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Newly formed excitatory pathways provide a substrate for hyperexcitability in experimental temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) in humans and animals is associated with axonal sprouting of glutamatergic neurons and neosynaptogenesis in the hippocampal formation. We examined whether this plasticity of excitatory pathways contributes to an increased level of glutamatergic excitation in the CA1 region of rats experiencing chronic spontaneous limbic seizures following kainic acid or pilocarpine treatment. In chronic cases, we report an extensive axonal sprouting of CA1 pyramidal neurons, with many axonal branches entering the pyramidal cell layer and stratum radiatum, regions that are not innervated by axonal collaterals of CA1 pyramidal neurons in control animals. Concurrently with this anatomical reorganization, a large increase of the spontaneous glutamatergic drive is observed in the dendrites and somata of CA1 pyramidal cells. Furthermore, electrical activation of the reorganized CA1 associational pathway evokes epileptiform bursts in CA1 pyramidal cells. These findings suggest that reactive plasticity could contribute to the hyperexcitability of CA1 pyramidal neurons and to the propagation of seizures in these two models of TLE.

Animals↗

Psychosis and epilepsy: seizure-type comparisons and high-risk variables.

Compared 153 patients with temporal lobe epilepsy (TLE) and 79 patients with generalized epilepsy on the Goldberg Index, an MMPI-derived measure of psychosis. Analysis of covariance indicated that seizure type was not related to psychosis. Multiple regression analyses indicated that, in TLE, being female was correlated positively with Goldberg Index scores. In the group with generalized epilepsy, none of the variables was associated significantly with psychosis scores.

Adult↗

Perfusion-weighted imaging of interictal hypoperfusion in temporal lobe epilepsy using FAIR-HASTE: comparison with H(2)(15)O PET measurements.

To detect perfusion abnormalities in areas of high magnetic susceptibility in the brain, an arterial spin-labeling MRI technique utilizing flow-sensitive alternating inversion recovery (FAIR) and half-Fourier single shot turbo spin-echo (HASTE) for spin preparation and image acquisition, respectively, was developed. It was initially tested in a functional study involving visual stimulation, and was able to detect significant activation with an increase (approximately 70%) in relative cerebral blood flow. Subsequently, it was applied in a clinical situation in eight patients with temporal lobe epilepsy (TLE). The perfusion-weighted images obtained showed no susceptibility artifacts even in the region of the inferior temporal lobe and were able to detect interictal hypoperfusion in TLE. The results were compared with those derived from H(2)(15)O PET perfusion imaging in each patient. A statistically significant correlation (r = 0.75, P < 0.05) was found between results acquired from these two modalities. Magn Reson Med 45:431-435, 2001.

Artifacts↗

Evidence for digenic inheritance in a family with both febrile convulsions and temporal lobe epilepsy implicating chromosomes 18qter and 1q25-q31.

We report a clinical and genetic study of a French family among whom febrile convulsions (FC) are associated with subsequent temporal lobe epilepsy (TLE) in the same individual, without magnetic resonance imaging-identifiable hippocampal abnormalities. Linkage analyses excluded the loci FEB1 and FEB2, previously implicated in FC; the GEFS+1 locus responsible for generalized epilepsy with febrile seizures plus; and the locus implicated in lateral temporal lobe epilepsy. After scanning the entire genome, significant lod scores (>3) for markers on 18qter and suggestive lod scores (>2) for markers on 1q25-q31 were obtained. An analysis of the haplotypes at these two loci supported the hypothesis that two genes segregated with the phenotype. All patients shared common haplotypes for both 1q25-q31 and 18qter chromosomes. All but one unaffected at-risk individuals carried only one, or none, of the disease haplotypes. Under the assumption of digenic inheritance, haplotype reconstruction defined a 26 cM interval on chromosome 1 and a 10 cM interval on chromosome 18. This family suggests that the association between FC and TLE may be observed in the absence of hippocampal structural abnormalities and that they may have, in some cases, a common genetic basis.

Adolescent↗

Functional connectivity networks are disrupted in left temporal lobe epilepsy.

OBJECTIVE: Functional connectivity maps the distributed network of brain regions fluctuating synchronously during a continuous brain state. This study sought to investigate whether patients with left temporal lobe epilepsy (TLE) differ from controls in their resting-state functional connectivity between typical language regions. METHODS: We studied 17 patients with left TLE, together with eight healthy controls, using seeded functional connectivity. Seed regions were defined using the regions of maximal activation and deactivation during a language functional magnetic resonance imaging (fMRI) task in a separate cohort of 30 controls. RESULTS: Language fMRI produced the expected activation pattern, which was not different between patients and controls. However, functional connectivity between language areas during rest was markedly different; whereas controls showed connectivity between each of the seed areas and the majority of the language areas, patients showed connectivity only with a few areas, particularly the seed area itself. This difference was significant in the direct comparison of patients and control connectivity maps. INTERPRETATION: We suggest that this reduced connectivity in left temporal lobe epilepsy may reflect a disturbance of the language network during resting state in patients and may be related to subtle language difficulties in this patient population.

Adult↗

Atrophy of mesial structures in patients with temporal lobe epilepsy: cause or consequence of repeated seizures?

We studied 70 epileptic patients by using magnetic resonance imaging volumetric measurements of amygdala (AM) and hippocampal formation (HF). Fifty patients presented with intractable temporal lobe epilepsy (TLE), 10 patients had focal extratemporal lobe epilepsy, and 10 had generalized epilepsy. In 91% of the 45 TLE patients without foreign tissue lesions, there was significant smallness of the AM and/or HF coinciding with the side of electroencephalographic seizure onset. No significant smallness or asymmetry was demonstrated in patients with focal extratemporal or generalized epilepsy. We performed a linear regression analysis, plotting the number of years of recurrent seizures and the estimated seizure frequency against the volumes of the AM and HF. There was no correlation between either of these two parameters and AM or HF volume (p > 0.9). There was also no correlation between the patient's age and volumetric measurements of AM or HF, nor did these measurements correlate with the occurrence of generalized seizures. On the other hand, patients with antecedent prolonged febrile convulsions in early childhood had significantly smaller AM and HF, compared with those without such a history (p < 0.001). The findings indicate that repeated seizures or longer duration of epilepsy do not cause increased atrophy of AM or HF that is measurable by volumetric magnetic resonance imaging.

Adolescent↗

Comparison of ictal SPECT and interictal PET in the presurgical evaluation of temporal lobe epilepsy.

We retrospectively compared ictal technetium 99m hexamethylpropyleneamineoxime single-photon emission computed tomography (SPECT) and interictal 18F-fluorodeoxyglucose positron emission tomography (PET) in 35 patients with well-lateralized temporal lobe epilepsy (TLE). Based on SPECT scans the two observers correctly lateralized seizure foci with certainty in 89% of patients; interobserver agreement was excellent. Both observers incorrectly lateralized the seizure focus on two SPECT scans; one error was explained by rapid electroencephalographic spread to the contralateral side and for the other patient, isotope was injected during a brief aura. Based on PET scans, observers correctly lateralized the foci with certainty in 63% and with lesser confidence in 83%; four incorrect lateralizations were made by one observer and none by the other. PET interobserver disagreement was explained by differences between observers in weighting the relative hypometabolism in medial and lateral temporal regions. The detection rate for PET was lower in the absence of structural imaging abnormalities (60 vs 87%). PET yielded correct lateralizations in the 2 patients for whom SPECT interpretation was difficult. We conclude that both ictal SPECT and interictal PET are sensitive methods for the lateralization of TLE, but SPECT can be interpreted with greater certainty and is more sensitive when magnetic resonance imaging findings are negative. False lateralization is rare with ictal SPECT and can be explained when interpreted in conjunction with electroclinical data. Both investigations have complementary roles when localization is difficult.

Adolescent↗

Depth electrode studies and intracellular dentate granule cell recordings in temporal lobe epilepsy.

Hippocampal depth electrodes are often used to localize seizure onset in patients who may have temporal lobe epilepsy (TLE). A number of features of the spontaneous seizures and of their ictal onset patterns can be analyzed from these recordings. We compared a number of the typical electroencephalographic (EEG) changes at seizure onset with several cellular parameters recorded in dentate granule cells from the same 14 patients diagnosed with medial temporal sclerosis (MTS) to examine the pathophysiological correlates of this spontaneous EEG activity in this form of TLE. The intracellularly recorded parameters include the propensity to fire evoked epileptiform bursts, the absence of evoked inhibitory potentials, the presence of polysynaptic excitatory postsynaptic potentials, and the presence of spontaneous excitatory activity. We noted several correlations between the EEG data and the intracellular recordings. The absence of synaptically evoked bursts was correlated with the presence of low-voltage fast activity at seizure onset. In addition, the loss of inhibitory postsynaptic potentials was correlated with the presence of periodic spiking pre-ictally. Several other correlations were also noted. These data indicate that EEG findings may be predictive of anatomical and cellular pathological changes and provide clues to the physiological mechanisms involved in this form of epilepsy.

Action Potentials↗

Presurgical multimodality neuroimaging in electroencephalographic lateralized temporal lobe epilepsy.

The purpose of this study was to compare 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), hippocampal volumetry (HV), T2 relaxometry, and proton magnetic resonance spectroscopic imaging (1H-MRSI) in the presurgical neuroimaging lateralization of patients with nonlesional, electroencephalogram (EEG)-defined unilateral temporal lobe epilepsy (TLE). Twenty-five patients were prospectively studied, along with age-matched controls. T2 relaxometry examinations were performed in 13 patients. Comparison of FDG-PET, HV, and 1H-MRSI was possible in 23 patients. FDG-PET lateralized 87% of patients, HV 65%, N-acetyl aspartate (NAA)/(choline [Cho] + creatine [Cr]) 61%, and [NAA] 57%. Combined HV and NAA/(Cho + Cr) results lateralized 83% of the patients, a value similar to PET. Of 10 patients with normal magnetic resonance imaging (MRI) scans, 2 were lateralized with HV, 6 with FDG-PET, 4 with NAA/(Cho + Cr), and 3 with [NAA]. T2 relaxometry lateralized no patients without hippocampal atrophy. Bilateral abnormality was present in 29 to 33% of patients with 1H-MRSI measures and 17% with HV. Only hippocampal atrophy correlated with postoperative seizure-free outcome. FDG-PET remains the most sensitive imaging method to correlate with EEG-lateralized TLE. Both FDG-PET and 1H-MRSI can lateralize patients with normal MRI, but only the presence of relative unilateral hippocampal atrophy is predictive of seizure-free outcome. Bilaterally abnormal MRI and 1H-MRSI measures do not preclude good surgical outcome.

Adult↗

Alterations of hippocampal GAbaergic system contribute to development of spontaneous recurrent seizures in the rat lithium-pilocarpine model of temporal lobe epilepsy.

Reorganization of excitatory and inhibitory circuits in the hippocampal formation following seizure-induced neuronal loss has been proposed to underlie the development of chronic seizures in temporal lobe epilepsy (TLE). Here, we investigated whether specific morphological alterations of the GABAergic system can be related to the onset of spontaneous recurrent seizures (SRS) in the rat lithium-pilocarpine model of TLE. Immunohistochemical staining for markers of interneurons and their projections, including parvalbumin (PV), calretinin (CR), calbindin (CB), glutamic acid decarboxylase (GAD), and type 1 GABA transporter (GAT1), was performed in brain sections of rats treated with lithium-pilocarpine and sacrificed after 24 h, during the silent phase (6 and 12 days), or after the onset of SRS (10-18 days after treatment). Semiquantitative analysis revealed a selective loss of interneurons in the stratum oriens of CA1, associated with a reduction of GAT1 staining in the stratum radiatum and stratum oriens. In contrast, interneurons in CA3 were largely preserved, although GAT1 staining was also reduced. These changes occurred within 6 days after treatment and were therefore insufficient to cause SRS. In the dentate gyrus, extensive cell loss occurred in the hilus. The pericellular innervation of granule cells by PV-positive axons was markedly reduced, although the loss of PV-interneurons was only partial. Most strikingly, the density of GABAergic axons, positive for both GAD and GAT1, was dramatically increased in the inner molecular layer. This change emerged during the silent period, but was most marked in animals with SRS. Finally, supernumerary CB-positive neurons were detected in the hilus, selectively in rats with SRS. These findings suggest that alterations of GABAergic circuits occur early after lithium-pilocarpine-induced status epilepticus and contribute to epileptogenesis. In particular, the reorganization of GABAergic axons in the dentate gyrus might contribute to synchronize hyperexcitability induced by the interneuron loss during the silent period, leading to the onset of chronic seizures.

Animals↗

EEG-fMRI using z-shimming in patients with temporal lobe epilepsy.

PURPOSE: To use z-shimming, a technique that reduces signal loss due to susceptibility artifacts that can result in reduced or absent activation in electroencephalography (EEG) functional MRI (fMRI) sessions in patients with temporal lobe epilepsy (TLE), to determine whether it would result in an increased ability to detect significant regions of blood oxygenation level-dependent (BOLD) signal change. MATERIALS AND METHODS: Eight patients with TL EEG spikes underwent an EEG-fMRI scanning session using z-shimming. The signal intensities in the z-shimmed images were compared with those in the standard images. BOLD activation maps were created from the two sets of images using the timings of the spikes observed on the EEG. RESULTS: The mean signal increase in the TLs as a result of z-shimming was 45.9%+/-4.5%. The percentage of TL voxels above a brain intensity threshold rose from 66.1%+/-7.6% to 77.6%+/-5.7%. This appreciable increase in signal did not lead to any significant differences in the statistical maps created with the two sets of functional images. CONCLUSION: The results suggest that loss of signal is not the limiting factor for the detection of spike-related BOLD signal changes in patients with TLE activity.

Algorithms↗

PET imaging of glucose metabolism in a mouse model of temporal lobe epilepsy.

Here we present the first demonstration that 2-deoxy-2[18F]fluoro-D-glucose (18FDG) and micro Positron Emission Tomography (microPET) can be used successfully to monitor regional changes in brain metabolism during acute seizure induction in C57Bl/6 mice. These longitudinal studies show a significant increase in 18FDG uptake in the hippocampus (33.2%) which correlates directly with seizure severity (R2=0.86). 18FDG microPET can potentially be used to monitor the development of TLE in mouse models from the acute phase of status epilepticus to the chronic phase of spontaneous recurrent seizures. These studies provide a foundation upon which we can begin to identify genetic contributions to the metabolic signature of TLE in mice, since many transgenics are in the C57Bl/6 background strain.

Animals↗

A cell-cycle nuclear autoantigen containing WD-40 motifs expressed mainly in S and G2 phase cells.

Recently a novel nuclear protein mainly expressed in S and G2 phase cells was characterized using autoantibodies from a cancer patient (Exp. Cell Res., 212, 255-261, 1994). cDNA clones were isolated by immunoscreening, and sequence analysis revealed that the cDNA clones encoded a 713-amino acid residue polypeptide which is provisionally named SG2NA (S/G2 nuclear antigen). In the carboxyl terminal half of SG2NA, there are 6 copies of WD-40 motifs characteristic of a large family of proteins of which the prototype is beta-transducin/enhancer of split (TLE). In addition, there are nuclear localization sequence and phosphorylation sites related to the TLE proteins. Autoantibodies occurring spontaneously in certain cancer patients have been useful reagents for identifying cellular proteins and this is the first report of a novel WD-40 protein which is the target of an autoimmune response.

Adenocarcinoma↗

Lateralization of auditory rhythm length in temporal lobe lesions.

In the visual modality, short rhythmic stimuli have been proven to be better processed (sequentially) by the left hemisphere, while longer rhythms appear to be better (holistically) processed by the right hemisphere. This study was set up to see if the same holds in the auditory modality. The rhythm task as originally designed by Seashore was computerized and is part of the Fepsy Neuropsychological battery. This task was performed by 85 patients with intractable temporal lobe epilepsy (left TLE = 32; right TLE = 53) enrolled in the Dutch Collaborative Epilepsy Surgery Program. They performed the task before and 6 months after surgery. The task consists of 30 pairs of rhythmic patterns in 3 series of 10 items. The series contains patterns of 5, 6, or 7 notes. The purpose is to indicate whether the two patterns are the same or different. Reaction times are also measured. If the hypothesis is true, the short-item sequence will be better processed by patients with right temporal lobe epilepsy (nonimpaired left temporal lobe), the longer sequence will be better processed by the left temporal epilepsy group (nonimpaired right temporal lobe). No overall laterality effect on rhythm perception could be found and no difference was found between both test moments. IQ did not correlate with rhythm performance. However, there was an interaction effect of laterality and rhythm length on performance and reaction time. This effect can be explained by the increase after the operation of the score of the left focus group and a decrease in the right focus group on the longer rhythms. This effect was somewhat less strong in the reaction times: a clear tendency for faster reaction times after surgery in the left and longer reaction times in the right focus group. The effect could not be explained for by the difference in extent of resection in either temporal lobe. This study showed that memory for and discrimination of auditory rhythm is dependent on which hemisphere is used in processing. The effect could be demonstrated for the right hemisphere, which uses a holistic processing of stimuli, which outperforms the left in rhythms consisting of a long sequence. In left temporal resections an improvement occurs on the longer rhythms and in right temporal resections the performance on the longest rhythms decreases.

Adult↗

Interictal discourse production in temporal lobe epilepsy.

Discourse production was investigated in 16 patients with left-temporal-lobe epilepsy (LTLE) and 17 neurologically normal relatives. Narrative was elicited with the Joanette and Goulet (1989) eight frame "Cowboy" cartoon on three immediately consecutive occasions. Variables of interest were fluency (words/s), speaking time, and word count. While controls produced increasingly concise forms of the story over repetitions, the TLE group became more verbose. Fluency did not not differentiate the groups. These findings suggest that LTLE is associated with macrolinguistic disturbances. The role of capacity limitations and motivational factors in TLE discourse production is discussed.

Adolescent↗

Nonlinear Trends in Hippocampal Metabolic Function and Verbal Memory: Evidence of Cognitive Reserve in Temporal Lobe Epilepsy?

The present study explored the possibility of nonlinear trends in the relationship between verbal memory and hippocampal function in a series of 33 patients with temporal lobe epilepsy (TLE). Right and left hippocampal metabolic function was quantified using levels of hippocampal creatine to N-acetylaspartate (Cr/NAA) derived from (1)H magnetic resonance spectroscopic imaging. An exploratory neural network analysis (multi-layer perceptron) suggested the possibility of either a quadratic or cubic trend in the relationship between left hippocampal Cr/NAA and verbal retention. Using regression-based curve estimation, the cubic function was found to optimally fit the data, explaining 41% of the variance in the relationship between verbal memory and hippocampal metabolic function. This was contrasted to the 28% variance explained by simple linear regression. These findings suggest that (1) the relationship between verbal retention and hippocampal function in patients with TLE is nonlinear, and (2) this could be explained in terms of a possible "cognitive reserve." Clinical implications are discussed.

Journal Article↗

Neuropsychological Outcome in Children after Frontal Lobe Epilepsy Surgery.

We investigated the neuropsychological performance of children with frontal lobe epilepsy (FLE, n = 12) before and 1 year after surgery. Children with temporal lobe epilepsy (TLE, n = 12) were included as control group. Preoperatively, children with FLE had a significantly higher IQ than children with TLE, but were significantly more often impaired in manual motor coordination. Postoperatively, both groups improved in attention, short-term and long-term memory, and manual coordination, although the latter was not significant. Neuropsychological outcome in FLE patients was not better in seizure-free patients than in patients with continuing seizures. To avoid deterioration in language functions of patients in whom surgery involved left area 44, correspondence of results in cortical stimulation and intracarotid amytal test may be essential. All in all, our data indicate a favorable cognitive outcome in children 1 year after frontal lobe surgery.

Journal Article↗

Overexpression of GluR6 in rat hippocampus produces seizures and spontaneous nonsynaptic bursting in vitro.

We hypothesized that overexpression of specific glutamate receptors within the hippocampus would induce seizures and the associated cellular changes seen in temporal lobe epilepsy (TLE). The GluR6 kainate receptor was overexpressed by injecting rat hippocampi with HSVGluR6, a viral vector transducing fully edited GluR6. These animals experienced limbic seizures approximately 4 h following the injection. Control animals injected with HSVlac, a vector expressing beta-galactosidase, did not have seizures. Recordings from hippocampal CA1 pyramidal cells were performed 12 to 48 h and 1 week to 1 month postinjection. We observed nonsynaptic Na(+)-mediated bursting in 77.5% of cells 12 to 48 h following injection of HSVGluR6 but not HSVlac. The synaptic responses were normal in both groups. However, the physiological properties of cells from HSVGluR6-injected hippocampi changed over time. Two weeks following HSVGluR6 injection, synaptic bursts could be evoked, but intrinsic bursting became rare. These changes persisted for at least 1 month. We postulate that this transition from intrinsic to synaptic hyperexcitability may be important in the development of TLE.

Action Potentials↗