Voxel-based T2 relaxation rate measurements in temporal lobe epilepsy (TLE) with and without mesial temporal sclerosis

INTRODUCTION: Quantitative measurements of T(2) relaxation in the hippocampus for focus lateralization in mesial temporal lobe epilepsy (mTLE) are well established. Less is known to what degree such relaxation abnormalities also affect regions beyond the ipsilateral hippocampus. Therefore, the aim of this study was to characterize extent and distribution pattern of extrahippocampal relaxation abnormalities in TLE with (TLE-MTS) and without MRI evidence of mesial-temporal sclerosis (TLE-no). METHODS: Double spin echo images (TE1/2: 20/80 ms) acquired in 24 TLE-MTS and 18 TLE-no were used to calculate relaxation rate maps. These maps were analyzed by SPM2 and by selecting regions of interest (ROI) in the hippocampus and several extrahippocampal brain regions. RESULTS: In TLE-MTS, the results of the SPM and ROI analysis were in good agreement and showed the most severe relaxation rate decreases in the ipsilateral hippocampus but also in other ipsilateral temporal regions, orbitofrontal, and parietal regions and to a lesser degree in contralateral frontal regions. The relaxation rate decreases in TLE-no were confined to small regions in the ipsilateral anterior inferior and medial temporal lobe in the SPM analysis while ROI analysis showed additional regions in the ipsilateral hippocampus, amygdala, and anterior cingulate. CONCLUSION: TLE-MTS showed extensive, widespread but predominantly ipsilateral temporal and also extratemporal T(2) relaxation rate decreases. In contrast, the findings of the SPM and ROI analyses in TLE-no suggested that if relaxation rate decreases are present, they are less uniform and generally milder than in TLE-MTS. This further supports the hypothesis that TLE-no is a distinct clinicopathological entity from TLE-MTS and probably heterogeneous in itself.     

Association between APOE polymorphisms and mesial temporal lobe epilepsy with hippocampal sclerosis.

To evaluate the hypothetical link between apolipoprotein E (APOE) polymorphisms and mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) and whether presence of APOE epsilon4 allele shortens the latent period between febrile seizures and epilepsy. A further interest is whether presence of APOE epsilon4 allele has an impact on severity of the disease. Forty-seven patients with MTLE-HS were compared with 62 controls. APOE polymorphisms were determined from lymphocytes by standard methods. Eight patients (17%) and 10 controls (16.1%) were demonstrated to have one APOE epsilon4 allele. There was not any statistically significant difference in APOE epsilon4 frequency between patients and controls (P > 0.05). There was not any difference statistically according to onset age of epilepsy and the presence of APOE epsilon4 allele within patient group. APOE epsilon4 polymorphisms did not influence the severity of epilepsy. APOE epsilon4 polymorphisms had no impact on outcome after surgery. Patients with bilateral memory deficits, bilateral hippocampal atrophy and with bilateral epileptiform interictal EEG transients, were independently compared with patients having unilateral features and there were not any statistically significant differences. This study has found no association between APOE epsilon4 polymorphisms and presentation of MTLE-HS in a group of Turkish patients.     

Voxel-based optimized morphometry (VBM) of gray and white matter in temporal lobe epilepsy (TLE) with and without mesial temporal sclerosis

PURPOSE: In temporal lobe epilepsy (TLE) with evidence of hippocampal sclerosis (TLE-MTS) volumetric gray (GM) and white (WM) matter abnormalities are not restricted to the hippocampus but also are found in extrahippocampal structures. Less is known about extrahippocampal volumetric abnormalities in TLE without hippocampal sclerosis (TLE-no). In this study, we used optimized voxel-based morphometry (VBM) with and without modulation with the following aims: (a) to identify WM and GM abnormalities beyond the hippocampus in TLE-MTS and TLE-no; and (b) to determine whether extratemporal WM and GM abnormalities differ between TLE-MTS and TLE-no. METHODS: Optimized VBM of GM and WM with and without modulation was performed in 26 TLE-MTS (mean age, 35.6 +/- 9.7 years), 17 TLE-no (mean age, 35.6 +/- 11.1 years), and 30 healthy controls (mean age, 30.3 +/- 11.1 years). RESULTS: In TLE-MTS, GM/WM volume and concentration reductions were found in the ipsilateral limbic system, ipsi- and contralateral neocortical regions, thalamus, cerebellum, internal capsule, and brainstem when compared with controls. In contrast, no differences of GM/WM volumes/concentrations were found between TLE-no and controls or between TLE-no and TLE-MTS. CONCLUSIONS: In TLE-MTS, optimized VBM showed extensive GM and WM volume reductions in the ipsilateral hippocampus and in ipsi- and contralateral extrahippocampal regions. In contrast, no GM/WM volume or concentration reductions were found in TLE-no. This further supports the hypothesis that TLE-no is a distinct clinicopathologic entity from TLE-MTS and probably heterogeneous in itself.     

Thalamic diffusion and volumetry in temporal lobe epilepsy with and without mesial temporal sclerosis

PURPOSE: As an important connection within the limbic system, considerable attention has been paid to thalamic pathology in temporal lobe epilepsy (TLE). Magnetic resonance imaging (MRI) volumetric studies have yielded variable results and have largely been focused on TLE with mesial temporal sclerosis (TLE+). Diffusion tensor imaging (DTI) provides unique information on microstructure based on the measurement of water diffusion. To date, DTI properties of thalamus have not been well characterized in adult TLE patients with unilateral MTS or without MTS (TLE-). The purpose of this study was to investigate the status of thalamic integrity by using DTI as well as volumetric MRI in adult TLE+ and TLE- patients. METHOD: In 17 unilateral TLE+ patients, 10 TLE- patients and 26 controls, the thalamus was segmented by using an automated atlas-based method. Mean diffusivity (MD), fractional anisotropy (FA) and volume were then quantified from DTI and 3D T1-weighted scans. RESULTS: No significant changes were found in either DTI parameters or volume of thalamus in TLE- patients, as compared to healthy controls. However, both DTI parameters and MRI volumetry showed bilateral thalamic pathology in TLE+ patients, as compared to healthy controls. Also, TLE+ patients showed significant reduction of thalamic volume as compared to TLE- patients. In addition, thalamic FA ipsilateral to seizure focus showed significant correlation with age at onset of epilepsy in TLE+ patients. CONCLUSION: Our finding demonstrates bilateral pathology of thalamus in unilateral TLE+ patients. The discrepancy in thalamic pathology between TLE+ and TLE- patients suggests that along with differences in mesial temporal pathology, TLE+ and TLE- have unique extratemporal structural abnormalities.     

Neuropathological features of mesial temporal sclerosis: Histochemical studies of surgically resected specimens from patients with temporal lobe epilepsy

Mesial temporal sclerosis (MTS) is the most common pathological finding in temporal lobe epilepsy (TLE), but the relationship between MTS and hyperexcitability has not been defined. The neuropathological findings of MTS on the basis of our histochemical investigations using surgically resected specimens from patients with intractable TLE will be reviewed and discussed. Various sclerotic changes including neuronal loss and astrogliosis were observed not only in the hippocampus but also in the other mesial temporal structures such as the amygdala and entorhinal cortex. Moreover, aberrant residual pyramidal neurons were recognized, which showed morphological abnormalities; abnormal distribution of zinc, γ-aminobutyric acid-A receptor and glutamate decarboxy-lase; and disorganization of the granule cell layer (dispersion and bilaminar distribution). Increases in density of the corpora amylacea and peripheral type benzodiazepine receptor binding corresponded with glial proliferation. Histochemical studies demonstrated the association of mossy fiber sprouting with synaptic reorg-anization and changes of several chemically defined inter-neuron systems in the dentate gyrus. Quantitative analysis using in vitro autoradiography showed that neurotrans-mitter receptor bindings related to neuronal excitation (AMPA and NMDA receptor) and inhibition (central type benzodiazepine receptor) were reduced differently as a function of neuronal loss in MTS. These cytochemical changes associated with neurotransmitters and their receptors in the sclerotic hippocampus may constitute the pathological background of epileptogenesis in TLE.     

Prognostic factors in the surgical treatment of medically intractable epilepsy associated with mesial temporal sclerosis

OBJECTIVES: To assess the prognostic factors determining seizure remission after temporal lobectomy for intractable epilepsy associated with mesial temporal sclerosis (MTS) at pathology. METHODS: The clinical and investigative features of 116 consecutive patients who had temporal lobe surgery for drug-resistant epilepsy and MTS at pathology were assessed using actuarial statistics and logistic regression analysis. RESULTS: At a median follow-up of 63 months the probability of achieving at least a 1-year period of continuous seizure freedom was 67%. Factors contributing to a favourable outcome were interictal EEG localization to the operated lobe and the absence of secondarily generalized seizures. These were also selected in the multivariate analysis, although at lower statistical significance (P=0.08 and 0.09, respectively). Perinatal complications were associated with a significantly worse outcome but overall, complicated febrile convulsions and congruent neuropsychological deficits were not significantly predictive variables. CONCLUSIONS: The present findings may aid in the non-invasive presurgical assessment of patients with intractable TLE and clinical and neuroimaging evidence of MTS.     

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.     

Memory in patients with drug-responsive mesial temporal lobe epilepsy and hippocampal sclerosis

PURPOSE: Mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS) is the most common of the antiepileptic drug (AED)-resistant seizure syndromes that are remediable mostly with surgery, although a small group of patients have benign prognosis with fewer seizures. Material-specific memory impairment is an important feature in these patients and may be related to both the structural abnormality and the frequent seizures. In this study, we investigated the relation between memory deficit and HS by taking seizure frequency into account. METHODS: The patients were evaluated according to a standard protocol and divided into two groups, considering their response to AEDs: the good-responder group (GRg, n = 18) and the pharmacoresistant group (PRg, n = 95). They were administered a neuropsychological test battery that included verbal and nonverbal memory tests, compared with each other and with a normal control group (n = 29). The responder group was evaluated by the same battery once again (mean, 23 months; SD, 8.25; range, 14-38 months). RESULTS: Both GR and PR patient groups had poorer memory than the normal controls in all memory tests (p < 0.05). However, the comparison of GRg with PRg revealed that only the digit-span test was significantly worse in PRg (p = 0.0061), and no difference was found in any other memory scores. The reevaluation of the GRg showed no significant difference between the first and second evaluation. CONCLUSIONS: We concluded that the memory impairment in patients with MTLE-HS was permanent and might be related to the direct effect of HS itself. Therefore patients with good response to AEDs can be used as a model for investigating the memory problems in patients with MTLE-HS.     

Outcome after corticoamygdalohippocampectomy in patients with refractory temporal lobe epilepsy and mesial temporal sclerosis without preoperative ictal recording

Purpose:   We report on the surgical outcome obtained in patients with refractory temporal lobe epilepsy with mesial temporal sclerosis (MTS) who were evaluated preoperatively without ictal recording and were submitted to corticoamygdalohippocampectomy.
Methods:   Two hundred twelve patients with refractory temporal lobe epilepsy were evaluated by means of clinical history, neurological examination, interictal electroencephalography (EEG), magnetic resonance imaging (MRI), and neuropsychological testing. MRI disclosed unilateral MTS in all patients. All patients were submitted to corticoamygdalohippocampectomy at the side determined by MRI.
Results:   Interictal EEG showed unilateral temporal lobe spiking in 176 patients; in 36 patients, bilateral discharges were found. Mean follow-up time was 2.7  years. One hundred ninety-four patients (92%) were classified as Engel's class I. Eighteen patients (8%) were rated as Engel's class II. Thirty-two out of 36  patients, in whom bilateral discharges were found, were in Engel's class I. Sixty percent of the patients had an improvement in memory function related to the nonoperated temporal lobe. Fifty-nine percent of the patients had a 10-point increase in general IQ postoperatively. Verbal memory decline was noted in three patients. Pathological examination showed MTS in all patients.
Conclusions:   It is possible to adequately select good surgical candidates for temporal lobe resection using MRI and interictal EEG alone. In patients with MRI-defined MTS, we should expect a 90% postoperative remission rate. Cognitive decline was very rarely seen in this patient population. The finding of MTS on MRI is the single most important prognostic factor for good outcome after temporal lobe surgery.     

Anomalous expression of chloride transporters in the sclerosed hippocampus of mesial temporal lobe epilepsy patients

The Na+-K+-Cl-cotransporter 1 and K+-Cl-cotransporter 2 regulate the levels of intracellular chloride in hippocampal cells.Impaired chloride transport by these proteins is thought to be involved in the pathophysiological mechanisms of mesial temporal lobe epilepsy.Imbalance in the relative expression of these two proteins can lead to a collapse of Cl-homeostasis,resulting in a loss of gamma-aminobutyric acid-ergic inhibition and even epileptiform discharges.In this study,we investigated the expression of Na+-K+-Cl-cotransporter 1 and K+-Cl-cotransporter 2 in the sclerosed hippocampus of patients with mesial temporal lobe epilepsy,using western blot analysis and immunohistochemistry.Compared with the histologically normal hippocampus,the sclerosed hippocampus showed increased Na+-K+-Cl-cotransporter 1 expression and decreased K+-Cl-cotransporter 2 expression,especially in CA2 and the dentate gyrus.The change was more prominent for the Na+-K+-Cl-cotransporter 1 than for the K+-Cl-cotransporter 2.These experimental findings indicate that the balance between intracellular and extracellular chloride may be disturbed in hippocampal sclerosis,contributing to the hyperexcitability underlying epileptic seizures.Changes in Na+-K+-Cl-cotransporter 1 expression seems to be the main contributor.Our study may shed new light on possible therapies for patients with mesial temporal lobe epilepsy with hippocampal sclerosis.     

Predictive value of MRI-identified mesial temporal sclerosis for surgical outcome in temporal lobe epilepsy: an intent-to-treat analysis

PURPOSE: Magnetic resonance imaging (MRI) accurately identifies mesial temporal sclerosis (MTS), but prediction of successful surgical outcome ranges from 62% to 96% in published studies. Prior investigations only used patients who had received anterior temporal lobectomy (ATL), potentially overestimating the predictive value of MRI-identified MTS (MRI-MTS). METHODS: The authors performed an intent-to-treat analysis of 90 consecutive patients assessed for possible ATL, including 13 who did not undergo ATL because of inconclusive intracranial ictal EEG. Four (31%) of these 13 patients had unilateral mesial temporal abnormalities on their MRIs. RESULTS: The positive predictive value of MRI-MTS for seizure cessation decreased from 0.69 to 0.63 after adjustment for these additional false positive results. Four previous studies had revealed a positive predictive value of 0.75 (0.72 after similar adjustment). CONCLUSIONS: The authors conclude that the predictive value of MRI-MTS for outcome from ATL may be overestimated by small retrospective studies of highly selected postoperative patients.     

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.     

Memory characteristics in mesial temporal lobe epilepsy: Insights from an eye tracking memory game and neuropsychological assessments

Aims

To compare different patterns of memory impairment in patients with two subtypes of mesial temporal lobe epilepsy (MTLE) and healthy controls.

Methods

Thirty-five healthy controls and 41 patients with MTLE were recruited, of which 25 patients were diagnosed as hippocampal sclerosis (HS-MTLE), and the rest 16 patients were lesion-negative (MRI-neg MTLE). Participants completed the Wechsler memory assessment and a short-term memory game on an automated computer-based memory assessment platform with an eye tracker.

Results

Both the MRI-neg MTLE and HS-MTLE groups took longer time to complete the short-term memory game than healthy controls (p < 0.001, Cohen's d = 1.087; p = 0.047, Cohen's d = 0.787). During the memory encoding phase, the MRI-neg MTLE group spent significantly shorter time than healthy controls on the difficult levels with three (p = 0.004, Cohen's d = 0.993) and four targets (p = 0.016, Cohen's d = 0.858). During the memory decoding phase, the HS-MTLE group spent less time looking on the targets compared to controls when recalling and finding four targets (p = 0.004, Cohen's d = −0.793), while the MRI-neg MTLE group spent significantly longer time on the distractors and shorter time on the region of interests (ROIs) for all difficulty levels (all p < 0.05) than controls. Furthermore, the eye tracking data were correlated with the scores of the Wechsler Memory Scale after Bonferroni correction (p < 0.05).

Conclusion

Patients with MRI-neg MTLE demonstrate impaired memory mostly due to attention deficits, while those with HS-MTLE show memory impairment with relative sparing of attention. Eye tracking technology has the potential of facilitating the investigation of the mechanism of memory defect in MTLE and can serve as a supplementary neuropsychological tool for clinical diagnosis and long-term monitoring.     

Periodic epileptiform discharges in mesial temporal lobe epilepsy with hippocampal sclerosis

PurposePeriodic epileptiform discharges (PEDs) are an uncommon, abnormal EEG pattern seen usually in patients with acute diseases and less frequently in chronic conditions, such as mesial temporal lobe epilepsy (mTLE). Evaluate the clinical histories, neuroimaging findings, and serial electrophysiological studies prior to the appearance of PEDs in patients with mTLE secondary to hippocampal sclerosis (HS).MethodsWe searched 19, 375 EEGs (2006–2012) for the presence of PEDs secondary to mTLE due to HS.Results12 patients were included. The patients with PEDs had a high prevalence of psychiatric comorbilities, including major depression (50%), interictal psychosis (16%) and dementia (8%). All of the patients had intractable epilepsy with similar clinical findings. We observed a sequential neurophysiological worsening of the EEG patterns prior to the appearance of PEDs. Five patients with PEDs underwent epilepsy surgery and four were seizure free at follow-up 15 (±9) months.ConclusionsPEDs are rare in patients with mTLE and HS and their presence in these cases could reflect clinical severity and neurophysiologic worsening, clinically manifested by intractable epilepsy and severe psychiatric comorbidities. The presence of PEDs in EEGs of patients with mTLE, however, was not associated with poor postsurgical seizure-freedom.     

Correlation study of optimized voxel-based morphometry and (1)H MRS in patients with mesial temporal lobe epilepsy and hippocampal sclerosis

Purpose:

To assess whether structural and metabolic brain abnormalities are correlated in MTLE/HS syndrome.

Methods:

Optimized voxel‐based morphometry (VBM) of gray matter concentration (GMC) and gray matter volume (GMV) and proton magnetic resonance spectroscopy measurements from both‐sided hippocampal and thalamic regions were performed in 20 MTLE/HS patients and 20 sex‐ and age‐matched healthy controls. The local GMC and GMV values were calculated in both the affected and unaffected hippocampi and ipsilateral and contralateral thalami in patients and healthy subjects, and these were compared. VBM variables and NAA, NAA/Cr and NAA/(Cr+Cho) values from the investigated brain regions were correlated.

Results:

(1) Analysis revealed significantly more extensive GMV reduction than GMC reduction in patients' affected hippocampus. In addition, significant GMV reduction was observed in the ipsilateral thalamus in MTLE/HS patients. (2) Significant decreases in all VBM and MRS variables were revealed in the affected hippocampus. Whilst practically normal GMC values were revealed in patients' both‐sided thalamic regions, a significant decrease in local GMV and metabolic measurements were found in the patients' ipsilateral thalamus. (3) Pearson's correlations between structural and metabolic abnormalities were significant for the ipsilateral thalamus only.

Conclusion:

Structural and metabolic abnormalities as detected by optimized voxel‐based morphometry and ¹H MRS in hippocampal and thalamic regions are only partially correlated in MTLE/HS patients. It seems therefore reasonable that both methods reflect different aspects of brain pathology, which, at least to some degree, might be independently ongoing. Hum Brain Mapp 2009. © 2008 Wiley‐Liss, Inc.