivo scans as a low-intensity signal band, which we subsequently identified as the stratum lacunosum through overlay analysis (Figs 1 and 4). Determining the histopathologic correlates of neuroimaging has become increasingly necessary as newly visualized radiologic features are used for diagnostics. It has been shown that T2 relaxation time is negatively correlated with neuronal loss (decreased NeuN staining) in gray matter but not in white matter tracts by using 1.5T MR imaging.¹⁹

Using 3T MR imaging, Eriksson et al⁴ analyzed T2-weighted images from patients with hippocampal sclerosis with a sequence designed to reduce head motion artifact (periodically rotated overlapping parallel lines with enhanced reconstruction) and correlated a band of myelinated tissue (seen as the band of low-intensity signal) with the stratum lacunosum and radiatum, supporting the findings in our study. In the 4 patients studied, they noted an abrupt transition to atrophy, neuronal loss, and gliosis in the CA1 region in particular. In contrast, we found that gliosis is extensive throughout the CA1, -2, and -3 regions, with loss of tissue thickness in the stratum pyramidale most pronounced in CA1. In our study, we had the advantage of being able to directly compare ex vivo scans with histopathologic specimens, eliminating discrepancies caused by tissue distortion when comparing in vivo preoperative scans with ex vivo specimens as in other studies. Indeed, the decreased tissue thickness on histopathologic analysis (MTS values, 500–1200 μm versus 1400–1700 μm for controls) is consistent with decreased tissue thickness calculated by using the stratum lacunosum landmark on 3T studies (200–1300 μm—superior margin measurement range), supporting a process that correlates with radiographic features of MTS. While ex vivo scans with 9.4T research magnets have detailed exceptional hippocampal structure,²⁰ these are not clinically available systems. Here we have shown for the first time, ultrastructural details of hippocampi in both the in vivo and ex vivo setting by using 3T MR imaging, a magnet strength now available at many centers, and we have correlated this with histopathologic features consistent with MTS.

In light of data suggesting 5 distinct MTS patterns with the classic pattern described as severe cell loss in CA1 and moderate loss in all other subfields,²¹ it is possible that our measurement technique will lead to bias toward identifying specific subsets of patients with MTS. Indeed, the most striking difference between ipsilateral and contralateral tissue measurements occurred in patients 4 and 5, both of whom also demonstrated the greatest neuronal loss in the CA1 region. A particularly key group of patients to identify, however, are those considered MR imaging “healthy.” Although we did not apply our measurement tool to a complete group of these patients, it is interesting that in 1 of 2 “MR imaging-healthy” patients who were excluded from the fast quantitative analysis study, post hoc evaluation showed the measurement tool would have accurately predicted the ultimate histologic diagnosis of MTS. Nevertheless, it seems unlikely that a test SN of 70% would be adequate for screening MR imaging–healthy patients at this time. Most interesting, these patients have been described as having a syndrome of paradoxic temporal lobe epilepsy with neuronal loss less pronounced in CA1 compared with a region of maximal loss in CA4.²² It may be that new ultrastructural features specific to this group or unique imaging modalities will be required.