Group‐specific regional white matter abnormality revealed in diffusion tensor imaging of medial temporal lobe epilepsy without hippocampal sclerosis

Purpose: In comparison to temporal lobe epilepsy (TLE) patients with hippocampal sclerosis (TLE‐HS), TLE patients without HS (TLE‐NH) have a similar clinical course but may result in worse surgical outcome. We investigated whether the clinical features related to the lack of HS in TLE patients (TLE‐NH) can be explained by water diffusion abnormalities throughout diffusion tensor imaging (DTI) by voxel‐based analysis. Methods: Nineteen patients with TLE‐HS (left/right TLE 12:7), 18 patients with TLE‐NH (left/right TLE 10:8), and 20 controls were included in the study. By statistical parametric mapping (SPM2), the diffusion properties specific to disease characteristics (TLE‐HS vs. TLE‐NH) were analyzed. Results: In TLE‐HS, we found the areas of increased mean diffusivity (MD) in their ipsilateral temporal and extratemporal areas including the hippocampus, parahippocampal, and frontoparietal regions. Left TLE‐HS showed a characteristic MD increase in the ipsilateral posterior cingulum, isthmus of corpus callosum, and contralateral occipital and temporal regions, which was not observed in right TLE‐HS group. In left TLE‐NH, two regions of increased MD were observed in the ipsilateral posterior fornix (within fusiform gyrus) and posterior cingulum. Right TLE‐NH did not show any increased MD. Discussion: In left TLE‐NH, we could find the water diffusion change along the posterior cingulum, which was quite different from the extensive abnormality from TLE‐HS. In addition, there was a lesion‐side–specific distribution (left predominant) of pathology in mesial TLE. This provides a possibility that TLE‐NH is a heterogenous or entity different from TLE‐HS.     

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.

     

The role of voxel-based morphometry in the detection of cortical dysplasia within the temporal pole in patients with intractable mesial temporal lobe epilepsy

Purpose: To determine whether voxel‐based morphometry (VBM) might contribute to the detection of cortical dysplasia within the temporal pole in patients with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE/HS). Methods: Eighteen patients with intractable MTLE/HS and 30 sex‐ and age‐matched healthy controls were included in the study. All of the patients fulfilled the diagnostic criteria for MTLE/HS and underwent anteromedial temporal resection. VBM without a modulation step was applied to the magnetic resonance (MR) images of the brain. Statistical parametric maps were used to compare structural characteristics such as gray matter concentration (GMC) within the temporal pole among patients and controls separately. The acquired data were then statistically analyzed to determine the congruency between visually inspected MR imaging (MRI) scans and VBM results in the detection of morphologic abnormalities in the temporal pole compared to postoperative histopathologic findings of cortical dysplasia. Key Findings: Histopathologic examination revealed cortical dysplasia within the temporal pole in 11 patients. In detail, according to Palmini’s classification, mild malformations of cortical development (mMCDs) were disclosed in three patients, focal cortical dysplasia (FCD) type Ia in three patients, and FCD type Ib in five patients. Some type of structural temporal pole abnormality was suggested by VBM in 14 patients and by visually inspected MRI scans in 11 patients. The results of VBM were in agreement with the presence/absence of cortical dysplasia in 13 patients (72.2%); this correspondence was significant (p = 0.047). In one case, VBM was false negative and in four cases it was false positive. There was congruence between the results of visual analysis and histologic proof in 55.6% of examined patients, which was not significant. Significance: We found that VBM made a superior contribution to the detection of temporopolar structural malformations (cortical dysplasia) compared to visual inspection. The agreement with postoperative histopathologic proof was clearly significant for VBM results and nonsignificant for visual inspection.     

Voxel‐based morphometry of sporadic epileptic patients with mesiotemporal sclerosis

Purpose : In refractory temporal lobe epilepsy (rTLE), gray matter (GM) abnormalities are not confined to the hippocampus but also are found in extrahippocampal structures. Very recently we observed in mild TLE (mTLE) with or without mesiotemporal sclerosis (MTS), GM reductions in regions outside the presumed epileptogenic focus. To date, there are no studies that directly investigate whether whole‐brain GM volume differs between rTLE and mTLE. Herein, we used optimized voxel‐based morphometry (VBM) to identify GM abnormalities beyond the hippocampus in both rTLE and mTLE with evidence of MTS. Methods : Brain magnetic resonance imaging (MRI) and optimized VBM were performed in 19 unrelated patients with mTLE, 19 patients with rTLE, and 37 healthy controls. MRI diagnosis of MTS was based on the atrophy of the hippocampal formation and/or mesiotemporal hyperintensity on fluid‐attenuated inversion recovery (FLAIR) or T₂ images, or both. Results : No patients (rTLE and mTLE) had generalized tonic–clonic or complex partial seizures for at least 3 weeks before scanning. Both mTLE and rTLE patients showed GM volume reduction of the bilateral thalamus, left hippocampus, and sensorimotor cortex compared with controls. No significant GM difference was found between rTLE and mTLE groups. Discussion : In both rTLE and mTLE, VBM shows GM reductions not confined to the hippocampus involving mainly the thalamus bilaterally. This finding together with the lack of significant GM differences between the two TLE groups supports the hypothesis that mTLE and rTLE might lie along a biologic continuum, suggesting a pathophysiologic role of the thalamus in partial epilepsy.     

Correlation between 1H MRS and memory before and after surgery in mesial temporal lobe epilepsy with hippocampal sclerosis

PURPOSE: Proton magnetic resonance spectroscopy (1H MRS), which can demonstrate neuronal loss and gliosis, may be used as a sensitive tool for lateralization of temporal lobe epilepsy (TLE). Although the correlation between the memory functions and 1H MRS has been investigated, its predictive value after surgery has not been studied previously. This study evaluated memory and 1H MRS values of medically intractable patients with mesial TLE and hippocampal sclerosis (MTLE-HS) before and after selective amygdalohippocampectomy (SAH). METHODS: Twenty-two patients underwent memory tests and 1H MRS investigation before and 6 months after SAH and were compared with nine control subjects. RESULTS: The 1H MRS scores were found to be significantly low on the pathological side of the patients. Both right-sided 1H MRS of right TLE and left-sided 1H MRS values of left TLE patients were correlated only with verbal memory scores. Statistical analysis did not reveal any significance for nonverbal memory scores for both TLE groups on either side, which showed no significant correlation between material specificity and 1H MRS findings. Conversely, regression analyses demonstrated that high right- and low left-sided 1H MRS values obtained before surgery may predict a decline in verbal learning scores after surgery. CONCLUSIONS: 1H MRS can be considered as a useful tool to determine the lateralization in patients with MTLE-HS before the surgery. Although only a weak relation exists between the MRS values and memory scores, presurgical MRS scores may be predictive for a possible deterioration in verbal memory after surgery. However, further studies with higher numbers of cases are needed for confirmation of the results.     

Cortical abnormalities and their cognitive correlates in patients with temporal lobe epilepsy and interictal psychosis

Purpose: To determine whether cortical abnormalities are more severe and widespread in patients with temporal lobe epilepsy (TLE) and interictal psychosis (IP) compared to those with TLE only (NIP) and healthy controls (HC), and to explore the associations between cortical parameters (area, thickness and volume), psychotic symptoms, and cognitive performance. Methods: Twenty‐two patients with IP (9 male; 10 hippocampal sclerosis, HS), 23 TLE nonpsychotic (NIP) patients (11 male; 13 HS) matched for duration of epilepsy and 20 HC participated. Surface‐based morphometry (SBM) was used to measure cortical parameters. Cognition was examined in IP and NIP patients. Associations between cortical parameters and cognition were examined using linear mixed models adjusted by age, gender, and brain volume. Key Findings: IP patients had an earlier onset of epilepsy, more status epilepticus, and worse cognitive performance than NIP patients. In IP patients, cortical thickness was reduced in the inferior frontal gyrus (IFG), and their current IQ was associated with decreases in area, but not thickness, in regions of the frontotemporal cortex. Significance: IP likely reflects the interplay of psychosis‐related genetic factors and the cumulative effects of seizure activity on the brain. Cortical thinning in the IFG, a region implicated in schizophrenia, is likely to be related to seizure activity, whereas changes in IQ, associated with reductions in area of frontotemporal cortex, may be related to the presence of psychosis.     

前颞叶切除术对癫痫患者记忆功能影响的临床研究

目的评估前颞叶切除术对癫痫患者记忆功能的影响。方法对30例颞叶癫痫病例往术前、术后2周和术后6个月以上时分别进行记忆测评,比较患者记忆评分的变化;对24例患者进行1H-MRS成像,评估1H-MRS值与韦氏记忆评分之间的相关关系。结果术前MQ均值与术后2周时有显著性差异,术后6个月以上较术后2周时有显著改善;短时记忆在术前、术后无明显变化;非海马硬化组中患侧NAA/Cr与术前、术后短时记忆差值有相关性,患侧NAA/(Cr Cho)以及健侧与患侧NAA/(Cr Cho)之差与术前、术后MQ差值有相关性。结论术后早期多数患者MQ、长时记忆、瞬时记忆有较明显下降,6个月以后有明显恢复,而短时记忆下降不明显。患侧海马1H-MRS值与术前、术后韦氏记忆评分之间存在一定的相关关系。     

Enhanced actions of adenosine in medial entorhinal cortex layer II stellate neurons in temporal lobe epilepsy are mediated via A(1)-receptor activation

Purpose: The adenosinergic system is known to exert an inhibitory affect in the brain, and as such adenosine has been considered an endogenous anticonvulsant. Entorhinal cortex (EC) layer II neurons, which serve as the primary input to the hippocampus, are spared in temporal lobe epilepsy (TLE) and become hyperexcitable. Because these neurons also express adenosine receptors, the activity of these neurons may be controlled by adenosine, specifically during seizure activity when adenosine levels are thought to rise. In light of this, we determined if the actions of adenosine on medial EC (mEC) layer II stellate neurons are augmented in TLE and by which receptor subtype. Methods: Horizontal brain slices were prepared from rats exhibiting spontaneous seizures (TLE) induced by electrical stimulation and compared with age‐matched control rats. mEC layer II stellate neurons were visually identified, and action potentials (APs) were evoked either by a series of depolarizing current injection steps or via presynaptic stimulation of mEC deep layers. The effects of adenosine were compared with actions of adenosine A₁ and A_2A receptor–specific agonists (CPA and CGS‐21680) and antagonists (DPCPX and ZM‐241385), respectively. Immunohistochemical and qPCR techniques were also employed to assess relative adenosine A₁‐receptor message and expression. Key Findings: mEC layer II stellate neurons were hyperexcitable in TLE, evoking a higher frequency of APs when depolarized and generating bursts of APs when synaptically stimulated. Adenosine reduced AP frequency and synaptically evoked APs in a dose‐dependent manner (500 nm –100 μm ); however, in TLE, the inhibitory actions of adenosine occurred at concentrations that were without affect in control neurons. In both cases, the inhibitory actions of adenosine were mediated via activation of the A₁‐ and not the A_2A‐receptor subtype. Quantitative polymerase chain reaction (qPCR) and immunohistochemical experiments revealed an upregulation of the adenosine A₁ mRNA and an increase in A₁‐receptor staining in TLE neurons compared to control. Significance: Our data indicate that the actions of adenosine on mEC layer II stellate neurons is accentuated in TLE due to an upregulation of adenosine A₁‐receptors. Because adenosine levels are thought to rise during seizure activity, activation of adenosine A₁‐receptors could provide a possible endogenous mechanism to suppress seizure activity and spread within the temporal lobe.     

Electroclinical features of a family with simple febrile seizures and temporal lobe epilepsy associated with SCN1A loss-of-function mutation

PURPOSE: To report in detail the electroclinical features of a large family in which we recently identified a missense mutation (M145T) of a well-conserved amino acid in the first transmembrane segment of domain I of the human SCN1A. We showed that the mutation is associated with a loss of SCN1A function. METHODS: The family originates from southern Italy and contains 35 members spread over four generations. Of the 14 affected individuals, the 13 still living members (7 males, mean age 36.6 +/- 20.4) underwent a complete electroclinical evaluation. RESULTS: All 13 affected family members had febrile seizures (FS) up to the age of 6 years. Age at onset of FS ranged from 5 to 45 months with a mean age of 12.8 +/- 12.9 months. One of the 13 was affected by post-traumatic epilepsy. Three of the 13 later developed temporal lobe epilepsy (TLE) with both simple focal seizures, and also very rare focal complex or nocturnal secondary generalized tonic-clonic seizures. In two of the three patients who later developed TLE, the MRI studies revealed mesial temporal sclerosis. CONCLUSIONS: Our findings illustrate that SCN1A mutations can cause simple FS associated with TLE, which differ from the characteristic clinical spectrum of GEFS+. It is open to conjecture if this unusual phenotype might at least in part be related to the fact that M145T is the first missense mutation found in DIS1 of SCN1A.     

The renin-angiotensin system is upregulated in the cortex and hippocampus of patients with temporal lobe epilepsy related to mesial temporal sclerosis

Purpose: As reported by several authors, angiotensin II (AngII) is a proinflammatory molecule that stimulates the release of inflammatory cytokines and activates nuclear factor κB (NFκB), being also associated with the increase of cellular oxidative stress. Its production depends on the activity of the angiotensin converting enzyme (ACE) that hydrolyzes the inactive precursor angiotensin I (AngI) into AngII. It has been suggested that AngII underlies the physiopathological mechanisms of several brain disorders such as stroke, bipolar disorder, schizophrenia, and disease. The aim of the present work was to localize and quantify AngII AT1 and AT2 receptors in the cortex and hippocampus of patients with temporal lobe epilepsy related to mesial temporal sclerosis (MTS) submitted to corticoamygdalohippocampectomy for seizure control.
Method: Immunohistochemistry, Western blot, and real-time PCR techniques were employed to analyze the expression of these receptors.
Results: The results showed an upregulation of AngII AT1 receptor as well as its messenger ribonucleic acid (mRNA) expression in the cortex and hippocampus of patients with MTS. In addition, an increased immunoexpression of AngII AT2 receptors was found only in the hippocampus of these patients with no changes in its mRNA levels.
Discussion: These data show, for the first time, changes in components of renin-angiotensin system (RAS) that could be implicated in the physiopathology of MTS.     

Long‐term employment of adults with childhood‐onset epilepsy: A prospective population‐based study

Purpose: Our aim was to determine the long‐term employment and predictive factors in adults with childhood‐onset epilepsy living in the community. Methods: A population‐based incidence cohort of 144 children prospectively followed since their first unprovoked seizure before the age of 16 years up to a mean age of 48. Results: At a mean age of 23 years (range 18–35 years) 85 (71%) of 119 patients living in the community were employed. Predictive of employment at a mean age of 23 were normal intelligence [odds ratio (OR) 14.5, 95% confidence interval (CI) 4.5–46.8, p < 0.01], vocational education (OR 15.2, 95% CI 2.9–79.9, p < 0.01), and age at onset of epilepsy older than 6 years (OR 4.9, 95% CI 1.3–19.2, p = 0.02). At the mean age of 48 years (range 43–59 years), 45 (59%) of 76 patients living in the community were employed, as were 63 (78%) of 81 controls (patients vs. controls, p = 0.01). In 40 (53%) of 76 surviving patients employed between age 23 and 48, four factors were found to predict employment: normal intelligence (OR 15.8; 95% CI 2.4–102.4, p < 0.01), having offspring (OR 6.1; 1.5–25.0, p = 0.01), uninterrupted 5‐year terminal remission (5YTR) from age 23 to age 48 (OR 4.8; 1.1–19.9, p = 0.03), and no history of status epilepticus (OR 12.8; 1.8–90.9, p = 0.01). Conclusions: Normal intelligence, onset of epilepsy at age older than 6, and good vocational education appear to predict employment in early adulthood. Normal intelligence, having offspring, uninterrupted remission, and no history of status epilepticus appear to predict lasting employment into middle age.     

Lack of GABABR1 gene variation (G1465A) in a Chinese population with temporal lobe epilepsy

GABA(B) receptor1 (GABA(B)R1) gene is one of the susceptibility genes for temporal lobe epilepsy (TLE). Recently, it is reported that the GABA(B)R1 polymorphism (G1465A) conferred a highly increased susceptibility to TLE. We performed a case-control study to confirm the findings. The study included a total of 112 nonlesional TLE patients and 124 controls of Chinese ancestry. Our study did not show any polymorphism in this locus, and suggested this polymorphism may not be a strong susceptibility factor for TLE among Chinese population.     

Reduced brain volumes in children of women with epilepsy: A neuropsychological and voxel based morphometric analysis in pre-adolescent children

Background and purpose

Children of Women with Epilepsy with antenatal exposure to antiepileptic drugs (CAED) have reduced neuropsychological functions. We aimed to explore the anatomical basis for this impairment by comparing the brain volumes of CAED with that of matched healthy children without antenatal AED exposure (COAED).

A meta-analysis of white matter changes in temporal lobe epilepsy as studied with diffusion tensor imaging

Purpose: Diffusion tensor imaging (DTI) is used increasingly to study white matter integrity in people with temporal lobe epilepsy (TLE). Most studies report fractional anisotropy (FA) decrease and mean diffusivity (MD) increase in multiple white matter regions. The disturbance of white matter integrity varies across studies and between regions. We aimed to obtain a more consistent estimate of white matter diffusion characteristics and relate these to the distance from the seizure focus. Methods: Studies comparing diffusion characteristics of people with epilepsy with those of healthy controls were systematically reviewed and quantified using random and mixed effects meta analysis. In addition to the overall meta‐analysis, pooled FA and MD differences were determined per hemisphere and white matter category separately. Key Findings: We included 13 cross‐sectional studies. The pooled FA difference for all white matter was ?0.026 (95% confidence interval [CI] ?0.033 to ?0.019) and MD difference was 0.028 × 10^?3 mm²/s (95% CI 0.015–0.04). FA was reduced significantly in people with TLE compared with healthy controls in both ipsilateral (mean difference ?0.03) and contralateral white matter (?0.02). MD was significantly increased ipsilaterally and contralaterally. MD differed significantly between white matter connected to the affected temporal lobe and remote white matter. Significance: The meta‐analysis provides a better estimation of the true diffusion characteristics. White matter structural integrity in TLE is disturbed more severely in the ipsilateral than in the contralateral hemisphere, and tracts closely connected with the affected temporal lobe are most disturbed. The exact underlying mechanisms remain to be elucidated.     

A case of temporal lobe epilepsy with improvement of clinical symptoms and single photon emission computed tomography findings after treatment with clonazepam

A 26-year-old female presented psychomotor seizures, deja vu and amnestic syndrome after meningitis at the age of 14 years. Repeated electroencephalograms (EEG) demonstrated occasional spikes localized in the right temporal region in addition to a considerable amount of theta waves mainly in the right fronto-temporal region. Single photon emission computed tomography (SPECT) showed a marked hypoperfusion corresponding to the region in which the EEG showed abnormal findings, although magnetic resonance imaging (MRI) demonstrated no abnormal findings associated with the clinical features. Treatment with clonazepam in addition to sodium valproate resulted in a remarkable improvement of clinical symptoms (i.e. psychomotor seizures and deja vu), as well as of the EEG and SPECT findings. The present study suggests that SPECT is a useful method not only to determine the localization of regions associated with temporal lobe epilepsy but also to evaluate the effect of treatment in temporal lobe epilepsy.