Structural and functional asymmetry of medial temporal subregions in unilateral temporal lobe epilepsy: A 7T MRI study

Mesial temporal lobe epilepsy (TLE) is a common neurological disorder affecting the hippocampus and surrounding medial temporal lobe (MTL). Although prior studies have analyzed whole‐brain network distortions in TLE patients, the functional network architecture of the MTL at the subregion level has not been examined. In this study, we utilized high‐resolution 7T T2‐weighted magnetic resonance imaging (MRI) and resting‐state BOLD‐fMRI to characterize volumetric asymmetry and functional network asymmetry of MTL subregions in unilateral medically refractory TLE patients and healthy controls. We subdivided the TLE group into mesial temporal sclerosis patients (TLE‐MTS) and MRI‐negative nonlesional patients (TLE‐NL). Using an automated multi‐atlas segmentation pipeline, we delineated 10 MTL subregions per hemisphere for each subject. We found significantly different patterns of volumetric asymmetry between the two groups, with TLE‐MTS exhibiting volumetric asymmetry corresponding to decreased volumes ipsilaterally in all hippocampal subfields, and TLE‐NL exhibiting no significant volumetric asymmetries other than a mild decrease in whole‐hippocampal volume ipsilaterally. We also found significantly different patterns of functional network asymmetry in the CA1 subfield and whole hippocampus, with TLE‐NL patients exhibiting asymmetry corresponding to increased connectivity ipsilaterally and TLE‐MTS patients exhibiting asymmetry corresponding to decreased connectivity ipsilaterally. Our findings provide initial evidence that functional neuroimaging‐based network properties within the MTL can distinguish between TLE subtypes. High‐resolution MRI has potential to improve localization of underlying brain network disruptions in TLE patients who are candidates for surgical resection.     

Serotonin 1A receptors, depression, and memory in temporal lobe epilepsy

Purpose: Memory deficits and depression are common in patients with temporal lobe epilepsy (TLE). Previous positron emission tomography (PET) studies have shown reduced mesial temporal 5HT1A‐receptor binding in these patients. We examined the relationships among verbal memory performance, depression, and 5HT1A‐receptor binding measured with 18F‐trans‐4‐fluoro‐N‐2‐[4‐(2‐methoxyphenyl)piperazin‐1‐yl]ethyl‐N‐(2‐pyridyl) cyclohexane carboxamide (18FCWAY) PET in a cross‐sectional study. Methods: We studied 40 patients (24 male; mean age 34.5 ± 10.7 years) with TLE. Seizure diagnosis and focus localization were based on ictal video–electroencephalography (EEG) recording. Patients had neuropsychological testing with Wechsler Adult Intelligence Score III (WAIS III) and Wechsler Memory Score III (WMS III) on stable antiepileptic drug (AED) regimens at least 24 h since the last seizure. Beck Depression Inventory (BDI) scores were obtained. We performed interictal PET with 18FCWAY, a fluorinated derivative of WAY 100635, a highly specific 5HT1A ligand, and structural magnetic resonance imaging (MRI) scans to estimate partial volume and plasma free fraction corrected 18FCWAY volume of distribution (V/f1). Key Findings: Hippocampal V/f1 was significantly lower in area ipsilateral than contralateral to the epileptic focus (73.7 ± 27.3 vs. 95.4 ± 28.4; p < 0.001). We found a significant relation between both left hippocampal 18FCWAY V/f1 (r = 0.41; p < 0.02) and left hippocampal volume (r = 0.36; p < 0.03) and delayed auditory memory score. On multiple regression, there was a significant effect of the interaction of left hippocampal 18FCWAY V/f1 and left hippocampal volume on delayed auditory memory, but not of either alone. High collinearity was present. In an analysis of variance including the side of the seizure focus, the effect of left hippocampal 18FCWAY V/f1 but not focus laterality retained significance. Mean BDI was 8.3 ± 7.0. There was a significant inverse relation between BDI and 18FCWAY V/f1 ipsilateral to the patient’s epileptic focus (r = 0.38 p < 0.02). There was no difference between patients with a right or left temporal focus. There was no relation between BDI and immediate or delayed auditory memory. Significance: Our study suggests that reduced left hippocampal 5HT1A‐receptor binding may play a role in memory impairment in patients with TLE.     

Automated volumetry and regional thickness analysis of hippocampal subfields and medial temporal cortical structures in mild cognitive impairment

We evaluate a fully automatic technique for labeling hippocampal subfields and cortical subregions in the medial temporal lobe in in vivo 3 Tesla MRI. The method performs segmentation on a T2‐weighted MRI scan with 0.4 × 0.4 × 2.0 mm³ resolution, partial brain coverage, and oblique orientation. Hippocampal subfields, entorhinal cortex, and perirhinal cortex are labeled using a pipeline that combines multi‐atlas label fusion and learning‐based error correction. In contrast to earlier work on automatic subfield segmentation in T2‐weighted MRI [Yushkevich et al., 2010], our approach requires no manual initialization, labels hippocampal subfields over a greater anterior‐posterior extent, and labels the perirhinal cortex, which is further subdivided into Brodmann areas 35 and 36. The accuracy of the automatic segmentation relative to manual segmentation is measured using cross‐validation in 29 subjects from a study of amnestic mild cognitive impairment (aMCI) and is highest for the dentate gyrus (Dice coefficient is 0.823), CA1 (0.803), perirhinal cortex (0.797), and entorhinal cortex (0.786) labels. A larger cohort of 83 subjects is used to examine the effects of aMCI in the hippocampal region using both subfield volume and regional subfield thickness maps. Most significant differences between aMCI and healthy aging are observed bilaterally in the CA1 subfield and in the left Brodmann area 35. Thickness analysis results are consistent with volumetry, but provide additional regional specificity and suggest nonuniformity in the effects of aMCI on hippocampal subfields and MTL cortical subregions. Hum Brain Mapp, 36:258–287, 2015. © 2014 Wiley Periodicals, Inc .     

Hippocampal subfield segmentation in temporal lobe epilepsy: Relation to outcomes

Objective

To investigate the clinical and surgical outcome correlates of preoperative hippocampal subfield volumes in patients with refractory temporal lobe epilepsy (TLE) using a new magnetic resonance imaging (MRI) multisequence segmentation technique.

Methods

We recruited 106 patients with TLE and hippocampal sclerosis (HS) who underwent conventional T1‐weighted and T2 short TI inversion recovery MRI. An automated hippocampal segmentation algorithm was used to identify twelve subfields in each hippocampus. A total of 76 patients underwent amygdalohippocampectomy and postoperative seizure outcome assessment using the standardized ILAE classification. Semiquantitative hippocampal internal architecture (HIA) ratings were correlated with hippocampal subfield volumes.

Results

Patients with left TLE had smaller volumes of the contralateral presubiculum and hippocampus‐amygdala transition area compared to those with right TLE. Patients with right TLE had reduced contralateral hippocampal tail volumes and improved outcomes. In all patients, there were no significant relationships between hippocampal subfield volumes and clinical variables such as duration and age at onset of epilepsy. There were no significant differences in any hippocampal subfield volumes between patients who were rendered seizure free and those with persistent postoperative seizure symptoms. Ipsilateral but not contralateral HIA ratings were significantly correlated with gross hippocampal and subfield volumes.

Conclusions

Our results suggest that ipsilateral hippocampal subfield volumes are not related to the chronicity/severity of TLE. We did not find any hippocampal subfield volume or HIA rating differences in patients with optimal and unfavorable outcomes. In patients with TLE and HS, sophisticated analysis of hippocampal architecture on MRI may have limited value for prediction of postoperative outcome.     

In vivo mapping of hippocampal subfields in mesial temporal lobe epilepsy: Relation to histopathology

A particularly popular automated magnetic resonance imaging (MRI) hippocampal subfield mapping technique is the one described by Van Leemput et al. (2009: Hippocampus 19:549–557) that is currently distributed with FreeSurfer software. This method assesses the probabilistic locations of subfields based on a priori knowledge of subfield topology determined from high‐field MRI. Many studies have applied this technique to conventionally acquired T1‐weighted MRI data. In the present study, we investigated the relationship between this technique applied to conventional T1‐weighted MRI data acquired at 3 T and postsurgical hippocampal histology in patients with medically intractable mesial temporal lobe epilepsy (mTLE) and hippocampal sclerosis (HS). Patients with mTLE (n = 82) exhibited significant volume loss of ipsilateral CA1, CA2‐3, CA4‐dentate gyrus (DG), subiculum, and fimbria relative to controls (n = 81). Histopathological analysis indicated that the most significant neuronal loss was observed in CA1, then CA4 and CA3, and more subtle neuronal loss in CA2, consistent with classical HS. Neuronal density of CA1 significantly correlated with MRI‐determined volume of CA1, and increasingly so with CA2‐3 and CA4–DG. Patients with increased HS based on histopathology had greater volume loss of the ipsilateral hippocampal regions on MRI. We conclude by suggesting that whilst time efficient and fully reproducible when applied to conventional single acquisition sequences, the use of the automated subfield technique described here may necessitate the application to multiacquisition high‐resolution MR sequences for accurate delineation of hippocampal subfields. Hum Brain Mapp 35:4718–4728, 2014. © 2014 Wiley Periodicals, Inc .     

Longitudinal trajectory of Amyloid‐related hippocampal subfield atrophy in nondemented elderly

Hippocampal atrophy and abnormal β‐Amyloid (Aβ) deposition are established markers of Alzheimer's disease (AD). Nonetheless, longitudinal trajectory of Aβ‐associated hippocampal subfield atrophy prior to dementia remains unclear. We hypothesized that elevated Aβ correlated with longitudinal subfield atrophy selectively in no cognitive impairment (NCI), spreading to other subfields in mild cognitive impairment (MCI). We analyzed data from two independent longitudinal cohorts of nondemented elderly, including global PET‐Aβ in AD‐vulnerable cortical regions and longitudinal subfield volumes quantified with a novel auto‐segmentation method (FreeSurfer v.6.0). Moreover, we investigated associations of Aβ‐related progressive subfield atrophy with memory decline. Across both datasets, we found a converging pattern that higher Aβ correlated with faster CA1 volume decline in NCI. This pattern spread to other hippocampal subfields in MCI group, correlating with memory decline. Our results for the first time suggest a longitudinal focal‐to‐widespread trajectory of Aβ‐associated hippocampal subfield atrophy over disease progression in nondemented elderly.     

The overall pathological status of the left hippocampus determines preoperative verbal memory performance in left mesial temporal lobe epilepsy

Studies on hippocampal cell loss in epilepsy have produced diverging evidence as to which subfields are specifically related to memory. This may be due to rather small and often heterogeneous samples, or to different memory measures. Therefore, the current study examined hippocampal cell densities and memory in a large sample of patients with solely mesial temporal lobe epilepsy (mTLE), employing measures with proven sensitivity to mesiotemporal pathology. In 104 patients who had undergone epilepsy surgery for mTLE, we evaluated the role of segmental hippocampal cell loss and its underlying factor structure with regard to presurgical verbal and figural memory while controlling for side‐of‐surgery and hemispheric dominance. First of all, patients showed material‐specific memory impairment concordant with the lateralization of epilepsy. Factor analysis of segmental cell loss revealed a single factor reflecting the overall integrity of the hippocampus. The overall pathological status of the left hippocampus correlated with verbal memory parameters (r = 0.33–0.34, P < 0.05), especially when controlling for atypical hemispheric dominance (r = 0.50–0.57, P < 0.01), and explained up to 33% of the observed variance. Further analyses revealed no superior role of a single subfield or cell loss pattern for memory performance. No systematic relations between neuronal cell densities of the right hippocampus and memory function were found, nor did left or right hippocampal pathology explain figural memory parameters. The results suggest that the overall pathological status of the left hippocampus – rather than a specific subfield pathology – is predictive for verbal memory in mTLE. The finding that figural memory parameters, although sensitive to right mTLE, were not related to neuronal cell densities of the right hippocampus, puts the left/right hippocampus verbal/nonverbal memory dichotomy into perspective. © 2014 Wiley Periodicals, Inc.     

The epileptogenic zone in pharmaco‐resistant temporal lobe epilepsy with amygdala enlargement

Aims. Temporal lobe epilepsy with amygdala enlargement (TLE‐AE) has been considered a subtype of TLE. We evaluated the epileptogenic zone in patients with TLE‐AE, who underwent intracranial video‐EEG (ivEEG) and/or intraoperative electrocorticography (ioECoG) as well as epilepsy surgery. Methods. Eleven patients with TLE‐AE were enrolled and investigated based on seizure profile, volumetric MRI, the Wechsler Memory Scale‐Revised (WMS‐R), the location of seizure onset zone (SOZ) and irritative zone (IZ) based on ivEEG (n=8), the location of interictal epileptiform discharges (IEDs) based on ioECoG (11), surgical procedure, and seizure outcome. Results. The mean age at seizure onset was 34.9 years (range: 23–57). The mean duration of seizures was 5.0 years (range: 1–10). The number of AEDs was 2.3 (range: 1–5). The mean seizure frequency was nine per month (range: 1–30/month). All patients presented with focal impaired awareness seizures with (n=9) and without (2) secondary generalized convulsions. Volumetric MRI analysis showed unilateral enlarged amygdala with statistical significance (p<0.01). None of the patients' hippocampi had any abnormality based on MRI. Pre‐operative mean verbal, visual, and delayed recall scores based on the WMS‐R were over 100. The SOZ and IZ were identified in both the amygdala and hippocampus in seven patients and in only the amygdala in one patient based on ivEEG. IEDs were identified in the hippocampus in six patients and in both the amygdala and hippocampus in four patients based on ioECoG. All 11 patients underwent anterior temporal lobectomy, including amygdala resection, with multiple hippocampal transections (dominant hemisphere: seven patients) and resection (non‐dominant hemisphere: three patients). Nine (81.8%) of 11 patients achieved seizure freedom with a mean follow‐up of 26 months (range: 12–47). Post‐operative WMS‐R results did not show any significant deterioration, with a mean follow‐up of 15 months (range: 12–24). The resected amygdala showed no histopathological abnormality. Conclusion. The epileptogenic zone of TLE‐AE involves both the amygdala and hippocampus. ivEEG may be needed to explore the SOZ in normal hippocampus in addition to enlarged amygdala. Amygdala resection and multiple hippocampal transections may control the epileptogenic limbic system and save memory function in patients with TLE‐AE.     

Age differences in hippocampal subfield volumes from childhood to late adulthood

The hippocampus is composed of distinct subfields: the four cornu ammonis areas (CA1‐CA4), dentate gyrus (DG), and subiculum. The few in vivo studies of human hippocampal subfields suggest that the extent of age differences in volume varies across subfields during healthy childhood development and aging. However, the associations between age and subfield volumes across the entire lifespan are unknown. Here, we used a high‐resolution imaging technique and manually measured hippocampal subfield and entorhinal cortex volumes in a healthy lifespan sample (N = 202), ages 8–82 yrs. The magnitude of age differences in volume varied among the regions. Combined CA1‐2 volume evidenced a negative linear association with age. In contrast, the associations between age and volumes of CA3‐DG and the entorhinal cortex were negative in mid‐childhood and attenuated in later adulthood. Volume of the subiculum was unrelated to age. The different magnitudes and patterns of age differences in subfield volumes may reflect dynamic microstructural factors and have implications for cognitive functions across the lifespan. © 2015 Wiley Periodicals, Inc.     

Contribution of nitric oxide, superoxide anion, and peroxynitrite to activation of mitochondrial apoptotic signaling in hippocampal CA3 subfield following experimental temporal lobe status epilepticus

Purpose: One cellular consequence of status epilepticus is apoptosis in the hippocampal CA3 subfield. We evaluated the hypothesis that the repertoire of cellular events that underlie such elicited cell death entails mitochondrial dysfunction induced by an excessive production of nitric oxide synthase II (NOS II)‐derived NO, increased superoxide anion (O₂^?) production, and peroxynitrite formation. Methods: In Sprague‐Dawley rats, kainic acid was microinjected unilaterally into the hippocampal CA3 subfield to induce bilateral seizure‐like electroencephalography (EEG) activity. The effects of pretreatments with various test agents on the induced O₂^? production, peroxynitrite formation, mitochondrial respiratory chain enzyme activities, cytochrome c/caspase‐3 signaling, and DNA fragmentation in bilateral CA3 subfields were examined. Results: Significantly and temporally correlated increase in O₂^? and peroxynitrite levels (3 to 24 h), depressed mitochondrial Complex I activity (3 h), enhanced translocation of cytochrome c to cytosol (day 1), and augmented activated caspase‐3 (day 7) and DNA fragmentation (day 7) were detected bilaterally in hippocampal CA3 subfields after the elicitation of sustained seizure. Pretreatment with microinjection into the bilateral hippocampal CA3 subfield of a water‐soluble formulation of coenzyme Q₁₀; a selective NOS II inhibitor, S‐methylisothiourea; a superoxide dismutase mimetic, 4‐hydroxy‐2,2,6,6‐tetramethylpiperidine‐1‐oxyl; an active peroxynitrite decomposition catalyst, 5,10, 15,20‐tetrakis‐(N‐methyl‐4‐pyridyl)‐ porphyrinato iron (III); or a peroxynitrite scavenger, L‐cysteine significantly blunted these cellular events. Discussion: Prolonged seizures prompted NO‐, O₂^?‐, and peroxynitrite‐dependent reduction in mitochondrial respiratory enzyme Complex I activity, leading to cytochrome c/caspase‐3‐dependent apoptotic cell death in the hippocampal CA3 subfield after induction of experimental temporal lobe status epilepticus.     

Auditory event‐related potentials (P300) and mesial temporal sclerosis in temporal lobe epilepsy patients

Aims. To investigate the role of centrally recorded P300 in patients suffering from mesial temporal sclerosis‐temporal lobe epilepsy (MTS‐TLE). Methods. Sixteen patients (3 men and 13 women; median age: 32.5 years old) suffering from TLE with MTS and 43 healthy controls (12 men and 31 women; median age: 35 years old) participated in the study. P300 was elicited using an auditory two‐stimulus oddball paradigm. In order to address the aim of the study, we adopted two statistical approaches; hierarchical linear regression analyses and ROC curves. Results. After adjusting for age, MTS patients had a mean reduction of P300 amplitude by 6.93 μV and a mean increase of P300 latency by 38.78 ms, compared to controls. Age and MTS‐TLE status accounted for 32 and 16% of the variance of latency and amplitude, respectively. Diagnostic analyses to detect MTS‐TLE status revealed a sensitivity and specificity of 88 and 65% for amplitude and 81 and 70% for latency, respectively. No association between duration of disease and P300 characteristics were found. Conclusions. This study, along with other studies, contributes to our understanding and clinical significance of centrally recorded P300s in MTS‐TLE patients. Future studies should focus on the association of these P300s with cognition in such patients.     

Bilateral hippocampal atrophy in temporal lobe epilepsy: effect of depressive symptoms and febrile seizures

Purpose: Neuroimaging studies suggest a history of febrile seizures, and depression, are associated with hippocampal volume reductions in patients with temporal lobe epilepsy (TLE). Methods: We used radial atrophy mapping (RAM), a three‐dimensional (3D) surface modeling tool, to measure hippocampal atrophy in 40 patients with unilateral TLE, with or without a history of febrile seizures and symptoms of depression. Multiple linear regression was used to single out the effects of covariates on local atrophy. Key Findings: Subjects with a history of febrile seizures (n = 15) had atrophy in regions corresponding to the CA1 and CA3 subfields of the hippocampus contralateral to seizure focus (CHC) compared to those without a history of febrile seizures (n = 25). Subjects with Beck Depression Inventory II (BDI‐II) score ≥14 (n = 11) had atrophy in the superoanterior portion of the CHC compared to subjects with BDI‐II <14 (n = 29). Significance: Contralateral hippocampal atrophy in TLE may be related to febrile seizures or depression.     

Involvement of the thalamocortical network in TLE with and without mesiotemporal sclerosis

Purpose: The thalamus plays an important role in seizure propagation in temporal lobe epilepsy (TLE). This study investigated how structural abnormalities in the focus, ipsilateral thalamus and extrafocal cortical structures relate to each other in TLE with mesiotemporal sclerosis (TLE‐MTS) and without hippocampal sclerosis (TLE‐no). Methods: T₁ and high‐resolution T₂ images were acquired on a 4T magnet in 29 controls, 15 TLE‐MTS cases, and 14 TLE‐no. Thalamus volumes were obtained by warping a labeled atlas onto each subject’s brain. Deformation‐based morphometry was used to identify regions of thalamic volume loss and FreeSurfer for cortical thickness measurements. CA1 volumes were obtained from high‐resolution T₂ images. Multiple regression analysis and correlation analyses for voxel‐ and vertex‐based analyses were performed in SPM2 and FreeSurfer. Results: TLE‐MTS had bilateral volume loss in the anterior thalamus, which was correlated with CA1 volume and cortical thinning in the mesiotemporal lobe. TLE‐no had less severe volume loss in the dorsal lateral nucleus, which was correlated with thinning in the mesiotemporal region but not with extratemporal thinning. Discussion: The findings suggest that seizure propagation from the presumed epileptogenic focus or regions close to it into the thalamus occurs in TLE‐MTS and TLE‐no and results in circumscribed neuronal loss in the thalamus. However, seizure spread beyond the thalamus seems not to be responsible for the extensive extratemporal cortical abnormalities in TLE.     

Distinct increased metabotropic glutamate receptor type 5 (mGluR5) in temporal lobe epilepsy with and without hippocampal sclerosis

Metabotropic glutamate receptor type 5 (mGluR5) upregulation in temporal lobe epilepsy (TLE) and the correlation of its expression with features of hippocampal sclerosis (HS) remains unclear. Here we characterized mGluR5 immunoreactivity in hippocampus, entorhinal cortex (EC), and subiculum of TLE specimens with confirmed HS, with neocortical TLE (non‐HS) and necropsy controls. We correlated mGluR5 immunoreactivity with neuronal density, mossy fiber sprouting, astrogliosis (GFAP), and dendritic alterations (MAP2). TLE specimens showed increased mGluR5 expression, which was most pronounced in the EC, subiculum, CA2, and dentate gyrus outer molecular layer. Increased mGluR5 expression was seen in hippocampal head and body segments and was independent of neuronal density, astrogliosis, or dendritic alterations. Positive correlation between mGluR5 expression with mossy fiber sprouting and with MAP2 in CA3 and CA1 was found only in HS specimens. Negative correlation between mGluR5 expression with seizure frequency and epilepsy duration was found only in non‐HS cases. Specimens from HS patients without previous history of febrile seizure (FS) showed higher mGluR5 and MAP2 expression in CA2. Our study suggests that mGluR5 upregulation is part of a repertoire of post‐synaptic adaptations that might control overexcitation and excessive glutamate release rather than a dysfunction that leads to seizure facilitation. That would explain why non‐HS cases, on which seizures are likely to originate outside the hippocampal formation, also exhibit upregulated mGluR5. On the other hand, lower mGluR5 expression was related to increased seizure frequency. In addition to its role in hyperexcitability, mGluR5 upregulation could play a role in counterbalance mechanisms along the hyperexcitable circuitry uniquely altered in sclerotic hippocampal formation. Inefficient post‐synaptic compensatory morphological (dendritic branching) and glutamatergic (mGluR5 expression) mechanisms in CA2 subfield could potentially underlie the association of FS with HS and TLE. © 2013 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

A new clinico-pathological classification system for mesial temporal sclerosis

We propose a histopathological classification system for hippocampal cell loss in patients suffering from mesial temporal lobe epilepsies (MTLE). One hundred and seventy-eight surgically resected specimens were microscopically examined with respect to neuronal cell loss in hippocampal subfields CA1–CA4 and dentate gyrus. Five distinct patterns were recognized within a consecutive cohort of anatomically well-preserved surgical specimens. The first group comprised hippocampi with neuronal cell densities not significantly different from age matched autopsy controls [no mesial temporal sclerosis (no MTS); n = 34, 19%]. A classical pattern with severe cell loss in CA1 and moderate neuronal loss in all other subfields excluding CA2 was observed in 33 cases (19%), whereas the vast majority of cases showed extensive neuronal cell loss in all hippocampal subfields (n = 94, 53%). Due to considerable similarities of neuronal cell loss patterns and clinical histories, we designated these two groups as MTS type 1a and 1b, respectively. We further distinguished two atypical variants characterized either by severe neuronal loss restricted to sector CA1 (MTS type 2; n = 10, 6%) or to the hilar region (MTS type 3, n = 7, 4%). Correlation with clinical data pointed to an early age of initial precipitating injury (IPI < 3 years) as important predictor of hippocampal pathology, i.e. MTS type 1a and 1b. In MTS type 2, IPIs were documented at a later age (mean 6 years), whereas in MTS type 3 and normal appearing hippocampus (no MTS) the first event appeared beyond the age of 13 and 16 years, respectively. In addition, postsurgical outcome was significantly worse in atypical MTS, especially MTS type 3 with only 28% of patients having seizure relief after 1-year follow-up period, compared to successful seizure control in MTS types 1a and 1b (72 and 73%). Our classification system appears suitable for stratifying the clinically heterogeneous group of MTLE patients also with respect to postsurgical outcome studies.     

Predictors of outcome after temporal lobectomy for refractory temporal lobe epilepsy

Objective – To identify predictors of outcome after epilepsy surgery in patients with temporal lobe epilepsy (TLE). Methods – Seventy‐six patients with normal magnetic resonance imaging (MRI) or hippocampal sclerosis on MRI who underwent anterior temporal lobe resections were included. Outcome 2 years after surgery was classified as good (Engel I and II) or poor (Engel III and IV). Gender, age at onset and duration of epilepsy, history of febrile convulsions, auras, right‐ or left‐sided TLE, memory ipsilateral to seizure onset (Wada test), hippocampal asymmetry (HA) and T2 relaxation time, amygdala, temporal lobe and hemispheral volume were tested for associations with outcome. Results – Sixty‐seven percent had a good outcome. Of all parameters tested, only a history of febrile convulsions and HA on quantitative MRI were significantly associated with a good seizure outcome. The absence of these parameters did not exclude a good outcome, but only five of 18 patients (28%) without HA and without a history of febrile convulsions had a good outcome. Conclusion – Febrile convulsions and HA were predictors of outcome after epilepsy surgery in TLE. Subtle volume loss in amygdala, temporal lobe or hemispheres and the memory ipsilateral to the side of resection were not associated with outcome.     

A High‐resolution study of hippocampal and medial temporal lobe correlates of spatial context and prospective overlapping route memory

When navigating our world we often first plan or retrieve an ideal route to our goal, avoiding alternative paths that lead to other destinations. The medial temporal lobe (MTL) has been implicated in processing contextual information, sequence memory, and uniquely retrieving routes that overlap or “cross paths.” However, the identity of subregions of the hippocampus and neighboring cortex that support these functions in humans remains unclear. The present study used high‐resolution functional magnetic resonance imaging (hr‐fMRI) in humans to test whether the CA3/DG hippocampal subfield and parahippocampal cortex are important for processing spatial context and route retrieval, and whether the CA1 subfield facilitates prospective planning of mazes that must be distinguished from alternative overlapping routes. During hr‐fMRI scanning, participants navigated virtual mazes that were well‐learned from prior training while also learning new mazes. Some routes learned during scanning shared hallways with those learned during pre‐scan training, requiring participants to select between alternative paths. Critically, each maze began with a distinct spatial contextual Cue period. Our analysis targeted activity from the Cue period, during which participants identified the current navigational episode, facilitating retrieval of upcoming route components and distinguishing mazes that overlap. Results demonstrated that multiple MTL regions were predominantly active for the contextual Cue period of the task, with specific regions of CA3/DG, parahippocampal cortex, and perirhinal cortex being consistently recruited across trials for Cue periods of both novel and familiar mazes. During early trials of the task, both CA3/DG and CA1 were more active for overlapping than non‐overlapping Cue periods. Trial‐by‐trial Cue period responses in CA1 tracked subsequent overlapping maze performance across runs. Together, our findings provide novel insight into the contributions of MTL subfields to processing spatial context and route retrieval, and support a prominent role for CA1 in distinguishing overlapping episodes during navigational “look‐ahead” periods. © 2014 Wiley Periodicals, Inc.     

Functional and structural changes in the memory network associated with left temporal lobe epilepsy

Understanding functional plasticity in memory networks associated with temporal lobe epilepsy (TLE) is central to predicting memory decline following surgery. However, the extent of functional reorganization within memory networks remains unclear. In this preliminary study, we used novel analysis methods assessing network‐level changes across the brain during memory task performance in patients with TLE to test the hypothesis that hippocampal functions may not readily shift between hemispheres, but instead may show altered intra‐hemispheric organization with unilateral damage. In addition, we wished to relate functional differences to structural changes along specific fibre pathways associated with memory function. Nine pre‐operative patients with intractable left TLE and 10 healthy controls underwent functional MRI during complex scene encoding. Diffusion tensor imaging was additionally performed in the same patients. In our study, we found no evidence of inter‐hemispheric shifts in memory‐related activity in TLE using standard general linear model analysis. However, tensor independent component analysis revealed significant reductions in functional connectivity between bilateral MTL, occipital and left orbitofrontal regions among others in left TLE. This altered orbitofrontal activity was directly related to measures of fornix tract coherence in patients (P < 0.05). Our results suggest that specific fibre pathways, potentially affected by MTL neurodegeneration, may play a central role in functional plasticity in TLE and highlight the importance of network‐based analysis approaches. Relative to standard model‐based methods, novel objective functional connectivity analyses may offer improved sensitivity to subtle changes in the distribution of memory functions relevant for surgical planning in TLE. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Ex vivo study of dentate gyrus neurogenesis in human pharmacoresistant temporal lobe epilepsy

M. Paradisi, M. Fernández, G. Del Vecchio, G. Lizzo, G. Marucci, M. Giulioni, E. Pozzati, T. Antonelli, G. Lanzoni, G. P. Bagnara, L. Giardino and L. Calzà (2010) Neuropathology and Applied Neurobiology 36, 535–550
Ex vivo study of dentate gyrus neurogenesis in human pharmacoresistant temporal lobe epilepsy Aims: Neurogenesis in adult humans occurs in at least two areas of the brain, the subventricular zone of the telencephalon and the subgranular layer of the dentate gyrus in the hippocampal formation. We studied dentate gyrus subgranular layer neurogenesis in patients subjected to tailored antero‐mesial temporal resection including amygdalohippocampectomy due to pharmacoresistant temporal lobe epilepsy (TLE) using the in vitro neurosphere assay. Methods: Sixteen patients were enrolled in the study; mesial temporal sclerosis (MTS) was present in eight patients. Neurogenesis was investigated by ex vivo neurosphere expansion in the presence of mitogens (epidermal growth factor + basic fibroblast growth factor) and spontaneous differentiation after mitogen withdrawal. Growth factor synthesis was investigated by qRT‐PCR in neurospheres. Results: We demonstrate that in vitro proliferation of cells derived from dentate gyrus of TLE patients is dependent on disease duration. Moreover, the presence of MTS impairs proliferation. As long as in vitro proliferation occurs, neurogenesis is maintained, and cells expressing a mature neurone phenotype (TuJ1, MAP2, GAD) are spontaneously formed after mitogen withdrawal. Finally, formed neurospheres express mRNAs encoding for growth (vascular endothelial growth factor) as well as neurotrophic factors (brain‐derived neurotrophic factor, ciliary neurotrophic factor, glial‐derived neurotrophic factor, nerve growth factor). Conclusion: We demonstrated that residual neurogenesis in the subgranular layer of the dentate gyrus in TLE is dependent on diseases duration and absent in MTS.