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Mossy fiber pathway, granule cell basal dendrites in relation to hippocampal sclerosis (HS) type and memory function. AE. ZnT3; F-G. MAP2. A. Intense labeling of a retained or normal mossy fiber pathway (MFP) trajectory is shown and absent sprouting. B. shows moderate labeling of the normal MPF as well as sprouting in the molecular layer and in C the pathway is indistinct (the two arrowheads indicate CA3 and one arrowhead CA4 in the MFP in each figure). D. ZnT3 labeling in the subgranular zone (SGZ) is present (arrow) with weak MFP sprouting in the molecular layer and a weak residual MFP in CA4 (arrowhead). E. shows more intense MFP sprouting in the molecular layer with ZnT3 also showing some sprouted fibers in the SGZ (arrow). F. Basal dendrites on granule cells are highlighted with MAP2 and in this case, are very numerous (arrows) forming a mesh of processes in the SGZ. G. In other cases, rarer granule cells (arrow) are observed to have basal dendrites. H.
Source publication
Neuropathological subtypes of hippocampal sclerosis (HS) in temporal lobe epilepsy (2013 ILAE 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...
Contexts in source publication
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... fiber pathway sprouting with ZnT3 was observed in all HS types ( Figure 2D,E). Intense ZnT3 mossy fiber pathway sprouting was more frequently observed in type 1 than type 2 HS cases (55% vs. 29%, respectively) with a trend for a significant difference between these groups (P 5 0.05) ( Figure 2H); there were no differ- ences in mossy fiber pathway sprouting patterns between type 1 and Ind-HS groups. A residual mossy fiber pathway was significantly Table 3. Results of statistical analysis between pathology measures and memory deficits. Abbreviation: MRA 5 multiple regression analysis performed with SPSS to predict the effect of the multiple variables on the memory ...
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... fiber pathway sprouting with ZnT3 was observed in all HS types ( Figure 2D,E). Intense ZnT3 mossy fiber pathway sprouting was more frequently observed in type 1 than type 2 HS cases (55% vs. 29%, respectively) with a trend for a significant difference between these groups (P 5 0.05) ( Figure 2H); there were no differ- ences in mossy fiber pathway sprouting patterns between type 1 and Ind-HS groups. A residual mossy fiber pathway was significantly Table 3. Results of statistical analysis between pathology measures and memory deficits. Abbreviation: MRA 5 multiple regression analysis performed with SPSS to predict the effect of the multiple variables on the memory ...
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... Figure 2I). There was a strong positive correlation in all HS cases between the presence of basal dendrites on granule cells and ZnT3 sprouted fibers in the subgranular zone (P < 0.0001). Statistical anal- ysis showed an association between severe preoperative verbal memory deficit and lack of a preserved mossy fiber pathway (Table 3, Figure 2K) and moderate preoperative verbal memory deficit and the presence of basal dendrites on granule cells (Table 3, Figure ...
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... Figure 2I). There was a strong positive correlation in all HS cases between the presence of basal dendrites on granule cells and ZnT3 sprouted fibers in the subgranular zone (P < 0.0001). Statistical anal- ysis showed an association between severe preoperative verbal memory deficit and lack of a preserved mossy fiber pathway (Table 3, Figure 2K) and moderate preoperative verbal memory deficit and the presence of basal dendrites on granule cells (Table 3, Figure ...
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... Figure 2I). There was a strong positive correlation in all HS cases between the presence of basal dendrites on granule cells and ZnT3 sprouted fibers in the subgranular zone (P < 0.0001). Statistical anal- ysis showed an association between severe preoperative verbal memory deficit and lack of a preserved mossy fiber pathway (Table 3, Figure 2K) and moderate preoperative verbal memory deficit and the presence of basal dendrites on granule cells (Table 3, Figure ...
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... LI/value* in cases with deficit/ decline (SD) N 5 number of cases Mean LI/value* in cases without deficit/ decline (SD) N 5 number of cases Characterising subtypes of hippocampal sclerosis and reorganization Prada Jardim et al better preserved in both type 2 HS (P 5 0.003) and Ind-HS cases (P 5 0.01) than type 1 HS (Figure 2A-C,I). Labeling of sprouted fibers in the subgranular zone with ZnT3 ( Figure 2D,E) was more prevalent in type 2 than type 1 HS (P 5 0.01). The presence of basal dendrites on granule cells as visualized with MAP2 varied dramati- cally between HS cases ( Figure 2F,G); although more prevalent in type 1 HS the presence of basal dendrites was not significantly dif- ferent from type 2 and Ind-HS based on semiquantitative scores Bar chart of the presence of MFP sprouting in the molecular layer between HS types showing differences between type 1 and type 2 HS (*P 5 0.05). I. The presence of a better preserved or residual MFP also showed significant differences between HS groups with better preservation in non-type 1 HS cases (*P 5 0.01, **P 5 0.003). J. The presence and density of basal dendrites on granule cells showed some variation between HS groups, but the differences were not sig- nificant. (Of note in the three bar graphs H to J, the values for Ind-HS group are always between observed values for type 1 and type 2 HS). K. In all HS/TLE cases, the presence of a better preserved or residual MFP (weak 1 intense) was associated with a lack of severe preopera- tive verbal memory deficit (*P 5 0.013). L. The presence of basal den- drites in granule cells was associated with the lack of moderate verbal memory deficit (*P 5 0.025). Bar is equivalent to approximately 1 mm in A to C, 100 microns in D and E and 50 lm in F and ...
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... LI/value* in cases with deficit/ decline (SD) N 5 number of cases Mean LI/value* in cases without deficit/ decline (SD) N 5 number of cases Characterising subtypes of hippocampal sclerosis and reorganization Prada Jardim et al better preserved in both type 2 HS (P 5 0.003) and Ind-HS cases (P 5 0.01) than type 1 HS (Figure 2A-C,I). Labeling of sprouted fibers in the subgranular zone with ZnT3 ( Figure 2D,E) was more prevalent in type 2 than type 1 HS (P 5 0.01). The presence of basal dendrites on granule cells as visualized with MAP2 varied dramati- cally between HS cases ( Figure 2F,G); although more prevalent in type 1 HS the presence of basal dendrites was not significantly dif- ferent from type 2 and Ind-HS based on semiquantitative scores Bar chart of the presence of MFP sprouting in the molecular layer between HS types showing differences between type 1 and type 2 HS (*P 5 0.05). I. The presence of a better preserved or residual MFP also showed significant differences between HS groups with better preservation in non-type 1 HS cases (*P 5 0.01, **P 5 0.003). J. The presence and density of basal dendrites on granule cells showed some variation between HS groups, but the differences were not sig- nificant. (Of note in the three bar graphs H to J, the values for Ind-HS group are always between observed values for type 1 and type 2 HS). K. In all HS/TLE cases, the presence of a better preserved or residual MFP (weak 1 intense) was associated with a lack of severe preopera- tive verbal memory deficit (*P 5 0.013). L. The presence of basal den- drites in granule cells was associated with the lack of moderate verbal memory deficit (*P 5 0.025). Bar is equivalent to approximately 1 mm in A to C, 100 microns in D and E and 50 lm in F and ...
Context 8
... LI/value* in cases with deficit/ decline (SD) N 5 number of cases Mean LI/value* in cases without deficit/ decline (SD) N 5 number of cases Characterising subtypes of hippocampal sclerosis and reorganization Prada Jardim et al better preserved in both type 2 HS (P 5 0.003) and Ind-HS cases (P 5 0.01) than type 1 HS (Figure 2A-C,I). Labeling of sprouted fibers in the subgranular zone with ZnT3 ( Figure 2D,E) was more prevalent in type 2 than type 1 HS (P 5 0.01). The presence of basal dendrites on granule cells as visualized with MAP2 varied dramati- cally between HS cases ( Figure 2F,G); although more prevalent in type 1 HS the presence of basal dendrites was not significantly dif- ferent from type 2 and Ind-HS based on semiquantitative scores Bar chart of the presence of MFP sprouting in the molecular layer between HS types showing differences between type 1 and type 2 HS (*P 5 0.05). I. The presence of a better preserved or residual MFP also showed significant differences between HS groups with better preservation in non-type 1 HS cases (*P 5 0.01, **P 5 0.003). J. The presence and density of basal dendrites on granule cells showed some variation between HS groups, but the differences were not sig- nificant. (Of note in the three bar graphs H to J, the values for Ind-HS group are always between observed values for type 1 and type 2 HS). K. In all HS/TLE cases, the presence of a better preserved or residual MFP (weak 1 intense) was associated with a lack of severe preopera- tive verbal memory deficit (*P 5 0.013). L. The presence of basal den- drites in granule cells was associated with the lack of moderate verbal memory deficit (*P 5 0.025). Bar is equivalent to approximately 1 mm in A to C, 100 microns in D and E and 50 lm in F and ...
Similar publications
Objective:
Neuropathological studies indicate that hippocampal sclerosis (HS) consists of three subtypes (ILAE types 1-3 HS). However, HS subtypes currently can only be diagnosed by pathological analysis of hippocampal tissue resected during epilepsy surgery or at autopsy. In vivo diagnosis of HS subtypes holds potential to improve our understandi...
Citations
... A recent study demonstrated that age-related increase in phosphoTau in temporal lobe resection specimens were significantly correlated with a decline in verbal skills [89]. More subtle hyperphosphorylated tau within the DG and subiculum in a younger series with HS was significantly associated with a decline in naming score one year post-operatively [92]. ...
... After full text screening, 15 cohort studies with 2485 patients were included in the meta-analysis of seizure outcomes. [14][15][16]18,20,[41][42][43][44][45][46][47][48][49][50] Seven articles including six cohorts with detailed information of postoperative memory outcome were included. 14,[17][18][19][20]50,51 Eight studies were conducted from four datasets , 16,18,19,44,46,[51][52][53] and only the larger cohort study reporting seizure outcomes was included. ...
... [14][15][16]18,20,[41][42][43][44][45][46][47][48][49][50] Seven articles including six cohorts with detailed information of postoperative memory outcome were included. 14,[17][18][19][20]50,51 Eight studies were conducted from four datasets , 16,18,19,44,46,[51][52][53] and only the larger cohort study reporting seizure outcomes was included. 16,18,44,46 The PRISMA flowchart literature search and study selection are presented in Figure 1. ...
... Risk of bias scores ranged from 5 to 7, with five (33.3%) studies of high quality (score ≥ 7; Table S2). 14,18,44,45,49,50 with moderate to substantial heterogeneity. Nevertheless, pooling of data showed no significant difference in postoperative seizure freedom between HS type 2 and type 1 (crude RR = .98, ...
We conducted a systematic review and meta‐analysis to evaluate postoperative seizure and memory outcomes of temporal lobe epilepsy with different hippocampal sclerosis (HS) subtypes classified by International League Against Epilepsy (ILAE) Consensus Guidelines in 2013. Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) and MOOSE (Meta‐Analysis of Observational Studies in Epidemiology) guidelines, we searched PubMed, Embase, Web of Science, and Cochrane Library from January 1, 2013 to August 6, 2023. Observational studies reporting seizure and memory outcomes among different HS subtypes were included. We used the Newcastle–Ottawa scale to assess the risk of bias and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to grade the quality of evidence. Seizure freedom and improved outcome (Engel 1 or ILAE class 1–2) ≥1 year after surgery were defined as the primary and secondary seizure outcome. A random‐effects meta‐analysis by DerSimonian and Laird method was performed to obtain pooled risk ratio (RRs) with 95% confidence interval (CIs). The memory impairment was narratively reviewed because of various evaluation tools. Fifteen cohort studies with 2485 patients were eligible for the meta‐analysis of seizure outcome. Six cohorts with detailed information on postoperative memory outcome were included. The pooled RRs of seizure freedom, with moderate to substantial heterogeneity, were .98 (95% CI = .84–1.15) between HS type 2 and type 1, 1.11 (95% CI = .82–1.52) between type 3 and type 1, and .80 (95% CI = .62–1.03) between the no‐HS and HS groups. No significant difference of improved outcome was found between different subtypes (p > .05). The quality of evidence was deemed to be low to very low according to GRADE. The long‐term seizure outcome (≥5 years after surgery) and memory impairment remained controversial.
... Interestingly, the degree of memory impairment correlates with the degree of overall hippocampal atrophy in patients with MTLE-HS (6). Similarly, the type of MTLE-HS [according to the ILAE classification (9)] may also influence memory impairment (10)(11)(12)(13)(14). In patients with type II MTLE-HS, in which neural loss is predominantly observed in CA1, it was reported that declarative memory was not impaired (12,15). ...
... This specific alteration in the subiculum could be related to the increased excitability of the subiculum observed in patients with TLE and in animal models of TLE (61)(62)(63)(64). Interestingly, Prada Jardim et al. (13) observed that postsurgical decline in memory at 1 year was associated with degeneration in the subiculum. ...
... In this sense, two recent studies suggest that multifactorial variables are likely to underlie the memory impairment associated with MTLE-HS. Prada Jardim et al. (13) were unable to observe any association between memory performance and neuropathological subtypes of hippocampal sclerosis either pre-or post-operatively [see also (14)]. Similarly, Lalani et al. (29) also indicated that there were no differences in the magnitude of pattern separation impairment in TLE with and without HS. ...
Introduction
Pattern separation (PS) is a fundamental aspect of memory creation that defines the ability to transform similar memory representations into distinct ones, so they do not overlap when storing and retrieving them. Experimental evidence in animal models and the study of other human pathologies have demonstrated the role of the hippocampus in PS, in particular of the dentate gyrus (DG) and CA3. Patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HE) commonly report mnemonic deficits that have been associated with failures in PS. However, the link between these impairments and the integrity of the hippocampal subfields in these patients has not yet been determined. The aim of this work is to explore the association between the ability to perform mnemonic functions and the integrity of hippocampal CA1, CA3, and DG in patients with unilateral MTLE-HE.
Method
To reach this goal we evaluated the memory of patients with an improved object mnemonic similarity test. We then analyzed the hippocampal complex structural and microstructural integrity using diffusion weighted imaging.
Results
Our results indicate that patients with unilateral MTLE-HE present alterations in both volume and microstructural properties at the level of the hippocampal subfields DG, CA1, CA3, and the subiculum, that sometimes depend on the lateralization of their epileptic focus. However, none of the specific changes was found to be directly related to the performance of the patients in a pattern separation task, which might indicate a contribution of various alterations to the mnemonic deficits or the key contribution of other structures to the function.
Discussion
we established for the first time the alterations in both the volume and the microstructure at the level of the hippocampal subfields in a group of unilateral MTLE patients. We observed that these changes are greater in the DG and CA1 at the macrostructural level, and in CA3 and CA1 in the microstructural level. None of these changes had a direct relation to the performance of the patients in a pattern separation task, which suggests a contribution of various alterations to the loss of function.
... The hippocampus is essential for memory formation and consolidation [6]. In patients with TLE, the loss of neurons in CA1, CA4, and the dentate gyrus (DG) subfields has been associated with impaired preoperative verbal and visual memories [7,8]. The more intense the hippocampal loss, the more severe the deficits in non-verbal memory are [9]. ...
... Tau pathology has been observed in hippocampal samples from patients with drug-resistant TLE and associated with post-surgical cognitive decline [8,29]. However, the results regarding Aβ deposition are less clear, with most studies not reporting this protein accumulation in sclerotic hippocampi [29,30], while some showing higher expression of beta amiloyd precursor protein (β-APP) in sclerotic hippocampi of patients with TLE than in control hippocampi [31]. ...
Temporal lobe epilepsy (TLE) often courses with cognitive deficits, but its underlying neuronal basis remains unclear. Confluent data suggest that epilepsy share pathophysiological mechanisms with neurodegenerative diseases. However, as most studies analyze subjects 60 years old and older, it is challenging to rule out that neurodegenerative changes arise from age-related mechanisms rather than epilepsy in these individuals. To fill this gap, we conducted a neuropathological investigation of the hippocampal formation of 22 adults with mesial TLE and 20 age- and sex-matched controls (both younger than 60 years). Moreover, we interrogated the relationship between these neuropathological metrics and cognitive performance. Hippocampal formation extracted from patients with drug-resistant mesial TLE undergoing surgery and postmortem non-sclerotic hippocampal formation of clinically and neuropathologically controls underwent immunohistochemistry against amyloid β (Aβ), hyperphosphorylated tau (p-tau), and TAR DNA-binding protein-43 (TDP-43) proteins, followed by quantitative analysis. Patients underwent a comprehensive neuropsychological evaluation prior to surgery. TLE hippocampi showed a significantly higher burden of p-tau than controls, whereas Aβ deposits and abnormal inclusions of TDP-43 were absent in both groups. Patients with hippocampal sclerosis (HS) type 2 had higher immunostaining for p-tau than patients with HS type 1. In addition, p-tau burden was associated with impairment in attention tasks and seizures frequency. In this series of adults younger than 60 years-old, the increase of p-tau burden associated with higher frequency of seizures and attention impairment suggests the involvement of tau pathology as a potential contributor to cognitive deficits in mesial TLE.
... 80 More subtle hyperphosphorylated tau within the dentate gyrus and subiculum in a younger series with HS was significantly associated with naming score decline 1 year postoperatively. 88 No "Secondary" Pathology. This group is mainly comprised of HS and temporal LEATs. ...
Objective:
Some patients unexpectedly display an unfavorable cognitive course after epilepsy surgery subsequent to any direct cognitive sequelae of the surgical treatment. Therefore, we conducted in-depth neuropathological examinations of resective specimens from corresponding patients to provide insights as to the underlying disease processes.
Methods:
In this study, cases with significant cognitive deterioration following a previous postoperative assessment were extracted from the neuropsychological database of a longstanding epilepsy surgical program. An extensive reanalysis of available specimens was performed using current, state-of-the-art neuropathological examinations. Patients without cognitive deterioration but matched in regard to basic pathologies served as controls.
Results:
Among the 355 operated patients who had undergone more than one postoperative neuropsychological examination, 30 (8%) showed significant cognitive decline in the period after surgery. Of the 24 patients with available specimens, 71% displayed further neuropathological changes in addition to the typical spectrum (ie, hippocampal sclerosis, focal cortical dysplasias, vascular lesions, and low-grade tumors), indicating (1) a secondary, putatively epilepsy-independent neurodegenerative disease process; (2) limbic inflammation; or (3) the enigmatic pathology pattern of "hippocampal gliosis" without segmental neurodegeneration. In the controls, the matched individual principal epilepsy-associated pathologies were not found in combination with the secondary pathology patterns of the study group.
Interpretation:
Our findings indicate that patients who unexpectedly displayed unfavorable cognitive development beyond any direct surgical effects show rare and very particular pathogenetic causes or parallel, presumably independent, neurodegenerative alterations. A multicenter collection of such cases would be appreciated to discern presurgical biomarkers that help with surgical decision-making. ANN NEUROL 2022.
... 39,40 The BIRT memory battery has also been validated against the histological severity of hippocampal sclerosis in temporal lobe epilepsy and is sensitive to decline following anterior temporal lobe resection. 41,42 While the WASI and BIRT are not commonly used in MS research, previous work has found that lower WASI Full Scale IQ was associated with slower walking speed and higher risk of falls in a cohort of 78 pwMS and baseline WASI performance has been reported in a randomised controlled trial of cognitive rehabilitation for pwMS. 43,44 In summary, we felt that the requirement for more comprehensive cognitive outcome measures was warranted given the aim and hypotheses of the original MS-STAT interventional trial. ...
Background
Cognitive impairment affects 50%–75% of people with secondary progressive multiple sclerosis (PwSPMS). Improving our ability to predict cognitive decline may facilitate earlier intervention.
Objective
The main aim of this study was to assess the relationship between longitudinal changes in cognition and baseline serum neurofilament light chain (sNfL) in PwSPMS. In a multi-modal analysis, MRI variables were additionally included to determine if sNfL has predictive utility beyond that already established through MRI.
Methods
Participants from the MS-STAT trial underwent a detailed neuropsychological test battery at baseline, 12 and 24 months. Linear mixed models were used to assess the relationships between cognition, sNfL, T2 lesion volume (T2LV) and normalised regional brain volumes.
Results
Median age and Expanded Disability Status Score (EDSS) were 51 and 6.0. Each doubling of baseline sNfL was associated with a 0.010 [0.003–0.017] point per month faster decline in WASI Full Scale IQ Z-score ( p = 0.008), independent of T2LV and normalised regional volumes. In contrast, lower baseline volume of the transverse temporal gyrus was associated with poorer current cognitive performance (0.362 [0.026–0.698] point reduction per mL, p = 0.035), but not change in cognition. The results were supported by secondary analyses on individual cognitive components.
Conclusion
Elevated sNfL is associated with faster cognitive decline, independent of T2LV and regional normalised volumes.
... In animal models of TLE, tau hyperphosphorylation is observed in relevant brain regions, including the amygdala, hippocampus, and cortex, following chemical and electrical amygdala kindling (Jones et al., 2012;Liu et al., 2016;Alves et al., 2019). And in humans with chronic epilepsy, elevated p-tau is present in post-mortem (Thom et al., 2011) as well as surgically resected tissue (Puvenna et al., 2016;Tai et al., 2016;Prada Jardim et al., 2018;Smith et al., 2019;Gourmaud et al., 2020). For instance, analysis of resected temporal lobe tissue by Tai et al. (2016) found pathological tau phosphorylation in the form of neuropil threads, NFTs, and pre-tangles in 31 of 33 TLE patients between 50 and 65 years of age. ...
... Created with BioRender.com. dentate gyrus suggest that tau-associated pathological changes in relevant brain regions over time may underlie progressive cognitive impairment seen in TLE (Prada Jardim et al., 2018). Furthermore, the neuroprotective effects of tau ablation against not only seizures but also cognitive deficits in animal models of ASD and Dravet syndrome (Gheyara et al., 2014;Tai et al., 2020) provide evidence for a role of tau in mediating cognitive impairment in these diseases as well. ...
Tau is a microtubule-associated protein known to bind and promote assembly of microtubules in neurons under physiological conditions. However, under pathological conditions, aggregation of hyperphosphorylated tau causes neuronal toxicity, neurodegeneration, and resulting tauopathies like Alzheimer’s disease (AD). Clinically, patients with tauopathies present with either dementia, movement disorders, or a combination of both. The deposition of hyperphosphorylated tau in the brain is also associated with epilepsy and network hyperexcitability in a variety of neurological diseases. Furthermore, pharmacological and genetic targeting of tau-based mechanisms can have anti-seizure effects. Suppressing tau phosphorylation decreases seizure activity in acquired epilepsy models while reducing or ablating tau attenuates network hyperexcitability in both Alzheimer’s and epilepsy models. However, it remains unclear whether tauopathy and epilepsy comorbidities are mediated by convergent mechanisms occurring upstream of epileptogenesis and tau aggregation, by feedforward mechanisms between the two, or simply by coincident processes. In this review, we investigate the relationship between tauopathies and seizure disorders, including temporal lobe epilepsy (TLE), post-traumatic epilepsy (PTE), autism spectrum disorder (ASD), Dravet syndrome, Nodding syndrome, Niemann-Pick type C disease (NPC), Lafora disease, focal cortical dysplasia, and tuberous sclerosis complex. We also explore potential mechanisms implicating the role of tau kinases and phosphatases as well as the mammalian target of rapamycin (mTOR) in the promotion of co-pathology. Understanding the role of these co-pathologies could lead to new insights and therapies targeting both epileptogenic mechanisms and cognitive decline.
... Our series consists of patients with different etiologies, with a majority of patients having hippocampal sclerosis (HS). TLE is an heterogeneous disease, even in patients with HS, were heterogeneity in impairment of cognitive domains is found (43). Individual differences are common, likely related to network plasticity (44) against different etiologies and ages of presentation. ...
Introduction
Learning new verbal information can be impaired in 20–40% of patients after mesial temporal lobe resection. In recent years, understanding epilepsy as a brain network disease, and investigating the relationship between large-scale resting networks and cognition has led to several advances. Aligned studies suggest that it is the integrity of the hippocampal connectivity with these large-scale networks what is relevant for cognition, with evidence showing a functional and structural heterogeneity along the long axis hippocampus bilaterally.
Objective
Our aim is to examine whether pre-operative resting-state connectivity along the long hippocampal axis is associated with verbal learning decline after anterior temporal lobe resection.
Methods
Thirty-one patients with epilepsy who underwent an anterior temporal lobe resection were pre-surgically scanned at 3-tesla, and pre/post-surgery evaluated for learning deficits using the Rey Auditory Verbal Learning Task (RAVLT). Eighteen controls matched by age, gender and handedness were also scanned and evaluated with the RAVLT. We studied the functional connectivity along the (anterior/posterior) long axis hippocampal subregions and resting-state functionally-defined brain networks involved in learning [executive (EXE), dorsal attention (DAN) and default-mode (DMN) networks]. Functional connectivity differences between the two groups of patients (learning intact or with learning decline) and controls were investigated with MANOVA and discriminant analysis.
Results
There were significant differences in the pattern of hippocampal connectivity among the groups. Regarding the anterior connectivity hippocampal pattern, our data showed an increase of connectivity in the pathological side with the DAN (p = 0.011) and the EXE (p = 0.008) when comparing learning-decline vs. learning-intact patients. Moreover, the non-pathological side showed an increase in the anterior connectivity pattern with the DAN (p = 0.027) between learning-decline vs. learning-intact patients. In contrast, the posterior hippocampus showed a reduction of connectivity in the learning-decline patients with the DMN, both in the pathological (p = 0.004) and the non-pathological sides (p = 0.036). Finally, the discriminant analysis based on the pre-operative connectivity pattern significantly differentiated the learning-decline patients from the other groups (p = 0.019).
Conclusion
Our findings reveal bilateral connectivity disruptions along the longitudinal axis of the hippocampi with resting-state networks, which could be key to identify those patients at risk of verbal learning decline after epilepsy surgery.
... We did not find a significant correlation of ILAE HS subtypes with the Engel outcome, but a trend to worse epilepsy outcome in patients with HS type 2. This is in accordance with the results of Coras et al., who additionally found greater post-operative memory decline in patients with type 2 pathology [32,33]. On the contrary, Jardim et al. could not replicate this finding in 92 HS patients including 15 with type 2 [34]. ...
Objective: The aim of this retrospective cohort study was to assess seizure and memory outcomes following temporal lobe surgery in patients suffering from medically refractory temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS).
Methods: A retrospective monocentric data analysis was performed in consecutive patients who were operated on during 2002–2018. In the first decennium, standard temporal lobe resections (TLR) were predominately performed, and later, antero-temporal lobe resections (ATLR) were mainly performed. Seizure and memory outcomes over time were assessed according to ILAE/Engel classification and the Berlin Amnesia Test (BTA), respectively.
Results: Altogether, 231 surgeries were performed on 226 patients (mean age, 40 years [range, 10–68 years]; male: female, 1:1.4; mean seizure duration, 25 years; and mean follow-up duration, 4.75 years [range, 1–16]). Recently, outcomes of 78.3% of the patients in the total cohort were classified as Engel class I, with 54.9% of patients being completely seizure free. The recent cohort of ATLR since 2012 showed significant more completely seizure-free patients than before 2012 (Engel IA 46.6% versus 67.7%, p < 0.0025, χ²), although the Kaplan Meier analysis of all patients favors TLR for better seizure outcome (61% ATLR vs 73% TLR seizure free after 5 yrs, log rank p < 0.001). Verbal memory improved significantly in non-dominant patients. Minor neurological complications were noted (permanent severe complications, 0.4%; temporary severe complications, 4.8%).
Conclusion: Significant improvements in seizure and memory outcomes were observed over time, with surgical technique and seizure duration as important prognostic factors. Early admittance for surgery may favor an excellent seizure outcome in patients undergoing temporal lobe resection for HS.
... In addition, individual variabilities and anatomical inhomogeneities complicate classification (Coras et al., 2014;Rodrigues et al., 2015;Saghafi et al., 2018). For instance, patchy neuronal loss has been described in the CA1 region in some cases, whereas in others, it seems to adopt a more laminar profile (Prada Jardim et al., 2018). In some affected individuals, cell loss concentrates in the CA4 region and the dentate gyrus and is frequently integrated in dual pathologies; e.g., TLE and malformations of cortical development, classified as type 3 hippocampal sclerosis (3%-7%) (Mathern et al., 1997). ...
... Hippocampal sclerosis is a heterogeneous histopathological entity (Bl€ umcke et al., 2013). The prognosis value of certain subtypes has been debated, but emerging data suggest that it deserves further consideration in light of cell type specificity (Prada Jardim et al., 2018). Superficial and deep CA1 pyramidal cells are innervated differently by local-circuit GABAergic interneurons, express different neuromodulatory receptors, project differentially to cortical and subcortical regions, and participate distinctly in hippocampal oscillations (Cembrowski et al., 2016a;Soltesz and Losonczy, 2018;Valero and de la Prida, 2018). ...
Hippocampal sclerosis, the major neuropathological hallmark of temporal lobe epilepsy, is characterized by different patterns of neuronal loss. The mechanisms of cell-type-specific vulnerability and their progression and histopathological classification remain controversial. Using single-cell electrophysiology in vivo and immediate-early gene expression, we reveal that superficial CA1 pyramidal neurons are overactive in epileptic rodents. Bulk tissue and single-nucleus expression profiling disclose sublayer-specific transcriptomic signatures and robust microglial pro-inflammatory responses. Transcripts regulating neuronal processes such as voltage channels, synaptic signaling, and cell adhesion are deregulated differently by epilepsy across sublayers, whereas neurodegenerative signatures primarily involve superficial cells. Pseudotime analysis of gene expression in single nuclei and in situ validation reveal separated trajectories from health to epilepsy across cell types and identify a subset of superficial cells undergoing a later stage in neurodegeneration. Our findings indicate that sublayer- and cell-type-specific changes associated with selective CA1 neuronal damage contribute to progression of hippocampal sclerosis.
