Abstract
Saghafi S, Ferguson F, Hogue O, Gales JM, Prayson R, Busch RM. Epilepsia 2018;59:825–833.
OBJECTIVE: The International League Against Epilepsy (ILAE) proposed a classification system for hippocampal sclerosis (HS) based on location and extent of hippocampal neuron loss. The literature debates the usefulness of this classification system when studying memory in people with temporal lobe epilepsy (TLE) and determining memory outcome after temporal lobe resection (TLR). This study further explores the relationship between HS ILAE subtypes and episodic memory performance in patients with TLE and examines memory outcomes after TLR. METHODS: This retrospective study identified 213 patients with TLE who underwent TLR and had histopathological evidence of HS (HS ILAE type 1a = 92; type 1b = 103; type 2 = 18). Patients completed the Wechsler Memory Scale—3rd Edition prior to surgery, and 78% of patients had postoperative scores available. Linear regressions examined differences in preoperative memory scores as a function of pathology classification, controlling for potential confounders. Fisher's exact tests were used to compare pathology subtypes on the magnitude of preoperative memory impairment and the proportion of patients who experienced clinically meaningful postoperative memory decline. RESULTS: Individuals with HS ILAE type 2 demonstrated better preoperative verbal memory performance than patients with HS ILAE type 1; however, individual data revealed verbal and visual episodic memory impairments in many patients with HS ILAE type 2. The base rate of postoperative memory decline was similar among all 3 pathology groups. SIGNIFICANCE: This is the largest reported overall sample and the largest subset of patients with HS ILAE type 2. Group data suggest that patients with HS ILAE type 2 perform better on preoperative memory measures, but individually there were no differences in the magnitude of memory impairment. Following surgery, there were no statistically significant differences between groups in the proportion of patients who declined. Future research should focus on quantitative measurements of hippocampal neuronal loss, and multicenter collaboration is encouraged.
Jardim AP, Liu J, Baber J, Michalak Z, Reeves C, Ellis M, Novy J, de Tisi J, McEvoy A, Miserocchi A, Targas Yacubian EM, Sisodiya S, Thompson P, Thom M. Brain Pathol 2018;28:143–154.
Neuropathological subtypes of hippocampal sclerosis (HS) in temporal lobe epilepsy (The 2013 International League Against Epilepsy classification) are based on the qualitative assessment of patterns of neuronal loss with NeuN. In practice, some cases appear indeterminate between type 1 (CA1 and CA4 loss) and type 2 HS (CA1 loss) and we predicted that MAP2 would enable a more stringent classification. HS subtypes, as well as the accompanying alteration of axonal networks, regenerative capacity and neurodegeneration have been previously correlated with outcome and memory deficits and may provide prognostic clinical information. We selected 92 cases: 52 type 1 HS, 15 type 2 HS, 18 indeterminate-HS and 7 no-HS. Quantitative analysis was carried out on NeuN and MAP2 stained sections and a labeling index (LI) calculated for six hippocampal subfields. We also evaluated hippocampal regenerative activity (MCM2, nestin, olig2, calbindin), degeneration (AT8/phosphorylated tau) and mossy-fiber pathway re-organization (ZnT3). Pathology measures were correlated with clinical epilepsy history, memory and naming test scores and postoperative outcomes, at 1 year following surgery. MAP2 LI in indeterminate-HS was statistically similar to type 2 HS but this clustering was not shown with NeuN. Moderate verbal and visual memory deficits were noted in all HS types, including 54% and 69% of type 2 HS. Memory deficits correlated with several pathology factors including lower NeuN or MAP2 LI in CA4, CA1, dentate gyrus (DG) and subiculum and poor preservation of the mossy fiber pathway. Decline in memory at 1 year associated with AT8 labeling in the subiculum and DG but not HS type. We conclude that MAP2 is a helpful addition in the classification of HS in some cases. Classification of HS subtype, however, did not significantly correlate with outcome or pre- or postoperative memory dysfunction, which was associated with multiple pathology factors including hippocampal axonal pathways, regenerative capacity and degenerative changes.
Commentary
Although hippocampal sclerosis (HS) has long been regarded as the most common form of histopathological abnormality in adults with drug-resistant temporal lobe epilepsy (TLE), its clinical significance has long remained a mystery (1). Over the years, a number of investigators examining postoperative and autopsy series have described several different patterns of neuronal cell loss within hippocampal subregions and adjacent structures in patients with HS. However, due to a lack of standardization in methods and classification, the overall incidence of HS and these histopathological subtypes is unknown. Additionally, while associations have been found between the development of HS and clinical variables such as age at epilepsy onset, febrile seizures, and genetic susceptibility, little is known about how HS or its histological subtypes relates to those variables or to the prediction of postsurgical outcome and development of comorbid conditions such as memory impairment.
Focusing on the issue of memory, a number of investigators during the 1990s sought to establish a basic relationship between pathological characteristics of the hippocampus and memory performance, with the goal of finding a means to predict those at risk for development of postoperative decline (2, 3). Although results were variable, there were indications from these studies that patients with lesser degrees of general hippocampal neuron loss or HS were at greater risk for postoperative memory decline. Similar findings were demonstrated in structural magnetic resonance imaging (MRI) studies using methods to calculate hippocampal volumes (4). The findings, taken together, supported a model where the functional adequacy of the tissue to be resected during epilepsy surgery determines the nature and extent of memory changes following the procedure (5).
Determining the incidence and significance of HS and its histological subtypes provided a challenge for many years due to a lack of standardization of definitions and methods. In 2013, a task force from the International League Against Epilepsy (ILAE) developed a consensus classification system for HS with the aim of providing standardized methods that could be used in both clinical and research settings (6). The resulting classification system identified three major types of HS based on the pattern and degree of cells loss observed in various segments of the hippocampus. In 2014, Coras and colleagues (7) reported that patients with HS ILAE type 2 subtype, characterized by predominant neuronal loss in CA1 and minimal loss in other CA segments, did not exhibit declarative memory dysfunction pre-operatively in contrast to patients with more widespread neuronal loss but did exhibit significant decline following surgery.
The memory findings reported in the Coras et al. study (7) provided what appeared to be an important first step in utilizing the new ILAE classification system for clinical prediction. The implication was that neurons in the CA1 were less involved in declarative memory processing, rendering patients with a profile of selective neuronal loss in that region more susceptible to postoperative memory decline. However, the findings reported in two recent studies suggest that the enthusiasm generated from that report might have been premature.
In the first of these studies, Saghafi and colleagues replicated the finding of superior memory performance in a new cohort of patients with the HS ILAE type 2 in comparison to other HS subtypes through analysis of group data. However, the investigators found equivalent rates of impairment among the groups when analyzing individual base rates of impairment. Results indicated that a substantial proportion (44%) of individuals with the HS ILAE type 2 pathology had moderate to severe impairment on two or more of the memory indices. Using similar analyses, the investigators found little difference between base rates of postoperative memory decline in the HS ILAE type 2 group in comparison to patients from the other two pathology subgroups.
In contrast, the second study from Jardim and colleagues found no association in any of their analyses between pre- or postoperative memory dysfunction in patients with various HS subtypes. However, one of the major aims of this investigation was to enhance classification of equivocal or indeterminate HS cases when using the ILAE criteria. Results showed that the addition of A3 microtubule-associated protein 2 (MAP2) staining to the pathological analysis led to enhanced identification of CA4 neurons and other improvements in dendritic labeling. Use of the MAP2 staining enhanced the ability to determine whether the indeterminate group was more closely associated with the type 1 or type 2 subgroup. Based on the lack of any association between memory performance and HS subtypes, the authors concluded that multifactorial pathomechanisms—including widespread neuronal loss and mossy fiber reorganization—are likely to be the operational cause for the memory impairment associated with HS/TLE.
Both papers bring attention to a number of factors that might have led to a failure to replicate findings from earlier studies. The sample sizes from all of the studies on this topic are rather small, given that HS ILAE type 2 pathology is seen in only a small percentage (5–10%) of TLE surgical cases. This point had been raised in another study with failed replication of the findings, leading to a call for future study of “atypical” HS on multicenter basis (8). Subjects in the initial study (7) were noted to have less severe pathology and had undergone different surgical procedures than did subjects from the other studies. Additionally, every investigation used different measures to assess memory, both pre- and postoperatively.
From a methodological standpoint, the first study's use of individual statistics provided an opportunity to identify important clinical information, which can be masked through group analysis. The second study's use of different staining procedures demonstrates that memory impairment in TLE is likely to result from a complex interplay of multiple pathological factors, involving integrity of neurons and associated pathways, regenerative capacity, and degenerative changes.
In the end, extending our knowledge of the association between temporal lobe pathology and memory will require continued investigation on a multidisciplinary basis using advanced technologies. There is no doubt that the ILAE task force's consensus classification for HS provides an important first step for standardization of the basic pathology, which needs to be followed closely by development of MRI technology sensitive to identification of the HS subtypes prior to surgery (9). After accounting for structural aspects of the equation, the logical next step is for neuropsychologists to either refine the use of existing clinical assessment methods or develop newer approaches for identifying memory impairment using advanced digital technology with input from cognitive neuroscience, as has been suggested from within the field (10). There is little doubt that, through continued development and investigation, a convergence of these advanced methods from multiple sources will enable us to eventually solve the puzzle of the relationship between HS and memory.