Seizures In Mesial Temporal Lobe Epilepsy Research Articles

The high frequency oscillations in the amygdala, hippocampus, and temporal cortex during mesial temporal lobe epilepsy.

The mesial temporal lobe epilepsy (MTLE) seizures are believed to originate from medial temporal structures, including the amygdala, hippocampus, and temporal cortex. Thus, the seizures onset zones (SOZs) of MTLE locate in these regions. However, whether the neural features of SOZs are specific to different medial temporal structures are still unclear and need more investigation. To address this question, the present study tracked the features of two different high frequency oscillations (HFOs) in the SOZs of these regions during MTLE seizures from 10 drug-resistant MTLE patients, who received the stereo electroencephalography (SEEG) electrodes implantation surgery in the medial temporal structures. Remarkable difference of HFOs features, including the proportions of HFOs contacts, percentages of HFOs contacts with significant coupling and firing rates of HFOs, could be observed in the SOZs among three medial temporal structures during seizures. Specifically, we found that the amygdala might contribute to the generation of MTLE seizures, while the hippocampus plays a critical role for the propagation of MTLE seizures. In addition, the HFOs firing rates in SOZ regions were significantly larger than those in NonSOZ regions, suggesting the potential biomarkers of HFOs for MTLE seizure. Moreover, there existed higher percentages of SOZs contacts in the HFOs contacts than in all SEEG contacts, especially those with significant coupling to slow oscillations, implying that specific HFOs features would help identify the SOZ regions. Taken together, our results displayed the features of HFOs in different medial temporal structures during MTLE seizures, and could deepen our understanding concerning the neural mechanism of MTLE.

CA3 principal cell activation triggers hypersynchronous-onset seizures in a mouse model of mesial temporal lobe epilepsy.

Mesial temporal lobe epilepsy (MTLE) is the most common form of focal epilepsy and it is characterized by seizures that are often refractory to medications. Seizures in MTLE have two main patterns of onset that have been termed hypersynchronous (HYP) and low-voltage fast (LVF) and are believed to mainly depend on the activity of excitatory principal cells and inhibitory interneurons, respectively. In this study, we investigated whether unilateral open-loop optogenetic activation of CaMKII-positive principal cells in the hippocampus CA3 region favors the generation of spontaneous HYP seizures in kainic acid-treated (KA) CaMKII-ChR2 mice. Optogenetic activation of CA3 principal cells (1 Hz, 180 s ON, 220 s OFF) was implemented for 15 days after KA-induced status epilepticus. We found that both LVF and HYP seizures occurred in nonstimulated CaMKII-ChR2 (n = 6) and stimulated CaMKII-Cre (n = 5) mice. In contrast, optogenetic activation of principal cells in CaMKII-ChR2 mice (n = 5) triggered only HYP seizures that were characterized by high fast ripple (250-500 Hz) rates during the pre-ictal and ictal periods. These results provide firm evidence that in MTLE spontaneous seizures with different onset patterns depend on distinct neuronal network mechanisms of generation. They also demonstrate that HYP seizures occurring in vivo along with their associated fast ripples depend on the activity of principal cells in the CA3 region.NEW & NOTEWORTHY Previous evidence suggested that different seizure onset patterns rely on the activity of distinct neuronal populations. In this study, we show for the first time that in vivo optogenetic stimulation of CaMKII principal cells in kainic acid-treated mice triggers hypersynchronous-onset seizures that are associated with fast ripples. Our findings indicate that in patients with predominant HYP-onset seizures, anticonvulsant treatments should be aimed at limiting the firing of principal neurons in the seizure onset zone.

Coherence between the hippocampus and anterior thalamic nucleus as a tool to improve the effect of neurostimulation in temporal lobe epilepsy: An experimental study

BackgroundAlthough the mechanisms by which deep brain stimulation (DBS) modifies the activity of the ictal network are mostly undefined, recent studies have suggested that DBS of the anterior nucleus of the thalamus (ANT) can be an effective treatment for mesial temporal lobe epilepsy (MTLE) when resective surgery cannot be performed. In a nonhuman primate (NHP) model of MTL seizures, we showed that the ANT was actively involved during interictal and ictal periods through different patterns and that the hippocampus (HPC) and ANT synchronously oscillate in the high beta-band during seizures. ObjectiveBased on those findings, we evaluated whether the frequency of stimulation is an important parameter that interferes with seizures and how to adapt stimulation protocols to it. MethodsWe investigated the effects of low-frequency (40 Hz - determined as the ictal frequency of correlation between structures) and high-frequency (130 Hz - as commonly used in clinic) ANT stimulation in three monkeys in which MTLE seizures were initiated. ResultsLow-frequency stimulation had a strong effect on the number of seizures and the total time spent in seizure, whereas high-frequency stimulation had no effect. The coherence of oscillations between the HPC and the ANT was significantly correlated with the success of low-frequency stimulation: the greater the coherence was, the greater the antiepileptic effect of ANT-DBS. ConclusionOur results suggest that low-frequency stimulation is efficient in treating seizures in a nonhuman primate model. More importantly, the study of the coherence between the ANT and HPC during seizures can help to predict the anti-epileptic effects of ANT stimulation. Furthermore, the DBS paradigm could be customized in frequency for each patient on the basis of the coherence spectral pattern.

Circadian-Like Rhythmicity of Extracellular Brain Glutamate in Epilepsy.

Seizures often exhibit striking circadian-like (~24-h) rhythms. While chronotherapy has shown promise in treating epilepsy, it is not widely used, in part because the patterns of seizure rhythmicity vary considerably among patients and types of epilepsy. A better understanding of the mechanisms underlying rhythmicity in epilepsy could be expected to result in more effective approaches which can be tailored to each individual patient. The excitatory neurotransmitter glutamate is an essential modulator of circadian rhythms, and changes in the extracellular levels of glutamate likely affect the threshold to seizures. We used a reverse translational rodent model of mesial temporal lobe epilepsy (MTLE) combined with long-term intracerebral microdialysis to monitor the hourly concentrations of glutamate in the seizure onset area (epileptogenic hippocampus) over several days. We observed significant 24-h oscillations of extracellular glutamate in the epileptogenic hippocampus (n = 4, JTK_CYCLE test, p < 0.05), but not in the hippocampus of control animals (n = 4). To our knowledge, circadian glutamate oscillations have not been observed in a seizure onset region, and we speculate that the oscillations contribute to the rhythmicity of seizures in MTLE.

Neuromodulation of Bilateral Hippocampal Foci, an Alternative for Mesial Temporal Lobe Seizures in Patients with Non-Lesional MRI: Long-Term Follow-up

Background: Patients with bilateral independent hippocampal refractory seizures, who show no evidence of lesion in the MRI, constitute a challenge for their treatment. The risk of severe retrograde amnesia and/or residual seizures is high when bilateral temporal lobectomy is performed. Several groups have reported electrical neuromodulation of the hippocampus as a reversible surgical alternative for mesial temporal lobe epilepsy seizures that are refractory to medical treatment. Methods: In the Epilepsy Clinic of the General Hospital we have had three patients with bilateral independent foci and non-lesional MRI. The present publication shows their long-term seizure status and their neuropsychological outcome. Stimulation parameters were 3.0 V amplitude, high frequency (130 Hz), 450 μs pulse width, one minute ON and 4 min OFF cyclic stimulation. Follow-up extended over 9 years. Results: Patients showed dramatic seizure reduction. In two patients in whom stimulation was stopped (due to battery depletion or skin erosion), seizure reduction persisted for months after stimulation stopped, but eventually seizures reappeared slowly. One patient has had uninterrupted stimulation and has been seizure free for nine years. The neuropsychological tests showed no functional decrease at the selected modulation parameters. Conclusion: Bilateral hippocampal stimulation is effective in seizure control in patients in whom ablative surgery is not recommended.

Patterns of seizure control in patients with mesial temporal lobe epilepsy with and without hippocampus sclerosis.

Patients with mesial temporal lobe epilepsy (MTLE) may present unstable pattern of seizures. We aimed to evaluate the occurrence of relapse-remitting seizures in MTLE with (MTLE-HS) and without (MTLE-NL) hippocampal sclerosis. We evaluated 172 patients with MTLE-HS (122) or MTLE-NL (50). Relapse-remitting pattern was defined as periods longer than two years of seizure-freedom intercalated with seizure recurrence. "Infrequent seizures" was considered as up to three seizures per year and "frequent seizures" as any period of seizures higher than that. Thirty-seven (30%) MTLE-HS and 18 (36%) MTLE-NL patients had relapse-remitting pattern (X2, p = 0.470). This was more common in those with infrequent seizures (X2, p < 0.001). Twelve MTLE-HS and one MTLE-NL patients had prolonged seizure remission between the first and second decade of life (X2, p = 0.06). Similar proportion of MTLE-HS or MTLE-NL patients present relapse-remitting seizures and this occurs more often in those with infrequent seizures.

Widespread grey matter changes and hemodynamic correlates to interictal epileptiform discharges in pharmacoresistant mesial temporal epilepsy

Focal onset epilepsies most often occur in the temporal lobes. To improve diagnosis and therapy of patients suffering from pharmacoresistant temporal lobe epilepsy it is highly important to better understand the underlying functional and structural networks. In mesial temporal lobe epilepsy (MTLE) widespread functional networks are involved in seizure generation and propagation. In this study we have analyzed the spatial distribution of hemodynamic correlates (HC) to interictal epileptiform discharges on simultaneous EEG/fMRI recordings and relative grey matter volume (rGMV) reductions in 10 patients with MTLE. HC occurred beyond the seizure onset zone in the hippocampus, in the ipsilateral insular/operculum, temporo-polar and lateral neocortex, cerebellum, along the central sulcus and bilaterally in the cingulate gyrus. rGMV reductions were detected in the middle temporal gyrus, inferior temporal gyrus and uncus to the hippocampus, the insula, the posterior cingulate and the anterior lobe of the cerebellum. Overlaps between HC and decreased rGMV were detected along the mesolimbic network ipsilateral to the seizure onset zone. We conclude that interictal epileptic activity in MTLE induces widespread metabolic changes in functional networks involved in MTLE seizure activity. These functional networks are spatially overlapping with areas that show a reduction in relative grey matter volumes.

Do subtle cortical structure changes indicate a developmental basis for temporal lobe epilepsy?

Mesial temporal lobe epilepsy (MTLE) is the most prevalent form of intractable epilepsy in adolescents and adults. It is also one of the most intensively studied. The pathologic hallmark of classic MTLE is hippocampal sclerosis (HS). This is characterized histologically by a specific pattern of neuronal loss and synaptic reorganization. On MRI, one often observes reduced hippocampal volume with increased T2 signal. One of the oldest debates in epilepsy is whether HS is a preexisting cause or effect of the seizures in MTLE. Cogent arguments have been made in both directions, but have been based on differing rationales and investigational methods. The coexistence of HS with cortical dysplasia and more subtle types of developmental anomalies at the histologic level suggest that, in some cases, HS and MTLE may represent later manifestations of a process that begins earlier in life.1,2 In this issue of Neurology ®, Voets et al.3 provide new insight into this question by demonstrating subtle changes in structure and spatial orientation of limbic cortex and hippocampus based on MRI in 43 patients with MTLE and HS. By documenting the presence of increased folding complexity of limbic cortex and malrotation of hippocampi in these …

Involvement of the Thalamic Parafascicular Nucleus in Mesial Temporal Lobe Epilepsy

Mesial temporal lobe epilepsy (MTLE) is characterized by focal seizures, associated with hippocampal sclerosis, and often resistance to antiepileptic drugs. The parafascicular nucleus (PF) of the thalamus is involved in the generation of physiological oscillatory rhythms. It receives excitatory inputs from the cortex and inhibitory inputs from the basal ganglia, a system implicated in the control of epileptic seizures. The aim of this study was to examine the involvement of the PF in the occurrence of hippocampal paroxysmal discharges (HPDs) in a chronic animal model of MTLE in male mice. We recorded the local field potential (LFP) and the extracellular and intracellular activity of hippocampal and PF neurons during spontaneous HPDs in vivo. The end of the HPDs was concomitant with a slow repolarization in hippocampal neurons leading to an electrical silence. In contrast, it was associated in the PF with a transient increase in the power of the 10-20 Hz band in LFPs and a depolarization of PF neurons resulting in a sustained firing. We tested the role of the PF in the control of HPDs by single 130 Hz electrical stimulation of this nucleus and bilateral intra-PF injection of NMDA and GABA(A) antagonist and agonist. High-frequency PF stimulation interrupted ongoing HPDs at an intensity devoid of behavioral effects. NMDA antagonist and GABA(A) agonist suppressed hippocampal discharges in a dose-dependent way, whereas NMDA agonist and GABA(A) antagonist increased HPDs. Altogether, these data suggest that the PF nucleus plays a role in the modulation of MTLE seizures.

Brain SPECT in mesial temporal lobe epilepsy: comparison between visual analysis and SPM

To compare the accuracy of SPM and visual analysis of brain SPECT in patients with mesial temporal lobe epilepsy (MTLE). Interictal and ictal SPECTs of 22 patients with MTLE were performed. Visual analysis were performed in interictal (VISUAL(inter)) and ictal (VISUAL(ictal/inter)) studies. SPM analysis consisted of comparing interictal (SPM(inter)) and ictal SPECTs (SPM(ictal)) of each patient to control group and by comparing perfusion of temporal lobes in ictal and interictal studies among themselves (SPM(ictal/inter)). For detection of the epileptogenic focus, the sensitivities were as follows: VISUAL(inter)=68%; VISUAL(ictal/inter)=100%; SPM(inter)=45%; SPM(ictal)=64% and SPM(ictal/inter)=77%. SPM was able to detect more areas of hyperperfusion and hypoperfusion. SPM did not improve the sensitivity to detect epileptogenic focus. However, SPM detected different regions of hypoperfusion and hyperperfusion and is therefore a helpful tool for better understand pathophysiology of seizures in MTLE.

Reply: On the Role of Medial Pulvinar Thalamic (PuM) Nucleus in Temporal Lobe Epilepsy

Sir, We thank Prof. Mauguiere for his comments concerning our article recently published in Brain (Guye et al ., 2006). Our article follows previous works from our group studying the interdependencies between signals from several regions of the brain during partial seizures (Bartolomei et al ., 1999; 2002; 2004; Wendling et al ., 2003). The main objective of these works was to anatomically and functionally define the networks that generate seizures and/or are involved in seizure propagation. Patients included in this study mainly presented with anteromesial temporal lobe epilepsy (10) and three had lateral temporal lobe epilepsy (TLE). We described a gradual synchronization between the temporal lobe and the thalamus (mainly PuM) that was particularly marked in mesial TLE seizures. In addition some patients had early synchronization of thalamic and temporal lobe signals. One of the main findings of our study was to correlate the degree of thalamocortical synchrony and ictal loss of consciousness, a finding confirming previous hypotheses about the mechanisms of consciousness alteration in TLE (Blumenfeld et al ., 2004). In the following we will discuss four points/concerns raised by F. Mauguiere

Prefrontal hypofunction in patients with intractable mesial temporal lobe epilepsy

We compared the cognitive functions and interictal cerebral glucose metabolism of 11 patients with mesial temporal lobe epilepsy (MTLE) with frequent seizures to those of 10 patients with MTLE with rare seizures; the groups were matched for age, sex, education, IQ, and focus side. The frequent-seizure group had more set-shifting impairment that correlated with glucose hypometabolism in the prefrontal cortices. Our results suggest that frequent seizures in MTLE are associated with hypofunction of the prefrontal cortex.

Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy

High extracellular glutamate concentrations have been identified as a likely trigger of epileptic seizures in mesial temporal lobe epilepsy (MTLE), but the underlying mechanism remains unclear. We investigated whether a deficiency in glutamine synthetase, a key enzyme in catabolism of extracellular glutamate in the brain, could explain the perturbed glutamate homoeostasis in MTLE. The anteromedial temporal lobe is the focus of the seizures in MTLE, and surgical resection of this structure, including the hippocampus, leads to resolution of seizures in many cases. By means of immunohistochemistry, western blotting, and functional enzyme assays, we assessed the distribution, quantity, and activity of glutamine synthetase in the MTLE hippocampus. In western blots, the expression of glutamine synthetase in the hippocampus was 40% lower in MTLE than in non-MTLE samples (median 44 [IQR 30-58] vs 69 [56-87]% of maximum concentration in standard curve; p=0.043; n=8 and n=6, respectively). The enzyme activity was lower by 38% in MTLE vs non-MTLE (mean 0.0060 [SD 0.0031] vs 0.0097 [0.0042] U/mg protein; p=0.045; n=6 and n=9, respectively). Loss of glutamine synthetase was particularly pronounced in areas of the MTLE hippocampus with astroglial proliferation, even though astrocytes normally have high content of the enzyme. Quantitative immunoblotting showed no significant change in the amount of EAAT2, the predominant glial glutamate transporter in the hippocampus. A deficiency in glutamine synthetase in astrocytes is a possible molecular basis for extracellular glutamate accumulation and seizure generation in MTLE. Further studies are needed to define the cause, but the loss of glutamine synthetase may provide a new focus for therapeutic interventions in MTLE.

Topography of foramen ovale electrodes by 3D image reconstruction

To date, the foramen ovale (FO) electrode recording technique has been used in 234 patients at our center to assist in the evaluation of epilepsy surgery. Most of the patients suffered from mesial temporal lobe epilepsy (MTLE) and were candidates for a selective amygdalohippocampectomy. Knowledge of the exact topography of the FO electrodes is mandatory for a more precise anatomo-electro-clinical correlation of seizures and for a better understanding of FO electrode recorded electroencephalogram (EEG) and evoked potentials generated in the hippocampal formation or in nearby thalamic relays or brainstem structures. Here, we describe and illustrate a 3D image reconstruction of FO electrodes in situ as an important step to better define the generators of MTLE seizures as well as of interictal spikes and physiological EEG signals recorded with FO electrodes.

1H MR spectroscopy in patients with mesial temporal epilepsy.

The study provides a review of the basic examination procedures and results of proton magnetic resonance spectroscopy (1H MRS) in patients suffering from mesial temporal lobe epilepsy (MTLE). The source of seizures in MTLE is most often an epileptogenic focus secondary to hippocampal sclerosis. 1H MRS currently plays an important role in the non-invasive diagnosis of this type of epileptogenic lesion. The decisive 1H MRS parameter characterizing an epileptogenic lesion is a statistically significantly decreased value of N-acetylaspartate levels compared with control values, most often associated with a decrease in the ratios of the intensities of NAA/Cr, NAA/Cho and NAA/(Cr + Cho) signals. Moreover, MRS makes it possible to distinguish bilateral involvement of mesial temporal structures typically associated with a bilateral decrease in the levels of metabolites and/or their ratios. As regards other metabolic compounds which play an important role in the pathobiochemistry of epilepsy, MRS is employed to study the action of gamma-aminobutyric acid (GABA), inositol, lactate, glutamine, and glutamate, the clinical function of which has not been fully clarified as yet. It is in this context that one should consider the application of 1H MRS in evaluating the action of some new anti-epileptic agents affecting excitatory and inhibitory amino acids. There is no doubt that in vivo 1H MRS, along with other imaging methods, has made a significant contribution to the clinical and biochemical description of epileptic seizures and has assumed a prominent position among the techniques of pre-operative examination in epileptic surgery.

Clinical and electrographic manifestations of lesional neocortical temporal lobe epilepsy.

To determine whether lesional neocortical temporal lobe epilepsy (NTLE) can be differentiated from mesial temporal lobe epilepsy (MTLE) during the noninvasive presurgical evaluation, we compared the historical features, seizure symptomatology, and surface EEG of 8 patients seizure free after neocortical temporal resection with preservation of mesial structures and 20 patients after anterior temporal lobectomy for MTLE. Seizure symptomatology of 107 seizures (28 NTLE, 79 MTLE) was analyzed. One hundred one ictal EEGs (19 NTLE, 82 MTLE) were reviewed for activity at seizure onset; presence, distribution, and frequency of lateralized rhythmic activity (LRA); and distribution of postictal slowing. Seizure symptomatology and EEG data were compared between groups, and sensitivity, specificity, and positive and negative predictive values were determined for variables that differed significantly. Multiple logistic regression was used to determine whether patients could be correctly classified as having MTLE or NTLE. MTLE patients were younger at onset of habitual seizures and more likely to have a prior history of febrile seizures, CNS infection, perinatal complications, or head injury. NTLE seizures lacked features commonly exhibited in MTLE, including automatisms, contralateral dystonia, searching head movements, body shifting, hyperventilation, and postictal cough or sigh. NTLE ictal EEG recordings demonstrated lower mean frequency of LRA that frequently had a hemispheric distribution, whereas LRA in MTLE seizures was maximal over the ipsilateral temporal region. We conclude that it may be possible to differentiate lesional NTLE from MTLE on the basis of historical features, seizure symptomatology, and ictal surface EEG recordings. This may assist in the identification of patients with medically refractory nonlesional NTLE who frequently require intracranial monitoring and more extensive or tailored resections.